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http://www.ncbi.nlm.nih.gov/pubmed/22033927 | 1. J Biol Chem. 2011 Dec 9;286(49):42099-42104. doi: 10.1074/jbc.C111.294462.
Epub 2011 Oct 27.
Crystal structure of the chromodomain helicase DNA-binding protein 1 (Chd1)
DNA-binding domain in complex with DNA.
Sharma A(1), Jenkins KR(1), Héroux A(2), Bowman GD(3).
Author information:
(1)Thomas C. Jenkins Department of Biophysics, Johns Hopkins University,
Baltimore, Maryland 21218.
(2)Biology Department, Brookhaven National Laboratory, Upton, New York 11973.
(3)Thomas C. Jenkins Department of Biophysics, Johns Hopkins University,
Baltimore, Maryland 21218. Electronic address: gdbowman@jhu.edu.
Chromatin remodelers are ATP-dependent machines that dynamically alter the
chromatin packaging of eukaryotic genomes by assembling, sliding, and displacing
nucleosomes. The Chd1 chromatin remodeler possesses a C-terminal DNA-binding
domain that is required for efficient nucleosome sliding and believed to be
essential for sensing the length of DNA flanking the nucleosome core. The
structure of the Chd1 DNA-binding domain was recently shown to consist of a SANT
and SLIDE domain, analogous to the DNA-binding domain of the ISWI family, yet
the details of how Chd1 recognized DNA were not known. Here we present the
crystal structure of the Saccharomyces cerevisiae Chd1 DNA-binding domain in
complex with a DNA duplex. The bound DNA duplex is straight, consistent with the
preference exhibited by the Chd1 DNA-binding domain for extranucleosomal DNA.
Comparison of this structure with the recently solved ISW1a DNA-binding domain
bound to DNA reveals that DNA lays across each protein at a distinct angle, yet
contacts similar surfaces on the SANT and SLIDE domains. In contrast to the
minor groove binding seen for Isw1 and predicted for Chd1, the SLIDE domain of
the Chd1 DNA-binding domain contacts the DNA major groove. The majority of
direct contacts with the phosphate backbone occur only on one DNA strand,
suggesting that Chd1 may not strongly discriminate between major and minor
grooves.
DOI: 10.1074/jbc.C111.294462
PMCID: PMC3234930
PMID: 22033927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21726377 | 1. Mol Plant Pathol. 2011 Oct;12(8):772-85. doi:
10.1111/j.1364-3703.2011.00710.x. Epub 2011 Mar 29.
Evidence for involvement of Dicer-like, Argonaute and histone deacetylase
proteins in gene silencing in Phytophthora infestans.
Vetukuri RR(1), Avrova AO, Grenville-Briggs LJ, Van West P, Söderbom F, Savenkov
EI, Whisson SC, Dixelius C.
Author information:
(1)Department of Plant Biology and Forest Genetics, Uppsala BioCenter, SLU, 750
07 Uppsala, Sweden. ramesh.vetukuri@slu.se
Gene silencing may have a direct or indirect impact on many biological processes
in eukaryotic cells, and is a useful tool for the determination of the roles of
specific genes. In this article, we report silencing in Phytophthora infestans,
an oomycete pathogen of potato and tomato. Gene silencing is known to occur in
P. infestans, but its genetic basis has yet to be determined. Genes encoding the
major components of the RNA interference (RNAi) pathway, Dicer-like (Pidcl1),
Argonaute (Piago1-5) and RNA-directed RNA polymerase (Pirdr1), were identified
in the P. infestans genome by comparative genomics, together with families of
other genes potentially involved in gene silencing, such as histone
deacetylases, histone methyltransferases, DEAD helicases, chromodomain proteins
and a class 1 RNaseIII. Real-time reverse transcription-polymerase chain
reaction demonstrated transcript accumulation for all candidate genes throughout
the asexual lifecycle and plant infection, but at different levels of mRNA
abundance. A functional assay was developed in which silencing of the
sporulation-associated Picdc14 gene was released by the treatment of protoplasts
with in vitro-synthesized double-stranded RNAs homologous to Pidcl1, Piago1/2
and histone deacetylase Pihda1. These results suggest that the components of
gene silencing, namely Dicer-like, Argonaute and histone deacetylase, are
functional in P. infestans. Our data demonstrate that this oomycete possesses
canonical gene silencing pathways similar to those of other eukaryotes.
© 2011 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2011 BSPP AND BLACKWELL
PUBLISHING LTD.
DOI: 10.1111/j.1364-3703.2011.00710.x
PMCID: PMC6640358
PMID: 21726377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23071088 | 1. Mol Cell Biol. 2012 Dec;32(24):5078-88. doi: 10.1128/MCB.00819-12. Epub 2012
Oct 15.
MBD2 and multiple domains of CHD4 are required for transcriptional repression by
Mi-2/NuRD complexes.
Ramírez J(1), Dege C, Kutateladze TG, Hagman J.
Author information:
(1)Integrated Department of Immunology, National Jewish Health, Denver,
Colorado, USA.
Mi-2/nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complexes
are important regulators of chromatin structure and DNA accessibility. We
examined requirements for individual domains of chromodomain helicase
DNA-binding protein 4 (CHD4), a core catalytic component of NuRD complexes, as
well as the NuRD subunit methyl-binding domain protein 2 (MBD2) and methylated
DNA, for NuRD function in the context of tissue-specific transcription. By
itself, loss of NuRD activity is not sufficient for transcriptional activation.
However, NuRD complexes greatly reduce activation of the B cell-specific mb-1
(Cd79a) gene by the transcription factors EBF1 and Pax5. Using our B cell model
system, we determined that the two chromodomains and ATPase/helicase and
C-terminal domains (CTD) of CHD4 are all necessary for repression of mb-1
promoters by NuRD. All of these domains except the CTD are required for
efficient association of CHD4 with mb-1 promoter chromatin. Loss of MBD2
expression or of DNA methylation impaired association of CHD4 with mb-1 promoter
chromatin and enhanced its transcription. We conclude that repressive functions
of MBD2-containing NuRD complexes are dependent on cooperative interactions
between the major domains of CHD4 with histones and DNA and on binding of
methylated DNA by MBD2.
DOI: 10.1128/MCB.00819-12
PMCID: PMC3510529
PMID: 23071088 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21224386 | 1. J Biol Chem. 2011 Mar 18;286(11):9308-20. doi: 10.1074/jbc.M110.143198. Epub
2011 Jan 11.
Role of Swi6/HP1 self-association-mediated recruitment of Clr4/Suv39 in
establishment and maintenance of heterochromatin in fission yeast.
Haldar S(1), Saini A, Nanda JS, Saini S, Singh J.
Author information:
(1)Institute of Microbial Technology, Sector 39A, Chandigarh 160036, India.
Swi6/HP1, an evolutionarily conserved protein, is critical for heterochromatin
assembly in fission yeast and higher eukaryotes. In fission yeast, histone
deacetylation by histone deacetylases is thought to be followed by H3-Lys-9
methylation by the histone methyltransferase Clr4/Suv39H1. H3-Lys-9-Me2
interacts with the chromodomain of Swi6/HP1. Swi6/HP1 is thought to act
downstream of Clr4/Suv39, and further self-association of Swi6/HP1 is assumed to
stabilize the heterochromatin structure. Here, we show that the
self-association-defective mutant of Swi6 does not interact with Clr4. It not
only fails to localize to heterochromatin loci but also interferes with
heterochromatic localization of H3-Lys-9-Me2 (and thereby Clr4) and the
endogenous Swi6 in a dominant negative manner. Thus, self-association of
Swi6/HP1 helps in binding to and recruitment of Clr4 and thereby in
establishment and maintenance of heterochromatin by a concerted rather than a
sequential mechanism.
DOI: 10.1074/jbc.M110.143198
PMCID: PMC3058978
PMID: 21224386 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21358630 | 1. Nat Struct Mol Biol. 2011 Mar;18(3):337-44. doi: 10.1038/nsmb.1995. Epub 2011
Feb 27.
Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative
exons.
Saint-André V(1), Batsché E, Rachez C, Muchardt C.
Author information:
(1)Institut Pasteur, Département de Biologie du Développement, Unité de
Régulation Epigénétique, Paris, France.
Pre-messenger RNAs (pre-mRNAs) maturation is initiated cotranscriptionally. It
is therefore conceivable that chromatin-borne information participates in
alternative splicing. Here we find that elevated levels of trimethylation of
histone H3 on Lys9 (H3K9me3) are a characteristic of the alternative exons of
several genes including CD44. On this gene the chromodomain protein HP1γ,
frequently defined as a transcriptional repressor, facilitates inclusion of the
alternative exons via a mechanism involving decreased RNA polymerase II
elongation rate. In addition, accumulation of HP1γ on the variant region of the
CD44 gene stabilizes association of the pre-mRNA with the chromatin. Altogether,
our data provide evidence for localized histone modifications impacting
alternative splicing. They further implicate HP1γ as a possible bridging
molecule between the chromatin and the maturating mRNA, with a general impact on
splicing decisions.
DOI: 10.1038/nsmb.1995
PMID: 21358630 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10908644 | 1. Mol Biol Evol. 2000 Aug;17(8):1240-50. doi:
10.1093/oxfordjournals.molbev.a026407.
Origin and evolution of the regulatory gene male-specific lethal-3.
Marín I(1), Baker BS.
Author information:
(1)Department of Biological Sciences, Stanford University, CA, USA.
ignacio.marin@uv.es
Dosage compensation in Drosophila is mediated by genes known as "male-specific
lethals" (msls). Several msls, including male-specific lethal-3 (msl-3), encode
proteins of unknown function. We cloned the Drosophila virilis msl-3 gene. Using
the information provided by the sequences of the Drosophila melanogaster and D.
virilis genes, we found that sequences of other species can be aligned along
their entire lengths with msl-3. Among them, there are genes in yeasts (the
Schizosaccharomyces pombe Alp13 gene, as well as a putative Alp13 homolog, found
in Saccharomyces cerevisae) and in mammals (MRG15 and MSL3L1 and their
relatives) plus uncharacterized sequences of the nematode Caenorhabditis elegans
and the plants Arabidopsis thaliana, Lycopersicon esculentum, and Zea mays. A
second Drosophila gene of this family has also been found. It is thus likely
that msl-3-like genes are present in all eukaryotes. Phylogenetic analyses
suggest that msl-3 is orthologous to the mammalian MSL3L1 genes, while the
second Drosophila melanogaster gene (which we have called Dm MRG15) is
orthologous to mammalian MRG15. These analyses also suggest that the msl-3/MRG15
duplication occurred after the fungus/animal split, while an independent
duplication occurred in plants. The proteins encoded by these genes have similar
structures, including a putative chromodomain close to their N-terminal end and
a putative leucine zipper at their C-terminus. The possible functional roles of
these proteins are discussed.
DOI: 10.1093/oxfordjournals.molbev.a026407
PMID: 10908644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11500496 | 1. J Biol Chem. 2001 Oct 19;276(42):39171-8. doi: 10.1074/jbc.M103435200. Epub
2001 Aug 10.
MRG15 activates the B-myb promoter through formation of a nuclear complex with
the retinoblastoma protein and the novel protein PAM14.
Leung JK(1), Berube N, Venable S, Ahmed S, Timchenko N, Pereira-Smith OM.
Author information:
(1)Roy M. and Phyllis Gough Huffington Center on Aging, Baylor College of
Medicine, Houston, Texas 77030-3498, USA. jl691785@bcm.tmc.edu
The MORF4-Related Gene on chromosome 15 (MRG15) is a member of a novel family of
genes originally identified in studies to reveal cell senescence-inducing
factors. MRG15 contains several predicted protein motifs, including a nuclear
localization signal, a helix-loop-helix region, a leucine zipper, and a
chromodomain. These motifs are commonly associated with transcription factors,
suggesting that MRG15 may likewise function as a transcriptional regulator. To
examine the potential function(s) of MRG15, we sought to identify cellular
factors associated with this MRG family member. In this regard, we have found
that both the retinoblastoma tumor suppressor (Rb) and a novel nuclear protein
PAM14 (Protein Associated with MRG, 14 kDa) specifically associate with MRG15.
We have further demonstrated that these interactions require the
helix-loop-helix and leucine zipper domains of MRG15. Interestingly we have
found all three proteins present in a multiprotein complex, suggesting that at
least some of their functions may be interdependent. Although the functions of
PAM14 have yet to be elucidated, Rb has several well characterized activities,
including repression of E2F-activated promoters such as that of B-myb.
Significantly we have demonstrated that MRG15 blocks the Rb-induced repression
of this promoter, leading to B-myb promoter activation. Collectively these
results suggest that MRG15 regulates transcription through interactions with a
cellular protein complex containing Rb and PAM14.
DOI: 10.1074/jbc.M103435200
PMID: 11500496 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21447119 | 1. Histopathology. 2011 Apr;58(5):660-8. doi: 10.1111/j.1365-2559.2011.03819.x.
Epub 2011 Mar 30.
Genetic and expressional alterations of CHD genes in gastric and colorectal
cancers.
Kim MS(1), Chung NG, Kang MR, Yoo NJ, Lee SH.
Author information:
(1)Department of Pathology, College of Medicine, The Catholic University of
Korea, Seoul, Korea.
AIMS: Chromodomain helicase DNA-binding protein (CHD) is a regulator of the
chromatin remodelling process. The aim was to determine the CHD1, CHD2, CHD3,
CHD4, CHD7, CHD8 and CHD9 mutational status of mononucleotide repeats in gastric
and colorectal cancers with microsatellite instability (MSI).
METHODS AND RESULTS: The repeats were determined in 28 gastric cancers (GCs)
with high MSI (MSI-H), 45 GCs with low MSI (MSI-L)/stable MSI (MSS), 35
colorectal cancers (CRCs) with MSI-H and 45 CRCs with MSI-L/MSS by single-strand
conformation polymorphism analysis. CHD4 and CHD8 expression was also examined
in GCs and CRCs by immunohistochemistry. CHD1, CHD2, CHD3, CHD4, CHD7, CHD8 and
CHD9 mutations were found in five, 19, three, five, seven, 10 and seven cancers,
respectively. They were detected in MSI-H cancers, but not in MSI-L/MSS cancers.
Loss of CHD4 expression was observed in 56.4% of the GCs and 55.7% of the CRCs,
and loss of CHD8 was observed in 35.7% of the GCs and 28.6% of the CRCs. The
cancers with CHD4 and CHD8 mutations showed loss of CHD4 and CHD8 expression,
respectively.
CONCLUSIONS: Frameshift mutation and loss of expression of CHD genes are common
in GCs and CRCs with MSI-H.These alterations might contribute to cancer
pathogenesis by deregulating CHD-mediated chromatin remodelling.
© 2011 Blackwell Publishing Limited.
DOI: 10.1111/j.1365-2559.2011.03819.x
PMID: 21447119 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22646239 | 1. Genes Cells. 2012 Jul;17(7):536-47. doi: 10.1111/j.1365-2443.2012.01606.x.
Epub 2012 May 31.
Identification of CHD7S as a novel splicing variant of CHD7 with functions
similar and antagonistic to those of the full-length CHD7L.
Kita Y(1), Nishiyama M, Nakayama KI.
Author information:
(1)Department of Molecular and Cellular Biology, Medical Institute of
Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582,
Japan.
CHD7 is one of the nine members of the chromodomain helicase DNA-binding family
of ATP-dependent chromatin remodeling enzymes. Mutations in CHD7 give rise to
CHARGE syndrome, a human condition characterized by malformation of various
organs. We have now identified a novel transcript of CHD7 that is generated by
alternative splicing of exon 6. The protein encoded by this variant transcript
(termed CHD7S) lacks one of the two chromodomains as well as the helicase/ATPase
domain, DNA-binding domain and BRK domains of the full-length protein (CHD7L).
CHD7S was found to localize specifically to the nucleolus in a manner dependent
on a nucleolar localization signal. Over-expression of CHD7S, as well as that of
CHD7L, resulted in an increase in 45S precursor rRNA production. Conversely,
depletion of both CHD7S and CHD7L by RNA interference inhibited both 45S
precursor rRNA production and cell proliferation to a greater extent than did
depletion of CHD7L alone. Furthermore, we found that, like CHD7L, CHD7S binds to
Sox2 in the nucleoplasm. Unexpectedly, however, whereas over-expression of CHD7L
promoted Sox2-mediated transcriptional regulation, over-expression of CHD7S
suppressed it. These results indicate that CHD7S functions cooperatively or
antagonistically with CHD7L in the nucleolus and nucleoplasm, respectively.
© 2012 The Authors Journal compilation © 2012 by the Molecular Biology Society
of Japan/Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-2443.2012.01606.x
PMID: 22646239 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20308527 | 1. Mol Endocrinol. 2010 Jun;24(6):1165-74. doi: 10.1210/me.2009-0421. Epub 2010
Mar 22.
Regulation of androgen-responsive transcription by the chromatin remodeling
factor CHD8.
Menon T(1), Yates JA, Bochar DA.
Author information:
(1)The Department of Biological Chemistry, University of Michigan, Ann Arbor,
Michigan 48109-0606, USA.
The androgen receptor (AR) mediates the effect of androgens through its
transcriptional function during both normal prostate development and in the
emergence and progression of prostate cancer. AR is known to assemble
coactivator complexes at target promoters to facilitate transcriptional
activation in response to androgens. Here we identify the ATP-dependent
chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8)
as a novel coregulator of androgen-responsive transcription. We demonstrate that
CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to
the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction
of CHD8 levels by small interfering RNA treatment severely diminishes
androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the
recruitment of AR to the TMPRSS2 promoter in response to androgen treatment
requires CHD8. Finally, CHD8 facilitates androgen-stimulated proliferation of
LNCaP cells, emphasizing the physiological importance of CHD8. Taken together,
we present evidence of a functional role for CHD8 in AR-mediated transcriptional
regulation of target genes.
DOI: 10.1210/me.2009-0421
PMCID: PMC2875808
PMID: 20308527 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16339723 | 1. Eukaryot Cell. 2005 Dec;4(12):2057-65. doi: 10.1128/EC.4.12.2057-2065.2005.
MYST family histone acetyltransferases in the protozoan parasite Toxoplasma
gondii.
Smith AT(1), Tucker-Samaras SD, Fairlamb AH, Sullivan WJ Jr.
Author information:
(1)Department of Pharmacology and Toxicology, Indiana University School of
Medicine, 635 Barnhill Drive, Medical Sciences Building Room A-525,
Indianapolis, IN 46202-5120, USA.
The restructuring of chromatin precedes tightly regulated events such as DNA
transcription, replication, and repair. One type of chromatin remodeling
involves the covalent modification of nucleosomes by histone acetyltransferase
(HAT) complexes. The observation that apicidin exerts antiprotozoal activity by
targeting a histone deacetyltransferase has prompted our search for more
components of the histone modifying machinery in parasitic protozoa. We have
previously identified GNAT family HATs in the opportunistic pathogen Toxoplasma
gondii and now describe the first MYST (named for members MOZ, Ybf2/Sas3, Sas2,
and Tip60) family HATs in apicomplexa (TgMYST-A and -B). The TgMYST-A genomic
locus is singular and generates a approximately 3.5-kb transcript that can
encode two proteins of 411 or 471 amino acids. TgMYST-B mRNA is approximately
7.0 kb and encodes a second MYST homologue. In addition to the canonical MYST
HAT catalytic domain, both TgMYST-A and -B possess an atypical C2HC zinc finger
and a chromodomain. Recombinant TgMYST-A exhibits a predilection to acetylate
histone H4 in vitro at lysines 5, 8, 12, and 16. Antibody generated to TgMYST-A
reveals that both the long and short (predominant) versions are present in the
nucleus and are also plentiful in the cytoplasm. Moreover, both TgMYST-A forms
are far more abundant in rapidly replicating parasites (tachyzoites) than
encysted parasites (bradyzoites). A bioinformatics survey of the Toxoplasma
genome reveals numerous homologues known to operate in native MYST complexes.
The characterization of TgMYST HATs represents another important step toward
understanding the regulation of gene expression in pathogenic protozoa and
provides evolutionary insight into how these processes operate in eukaryotic
cells in general.
DOI: 10.1128/EC.4.12.2057-2065.2005
PMCID: PMC1317489
PMID: 16339723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22715096 | 1. J Biol Chem. 2012 Aug 10;287(33):28122-31. doi: 10.1074/jbc.M112.368381. Epub
2012 Jun 18.
Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473
phosphorylation regulates heterochromatin protein 1β (HP1-β) mobilization and
DNA repair in heterochromatin.
