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http://www.ncbi.nlm.nih.gov/pubmed/34002695 | 1. Elife. 2021 May 18;10:e68217. doi: 10.7554/eLife.68217.
The hepcidin regulator erythroferrone is a new member of the
erythropoiesis-iron-bone circuitry.
Castro-Mollo M(#)(1), Gera S(#)(2), Ruiz-Martinez M(1), Feola M(1), Gumerova
A(2), Planoutene M(1), Clementelli C(1), Sangkhae V(3), Casu C(4), Kim SM(2),
Ostland V(5), Han H(5), Nemeth E(3), Fleming R(6), Rivella S(4), Lizneva D(2),
Yuen T(2), Zaidi M(2), Ginzburg Y(1).
Author information:
(1)Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of
Medicine at Mount Sinai, New York, United States.
(2)The Mount Sinai Bone Program, Departments of Medicine and Pharmacological
Sciences, and Center for Translational Medicine and Pharmacology, Icahn School
of Medicine at Mount Sinai, New York, United States.
(3)Center for Iron Disorders, University of California, Los Angeles (UCLA), Los
Angeles, United States.
(4)Department of Pediatrics, Division of Hematology, and Penn Center for
Musculoskeletal Disorders, Children's Hospital of Philadelphia (CHOP),
University of Pennsylvania, Perelman School of Medicine, Philadelphia, United
States.
(5)Intrinsic Lifesciences, LLC, LaJolla, United States.
(6)Department of Pediatrics, Saint Louis University School of Medicine, St
Louis, United States.
(#)Contributed equally
BACKGROUND: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin
expression by sequestering several bone morphogenetic protein (BMP) family
members to increase iron availability for erythropoiesis.
METHODS: To address whether ERFE functions also in bone and whether the
mechanism of ERFE action in bone involves BMPs, we utilize the Erfe-/- mouse
model as well as β-thalassemic (Hbbth3/+) mice with systemic loss of ERFE
expression. In additional, we employ comprehensive skeletal phenotyping analyses
as well as functional assays in vitro to address mechanistically the function of
ERFE in bone.
RESULTS: We report that ERFE expression in osteoblasts is higher compared with
erythroblasts, is independent of erythropoietin, and functional in suppressing
hepatocyte hepcidin expression. Erfe-/- mice display low-bone-mass arising from
increased bone resorption despite a concomitant increase in bone formation.
Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and
Rankl expression, and BMP-mediated signaling ex vivo. The ERFE effect on
osteoclasts is mediated through increased osteoblastic RANKL and sclerostin
expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe
loss in Hbbth3/+mice, a disease model with increased ERFE expression, triggers
profound osteoclastic bone resorption and bone loss.
CONCLUSIONS: Together, ERFE exerts an osteoprotective effect by modulating BMP
signaling in osteoblasts, decreasing RANKL production to limit
osteoclastogenesis, and prevents excessive bone loss during expanded
erythropoiesis in β-thalassemia.
FUNDING: YZG acknowledges the support of the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to YZG and DK095112 to RF,
SR, and YZG). MZ acknowledges the support of the National Institute on Aging
(U19 AG60917) and NIDDK (R01 DK113627). TY acknowledges the support of the
National Institute on Aging (R01 AG71870). SR acknowledges the support of NIDDK
(R01 DK090554) and Commonwealth Universal Research Enhancement (CURE) Program
Pennsylvania.
© 2021, Castro-Mollo et al.
DOI: 10.7554/eLife.68217
PMCID: PMC8205482
PMID: 34002695 [Indexed for MEDLINE]
Conflict of interest statement: MC, SG, MR, MF, AG, MP, CC, VS, CC, SK, EN, RF,
SR, DL, TY, YG No competing interests declared, VO, HH is affiliated with
Intrinsic Lifesciences, LLC. The author has no other competing interests to
declare. MZ Deputy editor, eLife |
http://www.ncbi.nlm.nih.gov/pubmed/31649559 | 1. Front Physiol. 2019 Oct 9;10:1294. doi: 10.3389/fphys.2019.01294. eCollection
2019.
Hepcidin and Anemia: A Tight Relationship.
Pagani A(1), Nai A(1)(2), Silvestri L(1)(2), Camaschella C(1).
Author information:
(1)Division of Genetics and Cell Biology, San Raffaele Scientific Institute,
Milan, Italy.
(2)Vita-Salute San Raffaele University, Milan, Italy.
Hepcidin, the master regulator of systemic iron homeostasis, tightly influences
erythrocyte production. High hepcidin levels block intestinal iron absorption
and macrophage iron recycling, causing iron restricted erythropoiesis and
anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin
synthesis and red blood cells production. Expanded erythropoiesis, as after
hemorrhage or erythropoietin treatment, blocks hepcidin through an acute
reduction of transferrin saturation and the release of the erythroblast hormone
and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis,
limiting iron consumption, increases transferrin saturation and stimulates
hepcidin transcription. Deregulation of hepcidin synthesis is associated with
anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the
common anemia of acute and chronic inflammatory disorders, and the extremely
rare hepcidin-producing adenomas that may develop in the liver of children with
an inborn error of glucose metabolism. Inappropriately high levels of hepcidin
cause iron-restricted or even iron-deficient erythropoiesis in all these
conditions. Patients with IRIDA or anemia of inflammation do not respond to oral
iron supplementation and show a delayed or partial response to intravenous iron.
In hepcidin-producing adenomas, anemia is reverted by surgery. Other
hepcidin-related anemias are the "iron loading anemias" characterized by
ineffective erythropoiesis and hepcidin suppression. This group of anemias
includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital
sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase
deficiency. The paradigm is non-transfusion-dependent thalassemia where the
release of erythroferrone from the expanded pool of immature erythroid cells
results in hepcidin suppression and secondary iron overload that in turn worsens
ineffective erythropoiesis and anemia. In thalassemia murine models, approaches
that induce iron restriction ameliorate both anemia and the iron phenotype.
Manipulations of hepcidin might benefit all the above-described anemias.
Compounds that antagonize hepcidin or its effect may be useful in inflammation
and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis.
Correcting ineffective erythropoiesis in animal models ameliorates not only
anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted
approaches are now in clinical trials: hopefully they will result in novel
treatments for a variety of anemias.
Copyright © 2019 Pagani, Nai, Silvestri and Camaschella.
DOI: 10.3389/fphys.2019.01294
PMCID: PMC6794341
PMID: 31649559 |
http://www.ncbi.nlm.nih.gov/pubmed/29157917 | 1. Steroids. 2018 May;133:8-14. doi: 10.1016/j.steroids.2017.11.007. Epub 2017
Nov 21.
The mediator complex in genomic and non-genomic signaling in cancer.
Weber H(1), Garabedian MJ(2).
Author information:
(1)Departments of Microbiology and Urology, NYU School of Medicine, 550 First
Ave, New York, NY 10012, United States.
(2)Departments of Microbiology and Urology, NYU School of Medicine, 550 First
Ave, New York, NY 10012, United States. Electronic address:
michael.garabedian@nyumc.org.
Mediator is a conserved, multi-subunit macromolecular machine divided
structurally into head, middle, and tail modules, along with a transiently
associating kinase module. Mediator functions as an integrator of
transcriptional regulatory activity by interacting with DNA-bound transcription
factors and with RNA polymerase II (Pol II) to both activate and repress gene
expression. Mediator has been shown to affect multiple steps in transcription,
including chromatin looping between enhancers and promoters, pre-initiation
complex formation, transcriptional elongation, and mRNA splicing. Individual
Mediator subunits participate in regulation of gene expression by the estrogen
and androgen receptors and are altered in a number of endocrine cancers,
including breast and prostate cancer. In addition to its role in genomic
signaling, MED12 has been implicated in non-genomic signaling by interacting
with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural
studies have revealed extensive inter-domain interactions and complex
architecture of the Mediator-Pol II complex, suggesting that Mediator is capable
of reorganizing its conformation and composition to fit cellular needs. We
propose that alterations in Mediator subunit expression that occur in various
cancers could impact the organization and function of Mediator, resulting in
changes in gene expression that promote malignancy. A better understanding of
the role of Mediator in cancer could reveal new approaches to the diagnosis and
treatment of Mediator-dependent endocrine cancers, especially in settings of
therapy resistance.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.steroids.2017.11.007
PMCID: PMC5864542
PMID: 29157917 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24088064 | 1. Crit Rev Biochem Mol Biol. 2013 Nov-Dec;48(6):575-608. doi:
10.3109/10409238.2013.840259. Epub 2013 Oct 3.
The Mediator complex and transcription regulation.
Poss ZC(1), Ebmeier CC, Taatjes DJ.
Author information:
(1)Department of Chemistry and Biochemistry, University of Colorado , Boulder,
CO , USA.
The Mediator complex is a multi-subunit assembly that appears to be required for
regulating expression of most RNA polymerase II (pol II) transcripts, which
include protein-coding and most non-coding RNA genes. Mediator and pol II
function within the pre-initiation complex (PIC), which consists of Mediator,
pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa
in size. Mediator serves as a central scaffold within the PIC and helps regulate
pol II activity in ways that remain poorly understood. Mediator is also
generally targeted by sequence-specific, DNA-binding transcription factors (TFs)
that work to control gene expression programs in response to developmental or
environmental cues. At a basic level, Mediator functions by relaying signals
from TFs directly to the pol II enzyme, thereby facilitating TF-dependent
regulation of gene expression. Thus, Mediator is essential for converting
biological inputs (communicated by TFs) to physiological responses (via changes
in gene expression). In this review, we summarize an expansive body of research
on the Mediator complex, with an emphasis on yeast and mammalian complexes. We
focus on the basics that underlie Mediator function, such as its structure and
subunit composition, and describe its broad regulatory influence on gene
expression, ranging from chromatin architecture to transcription initiation and
elongation, to mRNA processing. We also describe factors that influence Mediator
structure and activity, including TFs, non-coding RNAs and the CDK8 module.
DOI: 10.3109/10409238.2013.840259
PMCID: PMC3852498
PMID: 24088064 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22496666 | 1. PLoS Genet. 2012;8(4):e1002613. doi: 10.1371/journal.pgen.1002613. Epub 2012
Apr 5.
The functions of Mediator in Candida albicans support a role in shaping
species-specific gene expression.
Uwamahoro N(1), Qu Y, Jelicic B, Lo TL, Beaurepaire C, Bantun F, Quenault T,
Boag PR, Ramm G, Callaghan J, Beilharz TH, Nantel A, Peleg AY, Traven A.
Author information:
(1)Department of Biochemistry and Molecular Biology, Monash University, Clayton,
Victoria, Australia.
The Mediator complex is an essential co-regulator of RNA polymerase II that is
conserved throughout eukaryotes. Here we present the first study of Mediator in
the pathogenic fungus Candida albicans. We focused on the Middle domain subunit
Med31, the Head domain subunit Med20, and Srb9/Med13 from the Kinase domain. The
C. albicans Mediator shares some roles with model yeasts Saccharomyces
cerevisiae and Schizosaccharomyces pombe, such as functions in the response to
certain stresses and the role of Med31 in the expression of genes regulated by
the activator Ace2. The C. albicans Mediator also has additional roles in the
transcription of genes associated with virulence, for example genes related to
morphogenesis and gene families enriched in pathogens, such as the ALS adhesins.
Consistently, Med31, Med20, and Srb9/Med13 contribute to key virulence
attributes of C. albicans, filamentation, and biofilm formation; and ALS1 is a
biologically relevant target of Med31 for development of biofilms. Furthermore,
Med31 affects virulence of C. albicans in the worm infection model. We present
evidence that the roles of Med31 and Srb9/Med13 in the expression of the genes
encoding cell wall adhesins are different between S. cerevisiae and C. albicans:
they are repressors of the FLO genes in S. cerevisiae and are activators of the
ALS genes in C. albicans. This suggests that Mediator subunits regulate adhesion
in a distinct manner between these two distantly related fungal species.
© 2012 Uwamahoro et al.
DOI: 10.1371/journal.pgen.1002613
PMCID: PMC3320594
PMID: 22496666 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/32327563 | 1. Genetics. 2020 Jun;215(2):407-420. doi: 10.1534/genetics.120.303254. Epub 2020
Apr 23.
A Role for Mediator Core in Limiting Coactivator Recruitment in Saccharomyces
cerevisiae.
Yarrington RM(1), Yu Y(1), Yan C(2)(3)(4), Bai L(2)(3)(4), Stillman DJ(5).
Author information:
(1)Department of Pathology, University of Utah Health Sciences Center, Salt Lake
City, Utah 84112.
(2)Center for Eukaryotic Gene Regulation, The Pennsylvania State University,
University Park, Pennsylvania 16802.
(3)Department of Biochemistry and Molecular Biology, The Pennsylvania State
University, University Park, Pennsylvania 16802.
(4)Department of Physics, The Pennsylvania State University, University Park,
Pennsylvania 16802.
(5)Department of Pathology, University of Utah Health Sciences Center, Salt Lake
City, Utah 84112 david.stillman@path.utah.edu.
Mediator is an essential, multisubunit complex that functions as a
transcriptional coactivator in yeast and other eukaryotic organisms. Mediator
has four conserved modules, Head, Middle, Tail, and Kinase, and has been
implicated in nearly all aspects of gene regulation. The Tail module has been
shown to recruit the Mediator complex to the enhancer or upstream activating
sequence (UAS) regions of genes via interactions with transcription factors, and
the Kinase module facilitates the transition of Mediator from the UAS/enhancer
to the preinitiation complex via protein phosphorylation. Here, we analyze
expression of the Saccharomyces cerevisiaeHO gene using a sin4 Mediator Tail
mutation that separates the Tail module from the rest of the complex; the sin4
mutation permits independent recruitment of the Tail module to promoters without
the rest of Mediator. Significant increases in recruitment of the SWI/SNF and
SAGA coactivators to the HO promoter UAS were observed in a sin4 mutant, along
with increased gene activation. These results are consistent with recent studies
that have suggested that the Kinase module functions negatively to inhibit
activation by the Tail. However, we found that Kinase module mutations did not
mimic the effect of a sin4 mutation on HO expression. This suggests that at HO
the core Mediator complex (Middle and Head modules) must play a role in limiting
Tail binding to the promoter UAS and gene activation. We propose that the core
Mediator complex helps modulate Mediator binding to the UAS regions of genes to
limit coactivator recruitment and ensure proper regulation of gene
transcription.
Copyright © 2020 by the Genetics Society of America.
DOI: 10.1534/genetics.120.303254
PMCID: PMC7268993
PMID: 32327563 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35557691 | 1. ACS Omega. 2022 Apr 20;7(17):14867-14874. doi: 10.1021/acsomega.2c00368.
eCollection 2022 May 3.
Mediator Complex of the Malaria Parasite Plasmodium falciparum Associates with
Evolutionarily Novel Subunits.
Iyer UB(1), Park JE(1), Sze SK(1), Bozdech Z(1), Featherstone M(1).
Author information:
(1)School of Biological Sciences, Nanyang Technological University, 50 Nanyang
Avenue, Singapore 637551, Singapore.
The eukaryotic Mediator is a large and conserved multisubunit protein complex
that directly contacts RNA polymerase II and impinges on multiple aspects of
gene expression. The genome of the human malaria parasite Plasmodium falciparum
has been predicted to encode several Mediator subunits. We provide physical
evidence for the presence of a Mediator complex in P. falciparum by using
coimmunoprecipitation and mass spectrometry to identify interaction partners of
the highly conserved Mediator subunit PfMed31. We identify 11 of 14 predicted
Mediator subunits and the products of two uncharacterized genes, PF3D7_0526800
and PF3D7_1363600, which are strongly associated with PfMed31. As expected,
several additional interaction partners have known roles in the transcriptional
control of gene expression and mRNA processing. Intriguingly, multiple
interaction partners are implicated in endoplasmic reticulum function and the ER
stress (ERS) response, suggesting crosstalk between the ERS response and the
transcriptional machinery. Our results establish for the first time the physical
presence of the Mediator complex within P. falciparum and strongly suggest that
it plays both conserved and unique roles in the control of gene expression. Data
are available via ProteomeXchange with the identifier PXD027640.
© 2022 The Authors. Published by American Chemical Society.
DOI: 10.1021/acsomega.2c00368
PMCID: PMC9088918
PMID: 35557691
Conflict of interest statement: The authors declare no competing financial
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36445897 | 1. PLoS One. 2022 Nov 29;17(11):e0275613. doi: 10.1371/journal.pone.0275613.
eCollection 2022.
Inducible degradation of the Drosophila Mediator subunit Med19 reveals its role
in regulating developmental but not constitutively-expressed genes.
Jullien D(1), Guillou E(1), Bernat-Fabre S(1), Payet A(1), Bourbon HG(1), Boube
M(1)(2).
Author information:
(1)Center for Integrative Biology, Molecular Cellular and Developmental (MCD)
Biology Unit UMR 5077, Federal University of Toulouse, Toulouse, France.
(2)RESTORE Research Center, Université de Toulouse, INSERM 1301, CNRS 5070, EFS,
ENVT, Toulouse, France.
The multi-subunit Mediator complex plays a critical role in gene expression by
bridging enhancer-bound transcription factors and the RNA polymerase II
machinery. Although experimental case studies suggest differential roles of
Mediator subunits, a comprehensive view of the specific set of genes regulated
by individual subunits in a developing tissue is still missing. Here we address
this fundamental question by focusing on the Med19 subunit and using the
Drosophila wing imaginal disc as a developmental model. By coupling
auxin-inducible degradation of endogenous Med19 in vivo with RNA-seq, we got
access to the early consequences of Med19 elimination on gene expression.
Differential gene expression analysis reveals that Med19 is not globally
required for mRNA transcription but specifically regulates positively or
negatively less than a quarter of the expressed genes. By crossing our
transcriptomic data with those of Drosophila gene expression profile database,
we found that Med19-dependent genes are highly enriched with spatially-regulated
genes while the expression of most constitutively expressed genes is not
affected upon Med19 loss. Whereas globally downregulation does not exceed
upregulation, we identified a functional class of genes encoding
spatially-regulated transcription factors, and more generally developmental
regulators, responding unidirectionally to Med19 loss with an expression
collapse. Moreover, we show in vivo that the Notch-responsive wingless and the
E(spl)-C genes require Med19 for their expression. Combined with experimental
evidences suggesting that Med19 could function as a direct transcriptional
effector of Notch signaling, our data support a model in which Med19 plays a
critical role in the transcriptional activation of developmental genes in
response to cell signaling pathways.
Copyright: © 2022 Jullien et al. This is an open access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pone.0275613
PMCID: PMC9707739
PMID: 36445897 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist |
http://www.ncbi.nlm.nih.gov/pubmed/29209056 | 1. Nat Rev Mol Cell Biol. 2018 Apr;19(4):262-274. doi: 10.1038/nrm.2017.115. Epub
2017 Dec 6.
Transcription regulation by the Mediator complex.
Soutourina J(1).
Author information:
(1)Institute for Integrative Biology of the Cell (I2BC), Institute of Life
Sciences Frédéric Joliot, Commissariat à l'énergie Atomique et aux énergies
alternatives (CEA), Centre National de la Recherche Scientifique (CNRS),
University Paris Sud, University Paris Saclay, F-91198 Gif-sur-Yvette, France.
Alterations in the regulation of gene expression are frequently associated with
developmental diseases or cancer. Transcription activation is a key phenomenon
in the regulation of gene expression. In all eukaryotes, mediator of RNA
polymerase II transcription (Mediator), a large complex with modular
organization, is generally required for transcription by RNA polymerase II, and
it regulates various steps of this process. The main function of Mediator is to
transduce signals from the transcription activators bound to enhancer regions to
the transcription machinery, which is assembled at promoters as the
preinitiation complex (PIC) to control transcription initiation. Recent
functional studies of Mediator with the use of structural biology approaches and
functional genomics have revealed new insights into Mediator activity and its
regulation during transcription initiation, including how Mediator is recruited
to transcription regulatory regions and how it interacts and cooperates with PIC
components to assist in PIC assembly. Novel roles of Mediator in the control of
gene expression have also been revealed by showing its connection to the nuclear
pore and linking Mediator to the regulation of gene positioning in the nuclear
space. Clear links between Mediator subunits and disease have also encouraged
studies to explore targeting of this complex as a potential therapeutic approach
in cancer and fungal infections.
DOI: 10.1038/nrm.2017.115
PMID: 29209056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30637479 | 1. Curr Genet. 2019 Jun;65(3):621-630. doi: 10.1007/s00294-019-00932-8. Epub 2019
Jan 14.
Role of Mediator in virulence and antifungal drug resistance in pathogenic
fungi.
Moran GP(1)(2), Anderson MZ(3), Myers LC(4)(5), Sullivan DJ(6)(7).
Author information:
(1)Division of Oral Biosciences, Dublin Dental University Hospital, Dublin,
Ireland. gpmoran@dental.tcd.ie.
(2)School of Dental Science, Trinity College Dublin, University of Dublin,
Dublin, Ireland. gpmoran@dental.tcd.ie.
(3)Department of Microbial Infection and Immunity, The Ohio State University,
Columbus, OH, USA.
(4)Department of Medical Education, Geisel School of Medicine at Dartmouth,
Hanover, NH, USA.
(5)Department of Biochemistry and Cell Biology, Geisel School of Medicine at
Dartmouth, Hanover, NH, USA.
(6)Division of Oral Biosciences, Dublin Dental University Hospital, Dublin,
Ireland.
(7)School of Dental Science, Trinity College Dublin, University of Dublin,
Dublin, Ireland.
Mediator complex has recently emerged as an important regulator of gene
expression in pathogenic fungi. Mediator is a multi-subunit complex of
polypeptides involved in transcriptional activation in eukaryotes, with roles
including preinitiation complex (PIC) assembly and chromatin remodeling. Within
the last decade, Mediator has been shown to play an integral role in regulating
virulence gene expression and drug resistance in human fungal pathogens. In some
fungi, specific Mediator subunits have been shown to be required for virulence.
In Candida species, duplication and expansion of Mediator subunit encoding genes
has occurred on at least three occasions (CgMED15 in C. glabrata and MED2/TLO in
C. albicans and C. dubliniensis) suggesting important roles for Mediator in the
evolution of these pathogens. This review summarises recent developments in our
understanding of Mediator in fungal pathogens and the potential for the
development of therapeutic drugs to target Mediator functions.
DOI: 10.1007/s00294-019-00932-8
PMID: 30637479 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18691967 | 1. Mol Cell. 2008 Aug 8;31(3):347-59. doi: 10.1016/j.molcel.2008.05.023.
Mediator links epigenetic silencing of neuronal gene expression with x-linked
mental retardation.
Ding N(1), Zhou H, Esteve PO, Chin HG, Kim S, Xu X, Joseph SM, Friez MJ,
Schwartz CE, Pradhan S, Boyer TG.
Author information:
(1)Department of Molecular Medicine, University of Texas Health Science Center
at San Antonio, San Antonio, TX 78245, USA.
Comment in
Mol Cell. 2008 Aug 8;31(3):305-6. doi: 10.1016/j.molcel.2008.07.011.
Mediator occupies a central role in RNA polymerase II transcription as a sensor,
integrator, and processor of regulatory signals that converge on protein-coding
gene promoters. Compared to its role in gene activation, little is known
regarding the molecular mechanisms and biological implications of Mediator as a
transducer of repressive signals. Here we describe a protein interaction network
required for extraneuronal gene silencing comprising Mediator, G9a histone
methyltransferase, and the RE1 silencing transcription factor (REST; also known
as neuron restrictive silencer factor, NRSF). We show that the MED12 interface
in Mediator links REST with G9a-dependent histone H3K9 dimethylation to suppress
neuronal genes in nonneuronal cells. Notably, missense mutations in MED12
causing the X-linked mental retardation (XLMR) disorders FG syndrome and Lujan
syndrome disrupt its REST corepressor function. These findings implicate
Mediator in epigenetic restriction of neuronal gene expression to the nervous
system and suggest a pathologic basis for MED12-associated XLMR involving
impaired REST-dependent neuronal gene regulation.
DOI: 10.1016/j.molcel.2008.05.023
PMCID: PMC2583939
PMID: 18691967 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16634145 | 1. Rev Physiol Biochem Pharmacol. 2006;156:23-43. doi: 10.1007/s10254-005-0002-0.
Role of the mediator complex in nuclear hormone receptor signaling.
Belakavadi M(1), Fondell JD.
Author information:
(1)Department of Physiology and Biophysics, Robert Wood Johnson Medical School,
UMDNJ, Piscataway, NJ 08854, USA.
Mediator is an evolutionarily conserved multisubunit protein complex that plays
a key role in regulating transcription by RNA polymerase II. The complex
functions by serving as a molecular bridge between DNA-bound transcriptional
activators and the basal transcription apparatus. In humans, Mediator was first
characterized as a thyroid hormone receptor (TR)-associated protein (TRAP)
complex that facilitates ligand-dependent transcriptional activation by TR. More
recently, Mediator has been established as an essential coactivator for a broad
range of nuclear hormone receptors (NRs) as well as several other types of
gene-specific transcriptional activators. A single subunit of the complex,
MED1/TRAP220, is required for direct ligand-dependent interactions with NRs.