Bolderson E(1), Savage KI, Mahen R, Pisupati V, Graham ME, Richard DJ, Robinson
PJ, Venkitaraman AR, Khanna KK.
Author information:
(1)Signal Transduction Laboratory, Queensland Institute of Medical Research,
Brisbane, Queensland 4029, Australia.
The DNA damage response encompasses a complex series of signaling pathways that
function to regulate and facilitate the repair of damaged DNA. Recent studies
have shown that the repair of transcriptionally inactive chromatin, named
heterochromatin, is dependent upon the phosphorylation of the co-repressor,
Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia
telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to
regulate the rigid structure of heterochromatin by recruiting histone-modifying
enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3.
Here, we have characterized a phosphorylation site in the HP1-binding domain of
KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase
Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular
sensitivity to DNA-damaging agents and led to defective repair of DNA
double-strand breaks in heterochromatin. In addition, cells expressing S473A
also displayed defective mobilization of the HP1-β chromodomain protein. The DNA
repair defect observed in cells expressing S473A was alleviated by depletion of
HP1-β, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the
mobilization of HP1-β from heterochromatin and subsequent DNA repair. These
results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via
Chk2-regulated HP1-β exchange from heterochromatin, promoting DNA repair.
DOI: 10.1074/jbc.M112.368381
PMCID: PMC3431694
PMID: 22715096 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21448134 | 1. EMBO J. 2011 Apr 20;30(8):1473-84. doi: 10.1038/emboj.2011.91. Epub 2011 Mar
29.
KDM5B regulates embryonic stem cell self-renewal and represses cryptic
intragenic transcription.
Xie L(1), Pelz C, Wang W, Bashar A, Varlamova O, Shadle S, Impey S.
Author information:
(1)Oregon Stem Cell Center, Department of Pediatrics, Department of Cell and
Developmental Biology, Oregon Health and Science University, Portland, OR, USA.
Comment in
EMBO J. 2011 Apr 20;30(8):1420-1. doi: 10.1038/emboj.2011.99.
Although regulation of histone methylation is believed to contribute to
embryonic stem cell (ESC) self-renewal, the mechanisms remain obscure. We show
here that the histone H3 trimethyl lysine 4 (H3K4me3) demethylase, KDM5B, is a
downstream Nanog target and critical for ESC self-renewal. Although KDM5B is
believed to function as a promoter-bound repressor, we find that it
paradoxically functions as an activator of a gene network associated with
self-renewal. ChIP-Seq reveals that KDM5B is predominantly targeted to
intragenic regions and that it is recruited to H3K36me3 via an interaction with
the chromodomain protein MRG15. Depletion of KDM5B or MRG15 increases intragenic
H3K4me3, increases cryptic intragenic transcription, and inhibits
transcriptional elongation of KDM5B target genes. We propose that KDM5B
activates self-renewal-associated gene expression by repressing cryptic
initiation and maintaining an H3K4me3 gradient important for productive
transcriptional elongation.
DOI: 10.1038/emboj.2011.91
PMCID: PMC3102288
PMID: 21448134 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/22135401 | 1. Circ Cardiovasc Imaging. 2012 Jan;5(1):78-85. doi:
10.1161/CIRCIMAGING.111.963819. Epub 2011 Dec 1.
Intermediate-signal-intensity late gadolinium enhancement predicts ventricular
tachyarrhythmias in patients with hypertrophic cardiomyopathy.
Appelbaum E(1), Maron BJ, Adabag S, Hauser TH, Lesser JR, Haas TS, Riley AB,
Harrigan CJ, Delling FN, Udelson JE, Gibson CM, Manning WJ, Maron MS.
Author information:
(1)PERFUSE Core Laboratory and Data Coordinating Center, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA 02215, USA.
eappelba@bidmc.harvard.edu
Comment in
Circ Cardiovasc Imaging. 2012 Jan;5(1):2-5. doi:
10.1161/CIRCIMAGING.111.971135.
Circ Cardiovasc Imaging. 2012 May 1;5(3):e38. doi:
10.1161/CIRCIMAGING.112.973602.
JACC Cardiovasc Imaging. 2013 Nov;6(11):1216-8. doi:
10.1016/j.jcmg.2013.04.016.
BACKGROUND: In hypertrophic cardiomyopathy (HCM), the arrhythmic potential
associated with a variety of left ventricular myocardial signal intensities
evident on contrast-enhanced cardiovascular magnetic resonance with late
gadolinium enhancement (LGE) is unresolved.
METHODS AND RESULTS: In 145 HCM patients (43±15 years old), visually identified
areas of LGE in left ventricle were analyzed quantitatively for intermediate (≥4
but <6 SD) and high (≥6 SD above the mean signal intensity of normal myocardium)
LGE signal intensity (LGE-SI). Ambulatory Holter ECGs were obtained within
7.8±8.3 weeks of cardiovascular magnetic resonance. HCM patients with
nonsustained ventricular tachycardia, ventricular couplets, and premature
ventricular contractions showed greater amounts of intermediate LGE-SI (17±7
versus 10±10 g, 16±10 versus 10±11 g, and 13±8 versus 10±13 g, respectively;
P=0.003 to <0.001) and greater amounts of high LGE-SI (15±6 versus 10±8 g, 14±9
versus 10±12 g, and 12±7 versus 10±8 g, respectively; P=0.02-0.003) than
patients without these arrhythmias. In HCM patients with either nonsustained
ventricular tachycardia, couplets, or premature ventricular contractions, the
extent of intermediate LGE-SI exceeded that of high LGE-SI (17±7 versus 15±6 g,
16±10 versus 14±9 g, and 13±8 versus 12±7 g, respectively; P=0.01-0.04). In
addition, the receiver operating characteristic area under the curve established
intermediate LGE-SI as a better discriminator of patients with nonsustained
ventricular tachycardia than was high LGE-SI, with 7 additional patients with
this arrhythmia identified.
CONCLUSIONS: In patients with HCM, intermediate LGE-SI is a better predictor of
ventricular tachyarrhythmias (including nonsustained ventricular tachycardia, a
risk factor for sudden death) than is high LGE-SI. Longitudinal studies in
larger HCM cohorts are justified to define the independent prognostic impact of
intermediate LGE-SI.
DOI: 10.1161/CIRCIMAGING.111.963819
PMID: 22135401 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23193262 | 1. Nucleic Acids Res. 2013 Jan;41(Database issue):D700-5. doi:
10.1093/nar/gks1156. Epub 2012 Nov 27.
Genomicus: five genome browsers for comparative genomics in eukaryota.
Louis A(1), Muffato M, Roest Crollius H.
Author information:
(1)Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris,
France. alouis@biologie.ens.fr
Genomicus (http://www.dyogen.ens.fr/genomicus/) is a database and an online tool
that allows easy comparative genomic visualization in >150 eukaryote genomes. It
provides a way to explore spatial information related to gene organization
within and between genomes and temporal relationships related to gene and genome
evolution. For the specific vertebrate phylum, it also provides access to
ancestral gene order reconstructions and conserved non-coding elements
information. We extended the Genomicus database originally dedicated to
vertebrate to four new clades, including plants, non-vertebrate metazoa,
protists and fungi. This visualization tool allows evolutionary phylogenomics
analysis and exploration. Here, we describe the graphical modules of Genomicus
and show how it is capable of revealing differential gene loss and gain,
segmental or genome duplications and study the evolution of a locus through
homology relationships.
DOI: 10.1093/nar/gks1156
PMCID: PMC3531091
PMID: 23193262 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12224720 | 1. Tex Heart Inst J. 2002;29(3):176-80.
Magnetic resonance imaging of myocardial fibrosis in hypertrophic
cardiomyopathy.
Wilson JM(1), Villareal RP, Hariharan R, Massumi A, Muthupillai R, Flamm SD.
Author information:
(1)Department of Radiology/Cardiovascular Magnetic Resonance Imaging, St Luke's
Episcopal Hospital and Texas Heart Institute, Houston, USA.
Myocardial fibrosis can occur in patients who have hypertrophic cardiomyopathy
in the absence of epicardial coronary disease. In such patients, myocardial
fibrosis has been linked to a poorer prognosis than in those without fibrosis.
Gadolinium-DTPA delayed-enhancement magnetic resonance imaging (de-MRI)
accurately identifies regions of myocardial fibrosis. We used de-MRI to screen
for myocardial fibrosis in 8 patients with nonobstructive hypertrophic
cardiomyopathy that had been diagnosed by 2-dimensional echocardiography. After
localization of the heart and acquisition of electrocardiographically gated cine
images, gadolinium-DTPA (0.2 mmol/kg) was administered to the patient. Fifteen
minutes later, de-MRI images were obtained using a T1-weighted,
inversion-recovery fast, low-angle shot sequence. Images were gated to
end-diastole and obtained during a single breath-hold. The inversion time was
modified iteratively to obtain maximal nulling of the signal from the
ventricular myocardium. Regions of myocardium with abnormally high signals
(>300% of remote normal myocardium) were designated as fibrotic. Eight patients
with hypertrophic cardiomyopathy underwent de-MRI. The mean age was 52 years,
the mean left ventricular mass was 201 grams, and the mean ejection fraction was
0.68. In the 6 patients with recent clinical deterioration, de-MRI showed
clearly delineated areas of myocardial fibrosis; no such areas were seen in the
2 asymptomatic patients. We conclude that patients with symptomatic hypertrophic
cardiomyopathy display regions of abnormal signal intensity on de-MRI that
likely represent fibrosis. This technique may provide useful information in the
evaluation of such patients and warrants further study.
PMCID: PMC124756
PMID: 12224720 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21047797 | 1. J Biol Chem. 2011 Jan 7;286(1):521-9. doi: 10.1074/jbc.M110.191411. Epub 2010
Nov 3.
Recognition and specificity determinants of the human cbx chromodomains.
Kaustov L(1), Ouyang H, Amaya M, Lemak A, Nady N, Duan S, Wasney GA, Li Z,
Vedadi M, Schapira M, Min J, Arrowsmith CH.
Author information:
(1)Ontario Cancer Institute, Campbell Family Cancer Research Institute and
Department of Medical Biophysics, University of Toronto, Ontario M5G 1L7,
Canada.
The eight mammalian Cbx proteins are chromodomain-containing proteins involved
in regulation of heterochromatin, gene expression, and developmental programs.
They are evolutionarily related to the Drosophila HP1 (dHP1) and Pc (dPc)
proteins that are key components of chromatin-associated complexes capable of
recognizing repressive marks such as trimethylated Lys-9 and Lys-27,
respectively, on histone H3. However, the binding specificity and function of
the human homologs, Cbx1-8, remain unclear. To this end we employed structural,
biophysical, and mutagenic approaches to characterize the molecular determinants
of sequence contextual methyllysine binding to human Cbx1-8 proteins. Although
all three human HP1 homologs (Cbx1, -3, -5) replicate the structural and binding
features of their dHP counterparts, the five Pc homologs (Cbx2, -4, -6, -7, -8)
bind with lower affinity to H3K9me3 or H3K27me3 peptides and are unable to
distinguish between these two marks. Additionally, peptide permutation arrays
revealed a greater sequence tolerance within the Pc family and suggest
alternative nonhistone sequences as potential binding targets for this class of
chromodomains. Our structures explain the divergence of peptide binding
selectivity in the Pc subfamily and highlight previously unrecognized features
of the chromodomain that influence binding and specificity.
DOI: 10.1074/jbc.M110.191411
PMCID: PMC3013012
PMID: 21047797 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22498326 | 1. JACC Cardiovasc Imaging. 2012 Apr;5(4):370-7. doi: 10.1016/j.jcmg.2011.11.021.
Prognostic value of late gadolinium enhancement in clinical outcomes for
hypertrophic cardiomyopathy.
Green JJ(1), Berger JS, Kramer CM, Salerno M.
Author information:
(1)Department of Medicine, Cardiology Division, University of Virginia,
Charlottesville, Virginia 22908, USA.
Comment in
JACC Cardiovasc Imaging. 2012 Jul;5(7):761-2; author reply 762-3. doi:
10.1016/j.jcmg.2012.05.004.
OBJECTIVES: The objective of this study was to perform a systematic review and
meta-analysis of the predictive value of late gadolinium enhancement (LGE)
cardiac magnetic resonance (CMR) for future cardiovascular events and death in
hypertrophic cardiomyopathy (HCM).
BACKGROUND: The utility of LGE for detecting myocardial fibrosis is well
established. The prognostic value of LGE in HCM has been described in several
studies, but controversy exists given the limited power of these studies to
predict future events.
METHODS: We searched multiple databases including PubMed for studies of LGE in
HCM that reported selected clinical outcomes (cardiovascular mortality, sudden
cardiac death [SCD], aborted SCD, and heart failure death). We performed a
systematic review of the literature and meta-analysis to determine pooled odds
ratios for these clinical events.
RESULTS: Four studies evaluated 1,063 patients over an average follow-up of 3.1
years. The pooled prevalence of LGE was 60%. The pooled odds ratios (OR)
demonstrate that LGE by CMR correlated with cardiac death (pooled OR: 2.92, 95%
confidence interval [CI]: 1.01 to 8.42; p = 0.047), heart failure death (pooled
OR: 5.68, 95% CI: 1.04 to 31.07; p = 0.045), and all-cause mortality (pooled OR:
4.46, 95% CI: 1.53 to 13.01; p = 0.006), and showed a trend toward significance
for predicting sudden death/aborted sudden death (pooled OR: 2.39, 95% CI: 0.87
to 6.58; p = 0.091).
CONCLUSIONS: Late gadolinium enhancement by CMR has prognostic value in
predicting adverse cardiovascular events among HCM patients. There are
significant relationships between LGE and cardiovascular mortality, heart
failure death, and all-cause mortality in HCM. Additionally, LGE and SCD/aborted
SCD displayed a trend toward significance. The assessment of LGE by CMR has the
potential to provide important information to improve risk stratification in HCM
in clinical practice.
Copyright © 2012 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jcmg.2011.11.021
PMID: 22498326 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22348519 | 1. J Cardiovasc Magn Reson. 2012 Feb 20;14(1):17. doi: 10.1186/1532-429X-14-17.
The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic
resonance.
Noureldin RA(1), Liu S, Nacif MS, Judge DP, Halushka MK, Abraham TP, Ho C,
Bluemke DA.
Author information:
(1)Radiology and Imaging Sciences, National Institutes of Health Clinical
Center, Bethesda, MD, USA.
Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the
heart. HCM is characterized by a wide range of clinical expression, ranging from
asymptomatic mutation carriers to sudden cardiac death as the first
manifestation of the disease. Over 1000 mutations have been identified,
classically in genes encoding sarcomeric proteins. Noninvasive imaging is
central to the diagnosis of HCM and cardiovascular magnetic resonance (CMR) is
increasingly used to characterize morphologic, functional and tissue
abnormalities associated with HCM. The purpose of this review is to provide an
overview of the clinical, pathological and imaging features relevant to
understanding the diagnosis of HCM. The early and overt phenotypic expression of
disease that may be identified by CMR is reviewed. Diastolic dysfunction may be
an early marker of the disease, present in mutation carriers prior to the
development of left ventricular hypertrophy (LVH). Late gadolinium enhancement
by CMR is present in approximately 60% of HCM patients with LVH and may provide
novel information regarding risk stratification in HCM. It is likely that
integrating genetic advances with enhanced phenotypic characterization of HCM
with novel CMR techniques will importantly improve our understanding of this
complex disease.
DOI: 10.1186/1532-429X-14-17
PMCID: PMC3309929
PMID: 22348519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23020525 | 1. BMC Cancer. 2012 Sep 29;12:437. doi: 10.1186/1471-2407-12-437.
CHD1L protein is overexpressed in human ovarian carcinomas and is a novel
predictive biomarker for patients survival.
He WP(1), Zhou J, Cai MY, Xiao XS, Liao YJ, Kung HF, Guan XY, Xie D, Yang GF.
Author information:
(1)Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen
University, No, 78, Zhongshan Road II, 510080 Guangzhou, China.
BACKGROUND: Our recent studies suggested that the chromodomain helicase DNA
binding protein 1-like (CHD1L) gene plays an oncogenic role in human
hepatocellular carcinoma. However, the status of CHD1L protein expression in
ovarian cancer and its clinical/prognostic significance are obscure.
METHODS: In this study, immunohistochemistry (IHC) for CHD1L was performed on a
tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44
metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis
was used to evaluate patients' survival status.
RESULTS: There is an augmented tendency of CHD1L expression in ovarian carcinoma
metastasis than in primary lesions (P<0.05). A significant association was found
between positive expression of CHD1L and tumors histological type (P <0.05). By
univariate survival analysis of the ovarian carcinoma cohorts, positive
expression of CHD1L was significantly correlated with shortened patient survival
(mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was
evaluated to be a significant and independent prognostic factor in multivariate
analysis (P<0.05).
CONCLUSIONS: These findings provide evidence that positive expression of CHD1L
protein is significantly correlated with the metastasis proceeding of ovarian
carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel
prognostic biomarker for patients with ovarian carcinoma.
DOI: 10.1186/1471-2407-12-437
PMCID: PMC3551745
PMID: 23020525 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25378326 | 1. Nucleic Acids Res. 2015 Jan;43(Database issue):D682-9. doi:
10.1093/nar/gku1112. Epub 2014 Nov 6.
Genomicus update 2015: KaryoView and MatrixView provide a genome-wide
perspective to multispecies comparative genomics.
Louis A(1), Nguyen NT(2), Muffato M(3), Roest Crollius H(2).
Author information:
(1)Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris
F-75005, France Inserm U1024, Paris F-75005, France CNRS, UMR 8197, Paris
F-75005, France alouis@biologie.ens.fr.
(2)Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris
F-75005, France Inserm U1024, Paris F-75005, France CNRS, UMR 8197, Paris
F-75005, France.
(3)European Molecular Biology Laboratory, European Bioinformatics Institute,
Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
The Genomicus web server (http://www.genomicus.biologie.ens.fr/genomicus) is a
visualization tool allowing comparative genomics in four different phyla
(Vertebrate, Fungi, Metazoan and Plants). It provides access to genomic
information from extant species, as well as ancestral gene content and gene
order for vertebrates and flowering plants. Here we present the new features
available for vertebrate genome with a focus on new graphical tools. The
interface to enter the database has been improved, two pairwise genome
comparison tools are now available (KaryoView and MatrixView) and the multiple
genome comparison tools (PhyloView and AlignView) propose three new kinds of
representation and a more intuitive menu. These new developments have been
implemented for Genomicus portal dedicated to vertebrates. This allows the
analysis of 68 extant animal genomes, as well as 58 ancestral reconstructed
genomes. The Genomicus server also provides access to ancestral gene orders, to
facilitate evolutionary and comparative genomics studies, as well as
computationally predicted regulatory interactions, thanks to the representation
of conserved non-coding elements with their putative gene targets.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gku1112
PMCID: PMC4383929
PMID: 25378326 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22855185 | 1. Clin Transl Oncol. 2013 Mar;15(3):198-204. doi: 10.1007/s12094-012-0903-2.
Epub 2012 Jul 24.
Decreased expression of chromodomain helicase DNA-binding protein 5 is an
unfavorable prognostic marker in patients with primary gallbladder carcinoma.
Du X(1), Wu T, Lu J, Zang L, Song N, Yang T, Zhao H, Wang S.
Author information:
(1)Department of General Surgery, Tangdu Hospital, Fourth Military Medical
University, 710038, Xi'an, People's Republic of China. du.xilintd@gmail.com
AIM: Chromodomain helicase DNA-binding protein 5 (CHD5) plays a role in normal
neural development and in tumorigenesis of various human cancers. However, its
role in primary gallbladder carcinoma (PGC) is still unclear. The aim of this
study was to investigate CHD5 expression in PGC and its clinical significance.
METHODS: CHD5 mRNA and protein expression in 120 PGC and 20 normal gallbladder
specimens was determined by quantitative reverse transcription-polymerase chain
reaction (QRT-PCR) and Western blotting analysis, respectively.
RESULTS: The expression levels of CHD5 mRNA and protein in PGC tissues were both
significantly lower than those in the normal epithelium of the gallbladder
(mRNA: P = 0.006; protein: P = 0.01). CHD5 mRNA expression was closely
correlated with its protein expression (r = 0.8; P < 0.001). Additionally, the
low expression of CHD5 protein was significantly associated with high pathologic
T stage (P = 0.01) and clinical stage (P = 0.008), and advanced histologic grade
(P = 0.009). The expression levels of CHD5 protein in PGC tissues with positive
nodal metastasis were also significantly lower than those without (P = 0.01).
Survival analysis showed that low CHD5 expression was associated with shorter
disease-free (P = 0.01) and overall survival (P = 0.008) compared to those with
high CHD5 expression in PGC patients. Furthermore, multivariate analyses showed
that the decreased expression of CHD5 was an independent prognostic marker for
both unfavorable disease-free (P = 0.01) and overall survival (P = 0.006).
CONCLUSION: CHD5 may be involved in carcinogenesis of PGC and its
down-regulation may be significantly correlated with unfavorable
clinicopathologic features including poor overall and disease-free survival in
patients.
DOI: 10.1007/s12094-012-0903-2
PMID: 22855185 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20041841 | 1. Cardiovasc Hematol Disord Drug Targets. 2010 Mar;10(1):73-81. doi:
10.2174/187152910790780032.
Amiodarone - a 'broad spectrum' antiarrhythmic drug.
Punnam SR(1), Goyal SK, Kotaru VP, Pachika AR, Abela GS, Thakur RK.
Author information:
(1)Sparrow Health System, Division of Cardiology, Michigan State University,
East Lansing, MI, USA.
Amiodarone, an iodinated benzofuran derivative, introduced in 1960's as an
anti-anginal agent, emerged as a potent anti-arrhythmic agent by 1970's and is
currently one of the most commonly prescribed drugs in US for ventricular and
atrial arrhythmias. Although amiodarone is considered a class III
anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique
and effective anti-arrhythmic agent. Because of its minimal negative inotropic
activity and very low rate of pro-arrhythmia, it is considered safe in treating
arrhythmias in patients with Coronary Artery Disease and Left ventricular
systolic dysfunction. Despite these advantages, long term oral therapy with
amiodarone is limited by side effect profile involving various organs like
thyroid, lung, heart, liver, skin etc. Though the side effects can be decreased
significantly by keeping the maintenance dose at 200 to 300 mg/day, patients on
amiodarone should be followed closely. Amiodarone interacts with medications
such as Warfarin, Digoxin, Macrolides, Floroquinolones etc., which share
Cytochrome P450 metabolic pathway. Hence reducing their doses prior to starting
amiodarone is recommended. Amiodarone, a category D drug, is contraindicated in
pregnant and breast feeding women. This review discusses the pharmacokinetics of
amiodarone, its evolving clinical indications, management of toxicity and drug
interactions.
DOI: 10.2174/187152910790780032
PMID: 20041841 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17509240 | 1. Funct Neurol. 2007 Jan-Apr;22(1):23-8.
Are patients with hereditary spastic paraplegia different from patients with
spastic diplegia during walking? Gait evaluation using 3D gait analysis.
Cimolin V(1), Piccinini L, D'Angelo MG, Turconi AC, Berti M, Crivellini M,
Albertini G, Galli M.
Author information:
(1)Department of Bioengineering, Polytechnic of Milan, Italy.
veronica.cimolin@polimi.it
Patients with hereditary spastic paraplegia (HSP) often resemble patients with
mild spastic diplegia (SD), although their motor limitations differ. The aim of
this study was to analyse quantitatively the gait of HSP and SD subjects in
order to define the gait pattern in HSP and the differences between the two
conditions. Fifteen subjects with HSP, 40 patients with SD and 20 healthy
subjects underwent gait analysis (GA). The spatio-temporal and kinematic
parameters at the proximal joints were found to be similar in HSP and SD,
whereas the most significant differences were found at the knee and ankle
joints. Both groups displayed a tendency for knee hyperextension in the
midstance phase, but the duration of this hyperextension was longer in the HSP
patients. This study shows that GA complements traditional clinical evaluations,
making it possible to distinguish, clearly, between motor ability in HSP and in
SD patients; the duration of the knee hyperextension during midstance was found
to discriminate between the two gait patterns.
PMID: 17509240 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24013423 | 1. Cell Cycle. 2013 Oct 1;12(19):3194-202. doi: 10.4161/cc.26241. Epub 2013 Sep
4.
Recruitment into stress granules prevents irreversible aggregation of FUS
protein mislocalized to the cytoplasm.
Shelkovnikova TA(1), Robinson HK, Connor-Robson N, Buchman VL.
Author information:
(1)School of Biosciences; Cardiff University; Cardiff, UK; Institute of
Physiologically Active Compounds Russian Academy of Sciences; Moscow Region,
Russian Federation.
Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated
as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other
neurodegenerative diseases. Multiple FUS gene mutations have been linked to
hereditary forms, and aggregation of FUS protein is believed to play an
important role in pathogenesis of these diseases. In cultured cells, FUS
variants with disease-associated amino acid substitutions or short deletions
affecting nuclear localization signal (NLS) and causing cytoplasmic
mislocalization can be sequestered into stress granules (SGs). We demonstrated
that disruption of motifs responsible for RNA recognition and binding not only
prevents SG recruitment, but also dramatically increases the protein propensity
to aggregate in the cell cytoplasm with formation of juxtanuclear structures
displaying typical features of aggresomes. Functional RNA-binding domains from
TAR DNA-binding protein of 43 kDa (TDP-43) fused to highly aggregation-prone
C-terminally truncated FUS protein restored the ability to enter SGs and
prevented aggregation of the chimeric protein. Truncated FUS was also able to
trap endogenous FUS molecules in the cytoplasmic aggregates. Our data indicate
that RNA binding and recruitment to SGs protect cytoplasmic FUS from
aggregation, and loss of this protection may trigger its pathological
aggregation in vivo.
DOI: 10.4161/cc.26241
PMCID: PMC3865015
PMID: 24013423 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20656033 | 1. Vaccine. 2010 Sep 14;28(40):6621-6. doi: 10.1016/j.vaccine.2010.07.027. Epub
2010 Jul 23.
Vaccination against tick-borne encephalitis virus tests specific IgG production
ability in patients under immunoglobulin substitution therapy.
Seidel MG(1), Grohmann E, Sadeghi K, Pollak A, Heitger A, Förster-Waldl E.
Author information:
(1)St. Anna Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria.
To assess B-cell function in patients under immunoglobulin (IgG)-replacement
therapy, the non-licensed artificial bacteriophage (ΦX174)-neo-antigen may be
used despite limited availability and experience. Active immunization against
tick-borne encephalitis (TBE) is performed in few European countries. To test
the feasibility of using licensed TBE vaccination as (neo-)antigen to determine
residual or restored B-cell function in patients under regular IgG substitution,
TBE-IgG levels were analyzed in 18 patients with ≥ 1-2 years of regular
intravenous or subcutaneous IgG substitution and in pharmaceutical
IgG-preparations (n=21 batches, 10 products). Six individuals were boosted
against TBE. Although TBE-specific IgG was detectable in concentrates
(281-57,100 VieU/0.5 μL), levels were only borderline in patient sera (n=31, 18
individuals; median 132 VieU; positive >155). Thus, TBE vaccination may be used
to test B-cell function under IgG replacement therapy because IgG substitution
appears insufficient to yield protective TBE-specific antibody levels in
children.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.vaccine.2010.07.027
PMID: 20656033 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23919605 | 1. Vector Borne Zoonotic Dis. 2013 Oct;13(10):733-8. doi: 10.1089/vbz.2012.1159.
Epub 2013 Aug 6.
West Nile Virus equine serosurvey in the Czech and Slovak republics.
Hubálek Z(1), Ludvíková E, Jahn P, Treml F, Rudolf I, Svobodová P, Šikutová S,
Betášová L, Bíreš J, Mojžíš M, Tinák M, Boldižár M, Citsoňová G, Staššíková Z.
Author information:
(1)1 Institute of Vertebrate Biology , v.v.i., Academy of Sciences, 60365 Brno,
Czech Republic .
A serological survey for West Nile virus (WNV) infection involved 395 horses
from 43 administrative districts of the Czech Republic (163 animals) and 29
districts of Slovakia (232 animals), sampled between 2008 and 2011. Using a
plaque-reduction neutralization microtest, antibodies to WNV were not detected
in any horse from the Czech Republic, whereas 19 nonvaccinated horses from
Slovakia had specific antibodies to WNV (no cross-reactions were observed with
tick-borne encephalitis and Usutu flaviviruses in those animals). The
seropositivity rate of nonvaccinated horses in Slovakia was 8.3% (95% confidence
interval [CI] 4.7-11.9%), and autochthonous local infection with WNV occurred at
least in 11, i.e., 4.8% (95% CI 2.0-7.6%) of the animals. All seropositive
horses lived in six lowland districts of southern Slovakia; overall, 15.1% (95%
CI 8.8-21.4%) of 126 nonvaccinated horses were seropositive in those districts,
situated relatively closely to the border with Hungary, i.e., the country where
WNV disease cases have been reported in birds, horses and humans since 2003.
DOI: 10.1089/vbz.2012.1159
PMCID: PMC3787466
PMID: 23919605 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21669865 | 1. J Biol Chem. 2011 Aug 5;286(31):27176-82. doi: 10.1074/jbc.C111.229567. Epub
2011 Jun 12.
Synthetic reversal of epigenetic silencing.
Haynes KA(1), Silver PA.
Author information:
(1)Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
02115, USA.
Controlling cell fate-determining gene expression is key to stem cell
differentiation, tissue regeneration, and cancer therapy. To date, custom-built
transcription factors recognize the information encoded in specific DNA
sequences. Chromatin proteins undergo covalent modifications and form complexes
that encode a second layer of information that determines proximal gene
activity. Here, we employ a novel gene-targeting approach that exploits a
specific chromatin modification to reactivate silenced loci in human cells. We
used the human Polycomb chromatin protein and homologues from other species to
construct modular synthetic transcription factors, called Pc-TFs, that recognize
the repressive trimethyl-histone H3 lysine 27 (H3K27me3) signal and switch
silenced genes to an active state. Pc-TF expression in U2OS osteosarcoma cells
leads to increased transcription of the senescence locus CDKN2A (p16) and other
loci in a chromodomain- and activation module-dependent manner, a switch to a
senescence phenotype, and reduced cell proliferation. These results indicate
that silenced developmental regulators can be reactivated by a synthetic
transcription factor that interacts with chromatin rather than DNA, resulting in
an altered cell state. As such, our work extends the flexibility of
transcription factor engineering and is the first example of chromatin-mediated
synthetic transcription factor targeting.
DOI: 10.1074/jbc.C111.229567
PMCID: PMC3149311
PMID: 21669865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20185404 | 1. Bioinformatics. 2010 Apr 15;26(8):1119-21. doi: 10.1093/bioinformatics/btq079.
Epub 2010 Feb 24.
Genomicus: a database and a browser to study gene synteny in modern and
ancestral genomes.
Muffato M(1), Louis A, Poisnel CE, Roest Crollius H.
Author information:
(1)Dyogen Group, Institut de Biologie de l'Ecole Normale Supérieure (IBENS),
Centre National de la Recherche Scientifique UMR8197, Institut National de la
Santé et de la Recherche Médicale U1024, 75005 Paris, France.
Comparative genomics remains a pivotal strategy to study the evolution of gene
organization, and this primacy is reinforced by the growing number of full
genome sequences available in public repositories. Despite this growth,
bioinformatic tools available to visualize and compare genomes and to infer
evolutionary events remain restricted to two or three genomes at a time, thus
limiting the breadth and the nature of the question that can be investigated.
Here we present Genomicus, a new synteny browser that can represent and compare
unlimited numbers of genomes in a broad phylogenetic view. In addition,
Genomicus includes reconstructed ancestral gene organization, thus greatly
facilitating the interpretation of the data.
AVAILABILITY: Genomicus is freely available for online use at
http://www.dyogen.ens.fr/genomicus while data can be downloaded at
ftp://ftp.biologie.ens.fr/pub/dyogen/genomicus.
DOI: 10.1093/bioinformatics/btq079
PMCID: PMC2853686
PMID: 20185404 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22727684 | 1. Virus Res. 2012 Sep;168(1-2):48-55. doi: 10.1016/j.virusres.2012.06.012. Epub
2012 Jun 19.
NS2B/3 proteolysis at the C-prM junction of the tick-borne encephalitis virus
polyprotein is highly membrane dependent.
Kurz M(1), Stefan N, Zhu J, Skern T.
Author information:
(1)Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3,
A-1030 Vienna, Austria.
The replication of tick-borne encephalitis virus (TBEV), like that of all
flaviviruses, is absolutely dependent on proteolytic processing. Production of
the mature proteins C and prM from their common precursor requires the activity
of the viral NS2B/3 protease (NS2B/3(pro)) at the C-terminus of protein C and
the host signal peptidase I (SPaseI) at the N-terminus of protein prM. Recently,
we have shown in cell culture that the cleavage of protein C and the subsequent
production of TBEV particles can be made dependent on the activity of the
foot-and-mouth disease virus 3C protease, but not on the activity of the HIV-1
protease (HIV1(pro)) (Schrauf et al., 2012). To investigate this failure, we
developed an in vitro cleavage assay to assess the two cleavage reactions
performed on the C-prM precursor. Accordingly, a recombinant modular
NS2B/3(pro), consisting of the protease domain of NS3 linked to the core-domain
of cofactor NS2B, was expressed in E. coli and purified to homogeneity. This
enzyme could cleave a C-prM protein synthesised in rabbit reticulocyte lysates.
However, cleavage was only specific when protein synthesis was performed in the
presence of canine pancreatic microsomal membranes and required the prevention
of signal peptidase I (SPaseI) activity by lengthening the h-region of the
signal peptide. The presence of membranes allowed the concentration of
NS2B/3(pro) used to be reduced by 10-20 fold. Substitution of the NS2B/3(pro)
cleavage motif in C-prM by a HIV-1(pro) motif inhibited NS2B/3(pro) processing
in the presence of microsomal membranes but allowed cleavage by HIV-1(pro) at
the C-prM junction. This system shows that processing at the C-terminus of
protein C by the TBEV NS2B/3(pro) is highly membrane dependent and will allow
the examination of how the membrane topology of protein C affects both SPaseI
and NS2B/3(pro) processing.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.virusres.2012.06.012
PMCID: PMC3437442
PMID: 22727684 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19808288 | 1. Circ Heart Fail. 2008 Sep;1(3):184-91. doi:
10.1161/CIRCHEARTFAILURE.108.768119. Epub 2008 Jun 23.
Clinical profile and significance of delayed enhancement in hypertrophic
cardiomyopathy.
Maron MS(1), Appelbaum E, Harrigan CJ, Buros J, Gibson CM, Hanna C, Lesser JR,
Udelson JE, Manning WJ, Maron BJ.
Author information:
(1)Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical
Center, Boston, Massachusetts 02111, USA. mmaron@tuftsmedicalcenter.org
BACKGROUND: Contrast-enhanced cardiovascular magnetic resonance with delayed
enhancement (DE) can provide in vivo assessment of myocardial fibrosis. However,
the clinical significance of DE in hypertrophic cardiomyopathy (HCM) remains
unresolved.
METHODS AND RESULTS: Cine and cardiovascular magnetic resonance with DE were
performed in 202 HCM patients (mean age, 42+/-17 years; 71% male), DE was
compared with clinical and demographic variables, and patients were followed up
for 681+/-249 days for adverse disease events. DE was identified in 111 (55%)
HCM patients, occupying 9%+/-11% of left ventricular myocardial volume,
including >25% DE in 10% of patients. The presence of DE was related to
occurrence of heart failure symptoms (P=0.05) and left ventricular systolic
dysfunction (P=0.001). DE was present in all patients with ejection fraction <
or =50% but also in 53% (102/192) of patients with preserved ejection fraction
(P<0.001); %DE was both inversely related to (r=-0.3; P<0.001) and an
independent predictor of ejection fraction (r=-0.4; P<0.001). DE (7%+/-7% of
left ventricle) was present in 54 patients who were asymptomatic (and with
normal ejection fraction). Over the follow-up period, the annualized adverse
cardiovascular event rate in patients with DE exceeded that in patients without
DE but did not achieve statistical significance (5.5% versus 3.3%; P=0.5).
CONCLUSIONS: In a large HCM cohort, DE was an independent predictor of systolic
dysfunction but with only a modest relationship to heart failure symptoms. These
data suggest an important role for myocardial fibrosis in the clinical course of
HCM patients but are not sufficient at this time to consider DE as an
independent risk factor for adverse prognosis.
DOI: 10.1161/CIRCHEARTFAILURE.108.768119
PMID: 19808288 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24096319 | 1. J Gen Virol. 2014 Jan;95(Pt 1):60-65. doi: 10.1099/vir.0.058008-0. Epub 2013
Oct 4.
Production of single-round infectious chimeric flaviviruses with DNA-based
Japanese encephalitis virus replicon.
Suzuki R(1), Ishikawa T(2), Konishi E(3), Matsuda M(1), Watashi K(1), Aizaki
H(1), Takasaki T(4), Wakita T(1).
Author information:
(1)Department of Virology II, National Institute of Infectious Diseases, Toyama
1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
(2)Department of Microbiology, Dokkyo Medical University School of Medicine, 880
Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.
(3)BIKEN Endowed Department of Dengue Vaccine Development, Faculty of Tropical
Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchahewi, Bangkok 10440,
Thailand.
(4)Department of Virology I, National Institute of Infectious Diseases, Toyama
1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
A method for rapid production of single-round infectious particles (SRIPs) of
flavivirus would be useful for viral mutagenesis studies. Here, we established a
DNA-based production system for SRIPs of flavivirus. We constructed a Japanese
encephalitis virus (JEV) subgenomic replicon plasmid, which lacked the C-prM-E
(capsid-pre-membrane-envelope) coding region, under the control of the
cytomegalovirus promoter. When the JEV replicon plasmid was transiently
co-transfected with a JEV C-prM-E expression plasmid into 293T cells, SRIPs were
produced, indicating successful trans-complementation with JEV structural
proteins. Equivalent production levels were observed when C and prM-E proteins
were provided separately. Furthermore, dengue types 1-4, West Nile, yellow fever
or tick-borne encephalitis virus prM-E proteins could be utilized for production
of chimaeric flavivirus SRIPs, although the production was less efficient for
dengue and yellow fever viruses. These results indicated that our plasmid-based
system is suitable for investigating the life cycles of flaviviruses, diagnostic
applications and development of safer vaccine candidates.
DOI: 10.1099/vir.0.058008-0
PMID: 24096319 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23452322 | 1. Virol J. 2013 Mar 4;10:68. doi: 10.1186/1743-422X-10-68.
Development of simple and rapid assay to detect viral RNA of tick-borne
encephalitis virus by reverse transcription-loop-mediated isothermal
amplification.
Hayasaka D(1), Aoki K, Morita K.
Author information:
(1)Department of Virology, Institute of Tropical Medicine, Global COE Program,
Leading Graduate School Program, Nagasaki University, Nagasaki, Japan.
hayasaka@nagasaki-u.ac.jp
BACKGROUND: Tick-borne encephalitis virus (TBEV) is a causative agent of acute
central nervous system disease in humans. It has three subtypes, far eastern
(FE), Siberian (Sib) and European (Eu) subtypes, which are distributed over a
wide area of Europe and Asia. The objective of this study was to develop a
simple and rapid assay for the detection of TBEV RNA by using
reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) method
that can differentiate the three subtypes of TBEV and can be used for clinical
diagnosis and epidemiological study.
METHODS: Primers for TBEV-specific and subtype-specific RT-LAMP assay were
designed to target the consensus sequence in NS1 of all subtypes and the
consensus sequence in the E gene of each subtype, respectiveluy. In vitro
transcribed RNA of Oshima strain that belongs to FE subtype was serially diluted
and used to examine the sensitivity of the assay. Cross-reactivity of
subtype-specific RT-LAMP assay was tested by using the RNA of Oshima and Sofjin
(FE), IR-99 (Sib) and Hochosterwitz (Eu) strains. RNA extracted from the
mixtures of TBEV and ticks, and of TBEV and human blood, and the mouse tissues
infected with TBEV, were evaluated in the assay. Positive amplification was
observed by real-time monitoring of turbidity and by visual detection of color
change.