Mediator coactivates NR-regulated gene expression by facilitating the
recruitment and activation of the RNA polymerase II-associated basal
transcription apparatus. Importantly, Mediator acts in concert with other NR
coactivators involved in chromatin remodeling to initiate transcription of NR
target genes in a multistep manner. In this review, we summarize the functional
role of Mediator in NR signaling pathways with an emphasis on the underlying
molecular mechanisms by which the complex interacts with NRs and subsequently
facilitates their action. We also focus on recent advances in our understanding
of TRAP/Mediator's pathophysiological role in mammalian disease and development.
DOI: 10.1007/s10254-005-0002-0
PMID: 16634145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21854862 | 1. Semin Cell Dev Biol. 2011 Sep;22(7):769-75. doi: 10.1016/j.semcdb.2011.07.025.
Epub 2011 Aug 10.
Mediator complex proteins are required for diverse developmental processes.
Hentges KE(1).
Author information:
(1)Faculty of Life Sciences, University of Manchester, Michael Smith Building,
Oxford Road, Manchester M13 9PT, UK. kathryn.hentges@manchester.ac.uk
The Mediator complex serves a crucial function in gene regulation, forming a
link between gene-specific transcription factors and RNA polymerase II. Most
protein-coding genes therefore require Mediator complex activity for
transcriptional regulation. Given the essential functions performed by Mediator
complex proteins in gene regulation, it is not surprising that mutations in
Mediator complex genes disrupt animal and plant development. What is more
intriguing is that the phenotypes of individual Mediator complex mutants are
distinct from each other, demonstrating that certain developmental processes
have a greater requirement for specific Mediator complex genes. Additionally,
the range of developmental processes that are altered in Mediator complex
mutants is broad, affecting a variety of cell types and physiological systems.
Gene expression defects in Mediator complex mutants reveal distinct roles for
individual Mediator proteins in transcriptional regulation, suggesting that the
deletion of one Mediator complex protein does not interfere with transcription
in general, but instead alters the expression of specific target genes. Mediator
complex proteins may have diverse roles in different organisms as well, as
mutants in the same Mediator gene in different species can display dissimilar
phenotypes.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2011.07.025
PMID: 21854862 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33621520 | 1. J Mol Biol. 2021 Jul 9;433(14):166883. doi: 10.1016/j.jmb.2021.166883. Epub
2021 Feb 20.
What do Transcription Factors Interact With?
Chen H(1), Pugh BF(2).
Author information:
(1)Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY
14853, USA.
(2)Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY
14853, USA. Electronic address: fp265@cornell.edu.
Although we have made significant progress, we still possess a limited
understanding of how genomic and epigenomic information directs gene expression
programs through sequence-specific transcription factors (TFs). Extensive
research has settled on three general classes of TF targets in metazoans:
promoter accessibility via chromatin regulation (e.g., SAGA), assembly of the
general transcription factors on promoter DNA (e.g., TFIID), and recruitment of
RNA polymerase (Pol) II (e.g., Mediator) to establish a transcription
pre-initiation complex (PIC). Here we discuss TFs and their targets. We also
place this in the context of our current work with Saccharomyces (yeast), where
we find that promoters typically lack an architecture that supports TF function.
Moreover, yeast promoters that support TF binding also display interactions with
cofactors like SAGA and Mediator, but not TFIID. It is unknown to what extent
all genes in metazoans require TFs and their cofactors.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2021.166883
PMCID: PMC8184585
PMID: 33621520 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare the following financial interests/personal relationships which may be
considered as potential competing interests: BFP has a financial interest in
Peconic, LLC, which uses the ChIP-exo technology implemented in this study and
could potentially benefit from the outcomes of this research. |
http://www.ncbi.nlm.nih.gov/pubmed/26002960 | 1. J Biochem. 2015 Nov;158(5):373-84. doi: 10.1093/jb/mvv055. Epub 2015 May 22.
Mediator complex cooperatively regulates transcription of retinoic acid target
genes with Polycomb Repressive Complex 2 during neuronal differentiation.
Fukasawa R(1), Iida S(1), Tsutsui T(2), Hirose Y(1), Ohkuma Y(3).
Author information:
(1)Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical
Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
(2)Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical
Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500
Gilman Drive, La Jolla, California 92093, USA; and.
(3)Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical
Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
Department of Biochemistry, Nagasaki University School of Medicine, 1-12-4
Sakamoto, Nagasaki 852-8523, Japan ohkumay@pha.u-toyama.ac.jp.
The Mediator complex (Mediator) plays key roles in transcription and functions
as the nexus for integration of various transcriptional signals. Previously, we
screened for Mediator cyclin-dependent kinase (CDK)-interacting factors and
identified three proteins related to chromatin regulation. One of them, SUZ12 is
required for both stability and activity of Polycomb Repressive Complex 2
(PRC2). PRC2 primarily suppresses gene expression through histone H3 lysine 27
trimethylation, resulting in stem cell maintenance and differentiation;
perturbation of this process leads to oncogenesis. Recent work showed that
Mediator contributes to the embryonic stem cell state through DNA loop
formation, which is strongly associated with chromatin architecture; however, it
remains unclear how Mediator regulates gene expression in cooperation with
chromatin regulators (i.e. writers, readers and remodelers). We found that
Mediator CDKs interact directly with the PRC2 subunit EZH2, as well as SUZ12.
Known PRC2 target genes were deregulated by Mediator CDK knockdown during
neuronal differentiation, and both Mediator and PRC2 complexes co-occupied the
promoters of developmental genes regulated by retinoic acid. Our results provide
a mechanistic link between Mediator and PRC2 during neuronal differentiation.
© The Authors 2015. Published by Oxford University Press on behalf of the
Japanese Biochemical Society. All rights reserved.
DOI: 10.1093/jb/mvv055
PMID: 26002960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20299225 | 1. Trends Biochem Sci. 2010 Jun;35(6):315-22. doi: 10.1016/j.tibs.2010.02.004.
Epub 2010 Mar 17.
The human Mediator complex: a versatile, genome-wide regulator of transcription.
Taatjes DJ(1).
Author information:
(1)Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO
80309, USA. Taatjes@colorado.edu
The Mediator complex interacts extensively with the RNA polymerase II enzyme and
regulates its ability to express protein-coding genes. The mechanisms by which
Mediator regulates gene expression remain poorly understood, in part because the
structure of Mediator and even its composition can change, depending upon the
promoter context. Combined with the sheer size of the human Mediator complex (26
subunits, 1.2 MDa), this structural adaptability bestows seemingly unlimited
regulatory potential within the complex. Recent efforts to understand Mediator
structure and function have identified expanded roles that include control of
both pre- and post-initiation events; it is also evident that Mediator performs
both general and gene-specific roles to regulate gene expression.
Copyright 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tibs.2010.02.004
PMCID: PMC2891401
PMID: 20299225 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24550107 | 1. Development. 2014 Mar;141(5):977-87. doi: 10.1242/dev.098392.
The Mediator complex: a master coordinator of transcription and cell lineage
development.
Yin JW(1), Wang G.
Author information:
(1)State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell
Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of
Sciences, Shanghai 200031, China.
Mediator is a multiprotein complex that is required for gene transcription by
RNA polymerase II. Multiple subunits of the complex show specificity in relaying
information from signals and transcription factors to the RNA polymerase II
machinery, thus enabling control of the expression of specific genes. Recent
studies have also provided novel mechanistic insights into the roles of Mediator
in epigenetic regulation, transcriptional elongation, termination, mRNA
processing, noncoding RNA activation and super enhancer formation. Based on
these specific roles in gene regulation, Mediator has emerged as a master
coordinator of development and cell lineage determination. Here, we describe the
most recent advances in understanding the mechanisms of Mediator function, with
an emphasis on its role during development and disease.
DOI: 10.1242/dev.098392
PMID: 24550107 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28301289 | 1. Transcription. 2017 May 27;8(3):169-174. doi: 10.1080/21541264.2017.1291082.
Epub 2017 Feb 8.
Genome-wide characterization of Mediator recruitment, function, and regulation.
Grünberg S(1), Zentner GE(2).
Author information:
(1)a Basic Sciences Division , Fred Hutchinson Cancer Research Center , Seattle
, WA , USA.
(2)b Department of Biology , Indiana University , Bloomington , IN USA.
Mediator is a conserved and essential coactivator complex broadly required for
RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator
binding in budding yeast have revealed new insights into the functions of this
critical complex and raised new questions about its role in the regulation of
gene expression.
DOI: 10.1080/21541264.2017.1291082
PMCID: PMC5501378
PMID: 28301289 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29626929 | 1. Biochemistry (Mosc). 2018 Apr;83(4):423-436. doi: 10.1134/S0006297918040132.
Structure and Functions of the Mediator Complex.
Putlyaev EV(1), Ibragimov AN, Lebedeva LA, Georgiev PG, Shidlovskii YV.
Author information:
(1)Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334,
Russia. yul.biogen@gmail.com.
Mediator is a key factor in the regulation of expression of RNA polymerase
II-transcribed genes. Recent studies have shown that Mediator acts as a
coordinator of transcription activation and participates in maintaining
chromatin architecture in the cell nucleus. In this review, we present current
concepts on the structure and functions of Mediator.
DOI: 10.1134/S0006297918040132
PMID: 29626929 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20720539 | 1. Nature. 2010 Sep 23;467(7314):430-5. doi: 10.1038/nature09380. Epub 2010 Aug
18.
Mediator and cohesin connect gene expression and chromatin architecture.
Kagey MH(1), Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier
CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA.
Author information:
(1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
Massachusetts 02142, USA.
Erratum in
Nature. 2011 Apr 14;472(7342):247.
Comment in
Nature. 2010 Sep 23;467(7314):406-7. doi: 10.1038/467406a.
Cell Stem Cell. 2010 Oct 8;7(4):424-6. doi: 10.1016/j.stem.2010.09.006.
Transcription factors control cell-specific gene expression programs through
interactions with diverse coactivators and the transcription apparatus. Gene
activation may involve DNA loop formation between enhancer-bound transcription
factors and the transcription apparatus at the core promoter, but this process
is not well understood. Here we report that mediator and cohesin physically and
functionally connect the enhancers and core promoters of active genes in murine
embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex
with cohesin, which can form rings that connect two DNA segments. The
cohesin-loading factor Nipbl is associated with mediator-cohesin complexes,
providing a means to load cohesin at promoters. DNA looping is observed between
the enhancers and promoters occupied by mediator and cohesin. Mediator and
cohesin co-occupy different promoters in different cells, thus generating
cell-type-specific DNA loops linked to the gene expression program of each cell.
DOI: 10.1038/nature09380
PMCID: PMC2953795
PMID: 20720539 [Indexed for MEDLINE]
Conflict of interest statement: Competing Financial Interests The authors
declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/22402254 | 1. Biochim Biophys Acta. 2013 Jul;1830(7):3867-75. doi:
10.1016/j.bbagen.2012.02.012. Epub 2012 Feb 28.
The Mediator complex in thyroid hormone receptor action.
Fondell JD(1).
Author information:
(1)Department of Physiology & Biophysics, Robert Wood Johnson Medical School,
UMDNJ, 683 Hoes Lane, Piscataway, NJ 08854-5635, USA. fondeljd@umdnj.edu
BACKGROUND: Mediator is an evolutionarily conserved multisubunit complex that
plays an essential regulatory role in eukaryotic transcription of
protein-encoding genes. The human complex was first isolated as a
transcriptional coactivator bound to the thyroid hormone receptor (TR) and has
since been shown to play a key coregulatory role for a broad range of nuclear
hormone receptors (NRs) as well as other signal-activated transcription factors.
SCOPE OF REVIEW: We provide a general overview of Mediator structure and
function, summarize the mechanisms by which Mediator is targeted to NRs, and
outline recent evidence revealing Mediator as a regulatory axis for other
distinct coregulatory factors, chromatin modifying enzymes and cellular signal
transduction pathways.
MAJOR CONCLUSIONS: Besides serving as a functional interface with the RNA
polymerase II basal transcription machinery, Mediator plays a more versatile
role in regulating transcription including the ability to: a) facilitate
gene-specific chromatin looping events; b) coordinate chromatin modification
events with preinitiation complex assembly; and c) regulate critical steps that
occur during transcriptional elongation. The variably associated MED1 subunit
continues to emerge as a pivotal player in Mediator function, not only as the
primary interaction site for NRs, but also as a crucial interaction hub for
other coregulatory factors, and as an important regulatory target for
signal-activated kinases.
GENERAL SIGNIFICANCE: Mediator plays an integral coregulatory role at NR target
genes by functionally interacting with the basal transcription apparatus and by
coordinating the action of chromatin modifying enzymes and transcription
elongation factors. This article is part of a Special Issue entitled Thyroid
hormone signalling.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagen.2012.02.012
PMID: 22402254 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24882805 | 1. Cell. 2014 Jun 5;157(6):1430-1444. doi: 10.1016/j.cell.2014.05.015. Epub 2014
May 29.
Subunit architecture and functional modular rearrangements of the
transcriptional mediator complex.
Tsai KL(1), Tomomori-Sato C(2), Sato S(2), Conaway RC(3), Conaway JW(3),
Asturias FJ(4).
Author information:
(1)Department of Integrative Structural and Computational Biology, The Scripps
Research Institute, La Jolla, CA 92037, USA.
(2)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
(3)Stowers Institute for Medical Research, Kansas City, MO 64110, USA;
Department of Biochemistry & Molecular Biology, Kansas University Medical
Center, Kansas City, KS 66160, USA.
(4)Department of Integrative Structural and Computational Biology, The Scripps
Research Institute, La Jolla, CA 92037, USA. Electronic address:
asturias@scripps.edu.
Erratum in
Cell. 2014 Jul 17;158(2):463.
The multisubunit Mediator, comprising ∼30 distinct proteins, plays an essential
role in gene expression regulation by acting as a bridge between DNA-binding
transcription factors and the RNA polymerase II (RNAPII) transcription
machinery. Efforts to uncover the Mediator mechanism have been hindered by a
poor understanding of its structure, subunit organization, and conformational
rearrangements. By overcoming biochemical and image analysis hurdles, we
obtained accurate EM structures of yeast and human Mediators. Subunit
localization experiments, docking of partial X-ray structures, and biochemical
analyses resulted in comprehensive mapping of yeast Mediator subunits and a
complete reinterpretation of our previous Mediator organization model.
Large-scale Mediator rearrangements depend on changes at the interfaces between
previously described Mediator modules, which appear to be facilitated by factors
conducive to transcription initiation. Conservation across eukaryotes of
Mediator structure, subunit organization, and RNA polymerase II interaction
suggest conservation of fundamental aspects of the Mediator mechanism.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2014.05.015
PMCID: PMC4104964
PMID: 24882805 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32260277 | 1. Int J Mol Sci. 2020 Apr 3;21(7):2498. doi: 10.3390/ijms21072498.
Mapping the Gene Expression Spectrum of Mediator Subunits in Response to Viroid
Infection in Plants.
Nath VS(1), Shrestha A(1), Awasthi P(1), Mishra AK(1), Kocábek T(1), Matoušek
J(1), Sečnik A(2), Jakše J(2), Radišek S(3), Hallan V(4).
Author information:
(1)Biology Centre of the Czech Academy of Sciences, Department of Molecular
Genetics, Institute of Plant Molecular Biology, Branišovská 31, 370 05 Ceske
Budejovice, Czech Republic.
(2)Department of Agronomy, Biotechnical Faculty, University of Ljubljana,
Jamnikarjeva 101, SI-1000 Ljubljana, Slovenia.
(3)Slovenian Institute of Hop Research and Brewing, Plant Protection Department,
Cesta Žalskega Tabora 2, SI-3310 Žalec, Slovenia.
(4)CSIR-Institute of Himalayan Bioresource Technology, Palampur-176061 India.
The mediator (MED) represents a large, conserved, multi-subunit protein complex
that regulates gene expression through interactions with RNA polymerase II and
enhancer-bound transcription factors. Expanding research accomplishments suggest
the predominant role of plant MED subunits in the regulation of various
physiological and developmental processes, including the biotic stress response
against bacterial and fungal pathogens. However, the involvement of MED subunits
in virus/viroid pathogenesis remains elusive. In this study, we investigated for
the first time the gene expression modulation of selected MED subunits in
response to five viroid species (Apple fruit crinkle viroid (AFCVd), Citrus bark
cracking viroid (CBCVd), Hop latent viroid (HLVd), Hop stunt viroid (HSVd), and
Potato spindle tuber viroid (PSTVd)) in two model plant species (Nicotiana
tabacum and N. benthamiana) and a commercially important hop (Humulus lupulus)
cultivar. Our results showed a differential expression pattern of MED subunits
in response to a viroid infection. The individual plant MED subunits displayed a
differential and tailored expression pattern in response to different viroid
species, suggesting that the MED expression is viroid- and plant
species-dependent. The explicit evidence obtained from our results warrants
further investigation into the association of the MED subunit with symptom
development. Together, we provide a comprehensive portrait of MED subunit
expression in response to viroid infection and a plausible involvement of MED
subunits in fine-tuning transcriptional reprogramming in response to viroid
infection, suggesting them as a potential candidate for rewiring the defense
response network in plants against pathogens.
DOI: 10.3390/ijms21072498
PMCID: PMC7177877
PMID: 32260277 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35725906 | 1. Nat Rev Mol Cell Biol. 2022 Nov;23(11):732-749. doi:
10.1038/s41580-022-00498-3. Epub 2022 Jun 20.
The Mediator complex as a master regulator of transcription by RNA polymerase
II.
Richter WF(1), Nayak S(2), Iwasa J(2), Taatjes DJ(3).
Author information:
(1)Department of Biochemistry, University of Colorado, Boulder, CO, USA.
(2)Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
(3)Department of Biochemistry, University of Colorado, Boulder, CO, USA.
taatjes@colorado.edu.
The Mediator complex, which in humans is 1.4 MDa in size and includes 26
subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart
from its size, a defining feature of Mediator is its intrinsic disorder and
conformational flexibility, which contributes to its ability to undergo phase
separation and to interact with a myriad of regulatory factors. In this Review,
we discuss Mediator structure and function, with emphasis on recent cryogenic
electron microscopy data of the 4.0-MDa transcription preinitiation complex. We
further discuss how Mediator and sequence-specific DNA-binding transcription
factors enable enhancer-dependent regulation of Pol II function at distal gene
promoters, through the formation of molecular condensates (or transcription
hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also
discussed, in the context of transcription bursting. We propose a working model
for Mediator function that combines experimental results and theoretical
considerations related to enhancer-promoter interactions, which reconciles
contradictory data regarding whether enhancer-promoter communication is direct
or indirect. We conclude with a discussion of Mediator's potential as a
therapeutic target and of future research directions.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41580-022-00498-3
PMCID: PMC9207880
PMID: 35725906 [Indexed for MEDLINE]
Conflict of interest statement: D.J.T. is a member of the scientific advisory
board of Dewpoint Therapeutics. All the other authors declare no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33707221 | 1. Science. 2021 Apr 2;372(6537):52-56. doi: 10.1126/science.abg3074. Epub 2021
Mar 11.
Structure of the human Mediator-bound transcription preinitiation complex.
Abdella R(#)(1)(2), Talyzina A(#)(1)(2), Chen S(1)(2), Inouye CJ(3)(4)(5)(6),
Tjian R(7)(4)(5)(6), He Y(8)(2)(9)(10).
Author information:
(1)Department of Molecular Biosciences, Northwestern University, Evanston, IL,
USA.
(2)Interdisciplinary Biological Sciences Program, Northwestern University,
Evanston, IL, USA.
(3)Department of Molecular and Cell Biology, University of California, Berkeley,
Berkeley, CA, USA.
(4)Li Ka Shing Center for Biomedical and Health Sciences, University of
California, Berkeley, Berkeley, CA, USA.
(5)CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA,
USA.
(6)Howard Hughes Medical Institute, University of California, Berkeley,
Berkeley, CA, USA.
(7)Department of Molecular and Cell Biology, University of California, Berkeley,
Berkeley, CA, USA. yuanhe@northwestern.edu jmlim@berkeley.edu.
(8)Department of Molecular Biosciences, Northwestern University, Evanston, IL,
USA. yuanhe@northwestern.edu jmlim@berkeley.edu.
(9)Chemistry of Life Processes Institute, Northwestern University, Evanston, IL,
USA.
(10)Robert H. Lurie Comprehensive Cancer Center of Northwestern University,
Northwestern University, Chicago, IL, USA.
(#)Contributed equally
Eukaryotic transcription requires the assembly of a multisubunit preinitiation
complex (PIC) composed of RNA polymerase II (Pol II) and the general
transcription factors. The coactivator Mediator is recruited by transcription
factors, facilitates the assembly of the PIC, and stimulates phosphorylation of
the Pol II C-terminal domain (CTD) by the TFIIH subunit CDK7. Here, we present
the cryo-electron microscopy structure of the human Mediator-bound PIC at a
resolution below 4 angstroms. Transcription factor binding sites within Mediator
are primarily flexibly tethered to the tail module. CDK7 is stabilized by
multiple contacts with Mediator. Two binding sites exist for the Pol II CTD, one
between the head and middle modules of Mediator and the other in the active site
of CDK7, providing structural evidence for Pol II CTD phosphorylation within the
Mediator-bound PIC.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/science.abg3074
PMCID: PMC8117670
PMID: 33707221 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: Authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/28778422 | 1. Trends Cell Biol. 2017 Oct;27(10):765-783. doi: 10.1016/j.tcb.2017.07.001.
Epub 2017 Aug 1.
The Mediator Complex: At the Nexus of RNA Polymerase II Transcription.
Jeronimo C(1), Robert F(2).
Author information:
(1)Institut de recherches cliniques de Montréal, Montréal, Québec, H2W 1R7,
Canada.
(2)Institut de recherches cliniques de Montréal, Montréal, Québec, H2W 1R7,
Canada; Département de Médecine, Faculté de Médecine, Université de Montréal,
Montréal, Québec, H3T 1J4, Canada. Electronic address:
francois.robert@ircm.qc.ca.
Mediator is an essential, large, multisubunit, transcriptional co-activator
highly conserved across eukaryotes. Mediator interacts with gene-specific
transcription factors at enhancers as well as with the RNA polymerase II
(RNAPII) transcription machinery bound at promoters. It also interacts with
several other factors involved in various aspects of transcription, chromatin
regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII
transcription, regulating its many steps and connecting transcription with
co-transcriptional events. To achieve this flexible role, Mediator, which is
divided into several functional modules, reorganizes its conformation and
composition while making transient contacts with other components. Here, we
review the mechanisms of action of Mediator and propose a unifying model for its
function.
Copyright © 2017 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2017.07.001
PMID: 28778422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30278226 | 1. Semin Cell Dev Biol. 2020 Mar;99:20-30. doi: 10.1016/j.semcdb.2018.08.006.
Epub 2018 Oct 16.
The Mediator complex and the role of protein-protein interactions in the gene
regulation machinery.
Sierecki E(1).
Author information:
(1)EMBL Australia Node in Single Molecule Science, and School of Medical
Sciences, Faculty of Medecine, The University of New South Wales, Sydney,
Australia. Electronic address: e.sierecki@unsw.edu.au.
At the core of gene regulation, a complex network of dynamic interactions
between proteins, DNA and RNA has to be integrated in order to generate a binary
biological output. Large protein complexes, called adaptors, transfer
information from the transcription factors to the transcription machinery [1,2].
Here we focus on Mediator, one of the largest adaptor proteins in humans [3].
Assembled from 30 different subunits, this system provides extraordinary
illustrations for the various roles played by protein-protein interactions.
Recruitment of new subunits during evolution is an adaptive mechanism to the
growing complexity of the organism. Integration of information happens at
multiple scales, with allosteric effects at the level of individual subunits
resulting in large conformational changes. Mediator is also rich in disordered
regions that increase the potential for interactions by presenting a malleable
surface to its environment. Potentially, 3000 transcription factors can interact
with Mediator and so understanding the molecular mechanisms that support the
processing of this overload of information is one of the great challenges in
molecular biology.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2018.08.006
PMID: 30278226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25693131 | 1. Nat Rev Mol Cell Biol. 2015 Mar;16(3):155-66. doi: 10.1038/nrm3951. Epub 2015
Feb 18.
The Mediator complex: a central integrator of transcription.
Allen BL(1), Taatjes DJ(1).
Author information:
(1)Department of Chemistry and Biochemistry, University of Colorado, Boulder,
Colorado 80303, USA.