RESULTS: The sensitivity of TBEV-specific RT-LAMP assay was 102 copies of target
RNA per reaction volume. FE-specific RT-LAMP assay amplified viral genes of
Oshima and Sofjin strains but not of IR-99 and Hochosterwitz strains, and of
Japanese encephalitis virus. RT-LAMP assay for Sib and for Eu specifically
amplified viral genes of IR-99 and Hochosterwitz strains, respectively. We also
showed that tick or human blood extract did not inhibit the amplification of
viral gene during the assay. Furthermore, we confirmed that the TBEV RT-LAMP
could detect virus RNA from peripheral and central nervous system tissues of
laboratory mice infected with TBEV.
CONCLUSION: TBEV RT-LAMP assay offers a sensitive, specific, rapid and
easy-to-handle method for the detection of TBEV RNA in tick samples and this may
be applied in the clinical samples collected from TBE-suspected patients.
DOI: 10.1186/1743-422X-10-68
PMCID: PMC3599137
PMID: 23452322 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21234292 | 1. Clin Med Insights Cardiol. 2010 Dec 15;4:129-34. doi: 10.4137/CMC.S5900.
Characteristics and prognostic importance of myocardial fibrosis in patients
with dilated cardiomyopathy assessed by contrast-enhanced cardiac magnetic
resonance imaging.
Looi JL(1), Edwards C, Armstrong GP, Scott A, Patel H, Hart H, Christiansen JP.
Author information:
(1)Cardiovascular Division, North Shore Hospital, Takapuna, Auckland, New
Zealand.
INTRODUCTION: Dilated cardiomyopathy (DCM) is associated with significant
morbidity and mortality. Contrast-enhanced cardiac MRI (CE-CMR) can detect
potentially prognostic myocardial fibrosis in DCM. We investigated the role of
CE-CMR in New Zealand patients with DCM, both Maori and non-Maori, including the
characteristics and prognostic importance of fibrosis.
METHODS: One hundred and three patients (mean age 58 ± 13, 78 male) referred for
CMR assessment of DCM were followed for 660 ± 346 days. Major adverse cardiac
events (MACE) were defined as death, infarction, ventricular arrhythmias or
rehospitalisation. CE-CMR used cines for functional analysis, and delayed
enhancement to assess fibrosis.
RESULTS: Myocardial fibrosis was present in 30% of patients, the majority of
which was mid-myocardial (63%). Volumetric parameters were similar in patients
with or without fibrosis. At 2 years patients with fibrosis had an increased
rate of MACE (HR = 0.77, 95% CI 0.3-2.0). Patients with full thickness or
subendocardial fibrosis had the highest MACE, even in the absence of CAD). More
Maori had fibrosis on CE-CMR (40% vs. 28% for non-Maori), and the majority (75%)
was mid-myocardial. Maori and non-Maori had similar outcomes (25% vs. 24% with
events during follow-up).
CONCLUSIONS: DCM patients frequently have myocardial fibrosis detected on
CE-CMR, the majority of which is mid-myocardial. Fibrosis is associated with
worse outcome in the medium term. The information obtained using CE-CMR in DCM
may be of incremental clinical benefit.
DOI: 10.4137/CMC.S5900
PMCID: PMC3018894
PMID: 21234292 |
http://www.ncbi.nlm.nih.gov/pubmed/12788480 | 1. Free Radic Biol Med. 2003 Jun 15;34(12):1607-13. doi:
10.1016/s0891-5849(03)00211-9.
Nitric oxide-mediated upregulation of the TGF-beta-inducible early response
gene-1 (TIEG1) in human fibroblasts by mRNA stabilization independent of
TGF-beta.
Mitsumoto M(1), Mitsumoto A, Demple B.
Author information:
(1)Department of Cancer Cell Biology, Harvard School of Public Health, Boston,
MA 02115, USA.
Nitric oxide serves various roles in mammalian cells, including intracellular
signaling and cell killing. To recognize the dynamic molecular changes in
response to NO, microarray analysis was applied to human fibroblasts (IMR-90)
exposed to sublethal levels of NO. Among the > 300 transcripts induced by NO, we
focused on the mRNA encoded by the transforming growth factor-beta- (TGF-beta-)
inducible early response 1 gene (TIEG1), which plays a pivotal role in
TGF-beta-regulated cell growth control and apoptosis. Northern blotting analysis
demonstrated that NO upregulates TIEG1 mRNA in a dose-dependent manner.
Anti-TGF-beta antibodies prevented TIEG1 mRNA induction by TGF-beta, but not the
induction by NO. Conversely, NO had no effect on the amounts of total TGF-beta
or its active form in culture supernatants. However, the half-life of the TIEG1
transcript was strongly increased (6-fold) upon exposure of the cells to NO.
Thus, NO upregulates TIEG1 mRNA by stabilization independently of TGF-beta. The
TIEG1 mRNA now joins heme oxygenase-1 mRNA in displaying regulation by
NO-mediated stabilization. It remains to be determined whether the same control
mechanism operates on these and perhaps other messages.
DOI: 10.1016/s0891-5849(03)00211-9
PMID: 12788480 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20981772 | 1. Am J Med Genet C Semin Med Genet. 2010 Nov 15;154C(4):432-7. doi:
10.1002/ajmg.c.30278.
The behavioral phenotype of the Angelman syndrome.
Williams CA(1).
Author information:
(1)Division of Genetics and Metabolism, Department of Pediatrics, University of
Florida College of Medicine, Gainesville, Florida, USA. willicx@peds.ufl.edu
The Angelman syndrome is clinically delineated by the combination of seizures,
absent speech, hypermotoric and ataxic movements and certain remarkable
behaviors. Those with the syndrome have a predisposition toward apparent
happiness and paroxysms of laughter, and this finding helps distinguish Angelman
syndrome from other ones involving severe developmental handicap. In this review
the core neurological features of the syndrome are discussed with a focus on
those behaviors that make Angelman syndrome a prototypical genetic disorder
expressing a behavioral phenotype.
© 2010 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.c.30278
PMID: 20981772 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20821198 | 1. Eur J Clin Pharmacol. 2010 Nov;66(11):1091-7. doi: 10.1007/s00228-010-0886-2.
Epub 2010 Sep 7.
Paediatric investigation plans for pain: painfully slow!
Davies EH(1), Ollivier CM, Saint Raymond A.
Author information:
(1)Institute of Child Health, University College London, 30 Guilford Street,
London, WC1N 1EH, UK.
PURPOSE: To examine the early impact of the Paediatric Regulation, which entered
into force in Europe on 27 January 2007, on the development of pharmaceutical
drugs in the therapeutic field of pain submitted to the Paediatric Committee
(PDCO) and to the European Medicines Agency (EMA).
METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision
(outcome) reached between September 2007 and March 2010 were included in the
analysis.
RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in
an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full
waiver from development, and 1 resulted in a negative opinion. Decisions as
issued included 15 clinical trials, with at least 1,282 children to be recruited
into studies across five different products. Neonates were included in four of
the products.
CONCLUSIONS: The small number of submissions indicates a lack of new drugs being
developed for the management of pain. Ethical concerns that too many vulnerable
children will be recruited into clinical trials must be balanced against
limiting the number of off-label prescribing and obtaining age-appropriate
information on paediatric use. Now is an opportune time for clinicians,
academics, learned societies and industry to collaborate for the benefit of
children in pain.
DOI: 10.1007/s00228-010-0886-2
PMID: 20821198 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21524276 | 1. Cell Biol Int. 2011 Sep;35(9):891-6. doi: 10.1042/CBI20100896.
Lentivirus-mediated overexpression of TGF-β inducible early gene 1 inhibits
SW1990 pancreatic cancer cell growth.
Jiang L(1), Wang F, Lin F, Gao SM, Tan Y, Han Y, Chen C, Wu J.
Author information:
(1)Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou
Medical College, Wenzhou, Zhejiang, Peoples Republic of China.
jiangleistone@yahoo.com.cn
TIEG1 (TGF-β inducible early gene 1) plays a significant role in regulating cell
proliferation and apoptosis in various cell types. Previous studies have shown a
close relationship between the expression level of TIEG1 and various cancers,
including breast, prostate, colorectal and pancreatic cancer. In this study, we
up-regulated the gene expression of TIEG1 in SW1990 pancreatic cancer cell line
by a lentivirus transfection system and investigated its potential as a
therapeutic target for pancreatic cancer. The results showed that
lentivirus-mediated overexpression of TIEG1 gene inhibited human pancreatic
cancer SW1990 cell proliferation and caused the cell cycle arrest at the
G1-phase in vitro. SW1990 cells transduced with lenti-TIEG1 showed significant
inhibition of colony formation and cancer cell growth in 3-D culture model.
Moreover, overexpression of TIEG1 gene significantly slowed the growth of SW1990
xenografts in nude mice. Taken together, these data provided evidence that
overexpression of TIEG1 gene by a lentivirus transfection system led to
suppressed human pancreatic cancer cell growth and might therefore be a feasible
approach in the clinical management of pancreatic cancer.
DOI: 10.1042/CBI20100896
PMID: 21524276 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24690898 | 1. PLoS One. 2014 Apr 1;9(4):e93771. doi: 10.1371/journal.pone.0093771.
eCollection 2014.
Genetic variations in the human cannabinoid receptor gene are associated with
happiness.
Matsunaga M(1), Isowa T(2), Yamakawa K(3), Fukuyama S(4), Shinoda J(4), Yamada
J(4), Ohira H(3).
Author information:
(1)Department of Health and Psychosocial Medicine, Aichi Medical University
School of Medicine, Aichi, Japan.
(2)Department of Gerontological Nursing, Mie University Faculty of Medicine,
Mie, Japan.
(3)Department of Psychology, Graduate School of Environmental Studies, Nagoya
University, Aichi, Japan.
(4)Chubu Medical Center for Prolonged Traumatic Brain Dysfunction, Kizawa
Memorial Hospital, Gifu, Japan.
Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a
relatively stable state of being happy (subjective happiness level). As previous
studies demonstrated that individuals with high subjective happiness level rated
their current affective states more positively when they experience positive
events, these two aspects of happiness are interrelated. According to a recent
neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of
the human cannabinoid receptor 1 gene is associated with sensitivity to positive
emotional stimuli. Thus, we hypothesized that our genetic traits, such as the
human cannabinoid receptor 1 genotypes, are closely related to the two aspects
of happiness. In Experiment 1, 198 healthy volunteers were used to compare the
subjective happiness level between cytosine allele carriers and thymine-thymine
carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used
positron emission tomography with 20 healthy participants to compare the brain
responses to positive emotional stimuli of cytosine allele carriers to that of
thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele
carriers have a higher subjective happiness level. Regression analysis indicated
that the cytosine allele is significantly associated with subjective happiness
level. The positive mood after watching a positive film was significantly higher
for the cytosine allele carriers compared to the thymine-thymine carriers.
Positive emotion-related brain region such as the medial prefrontal cortex was
significantly activated when the cytosine allele carriers watched the positive
film compared to the thymine-thymine carriers. Thus, the human cannabinoid
receptor 1 genotypes are closely related to two aspects of happiness. Compared
to thymine-thymine carriers, the cytosine allele carriers of the human
cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli,
exhibited greater magnitude positive emotions when they experienced positive
events and had a higher subjective happiness level.
DOI: 10.1371/journal.pone.0093771
PMCID: PMC3972248
PMID: 24690898 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/24035586 | 1. Ticks Tick Borne Dis. 2014 Feb;5(1):7-13. doi: 10.1016/j.ttbdis.2012.11.016.
Epub 2013 Sep 10.
Detection and genetic characterization of tick-borne encephalitis virus (TBEV)
derived from ticks removed from red foxes (Vulpes vulpes) and isolated from
spleen samples of red deer (Cervus elaphus) in Croatia.
Jemeršić L(1), Dežđek D, Brnić D, Prpić J, Janicki Z, Keros T, Roić B, Slavica
A, Terzić S, Konjević D, Beck R.
Author information:
(1)Croatian Veterinary Institute, Savska cesta 143, 10 000 Zagreb, Croatia.
Electronic address: jemersic@veinst.hr.
Tick-borne encephalitis (TBE) is a growing public health concern in central and
northern European countries. Even though TBE is a notifiable disease in Croatia,
there is a significant lack of information in regard to vector tick
identification, distribution as well as TBE virus prevalence in ticks or
animals. The aim of our study was to identify and to investigate the viral
prevalence of TBE virus in ticks removed from red fox (Vulpes vulpes) carcasses
hunted in endemic areas in northern Croatia and to gain a better insight in the
role of wild ungulates, especially red deer (Cervus elaphus) in the maintenance
of the TBE virus in the natural cycle. We identified 5 tick species (Ixodes
ricinus, Ixodes hexagonus, Haemaphysalis punctata, Dermacentor reticulatus,
Rhipicephalus sanguineus) removed from 40 red foxes. However, TBE virus was
isolated only from adult I. ricinus and I. hexagonus ticks showing a viral
prevalence (1.6%) similar to or higher than reported in endemic areas of other
European countries. Furthermore, 2 positive spleen samples from 182 red deer
(1.1%) were found. Croatian TBE virus isolates were genetically analyzed, and
they were shown to be closely related, all belonging to the European TBE virus
subgroup. However, on the basis of nucleotide and amino acid sequence analysis,
2 clusters were identified. Our results show that further investigation is
needed to understand the clustering of isolates and to identify the most common
TBE virus reservoir hosts in Croatia. Sentinel surveys based on wild animal
species would give a better insight in defining TBE virus-endemic and possible
risk areas in Croatia.
Copyright © 2013. Published by Elsevier GmbH.
DOI: 10.1016/j.ttbdis.2012.11.016
PMID: 24035586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21423731 | 1. PLoS One. 2011 Mar 14;6(3):e17522. doi: 10.1371/journal.pone.0017522.
TGF-β inducible early gene 1 regulates osteoclast differentiation and survival
by mediating the NFATc1, AKT, and MEK/ERK signaling pathways.
Cicek M(1), Vrabel A, Sturchio C, Pederson L, Hawse JR, Subramaniam M, Spelsberg
TC, Oursler MJ.
Author information:
(1)Department of Biochemistry and Molecular Biology, Mayo Clinic College of
Medicine, Rochester, Minnesota, United States of America.
cicek.muzaffer@mayo.edu
TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor
(KLF10) that was originally cloned from human osteoblasts as an early response
gene to TGF-β treatment. As reported previously, TIEG1(-/-) mice have decreased
cortical bone thickness and vertebral bone volume and have increased spacing
between the trabeculae in the femoral head relative to wildtype controls. Here,
we have investigated the role of TIEG1 in osteoclasts to further determine their
potential role in mediating this phenotype. We have found that TIEG1(-/-)
osteoclast precursors differentiated more slowly compared to wildtype precursors
in vitro and high RANKL doses are able to overcome this defect. We also
discovered that TIEG1(-/-) precursors exhibit defective RANKL-induced
phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP.
Higher RANKL concentrations reversed defective NFATc1 signaling and restored
differentiation. After differentiation, wildtype osteoclasts underwent apoptosis
more quickly than TIEG1(-/-) osteoclasts. We observed increased AKT and MEK/ERK
signaling pathway activation in TIEG1(-/-) osteoclasts, consistent with the
roles of these kinases in promoting osteoclast survival. Adenoviral delivery of
TIEG1 (AdTIEG1) to TIEG1(-/-) cells reversed the RANKL-induced NFATc1 signaling
defect in TIEG1(-/-) precursors and eliminated the differentiation and apoptosis
defects. Suppression of TIEG1 with siRNA in wildtype cells reduced
differentiation and NFATc1 activation. Together, these data provide evidence
that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway
activation and reduces osteoclast survival by suppressing AKT and MEK/ERK
signaling.
DOI: 10.1371/journal.pone.0017522
PMCID: PMC3056664
PMID: 21423731 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/14743447 | 1. J Neurosci Res. 2004 Feb 1;75(3):344-52. doi: 10.1002/jnr.10856.
TIEG1 facilitates transforming growth factor-beta-mediated apoptosis in the
oligodendroglial cell line OLI-neu.
Bender H(1), Wang Z, Schuster N, Krieglstein K.
Author information:
(1)Center of Anatomy, University of Goettingen, Goettingen, Germany.
Transforming growth factor-beta (TGF-beta) plays an important role during the
period of developmental cell death in the nervous system. Using the
oligodendroglial precursor cell line OLI-neu, we have previously established an
in vitro system to analyze TGF-beta-mediated cell death on the molecular level.
We could show that the Krüppel-like Zn-finger transcription factor TIEG1 was
up-regulated after TGF-beta stimulation of OLI-neu cells and mimicked TGF-beta
effects in these cells; i.e., overexpression of TIEG1 in OLI-neu cells induced
apoptosis as shown by apoptosis ELISA, DNA fragmentation, and caspases-3
activation. The apoptotic pathway seemed to be initiated by repressing the
expression of the antiapoptotic protein Bcl-XL. In contrast, the reporter
activity of a SMAD consensus promoter was induced, whereas the promoter activity
of the inhibitory SMAD7 was reduced, suggesting that SMAD-dependent TGF-beta
responses, such as TGF-beta-induced apoptosis, are enhanced in the presence of
TIEG1.
Copyright 2003 Wiley-Liss, Inc.
DOI: 10.1002/jnr.10856
PMID: 14743447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17826455 | 1. Arch Phys Med Rehabil. 2007 Sep;88(9):1114-20. doi:
10.1016/j.apmr.2007.06.011.
Relationships between spasticity, strength, gait, and the GMFM-66 in persons
with spastic diplegia cerebral palsy.
Ross SA(1), Engsberg JR.
Author information:
(1)Department of Physical Therapy, Maryville University, St. Louis, MO
63141-7299, USA. sross@maryville.edu
OBJECTIVE: To determine the relationships between spasticity, strength, and the
functional measures of gait and gross motor function in persons with spastic
diplegia cerebral palsy (CP).
DESIGN: Retrospective, cross-sectional study.
SETTING: Hospital clinic.
PARTICIPANTS: Ninety-seven participants (49 boys, 48 girls; mean age+/-standard
deviation, 9.11+/-4.8 y) with spastic diplegia CP were tested once.
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: A KinCom dynamometer was used to objectively measure
spasticity (ankle plantarflexors, knee flexors, hip adductors) and maximum
strength (ankle dorsiflexors and plantarflexors, knee flexors and extensors, hip
abductors and adductors). A gait analysis was conducted to evaluate linear
variables (gait speed, stride length, cadence) and kinematic variables (ankle
dorsiflexion, foot progression, knee and hip flexion, pelvic tilt at initial
contact and ankle dorsiflexion, knee and hip flexion, pelvic tilt, trunk
rotation range of motion) during gait. Gross motor function was measured using
the Gross Motor Function Measure (GMFM-66) and separately, the GMFM walking,
running & jumping dimension. Multiple linear regression analysis was used to
determine the relationships between spasticity, strength, gait, and the GMFM
(P<.05).
RESULTS: Spasticity did not account for a substantial amount of explained
variance in gait and gross motor function (up to 8% for the GMFM walking,
running & jumping dimension). Moderate to high correlations existed between
strength and gait linear data and function, accounting for up to 69% of the
explained variance (strength and GMFM-66, r2=.69).
CONCLUSIONS: For this cohort of participants with spastic diplegia CP who
ambulated with or without an assistive device, strength was highly related to
function and explained far more of the variance than spasticity. The results may
not be generalized to those with more severe forms of CP.
DOI: 10.1016/j.apmr.2007.06.011
PMID: 17826455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22730949 | 1. J Biomol Struct Dyn. 2012;30(6):638-51. doi: 10.1080/07391102.2012.689697.
Epub 2012 Jun 26.
NS2B/NS3 protease: allosteric effect of mutations associated with the
pathogenicity of tick-borne encephalitis virus.
Potapova UV(1), Feranchuk SI, Potapov VV, Kulakova NV, Kondratov IG, Leonova GN,
Belikov SI.
Author information:
(1)Limnological Institute, Siberian Branch of the Russian Academy of Sciences,
3, Ulan-Batorskaya St., Irkutsk, 664033, Russian Federation. potapova@lin.irk.ru
The sequences of the protease domain of the tick-borne encephalitis (TBE) virus
NS3 protein have two amino acid substitutions, 16 R→K and 45 S→F, in the highly
pathogenic and poorly pathogenic strains of the virus, respectively. Two models
of the NS2B-NS3 protease complex for the highly pathogenic and poorly pathogenic
strains of the virus were constructed by homology modeling using the crystal
structure of West Nile virus NS2B-NS3 protease as a template; 20 ns molecular
dynamic simulations were performed for both models, the trajectories of the
dynamic simulations were compared, and the averaged distance between the two
models was calculated for each residue. Conformational differences between two
models were revealed in the identified pocket. The different conformations of
the pocket resulted in different orientations of the NS2B segment located near
the catalytic triad. In the model of the highly pathogenic TBE virus the
identified pocket had a more open conformation compared to the poorly pathogenic
model. We propose that conformational changes in the active protease center,
caused by two amino acid substitutions, can influence enzyme functioning and the
virulence of the virus.