The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most
non-coding RNA genes and is globally regulated by Mediator - a large,
conformationally flexible protein complex with a variable subunit composition
(for example, a four-subunit cyclin-dependent kinase 8 module can reversibly
associate with it). These biochemical characteristics are fundamentally
important for Mediator's ability to control various processes that are important
for transcription, including the organization of chromatin architecture and the
regulation of Pol II pre-initiation, initiation, re-initiation, pausing and
elongation. Although Mediator exists in all eukaryotes, a variety of Mediator
functions seem to be specific to metazoans, which is indicative of more diverse
regulatory requirements.
DOI: 10.1038/nrm3951
PMCID: PMC4963239
PMID: 25693131 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22983086 | 1. Biochim Biophys Acta. 2013 Jan;1829(1):69-75. doi:
10.1016/j.bbagrm.2012.08.017. Epub 2012 Sep 13.
The Mediator complex and transcription elongation.
Conaway RC(1), Conaway JW.
Author information:
(1)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
RCC@stowers.org
BACKGROUND: Mediator is an evolutionarily conserved multisubunit RNA polymerase
II (Pol II) coregulatory complex. Although Mediator was initially found to play
a critical role in the regulation of the initiation of Pol II transcription,
recent studies have brought to light an expanded role for Mediator at
post-initiation stages of transcription.
SCOPE OF REVIEW: We provide a brief description of the structure of Mediator and
its function in the regulation of Pol II transcription initiation, and we
summarize recent findings implicating Mediator in the regulation of various
stages of Pol II transcription elongation.
MAJOR CONCLUSIONS: Emerging evidence is revealing new roles for Mediator in
nearly all stages of Pol II transcription, including initiation, promoter
escape, elongation, pre-mRNA processing, and termination.
GENERAL SIGNIFICANCE: Mediator plays a central role in the regulation of gene
expression by impacting nearly all stages of mRNA synthesis. This article is
part of a Special Issue entitled: RNA polymerase II Transcript Elongation.
Copyright © 2012. Published by Elsevier B.V.
DOI: 10.1016/j.bbagrm.2012.08.017
PMCID: PMC3693936
PMID: 22983086 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10966474 | 1. Annu Rev Biochem. 2000;69:729-49. doi: 10.1146/annurev.biochem.69.1.729.
Mediator of transcriptional regulation.
Myers LC(1), Kornberg RD.
Author information:
(1)Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire
03755, USA.
Three lines of evidence have converged on a multiprotein Mediator complex as a
conserved interface between gene-specific regulatory proteins and the general
transcription apparatus of eukaryotes. Mediator was discovered as an activity
required for transcriptional activation in a reconstituted system from yeast.
Upon resolution to homogeneity, the activity proved to reside in a 20-protein
complex, which could exist in a free state or in a complex with RNA polymerase
II, termed holoenzyme. A second line of evidence came from screens in yeast for
mutations affecting transcription. Two-thirds of Mediator subunits are encoded
by genes revealed by these screens. Five of the genetically defined subunits,
termed Srbs, were characterized as interacting with the C-terminal domain of RNA
polymerase II in vivo, and were shown to bind polymerase in vitro. A third line
of evidence has come recently from studies in mammalian transcription systems.
Mammalian counterparts of yeast Mediator were shown to interact with
transcriptional activator proteins and to play an essential role in
transcriptional regulation. Mediator evidently integrates and transduces
positive and negative regulatory information from enhancers and operators to
promoters. It functions directly through RNA polymerase II, modulating its
activity in promoter-dependent transcription. Details of the Mediator mechanism
remain obscure. Additional outstanding questions include the patterns of
promoter-specificity of the various Mediator subunits, the possible
cell-type-specificity of Mediator subunit composition, and the full structures
of both free Mediator and RNA polymerase II holoenzyme.
DOI: 10.1146/annurev.biochem.69.1.729
PMID: 10966474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33226222 | 1. J Med Chem. 2020 Dec 24;63(24):15494-15507. doi: 10.1021/acs.jmedchem.0c01608.
Epub 2020 Nov 23.
Fragment-to-Lead Medicinal Chemistry Publications in 2019.
Jahnke W(1), Erlanson DA(2), de Esch IJP(3), Johnson CN(4), Mortenson PN(4),
Ochi Y(4), Urushima T(4).
Author information:
(1)Chemical Biology and Therapeutics, Novartis Institutes for Biomedical
Research, 4002 Basel, Switzerland.
(2)Frontier Medicines, 151 Oyster Point Boulevard, South San Francisco,
California 94080, United States of America.
(3)Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines
and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ
Amsterdam, The Netherlands.
(4)Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4
0QA, United Kingdom.
Fragment-based drug discovery (FBDD) has grown and matured to a point where it
is valuable to keep track of its extent and details of application. This
Perspective summarizes successful fragment-to-lead stories published in 2019. It
is the fifth in a series that started with literature published in 2015. The
analysis of screening methods, optimization strategies, and molecular properties
of hits and leads are presented in the hope of informing best practices for
FBDD. Moreover, FBDD is constantly evolving, and the latest technologies and
emerging trends are summarized. These include covalent FBDD, FBDD for the
stabilization of proteins or protein-protein interactions, FBDD for enzyme
activators, new screening technologies, and advances in library design and
chemical synthesis.
DOI: 10.1021/acs.jmedchem.0c01608
PMID: 33226222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35025062 | 1. Dermatol Ther (Heidelb). 2022 Feb;12(2):495-510. doi:
10.1007/s13555-021-00649-y. Epub 2022 Jan 13.
Deucravacitinib in Moderate to Severe Psoriasis: Clinical and Quality-of-Life
Outcomes in a Phase 2 Trial.
Thaçi D(1), Strober B(2), Gordon KB(3), Foley P(4), Gooderham M(5), Morita A(6),
Papp KA(7), Puig L(8), Menter MA(9), Colombo MJ(10), Elbez Y(10), Kisa RM(10),
Ye J(10), Napoli AA(10), Wei L(10), Banerjee S(10), Merola JF(11), Gottlieb
AB(12).
Author information:
(1)Institute and Comprehensive Center for Inflammation Medicine, University of
Luebeck, Ratzeburger Allee 160, 23538, Luebeck, Germany. diamant.thaci@uksh.de.
(2)Yale University, Central Connecticut Dermatology Research, New Haven, CT,
USA.
(3)Medical College of Wisconsin, Milwaukee, WI, USA.
(4)St Vincent's Hospital Melbourne, Probity Medical Research, Skin Health
Institute, The University of Melbourne, Melbourne, VIC, Australia.
(5)SKiN Centre for Dermatology, Queen's University and Probity Medical Research,
Peterborough, ON, Canada.
(6)Nagoya City University, Graduate School of Medical Sciences, Nagoya, Aichi,
Japan.
(7)Clinical Research and Probity Medical Research, Waterloo, ON, Canada.
(8)Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona,
Barcelona, Spain.
(9)Baylor University Medical Center, Dallas, TX, USA.
(10)Bristol Myers Squibb, Princeton, NJ, USA.
(11)Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
(12)Icahn School of Medicine at Mount Sinai, New York, NY, USA.
INTRODUCTION: Deucravacitinib is an oral, selective tyrosine kinase 2 inhibitor
that demonstrated therapeutic benefit in a Phase 2 clinical trial of adults with
moderate to severe plaque psoriasis. This analysis was designed to evaluate the
effect of deucravacitinib on additional clinical and quality-of-life (QoL)
outcomes and assess the relationship between these outcomes in adults with
psoriasis.
METHODS: Post-hoc analysis of a 12-week Phase 2 trial was conducted for the
three most efficacious dosage groups (3 mg twice daily, 6 mg twice daily, 12 mg
once daily) and placebo. Investigator assessments for efficacy included
Psoriasis Area and Severity Index (PASI), body surface area (BSA) involvement,
and static Physician's Global Assessment; QoL was assessed using the Dermatology
Life Quality Index (DLQI). Treatment responses and their associations were
evaluated over time.
RESULTS: Deucravacitinib elicited improvement versus placebo as early as Week 4
for most efficacy measures (including changes in absolute PASI and BSA), with
efficacy trends observed from Week 2 to Week 12. Improvements in QoL, assessed
by achievement of a DLQI overall score of 0/1 (no effect at all on patient's
life), followed a pattern similar to deucravacitinib-related clinical outcomes
over 12 weeks. Overall, patients with greater improvements in psoriasis-related
clinical signs and symptoms also reported greater improvement in QoL. However,
complete skin clearance was not required for achieving DLQI 0/1.
CONCLUSION: Deucravacitinib treatment produced early response and similar trends
in improvements across multiple efficacy assessments and QoL in moderate to
severe plaque psoriasis. Deucravacitinib has the potential to become a promising
new oral therapy for this condition.
TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT02931838.
Plain Language Summary: Psoriasis is a skin disease that affects up to 2% of the
population. In psoriasis, red, scaly lesions develop on the skin driven by an
aberrant immune response. Psoriasis impacts not only physical and mental health
but also quality of life (QoL). Deucravacitinib is being investigated as a
treatment for psoriasis. We performed a Phase 2 dose-ranging,
placebo-controlled, 12-week study of deucravacitinib in adults with moderate to
severe psoriasis. Patients in the USA, Australia, Canada, Germany, Japan,
Latvia, Mexico, and Poland participated. The study showed that oral treatment
with deucravacitinib was effective using a disease severity score (percentage of
patients with ≥ 75% reduction from baseline in Psoriasis Area and Severity Index
score) at Week 12—placebo 7% and deucravacitinib 67%–75% for the three highest
dosages—and was generally well tolerated. We further analyzed the association
between efficacy and a QoL measure, the Dermatology Life Quality Index (DLQI),
in patients who received placebo or the most effective dosages of
deucravacitinib (≥ 3 mg twice daily). Deucravacitinib was effective at the three
dosage levels tested. Skin improvement occurred early during treatment and was
mirrored by improvements in DLQI score during the 12 weeks of treatment.
Although some patients did not have complete clearance of their psoriasis, a
large percentage of those patients still achieved considerable improvement in
QoL as measured by achieving a DLQI score of 0/1 (i.e., no effect at all on the
patient’s QoL).
© 2022. The Author(s).
DOI: 10.1007/s13555-021-00649-y
PMCID: PMC8850503
PMID: 35025062 |
http://www.ncbi.nlm.nih.gov/pubmed/35960487 | 1. Am J Clin Dermatol. 2022 Nov;23(6):813-822. doi: 10.1007/s40257-022-00720-0.
Epub 2022 Aug 12.
Deucravacitinib for the Treatment of Psoriatic Disease.
Lé AM(1), Puig L(2), Torres T(3)(4).
Author information:
(1)Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto,
Portugal.
(2)Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain.
(3)Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto,
Portugal. torres.tiago@outlook.com.
(4)Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto,
Portugal. torres.tiago@outlook.com.
Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis
currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is
responsible for mediating immune signalling of IL-12, IL-23 and type I
interferons, without interfering with other critical systemic functions as other
JAK proteins do. This article aims to review the current knowledge on
deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a
low risk of off-target effects. After good efficacy and safety results in a
phase II, placebo-controlled trial, two phase III, 52-week trials evaluated
deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK
PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After
16 weeks, in both studies, over 50% of patients treated with deucravacitinib
reached PASI75, which was significantly superior to placebo and apremilast. In
POETYK PSO-1, these results improved until week 24 and were maintained through
week 52, with over 65% of patients achieving PASI75 at this point. A reduction
in signs and symptoms was also reported by patients, with greater impact on
itch. Deucravacitinib was well tolerated and safe. There were no reports of
serious infections, thromboembolic events, or laboratory abnormalities, which
are a concern among other JAK inhibitors. Persistent efficacy and consistent
safety profiles were reported for up to 2 years. Despite advances in the
treatment of psoriasis, namely among biologic agents, an oral, effective and
safe new drug can bring several advantages to prescribers and patients. Further
investigation is required to understand where to place deucravacitinib among
current psoriasis treatment options.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40257-022-00720-0
PMCID: PMC9372960
PMID: 35960487 [Indexed for MEDLINE]
Conflict of interest statement: Ana Maria Lé has no conflicts of interest. Luis
Puig has served as a scientific adviser and/or clinical study investigator for,
or has received consultancy and/or speaker’s honoraria from and/or participated
in clinical trials sponsored by AbbVie, Almirall, Amgen, Baxalta, Biogen,
Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius-Kabi, Janssen, JS
BIOCAD, LEO Pharma, Lilly, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz,
Samsung-Bioepis, Sanofi and UCB. Tiago Torres has received consultancy and/or
speaker’s honoraria from and/or participated in clinical trials sponsored by
AbbVie, Amgen, Almirall, Amgen, Arena Pharmaceuticals, Biocad, Biogen,
Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius-Kabi, Janssen,
LEO Pharma, Eli Lilly, MSD, Mylan, Novartis, Pfizer, Samsung-Bioepis,
Sanofi-Genzyme, Sandoz and UCB. |
http://www.ncbi.nlm.nih.gov/pubmed/35820547 | 1. J Am Acad Dermatol. 2023 Jan;88(1):29-39. doi: 10.1016/j.jaad.2022.07.002.
Epub 2022 Jul 9.
Deucravacitinib versus placebo and apremilast in moderate to severe plaque
psoriasis: Efficacy and safety results from the 52-week, randomized,
double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial.
Armstrong AW(1), Gooderham M(2), Warren RB(3), Papp KA(4), Strober B(5), Thaçi
D(6), Morita A(7), Szepietowski JC(8), Imafuku S(9), Colston E(10), Throup
J(10), Kundu S(10), Schoenfeld S(10), Linaberry M(10), Banerjee S(10), Blauvelt
A(11).
Author information:
(1)Department of Dermatology, Keck School of Medicine, University of Southern
California, Los Angeles, California. Electronic address:
aprilarmstrong@post.harvard.edu.
(2)SKiN Centre for Dermatology, Department of Dermatology at Queen's University,
and Probity Medical Research, Peterborough, Ontario, Canada.
(3)Dermatology Centre at Salford Royal NHS Foundation Trust Hospital, NIHR
Manchester Biomedical Research Centre at the University of Manchester,
Manchester, United Kingdom.
(4)K Papp Clinical Research and Probity Medical Research, Waterloo, Ontario,
Canada.
(5)Department of Dermatology, Yale University School of Medicine, New Haven, and
Central Connecticut Dermatology Research, Cromwell, Connecticut.
(6)Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck,
Germany.
(7)Department of Geriatric and Environmental Dermatology, Nagoya City University
Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
(8)Department of Dermatology, Venereology and Allergology, Wroclaw Medical
University, Wrocław, Poland.
(9)Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
(10)Bristol Myers Squibb, Princeton, New Jersey.
(11)Oregon Medical Research Center, Portland, Oregon.
BACKGROUND: Effective, well-tolerated oral psoriasis treatments are needed.
OBJECTIVE: To compare the efficacy and safety of deucravacitinib, an oral,
selective, allosteric tyrosine kinase 2 inhibitor, versus placebo and apremilast
in adults with moderate to severe plaque psoriasis.
METHODS: Participants were randomized 2:1:1 to deucravacitinib 6 mg every day
(n = 332), placebo (n = 166), or apremilast 30 mg twice a day (n = 168) in the
52-week, double-blinded, phase 3 POETYK PSO-1 trial (NCT03624127). Coprimary end
points included response rates for ≥75% reduction from baseline in Psoriasis
Area and Severity Index (PASI 75) and static Physician's Global Assessment score
of 0 or 1 (sPGA 0/1) with deucravacitinib versus placebo at week 16.
RESULTS: At week 16, response rates were significantly higher with
deucravacitinib versus placebo or apremilast for PASI 75 (194 [58.4%] vs 21
[12.7%] vs 59 [35.1%]; P < .0001) and sPGA 0/1 (178 [53.6%] vs 12 [7.2%] vs 54
[32.1%]; P < .0001). Efficacy improved beyond week 16 and was maintained through
week 52. Adverse event rates with deucravacitinib were similar to those with
placebo and apremilast.
LIMITATIONS: One-year duration, limited racial diversity.
CONCLUSION: Deucravacitinib was superior to placebo and apremilast across
multiple efficacy end points and was well tolerated in moderate to severe plaque
psoriasis.
Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.jaad.2022.07.002
PMID: 35820547 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest Dr Armstrong has received
research grants and personal fees from Bristol Myers Squibb, Eli Lilly, Janssen,
Leo Pharma, and Novartis; has received personal fees from Boehringer
Ingelheim/Parexel, Celgene, Dermavant, Genentech, GlaxoSmithKline, Menlo
Therapeutics, Merck, Modernizing Medicine, Ortho Dermatologics, Pfizer,
Regeneron, Sanofi Genzyme, Science 37, Sun Pharma, and Valeant; and has received
grants from Dermira, Kyowa Hakko Kirin, and UCB, outside the submitted work. Dr
Gooderham has served on an advisory board and as a principal investigator for,
and has received lecture fees from, AbbVie, Galderma, Leo Pharma, Pfizer, and
Regeneron; has served on an advisory board for, and has received lecture fees
from, Actelion; has served as a principal investigator for, and received
consulting fees from, Akros Pharma; has served on an advisory board and as a
principal investigator for, and received lecture and consulting fees from,
Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Sanofi
Genzyme, and Valeant; has served as a principal investigator for Arcutis,
Bristol Myers Squibb, Dermira, GlaxoSmithKline, MedImmune, Merck, Roche
Laboratories, and UCB; and has served as a principal investigator for, and
received lecture fees from, Glenmark. Dr Warren has received research grants
from AbbVie, Almirall, Amgen, Celgene, Eli Lilly, Janssen, Leo Pharma, Novartis,
Pfizer, and UCB and has received consulting fees from AbbVie, Almirall, Amgen,
Biogen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Leo Pharma, Novartis,
Pfizer, Sanofi, UCB, and UNION. Dr Papp has served on a speakers bureau for
AbbVie, Amgen, Astellas, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko
Kirin, Leo Pharma, Merck Sharp & Dohme, Novartis, Pfizer, and Valeant; has
received grant/research support from AbbVie, Akros, Allergan, Amgen, Anacor,
Arcutis, AstraZeneca, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb,
Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech,
GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Leo Pharma, MedImmune, Meiji Seika
Pharma, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme,
Takeda, UCB, and Valeant; has served as a consultant for AbbVie, Akros, Amgen,
Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol
Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward
Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, Leo Pharma, Meiji Seika
Pharma, Merck Serono, Merck Sharp & Dohme, Mitsubishi Pharma, Novartis, Pfizer,
Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, and Valeant; has received
honoraria from AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene,
Coherus, Eli Lilly, Forward Pharma, Galderma, GlaxoSmithKline, Janssen, Kyowa
Hakko Kirin, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, UCB,
and Valeant; and has served as a scientific officer, on a steering committee,
and on an advisory board for AbbVie, Akros, Amgen, Anacor, Astellas, Baxter,
Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dow Pharma, Eli Lilly,
Galderma, Janssen, Kyowa Hakko Kirin, Merck Serono, Merck Sharp & Dohme,
Novartis, Pfizer, Regeneron, Sanofi Genzyme, and Valeant. Dr Strober has served
as a consultant (honoraria) for AbbVie, Almirall, Amgen, Arcutis, Arena,
Aristea, Asana, Boehringer Ingelheim, Bristol Myers Squibb, Connect Biopharma,
Dermavant, Equillium, GlaxoSmithKline, Immunic Therapeutics, Janssen, Leo
Pharma, Eli Lilly, Maruho, Meiji Seika Pharma, Mindera, Novartis, Ortho
Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, Ventyxbio,
and vTv Therapeutics; has served as a speaker for AbbVie, Eli Lilly, Janssen,
and Sanofi Genzyme; has served as coscientific director for, and received
consulting fees from, CorEvitas' (Corrona) Psoriasis Registry; and has served as
an investigator for AbbVie, Cara, CorEvitas' (Corrona) Psoriasis Registry,
Dermavant, Dermira, and Novartis. Dr Thaçi has received grant/research support
from, and served on a scientific advisory board member and a speaker's bureau
for, AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Eli Lilly,
Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron,
Roche, Sandoz-Hexal, Sanofi, Target-Solution, and UCB. Dr Morita has received
honoraria as a meeting chair or lecturer from AbbVie, AYUMI, Boehringer
Ingelheim Japan, Celgene K.K., Eisai, Eli Lilly Japan K.K., Inforward, Janssen
Pharmaceutical K.K., Kyowa Kirin, Maruho Co., Mitsubishi Tanabe Pharma, Nippon
Kayaku, Novartis Pharma K.K., Taiho Pharmaceutical, Torii Pharmaceutical, and
Ushio; has received funding from AbbVie GK, Eisai, Eli Lilly Japan K.K., Kyowa
Hakko Kirin, Leo Pharma K.K., Maruho, Mitsubishi Tanabe Pharma, Novartis Pharma
K.K., Taiho Pharmaceutical, and Torii Pharmaceutical; has received consulting
fees from AbbVie, Boehringer Ingelheim Japan, Bristol Myers Squibb, Celgene
K.K., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K.,
Kyowa Hakko Kirin, Maruho, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical,
Nippon Kayaku, Novartis Pharma K.K., NPO Health Institute Research of Skin,
Pfizer Japan, Sun Pharma, Taiho Pharmaceutical, and UCB Japan. Dr Szepietowski
has served as an advisory board member/consultant for AbbVie, Leo Pharma,
Novartis, Pierre-Fabre, Sanofi Genzyme, and Trevi; has served as a speaker for
AbbVie, Eli Lilly, Janssen-Cilag, Leo Pharma, Novartis, and Sanofi Genzyme; and
has served as an investigator for AbbVie, Amgen, Bristol Myers Squibb,
Galapagos, Galderma, Incyte, InfraRX, Janssen-Cilag, Menlo Therapeutics, Merck,
Novartis, Pfizer, Regeneron, UCB, and Trevi. Dr Imafuku has received grants and
personal fees from AbbVie, Eisai, Janssen, Kyowa Kirin, Leo Pharma, Maruho, Sun
Pharma, Taiho Yakuhin, Tanabe Mitsubishi, and Torii Yakuhin and has received
personal fees from Amgen (Celgene), Bristol Myers Squibb, Daiichi Sankyo, Eli
Lilly, Novartis, and UCB. Dr Colston, Ms Linaberry, and Dr Banerjee are
employees of and shareholders in Bristol Myers Squibb. Dr Throup, Dr Kundu, and
Dr Schoenfeld were employees of and shareholders in Bristol Myers Squibb at the
time of study conduct. Dr Blauvelt has served as a speaker/received honoraria
from AbbVie and UCB; served as a scientific adviser/received honoraria from
AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio,
Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Cara
Therapeutics, Dermavant, EcoR1, Eli Lilly and Company, Evelo, Evommune, Forte
Biosciences, Galderma, HighlightII Pharma, Incyte, Janssen, Landos, Leo Pharma,
Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Spherix Global
Insights, Sun Pharma, TLL Pharmaceutical, TrialSpark, UCB, Vibliome, and Xencor;
and has acted as a clinical study investigator for (institution has received
clinical study funds from) AbbVie, Acelyrin, Amgen, Arcutis, Athenex, Boehringer
Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, Evelo,
Galderma, Incyte, Janssen, Leo, Merck, Novartis, Pfizer, Regeneron, Sun Pharma,
and UCB. |
http://www.ncbi.nlm.nih.gov/pubmed/34279849 | 1. Reprod Sci. 2022 Jan;29(1):243-249. doi: 10.1007/s43032-021-00682-4. Epub 2021
Jul 19.
Activation of Hypocretin Neurons in Endometriosis.
Mamillapalli R(1), Dang T(2), Habata S(2), Gao XB(2), Taylor HS(2).
Author information:
(1)Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School
of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
ramana.mamillapalli@yale.edu.
(2)Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School
of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
Endometriosis is a gynecological disease affecting 6-10% of women of
reproductive age. In addition to gynecologic symptoms, endometriosis is
associated with various systemic effects, including inflammation, altered body
weight, and behavioral changes. Previous murine studies demonstrate that
endometriosis is causally inked to increased pain sensitization, behavioral
changes, and low body mass index (BMI). One possible cellular target that may
mediate some of these findings is the hypocretin/orexin neurons. This neuronal
system plays a role in regulating wakefulness/sleep cycles, pain perception, and
appetite. We hypothesize that endometriosis alters activity level of the
hypocretin/orexin (Hcrt) neuronal system. Mice underwent endometriosis induction
surgeries (endo) or sham surgeries (sham) for the development of the
experimental model. Immunocytochemistry was performed on harvested samples from
the lateral hypothalamus, and activation levels of Hcrt cells were examined by
quantifying the expression of phosphorylation of cAMP-responsive element binding
protein (CREB) in these cells after an acute stress in sham and endo mice. Mice
with endometriosis had greater Hcrt neurons activation than sham mice. Mice with
endometriosis fed with high fat diet showed a lower fat/body weight and fat/lean
tissue ratio compared to mice without endometriosis. There was no significant
difference in food intake between sham and endometriosis mice. These results
demonstrate that endometriosis is associated with low body mass and increased
hypocretin/orexin activity, which could be implicated in the behavioral changes
and to differences in body composition.