DOI: 10.1080/07391102.2012.689697
PMID: 22730949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11847212 | 1. J Biol Chem. 2002 May 3;277(18):15834-42. doi: 10.1074/jbc.M109260200. Epub
2002 Feb 14.
Primary structure of a dynamin-related mouse mitochondrial GTPase and its
distribution in brain, subcellular localization, and effect on mitochondrial
morphology.
Misaka T(1), Miyashita T, Kubo Y.
Author information:
(1)Department of Physiology, Tokyo Medical and Dental University, Graduate
School and Faculty of Medicine, Bunkyo, Tokyo 113-8519, Japan.
A new member of the dynamin GTPase family (OPA1) was recently identified in
humans and shown to be mutated in patients with dominant optic atrophy. To
understand better the function of mammalian OPA1, we isolated a mouse ortholog
(mOPA1) from brain and raised a specific antibody against its C terminus. The
subcellular distribution of mOPA1 overexpressed in COS-7 cells largely
overlapped that of endogenous cytochrome c, a well known mitochondrial marker,
and dramatically affected mitochondrial morphology, altering it from tubular to
vesicular. Mitochondrial targeting was mediated by the N-terminal region of
mOPA1 as follows: deletion of the 124 N-terminal amino acids eliminated
mitochondrial targeting, although fusion of the N-terminal 60 or 90 amino acids
of mOPA1 with green fluorescent protein resulted in its mitochondrial targeting.
mOPA1 was expressed widely in the mouse brain, especially in neurons of
olfactory bulb, cerebral cortex, piriform cortex, hypothalamus, hippocampus, red
nucleus, cochlear nucleus, motor trigeminal nucleus, facial nucleus, cerebellar
nucleus, and Purkinje cells. Within dissociated cerebellar cells, mOPA1 protein
was clearly observed in the dendrites and somas of neuronal cells, as well as in
astrocytes and meningeal cells. In each case, it was distributed in the
vesicular pattern seen in other cell types.
DOI: 10.1074/jbc.M109260200
PMID: 11847212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24282027 | 1. Hum Mol Genet. 2014 Apr 15;23(8):2055-77. doi: 10.1093/hmg/ddt600. Epub 2013
Nov 26.
Functional interaction of Parkinson's disease-associated LRRK2 with members of
the dynamin GTPase superfamily.
Stafa K(1), Tsika E, Moser R, Musso A, Glauser L, Jones A, Biskup S, Xiong Y,
Bandopadhyay R, Dawson VL, Dawson TM, Moore DJ.
Author information:
(1)Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale
de Lausanne (EPFL), Lausanne 1015, Switzerland.
Mutations in LRRK2 cause autosomal dominant Parkinson's disease (PD). LRRK2
encodes a multi-domain protein containing GTPase and kinase domains, and
putative protein-protein interaction domains. Familial PD mutations alter the
GTPase and kinase activity of LRRK2 in vitro. LRRK2 is suggested to regulate a
number of cellular pathways although the underlying mechanisms are poorly
understood. To explore such mechanisms, it has proved informative to identify
LRRK2-interacting proteins, some of which serve as LRRK2 kinase substrates.
Here, we identify common interactions of LRRK2 with members of the dynamin
GTPase superfamily. LRRK2 interacts with dynamin 1-3 that mediate membrane
scission in clathrin-mediated endocytosis and with dynamin-related proteins that
mediate mitochondrial fission (Drp1) and fusion (mitofusins and OPA1). LRRK2
partially co-localizes with endosomal dynamin-1 or with mitofusins and OPA1 at
mitochondrial membranes. The subcellular distribution and oligomeric complexes
of dynamin GTPases are not altered by modulating LRRK2 in mouse brain, whereas
mature OPA1 levels are reduced in G2019S PD brains. LRRK2 enhances mitofusin-1
GTP binding, whereas dynamin-1 and OPA1 serve as modest substrates of
LRRK2-mediated phosphorylation in vitro. While dynamin GTPase orthologs are not
required for LRRK2-induced toxicity in yeast, LRRK2 functionally interacts with
dynamin-1 and mitofusin-1 in cultured neurons. LRRK2 attenuates neurite
shortening induced by dynamin-1 by reducing its levels, whereas LRRK2 rescues
impaired neurite outgrowth induced by mitofusin-1 potentially by reversing
excessive mitochondrial fusion. Our study elucidates novel functional
interactions of LRRK2 with dynamin-superfamily GTPases that implicate LRRK2 in
the regulation of membrane dynamics important for endocytosis and mitochondrial
morphology.
DOI: 10.1093/hmg/ddt600
PMCID: PMC3959816
PMID: 24282027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20045077 | 1. Semin Cell Dev Biol. 2010 Aug;21(6):593-8. doi: 10.1016/j.semcdb.2009.12.012.
Epub 2010 Jan 4.
OPA1 (dys)functions.
Landes T(1), Leroy I, Bertholet A, Diot A, Khosrobakhsh F, Daloyau M, Davezac N,
Miquel MC, Courilleau D, Guillou E, Olichon A, Lenaers G, Arnauné-Pelloquin L,
Emorine LJ, Belenguer P.
Author information:
(1)Université de Toulouse, UPS, CNRS, UMR 52412, Laboratoire Métabolisme
Plasticité Mitochondries, Toulouse, France.
Mitochondrial morphology varies according to cell type and cellular context from
an interconnected filamentous network to isolated dots. This morphological
plasticity depends on mitochondrial dynamics, a balance between antagonistic
forces of fission and fusion. DRP1 and FIS1 control mitochondrial outer membrane
fission and Mitofusins its fusion. This review focuses on OPA1, one of the few
known actors of inner membrane dynamics, whose mutations provoke an optic
neuropathy. Since its first identification in 2000 the characterization of the
functions of OPA1 has made rapid progress thus providing numerous clues to
unravel the pathogenetic mechanisms of ADOA-1.
Copyright 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2009.12.012
PMID: 20045077 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23663851 | 1. Biophys J. 2013 May 7;104(9):2077-88. doi: 10.1016/j.bpj.2013.03.025.
Mitochondrial localization and the persistent migration of epithelial cancer
cells.
Desai SP(1), Bhatia SN, Toner M, Irimia D.
Author information:
(1)Harvard-MIT Division of Health-Science Technology, Massachusetts Institute of
Technology, Cambridge, Massachusetts, USA.
During cancer cell invasion, faster moving cancer cells play a dominant role by
invading further and metastasizing earlier. Despite the importance of these
outlier cells, the source of heterogeneity in their migratory behavior remains
poorly understood. Here, we show that anterior localization of mitochondria, in
between the nucleus and the leading edge of migrating epithelial cancer cells,
correlates with faster migration velocities and increased directional
persistence. The asymmetry of mitochondrial localization along the axis of
migration is absent during spontaneous cell migration on two-dimensional
surfaces and only occurs in the presence of chemical attractant cues or in
conditions of mechanical confinement. Moreover, perturbing the asymmetric
distribution of mitochondria within migrating cells by interfering with
mitochondrial fusion (opa-1) or fission (drp-1) proteins, significantly reduces
the number of cells with anterior localization of mitochondria and significantly
decreases the velocity and directional persistence of the fastest moving cells.
We also observed similar changes after perturbing the linkage between
mitochondria and microtubules by the knockdown of mitochondrial rhoGTPase-1
(miro-1). Taken together, the changes in migration velocity and directional
persistence in cells with anterior-localized mitochondria could account for an
order of magnitude differences in invasive abilities between cells from
otherwise homogenous cell populations.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.bpj.2013.03.025
PMCID: PMC3647149
PMID: 23663851 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21980395 | 1. PLoS One. 2011;6(9):e25199. doi: 10.1371/journal.pone.0025199. Epub 2011 Sep
29.
The effect of OPA1 on mitochondrial Ca²⁺ signaling.
Fülöp L(1), Szanda G, Enyedi B, Várnai P, Spät A.
Author information:
(1)Department of Physiology, Faculty of Medicine, Semmelweis University,
Hungarian Academy of Sciences, Budapest, Hungary.
The dynamin-related GTPase protein OPA1, localized in the intermembrane space
and tethered to the inner membrane of mitochondria, participates in the fusion
of these organelles. Its mutation is the most prevalent cause of Autosomal
Dominant Optic Atrophy. OPA1 controls the diameter of the junctions between the
boundary part of the inner membrane and the membrane of cristae and reduces the
diffusibility of cytochrome c through these junctions. We postulated that if
significant Ca²⁺ uptake into the matrix occurs from the lumen of the cristae,
reduced expression of OPA1 would increase the access of Ca²⁺ to the transporters
in the crista membrane and thus would enhance Ca²⁺ uptake. In intact H295R
adrenocortical and HeLa cells cytosolic Ca²⁺ signals evoked with K⁺ and
histamine, respectively, were transferred into the mitochondria. The rate and
amplitude of mitochondrial [Ca²⁺] rise (followed with confocal laser scanning
microscopy and FRET measurements with fluorescent wide-field microscopy) were
increased after knockdown of OPA1, as compared with cells transfected with
control RNA or mitofusin1 siRNA. Ca²⁺ uptake was enhanced despite reduced
mitochondrial membrane potential. In permeabilized cells the rate of Ca²⁺ uptake
by depolarized mitochondria was also increased in OPA1-silenced cells. The
participation of Na⁺/Ca²⁺ and Ca²⁺/H⁺ antiporters in this transport process is
indicated by pharmacological data. Altogether, our observations reveal the
significance of OPA1 in the control of mitochondrial Ca²⁺ metabolism.
DOI: 10.1371/journal.pone.0025199
PMCID: PMC3182975
PMID: 21980395 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/10573529 | 1. Hepatology. 1999 Dec;30(6):1490-7. doi: 10.1002/hep.510300620.
The transforming growth factor beta(1)-inducible transcription factor TIEG1,
mediates apoptosis through oxidative stress.
Ribeiro A(1), Bronk SF, Roberts PJ, Urrutia R, Gores GJ.
Author information:
(1)Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
55905, USA.
Transforming growth factor beta(1) (TGF-beta(1))-inducible transcription factors
have recently elicited interest because of their critical role in the regulation
of cell proliferation, differentiation, and apoptosis. We have previously
reported that the TGF-beta(1)-inducible transcription factor, TIEG1, induces
apoptosis in a pancreas-derived cell line. However, the mechanisms underlying
the apoptotic effects of this transcription factor remain to be defined. In this
study, using the TGF-beta(1)-sensitive Hep 3B cell line, we have defined the
mechanistic sequence of events that characterize TIEG1-mediated apoptosis and
compared these events with the changes observed during TGF-beta(1)-induced
apoptosis. Both TGF-beta(1)- and TIEG1-induced cell death were accompanied by an
increase in the generation of reactive oxygen species and a loss of the
mitochondrial membrane potential preceding the morphological changes of
apoptosis. In contrast, increases in caspase 3-like activity and glutathione
(GSH) depletion occurred later in the apoptotic process, concurrent with the
morphological features of apoptosis. The antioxidant, trolox, decreased the
formation of reactive oxygen species and apoptosis. These results demonstrate
that similar to TGF-beta(1), TIEG1 induces apoptosis by a mechanism involving
the formation of reactive oxygen species.
DOI: 10.1002/hep.510300620
PMID: 10573529 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23638205 | 1. PLoS Negl Trop Dis. 2013 Apr 25;7(4):e2184. doi: 10.1371/journal.pntd.0002184.
Print 2013.
Second international diagnostic accuracy study for the serological detection of
West Nile virus infection.
Sanchini A(1), Donoso-Mantke O, Papa A, Sambri V, Teichmann A, Niedrig M.
Author information:
(1)Centre for Biological Threats and Special Pathogens 1 (ZBS1) - Highly
Pathogenic Viruses, Robert Koch-Institut, Nordufer, Berlin, Germany.
sanchinia@rki.de
BACKGROUND: In recent decades, sporadic cases and outbreaks in humans of West
Nile virus (WNV) infection have increased. Serological diagnosis of WNV
infection can be performed by enzyme-linked immunosorbent assay (ELISA),
immunofluorescence assay (IFA) neutralization test (NT) and by
hemagglutination-inhibition assay. The aim of this study is to collect updated
information regarding the performance accuracy of WNV serological diagnostics.
METHODOLOGY/PRINCIPAL FINDINGS: In 2011, the European Network for the
Diagnostics of Imported Viral Diseases-Collaborative Laboratory Response Network
(ENIVD-CLRN) organized the second external quality assurance (EQA) study for the
serological diagnosis of WNV infection. A serum panel of 13 samples (included
sera reactive against WNV, plus specificity and negative controls) was sent to
48 laboratories involved in WNV diagnostics. Forty-seven of 48 laboratories from
30 countries participated in the study. Eight laboratories achieved 100% of
concurrent and correct results. The main obstacle in other laboratories to
achieving similar performances was the cross-reactivity of antibodies amongst
heterologous flaviviruses. No differences were observed in performances of
in-house and commercial test used by the laboratories. IFA was significantly
more specific compared to ELISA in detecting IgG antibodies. The overall
analytical sensitivity and specificity of diagnostic tests for IgM detection
were 50% and 95%, respectively. In comparison, the overall sensitivity and
specificity of diagnostic tests for IgG detection were 86% and 69%,
respectively.
CONCLUSIONS/SIGNIFICANCE: This EQA study demonstrates that there is still need
to improve serological tests for WNV diagnosis. The low sensitivity of IgM
detection suggests that there is a risk of overlooking WNV acute infections,
whereas the low specificity for IgG detection demonstrates a high level of
cross-reactivity with heterologous flaviviruses.
DOI: 10.1371/journal.pntd.0002184
PMCID: PMC3636139
PMID: 23638205 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/18930345 | 1. Cancer Lett. 2009 Feb 8;274(1):101-8. doi: 10.1016/j.canlet.2008.09.017. Epub
2008 Oct 18.
Down-regulation of stathmin is required for TGF-beta inducible early gene 1
induced growth inhibition of pancreatic cancer cells.
Jiang L(1), Chen Y, Chan CY, Wang X, Lin L, He ML, Lin MC, Yew DT, Sung JJ, Li
JC, Kung HF.
Author information:
(1)Institute of Cell Biology, Zhejiang University, Hangzhou, 310058, Zhejiang
Province, People's Republic of China.
Transforming growth factor-beta (TGF-beta) inducible early gene 1 (TIEG1) is
known to induce apoptosis in TGF-beta sensitive pancreatic cancer cells, yet its
effect on TGF-beta resistant cancer cells remains unclear. In this study, TIEG1
was found to induce apoptosis in TGF-beta resistant cancer cells and
concurrently enhanced gemcitabine chemosensitivity. Down-regulation of stathmin
was noted to associate with TIEG1 expression, whilst ectopic overexpression of
stathmin prevented TIEG1 mediated growth inhibition of tumor cells. Small
interfering RNAs targeting stathmin inhibited pancreatic cancer cell growth.
These suggest that stathmin is a downstream target of TIEG1.
DOI: 10.1016/j.canlet.2008.09.017
PMID: 18930345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20079867 | 1. Semin Cell Dev Biol. 2010 Aug;21(6):566-74. doi: 10.1016/j.semcdb.2010.01.002.
Epub 2010 Jan 15.
Mitochondrial fusion proteins: dual regulators of morphology and metabolism.
Zorzano A(1), Liesa M, Sebastián D, Segalés J, Palacín M.
Author information:
(1)Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
antonio.zorzano@irbbarcelona.org
Mitochondria in mammalian cells are visualized as a network or as filaments that
undergo continuous changes in shape and in localization within the cells. These
changes are a consequence of the activity of different processes such as
mitochondrial fusion and fission, and mitochondrial remodelling. In all, these
processes are referred to as mitochondrial dynamics, and relevant questions,
still unexplained, are why cells require such an active dynamics, or why
mitochondria move to specific cellular regions. In this review we will summarize
some of the biological functions assigned to the proteins identified as
participating in mitochondrial fusion, namely mitofusin 1, mitofusin 2 and OPA1.
In addition to the capacity of these proteins to promote fusion, mitofusin 2 or
OPA1 regulate mitochondrial metabolism and loss-of-function reduces oxygen
consumption and the capacity to oxidize substrates. We propose that
mitochondrial fusion proteins operate as integrators of signals so they regulate
both mitochondrial fusion and metabolism.
Copyright 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2010.01.002
PMID: 20079867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16737747 | 1. Biochim Biophys Acta. 2006 May-Jun;1763(5-6):500-9. doi:
10.1016/j.bbamcr.2006.04.003. Epub 2006 Apr 20.
Mitochondrial dynamics and disease, OPA1.
Olichon A(1), Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ,
Mils V, Daloyau M, Hamel C, Amati-Bonneau P, Bonneau D, Reynier P, Lenaers G,
Belenguer P.
Author information:
(1)Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la
Prolifération, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse,
France.
The mitochondria are dynamic organelles that constantly fuse and divide. An
equilibrium between fusion and fission controls the morphology of the
mitochondria, which appear as dots or elongated tubules depending the prevailing
force. Characterization of the components of the fission and fusion machineries
has progressed considerably, and the emerging question now is what role
mitochondrial dynamics play in mitochondrial and cellular functions. Its
importance has been highlighted by the discovery that two human diseases are
caused by mutations in the two mitochondrial pro-fusion genes, MFN2 and OPA1.
This review will focus on data concerning the function of OPA1, mutations in
which cause optic atrophy, with respect to the underlying pathophysiological
processes.
DOI: 10.1016/j.bbamcr.2006.04.003
PMID: 16737747 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20690412 | 1. Int J Oral Sci. 2010 Mar;2(1):1-4. doi: 10.4248/IJOS10008.
Burning mouth syndrome.
Mock D(1), Chugh D.
Author information:
(1)Faculty of Dentistry, University of Toronto, Wasser Pain Management Centre,
Mount Sinai Hospital, Toronto, Canada. david.mock@dentistry.utoronto.ca
Most clinicians dread seeing the patient presenting with a primary complaint of
a burning pain on one or more oral mucosal surfaces. Unlike most other clinical
conditions presenting in a dental office, burning mouth syndrome is recently,
advances have been made towards clarifying the possible etiology of the disorder
and testing the possible therapeutic modalities available. This article attempts
to summarize the "state of the art" today.
DOI: 10.4248/IJOS10008
PMCID: PMC3475590
PMID: 20690412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14970223 | 1. J Biol Chem. 2004 Apr 30;279(18):18792-8. doi: 10.1074/jbc.M400920200. Epub
2004 Feb 16.
Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized
constrictions along the lengths of mitochondria.
Griparic L(1), van der Wel NN, Orozco IJ, Peters PJ, van der Bliek AM.
Author information:
(1)Department of Biological Chemistry, David Geffen School of Medicine, UCLA,
Los Angeles, California 90095, USA.
Mgm1 is a member of the dynamin family of GTP-binding proteins. Mgm1 was first
identified in yeast, where it affects mitochondrial morphology. The human
homologue of Mgm1 is called OPA1. Mutations in the OPA1 gene are the prevailing
cause of dominant optic atrophy, a hereditary disease in which progressive
degeneration of the optic nerve can lead to blindness. Here we investigate the
properties of the Mgm1/OPA1 protein in mammalian cells. We find that Mgm1/OPA1
is localized to the mitochondrial intermembrane space, where it is tightly bound
to the outer surface of the inner membrane. Overexpression of wild type or
mutant forms of the Mgm1/OPA1 protein cause mitochondria to fragment and, in
some cases, cluster near the nucleus, whereas the loss of protein caused by
small interfering RNA (siRNA) leads to dispersal of mitochondrial fragments
throughout the cytosol. The cristae of these fragmented mitochondria are
disorganized. At early time points after transfection with Mgm1/OPA1 siRNA, the
mitochondria are not yet fragmented. Instead, the mitochondria swell and
stretch, after which they form localized constrictions similar to the
mitochondrial abnormalities observed during the early stages of apoptosis. These
abnormalities might be the earliest effects of losing Mgm1/OPA1 protein.
DOI: 10.1074/jbc.M400920200
PMID: 14970223 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25112877 | 1. J Biol Chem. 2014 Sep 26;289(39):27134-27145. doi: 10.1074/jbc.M114.594812.
Epub 2014 Aug 11.
p53 is required for cisplatin-induced processing of the mitochondrial fusion
protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in
gynecologic cancers.
Kong B(1), Wang Q(1), Fung E(1), Xue K(2), Tsang BK(3).
Author information:
(1)Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine,
and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa,
Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research
Institute, Ottawa, Ontario K1H 8L6, Canada, and.
(2)Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario
K1H 8L6, Canada, and; State Key Laboratory of Reproductive Medicine, Clinical
Reproductive Medicine Centre, Nanjing Medical University, Nanjing 210029, China.
(3)Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine,
and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa,
Ontario K1H 8L6, Canada,; Chronic Disease Program, Ottawa Hospital Research
Institute, Ottawa, Ontario K1H 8L6, Canada, and. Electronic address:
btsang@ohri.ca.
Mitochondria are highly dynamic organelles, and mitochondrial fission is a
crucial step of apoptosis. Although Oma1 is believed to be responsible for long
form Opa1 (L-Opa1) processing during mitochondrial fragmentation, whether and
how Oma1 is involved in L-Opa1 processing and participates in the regulation of
chemoresistance is unknown. Chemosensitive and chemoresistant ovarian (OVCA) and
cervical (CECA) cancer cells were treated with cisplatin (CDDP). Mitochondrial
dynamics and protein contents were assessed by immunofluorescence and Western
blot, respectively. The requirements of Oma1 and p53 for CDDP-induced L-Opa1
processing, mitochondrial fragmentation, and apoptosis were examined by siRNA or
cDNA. CDDP induces L-Opa1 processing and mitochondrial fragmentation in
chemosensitive but not in chemoresistant cells. CDDP induced Oma1 40-kDa form
increases in OV2008 cells, not in C13* cells. Oma1 knockdown inhibited L-Opa1
processing, mitochondrial fragmentation, and apoptosis. Silencing p53 expression
attenuated the effects of CDDP in Oma1 (40 kDa) increase, L-Opa1 processing,
mitochondrial fragmentation, and apoptosis in chemosensitive OVCA cells, whereas
reconstitution of p53 in p53 mutant or null chemoresistant OVCA cells induced
Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and
apoptosis irrespective of the presence of CDDP. Prohibitin 1 (Phb1) dissociates
from Opa1-Phb1 complex and binds phosphorylated p53 (serine 15) in response to
CDDP in chemosensitive but not chemoresistant CECA cells. These findings
demonstrate that (a) p53 and Oma1 mediate L-Opa1 processing, (b) mitochondrial
fragmentation is involved in CDDP-induced apoptosis in OVCA and CECA cells, and
(c) dysregulated mitochondrial dynamics may in part be involved in the
pathophysiology of CDDP resistance.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M114.594812
PMCID: PMC4175349
PMID: 25112877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17951258 | 1. J Biol Chem. 2007 Dec 21;282(51):37170-80. doi: 10.1074/jbc.M705414200. Epub
2007 Oct 19.
Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar
granule cells through a TIEG-1-based regulation of Nmyc.
Alvarez-Rodríguez R(1), Barzi M, Berenguer J, Pons S.
Author information:
(1)Department of Cell Death and Proliferation, Institute for Biomedical Research
of Barcelona, IIBB-CSIC-IDIBAPS, 08036 Barcelona, Spain.
Nmyc is a potent regulator of cell cycle in cerebellar granular neuron
precursors (CGNPs) and has been proposed to be the main effector of Shh (Sonic
hedgehog) proliferative activity. Nmyc ectopic expression is sufficient to
promote cell autonomous proliferation and can lead to tumorigenesis. Bone
morphogenetic protein 2 (BMP2) antagonizes Shh proliferative effect by promoting
cell cycle exit and differentiation in CGNPs. Here we report that BMP2 opposes
Shh mitogenic activity by blocking Nmyc expression. We have identified TIEG-1
(KLF10) as the intermediary factor that blocks Nmyc expression through the
occupancy of the Sp1 sites present in its promoter. We also demonstrate that
TIEG-1 ectopic expression in CGNPs induces cell cycle arrest that can lead to
apoptosis but fails to promote differentiation. Moreover, TIEG-1 synergizes with
BMP2 activity to terminally differentiate CGNPs and independent differentiator
signals such as dibutyryl cAMP and prevents apoptosis in TIEG-1 arrested cells.
All together, these data strongly suggest that the BMP2 pathway triggers cell
cycle exit and differentiation as two separated but coordinated processes, where
TIEG-1 acts as a mediator of the cell cycle arrest.
DOI: 10.1074/jbc.M705414200
PMID: 17951258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18625105 | 1. Curr Pain Headache Rep. 2008 Aug;12(4):279-84. doi: 10.1007/s11916-008-0047-9.
Burning mouth syndrome.
Speciali JG(1), Stuginski-Barbosa J.
Author information:
(1)Hospital das Clínicas de Ribeirão Preto (Departamento de Neurologia), Avenida
Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14400-000, Brazil.
speciali@netsite.com.br
Burning mouth syndrome (BMS) is a chronic disease characterized by burning of
the oral mucosa associated with a sensation of dry mouth and/or taste
alterations. BMS occurs more frequently among postmenopausal women. The
pathophysiology of the disease is still unknown, and evidence is conflicting;
although some studies suggest a central origin, others point to a peripheral
neuropathic origin. The efficacy of some medications in the treatment of BMS
suggests that the dopaminergic system may be involved.
DOI: 10.1007/s11916-008-0047-9
PMID: 18625105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14650993 | 1. Hua Xi Kou Qiang Yi Xue Za Zhi. 2003 Oct;21(5):372-3, 382.
[Clinical analysis of the patients with burning mouth syndrome].
[Article in Chinese]
He Y(1), Lin M, Zhang G.
Author information:
(1)Department of Oral Medicine, West China College of Stomatology, Sichuan
University, Chengdu, 610041, China.
OBJECTIVE: Clinical data of burning mouth syndrome were investigated in detail
and the relation to pain was analyzed in order to find a clue to clinical
treatment.
METHODS: 78 patients with burning mouth syndrome were examined carefully and 7
factors that related to the degree of pain were analyzed with multivariate
stepwise regression.
RESULTS: The study demonstrated that the psychological disorder, autonomic
nerves system abnormity, oral dryness and high-extravasated blood level were
positively related to the degree of pain.
CONCLUSION: The study suggested that psychotherapy, improvement of autonomic
nerves system, treatment for oral dryness and Chinese traditional therapy of
invigoration of blood circulation were of great importance in curing burning
mouth syndrome.
PMID: 14650993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12536654 | 1. Hunan Yi Ke Da Xue Xue Bao. 2001 Apr 28;26(2):157-8.
[Clinical efficacy of burning mouth syndrome treated by livial].
[Article in Chinese]
Peng JY(1), Wu YF, Han WN.
Author information:
(1)Department of Stomatology, Xiangya Hospital, Central South University,
Changsha 410008, China.
OBJECTIVE: To observe the clinical efficacy of livial on postmenopause women
with burning mouth syndrome.
METHODS: Fifty six postmenopause women with burning mouth syndrome were randomly
divided into two groups, 26 patients were treated with livial as the treatment
group, 30 patients were treated with oryzanol and vitamin E as the control. To
evaluate the effect, all the patients were observed in 3-6 months after therapy.
RESULTS: The result showed that the total effective rate of the treatment group
was 84.62% after 3 months, 88.46% after 6 months, and significantly higher than
that in the control(P < 0.005).
CONCLUSION: It is indicated that livial is safer and more effective than
nylestriol in treatment with burning mouth syndrome.
PMID: 12536654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10471833 | 1. FEBS Lett. 1999 Sep 3;457(3):478-82. doi: 10.1016/s0014-5793(99)01051-0.
A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell
death in epithelial Mv1Lu cells.
Chalaux E(1), López-Rovira T, Rosa JL, Pons G, Boxer LM, Bartrons R, Ventura F.
Author information:
(1)Departament Ciències Fisiològiques II, Campus de Bellvitge, Universitat de
Barcelona, C/ Feixa Llarga s/n., 08907, Hospitalet de Llobregat, Spain.
Transforming growth factor-beta (TGF-beta) superfamily members constitute a
group of multifunctional factors that are able to stimulate apoptotic cell death
in a variety of cells. In this report, we show that a zinc-finger transcription
factor (TIEG) is an immediate early gene transcriptionally induced by TGF-beta
in the epithelial Mv1Lu cell line. We also demonstrate that, mimicking TGF-beta
effects, ectopic overexpression of TIEG is sufficient to trigger the apoptotic
cell program in these cells, which is preceded by a decrease of Bcl-2 protein
levels. Finally, apoptotic events elicited by TIEG overexpression can be
effectively prevented by ectopic co-expression of Bcl-2. On the basis of these
results we suggest that induction of TIEG expression has a role in the
pro-apoptotic properties of TGF-beta.
DOI: 10.1016/s0014-5793(99)01051-0
PMID: 10471833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12504110 | 1. Biochem Biophys Res Commun. 2003 Jan 10;300(2):482-93. doi:
10.1016/s0006-291x(02)02874-7.
Differential sublocalization of the dynamin-related protein OPA1 isoforms in
mitochondria.
Satoh M(1), Hamamoto T, Seo N, Kagawa Y, Endo H.
Author information:
(1)Department of Biochemistry, Jichi Medical School, 3311-1 Yakushiji,
Minamikawachi-mach, Tochigi 329-0498, Japan.
OPA1 is a cause gene for autosomal dominant optic atrophy and possesses eight
alternative splicing variants. Here, we identified two isoforms of OPA1 proteins
in HeLa cells and examined their submitochondrial localization and complex
formations. RT-PCR shows that HeLa cells mainly express isoforms 7 and 1 of
OPA1. Since the third cleavage site is mainly utilized in HeLa cells, the
predicted molecular masses of their processed proteins are consistent with the
93- and 88-kDa proteins. Biochemical examinations indicate that both of the OPA1
isoforms are present in the intermembrane space. Submitochondrial fractionation
by sucrose density-gradient centrifugation shows that the 88-kDa protein
predominantly associates with the mitochondrial outer membrane, on the contrary,
the 93-kDa protein associates with the inner membrane. Gel filtration analysis
indicates that they compose the different molecular mass complexes in
mitochondria. These differences between two isoforms of OPA1 would suggest their
crucial role involved in the mitochondrial membrane formation.
DOI: 10.1016/s0006-291x(02)02874-7
PMID: 12504110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17308981 | 1. J Neural Transm (Vienna). 2007 Jul;114(7):867-75. doi:
10.1007/s00702-007-0635-6. Epub 2007 Feb 19.
Human TIEG2/KLF11 induces oligodendroglial cell death by downregulation of
Bcl-XL expression.
Wang Z(1), Spittau B, Behrendt M, Peters B, Krieglstein K.
Author information:
(1)Center of Anatomy, Department of Neuroanatomy, University of Goettingen,
Goettingen, Germany.
TGF-beta-induced apoptosis is essential for embryonic development and
mainteanance of adult tissues. Impairment of the apoptotic pathway, regulated by
TGF-beta, plays a center role in tumorigenesis and manifestations of different
diseases. TIEG2/KLF11 is a recently identified human TGF-beta-inducible zinc
finger protein belonging to the family of Sp1/KLF-like transcription factors. In
human and murine tissues it has been shown that TIEG1 and TIEG2 induce apoptosis
and inhibit cell growth. Since TGF-beta and Tieg1 are able to induce apoptosis
in the oligodendroglial cell line OLI-neu, we analysed the ability of TIEG2 to
mimic the effects observed after treatment with TGF-beta and overexpression of
Tieg1. Herein we report that TIEG2 induces Caspase3-dependent apoptosis in
murine OLI-neu cells. Furthermore, we could demonstrate that TIEG2 decreases the
levels of the anti-apoptotic protein Bcl-X(L) and inhibits transcription driven
by the Bcl-X(L) promoter. These data suggest that TIEG2 serves as a downstream
mediator of TGF-beta, bridging TGF-beta-dependent signaling to the intracellular
pathway of apoptosis.
DOI: 10.1007/s00702-007-0635-6
PMID: 17308981 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23772971 | 1. J Oral Pathol Med. 2013 Oct;42(9):649-55. doi: 10.1111/jop.12101. Epub 2013
Jun 16.
Burning mouth syndrome: a review and update.
Sun A(1), Wu KM, Wang YP, Lin HP, Chen HM, Chiang CP.
Author information:
(1)Department of Dentistry, National Taiwan University Hospital, College of
Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of
Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei,
Taiwan.
Burning mouth syndrome (BMS) is characterized by the presence of burning
sensation of the oral mucosa in the absence of clinically apparent mucosal
alterations. It occurs more commonly in middle-aged and elderly women and often
affects the tongue tip and lateral borders, lips, and hard and soft palate. In
addition to a burning sensation, the patients with BMS may also complain
unremitting oral mucosal pain, dysgeusia, and xerostomia. BMS can be classified
into two clinical forms: primary and secondary BMS. The primary BMS is essential
or idiopathic, in which the organic local/systemic causes cannot be identified
and a neuropathological cause is likely. The diagnosis of primary BMS depends
mainly on exclusion of etiological factors. The secondary BMS is caused by
local, systemic, and/or psychological factors; thus, its diagnosis depends on
identification of the exact causative factor. When local, systemic or
psychological factors are present, treatment or elimination of these factors
usually results in a significant clinical improvement of BMS symptoms. Vitamin,
zinc, or hormone replacement therapy has been found to be effective for reducing
the oral burning or pain symptom in some BMS patients with deficiency of the
corresponding factor. If patients still have the symptoms after the removal of
potential causes, drug therapy should be instituted. Previous randomized
controlled clinical trials found that drug therapy with capsaicin, alpha-lipoic
acid, clonazepam, and antidepressants may provide relief of oral burning or pain
symptom. In addition, psychotherapy and behavioral feedback may also help
eliminate the BMS symptoms.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/jop.12101
PMID: 23772971 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19450321 | 1. BMJ Clin Evid. 2008 Mar 14;2008:1301.
Burning mouth syndrome.
Buchanan J(1), Zakrzewska J.
Author information:
(1)Barts and The London School of Medicine and Dentistry, Dental Institute,
Royal London Hospital, London, UK.
INTRODUCTION: Burning mouth syndrome mainly affects women, particularly after
the menopause, when its prevalence may be 18-33%.
METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the
following clinical question: What are the effects of treatments for burning
mouth syndrome? We searched: Medline, Embase, The Cochrane Library, and other
important databases up to February 2007 (Clinical Evidence reviews are updated
periodically, please check our website for the most up-to-date version of this
review). We included harms alerts from relevant organisations such as the US
Food and Drug Administration (FDA) and the UK Medicines and Healthcare products
Regulatory Agency (MHRA).
RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met
our inclusion criteria. We performed a GRADE evaluation of the quality of
evidence for interventions.
CONCLUSIONS: In this systematic review we present information relating to the
effectiveness and safety of the following interventions: anaesthetics (local),
antidepressants, benzodiazepines (topical clonazepam), benzydamine
hydrochloride, cognitive behavioural therapy (CBT), dietary supplements, and
hormone replacement therapy (HRT) in postmenopausal women.
PMCID: PMC2907957
PMID: 19450321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22612823 | 1. Gerodontology. 2012 Jun;29(2):84-9. doi: 10.1111/j.1741-2358.2010.00384.x.
Aetiology and therapeutics of burning mouth syndrome: an update.
Spanemberg JC(1), Cherubini K, de Figueiredo MA, Yurgel LS, Salum FG.
Author information:
(1)Stomatology and Bucomaxillofacial Cancer Prevent Division, São Lucas
Hospital, Pontifical Catholical University of Rio Grande do Sul (PUCRS), Porto
Alegre, Brazil.
OBJECTIVE: To provide a review on the aetiology and therapeutic options for the
management of patients with burning mouth syndrome (BMS).
BACKGROUND: BMS is a chronic disorder that frequently affects women and is
characterised by burning symptoms of the oral mucosa without clinical signs.
This syndrome has a complex and multifactorial characteristics, but its
aetiology remains unknown and this makes it difficult with regard to the
treatment and management of such patients. Despite not being accompanied by
evident organic changes and not presenting risks to health, BMS can
significantly reduce the quality of life for patients.
METHODS AND MATERIALS: The article reviews the literature regarding aetiologic
factors, clinical implications and treatment of BMS.
CONCLUSION: involvement of neurological, emotional and hormonal alterations is
proposed in BMS aetiology. However the mechanisms of its development are complex
and not completely understood. Tricyclic antidepressants, benzodiazepines and
antipsychotic drugs are the most accepted options in treatment and show variable
results. The correct diagnosis of BMS and the exclusion of possible local or
systemic factors that can be associated with the symptoms are fundamental. It is
also important to evaluate the quality of life for these patients to recognise
the potential impact of this condition on their lives.
© 2012 The Gerodontology Society and John Wiley & Sons A/S.
DOI: 10.1111/j.1741-2358.2010.00384.x
PMID: 22612823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11441716 | 1. Ned Tijdschr Tandheelkd. 2001 Jun;108(6):237-41.
[Burning mouth syndrome].
[Article in Dutch]
van der Waal I(1).
Author information:
(1)Uit de afdeling Mondziekten en kaakchirurgie/Orale pathologie/Algemene
ziekteleer van het Vrije Universiteit Medisch Centrum, Amsterdam/Academisch
Centrum Tandheelkunde Amsterdam (ACTA).
Symptoms of a burning sensation of the oral mucosa mainly occur in the elderly,
more often in women than in men. Often accompanying symptoms are complaints of a
dry mouth and taste disturbances, all together referred to as the burning mouth
syndrome. In the majority of cases there is no detectable cause. Although a
psychogenic aetiology has often been put forward, no scientific evidence has
ever been provided on this matter. In the majority of patients the burning mouth
syndrome will disappear spontaneously, although this may take many years.
PMID: 11441716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24164777 | 1. Oral Dis. 2014 Apr;20(3):e1-6. doi: 10.1111/odi.12192. Epub 2013 Oct 25.
Placebo effect in burning mouth syndrome: a systematic review.
Kuten-Shorrer M(1), Kelley JM, Sonis ST, Treister NS.
Author information:
(1)Department of Oral Medicine, Infection, and Immunity, Harvard School of
Dental Medicine, Boston, MA, USA.
Placebo controls play a critical role in the evaluation of any pharmacotherapy.
This review surveys the placebo arm in 12 randomized controlled trials (RCTs)
investigating burning mouth syndrome (BMS) and documents a positive placebo
response in 6 of them. On average, treatment with placebos produced a response
that was 72% as large as the response to active drugs. The lack of homogeneity
in the use of placebos adds to the difficulty in comparing results and
aggregating data. Future RCTs investigating BMS would benefit from larger sample
sizes, adequate follow-up periods, and use of a standard placebo.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/odi.12192
PMID: 24164777 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18343329 | 1. Oral Maxillofac Surg Clin North Am. 2008 May;20(2):255-71, vii. doi:
10.1016/j.coms.2007.12.012.
Burning mouth syndrome: recognition, understanding, and management.
Klasser GD(1), Fischer DJ, Epstein JB.
Author information:
(1)Department of Oral Medicine and Diagnostic Sciences, University of Illinois
at Chicago, College of Dentistry, 801 South Paulina Street, Chicago, IL
60612-7213, USA. gklasser@uic.edu
Burning mouth syndrome (BMS) can be a frustrating condition to the patient and
the practitioner because the patient often experiences a continuous burning pain
in the mouth without any apparent clinical signs, but the practitioner is unable
to definitively diagnose symptoms even with the use of diagnostic testing or
imaging. To overcome this dilemma, it is important for the practitioner to
recognize and understand the complexities of BMS. The practitioner can then
develop a sound approach to management of this condition and patients can be
educated and reassured regarding BMS.
DOI: 10.1016/j.coms.2007.12.012
PMID: 18343329 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21528119 | 1. J Orofac Pain. 2011 Spring;25(2):125-30.
Combined topical and systemic clonazepam therapy for the management of burning
mouth syndrome: a retrospective pilot study.
Amos K(1), Yeoh SC, Farah CS.
Author information:
(1)School of Dentistry, The University of Queensland, Australia.
AIMS: To evaluate retrospectively the efficacy of administering an
anticonvulsant medication, clonazepam, by dissolving tablets slowly orally
before swallowing, for the management of burning mouth syndrome (BMS).