© 2021. Society for Reproductive Investigation.
DOI: 10.1007/s43032-021-00682-4
PMID: 34279849 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34228879 | 1. FEBS J. 2022 Nov;289(21):6543-6558. doi: 10.1111/febs.16109. Epub 2021 Jul 16.
Eat, sleep, repeat - endocrine regulation of behavioural circadian rhythms.
Koop S(1), Oster H(1).
Author information:
(1)Centre of Brain, Behavior and Metabolism, Institute of Neurobiology,
University of Lübeck, Germany.
The adaptation of organisms to a rhythmic environment is mediated by an internal
timing system termed the circadian clock. In mammals, molecular clocks are found
in all tissues and organs. This circadian clock network regulates the release of
many hormones, which in turn influence some of the most vital behavioural
functions. Sleep-wake cycles are under strict circadian control with strong
influence of rhythmic hormones such as melatonin, cortisol and others. Food
intake, in contrast, receives circadian modulation through hormones such as
leptin, ghrelin, insulin and orexin. A third behavioural output covered in this
review is mating and bonding behaviours, regulated through circadian rhythms in
steroid hormones and oxytocin. Together, these data emphasize the pervasive
influence of the circadian clock system on behavioural outputs and its mediation
through endocrine networks.
© 2021 Federation of European Biochemical Societies.
DOI: 10.1111/febs.16109
PMID: 34228879 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35624073 | 1. J Sleep Res. 2022 Aug;31(4):e13631. doi: 10.1111/jsr.13631. Epub 2022 May 27.
Narcolepsy.
Barateau L(1)(2)(3), Pizza F(4)(5), Plazzi G(5)(6), Dauvilliers Y(1)(2)(3).
Author information:
(1)Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital,
CHU Montpellier, Montpellier, France.
(2)National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic
Hypersomnia, and Kleine-Levin Syndrome, Montpellier, France.
(3)Institute for Neurosciences of Montpellier, University of Montpellier,
INSERM, Montpellier, France.
(4)Department of Biomedical and Neuromotor Sciences, University of Bologna,
Bologna, Italy.
(5)IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
(6)Department of Biomedical, Metabolic and Neural Sciences, University of Modena
and Reggio Emilia, Modena, Italy.
This article addresses the clinical presentation, diagnosis, pathophysiology and
management of narcolepsy type 1 and 2, with a focus on recent findings. A low
level of hypocretin-1/orexin-A in the cerebrospinal fluid is sufficient to
diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and
the irreversible loss of hypocretin neurons is responsible for the main symptoms
of the disease: sleepiness, cataplexy, sleep-related hallucinations and
paralysis, and disrupted nocturnal sleep. The process responsible for the
destruction of hypocretin neurons is highly suspected to be autoimmune, or
dysimmune. Over the last two decades, remarkable progress has been made for the
understanding of these mechanisms that were made possible with the development
of new techniques. Conversely, narcolepsy type 2 is a less well-defined
disorder, with a variable phenotype and evolution, and few reliable biomarkers
discovered so far. There is a dearth of knowledge about this disorder, and its
aetiology remains unclear and needs to be further explored. Treatment of
narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy
and disrupted nocturnal sleep. However, new psychostimulants have been recently
developed, and the upcoming arrival of non-peptide hypocretin receptor-2
agonists should be a revolution in the management of this rare sleep disease,
and maybe also for disorders beyond narcolepsy.
© 2022 European Sleep Research Society.
DOI: 10.1111/jsr.13631
PMID: 35624073 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34628482 | 1. Neuropsychopharmacology. 2022 Feb;47(3):719-727. doi:
10.1038/s41386-021-01175-3. Epub 2021 Oct 9.
Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep
initiated in the circadian wake maintenance zone: a randomised trial.
Revell VL(1), Della Monica C(1), Mendis J(2), Hassanin H(3), Halter RJ(4),
Chaplan SR(4), Dijk DJ(5)(6).
Author information:
(1)Surrey Sleep Research Centre, University of Surrey, Guildford, Surrey, GU2
7XP, UK.
(2)Surrey Clinical Trials Unit, University of Surrey, Guildford, Surrey, GU2
7XP, UK.
(3)Surrey Clinical Research Facility, University of Surrey, Guildford, Surrey,
GU2 7XP, UK.
(4)Janssen Research & Development, LLC, San Diego, CA, USA.
(5)Surrey Sleep Research Centre, University of Surrey, Guildford, Surrey, GU2
7XP, UK. d.j.dijk@surrey.ac.uk.
(6)UK Dementia Research Institute Care Research and Technology Centre, Imperial
College London and the University of Surrey, Guildford, UK.
d.j.dijk@surrey.ac.uk.
The effects of orexinergic peptides are diverse and are mediated by orexin-1 and
orexin-2 receptors. Antagonists that target both receptors have been shown to
promote sleep initiation and maintenance. Here, we investigated the role of the
orexin-2 receptor in sleep regulation in a randomised, double-blind,
placebo-controlled, three-period crossover clinical trial using two doses (20
and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA)
(JNJ-48816274). We used a phase advance model of sleep disruption where sleep
initiation is scheduled in the circadian wake maintenance zone. We assessed
objective and subjective sleep parameters, pharmacokinetic profiles and residual
effects on cognitive performance in 18 healthy male participants without sleep
disorders. The phase advance model alone (placebo condition) resulted in
disruption of sleep at the beginning of the sleep period compared to baseline
sleep (scheduled at habitual time). Compared to placebo, both doses of
JNJ-48816274 significantly increased total sleep time, REM sleep duration and
sleep efficiency, and reduced latency to persistent sleep, sleep onset latency,
and REM latency. All night EEG spectral power density for both NREM and REM
sleep were unaffected by either dose. Participants reported significantly better
quality of sleep and feeling more refreshed upon awakening following
JNJ-48816274 compared to placebo. No significant residual effects on objective
performance measures were observed and the compound was well tolerated. In
conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly
induced sleep when sleep was scheduled earlier in the circadian cycle and
improved self-reported sleep quality without impact on waking performance.
© 2021. The Author(s).
DOI: 10.1038/s41386-021-01175-3
PMCID: PMC8782905
PMID: 34628482 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35886210 | 1. Int J Environ Res Public Health. 2022 Jul 8;19(14):8353. doi:
10.3390/ijerph19148353.
Physiological Role of Orexinergic System for Health.
Villano I(1), La Marra M(1), Di Maio G(1), Monda V(2), Chieffi S(1), Guatteo
E(2), Messina G(3), Moscatelli F(3), Monda M(1), Messina A(1).
Author information:
(1)Department of Experimental Medicine, University of Campania "Luigi
Vanvitelli", 80138 Naples, Italy.
(2)Department of Movement Sciences and Wellbeing, University of Naples
"Parthenope", 80138 Naples, Italy.
(3)Department of Clinical and Experimental Medicine, University of Foggia, 71100
Foggia, Italy.
Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation
of feeding behavior and the sleep and wakefulness states. Since their discovery,
several lines of evidence have highlighted that orexin neurons regulate a great
range of physiological functions, giving it the definition of a multitasking
system. In the present review, we firstly describe the mechanisms underlining
the orexin system and their interactions with the central nervous system (CNS).
Then, the system's involvement in goal-directed behaviors, sleep/wakefulness
state regulation, feeding behavior and energy homeostasis, reward system, and
aging and neurodegenerative diseases are described. Advanced evidence suggests
that the orexin system is crucial for regulating many physiological functions
and could represent a promising target for therapeutical approaches to obesity,
drug addiction, and emotional stress.
DOI: 10.3390/ijerph19148353
PMCID: PMC9323672
PMID: 35886210 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32804153 | 1. J Clin Invest. 2020 Sep 1;130(9):4540-4542. doi: 10.1172/JCI140585.
Coordination of metabolism, arousal, and reward by orexin/hypocretin neurons.
Michael NJ(1), Elmquist JK(2).
Author information:
(1)Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec
City, Quebec, Canada.
(2)Center for Hypothalamic Research, Department of Internal Medicine and
Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA.
Comment on
J Clin Invest. 2020 Sep 1;130(9):4985-4998. doi: 10.1172/JCI130889.
Orexin/hypocretin neurons located in the lateral hypothalamus play a critical
role in the maintenance of arousal and contribute to the regulation of multiple
homeostatic and behavioral processes. In this issue of the JCI, Tan and Hang et
al. report that feeding a high-fat diet to mice compromised the function of the
orexin system, leading to impairments in reward-seeking and active coping
mechanisms. The researchers observed changes at the cellular and circuit levels
suggesting that reduced excitability of orexin neurons affects behavior through
induction of a hypoarousal state.
DOI: 10.1172/JCI140585
PMCID: PMC7456245
PMID: 32804153 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: The authors have declared
that no conflict of interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/23508038 | 1. Front Endocrinol (Lausanne). 2013 Mar 6;4:18. doi: 10.3389/fendo.2013.00018.
eCollection 2013.
The physiological role of orexin/hypocretin neurons in the regulation of
sleep/wakefulness and neuroendocrine functions.
Inutsuka A(1), Yamanaka A.
Author information:
(1)Department of Neuroscience II, Research Institute of Environmental Medicine
Nagoya University, Nagoya, Japan.
The hypothalamus monitors body homeostasis and regulates various behaviors such
as feeding, thermogenesis, and sleeping. Orexins (also known as hypocretins)
were identified as endogenous ligands for two orphan G-protein-coupled receptors
in the lateral hypothalamic area. They were initially recognized as regulators
of feeding behavior, but they are mainly regarded as key modulators of the
sleep/wakefulness cycle. Orexins activate orexin neurons, monoaminergic and
cholinergic neurons in the hypothalamus/brainstem regions, to maintain a long,
consolidated awake period. Anatomical studies of neural projections from/to
orexin neurons and phenotypic characterization of transgenic mice revealed
various roles for orexin neurons in the coordination of emotion, energy
homeostasis, reward system, and arousal. For example, orexin neurons are
regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose
concentration. This suggests that they may provide a link between energy
homeostasis and arousal states. A link between the limbic system and orexin
neurons might be important for increasing vigilance during emotional stimuli.
Orexins are also involved in reward systems and the mechanisms of drug
addiction. These findings suggest that orexin neurons sense the outer and inner
environment of the body and maintain the proper wakefulness level of animals for
survival. This review discusses the mechanism by which orexins maintain
sleep/wakefulness states and how this mechanism relates to other systems that
regulate emotion, reward, and energy homeostasis.
DOI: 10.3389/fendo.2013.00018
PMCID: PMC3589707
PMID: 23508038 |
http://www.ncbi.nlm.nih.gov/pubmed/27683906 | 1. J Neurosci. 2016 Sep 28;36(39):10097-115. doi: 10.1523/JNEUROSCI.0635-16.2016.
Epub 2016 Sep 28.
Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe
Neurons through Two Distinct Mechanisms That Increase the Late
Afterhyperpolarization.
Ishibashi M(1), Gumenchuk I(1), Miyazaki K(1), Inoue T(2), Ross WN(1), Leonard
CS(3).
Author information:
(1)Department of Physiology, New York Medical College, Valhalla, New York 10595,
and.
(2)Department of Life Science and Medical Bioscience, Faculty of Science and
Engineering, Waseda University, Tokyo 162-8480, Japan.
(3)Department of Physiology, New York Medical College, Valhalla, New York 10595,
and chris_leonard@nymc.edu.
Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic
processes, including reward and arousal, in part by exciting serotonergic dorsal
raphe neurons, the major source of forebrain serotonin. Here, using mouse brain
slices, we found that, instead of simply depolarizing these neurons, orexin-A
altered the spike encoding process by increasing the postspike
afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced
AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx,
reversed near EK, and decayed with two components, the faster of which resulted
from enhanced SK channel activation, whereas the slower component decayed like a
slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some
neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire
oeAHP, but neither component was sensitive to PKC inhibition or altered PKA
signaling, unlike classical sAHPs. The enhanced SK current did not depend on
IP3-mediated Ca(2+) release but resulted from A-current inhibition and the
resultant spike broadening, which increased Ca(2+) influx and
Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to
these factors. Functionally, the oeAHP slowed and stabilized orexin-induced
firing compared with firing produced by a virtual orexin conductance lacking the
oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in
response to stimulation, without affecting the initial rate or fidelity.
Collectively, these findings reveal a new orexin action in serotonergic raphe
neurons and suggest that, when orexin is released during arousal and reward, it
enhances the spike encoding of phasic over tonic inputs, such as those related
to sensory, motor, and reward events.
SIGNIFICANCE STATEMENT: Orexin peptides are known to excite neurons via slow
postsynaptic depolarizations. Here we elucidate a significant new orexin action
that increases and prolongs the postspike afterhyperpolarization (AHP) in 5-HT
dorsal raphe neurons and other arousal-system neurons. Our mechanistic studies
establish involvement of two distinct Ca(2+)-dependent AHP currents dependent on
phospholipase C signaling but independent of IP3 or PKC. Our functional studies
establish that this action preserves responsiveness to phasic inputs while
attenuating responsiveness to tonic inputs. Thus, our findings bring new insight
into the actions of an important neuropeptide and indicate that, in addition to
producing excitation, orexins can tune postsynaptic excitability to better
encode the phasic sensory, motor, and reward signals expected during aroused
states.
Copyright © 2016 the authors 0270-6474/16/3610097-19$15.00/0.
DOI: 10.1523/JNEUROSCI.0635-16.2016
PMCID: PMC5039256
PMID: 27683906 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28620314 | 1. Front Physiol. 2017 May 31;8:357. doi: 10.3389/fphys.2017.00357. eCollection
2017.
Orexin System: The Key for a Healthy Life.
Chieffi S(1), Carotenuto M(2), Monda V(1), Valenzano A(3), Villano I(1),
Precenzano F(2), Tafuri D(4), Salerno M(2), Filippi N(1), Nuccio F(1), Ruberto
M(5), De Luca V(6), Cipolloni L(7), Cibelli G(3), Mollica MP(8), Iacono
D(9)(10)(11), Nigro E(12), Monda M(1), Messina G(1)(3), Messina A(1).
Author information:
(1)Department of Experimental Medicine, Section of Human Physiology and Unit of
Dietetic and Sport Medicine, Università degli Studi della Campania "Luigi
Vanvitelli"Naples, Italy.
(2)Department of Mental Health, Physical and Preventive Medicine, Clinic of
Child and Adolescent Neuropsychiatry, Università degli Studi della Campania
"Luigi Vanvitelli"Naples, Italy.
(3)Department of Clinical and Experimental Medicine, University of FoggiaFoggia,
Italy.
(4)Department of Motor Sciences and Wellness, University of Naples
"Parthenope"Naples, Italy.
(5)Department of Medical-Surgical and Dental Specialties, Università degli Studi
della Campania "Luigi Vanvitelli"Naples, Italy.
(6)Department of Psychiatry, University of TorontoToronto, ON, Canada.
(7)Department of Anatomical, Histological, Forensic and Orthopaedic Sciences,
Università degli Studi di Roma La SapienzaRome, Italy.
(8)Department of Biology Università degli Studi di Napoli Federico IINaples,
Italy.
(9)Neurodevelopmental Research Lab, Biomedical Research Institute of New
JerseyMorristown, NJ, United States.
(10)Neuroscience Research, MidAtlantic Neonatology Associates, Atlantic Health
SystemMorristown, NJ, United States.
(11)Neuropathology Research, MANA/Biomedical Research Institute of New
JerseyMorristown, NJ, United States.
(12)CEINGE-Biotecnologie Avanzate ScarlNaples, Italy.
The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides
synthesized by a cluster of neurons in the lateral hypothalamus and perifornical
area. Orexin neurons receive a variety of signals related to environmental,
physiological and emotional stimuli, and project broadly to the entire CNS.
Orexin neurons are "multi-tasking" neurons regulating a set of vital body
functions, including sleep/wake states, feeding behavior, energy homeostasis,
reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic
system may underlie different pathological conditions. A selective loss orexin
neurons was found in narcolepsia, supporting the crucial role of orexins in
maintaining wakefulness. In animal models, orexin deficiency lead to obesity
even if the consume of calories is lower than wildtype counterpart. Reduced
physical activity appears the main cause of weight gain in these models
resulting in energy imbalance. Orexin signaling promotes obesity resistance via
enhanced spontaneous physical activity and energy expenditure regulation and the
deficiency/dysfunction in orexins system lead to obesity in animal models
despite of lower calories intake than wildtype associated with reduced physical
activity. Interestingly, orexinergic neurons show connections to regions
involved in cognition and mood regulation, including hippocampus. Orexins
enhance hippocampal neurogenesis and improve spatial learning and memory
abilities, and mood. Conversely, orexin deficiency results in learning and
memory deficits, and depression.
DOI: 10.3389/fphys.2017.00357
PMCID: PMC5450021
PMID: 28620314 |
http://www.ncbi.nlm.nih.gov/pubmed/22005675 | 1. J Physiol. 2011 Dec 1;589(Pt 23):5701-8. doi: 10.1113/jphysiol.2011.217000.
Epub 2011 Oct 17.
Orexin neurons as conditional glucosensors: paradoxical regulation of sugar
sensing by intracellular fuels.
Venner A(1), Karnani MM, Gonzalez JA, Jensen LT, Fugger L, Burdakov D.
Author information:
(1)Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Central orexin/hypocretin neurons promote wakefulness, feeding and
reward-seeking, and control blood glucose levels by regulating sympathetic
outflow to the periphery. Glucose itself directly suppresses the electrical
activity and cytosolic calcium levels of orexin cells. Recent in vitro studies
suggested that glucose inhibition of orexin cells may be mechanistically
unusual, because it persists under conditions where glucose metabolism is
unlikely. To investigate this further, and to clarify whether background
metabolic state regulates orexin cell glucosensing, here we analysed glucose
responses of orexin cells in mouse brain slices, in the presence and absence of
metabolic inhibitors and physiological energy substrates. Consistent with their
documented insensitivity to glucokinase inhibitors, the glucose responses of
orexin cells persisted in the presence of the mitochondrial poison oligomycin or
the glial toxin fluoroacetate. Unexpectedly, in the presence of oligomycin, the
magnitude of the glucose response was significantly enhanced. In turn,
2-deoxyglucose, a non-metabolizable glucose analogue, elicited larger responses
than glucose. Conversely, intracellular pyruvate dose-dependently suppressed the
glucose responses, an effect that was blocked by oligomycin. The glucose
responses were also suppressed by intracellular lactate and ATP. Our new data
suggest that other energy substrates not only fail to mimic the orexin glucose
response, but paradoxically suppress it in a metabolism-dependent manner. We
propose that this unexpected intrinsic property of orexin cells allows them to
act as 'conditional glucosensors' that preferentially respond to glucose during
reduced background energy levels.
DOI: 10.1113/jphysiol.2011.217000
PMCID: PMC3249044
PMID: 22005675 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26322330 | 1. eNeuro. 2015 Jan-Feb;2(1):ENEURO.0052-14.2015. doi:
10.1523/ENEURO.0052-14.2015.
Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a
Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct
Presynaptic and Postsynaptic Mechanisms().
Zhou WL(1), Gao XB(1), Picciotto MR(1).
Author information:
(1)Departments of Psychiatry and Comparative Medicine, Kavli Insitute for
Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06508.
Hypocretin/orexin neurons regulate many behavioral functions, including
addiction. Nicotine acts through nicotinic acetylcholine receptors (nAChRs) to
alter firing rate of neurons throughout the brain, leading to addiction-related
behaviors. While nAChRs are expressed in the hypothalamus and cholinergic fibers
project to this structure, it is unclear how acetylcholine modulates the
activity of hypocretin neurons. In this study, we stimulated hypocretin neurons
in mouse brain slices with ACh in the presence of atropine to dissect
presynaptic and postsynaptic modulation of these neurons through nAChRs.
Approximately one-third of tested hypocretin neurons responded to pressure
application of ACh (1 mM) with an increase in firing frequency. Stimulation of
postsynaptic nAChRs with ACh or nicotine resulted in a highly variable inward
current in approximately one-third of hypocretin neurons. In contrast, ACh or
nicotine (1 μM) reliably decreased the frequency of miniature EPSCs (mEPSCs).
Antagonism of nAChRs with mecamylamine also suppressed mEPSC frequency,
suggesting that an endogenous, tonic activation of presynaptic nAChRs might be
required for maintaining functional mEPSC frequency. Antagonism of heteromeric
(α4β2) or homomeric (α7) nAChRs alone suppressed mEPSCs to a lesser extent.
Finally, blocking internal calcium release reduced the frequency of mEPSCs,
occluding the suppressive effect of presynaptic ACh. Taken together, these data
provide a mechanism by which phasic ACh release enhances the firing of a subset
of hypocretin neurons through postsynaptic nAChRs, but disrupts tonic,
presynaptic nAChR-mediated glutamatergic inputs to the overall population of
hypocretin neurons, potentially enhancing the signal-to-noise ratio during the
response of the nAChR-positive subset of neurons.
DOI: 10.1523/ENEURO.0052-14.2015
PMCID: PMC4551500
PMID: 26322330
Conflict of interest statement: The authors declare no competing financial
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33828450 | 1. Front Neurosci. 2021 Mar 22;15:639313. doi: 10.3389/fnins.2021.639313.
eCollection 2021.
Orexin/Hypocretin and MCH Neurons: Cognitive and Motor Roles Beyond Arousal.
Concetti C(1), Burdakov D(1).
Author information:
(1)Department of Health Sciences and Technology, ETH Zürich, Zurich,
Switzerland.
The lateral hypothalamus (LH) is classically implicated in sleep-wake control.
It is the main source of orexin/hypocretin and melanin-concentrating hormone
(MCH) neuropeptides in the brain, which have been both implicated in arousal
state switching. These neuropeptides are produced by non-overlapping LH neurons,
which both project widely throughout the brain, where release of orexin and MCH
activates specific postsynaptic G-protein-coupled receptors. Optogenetic
manipulations of orexin and MCH neurons during sleep indicate that they promote
awakening and REM sleep, respectively. However, recordings from orexin and MCH
neurons in awake, moving animals suggest that they also act outside sleep/wake
switching. Here, we review recent studies showing that both orexin and MCH
neurons can rapidly (sub-second-timescale) change their firing when awake
animals experience external stimuli, or during self-paced exploration of objects
and places. However, the sensory-behavioral correlates of orexin and MCH neural
activation can be quite different. Orexin neurons are generally more dynamic,
with about 2/3rds of them activated before and during self-initiated running,
and most activated by sensory stimulation across sensory modalities. MCH neurons
are activated in a more select manner, for example upon self-paced investigation
of novel objects and by certain other novel stimuli. We discuss optogenetic and
chemogenetic manipulations of orexin and MCH neurons, which combined with
pharmacological blockade of orexin and MCH receptors, imply that these rapid LH
dynamics shape fundamental cognitive and motor processes due to orexin and MCH
neuropeptide actions in the awake brain. Finally, we contemplate whether the
awake control of psychomotor brain functions by orexin and MCH are distinct from
their "arousal" effects.
Copyright © 2021 Concetti and Burdakov.
DOI: 10.3389/fnins.2021.639313
PMCID: PMC8019792
PMID: 33828450
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. The reviewer TS declared a
past co-authorship with one of the authors DB to the handling Editor. |
http://www.ncbi.nlm.nih.gov/pubmed/20861370 | 1. J Neurosci. 2010 Sep 22;30(38):12642-52. doi: 10.1523/JNEUROSCI.2120-10.2010.
Orexin directly excites orexin neurons through orexin 2 receptor.
Yamanaka A(1), Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M.
Author information:
(1)Section of Cell Signaling, Okazaki Institute for Integrative Bioscience,
National Institute of Natural Sciences, Okazaki 444-8787, Japan.
yamank@nips.ac.jp
Orexin neurons (hypocretin neurons) have a critical role in the regulation of
sleep/wakefulness, especially in the maintenance of arousal. Here, we revealed
that orexin neurons are directly and indirectly activated by orexin via the
orexin 2 receptor (OX2R). Orexin B (1 μM) induced depolarization in orexin
neurons, which was still observed in the presence of TTX (1 μM), AP-5 (50 μM),
and CNQX (20 μM). In addition, orexin B induced inward currents in the presence
of TTX, suggesting a direct activation of orexin neurons. Although orexin B
application induced depolarization in orexin neurons of OX1R knock-out mice at
comparable levels to wild-type mice, the observation that orexin B failed to
depolarize orexin neurons in the OX2R knock-out mice suggested that OX2R was a
primary receptor for this response. Moreover, immunoelectron microscopic
analyses revealed direct contacts among orexin neurons, which exhibited
structural similarities to the glutamatergic synapses. Together, these results
suggest that orexin neurons form a positive-feedback circuit through indirect
and direct pathways, which results in the preservation of the orexin neuron
network at a high activity level and/or for a longer period. Therefore, the
activation of orexin neurons through OX2R might have an important role in the
maintenance of arousal.
DOI: 10.1523/JNEUROSCI.2120-10.2010
PMCID: PMC6633594
PMID: 20861370 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10624957 | 1. Neuron. 1999 Dec;24(4):941-51. doi: 10.1016/s0896-6273(00)81041-7.
Orexin synthesis and response in the gut.
Kirchgessner AL(1), Liu M.
Author information:
(1)Department of Physiology and Pharmacology, State University of New York,
Health Science Center at Brooklyn, 11203, USA.
akirchgessner@netmail.hscbklyn.edu
Orexin (hypocretin) appears to play a role in the regulation of energy balances.
Previous reports have indicated that orexin-containing neurons are found only in
the lateral hypothalamic (LH) area. We show that a subset of neurons in the gut
which also express leptin receptors display orexin-like immunoreactivity and
express functional orexin receptors. Orexin excites secretomotor neurons in the
guinea pig submucosal plexus and increases motility. Moreover, fasting
upregulates the phosphorylated form of cAMP response element-binding protein
(pCREB) in orexin-immunoreactive neurons, indicating a functional response to
food status in these cells. Together, these data suggest that orexin in the gut
may play an even more intimate role in regulating energy homeostasis than it
does in the CNS.
DOI: 10.1016/s0896-6273(00)81041-7
PMID: 10624957 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23683477 | 1. Curr Opin Neurobiol. 2013 Oct;23(5):752-9. doi: 10.1016/j.conb.2013.04.008.
Epub 2013 May 15.
Control of arousal by the orexin neurons.
Alexandre C(1), Andermann ML, Scammell TE.
Author information:
(1)Department of Neurology, Beth Israel Medical Deaconess Center, Boston, MA
02215, United States.
The orexin-producing neurons in the lateral hypothalamus play an essential role
in promoting arousal and maintaining wakefulness. These neurons receive a broad
variety of signals related to environmental, physiological and emotional
stimuli; they project to almost every brain region involved in the regulation of
wakefulness; and they fire most strongly during active wakefulness, high motor
activation, and sustained attention. This review focuses on the specific
neuronal pathways through which the orexin neurons promote wakefulness and
maintain high level of arousal, and how recent studies using optogenetic and
pharmacogenetic methods have demonstrated that the locus coeruleus, the
tuberomammillary nucleus, and the basal forebrain are some of the key sites
mediating the arousing actions of orexins.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.conb.2013.04.008
PMCID: PMC3783629
PMID: 23683477 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19815001 | 1. Brain Res. 2010 Feb 16;1314:74-90. doi: 10.1016/j.brainres.2009.09.106. Epub
2009 Oct 6.
Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and
addiction.
Aston-Jones G(1), Smith RJ, Sartor GC, Moorman DE, Massi L, Tahsili-Fahadan P,
Richardson KA.
Author information:
(1)Department of Neurosciences, Medical University of South Carolina, Basic
Science Building 403, 173 Ashley Ave, MSC 510, Charleston, SC 29425-5100, USA.
astong@musc.edu
Orexins (synonymous with hypocretins) are recently discovered neuropeptides made
exclusively in hypothalamus. Behavioral, anatomical, and neurophysiological
studies show that a subset of these cells, specifically those in lateral
hypothalamus (LH), are involved in reward processing and addictive behaviors.
Fos expression in LH orexin neurons varied in proportion to conditioned place
preference (CPP) for morphine, cocaine, or food. This relationship occurred both
in drug-naïve rats and in animals during protracted morphine withdrawal, when
drug preference was elevated but food preference was decreased. Inputs to the LH
orexin cell field from lateral septum and bed nucleus of the stria terminalis
were Fos-activated during cocaine CPP in proportion to the preference expressed
in each animal. This implies that these inputs may be involved in driving the
conditioned responses in LH orexin neurons. Related studies showed that LH
orexin neurons that project to ventral tegmental area (VTA) had greater Fos
induction in association with elevated morphine preference during protracted
withdrawal than non-VTA-projecting orexin neurons, indicating that the VTA is an
important site of action for orexin's role in reward processing. In addition,
stimulation of LH orexin neurons, or microinjection of orexin into VTA,
reinstated an extinguished morphine preference. In self-administration studies,
the orexin 1 receptor antagonist SB-334867 (SB) blocked cocaine-seeking induced
by discrete or contextual cues previously associated with cocaine, but not by a
priming injection of cocaine. There was no effect of SB on cocaine
self-administration itself, indicating that it did not interfere with the drug's
reinforcing properties. Neurophysiological studies revealed that locally applied
orexin often augmented responses of VTA dopamine (DA) neurons to activation of
the medial prefrontal cortex (mPFC), consistent with the view that orexin
facilitates activation of VTA DA neurons by stimulus-reward associations. This
LH-to-VTA orexin pathway was found to be necessary for learning a morphine place
preference. These findings are consistent with results showing that orexin
facilitates glutamate-mediated responses, and is necessary for
glutamate-dependent long-term potentiation in VTA DA neurons. We surmise from
these studies that LH orexin neurons play an important role in reward processing
and addiction and that LH orexin cells are an important input to VTA for
behavioral effects associated with reward-paired stimuli.
Copyright 2009 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.brainres.2009.09.106
PMCID: PMC2819557
PMID: 19815001 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20353399 | 1. Curr Protein Pept Sci. 2010 Mar;11(2):148-55. doi: 10.2174/138920310790848377.
Orexins and gastrointestinal functions.
Baccari MC(1).
Author information:
(1)Department of Physiological Sciences, University of Florence, Viale G.B.
Morgagni 63, I-50134 Florence, Italy. mcaterina.baccari@unifi.it
Orexin A (OXA) and orexin B (OXB) are recently discovered neuropeptides that
appear to play a role in various distinct functions such as arousal and the
sleep-wake cycle as well as on appetite and regulation of feeding and energy
homeostasis. Orexins were first described as neuropeptides expressed by a
specific population of neurons in the lateral hypothalamic area, a region
classically implicated in feeding behaviour. Orexin neurons project to numerous
brain regions, where orexin receptors have been shown to be widely distributed:
both OXA and OXB act through two subtypes of receptors (OX1R and OX2R) that
belong to the G protein-coupled superfamily of receptors. Growing evidence
indicates that orexins act in the central nervous system also to regulate
gastrointestinal functions: animal studies have indeed demonstrated that
centrally-injected orexins or endogenously released orexins in the brain
stimulates gastric secretion and influence gastrointestinal motility. The
subsequent identification of orexins and their receptors in the enteric nervous
system (including the myenteric and the submucosal plexuses) as well as in
mucosa and smooth muscles has suggested that these neuropeptides may also play a
local action. In this view, emerging studies indicate that orexins also exert
region-specific contractile or relaxant effects on isolated gut preparations.
The aim of the proposed review is to summarize both centrally- and
peripherally-mediated actions of orexins on gastrointestinal functions and to
discuss the related physiological role on the basis of the most recent findings.
DOI: 10.2174/138920310790848377
PMID: 20353399 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33438356 | 1. J Integr Plant Biol. 2021 Apr;63(4):707-722. doi: 10.1111/jipb.13068. Epub
2021 Mar 3.
Genome-wide distribution and functions of the AAE complex in epigenetic
regulation in Arabidopsis.
Zhang YZ(1)(2), Lin J(3), Ren Z(1), Chen CX(1)(2), Miki D(1), Xie SS(1)(2),
Zhang J(1)(2), Chang YN(1)(2), Jiang J(4), Yan J(5), Li QQ(3)(6), Zhu JK(1)(7),
Duan CG(1)(4).
Author information:
(1)Shanghai Center for Plant Stress Biology and CAS Center of Excellence for
Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 201602, China.
(2)University of Chinese Academy of Sciences, Beijing, 100049, China.
(3)Key Laboratory of the Ministry of Education for Coastal and Wetland
Ecosystems, College of the Environment and Ecology, Xiamen University, Xiamen,
361102, China.
(4)State Key Laboratory of Crop Stress Adaptation and Improvement, School of
Life Sciences, Henan University, Kaifeng, 475004, China.
(5)School of Life Sciences, East China Normal University, Shanghai, 200241,
China.
(6)Graduate College of Biomedical Sciences, Western University of Health
Sciences, Pomona, 91766, USA.
(7)Department of Horticulture and Landscape Architecture, Purdue University,
West Lafayette, 47907, USA.
Heterochromatin is widespread in eukaryotic genomes and has diverse impacts
depending on its genomic context. Previous studies have shown that a protein
complex, the ASI1-AIPP1-EDM2 (AAE) complex, participates in polyadenylation
regulation of several intronic heterochromatin-containing genes. However, the
genome-wide functions of AAE are still unknown. Here, we show that the ASI1 and
EDM2 mostly target the common genomic regions on a genome-wide level and
preferentially interacts with genetic heterochromatin. Polyadenylation (poly(A)
sequencing reveals that AAE complex has a substantial influence on poly(A) site
usage of heterochromatin-containing genes, including not only intronic
heterochromatin-containing genes but also the genes showing overlap with
heterochromatin. Intriguingly, AAE is also involved in the alternative splicing
regulation of a number of heterochromatin-overlapping genes, such as the disease
resistance gene RPP4. We provided evidence that genic heterochromatin is
indispensable for the recruitment of AAE in polyadenylation and splicing
regulation. In addition to conferring RNA processing regulation at genic
heterochromatin-containing genes, AAE also targets some transposable elements
(TEs) outside of genes (including TEs sandwiched by genes and island TEs) for
epigenetic silencing. Our results reveal new functions of AAE in RNA processing
and epigenetic silencing, and thus represent important advances in epigenetic
regulation.
© 2021 Institute of Botany, Chinese Academy of Sciences.
DOI: 10.1111/jipb.13068
PMID: 33438356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22580822 | 1. EMBO J. 2012 Jun 29;31(13):2981-93. doi: 10.1038/emboj.2012.141. Epub 2012 May
11.
DNA methylation in an intron of the IBM1 histone demethylase gene stabilizes
chromatin modification patterns.
Rigal M(1), Kevei Z, Pélissier T, Mathieu O.
Author information:
(1)Centre National de la Recherche Scientifique (CNRS), UMR6293, GReD, INSERM U
1103, Clermont Université, Aubière, France.
The stability of epigenetic patterns is critical for genome integrity and gene
expression. This highly coordinated process involves interrelated positive and
negative regulators that impact distinct epigenetic marks, including DNA
methylation and dimethylation at histone H3 lysine 9 (H3K9me2). In Arabidopsis,
mutations in the DNA methyltransferase MET1, which maintains CG methylation,
result in aberrant patterns of other epigenetic marks, including ectopic non-CG
methylation and the relocation of H3K9me2 from heterochromatin into gene-rich
chromosome regions. Here, we show that the expression of the H3K9 demethylase
IBM1 (increase in BONSAI methylation 1) requires DNA methylation. Surprisingly,
the regulatory methylated region is contained in an unusually large intron that
is conserved in IBM1 orthologues. The re-establishment of IBM1 expression in
met1 mutants restored the wild-type H3K9me2 nuclear patterns, non-CG DNA
methylation and transcriptional patterns at selected loci, which included DNA
demethylase genes. These results provide a mechanistic explanation for
long-standing puzzling observations in met1 mutants and reveal yet another layer
of control in the interplay between DNA methylation and histone modification,
which stabilizes DNA methylation patterns at genes.
DOI: 10.1038/emboj.2012.141
PMCID: PMC3395095
PMID: 22580822 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33506534 | 1. Plant J. 2021 Apr;106(2):435-453. doi: 10.1111/tpj.15174. Epub 2021 Mar 23.
Whole-genome characterization of chronological age-associated changes in
methylome and circular RNAs in moso bamboo (Phyllostachys edulis) from
vegetative to floral growth.
Zhang Z(1), Wang H(1), Wang Y(2), Xi F(2), Wang H(1), Kohnen MV(1), Gao P(1),
Wei W(1), Chen K(2), Liu X(1), Gao Y(2), Han X(1), Hu K(1), Zhang H(1), Zhu
Q(1), Zheng Y(3), Liu B(3), Ahmad A(4), Hsu YH(5), Jacobsen SE(6), Gu L(1).
Author information:
(1)Basic Forestry and Proteomics Research Center, College of Forestry, Fujian
Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian
Agriculture and Forestry University, Fuzhou, 350002, China.
(2)Basic Forestry and Proteomics Research Center, College of life science,
Fuzhou, 350002, China.
(3)College of Forestry, Fujian Agriculture and Forestry University, Fuzhou,
350002, China.
(4)Department of Biotechnology, Abdul Wali Khan University Mardan, Mardan,
Pakistan.
(5)Graduate Institute of Biotechnology, National Chung Hsing University,
Taichung, Taiwan.
(6)Department of Molecular, Cell & Developmental Biology, Howard Hughes Medical
Institute, University of California, Los Angeles, CA, 90095, USA.
In mammals, DNA methylation is associated with aging. However, age-related DNA
methylation changes during phase transitions largely remain unstudied in plants.
Moso bamboo (Phyllostachys edulis) requires a very long time to transition from
the vegetative to the floral phase. To comprehensively investigate the
association of DNA methylation with aging, we present here
single-base-resolution DNA methylation profiles using both high-throughput
bisulfite sequencing and single-molecule nanopore-based DNA sequencing, covering
the long period of vegetative growth and transition to flowering in moso bamboo.
We discovered that CHH methylation gradually accumulates from vegetative to
reproductive growth in a time-dependent fashion. Differentially methylated
regions, correlating with chronological aging, occurred preferentially at both
transcription start sites and transcription termination sites. Genes with CG
methylation changes showed an enrichment of Gene Ontology (GO) categories in
'vegetative to reproductive phase transition of meristem'. Combining methylation
data with mRNA sequencing revealed that DNA methylation in promoters, introns
and exons may have different roles in regulating gene expression. Finally,
circular RNA (circRNA) sequencing revealed that the flanking introns of circRNAs
are hypermethylated and enriched in long terminal repeat (LTR) retrotransposons.
Together, the observations in this study provide insights into the dynamic DNA
methylation and circRNA landscapes, correlating with chronological age, which
paves the way to study further the impact of epigenetic factors on flowering in
moso bamboo.
© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.
DOI: 10.1111/tpj.15174
PMID: 33506534 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28808009 | 1. Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7377-E7384. doi:
10.1073/pnas.1710683114. Epub 2017 Aug 14.
A protein complex regulates RNA processing of intronic
heterochromatin-containing genes in Arabidopsis.
Duan CG(1)(2)(3), Wang X(3), Zhang L(4)(2)(3), Xiong X(4)(2), Zhang Z(4)(2),
Tang K(3), Pan L(5), Hsu CC(5), Xu H(4)(2)(6), Tao WA(5), Zhang H(4)(2), Zhu
JK(1)(2)(3).
Author information:
(1)Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences,
Shanghai 200032, China; cgduan@sibs.ac.cn jkzhu@sibs.ac.cn.
(2)Center of Excellence in Molecular Plant Sciences, Chinese Academy of
Sciences, Shanghai 200032, China.
(3)Department of Horticulture and Landscape Architecture, Purdue University,
West Lafayette, IN 47907.
(4)Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences,
Shanghai 200032, China.
(5)Department of Biochemistry, Purdue University, West Lafayette, IN 47907.
(6)College of Agriculture, Henan University of Science and Technology, Luoyang
471023, China.
In several eukaryotic organisms, heterochromatin (HC) in the introns of genes
can regulate RNA processing, including polyadenylation, but the mechanism
underlying this regulation is poorly understood. By promoting distal
polyadenylation, the bromo-adjacent homology (BAH) domain-containing and RNA
recognition motif-containing protein ASI1 and the H3K9me2-binding protein EDM2
are required for the expression of functional full-length transcripts of
intronic HC-containing genes in Arabidopsis Here we report that ASI1 and EDM2
form a protein complex in vivo via a bridge protein, ASI1-Immunoprecipitated
Protein 1 (AIPP1), which is another RNA recognition motif-containing protein.
The complex also may contain the Pol II CTD phosphatase CPL2, the plant
homeodomain-containing protein AIPP2, and another BAH domain protein, AIPP3. As
is the case with dysfunction of ASI1 and EDM2, dysfunction of AIPP1 impedes the
use of distal polyadenylation sites at tested intronic HC-containing genes, such
as the histone demethylase gene IBM1, resulting in a lack of functional
full-length transcripts. A mutation in AIPP1 causes silencing of the 35S-SUC2
transgene and genome-wide CHG hypermethylation at gene body regions, consistent
with the lack of full-length functional IBM1 transcripts in the mutant.
Interestingly, compared with asi1, edm2, and aipp1 mutations, mutations in CPL2,
AIPP2, and AIPP3 cause the opposite effects on the expression of intronic
HC-containing genes and other genes, suggesting that CPL2, AIPP2, and AIPP3 may
form a distinct subcomplex. These results advance our understanding of the
interplay between heterochromatic epigenetic modifications and RNA processing in
higher eukaryotes.
DOI: 10.1073/pnas.1710683114
PMCID: PMC5584460
PMID: 28808009 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/25765649 | 1. Nucleic Acids Res. 2015 Apr 20;43(7):3498-508. doi: 10.1093/nar/gkv153. Epub
2015 Mar 12.
A diverse epigenetic landscape at human exons with implication for expression.
Singer M(1), Kosti I(2), Pachter L(3), Mandel-Gutfreund Y(4).
Author information:
(1)Department of Computer Science, University of California at Berkeley,
Berkeley, CA 94720 USA.
(2)Department of Molecular & Cell Biology, University of California at Berkeley,
Berkeley, CA 94720, USA.
(3)Department of Computer Science, University of California at Berkeley,
Berkeley, CA 94720 USA Department of Mathematics, University of California at
Berkeley, Berkeley, CA 94720, USA Department of Molecular & Cell Biology,
University of California at Berkeley, Berkeley, CA 94720, USA.
(4)Department of Molecular & Cell Biology, University of California at Berkeley,
Berkeley, CA 94720, USA yaelmg@tx.technion.ac.il.
DNA methylation is an important epigenetic marker associated with gene
expression regulation in eukaryotes. While promoter methylation is relatively
well characterized, the role of intragenic DNA methylation remains unclear.
Here, we investigated the relationship of DNA methylation at exons and flanking
introns with gene expression and histone modifications generated from a human
fibroblast cell-line and primary B cells. Consistent with previous work we found
that intragenic methylation is positively correlated with gene expression and
that exons are more highly methylated than their neighboring intronic
environment. Intriguingly, in this study we identified a unique subset of
hypomethylated exons that demonstrate significantly lower methylation levels
than their surrounding introns. Furthermore, we observed a negative correlation
between exon methylation and the density of the majority of histone
modifications. Specifically, we demonstrate that hypo-methylated exons at highly
expressed genes are associated with open chromatin and have a characteristic
histone code comprised of significantly high levels of histone markings.
Overall, our comprehensive analysis of the human exome supports the presence of
regulatory hypomethylated exons in protein coding genes. In particular our
results reveal a previously unrecognized diverse and complex role of the
epigenetic landscape within the gene body.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkv153
PMCID: PMC4402514
PMID: 25765649 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28835513 | 1. Oncologist. 2017 Nov;22(11):1392-1399. doi: 10.1634/theoncologist.2017-0078.
Epub 2017 Aug 23.
FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell
Lung Cancer: First-Line Therapy and Beyond.
Pai-Scherf L(1), Blumenthal GM(2), Li H(2), Subramaniam S(2), Mishra-Kalyani
PS(2), He K(2), Zhao H(2), Yu J(2), Paciga M(2), Goldberg KB(2), McKee AE(2),
Keegan P(2), Pazdur R(2).
Author information:
(1)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA Lee.Pai-Scherf@fda.hhs.gov.
(2)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA.
On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved
pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment
of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors
express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test,
as follows: (a) first-line treatment of patients with mNSCLC whose tumors have
high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal
growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor
aberrations, and (b) treatment of patients with mNSCLC whose tumors express
PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
disease progression on FDA-approved therapy for these aberrations prior to
receiving pembrolizumab.Approval was based on two randomized, open-label,
active-controlled trials demonstrating statistically significant improvements in
progression-free survival (PFS) and overall survival (OS) for patients
randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients
with previously untreated mNSCLC who received pembrolizumab (200 mg
intravenously [IV] every 3 weeks) had a statistically significant improvement in
OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005),
and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In
KEYNOTE-010, patients with disease progression on or after platinum-containing
chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2
every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001
comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS
was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with
chemotherapy.
IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration
approval of a checkpoint inhibitor for first-line treatment of lung cancer. This
approval expands the pembrolizumab indication in second-line treatment of lung
cancer to include all patients with programmed death-ligand 1-expressing
non-small cell lung cancer.
Published 2017. This article is a U.S. Government work and is in the public
domain in the USA.
DOI: 10.1634/theoncologist.2017-0078
PMCID: PMC5679831
PMID: 28835513 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures of potential conflicts of interest
may be found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/24173296 | 1. Diabetologia. 1966 Apr;1(3-4):155-61. doi: 10.1007/BF01257906.
Diabetes in bearded women (Achard-Thiers-Syndrome) : A clinical and metabolic
study of 20 cases.
Malaisse W(1), Lauvaux JP, Franckson JR, Bastenie PA.
Author information:
(1)Clinique Médicale, Hôpital universitaire St. Pierre, University of Brussels,
Belgium.
Twenty patients, selected on the basis of simultaneous existence of overt
diabetes and marked hirsutism, were submitted to clinical and biological
investigations. Obesity, hypertension and angiopathy were present in most of
these patients. Metabolic investigations afforded valuable proof of
hypercorticism associated with depressed activity of insulin. Nevertheless,
increased steroiduria was also observed in groups of non-hirsute diabetic women
carefully paired for age. Thus the Achard-Thiers syndrome cannot be separated
with certainty from common overt diabetes.
DOI: 10.1007/BF01257906
PMID: 24173296 |
http://www.ncbi.nlm.nih.gov/pubmed/29330282 | 1. Mol Cancer Res. 2018 Mar;16(3):461-469. doi: 10.1158/1541-7786.MCR-17-0227.
Epub 2018 Jan 12.
Population-dependent Intron Retention and DNA Methylation in Breast Cancer.
Kim D(1), Shivakumar M(2), Han S(1), Sinclair MS(1), Lee YJ(3), Zheng Y(4),
Olopade OI(4), Kim D(5)(6), Lee Y(7)(8).
Author information:
(1)Department of Biomedical Informatics, University of Utah School of Medicine,
Salt Lake City, Utah.
(2)Department of Biomedical and Translational Informatics, Geisinger Health
System, Danville, Pennsylvania.
(3)Department of Health and Community Systems, University of Pittsburgh School
of Nursing, Pittsburgh, Pennsylvania.
(4)Department of Medicine, University of Chicago, Chicago, Illinois.
(5)Department of Biomedical and Translational Informatics, Geisinger Health
System, Danville, Pennsylvania. younghee.lee@utah.edu dkim@geisinger.edu.
(6)The Huck Institutes of the Life Sciences, Pennsylvania State University,
University Park, Pennsylvania.
(7)Department of Biomedical Informatics, University of Utah School of Medicine,
Salt Lake City, Utah. younghee.lee@utah.edu dkim@geisinger.edu.
(8)Huntsman Cancer Institute, Salt Lake City, Utah.
Regulation of gene expression by DNA methylation in gene promoter regions is
well studied; however, the effects of methylation in the gene body (exons and
introns) on gene expression are comparatively understudied. Recently,
hypermethylation has been implicated in the inclusion of alternatively spliced
exons; moreover, exon recognition can be enhanced by recruiting the
methyl-CpG-binding protein (MeCP2) to hypermethylated sites. This study examines
whether the methylation status of an intron is correlated with how frequently
the intron is retained during splicing using DNA methylation and RNA sequencing
data from breast cancer tissue specimens in The Cancer Genome Atlas.
Interestingly, hypomethylation of introns is correlated with higher levels of
intron expression in mRNA and the methylation level of an intron is inversely
correlated with its retention in mRNA from the gene in which it is located.
Furthermore, significant population differences were observed in the methylation
level of retained introns. In African-American donors, retained introns were not
only less methylated compared to European-American donors, but also were more
highly expressed. This underscores the need for understanding epigenetic
differences in populations and their correlation with breast cancer is an
important step toward achieving personalized cancer care.Implications: This
research contributes to the understanding of how epigenetic markers in the gene
body communicate with the transcriptional machinery to control transcript
diversity and differential biological response to changes in methylation status
could underlie some of the known, yet unexplained, disparities in certain breast
cancer patient populations. Mol Cancer Res; 16(3); 461-9. ©2018 AACR.
©2018 American Association for Cancer Research.