METHODS: A retrospective clinical records audit was performed of patients
diagnosed with BMS between January 2006 and June 2009. Patients were prescribed
0.5 mg clonazepam three times daily, and changes were made to this regimen based
on their individual response. Patients were asked to dissolve the tablet orally
before swallowing and were reviewed over a 6-month period. Pain was assessed by
patients on an 11-point numerical scale (0 to 10). A nonparametric (Spearman)
two-tailed correlation matrix and a two-tailed Mann-Whitney test were performed.
RESULTS: A total of 36 patients (27 women, 9 men) met the criteria for
inclusion. The mean (± SEM) pain score reduction between pretreatment and final
appointment was 4.7 ± 0.4 points. A large percentage (80%) of patients obtained
more than a 50% reduction in pain over the treatment period. One patient
reported no reduction in pain symptoms, and one third of the patients had
complete pain resolution. Approximately one third of patients experienced side
effects that were transient and mild.
CONCLUSION: This pilot study provides preliminary evidence that the novel
protocol of combined topical and systemic clonazepam administration provides an
effective BMS management tool.
PMID: 21528119 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11485137 | 1. Ann Pharmacother. 2001 Jul-Aug;35(7-8):874-6. doi: 10.1345/aph.1Z434.
Burning mouth syndrome after taking clonazepam.
Culhane NS(1), Hodle AD.
Author information:
(1)Pharmacy Practice, Nesbitt School of Pharmacy, Wilkes University,
Wilkes-Barre, PA, USA. sparano@wilkes.edu
OBJECTIVE: To report the first published case of clonazepam-induced burning
mouth syndrome (BMS).
CASE SUMMARY: A 52-year-old white woman presented to the clinic with burning
mouth symptoms. The patient was previously maintained on alprazolam therapy for
anxiety, but was switched to clonazepam because of increased anxiety and panic.
Clonazepam significantly relieved her symptoms, but after four weeks of therapy,
she reported a constant, mild, oral burning sensation. An oral examination was
negative for mucosal abnormalities, and laboratory tests were unremarkable. The
clonazepam dose was reduced, and the symptoms decreased, but remained
intolerable. Clonazepam was discontinued, and the burning mouth symptoms
completely resolved. Since no other medications relieved the anxiety and panic
symptoms, the patient requested clonazepam to be reinitiated, but she again
developed intolerable burning mouth symptoms. As clonazepam was discontinued,
the symptoms resolved.
DISCUSSION: The clinical presentation of BMS includes burning and painful
sensations of the mouth in the absence of mucosal abnormalities. Candidiasis,
anemia, menopause, diabetes mellitus, medications, anxiety, and depression are
some causes of this syndrome. Paradoxically, clonazepam has been studied for the
treatment of BMS and has demonstrated mild to moderate improvement. In this
patient, underlying causes of BMS were eliminated when possible. The association
between clonazepam and BMS was highly probable according to the Naranjo
probability scale.
CONCLUSIONS: This is the first published report describing BMS with a
benzodiazepine. Although uncommon, clinicians should be aware of this potential
adverse effect due to the widespread use of benzodiazepines.
DOI: 10.1345/aph.1Z434
PMID: 11485137 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2811814 | 1. Minerva Stomatol. 1989 Sep;38(9):999-1002.
[Burning mouth syndrome].
[Article in Italian]
Nicolò M, Amato M, Bolletti Censi M.
The burning mouth syndrome is a pathology characterized by burning oral mucoses.
The etiological factors can be numerous. The Authors suggest a nosologic
classification of this disease.
PMID: 2811814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1508523 | 1. Oral Surg Oral Med Oral Pathol. 1992 Aug;74(2):158-67. doi:
10.1016/0030-4220(92)90376-2.
Burning mouth syndrome. Critical review and proposed clinical management.
Tourne LP(1), Fricton JR.
Author information:
(1)Department of TMJ and Craniofacial Pain, University of Minnesota,
Minneapolis.
Burning mouth syndrome is characterized by a burning sensation in one or several
oral structures. Multiple causal factors have been proposed, and reports on
their relative importance are conflicting. Lack of diagnostic criteria,
differences in sampling procedures, incomplete workups, and lack of controlled
studies make the reliable interpretation of the importance of proposed causal
factors and the efficacy of specific treatment modalities difficult. This
article summarizes the available data, critically analyzes their scientific
merit, and proposes a protocol for clinical management.
DOI: 10.1016/0030-4220(92)90376-2
PMID: 1508523 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22750263 | 1. Bull Group Int Rech Sci Stomatol Odontol. 2010 May 21;49(1):19-29.
Response to topical clonazepam in patients with burning mouth syndrome: a
clinical study.
Rodríguez de Rivera Campillo E(1), López-López J, Chimenos-Küstner E.
Author information:
(1)Dentistry Department, Faculty of Dentistry, University of Barcelona, Spain.
Burning Mouth Syndrome (BMS) is a difficult disease for patients and clinicians.
Moreover, there is not a general consensus on how to treat the disease. The main
objective of this paper is to evaluate BMS patients' response to topical
clonazepam treatment. A double blind study was performed. Among a total of 66
patients, 33 were treated with tablets of clonazepam and another 33 were treated
with a placebo. Symptoms were evaluated after 1 month and 6 months of treatment
and scored on an analogical scale from 0 to 10. Among the 33 patients treated
with clonazepam, 23 showed at least a 50% reduction in symptoms after 1 month of
treatment. On the contrary, only 4 in the placebo group exhibited significant
improvement. After 6 months, significant differences were observed again, as 23
of the 33 patients treated with the drug reported at least a 50% reduction in
symptoms, whereas only 2 among those treated with the placebo significantly
improved. However, when measured in terms of a complete cure (lack of symptoms),
the differences were not significant: 5 drug-treated patients and one belonging
to the placebo group were asymptomatic after one month of treatment. In summary,
it seems that clonazepam applied topically was effective in treating BMS in a
large proportion of patients.
PMID: 22750263 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16903201 | 1. Gen Dent. 2006 Jul-Aug;54(4):267-71; quiz 272, 289-90.
A retrospective evaluation of 56 patients with oral burning and limited clinical
findings.
Brown RS(1), Farquharson AA, Sam FE, Reid E.
Author information:
(1)Department of Oral Diagnostic Services, Howard University College of
Dentistry, Washington, DC, USA.
This study retrospectively evaluated the charts of 56 patients who had been
referred to an oral medicine clinic between 1995 and 2004 with oral burning and
limited clinical findings. Of the 56 patients, 35 had a final diagnosis of
essential burning mouth disorder (EBMD). Five patients with EBMD had a family
history of diabetes and two had been diagnosed with late-onset diabetes. Other
oral burning diagnoses included sialoadenitis (burning lips syndrome),
irritation or allergic reactions to triclosan, diabetic neuropathy, subclinical
oral candidiasis, nutritional deficiency/neuropathy, and a drug reaction to an
ACE inhibitor (scalded mouth syndrome) that resulted in oral burning.
PMID: 16903201 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8323246 | 1. Ann Dent. 1993 Summer;52(1):21-5.
Burning mouth syndrome: a selective review.
Maresky LS(1), Gird I, van der Bijl P.
Author information:
(1)Department of Oral Medicine and Periodontics, Faculty of Dentistry,
University of Stellenbosch, Tygerberg, South Africa.
Burning mouth syndrome (BMS) has been associated with a wide variety of
etiological factors. A selective review of these factors as well as an approach
to the management of this condition are presented.
PMID: 8323246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9844361 | 1. Mt Sinai J Med. 1998 Oct-Nov;65(5-6):343-7.
Burning mouth syndrome.
Miyamoto SA(1), Ziccardi VB.
Author information:
(1)Department of Oral and Maxillofacial Surgery, New Jersey Dental School,
University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA.
Complaint of a burning mouth is an increasingly common problem in the aging
population. This has remained an enigma for the treating clinician, because
visible pathologic lesions or processes are usually not evident. Local, systemic
and environmental causes must be assessed to elicit the predisposing factors.
Some suggestions for managing burning mouth syndrome are offered.
PMID: 9844361 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14765022 | 1. Minerva Stomatol. 2003 Dec;52(11-12):507-21.
[Burning mouth syndrome].
[Article in Italian]
Forabosco A(1), Negro C.
Author information:
(1)Cattedra di Parodontologia, Istituto di Clinica Odontoiatrica, Università
degli Studi di Modena e Reggio Emilia, Modena e Reggio Emilia, Italy.
forabosco.andrea@unimo.it
Burning Mouth Syndrome (BMS) is a frequent disease characterized by a burning or
painful sensation in the tongue and/or other oral sites without clinical mucosal
abnormalities or lesions. The etiopathology is unknown although local, systemic
and psychological factors have been connected with BMS. As this syndrome is a
multifactorial disease, the diagnostic and therapeutic approach should be
multidisciplinary. In this paper a review of the literature is presented and the
most recent advancement on clinical, etiologic, diagnostic and therapeutic
aspects of BMS are discussed.
PMID: 14765022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2726203 | 1. Oral Surg Oral Med Oral Pathol. 1989 Apr;67(4):390-2. doi:
10.1016/0030-4220(89)90379-4.
The usefulness of the HAD scale in assessing anxiety and depression in patients
with burning mouth syndrome.
Lamey PJ(1), Lamb AB.
Author information:
(1)Department of Oral Medicine and Pathology, Glascon Dental Hospital and
School, Scotland.
A recent index of anxiety and depression (Hospital Anxiety and Depression Scale)
was applied to 74 patients with burning mouth syndrome. The scale pointed to
anxiety, more than depression, being a feature of burning mouth syndrome. The
validity and clinical application of this scale to assess anxiety and depression
in such patients are discussed.
DOI: 10.1016/0030-4220(89)90379-4
PMID: 2726203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8543701 | 1. J Am Acad Dermatol. 1996 Jan;34(1):91-8. doi: 10.1016/s0190-9622(96)90840-3.
The burning mouth syndrome.
Huang W(1), Rothe MJ, Grant-Kels JM.
Author information:
(1)Department of Oral Diagnosis/Pathology, University of Connecticut Health
Center, Farmington, USA.
The burning mouth syndrome is characterized by burning and painful sensations of
the mouth in the absence of significant mucosal abnormalities. For patients in
whom no causative factor can be identified, empiric antifungal, nutritional, and
estrogen replacement therapy can be initiated. If these fail, long-term therapy
with antidepressants, benzodiazepines, and clonazepam can be considered. Topical
capsaicin and laser therapy have been reported beneficial in a few patients.
DOI: 10.1016/s0190-9622(96)90840-3
PMID: 8543701 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24558551 | 1. J Clin Exp Dent. 2012 Jul 1;4(3):e180-5. doi: 10.4317/jced.50764. eCollection
2012 Jul.
Burning mouth syndrome: A diagnostic and therapeutic dilemma.
Aggarwal A(1), Panat SR(2).
Author information:
(1)MDS, Senior Lecturer. Department of Oral Medicine and Radiology, Institute of
Dental Sciences, Bareilly (U.P), India.
(2)MDS, Principal, Professor and Head. Department of Oral Medicine and
Radiology, Institute of Dental Sciences, Bareilly (U.P), India.
Burning mouth syndrome (BMS) has been considered an enigmatic condition because
the intensity of pain rarely corresponds to the clinical signs of the disease.
Various local, systemic and psychological factors are associated with BMS, but
its etiology is not fully understood. Also there is no consensus on the
diagnosis and classification of BMS. A substantial volume of research has been
focused on BMS during the last two decades. Progress has been made but the
condition remains a fascinating, yet poorly understood area, in the field of
oral medicine. Recently, there has been a resurgence of interest in this
disorder with the discovery that the pain of BMS may be neuropathic in origin
and originate both centrally and peripherally. The aim of this paper is to
explore the condition of BMS with the specific outcome of increasing awareness
of the condition. Key words:Burning mouth syndrome, stomatodynia, oral
dysesthesia, pain management.
DOI: 10.4317/jced.50764
PMCID: PMC3917644
PMID: 24558551 |
http://www.ncbi.nlm.nih.gov/pubmed/22669143 | 1. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Mar;113(3):373-7. doi:
10.1016/j.oooo.2011.09.005.
Effect of an herbal compound for treatment of burning mouth syndrome:
randomized, controlled, double-blind clinical trial.
Spanemberg JC(1), Cherubini K, de Figueiredo MA, Gomes AP, Campos MM, Salum FG.
Author information:
(1)School of Dentistry, Oral Medicine Division, São Lucas Hospital, Pontifical
Catholical University of Rio Grande do Sul, Porto Alegre, Brazil.
jcs.odonto@yahoo.com.br
OBJECTIVE: This randomized, double-blind, placebo-controlled clinical study
aimed at evaluating the effect of the systemic use of an herbal compound
(Catuama) on the symptoms of burning mouth syndrome (BMS).
STUDY DESIGN: Seventy-two patients with BMS were randomly allocated into test (n
= 38) and control (n = 34) groups. Patients were instructed to take 2 capsules
each day for 8 weeks. They were reassessed at 4, 8, and 12 weeks after treatment
onset using a faces scale (FS) and a visual numeric scale (VNS).
RESULTS: Although both groups demonstrated a reduction in symptoms, the
improvement observed in the test group was significantly greater than in the
control group after 4 (FS: P = .010) and 8 (VNS: P = .03; FS: P < .001) weeks of
treatment. This significant reduction was maintained 12 weeks after treatment
onset (FS, VNS: P = .001).
CONCLUSIONS: The systemic administration of Catuama reduces the symptoms of BMS
and may be a novel therapeutic strategy for the treatment of this disease.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.oooo.2011.09.005
PMID: 22669143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22344742 | 1. Laryngoscope. 2012 Apr;122(4):813-6. doi: 10.1002/lary.22490. Epub 2012 Feb
16.
A double-blind study on clonazepam in patients with burning mouth syndrome.
Heckmann SM(1), Kirchner E, Grushka M, Wichmann MG, Hummel T.
Author information:
(1)School of Dental Medicine, University of Erlangen-Nuremberg, Erlangen,
Germany.
OBJECTIVES/HYPOTHESIS: In the treatment of burning mouth syndrome (BMS), various
approaches have been tried with equivocal results. The aim of the present
randomized clinical trial was to determine the efficacy of clonazepam, a GABA
agonist designed as an antiepileptic drug that exerts the typical effects of
benzodiazepines.
STUDY DESIGN: Randomized clinical trial.
METHODS: Twenty patients with idiopathic BMS were carefully selected. Clonazepam
(0.5 mg/day, n = 10) or placebo (lactose, n = 10) were randomly assigned to the
patients.
RESULTS: Patients on clonazepam significantly improved in pain ratings (P <
.001). These changes were less pronounced in the placebo group (P < .11). No
significant changes were observed in a mood scale (P = .56) or for depression
scores (P = .56). Taste test and salivary flow increased over sessions, but were
not different between groups (P = .83 and P = .06, respectively).
CONCLUSIONS: Clonazepam appears to have a positive effect on pain in BMS
patients.
Copyright © 2011 The American Laryngological, Rhinological, and Otological
Society, Inc.
DOI: 10.1002/lary.22490
PMID: 22344742 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21743415 | 1. Med Oral Patol Oral Cir Bucal. 2012 Jan 1;17(1):e1-4. doi:
10.4317/medoral.17219.
Application of a capsaicin rinse in the treatment of burning mouth syndrome.
Silvestre FJ(1), Silvestre-Rangil J, Tamarit-Santafé C, Bautista D.
Author information:
(1)Department of Stomatology, University of Valencia, Valencia, Spain.
francisco.silvestre@uv.es
OBJECTIVE: To examine the efficacy of a new topical capsaicin presentation as an
oral rinse in improving the symptoms of burning mouth syndrome (BMS).
STUDY DESIGN: A prospective, double-blind, cross-over study was made of 30
patients with BMS. There were 7 dropouts; the final study series thus comprised
23 individuals. The patients were randomized to two groups: (A) capsaicin rinse
(0.02%) or (B) placebo rinse, administered during one week. After a one-week
washout period, the patients were then assigned to the opposite group. Burning
discomfort was scored using a visual analog scale (VAS): in the morning before
starting the treatment, in the afternoon on the first day of treatment, and at
the end of the week of treatment in the morning and in the afternoon. The same
scoring sequence was again applied one week later with the opposite rinse.
RESULTS: The mean patient age was 72.65 ± 12.10 years, and the duration of BMS
was 5.43 ± 3.23 years on average. Significant differences in VAS score were
recorded in the capsaicin group between baseline in the morning (AM1) or
afternoon (AA1) and the end of the week of treatment (AA7)(p=0.003 and p=0.002,
respectively).
CONCLUSION: The topical application of capsaicin may be useful in treating the
discomfort of BMS, but has some limitations.
DOI: 10.4317/medoral.17219
PMCID: PMC3448200
PMID: 21743415 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11297621 | 1. J Clin Endocrinol Metab. 2001 Apr;86(4):1801-5. doi: 10.1210/jcem.86.4.7419.
Somatic mutation and germline variants of MINPP1, a phosphatase gene located in
proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.
Gimm O(1), Chi H, Dahia PL, Perren A, Hinze R, Komminoth P, Dralle H, Reynolds
PR, Eng C.
Author information:
(1)Clinical Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State
University, Columbus, Ohio 43210, USA.
Various genes have been identified to play a role in the pathogenesis of
follicular thyroid tumors. Cowden syndrome is the only known familial syndrome
with an increased risk of both follicular thyroid adenoma (FA) and carcinoma
(FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a
dual-specificity phosphatase, have been found in up to 80% of patients with
Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular
thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to
10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of
markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene,
MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove
3-phosphate from inositol phosphate substrates, a function that overlaps that of
PTEN. Because of this overlapping function with PTEN and the physical location
of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we
considered it to be an excellent candidate gene that could contribute to the
pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and
corresponding normal tissue from 23 patients with FA and 15 patients with FTC
for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant
and three benign tumors. One of these FTCs with LOH was found to harbor a
somatic c.122C > T or S41L mutation. We also found two germline sequence
variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was
found in only one patient with FA but not in patients with FTC or normal
controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases
and normal controls but not in patients with FTC. These results suggest a role
for MINPP1 in the pathogenesis of at least a subset of malignant follicular
thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele
for FTC.
DOI: 10.1210/jcem.86.4.7419
PMID: 11297621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3101339 | 1. Acta Endocrinol (Copenh). 1987 Jan;114(1):41-6. doi: 10.1530/acta.0.1140041.
Serum concentrations of thyrotropin, thyroxine, triiodothyronine and thyroxine
binding globulin in female endurance runners and joggers.
Hohtari H, Pakarinen A, Kauppila A.
The effects of endurance training and season on the function of the anterior
pituitary-thyroid axis were studied in 18 female runners and their 12 controls,
and in 13 joggers and their 11 controls in Northern Finland, with a large
seasonal difference in environmental factors. The serum concentrations of
thyrotropin (TSH), thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3),
thyroxine binding globulin (TBG) and oestradiol (E2) were measured during one
menstrual cycle in the light training season (autumn) and in the hard training
season (spring). The responses of TSH to intravenous TRH stimulation were also
measured in the luteal phase of the cycle during the hard training season.
Endurance running did not affect the basal or TRH-stimulated serum TSH
concentrations, while those of T4 and fT4 in runners were lowered in both
seasons and that of T3 in the light training season in relation to control
subjects. The serum concentrations of TBG were also significantly lower in
runners than their controls in the luteal phase in both seasons. The effect of
jogging on thyroid hormones was less pronounced. Serum concentrations of TSH,
T4, fT4, T3 and TBG were generally slightly higher in spring than in autumn.
Strenuous endurance training seems to have minor changes on the function of the
thyroid gland. Depressed T4 levels in runners may rather be due to lowered TBG
levels than due to direct effect of training. In spring the function of anterior
pituitary-thyroid axis is more active than in autumn.
DOI: 10.1530/acta.0.1140041
PMID: 3101339 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7198038 | 1. Eur J Appl Physiol Occup Physiol. 1981;47(3):281-8. doi: 10.1007/BF00422473.
Circulating reverse triiodothyronine in humans during exercise.
Premachandra BN, Winder WW, Hickson R, Lang S, Holloszy JO.