DOI: 10.1158/1541-7786.MCR-17-0227
PMCID: PMC5835176
PMID: 29330282 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest:
No potential conflicts of interest were disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/33398820 | 1. Adv Exp Med Biol. 2021;1293:281-293. doi: 10.1007/978-981-15-8763-4_17.
Bioluminescence-Optogenetics.
Berglund K(1), Stern MA(2), Gross RE(2).
Author information:
(1)Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA,
USA. ken.berglund@emory.edu.
(2)Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA,
USA.
In this chapter, we introduce a relatively new, emerging method for molecular
neuromodulation-bioluminescence-optogenetics. Bioluminescence-optogenetics is
mediated by luminopsin fusion proteins-light-sensing opsins fused to
light-emitting luciferases. We describe their structures and working mechanisms
and discuss their unique benefits over conventional optogenetics and
chemogenetics. We also summarize applications of bioluminescence-optogenetics in
various neurological disease models in rodents.
DOI: 10.1007/978-981-15-8763-4_17
PMID: 33398820 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28862809 | 1. J Neurosci Res. 2020 Mar;98(3):410-421. doi: 10.1002/jnr.24152. Epub 2017 Sep
1.
Novel luciferase-opsin combinations for improved luminopsins.
Park SY(1), Song SH(2)(3), Palmateer B(4)(5), Pal A(4)(5), Petersen ED(4)(5),
Shall GP(4), Welchko RM(4), Ibata K(6)(7), Miyawaki A(6), Augustine GJ(1)(2)(3),
Hochgeschwender U(4)(5).
Author information:
(1)Center for Functional Connectomics, Korea Institute of Science and
Technology, Seoul, Republic of Korea.
(2)Lee Kong Chian School of Medicine, Nanyang Technological University,
Singapore.
(3)Institute of Molecular and Cell Biology, Singapore.
(4)Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan.
(5)College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.
(6)Laboratory for Cell Function Dynamics, Brain Science Institute, Riken,
Saitama, Japan.
(7)School of Medicine, Keio University, Tokyo, Japan.
Previous work has demonstrated that fusion of a luciferase to an opsin, to
create a luminescent opsin or luminopsin, provides a genetically encoded means
of manipulating neuronal activity via both chemogenetic and optogenetic
approaches. Here we have expanded and refined the versatility of luminopsin
tools by fusing an alternative luciferase variant with high light emission,
Gaussia luciferase mutant GLucM23, to depolarizing and hyperpolarizing
channelrhodopsins with increased light sensitivity. The combination of GLucM23
with Volvox channelrhodopsin-1 produced LMO4, while combining GLucM23 with the
anion channelrhodopsin iChloC yielded iLMO4. We found efficient activation of
these channelrhodopsins in the presence of the luciferase substrate, as
indicated by responses measured in both single neurons and in neuronal
populations of mice and rats, as well as by changes in male rat behavior during
amphetamine-induced rotations. We conclude that these new luminopsins will be
useful for bimodal opto- and chemogenetic analyses of brain function.
© 2017 Wiley Periodicals, Inc.
DOI: 10.1002/jnr.24152
PMCID: PMC5832519
PMID: 28862809 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST STATEMENT All authors
declare that they have no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/30957296 | 1. J Neurosci Res. 2020 Mar;98(3):422-436. doi: 10.1002/jnr.24424. Epub 2019 Apr
7.
Step-function luminopsins for bimodal prolonged neuromodulation.
Berglund K(1), Fernandez AM(1), Gutekunst CN(1), Hochgeschwender U(2), Gross
RE(1).
Author information:
(1)Department of Neurosurgery, Emory University School of Medicine, Atlanta,
Georgia.
(2)Neuroscience Program and College of Medicine, Central Michigan University, Mt
Pleasant, Michigan.
Although molecular tools for controlling neuronal activity by light have vastly
expanded, there are still unmet needs which require development and refinement.
For example, light delivery into the brain is still a major practical challenge
that hinders potential translation of optogenetics in human patients. In
addition, it would be advantageous to manipulate neuronal activity acutely and
precisely as well as chronically and non-invasively, using the same genetic
construct in animal models. We have previously addressed these challenges by
employing bioluminescence and have created a new line of opto-chemogenetic
probes termed luminopsins by fusing light-sensing opsins with light-emitting
luciferases. In this report, we incorporated Chlamydomonas channelrhodopsin 2
with step-function mutations as the opsin moiety in the new luminopsin fusion
protein termed step-function luminopsin (SFLMO). Bioluminescence-induced
photocurrent lasted longer than the bioluminescence signal due to very slow
deactivation of the mutated channel. In addition, bioluminescence was able to
activate most of the channels on the cell surface due to the extremely high
light sensitivity of the channel. This efficient channel activation was partly
mediated by radiationless bioluminescence resonance energy transfer due to the
proximity of luciferase and opsin. To test the utility of SFLMOs in vivo, we
transduced the substantia nigra unilaterally via a viral vector in male rats.
Injection of the luciferase substrate as well as conventional photostimulation
via fiber optics elicited circling behaviors. Thus, SFLMOs expand the current
approaches for manipulation of neuronal activity in the brain and add more
versatility and practicality to optogenetics in freely behaving animals.
© 2019 Wiley Periodicals, Inc.
DOI: 10.1002/jnr.24424
PMCID: PMC6779499
PMID: 30957296 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST The automated behavioral
device (Raturn and Activity Monitor) used in this study was awarded by
Bioanalytical Systems, Inc. (BASi), West Lafayette, IN. |
http://www.ncbi.nlm.nih.gov/pubmed/31263065 | 1. J Neurosci. 2019 Aug 14;39(33):6571-6594. doi: 10.1523/JNEUROSCI.2010-18.2019.
Epub 2019 Jul 1.
Optochemogenetic Stimulation of Transplanted iPS-NPCs Enhances Neuronal Repair
and Functional Recovery after Ischemic Stroke.
Yu SP(1)(2), Tung JK(3), Wei ZZ(1)(2), Chen D(1), Berglund K(3)(2), Zhong
W(1)(2), Zhang JY(1), Gu X(1)(2), Song M(1), Gross RE(3), Lin SZ(4), Wei
L(5)(6).
Author information:
(1)Departments of Anesthesiology.
(2)Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs
Medical Center, Decatur, Georgia 30033.
(3)Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322.
(4)Department of Neurosurgery, Tzu Chi Hospital, Tzu Chi University, Buddhist
Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien, Taiwan 970, and.
(5)Departments of Anesthesiology, lwei7@emory.edu.
(6)Neurology.
Cell transplantation therapy provides a regenerative strategy for neural repair.
We tested the hypothesis that selective excitation of transplanted induced
pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) could
recapitulate an activity-enriched microenvironment that confers regenerative
benefits for the treatment of stroke. Mouse iPS-NPCs were transduced with a
novel optochemogenetics fusion protein, luminopsin 3 (LMO3), which consisted of
a bioluminescent luciferase, Gaussia luciferase, and an opsin, Volvox
Channelrhodopsin 1. These LMO3-iPS-NPCs can be activated by either
photostimulation using light or by the luciferase substrate coelenterazine
(CTZ). In vitro stimulations of LMO3-iPS-NPCs increased expression of
synapsin-1, postsynaptic density 95, brain derived neurotrophic factor (BDNF),
and stromal cell-derived factor 1 and promoted neurite outgrowth. After
transplantation into the ischemic cortex of mice, LMO3-iPS-NPCs differentiated
into mature neurons. Synapse formation between implanted and host neurons was
identified using immunogold electron microscopy and patch-clamp recordings.
Stimulation of transplanted cells with daily intranasal administration of CTZ
enhanced axonal myelination, synaptic transmission, improved thalamocortical
connectivity, and functional recovery. Patch-clamp and multielectrode array
recordings in brain slices showed that CTZ or light stimulation facilitated
synaptic transmission and induced neuroplasticity mimicking the LTP of EPSPs.
Stroke mice received the combined LMO3-iPS-NPC/CTZ treatment, but not cell or
CTZ alone, showed enhanced neural network connections in the peri-infarct
region, promoted optimal functional recoveries after stroke in male and female,
young and aged mice. Thus, excitation of transplanted cells via the noninvasive
optochemogenetics treatment provides a novel integrative cell therapy with
comprehensive regenerative benefits after stroke.SIGNIFICANCE STATEMENT Neural
network reconnection is critical for repairing damaged brain. Strategies that
promote this repair are expected to improve functional outcomes. This study
pioneers the generation and application of an optochemogenetics approach in stem
cell transplantation therapy after stroke for optimal neural repair and
functional recovery. Using induced pluripotent stem cell-derived neural
progenitor cells (iPS-NPCs) expressing the novel optochemogenetic probe
luminopsin (LMO3), and intranasally delivered luciferase substrate
coelenterazine, we show enhanced regenerative properties of LMO3-iPS-NPCs in
vitro and after transplantation into the ischemic brain of different genders and
ages. The noninvasive repeated coelenterazine stimulation of transplanted cells
is feasible for clinical applications. The synergetic effects of the
combinatorial cell therapy may have significant impacts on regenerative approach
for treatments of CNS injuries.
Copyright © 2019 the authors.
DOI: 10.1523/JNEUROSCI.2010-18.2019
PMCID: PMC6697405
PMID: 31263065 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11893487 | 1. Curr Opin Genet Dev. 2002 Apr;12(2):149-55. doi:
10.1016/s0959-437x(02)00280-0.
Coactivators in transcription initiation: here are your orders.
Featherstone M(1).
Author information:
(1)McGill Cancer Centre, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6,
Canada. mfeather@med.mcgill.ca
Coactivators are diverse and multifunctional proteins that act downstream of
DNA-binding activators to stimulate transcription. Recent studies elucidate the
temporal sequence in which coactivators are recruited to target promoters, and
how their enzymatic properties and molecular interactions culminate in
transcriptional initiation.
DOI: 10.1016/s0959-437x(02)00280-0
PMID: 11893487 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11395415 | 1. Annu Rev Biochem. 2001;70:475-501. doi: 10.1146/annurev.biochem.70.1.475.
Transcriptional coactivator complexes.
Näär AM(1), Lemon BD, Tjian R.
Author information:
(1)Howard Hughes Medical Institute, Department of Molecular and Cell Biology,
401 Barker Hall, University of California, Berkeley, California 94720, USA.
anders@uclink4.berkeley.edu
The last two decades have witnessed a tremendous expansion in our knowledge of
the mechanisms employed by eukaryotic cells to control gene activity. A critical
insight to transcriptional control mechanisms was provided by the discovery of
coactivators, a diverse array of cellular factors that connect sequence-specific
DNA binding activators to the general transcriptional machinery, or that help
activators and the transcriptional apparatus to navigate through the constraints
of chromatin. A number of coactivators have been isolated as large
multifunctional complexes, and biochemical, genetic, molecular, and cellular
strategies have all contributed to uncovering many of their components,
activities, and modes of action. Coactivator functions can be broadly divide
into two classes: (a) adaptors that direct activator recruitment of the
transcriptional apparatus, (b) chromatin-remodeling or -modifying enzymes.
Strikingly, several distinct coactivator complexes nonetheless share many
subunits and appear to be assembled in a modular fashion. Such structural and
functional modularity could provide the cell with building blocks from which to
construct a versatile array of coactivator complexes according to its needs. The
extent of functional interplay between these different activities in
gene-specific transcriptional regulation is only now becoming apparent, and will
remain an active area of research for years to come.
DOI: 10.1146/annurev.biochem.70.1.475
PMID: 11395415 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14973393 | 1. J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):307-24. doi:
10.1023/a:1009503029176.
The role of coactivators and corepressors in the biology and mechanism of action
of steroid hormone receptors.
Edwards DP(1).
Author information:
(1)University of Colorado Health Sciences Center, Department of Pathology,
Denver 80262, USA. Dean.Edwards@uchsc.edu
Steroid hormone receptors are members of a superfamily of ligand-dependent
transcription factors. As such they have a DNA binding domain that recognizes
specific target gene sequences along with separate transcriptional activation
domains. What sets steroid hormone receptors (and other nuclear hormone
receptors) apart from other families of sequence specific transcriptional
activators is the presence of a ligand binding domain (LBD) that acts as a
molecular switch to turn on transcriptional activity when a hormonal ligand
induces a conformational change in the receptor. Upon binding hormone, steroid
receptors recruit a novel coactivator protein complex with an essential role in
receptor-mediated transcriptional activation. Coactivators function as adaptors
in a signaling pathway that transmits transcriptional responses from the DNA
bound receptor to the basal transcriptional machinery. Hormone agonists induce a
conformational change in the carboxyl-terminal transcriptional activation
domain, AF-2, that creates a new protein interaction site on the surface of the
LBD that is recognized by LXXLL motifs in the p160 family of coactivators. In
contrast, steroid antagonists such as the antiestrogen tamoxifen for the
estrogen receptor induce an alternate conformation in AF-2 that occludes the
coactivator binding site and recruits corepressors that can actively silence
steroid responsive genes. Thus, the cellular availability of coactivators and
corepressors is an important determinant in the biological response to both
steroid hormone agonists and antagonists. This paper provides an update on the
properties and mechanism of action of nuclear receptor coactivators, the nature
of the coactivator-binding site, and the structural and mechanistic basis for
ligand-dependent binding of coactivators to receptors.
DOI: 10.1023/a:1009503029176
PMID: 14973393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8571454 | 1. Trends Biochem Sci. 1995 Dec;20(12):517-21. doi:
10.1016/s0968-0004(00)89120-3.
Transcriptional coactivators in yeast and beyond.
Guarente L(1).
Author information:
(1)Department of Biology, Massachusetts Institute of Technology, Cambridge
02139-4307, USA.
Coactivators are a novel class of transcriptional activator required at many
eukaryotic promoters. Several coactivators have now been isolated, their
identification often facilitated by genetic studies in yeast. Some of the
proposed mechanisms of coactivator function may help explain synergy between
transcriptional activators at eukaryotic promoters.
DOI: 10.1016/s0968-0004(00)89120-3
PMID: 8571454 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27654711 | 1. Clin Cancer Res. 2016 Nov 15;22(22):5403-5407. doi:
10.1158/1078-0432.CCR-15-1958. Epub 2016 Sep 21.
Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer.
Lonard DM(1), O'Malley BW(2).
Author information:
(1)Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, Texas.
(2)Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, Texas. berto@bcm.edu.
Coactivators represent a large class of proteins that partner with nuclear
receptors and other transcription factors to regulate gene expression. Given
their pleiotropic roles in the control of transcription, coactivators have been
implicated in a broad range of human disease states, including cancer. This is
best typified by the three members of the steroid receptor coactivator (SRC)
family, each of which integrates steroid hormone signaling and growth factor
pathways to drive oncogenic gene expression programs in breast, endometrial,
ovarian, prostate, and other cancers. Because of this, coactivators represent
emerging targets for cancer therapeutics, and efforts are now being made to
develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC
stimulator, MCB-613, that are able to block cancer growth in cell culture and
animal model systems. Here, we will discuss the mechanisms through which
coactivators drive cancer progression and how targeting coactivators represent a
novel conceptual approach to combat tumor growth that is distinct from the use
of other targeted therapeutic agents. We also will describe efforts to develop
next-generation SRC inhibitors and stimulators that can be taken into the clinic
for the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; 22(22);
5403-7. ©2016 AACR.
©2016 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-15-1958
PMCID: PMC5290137
PMID: 27654711 [Indexed for MEDLINE]
Conflict of interest statement: DML and BWO are co-founders and hold stock in
Coregon, Inc. which is developing steroid receptor coactivator stimulators for
clinical use. |
http://www.ncbi.nlm.nih.gov/pubmed/26733686 | 1. Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E358-67. doi:
10.1073/pnas.1510899113. Epub 2016 Jan 5.
Luminopsins integrate opto- and chemogenetics by using physical and biological
light sources for opsin activation.
Berglund K(1), Clissold K(2), Li HE(2), Wen L(3), Park SY(4), Gleixner J(5),
Klein ME(5), Lu D(2), Barter JW(2), Rossi MA(2), Augustine GJ(3), Yin HH(6),
Hochgeschwender U(7).
Author information:
(1)Department of Neurobiology, Duke University, Durham, NC 27710; Department of
Neurosurgery, Emory University, Atlanta, GA 30322;
(2)Department of Psychology and Neuroscience, Duke University, Durham, NC 27708;
(3)Center for Functional Connectomics, Korea Institute of Science and
Technology, 39-1 Hawolgokdong, Seongbukgu, Seoul 136-791, Republic of Korea; Lee
Kong Chian School of Medicine, Nanyang Technological University, Singapore
637553;
(4)Center for Functional Connectomics, Korea Institute of Science and
Technology, 39-1 Hawolgokdong, Seongbukgu, Seoul 136-791, Republic of Korea;
(5)Department of Neurobiology, Duke University, Durham, NC 27710;
(6)Department of Neurobiology, Duke University, Durham, NC 27710; Department of
Psychology and Neuroscience, Duke University, Durham, NC 27708; Center for
Cognitive Neuroscience, Duke University, Durham, NC 27708;
ute.hochgeschwender@cmich.edu hy43@duke.edu.
(7)Department of Neurobiology, Duke University, Durham, NC 27710; Neuroscience
Program, Central Michigan University, Mt Pleasant, MI 48859; College of
Medicine, Central Michigan University, Mt Pleasant, MI 48859
ute.hochgeschwender@cmich.edu hy43@duke.edu.
Luminopsins are fusion proteins of luciferase and opsin that allow interrogation
of neuronal circuits at different temporal and spatial resolutions by choosing
either extrinsic physical or intrinsic biological light for its activation.
Building on previous development of fusions of wild-type Gaussia luciferase with
channelrhodopsin, here we expanded the utility of luminopsins by fusing bright
Gaussia luciferase variants with either channelrhodopsin to excite neurons
(luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO,
iLMO). These improved LMOs could reliably activate or silence neurons in vitro
and in vivo. Expression of the improved LMO in hippocampal circuits not only
enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal
resolution but also could drive rhythmic circuit excitation over a large
spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or
iLMO in the substantia nigra in vivo produced not only the expected
bidirectional control of single unit activity but also opposing effects on
circling behavior in response to systemic injection of a luciferase substrate.
Thus, although preserving the ability to be activated by external light sources,
LMOs expand the use of optogenetics by making the same opsins accessible to
noninvasive, chemogenetic control, thereby allowing the same probe to manipulate
neuronal activity over a range of spatial and temporal scales.
DOI: 10.1073/pnas.1510899113
PMCID: PMC4725499
PMID: 26733686 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/25024406 | 1. J Mol Endocrinol. 2014 Oct;53(2):R47-59. doi: 10.1530/JME-14-0080. Epub 2014
Jul 14.
Transcriptional coregulators: emerging roles of SRC family of coactivators in
disease pathology.
Dasgupta S(1), O'Malley BW(2).
Author information:
(1)Department of Molecular and Cellular BiologyBaylor College of Medicine, One
Baylor Plaza, Houston, Texas 77030, USA.
(2)Department of Molecular and Cellular BiologyBaylor College of Medicine, One
Baylor Plaza, Houston, Texas 77030, USA berto@bcm.edu.
Transcriptional coactivators have evolved as an important new class of
functional proteins that participate with virtually all transcription factors
and nuclear receptors (NRs) to intricately regulate gene expression in response
to a wide variety of environmental cues. Recent findings have highlighted that
coactivators are important for almost all biological functions, and
consequently, genetic defects can lead to severe pathologies. Drug discovery
efforts targeting coactivators may prove valuable for treatment of a variety of
diseases.
© 2014 Society for Endocrinology.
DOI: 10.1530/JME-14-0080
PMCID: PMC4152414
PMID: 25024406 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interest The authors declare that
there is no conflict of interest that could be perceived as prejudicing the
impartiality of the review reported. |
http://www.ncbi.nlm.nih.gov/pubmed/15814849 | 1. Endocr Rev. 2005 May;26(3):393-9. doi: 10.1210/er.2004-0018. Epub 2005 Apr 6.
Transcriptional regulation by steroid receptor coactivator phosphorylation.
Wu RC(1), Smith CL, O'Malley BW.
Author information:
(1)Molecular and Cellular Biology, One Baylor Plaza, Houston, Texas 77030, USA.
carolyns@bcm.tmc.edu
The basic mechanisms underlying ligand-dependent transcriptional activation by
nuclear receptors (NRs) require the sequential recruitment of various
coactivators. Increasing numbers of coactivators have been identified in recent
years, and both biochemical and genetic studies demonstrate that these
coactivators are differentially used by transcription factors, including NRs, in
a cell/tissue type- and promoter-specific manner. However, the molecular basis
underlying this specificity remains largely unknown. Recently, NRs and
coregulators were shown to be targets of posttranslational modifications
activated by diverse cellular signaling pathways. It is argued that
posttranslational modifications of these proteins provide the basis for a
combinatorial code required for specific gene activation by NRs and
coactivators, and that this code also enables coactivators to efficiently
stimulate the activity of other classes of transcription factors. In this
review, we will focus on coactivators and discuss the recent progress in
understanding the role of phosphorylation of the steroid receptor coactivator
family and the potential ramifications of this posttranslational modification
for regulation of gene expression.
DOI: 10.1210/er.2004-0018
PMID: 15814849 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19019695 | 1. Trends Endocrinol Metab. 2009 Jan;20(1):8-15. doi: 10.1016/j.tem.2008.10.001.
Epub 2008 Nov 18.
Multi-modulation of nuclear receptor coactivators through posttranslational
modifications.
Han SJ(1), Lonard DM, O'Malley BW.
Author information:
(1)Department of Molecular and Cellular Biology, Baylor College of Medicine, 1
Baylor Plaza, Houston, Texas 77030, USA.
Nuclear receptor (NR) coactivators are recruited to DNA by NRs, potentiating
NR-dependent gene transcription. To obtain the complexity of NR-mediated gene
regulation with a finite number of coactivators, the molecular properties of
coactivators are dynamically modulated by posttranslational modifications (PTMs)
in response to external stimuli. PTMs can regulate the molecular interactions of
coactivators with transcription factors and other coactivators, in addition to
their cellular location, protein stability, conformation and enzymatic activity.
Therefore, dynamic regulation of the molecular properties of coactivators by
PTMs allows for the complexity of NR-dependent gene expression and influences
the regulation of NR-mediated physiological processes. This review focuses on
recent progress in our understanding of how coactivator PTMs influence
NR-mediated gene transcription and addresses their biological relevance.
DOI: 10.1016/j.tem.2008.10.001
PMCID: PMC3642869
PMID: 19019695 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11454227 | 1. Physiol Plant. 2001 Jun;112(2):217-222. doi:
10.1034/j.1399-3054.2001.1120210.x.
Identification of a putative Solanum tuberosum transcriptional coactivator
up-regulated in potato tubers by Fusarium solani f. sp. eumartii infection and
wounding.
Godoy AV(1), Zanetti ME, San Segundo B, Casalongué CA.
Author information:
(1)Instituto de Investigaciones Biológicas-Departamento de Biología, Universidad
Nacional de Mar del Plata, Funes 3250, CC 1245, 7600 Mar del Plata, Argentina
Instituto de Biología Molecular de Barcelona, Centro de Investigación y
Desarrollo (CSIC), Jordi Girona 18-24, 08034 Barcelona, España.
Coadaptors or coactivators are a new class of transcription factors capable of
interconnecting a regulator DNA-binding protein with a component of the basal
transcription machinery allowing transcriptional activation to proceed. We
report the identification of a novel Solanum tuberosum ssp. tuberosum putative
transcription coactivator, named StMBF1 (Solanum tuberosum multiprotein bridging
factor 1). The StMBF1 cDNA was isolated from a Fusarium solani f. sp.
eumartii-infected potato tuber cDNA library, using a differential screening
approach. StMBF1 is up-regulated during fungal attack as well as on wounding. A
Fusarium elicitor source and ethylene precursor and salicylic acid also regulate
StMBF1 expression. The precise role of StMBF1 during the plant response against
environmental stresses remains to be elucidated.
DOI: 10.1034/j.1399-3054.2001.1120210.x
PMID: 11454227 |
http://www.ncbi.nlm.nih.gov/pubmed/12917354 | 1. J Cell Sci. 2003 Sep 15;116(Pt 18):3667-75. doi: 10.1242/jcs.00734.
The mediator coactivator complex: functional and physical roles in
transcriptional regulation.
Lewis BA(1), Reinberg D.
Author information:
(1)Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Robert
Wood Johnson Medical School, Piscataway, NJ 08854, USA.
In vivo, the DNA is packed into chromatin and transcription is dependent upon
activators that recruit other factors to reverse the repressive effects of
chromatin. The response to activators requires additional factors referred to as
coactivators. One such coactivator, mediator, is a multi-subunit complex capable
of responding to different activators. It plays an key role in activation,
bridging DNA-bound activators, the general transcriptional machinery, especially
RNA polymerase II, and the core promoter. Its subunits are necessary for a
variety of positive and negative regulatory processes and serve as the direct
targets of activators themselves. In vivo and in vitro studies support various
roles for mediator in transcription initiation, while structural studies
demonstrate that it engages in multiple interactions with RNA polymerase II, and
adopts conformations that are activator specific.
DOI: 10.1242/jcs.00734
PMID: 12917354 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17046230 | 1. Curr Opin Cell Biol. 2006 Dec;18(6):715-22. doi: 10.1016/j.ceb.2006.10.003.
Epub 2006 Oct 12.
Coactivator control of cardiovascular growth and remodeling.
Liu N(1), Olson EN.
Author information:
(1)Department of Molecular Biology, University of Texas Southwestern Medical
Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.
Transcriptional coactivators enhance gene expression by associating with
sequence-specific transcription factors and serve as the primary targets of
developmental and physiological signals in diverse biological processes. Recent
studies have revealed key roles for transcriptional coactivators in the control
of gene expression during development, growth and remodeling of the
cardiovascular system. Based on the importance of the cardiovascular
coactivators identified to date, coactivator control is emerging as a central
regulatory mechanism in development and homeostasis of the cardiovascular system
and other tissues.
DOI: 10.1016/j.ceb.2006.10.003
PMID: 17046230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24794975 | 1. Cell Metab. 2014 Jul 1;20(1):26-40. doi: 10.1016/j.cmet.2014.03.027. Epub 2014
May 1.
Transcriptional coregulators: fine-tuning metabolism.
Mouchiroud L(1), Eichner LJ(2), Shaw RJ(3), Auwerx J(4).
Author information:
(1)Laboratory for Integrative and Systems Physiology, Ecole Polytechnique
Fédérale de Lausanne, 1015 Lausanne, Switzerland.
(2)Molecular and Cell Biology Laboratory, The Salk Institute for Biological
Studies, La Jolla, CA 92037, USA.
(3)Molecular and Cell Biology Laboratory, The Salk Institute for Biological
Studies, La Jolla, CA 92037, USA. Electronic address: shaw@salk.edu.
(4)Laboratory for Integrative and Systems Physiology, Ecole Polytechnique
Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address:
admin.auwerx@epfl.ch.
Metabolic homeostasis requires that cellular energy levels are adapted to
environmental cues. This adaptation is largely regulated at the transcriptional
level, through the interaction between transcription factors, coregulators, and
the basal transcriptional machinery. Coregulators, which function as both
metabolic sensors and transcriptional effectors, are ideally positioned to
synchronize metabolic pathways to environmental stimuli. The balance between
inhibitory actions of corepressors and stimulatory effects of coactivators
enables the fine-tuning of metabolic processes. This tight regulation opens
therapeutic opportunities to manage metabolic dysfunction by directing the
activity of cofactors toward specific transcription factors, pathways, or
cells/tissues, thereby restoring whole-body metabolic homeostasis.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2014.03.027
PMCID: PMC4079747
PMID: 24794975 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflict of interest related
to this work. |
http://www.ncbi.nlm.nih.gov/pubmed/36107325 | 1. Adv Exp Med Biol. 2022;1390:277-293. doi: 10.1007/978-3-031-11836-4_16.
Epigenetic Coregulation of Androgen Receptor Signaling.
Fernandes RC(1), Leach DA(1), Bevan CL(2).
Author information:
(1)Department of Surgery & Cancer, Imperial College London, London, UK.
(2)Department of Surgery & Cancer, Imperial College London, London, UK.
charlotte.bevan@imperial.ac.uk.
The androgen receptor (AR) is a ligand-activated transcription factor belonging
to the nuclear receptor (NR) superfamily. As with other members of the NR
family, transcriptional activity of the AR is regulated by interactions with
coregulatory proteins, which either enhance (coactivators) or repress
(corepressors) its transcriptional activity. AR associated coregulators are
functionally diverse, but a large fraction are epigenetic histone and chromatin
modifiers. Epigenetic coregulators are recruited to gene regulatory regions as
part of multi-protein complexes, often acting in a dynamic and inter-dependent
manner to remodel chromatin, thereby allowing or inhibiting the access of
AR-associated transcriptional machinery to target genes; functional consequences
being regulation of transcriptional output. Epigenetic modifiers, including
those that function as AR coregulators, are frequently mutated or aberrantly
expressed in prostate cancer and are implicated in disease progression. Some of
these modifiers are being investigated as therapeutic targets in several cancer
types and could potentially be used to modulate aberrant AR activity in prostate
cancer. In this chapter we will summarise the functional role of epigenetic
coregulators in AR signalling, their dysregulation during prostate cancer
progression and the current status of drugs targeting these enzymes.
© 2022. The Author(s), under exclusive license to Springer Nature Switzerland
AG.
DOI: 10.1007/978-3-031-11836-4_16
PMID: 36107325 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36255625 | 1. Methods Mol Biol. 2023;2589:179-193. doi: 10.1007/978-1-0716-2788-4_12.
Synthesis, Biochemical, and Cellular Evaluation of HDAC6 Targeting Proteolysis
Targeting Chimeras.
Darwish S(1)(2), Heimburg T(1), Ridinger J(3)(4), Herp D(5), Schmidt M(1),
Romier C(6), Jung M(5), Oehme I(3)(4), Sippl W(7).
Author information:
(1)Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther
University of Halle-Wittenberg, Halle/Saale, Germany.
(2)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria
University, Alexandria, Egypt.
(3)Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
(4)Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center
(DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
(5)Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg,
Germany.
(6)Département de Biologie Structurale Intégrative, Université de Strasbourg,
CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire
(IGBMC), Illkirch Cedex, France.
(7)Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther
University of Halle-Wittenberg, Halle/Saale, Germany.
wolfgang.sippl@pharmazie.uni-halle.de.
Histone deacetylases are considered promising epigenetic targets for chemical
protein degradation due to their diverse roles in physiological cellular
functions and in the diseased state. Proteolysis-targeting chimeras (PROTACs)
are bifunctional molecules that hijack the cell's ubiquitin-proteasome system
(UPS). One of the promising targets for this approach is histone deacetylase 6
(HDAC6), which is highly expressed in several types of cancers and is linked to
the aggressiveness of tumors. In the present work, we describe the synthesis of
HDAC6 targeting PROTACs based on previously synthesized benzohydroxamates
selectively inhibiting HDAC6 and how to assess their activities in different
biochemical in vitro assays and in cellular assays. HDAC inhibition was
determined using fluorometric assays, while the degradation ability of the
PROTACs was assessed using western blot analysis.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2788-4_12
PMID: 36255625 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32281043 | 1. Dig Dis Sci. 2021 Mar;66(3):899-911. doi: 10.1007/s10620-020-06245-y. Epub
2020 Apr 12.
Selective Internal Radiation Therapy for Hepatocellular Carcinoma Across the
Barcelona Clinic Liver Cancer Stages.
Moctezuma-Velazquez C(1), Montano-Loza AJ(2), Meza-Junco J(3), Burak K(4), Ma
M(2), Bain VG(2), Kneteman N(5), Sarlieve P(6), Owen RJ(7).
Author information:
(1)Division of Gastroenterology, Instituto Nacional de Ciencias Medicas y
Nutricion "Salvador Zubiran", Avenida Vasco de Quiroga No 15, Seccion XVI,
Tlalpan, 14080, Mexico City, Mexico.
(2)Division of Gastroenterology and Liver Unit, University of Alberta Hospital,
8440 112th Street, Edmonton, AB, T6G 2B7, Canada.
(3)Department of Medical Oncology, Cross Cancer Institute, 11560 University Ave,
Edmonton, AB, T6G 1Z2, Canada.
(4)Liver Unit, University of Calgary, 1403 - 29 St. N.W., Calgary, AB, T2N 2T9,
Canada.
(5)Division of Transplantation, Department of Surgery, University of Alberta
Hospital, 8440 112th Street, Edmonton, AB, T6G 2B7, Canada.
(6)Department of Radiology and Diagnostic Imaging, Walter Mackenzie Health
Sciences Centre, University of Alberta Hospital, 8440 112th Street, Edmonton,
AB, T6G 2B7, Canada.
(7)Department of Radiology and Diagnostic Imaging, Walter Mackenzie Health
Sciences Centre, University of Alberta Hospital, 8440 112th Street, Edmonton,
AB, T6G 2B7, Canada. rowen@ualberta.ca.
BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common lethal
cancer, and there is a need for effective therapies. Selective internal
radiation therapy (SIRT) has been increasingly used, but is not supported by
guidelines due to a lack of solid evidence.
AIMS: Determine the efficacy and safety of SIRT in HCC across the Barcelona
Clinic Liver Cancer (BCLC) stages A, B, and C.
METHODS: Consecutive patients that received SIRT between 2006 and 2016 at two
centers in Canada were evaluated.
RESULTS: We analyzed 132 patients, 12 (9%), 62 (47%), and 58 (44%) belonged to
BCLC stages A, B, and C; mean age was 61.2 (SD ± 9.2), and 89% were male. Median
survival was 12.4 months (95% CI 9.6-16.6), and it was different across the
stages: 59.7 (95% CI NA), 12.8 (95% CI 10.2-17.5), and 9.3 months (95% CI
5.9-11.8) in BCLC A, B, and C, respectively (p = 0.009). Independent factors
associated with survival were previous HCC treatment (HR 2.01, 95% CI 1.23-3.27,
p = 0.005), bi-lobar disease (HR 2.25, 95% CI 1.30-3.89, p = 0.003), ascites (HR
1.77, 95% CI 0.99-3.13, p = 0.05), neutrophil-to-lymphocyte ratio (HR 1.11, 95%
CI 1.02-1.20, p = 0.01), Albumin-Bilirubin (ALBI) grade-3 (HR 2.69, 95% CI
1.22-5.92, p = 0.01), tumor thrombus (HR 2.95, 95% CI 1.65-5.24, p < 0.001), and
disease control rate (HR 0.62, 95% CI 0.39-0.96, p = 0.03). Forty-four (33%)
patients developed severe adverse events, and ALBI-3 was associated with higher
risk of these events.
CONCLUSIONS: SIRT has the potential to be used across the BCLC stages in cases
with preserved liver function. When using it as a rescue treatment, one should
consider variables reflecting liver function, HCC extension, and systemic
inflammation, which are associated with mortality.
DOI: 10.1007/s10620-020-06245-y
PMID: 32281043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1638117 | 1. Curr Opin Genet Dev. 1992 Apr;2(2):236-42. doi: 10.1016/s0959-437x(05)80279-5.
Eukaryotic coactivators associated with the TATA box binding protein.
Gill G(1), Tjian R.
Author information:
(1)Howard Hughes Medical Institute, Department of Molecular and Cell Biology,
University of California, Berkeley 94720.
Recent studies of regulated RNA polymerase II transcription have uncovered a new
class of molecules called coactivators. These are tightly associated with the
TATA box binding protein and are required in addition to promoter-specific
activators and the basal transcription factors in order to achieve stimulated
levels of transcription.
DOI: 10.1016/s0959-437x(05)80279-5
PMID: 1638117 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23131664 | 1. Transcription. 2013 Jan-Feb;4(1):18-23. doi: 10.4161/trns.22601. Epub 2012 Nov
6.
Genomic occupancy of the transcriptional co-activators p300 and CBP.
Holmqvist PH(1), Mannervik M.
Author information:
(1)The Wenner-Gren Institute, Developmental Biology, Stockholm University,
Arrheniuslaboratories E3, SE-106 91 Stockholm, Sweden.
The p300 and CBP co-activators are histone acetylases and central regulators of
transcription in metazoans. The genomic occupancy of p300/CBP detected by
ChIP-seq experiments can be used to identify transcriptional enhancers. However,
studies in Drosophila embryos suggest that there is a preference for some
transcription factors in directing p300/CBP to the genome. Although p300/CBP
occupancy in general correlates with gene activation, they can also be found at
silent genomic regions, which does not result in histone acetylation.
Polycomb-mediated H3K27me3 is associated with repression, but does not preclude
p300/CBP binding. An antagonism between H3K27ac and H3K27me3 indicates that
p300/CBP may be involved in switching between repressed and active chromatin
states.
DOI: 10.4161/trns.22601
PMCID: PMC3644037
PMID: 23131664 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32744764 | 1. J Gastroenterol Hepatol. 2021 Mar;36(3):790-799. doi: 10.1111/jgh.15206. Epub
2020 Aug 14.
The relationship between oral-origin bacteria in the fecal microbiome and
albumin-bilirubin grade in patients with hepatitis C.
Yamamoto K(1), Honda T(1), Ito T(1), Ishizu Y(1), Kuzuya T(1), Nakamura M(1),
Miyahara R(1), Kawashima H(1), Ishigami M(1), Fujishiro M(1).
Author information:
(1)Department of Gastroenterology and Hepatology, Nagoya University Graduate
School of Medicine, Nagoya, Japan.
BACKGROUND: Bacteria of oral origin (BO) in the gut are associated with
prognosis in patients with cirrhosis. The Greengenes database (gg_13_8) is
widely used in microbiome analysis, but the expanded Human Oral Microbiome
Database (eHOMD), a specialized database for BO, can add more detailed
information. We used each database to evaluate the relationship between the
albumin-bilirubin grade (ALBI) and the microbiome in patients with hepatitis C.
METHODS: Eighty patients were classified into the low ALBI group (LA; n = 34) or
high ALBI group (HA; n = 46). Isolated DNA from stool was amplified to target
the V3-4 regions of 16S rRNA. The microbiomes of the two groups were compared
using gg_13_8 or eHOMD. We evaluated the associations between microbiomes and
prognoses using Cox proportional hazards models.
RESULTS: At the genus level, the two groups differed significantly regarding 6
(gg_13_8) and 7 (eHOMD) types of bacteria. All types except Akkermansia are
classified as BO. Both databases showed an increase in Streptococcus and
Veillonella. eHOMD showed a decrease in Fusobacterium and an increase in
Fretibacterium; both produce various types of short-chain fatty acids. At the
species level, the two groups demonstrated significant differences in 2
(gg_13_8) and 6 (eHOMD) bacterial types. Selenomonas noxia and Streptococcus
salivarius were related to poor prognosis in univariate analysis.
CONCLUSION: The HA group demonstrated increased BO, most of which produce lactic
acid or acetic acid. The correlation between the microbiome and metabolism might
be related to prognosis. eHOMD was a useful database for analyzing BO.
© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley &
Sons Australia, Ltd.
DOI: 10.1111/jgh.15206
PMID: 32744764 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34534392 | 1. Hepatol Res. 2021 Dec;51(12):1207-1218. doi: 10.1111/hepr.13714. Epub 2021 Oct
1.
Association between the albumin-bilirubin (ALBI) score and severity of
portopulmonary hypertension (PoPH): A data-mining analysis.
Kawaguchi T(1), Honda A(2), Sugiyama Y(2), Nakano D(1), Tsutsumi T(1), Tahara
N(2), Torimura T(1), Fukumoto Y(2).
Author information:
(1)Division of Gastroenterology, Department of Medicine, Kurume University
School of Medicine, Kurume, Japan.
(2)Division of Cardiovascular Medicine, Department of Medicine, Kurume
University School of Medicine, Kurume, Japan.
INTRODUCTION: Portopulmonary hypertension (PoPH) is a severe complication of
chronic liver disease. We aimed to investigate the etiology of chronic liver
disease and the factors associated with the severity of PoPH.
SUBJECTS AND METHODS: Echocardiography was undergone in 833 patients with
chronic liver disease during 2005-2019 and 13 patients (1.6%) were diagnosed
with PoPH in this observational study. At the diagnosis of PoPH, liver function
was evaluated by albumin-bilirubin (ALBI) score. Severe PoPH was defined as (1)
mean pulmonary arterial pressure (mPAP) ≥50 mmHg or (2) mPAP: 35-49 mmHg and
pulmonary vascular resistance ≥400 dyne/s/cm5 . Factors associated with severe
PoPH were evaluated by decision-tree analysis.
RESULTS: In patients with PoPH, the leading etiology of chronic liver disease
was hepatitis C virus (HCV) (46.2% [sustained virological response (SVR): 23.1%
and non-SVR: 15.4%]). Severe PoPH was observed in 53.8% of patients and the
5-year survival rate was 48.1%. There was a significant correlation of mPAP with
ALBI score (r = 0.6456, p = 0.0171). In the decision-tree and random forest
analyses, the most impacted classifier for severe PoPH was the ALBI score. In
patients with ALBI score ≥-1.45, all patients showed severe PoPH, while the
prevalence of severe PoPH was 25.0% in patients with ALBI score <-1.45.
CONCLUSIONS: We found that HCV including SVR was the major etiology of chronic
liver disease in patients with PoPH. Moreover, we revealed that the ALBI score
was the most impacted factor associated with severe PoPH. Thus, ALBI score may
be useful for the estimation of pulmonary vascular resistance.
© 2021 Japan Society of Hepatology.
DOI: 10.1111/hepr.13714
PMID: 34534392 |
http://www.ncbi.nlm.nih.gov/pubmed/34534398 | 1. Hepatol Res. 2021 Dec;51(12):1219-1228. doi: 10.1111/hepr.13713. Epub 2021 Sep
29.
Sequential therapy including regorafenib for unresectable hepatocellular
carcinoma: Effect of early relative changes in hepatic functional reserve after
regorafenib administration on prognosis.
Ochi H(1), Tani J(2), Tomonari T(3), Taniguchi T(3), Koizumi Y(4), Hirose A(5),
Ogawa C(6), Hiraoka A(7), Morishita A(2), Moriya A(8), Hirooka M(4), Deguchi
A(9), Symple Study Group.
Author information:
(1)Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital,
Matsuyama, Japan.
(2)Department of Gastroenterology and Neurology, Kagawa University Graduate
School of Medicine, Miki-cho, Japan.
(3)Department of Gastroenterology and Oncology, Tokushima University Graduate
School of Medicine, Institute of Biomedical Sciences, Tokushima, Japan.
(4)Department of Gastroenterology and Metabology, Ehime University Graduate
School of Medicine, Toon, Japan.
(5)Department of Gastroenterology and Hepatology, Kochi University Graduate
School of Medicine, Kōchi, Japan.
(6)Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital,
Takamatsu, Japan.
(7)Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama,
Japan.
(8)Department of Gastroenterology, Mitoyo General Hospital, Kannonji, Japan.
(9)Department of Gastroenterology, Kagawa Rosai Hospital, Marugame, Japan.
AIM: Regorafenib is a second-line treatment for unresectable hepatocellular
carcinoma after sorafenib-refractory treatment. This study examined the effects
of regorafenib administration on hepatic functional reserve and the treatment
course after regorafenib discontinuation.
METHODS: This retrospective, multicenter study involved 51 patients treated with
regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions
before March 2021.
RESULTS: Fourteen, 13, and 24 patients were classified based on modified
albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival
time and progression-free survival were 16.7 and 3.3 months, respectively. Only
mALBI grade 2b or 3 was significantly associated with survival rate (hazard
ratio, 2.13; 95% confidence interval, 1.01-4.49; p = 0.047). A comparison of
median ALBI scores at the initiation of regorafenib (-2.35) with those at
4 weeks (-1.93) revealed a significant relative change (p = 0.0001). After
4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a
deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib
administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and
11.3 months in the three groups, respectively (p = 0.05). Patients treated with
lenvatinib (LEN) (n = 27, MST = 23.4 months) after regorafenib had a
significantly longer survival time from regorafenib initiation than those not
treated with LEN (n = 24, 11.8 months; p = 0.043).
CONCLUSIONS: Hepatic functional reserve significantly declined after regorafenib
administration. During regorafenib treatment, favorable hepatic functional
reserve before administration and maintenance of favorable hepatic reserve after
administration lead to prolonged prognosis.
© 2021 Japan Society of Hepatology.
DOI: 10.1111/hepr.13713
PMID: 34534398 |
http://www.ncbi.nlm.nih.gov/pubmed/18395801 | 1. Vet Immunol Immunopathol. 2008 May 15;123(1-2):172-5. doi:
10.1016/j.vetimm.2008.01.026. Epub 2008 Jan 19.
Treatment of cats with feline infectious peritonitis.
Hartmann K(1), Ritz S.
Author information:
(1)Department of Small Animal Internal Medicine, LMU University of Munich,
Veterinaerstrasse 13, 80539 Muenchen, Germany. Hartmann@uni-muenchen.de
Feline infectious peritonitis (FIP) infection resulting in clinical signs is
invariably fatal despite clinical intervention. As FIP is an immune-mediated
disease, treatment is mainly aimed at controlling the immune response triggered
by the infection with the feline coronavirus (FCoV). Immune suppressive drugs
such as prednisone or cyclophosphamide may slow disease progression but do not
produce a cure. In nearly every published case report of attempted therapy for
clinical FIP, glucocorticoids have been used; there are, however, no controlled
studies that evaluate the effect of glucocorticoids as a therapy for FIP. Some
veterinarians prescribe immune modulators to treat cats with FIP with no
documented controlled evidence of efficacy. It has been suggested that these
agents may benefit infected animals by restoring compromised immune function,
thereby allowing the patient to control viral burden and recover from clinical
signs. However, a non-specific stimulation of the immune system may be
contraindicated as clinical signs develop and progress as a result of an
immune-mediated response to the mutated FCoV.
DOI: 10.1016/j.vetimm.2008.01.026
PMCID: PMC7132371
PMID: 18395801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15123155 | 1. J Feline Med Surg. 2004 Apr;6(2):107-9. doi: 10.1016/j.jfms.2003.08.011.
Use of recombinant feline interferon and glucocorticoid in the treatment of
feline infectious peritonitis.
Ishida T(1), Shibanai A, Tanaka S, Uchida K, Mochizuki M.
Author information:
(1)Akasaka Animal Hospital, 4-1-29 Akasaka, Minato-ku, Tokyo 107-0052, Japan.
ishida.dvm@jcom.home.ne.jp
A total of 12 clinically ill cats previously diagnosed as feline infectious
peritonitis (FIP) were treated with a combination of recombinant feline
interferon and glucocorticoid. A complete remission (over 2 years) and a partial
remission (2 to 5 months) were observed in four (33.3%) and four (33.3%) cases,
respectively. Those that survived for more than 2 years were all older cats (6
to 16 years old) with the effusive form of FIP.
DOI: 10.1016/j.jfms.2003.08.011
PMCID: PMC7129501
PMID: 15123155 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18196725 | 1. J Vet Intern Med. 2007 Nov-Dec;21(6):1193-7. doi: 10.1892/06-302.1.
Effect of feline interferon-omega on the survival time and quality of life of
cats with feline infectious peritonitis.
Ritz S(1), Egberink H, Hartmann K.
Author information:
(1)Clinic of Small Animal Internal Medicine, Ludwig Maximilian University
Munich, Germany.
BACKGROUND: There is no therapy with proven efficacy to treat cats with feline
infectious peritonitis (FIP).
HYPOTHESIS: Feline interferon-omega (FeIFN-omega) prolongs survival time and
increases quality of life in cats with FIP.
ANIMALS: Thirty-seven privately owned cats were subjects of this study.
METHODS: The study was performed as a placebo-controlled double-blind trial.
Feline infectious peritonitis was confirmed by histology or immunostaining of
feline coronavirus (FCoV) antigen in effusion or tissue macrophages or both. The
cats were randomly selected for treatment with either FeIFN-omega or a placebo.
All cats received adjunctive treatment with glucocorticoids and antibiotics and
passive immunization with Feliserin.
RESULTS: There was no statistically significant difference in the survival time
of cats treated with FeIFN-omega versus placebo or in any other variable
evaluated (with the exception of the lymphocyte count). The cats survived
between 3 and 200 days (median, 9 days). There was only 1 long-term survivor (>
3 months), and the cat was in the FeIFN-omega group.
CONCLUSION AND CLINICAL RELEVANCE: No effect of FeIFN-omega on survival time or
quality of life could be demonstrated in this study.
DOI: 10.1892/06-302.1
PMCID: PMC7197507
PMID: 18196725 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31585653 | 1. Vet Microbiol. 2019 Oct;237:108398. doi: 10.1016/j.vetmic.2019.108398. Epub
2019 Aug 23.
Characterization of amino acid substitutions in feline coronavirus 3C-like
protease from a cat with feline infectious peritonitis treated with a protease
inhibitor.
Perera KD(1), Rathnayake AD(2), Liu H(3), Pedersen NC(3), Groutas WC(2), Chang
KO(1), Kim Y(4).
Author information:
(1)Department of Diagnostic Medicine and Pathobiology, College of Veterinary
Medicine, Kansas State University, Manhattan, KS, USA.
(2)Department of Chemistry, Wichita State University, Wichita, KS, USA.
(3)Center for Companion Animal Health, School of Veterinary Medicine, University
of California, Davis, CA, USA.
(4)Department of Diagnostic Medicine and Pathobiology, College of Veterinary
Medicine, Kansas State University, Manhattan, KS, USA. Electronic address:
ykim@ksu.edu.