Circulating thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine
(rT3) as well as blood lactate and glucose concentrations were measured in a
group of 12 trained volunteer subjects prior to and after swimming 0.18 or 0.9
km, to determine if increase in metabolic activity was accompanied by diversion
of T4 monodeiodination from the active (T4 to T3) to the inactive (T4 to rT3)
pathway. The resting T4, T3, and rT3 levels were 8.5 micrograms . 100 ml-1, 108
ng . 100 ml-1, and 57 ng . 100 ml-1, respectively, whereas after 0.18 km of
swimming the corresponding levels were 9.5 micrograms . 100 ml-1, 135 ng. 100
ml-1 and 70 ng . 100 ml-1. After 0.9 km of swimming, T4, T3, and rT3 levels were
9.0 micrograms . 100 ml-1, 126 ng . 100 ml-1, and 66 ng . 100 ml-1,
respectively. The swimming was accompanied by hemoconcentration and increase in
blood lactate but not in glucose concentrations. In two other investigations
thyroid hormones were measured prior to and after 60 or 90 min of moderate
exercise on a bicycle ergometer. This exercise had no effect on circulating
thyroid hormone levels. Free thyroxine (FT4) concentration and thyroxine binding
globulin (TBG) capacity were unaltered after exercise. In conclusion, brief
strenuous swimming or moderate bicycle exercise had minor or no effect on
thyroid hormone concentrations when consideration was given to the attendant
hemoconcentration. Even when exercise induced small T3 and rT3 changes were
noted, they were in the same direction (increase) thus demonstrating a lack of
diversion of peripheral T4 monodeiodination.
DOI: 10.1007/BF00422473
PMID: 7198038 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14637241 | 1. Physiol Behav. 2003 Nov;80(2-3):399-403. doi: 10.1016/j.physbeh.2003.09.005.
Deiodinating activity in the brown adipose tissue of rats following short cold
exposure after strenuous exercise.
Sullo A(1), Brizzi G, Maffulli N.
Author information:
(1)Department of Experimental Medicine, Human Physiology Section, Faculty of
Medicine and Surgery, Second University of Naples, Napoli, Via Costantinopoli
16, 80138, Naples, Italy. alessiosulo@virgilio.it
Interscapular brown adipose tissue (IBAT) activity is controlled by the
sympathetic nervous system, and factors that influence thermogenesis appear to
act centrally to modify the sympathetic outflow to IBAT. Cold exposure produces
a rise in IBAT temperature as a result of the increase in sympathetic outflow to
IBAT. This is associated with an increased thyroid activity.
3,5,3'-triiodothyronine (T3) and T4 levels increase during strenuous exercise,
and, at the end of the exercise bout, a decrease of T3 and T4 levels, with an
increase in TSH during the following 4-5 days, is seen. We evaluated the effect
of strenuous exercise on 5'-deiodinase (5'-D) activity in IBAT in normal
environmental conditions and after short (30 min) cold exposure. 5'-D activity
is lower in rats at basal condition. Short cold exposure (SCE) increases 5'-D in
IBAT both in exercising rats and in sedentary rats. However, this increase is
lower in exercising animals. Strenuous exercise can reduce 5'-D activity in
normal environmental conditions and after SCE. Probably, other compensatory
mechanisms of heat production are active in exercising rodents.
DOI: 10.1016/j.physbeh.2003.09.005
PMID: 14637241 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8743723 | 1. Jpn J Physiol. 1996 Feb;46(1):93-8. doi: 10.2170/jjphysiol.46.93.
Hormonal responses in strenuous jumping effort.
Bosco C(1), Tihanyl J, Rivalta L, Parlato G, Tranquilli C, Pulvirenti G, Foti C,
Viru M, Viru A.
Author information:
(1)University of Rome-Tor Vergata, Fondazione Don Gnocchi, Italy.
In order to test the possibility for rapid responses of blood hormone levels in
short-term supramaximal exercises, serum concentrations of corticotropin (ACTH),
cortisol (C), total testosterone (tT), free testosterone (fT), growth hormone
(GH), thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3),
prolactin (PRL), insulin-like growth factor (IGF-I), and sex hormone-binding
globulin (SHBG) were determined by RIA procedures in blood samples obtained
before and immediately after a 60-s period of consecutive vertical jumps (Bosco
test). The study subjects were 16 Italian professional soccer players.
Immediately after exercise, significant increases (p < 0.05) were found in the
concentrations of ACTH (by 39%), C (by 14%), TSH (by 20%), fT3 (by 28%), fT4 (by
30%), tT (by 12%), fT (by 13%), and SHBG (by 21%). Significant changes were not
detected in the blood levels of GH, IGF-I and PRL. Most pronounced testosterone
responses were typical for persons of high jumping performance (the increase of
serum tT correlated with average power output, r = 0.61 and jumping height, r =
0.66). The larger the drop in power output during 60-s jumping, the higher was
the thyroid response: the difference in jumping height between the first and
last 15-s period correlated with increases in TSH (r = 0.52) and in fT4, (r =
0.55). In conclusion, the obtained results indicate that in intense exercise,
causing the rapid development of fatigue, rapid increases in serum levels of
hormones of the pituitary-adrenocortical, pituitary-gonadal and
pituitary-thyroid systems occur.
DOI: 10.2170/jjphysiol.46.93
PMID: 8743723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18057380 | 1. Eur J Endocrinol. 2007 Dec;157(6):733-40. doi: 10.1530/EJE-07-0355.
Endocrine and metabolic responses to extreme altitude and physical exercise in
climbers.
Benso A(1), Broglio F, Aimaretti G, Lucatello B, Lanfranco F, Ghigo E, Grottoli
S.
Author information:
(1)Division of Endocrinology and Metabolism, Department of Internal Medicine,
Molinette Hospital, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.
CONTEXT: Chronic hypoxia induces complex metabolic and endocrine adaptations.
High-altitude (HA) exposure is a physiological model of hypoxia.
OBJECTIVE: To further investigate the endocrine and metabolic responses to
extreme HA.
METHODS: We studied nine male elite climbers at sea level and at 5200 m after
climbing Mt. Everest.
RESULTS: After 7 weeks at HA, body weight was reduced (P<0.05); regarding
endocrine variables we observed: a) an increase of 2-h mean GH concentration
(P<0.05) as well as of total IGF-I and IGF binding protein-3 levels (P<0.05 for
both); b) a prolactin increase (P<0.05) coupled with testosterone decrease
(P<0.01) and progesterone increase (P<0.05) without any change in estradiol
levels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate
(DHEAS) levels; d) an increase in free thyroxine (P<0.05) and free
tri-iodothyronine (T(3)) decrease (P<0.05) but no change in TSH levels; e) a
plasma glucose decrease (P<0.05) without any change in insulin levels; f) an
increase in mean free fatty acid levels (P<0.05); g) despite body weight loss,
leptin levels showed non-significant trend toward decrease, while ghrelin levels
did not change at all.
CONCLUSIONS: The results of the present study in a unique experimental human
model of maximal exposure to altitude and physical exercise demonstrate that
extreme HA and strenuous physical exercise are coupled with specific endocrine
adaptations. These include increased activity of the GH/IGF-I axis and a low
T(3) syndrome but no change in ghrelin and leptin that was expected taking into
account body weight decrease. These findings would contribute to better
understanding human endocrine and metabolic physiology in hypoxic conditions.
DOI: 10.1530/EJE-07-0355
PMID: 18057380 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/596247 | 1. Acta Med Scand. 1977;202(6):463-7. doi: 10.1111/j.0954-6820.1977.tb16866.x.
Effects of prolonged, strenuous exercise on lipids and thyroxine in serum.
Kirkeby K, Srömme SB, Bjerkedal I, Hertzenberg L, Refsum HE.
Serum lipids and thyroxine were determined in 26 men participating in a 90-km
cross-country ski race, before, immediately after, and on the following days.
Serum cholesterol was unchanged immediately after the race, but then fell
significantly and remained low during the observation period. During the race
the fatty acid composition of serum free fatty acids changed towards the
composition of ordinary adipose tissue. The compostiion of serum triglycerides
showed similar but less pronouced changes. On the following days an increase in
the arachidonic, and a decrease in the linoleic acid fraction of the total serum
lipids were observed. Total thyroxine and free thyroxine in serum were
significantly increased at the end of the race, but had returned to the
pre-raced levels during the rest of the observation period. The observations
correspond to the findings during acute, severe illness, and are compatible with
the hypothesis that some of the changes in serum lipids following severe somatic
stress are due to increased thyroid hormone activity.
DOI: 10.1111/j.0954-6820.1977.tb16866.x
PMID: 596247 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8325717 | 1. Int J Sports Med. 1993 May;14(4):191-5. doi: 10.1055/s-2007-1021162.
Endocrine parameters in amenorrheic and eumenorrheic adolescent female runners.
Baer JT(1).
Author information:
(1)Virginia Polytechnic Institue and State University, Department of Human
Nutrition and Foods, Blacksburg 24061.
The purpose of the present study was to compare endocrine parameters reflecting
reproductive function and metabolism in ten amenorrheic (AR) and eumenorrheic
(ER) adolescent female runners and seven untrained controls (SE). Additionally,
responses to diagnostic criteria for eating disorders (DSM-III) were compared
among groups. AR ran more miles/day and consumed fewer kcal/d to support energy
expenditure compared to ER (p < 0.05). Mean levels of fasting plasma estradiol,
luteinizing hormone, follicle-stimulating hormone, free thyroxine and
triiodothyronine were significantly lower in AR compared to ER and SE. AR
indicated they were very concerned about their weight and were fearful of
gaining fat mass. Female adolescents who participate in strenuous training
exhibit alterations in hormone levels reflecting reproductive function and
metabolism.
DOI: 10.1055/s-2007-1021162
PMID: 8325717 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23446346 | 1. Nature. 2013 Mar 21;495(7441):384-8. doi: 10.1038/nature11993. Epub 2013 Feb
27.
Natural RNA circles function as efficient microRNA sponges.
Hansen TB(1), Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J.
Author information:
(1)Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers
Alle 3, 8000C, Aarhus, Denmark.
Comment in
Nature. 2013 Mar 21;495(7441):322-4. doi: 10.1038/nature11956.
Mol Ther. 2013 Jun;21(6):1112-4. doi: 10.1038/mt.2013.101.
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene
expression that act by direct base pairing to target sites within untranslated
regions of messenger RNAs. Recently, miRNA activity has been shown to be
affected by the presence of miRNA sponge transcripts, the so-called competing
endogenous RNA in humans and target mimicry in plants. We previously identified
a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show
that this circRNA acts as a miR-7 sponge; we term this circular transcript
ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively
conserved miRNA target sites, and it is highly and widely associated with
Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is
completely resistant to miRNA-mediated target destabilization, it strongly
suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In
the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7,
particularly in neocortical and hippocampal neurons, suggesting a high degree of
endogenous interaction. We further show that the testis-specific circRNA,
sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that
miRNA sponge effects achieved by circRNA formation are a general phenomenon.
This study serves as the first, to our knowledge, functional analysis of a
naturally expressed circRNA.
DOI: 10.1038/nature11993
PMID: 23446346 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22044166 | 1. Community Dent Oral Epidemiol. 2012 Apr;40(2):185-92. doi:
10.1111/j.1600-0528.2011.00645.x. Epub 2011 Nov 1.
Cost-effectiveness analysis of burning mouth syndrome therapy.
Hens MJ(1), Alonso-Ferreira V, Villaverde-Hueso A, Abaitua I, Posada de la Paz
M.
Author information:
(1)Rare Diseases Research Institute, Instituto de Salud Carlos III, Madrid,
Spain.
OBJECTIVE: To study the cost-effectiveness of four alternative treatments for
burning mouth syndrome (BMS).
METHODS: A cost-effectiveness analysis was conducted from a healthcare payer
perspective of four therapy strategies (amisulpride, paroxetine, sertraline and
topical clonazepam), using a decision-tree model that incorporated direct
healthcare costs and probabilities associated with the possible events and
outcomes. Average cost-effectiveness and incremental cost-effectiveness ratios
were calculated. Sensitivity analyses included the costs of brand name and
generic drugs in five European countries (France, Italy, the Netherlands, Spain
and UK), as well as two scenarios with different treatment length.
RESULTS: Of the drugs analysed, topical clonazepam proved to be the most
cost-effective therapy. Although generic proved more efficient than brand name
drugs, they displayed no advantage over brand name topical clonazepam. The
Netherlands was the country with the highest overall drug efficiency.
Sensitivity analyses highlighted the robustness of the model, because topical
clonazepam proved to be the most efficient therapy under all the different
scenarios.
CONCLUSIONS: Topical clonazepam, which previous analyses of clinical evidence
have shown to be the drug of choice for BMS, also proved to be the most
cost-effective of the drugs analysed for this condition.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0528.2011.00645.x
PMID: 22044166 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16175495 | 1. Horm Metab Res. 2005 Sep;37(9):563-5. doi: 10.1055/s-2005-870428.
The impact of exercise on thyroid hormone metabolism in children and
adolescents.
Kanaka-Gantenbein C(1).
Author information:
(1)Unit of Endocrinology, Diabetes and Metabolism, Agia Sophia Children's
Hospital, Thivon & Livadias, 11527 Athens, Greece. ganten@hol.gr
Thyroid hormones are important regulators of energy metabolism and may influence
energy processes during physical exercise. There are controversial results
concerning thyroid hormone metabolism during strenuous exercise in adult
athletes and only scant data concerning the impact of strenuous exercise on
thyroid hormone metabolism in children and adolescents. Although some studies
demonstrate a transient change in thyroid hormones during intense physical
performance, most studies agree that these changes are of minor impact,
practically reflecting the relative negative energy balance during strenuous
exercise. This state of hypometabolism during intense physical performance has
also been confirmed in highly trained female young athletes, who may be also
characterized by reproductive axis dysfunction, manifested either as
luteal-phase deficiency or amenorrhea, alongside the typical constellation of
low T3, insulin and leptin levels. More importantly, strenuous exercise during
childhood or adolescence is mostly accompanied by a delay of skeletal
maturation, and height and may have a long-lasting negative effect on growth and
acquisition of maximum bone mass. In conclusion, although thyroid hormones are
only transiently or insignificantly changed during strenuous exercise, adequate
caloric intake should be guaranteed in highly performing young athletes in order
to counteract the relative negative energy balance and prevent alterations in
endocrine-metabolic profile. Moreover, when growth and pubertal progression in
very young athletes are significantly impaired, a reduction in the intensity of
the physical exercise should be advocated in order to guarantee better final
height and adequate acquisition of bone mass.
DOI: 10.1055/s-2005-870428
PMID: 16175495 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2807143 | 1. Horm Metab Res. 1989 Oct;21(10):542-5. doi: 10.1055/s-2007-1009283.
Flight effects on plasma levels of lipid, glucagon and thyroid hormones in
homing pigeons.
George JC(1), John TM, Mitchell MA.
Author information:
(1)Department of Zoology, University of Guelph, Ontario, Canada.
Significant increases in the concentration of plasma glucagon-like
immunoreactivity (GLI) and plasma levels of free fatty acids (FFA) and
triglycerides (TG) concomitant with decreases in circulating levels of thyroxine
(T4) and triiodothyronine (T3) and T3/T4 ratio were observed in homing pigeons,
untrained for 3 months, after a flight of 48 km lasting 90-160 min. The
increased level of FFA is attributed to glucagon stimulated lipolysis. The
elevation of TG levels may be due to altered partitioning and utilization of
lipoprotein in adipose tissue and muscle. Reductions in plasma T4, T3 and T3/T4
ratio are probably due to inhibition of T4 secretion and 5'-monodeiodination
with possible conversion of T4 to reverse T3 (rT3). These processes may
represent a mechanism for regulation of thyroid hormone metabolism during
strenuous and extended flight.
DOI: 10.1055/s-2007-1009283
PMID: 2807143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22137083 | 1. Am Heart J. 2011 Dec;162(6):1088-1095.e1. doi: 10.1016/j.ahj.2011.07.028. Epub
2011 Nov 8.
Mutations in the human phospholamban gene in patients with heart failure.
Medeiros A(1), Biagi DG, Sobreira TJ, de Oliveira PS, Negrão CE, Mansur AJ,
Krieger JE, Brum PC, Pereira AC.
Author information:
(1)Department of Biosciences, Federal University of São Paulo, Santos, Brazil.
BACKGROUND: Phospholamban (PLN) is a crucial Ca(2+) cycling protein and a
primary mediator of the β-adrenergic effects resulting in enhanced cardiac
output. Mutations in the gene encoding PLN have been associated with idiopathic
dilated cardiomyopathy; however, no systematic search for PLN mutations in heart
failure has been conducted.
METHODS: We screened a cohort of 1,014 Brazilian patients with heart failure for
mutations in the PLN gene. Molecular modeling studies of the mutations found
were developed. Different disease etiologies were present in our sample:
idiopathic, ischemic, Chagas, valvular, hypertensive, and others.
RESULTS: We identified 4 unrelated patients with PLN mutations (prevalence of
0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a
G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu
substitution at codon 9 (R9L). One patient presented a G-A missense mutation at
the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The
fourth affected patient presented a T-G nonsense mutation at the nucleotide 116,
substituting a termination codon for Leu-39 (L39stop). Molecular modeling
studies suggested that R9L and R9H mutations might affect the region involved in
protein kinase A docking and probably affect the mechanism modulating the
release of phosphorylated PLN from the substrate binding site of protein kinase
A.
CONCLUSIONS: Mutations in the PLN gene are a rare cause of heart failure,
present almost exclusively in patients with dilated cardiomyopathy etiology. The
Arg9 and Leu39 residues are the leading location of mutations described at this
locus to date. Despite the few mutated residues described to date, the clinical
spectrum of presentation appears to vary considerably.
Copyright © 2011 Mosby, Inc. All rights reserved.
DOI: 10.1016/j.ahj.2011.07.028
PMID: 22137083 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22707725 | 1. J Biol Chem. 2012 Aug 3;287(32):26596-605. doi: 10.1074/jbc.M112.382713. Epub
2012 Jun 15.
Lethal, hereditary mutants of phospholamban elude phosphorylation by protein
kinase A.
Ceholski DK(1), Trieber CA, Holmes CF, Young HS.
Author information:
(1)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada.
The sarcoplasmic reticulum calcium pump (SERCA) and its regulator,
phospholamban, are essential components of cardiac contractility. Phospholamban
modulates contractility by inhibiting SERCA, and this process is dynamically
regulated by β-adrenergic stimulation and phosphorylation of phospholamban.
Herein we reveal mechanistic insight into how four hereditary mutants of
phospholamban, Arg(9) to Cys, Arg(9) to Leu, Arg(9) to His, and Arg(14)
deletion, alter regulation of SERCA. Deletion of Arg(14) disrupts the protein
kinase A recognition motif, which abrogates phospholamban phosphorylation and
results in constitutive SERCA inhibition. Mutation of Arg(9) causes more complex
changes in function, where hydrophobic substitutions such as cysteine and
leucine eliminate both SERCA inhibition and phospholamban phosphorylation,
whereas an aromatic substitution such as histidine selectively disrupts
phosphorylation. We demonstrate that the role of Arg(9) in phospholamban
function is multifaceted: it is important for inhibition of SERCA, it increases
the efficiency of phosphorylation, and it is critical for protein kinase A
recognition in the context of the phospholamban pentamer. Given the synergistic
consequences on contractility, it is not surprising that the mutants cause
lethal, hereditary dilated cardiomyopathy.
DOI: 10.1074/jbc.M112.382713
PMCID: PMC3411000
PMID: 22707725 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15907788 | 1. Biochem Biophys Res Commun. 2005 Aug 5;333(3):661-3. doi:
10.1016/j.bbrc.2005.05.014.
Beta-lactam antibiotics are multipotent agents to combat neurological diseases.
Ji HF(1), Shen L, Zhang HY.
Author information:
(1)Shandong Provincial Research Center for Bioinformatic Engineering and
Technique, Center for Advanced Study, Shandong University of Technology, Zibo
255049, PR China.
Recently, Rothstein et al. reported that beta-lactam antibiotics, including
penicillin and ceftriaxone, are potential therapeutic drugs to treat some
neurological disorders, e.g., amyotrophic lateral sclerosis (ALS), by modulating
the expression of glutamate transporter GLT1 via gene activation. However,
considering the facts that: (i) many neurological diseases (including ALS) are
associated with transition metal ions and redox stress, and ALS can be
efficiently prevented by metal chelators, e.g., diethyl-dithiocarbamate (DDC);
(ii) beta-lactam antibiotics have long been known as metal chelators, we argue
that the beneficial effect of beta-lactam antibiotics on ALS likely involves
Cu(II)-attenuating ability. This is partially supported by our theoretical
calculations.
DOI: 10.1016/j.bbrc.2005.05.014
PMID: 15907788 [Indexed for MEDLINE] |