Feline infectious peritonitis (FIP) is a highly fatal disease caused by a
virulent feline coronavirus in domestic and wild cats. We have previously
reported the synthesis of potent coronavirus 3C-like protease (3CLpro)
inhibitors and the efficacy of a protease inhibitor, GC376, in client-owned cats
with FIP. In this study, we studied the effect of the amino acid changes in
3CLpro of feline coronavirus from a feline patient who received antiviral
treatment for prolonged duration. We generated recombinant 3CLpro containing the
identified amino acid changes (N25S, A252S or K260 N) and determined their
susceptibility to protease inhibitors in the fluorescence resonance energy
transfer assay. The assay showed that N25S in 3CLpro confers a small change (up
to 1.68-fold increase in the 50% inhibitory concentration) in susceptibility to
GC376, but other amino acid changes do not affect susceptibility. Modelling of
3CLpro carrying the amino acid changes was conducted to probe the structural
basis for these findings. The results of this study may explain the observed
absence of clinical resistance to the long-term antiviral treatment in the
patients.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.vetmic.2019.108398
PMCID: PMC6779346
PMID: 31585653 [Indexed for MEDLINE]
Conflict of interest statement: The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of
the manuscript, or in the decision to publish the results. Y.K. K.O. and W.C.G.
have patent claims on the protease inhibitors in the manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/19482534 | 1. J Feline Med Surg. 2009 Aug;11(8):624-6. doi: 10.1016/j.jfms.2008.12.002. Epub
2009 May 24.
Effect of Polyprenyl Immunostimulant on the survival times of three cats with
the dry form of feline infectious peritonitis.
Legendre AM(1), Bartges JW.
Author information:
(1)College of Veterinary Medicine, University of Tennessee, 2407 River Road,
Knoxville, TN 37996-4544, United States. alegendr@utk.edu
Feline infectious peritonitis (FIP) is considered a fatal disease. Three cats
with dry form FIP were treated with Polyprenyl Immunostimulant. Two of the three
cats are still on treatment and are alive and well 2 years after diagnosis. The
third cat survived 14 months but was treated for only 4.5 months. Further
studies are necessary to assess the potential of the Polyprenyl Immunostimulant.
DOI: 10.1016/j.jfms.2008.12.002
PMCID: PMC7130077
PMID: 19482534 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22092616 | 1. J Vet Intern Med. 2011 Nov-Dec;25(6):1270-6. doi:
10.1111/j.1939-1676.2011.00806.x. Epub 2011 Oct 12.
Randomized, placebo controlled study of the effect of propentofylline on
survival time and quality of life of cats with feline infectious peritonitis.
Fischer Y(1), Ritz S, Weber K, Sauter-Louis C, Hartmann K.
Author information:
(1)Clinic of Small Animal Medicine, University of Munich, Munich, Germany.
BACKGROUND: Currently there is no drug proven to effectively treat cats with
feline infectious peritonitis (FIP).
HYPOTHESIS: Propentofylline (PPF) can decrease vasculitis, and therefore prolong
survival time in cats with FIP, and increase their quality of life.
ANIMALS: Twenty-three privately owned cats with FIP.
METHODS: Placebo-controlled double-blind trial. FIP was confirmed by histology
or immunostaining of feline coronavirus (FCoV) antigen in effusion or tissue
macrophages or both. The cats were randomly selected for treatment with either
PPF or placebo. All cats received additional treatment with glucocorticoids,
antibiotics, and low molecular weight heparin according to methods.
RESULTS: There was no statistically significant difference in the survival time
of cats treated with PPF (8 days, 95% CI 5.4-10.6) versus placebo (7.5 days, 95%
CI 4.4-9.6). The median survival time of all cats was 8 days (4-36 days). There
was neither a difference in quality of life (day 7, P = .892), in the amount of
effusion (day 7, P = .710), the tumor necrosis factor-alpha (TNF-α)
concentration (day 7, P = .355), nor in any other variable investigated in this
study, including a complete blood count, and a small animal biochemistry
profile.
CONCLUSIONS AND CLINICAL IMPORTANCE: This study did not detect an effect of PPF
on the survival time, the quality of life, or any clinical or laboratory
parameter in cats with FIP. Therefore, PPF does not appear to be an effective
treatment option in cats with a late stage of the disease FIP.
Copyright © 2011 by the American College of Veterinary Internal Medicine.
DOI: 10.1111/j.1939-1676.2011.00806.x
PMCID: PMC7166892
PMID: 22092616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25596968 | 1. Vet Microbiol. 2015 Mar 23;176(1-2):10-8. doi: 10.1016/j.vetmic.2014.12.009.
Epub 2014 Dec 19.
Combination siRNA therapy against feline coronavirus can delay the emergence of
antiviral resistance in vitro.
McDonagh P(1), Sheehy PA(2), Norris JM(3).
Author information:
(1)Faculty of Veterinary Science, Building B14, The University of Sydney,
Sydney, NSW 2006, Australia.
(2)Faculty of Veterinary Science, Building B19, The University of Sydney,
Sydney, NSW 2006, Australia.
(3)Faculty of Veterinary Science, Building B14, The University of Sydney,
Sydney, NSW 2006, Australia. Electronic address: jacqui.norris@sydney.edu.au.
Virulent biotypes of feline coronavirus (FCoV), commonly referred to as feline
infectious peritonitis virus (FIPV), can result in the development of feline
infectious peritonitis (FIP), a typically fatal immune mediated disease for
which there is currently no effective antiviral treatment. We previously
reported the successful in vitro inhibition of FIPV replication by synthetic
siRNA mediated RNA interference (RNAi) in an immortalised cell line (McDonagh et
al., 2011). A major challenge facing the development of any antiviral strategy
is that of resistance, a problem which is particularly acute for RNAi based
therapeutics due to the exquisite sequence specificity of the targeting
mechanism. The development of resistance during treatment can be minimised using
combination therapy to raise the genetic barrier or using highly potent
compounds which result in a more rapid and pronounced reduction in the viral
replication rate, thereby reducing the formation of mutant, and potentially
resistant viruses. This study investigated the efficacy of combination siRNA
therapy and its ability to delay or prevent viral escape. Virus serially
passaged through cells treated with a single or dual siRNAs rapidly acquired
resistance, with mutations identified in the siRNA target sites. Combination
therapy with three siRNA prevented viral escape over the course of five
passages. To identify more potent silencing molecules we also compared the
efficacy, in terms of potency and duration of action, of canonical versus
Dicer-substrate siRNAs for two previously identified effective viral motifs.
Dicer-substrate siRNAs showed equivalent or better potency than canonical siRNAs
for the target sites investigated, and may be a more appropriate molecule for in
vivo use. Combined, these data inform the potential therapeutic application of
antiviral RNAi against FIPV.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.vetmic.2014.12.009
PMCID: PMC7117502
PMID: 25596968 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26850532 | 1. Res Vet Sci. 2016 Feb;104:17-23. doi: 10.1016/j.rvsc.2015.11.005. Epub 2015
Nov 12.
Therapeutic effect of anti-feline TNF-alpha monoclonal antibody for feline
infectious peritonitis.
Doki T(1), Takano T(2), Kawagoe K(3), Kito A(4), Hohdatsu T(5).
Author information:
(1)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan. Electronic address:
dv12003f@st.kitasato-u.ac.jp.
(2)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan. Electronic address:
takanot@vmas.kitasato-u.ac.jp.
(3)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan. Electronic address:
tachikoma893@yahoo.co.jp.
(4)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan. Electronic address:
kitasato8852@yahoo.co.jp.
(5)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan. Electronic address:
hohdatsu@vmas.kitasato-u.ac.jp.
Feline infectious peritonitis virus (FIPV) replication in macrophages/monocytes
induced tumor necrosis factor (TNF)-alpha production, and that the TNF-alpha
produced was involved in aggravating the pathology of FIP. We previously
reported the preparation of a feline TNF-alpha (fTNF-alpha)-neutralizing mouse
monoclonal antibody (anti-fTNF-alpha mAb). This anti-fTNF-alpha mAb 2-4 was
confirmed to inhibit the following fTNF-alpha-induced conditions in vitro. In
the present study, we investigated whether mAb 2-4 improved the FIP symptoms and
survival rate of experimentally FIPV-inoculated SPF cats. Progression to FIP was
prevented in 2 out of 3 cats treated with mAb 2-4, whereas all 3 cats developed
FIP in the placebo control group. Plasma alpha1-glycoprotein and vascular
endothelial growth factor levels were improved by the administration of mAb 2-4,
and the peripheral lymphocyte count also recovered. These results strongly
suggested that the anti-fTNF-alpha antibody is effective for the treatment of
FIP.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.rvsc.2015.11.005
PMCID: PMC7111801
PMID: 26850532 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25701212 | 1. Arch Virol. 2015 May;160(5):1163-70. doi: 10.1007/s00705-015-2370-x. Epub 2015
Feb 21.
Differential effects of viroporin inhibitors against feline infectious
peritonitis virus serotypes I and II.
Takano T(1), Nakano K, Doki T, Hohdatsu T.
Author information:
(1)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori, 034-8628, Japan.
Feline infectious peritonitis virus (FIP virus: FIPV), a feline coronavirus of
the family Coronaviridae, causes a fatal disease called FIP in wild and domestic
cat species. The genome of coronaviruses encodes a hydrophobic transmembrane
protein, the envelope (E) protein. The E protein possesses ion channel activity.
Viral proteins with ion channel activity are collectively termed "viroporins".
Hexamethylene amiloride (HMA), a viroporin inhibitor, can inhibit the ion
channel activity of the E protein and replication of several coronaviruses.
However, it is not clear whether HMA and other viroporin inhibitors affect
replication of FIPV. We examined the effect of HMA and other viroporin
inhibitors (DIDS [4,4'-disothiocyano-2,2'-stilbenedisulphonic acid] and
amantadine) on infection by FIPV serotypes I and II. HMA treatment drastically
decreased the titers of FIPV serotype I strains Black and KU-2 in a
dose-dependent manner, but it only slightly decreased the titer of FIPV serotype
II strain 79-1146. In contrast, DIDS treatment decreased the titer of FIPV
serotype II strain 79-1146 in dose-dependent manner, but it only slightly
decreased the titers of FIPV serotype I strains Black and KU-2. We investigated
whether there is a difference in ion channel activity of the E protein between
viral serotypes using E. coli cells expressing the E protein of FIPV serotypes I
and II. No difference was observed, suggesting that a viroporin other than the E
protein influences the differences in the actions of HMA and DIDS on FIPV
serotypes I and II.
DOI: 10.1007/s00705-015-2370-x
PMCID: PMC7086594
PMID: 25701212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27027316 | 1. PLoS Pathog. 2016 Mar 30;12(3):e1005531. doi: 10.1371/journal.ppat.1005531.
eCollection 2016 Mar.
Reversal of the Progression of Fatal Coronavirus Infection in Cats by a
Broad-Spectrum Coronavirus Protease Inhibitor.
Kim Y(1), Liu H(2), Galasiti Kankanamalage AC(3), Weerasekara S(4), Hua DH(4),
Groutas WC(3), Chang KO(1), Pedersen NC(2).
Author information:
(1)Department of Diagnostic Medicine and Pathobiology, College of Veterinary
Medicine, Kansas State University, Manhattan, Kansas, United States of America.
(2)Department of Medicine and Epidemiology, School of Veterinary Medicine,
University of California at Davis, Davis, California, United States of America.
(3)Department of Chemistry, Wichita State University, Wichita, Kansas, United
States of America.
(4)Department of Chemistry, Kansas State University, Manhattan, Kansas, United
States of America.
Erratum in
PLoS Pathog. 2016 May 11;12(5):e1005650. doi: 10.1371/journal.ppat.1005650.
Coronaviruses infect animals and humans causing a wide range of diseases. The
diversity of coronaviruses in many mammalian species is contributed by
relatively high mutation and recombination rates during replication. This
dynamic nature of coronaviruses may facilitate cross-species transmission and
shifts in tissue or cell tropism in a host, resulting in substantial change in
virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis
in cats, but a highly fatal disease, called feline infectious peritonitis (FIP),
can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP
is intimately associated with immune responses and involves depletion of T
cells, features shared by some other coronaviruses like Severe Acute Respiratory
Syndrome Coronavirus. The increasing risks of highly virulent coronavirus
infections in humans or animals call for effective antiviral drugs, but no such
measures are yet available. Previously, we have reported the inhibitors that
target 3C-like protease (3CLpro) with broad-spectrum activity against important
human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of
our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal
once certain clinical and laboratory signs become apparent. We found that
antiviral treatment led to full recovery of cats when treatment was started at a
stage of disease that would be otherwise fatal if left untreated. Antiviral
treatment was associated with a rapid improvement in fever, ascites, lymphopenia
and gross signs of illness and cats returned to normal health within 20 days or
less of treatment. Significant reduction in viral titers was also observed in
cats. These results indicate that continuous virus replication is required for
progression of immune-mediated inflammatory disease of FIP. These findings may
provide important insights into devising therapeutic strategies and selection of
antiviral compounds for further development for important coronaviruses in
animals and humans.
DOI: 10.1371/journal.ppat.1005531
PMCID: PMC4814111
PMID: 27027316 [Indexed for MEDLINE]
Conflict of interest statement: I have read the journal's policy and the authors
of this manuscript have the following competing interests: YK, KOC, DHH, and WCG
have patent claims on the protease inhibitors in the manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/32521771 | 1. Animals (Basel). 2020 Jun 8;10(6):1000. doi: 10.3390/ani10061000.
Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically
Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline
Infectious Peritonitis (FIP).
Yu J(1), Kimble B(1), Norris JM(1), Govendir M(1).
Author information:
(1)Sydney School of Veterinary Science, Faculty of Science, The University of
Sydney, Sydney, NSW 2006, Australia.
The pharmacokinetic profile of mefloquine was investigated as a preliminary
study towards a potential treatment for feline coronavirus infections (such as
feline infectious peritonitis) or feline calicivirus infections. Mefloquine was
administered at 62.5 mg orally to seven clinically healthy cats twice weekly for
four doses and mefloquine plasma concentrations over 336 h were measured using
high pressure liquid chromatography (HPLC). The peak plasma concentration (Cmax)
after a single oral dose of mefloquine was 2.71 ug/mL and time to reach Cmax
(Tmax) was 15 h. The elimination half-life was 224 h. The plasma concentration
reached a higher level at 4.06 ug/mL when mefloquine was administered with food.
Adverse effects of dosing included vomiting following administration without
food in some cats. Mild increases in serum symmetric dimethylarginine (SDMA),
but not creatinine, concentrations were observed. Mefloquine may provide a safe
effective treatment for feline coronavirus and feline calicivirus infections in
cats.
DOI: 10.3390/ani10061000
PMCID: PMC7341284
PMID: 32521771
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to
publish the results. |
http://www.ncbi.nlm.nih.gov/pubmed/32848107 | 1. J Vet Med Sci. 2020 Oct 20;82(10):1492-1496. doi: 10.1292/jvms.20-0049. Epub
2020 Aug 27.
Clinical efficacy of combination therapy of itraconazole and prednisolone for
treating effusive feline infectious peritonitis.
Kameshima S(1), Kimura Y(1), Doki T(2), Takano T(2), Park CH(3), Itoh N(1).
Author information:
(1)Laboratory of Small Animal Internal Medicine 1, School of Veterinary
Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
(2)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan.
(3)Laboratory of Veterinary Pathology, School of Veterinary Medicine, Kitasato
University, Towada, Aomori 034-8628, Japan.
A 3-month-old male Scottish Fold kitten with pleural fluid and low ratio of
albumin to globulin (A/G ratio) was brought to our small animal hospital. Since
RNA from the type I feline coronavirus (FCoV) were detected in drained pleural
fluid, the cat was tentatively diagnosed with effusive feline infectious
peritonitis (FIP). Following the administration of itraconazole and
prednisolone, the A/G ratio increased, and the pleural fluid mostly disappeared.
The fecal FCoV levels temporarily decreased. However, the cat showed
neurological manifestations and was eventually euthanized due to status
epilepticus after 38 days of treatment. In conclusion, itraconazole partly
exerted a beneficial effect in a cat with FIP. However, further investigation of
a possible role of itraconazole in FIP treatment is warranted.
DOI: 10.1292/jvms.20-0049
PMCID: PMC7653327
PMID: 32848107 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35934910 | 1. J S Afr Vet Assoc. 2022 Nov;93(2):112-115. doi: 10.36303/JSAVA.238. Epub 2022
Jul 1.
Successful treatment of a South African cat with effusive feline infectious
peritonitis with remdesivir.
Bohm M(1).
Author information:
(1)King Edward Veterinary Referral Hospital, South Africa.
Historically, feline infectious peritonitis (FIP) has been considered almost
invariably fatal. The recent COVID-19 pandemic has fuelled research in
coronavirus pathophysiology and treatment. An unintended consequence is that we
now have an effective treatment accessible for FIP. This paper reports on the
successful resolution of immunohistochemistry-confirmed effusive FIP in an
adolescent cat in South Africa following monotherapy with remdesivir at 4.9-5.6
mg/kg daily for 80 days.
DOI: 10.36303/JSAVA.238
PMID: 35934910 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30755068 | 1. J Feline Med Surg. 2019 Apr;21(4):271-281. doi: 10.1177/1098612X19825701. Epub
2019 Feb 13.
Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats
with naturally occurring feline infectious peritonitis.
Pedersen NC(1), Perron M(2), Bannasch M(1), Montgomery E(1), Murakami E(2),
Liepnieks M(3), Liu H(3).
Author information:
(1)1 Center for Companion Animal Health, School of Veterinary Medicine,
University of California, Davis, CA, USA.
(2)2 Gilead Sciences, Foster City, CA, USA.
(3)3 Department of Pathology, Microbiology and Immunology, School of Veterinary
Medicine, University of California, Davis, CA, USA.
OBJECTIVES: The aim of this study was to determine the safety and efficacy of
the nucleoside analog GS-441524 for cats suffering from various forms of
naturally acquired feline infectious peritonitis (FIP).
METHODS: Cats ranged from 3.4-73 months of age (mean 13.6 months); 26 had
effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with
severe neurological and ocular FIP were not recruited. The group was started on
GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased
when indicated to 4.0 mg/kg SC q24h.
RESULTS: Four of the 31 cats that presented with severe disease died or were
euthanized within 2-5 days and a fifth cat after 26 days. The 26 remaining cats
completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats
remain healthy at the time of publication (OnlineFirst, February 2019) after one
round of treatment, while eight others suffered disease relapses within 3-84
days. Six of the relapses were non-neurological and two neurological. Three of
the eight relapsing cats were treated again at the same dosage, while five cats
had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a
second time at the higher dosage, including one with neurological disease,
responded well and also remain healthy at the time of publication. However, one
of the three cats re-treated at the original lower dosage relapsed with
neurological disease and was euthanized, while the two remaining cats responded
favorably but relapsed a second time. These two cats were successfully treated a
third time at the higher dosage, producing 25 long-time survivors. One of the 25
successfully treated cats was subsequently euthanized due to presumably
unrelated heart disease, while 24 remain healthy.
CONCLUSIONS AND RELEVANCE: GS-441524 was shown to be a safe and effective
treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at
least 12 weeks.
DOI: 10.1177/1098612X19825701
PMCID: PMC6435921
PMID: 30755068 [Indexed for MEDLINE]
Conflict of interest statement: MP and EM are employees of Gilead Sciences,
Foster City, CA, USA, and hold stock interests in the company. |
http://www.ncbi.nlm.nih.gov/pubmed/32441826 | 1. J Vet Intern Med. 2020 Jul;34(4):1587-1593. doi: 10.1111/jvim.15780. Epub 2020
May 22.
Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats
with clinically diagnosed neurological feline infectious peritonitis.
Dickinson PJ(1), Bannasch M(2), Thomasy SM(1)(3), Murthy VD(2), Vernau KM(1),
Liepnieks M(4), Montgomery E(2), Knickelbein KE(2), Murphy B(4), Pedersen NC(5).
Author information:
(1)Department of Surgical and Radiological Sciences, School of Veterinary
Medicine, Davis, California, USA.
(2)Veterinary Medical Teaching Hospital, School of Veterinary Medicine, Davis,
California, USA.
(3)Department of Ophthalmology and Vision Science, University of
California-Davis, Davis, California, USA.
(4)Department of Pathology, Microbiology and Immunology, School of Veterinary
Medicine, Davis, California, USA.
(5)Center for Companion Animal Health, School of Veterinary Medicine, Davis,
California, USA.
Feline infectious peritonitis (FIP) is caused by a mutant biotype of the feline
enteric coronavirus. The resulting FIP virus (FIPV) commonly causes central
nervous system (CNS) and ocular pathology in cases of noneffusive disease. Over
95% of cats with FIP will succumb to disease in days to months after diagnosis
despite a variety of historically used treatments. Recently developed antiviral
drugs have shown promise in treatment of nonneurological FIP, but data from
neurological FIP cases are limited. Four cases of naturally occurring FIP with
CNS involvement were treated with the antiviral nucleoside analogue GS-441524
(5-10 mg/kg) for at least 12 weeks. Cats were monitored serially with physical,
neurologic, and ophthalmic examinations. One cat had serial magnetic resonance
imaging (MRI), cerebrospinal fluid (CSF) analysis (including feline coronavirus
[FCoV]) titers and FCoV reverse transcriptase [RT]-PCR) and serial ocular
imaging using Fourier-domain optical coherence tomography (FD-OCT) and in vivo
confocal microscopy (IVCM). All cats had a positive response to treatment. Three
cats are alive off treatment (528, 516, and 354 days after treatment initiation)
with normal physical and neurologic examinations. One cat was euthanized
216 days after treatment initiation following relapses after primary and
secondary treatment. In 1 case, resolution of disease was defined based on
normalization of MRI and CSF findings and resolution of cranial and caudal
segment disease with ocular imaging. Treatment with GS-441524 shows clinical
efficacy and may result in clearance and long-term resolution of neurological
FIP. Dosages required for CNS disease may be higher than those used for
nonneurological FIP.
© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley
Periodicals, Inc. on behalf of the American College of Veterinary Internal
Medicine.
DOI: 10.1111/jvim.15780
PMCID: PMC7379040
PMID: 32441826 [Indexed for MEDLINE]
Conflict of interest statement: Authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32220667 | 1. Res Vet Sci. 2020 Jun;130:222-229. doi: 10.1016/j.rvsc.2020.02.012. Epub 2020
Feb 19.
Oral Mutian®X stopped faecal feline coronavirus shedding by naturally infected
cats.
Addie DD(1), Curran S(2), Bellini F(3), Crowe B(3), Sheehan E(4), Ukrainchuk
L(5), Decaro N(6).
Author information:
(1)Maison Zabal, 64470, Etchebar, France. Electronic address:
draddie@catvirus.com.
(2)Baker Street Ragdoll Cats, Liverpool, UK.
(3)Uxbridge, Middlesex, UK.
(4)Spinney Lodge Vets, Northampton, UK. Electronic address:
Emily.Sheehan@Spinneylodgevets.com.
(5)Carbon Valley Animal Hospital, 101 W. Grant Ave, Firestone, CO 80520, USA.
(6)Department of Veterinary Medicine, University of Bari, Strada Provinciale per
Casamassima, km 3, 70010, Valenzano (Bari), Bari, Italy. Electronic address:
nicola.decaro@uniba.it.
Feline coronavirus (FCoV) is common among cats living indoors in groups. In
about 10% of infected cats, a potentially lethal disease, feline infectious
peritonitis (FIP) occurs. Virus transmission is faecal-oral. Mutian® Xraphconn
(Mutian X) is a product marketed to treat cats with FIP but is also being used
to stop virus shedding, although no clear guidelines exist for its use for this
purpose. The aim of this study was to establish the minimum dose and treatment
duration required to ensure viral clearance from the faeces of asymptomatic
virus-shedding cats. In five multicat households, 29 cats naturally infected
with FCoV and actively shedding virus in the faeces were given Mutian X pills.
Virus shedding was monitored using reverse-transcription quantitative polymerase
chain reaction (RT-qPCR) controlled for faecal inhibitors to ensure sensitivity.
Mutian X given orally cleared the virus in 29 cats; although four cats required
a repeated course to finally stop virus shedding. A dose of 4 mg/kg q24 h for
four days was found to be the optimal treatment protocol: 2 mg/kg cleared only
80% of cats. Post-treatment using a sensitive RT-qPCR test was essential to
ensure that virus clearance had been achieved, since failure to clear even one
cat can result in re-infection of the others. Records of virus shedding by cats
before treatment provided a retrospective control: significantly more cats
stopped shedding virus after Mutian X than recovered from infection during the
control period (p < .00001). This is the first report of the successful
elimination of faecal FCoV shedding in chronically infected cats.
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.rvsc.2020.02.012
PMCID: PMC7102653
PMID: 32220667 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest There is no
conflict of interest of any authors in relation to the submission. |