pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/16921380 | 1. Nat Struct Mol Biol. 2006 Sep;13(9):815-22. doi: 10.1038/nsmb1135. Epub 2006
Aug 20.
Cotranscriptional coupling of splicing factor recruitment and precursor
messenger RNA splicing in mammalian cells.
Listerman I(1), Sapra AK, Neugebauer KM.
Author information:
(1)Max Planck Institute of Molecular Cell Biology and Genetics,
Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Coupling between transcription and RNA processing is a key gene regulatory
mechanism. Here we use chromatin immunoprecipitation to detect
transcription-dependent accumulation of the precursor mRNA (pre-mRNA) splicing
factors hnRNP A1, U2AF65 and U1 and U5 snRNPs on the intron-containing human FOS
gene. These factors were poorly detected on intronless heat-shock and histone
genes, a result that opposes direct recruitment by RNA polymerase II (Pol II) or
the cap-binding complex in vivo. However, an observed RNA-dependent interaction
between U2AF65 and active forms of Pol II may stabilize U2AF65 binding to
intron-containing nascent RNA. We establish chromatin-RNA immunoprecipitation
and show that FOS pre-mRNA is cotranscriptionally spliced. Notably, the
topoisomerase I inhibitor camptothecin, which stalls elongating Pol II,
increased cotranscriptional splicing factor accumulation and splicing in
parallel. This provides direct evidence for a kinetic link between
transcription, splicing factor recruitment and splicing catalysis.
DOI: 10.1038/nsmb1135
PMID: 16921380 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19411283 | 1. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H322-30. doi:
10.1152/ajpheart.01337.2008. Epub 2009 May 1.
Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine
and beta blockade therapy.
Christensen LP(1), Zhang RL, Zheng W, Campanelli JJ, Dedkov EI, Weiss RM,
Tomanek RJ.
Author information:
(1)Department of Anatomy and Cell Biology, Department of Internal Medicine, and
Cardiovascular Center, University of Iowa, Iowa City, IA 52242, USA.
We compared the effects of heart rate reduction (HRR) by the
hyperpolarization-activated pacemaker current (I(f)) channel inhibitor
ivabradine (MI+Iva) and the beta(1)-blocker atenolol (MI+Aten) on ventricular
remodeling and perfusion after myocardial infarction (MI) in middle-aged (12 mo)
Sprague-Dawley rats. Mean HRR was virtually identical in the two treated groups
(19%). Four weeks after coronary artery ligation, maximal myocardial perfusion
fell in the MI group but was preserved in infarcted rats treated with either Iva
or Aten. However, coronary reserve in the remodeled hearts was preserved only
with Iva, since Aten treatment elevated baseline perfusion in response to a
higher wall stress. The higher maximal perfusion noted in the two treated groups
was not due to arteriogenesis or angiogenesis. Plasma levels of angiotensin
(ANG) II and myocardial ANG type 1 (AT(1)) receptor and transforming growth
factor (TGF)-beta1 were reduced during the first week of treatment by both Iva
and Aten. Moreover, treatment also reduced arteriolar perivascular collagen
density. Despite these similar effects of Iva and Aten on vascularity and ANG
II, Iva, but not Aten, attenuated the decline in ejection fraction and lowered
left ventricular (LV) end-diastolic volume (LVEDV)-to-LV mass ratio, determined
by echocardiography. In conclusion, 1) Iva has advantages over Aten in
postinfarction therapy that are not due to differential effects of the drugs on
heart rate, and 2) age limits growth factor upregulation, angiogenesis, and
arteriogenesis in the postinfarcted heart.
DOI: 10.1152/ajpheart.01337.2008
PMID: 19411283 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24971511 | 1. PLoS One. 2014 Jun 27;9(6):e100429. doi: 10.1371/journal.pone.0100429.
eCollection 2014.
Alu and LINE-1 hypomethylation is associated with HER2 enriched subtype of
breast cancer.
Park SY(1), Seo AN(2), Jung HY(2), Gwak JM(3), Jung N(4), Cho NY(4), Kang GH(5).
Author information:
(1)Department of Pathology, Seoul National University College of Medicine,
Jongno-gu, Seoul, Korea; Department of Pathology, Seoul National University
Bundang Hospital, Bundang-gu, Seongnam, Gyeonggi, Korea.
(2)Department of Pathology, Seoul National University Bundang Hospital,
Bundang-gu, Seongnam, Gyeonggi, Korea.
(3)Department of Pathology, Seoul National University College of Medicine,
Jongno-gu, Seoul, Korea.
(4)Laboratory of Epigenetics, Cancer Research Institute, Seoul National
University, Jongno-gu, Seoul, Korea.
(5)Department of Pathology, Seoul National University College of Medicine,
Jongno-gu, Seoul, Korea; Laboratory of Epigenetics, Cancer Research Institute,
Seoul National University, Jongno-gu, Seoul, Korea.
The changes in DNA methylation status in cancer cells are characterized by
hypermethylation of promoter CpG islands and diffuse genomic hypomethylation.
Alu and long interspersed nucleotide element-1 (LINE-1) are non-coding genomic
repetitive sequences and methylation of these elements can be used as a
surrogate marker for genome-wide methylation status. This study was designed to
evaluate the changes of Alu and LINE-1 hypomethylation during breast cancer
progression from normal to pre-invasive lesions and invasive breast cancer
(IBC), and their relationship with characteristics of IBC. We analyzed the
methylation status of Alu and LINE-1 in 145 cases of breast samples including
normal breast tissue, atypical ductal hyperplasia/flat epithelial atypia
(ADH/FEA), ductal carcinoma in situ (DCIS) and IBC, and another set of 129 cases
of IBC by pyrosequencing. Alu methylation showed no significant changes during
multistep progression of breast cancer, although it tended to decrease during
the transition from DCIS to IBC. In contrast, LINE-1 methylation significantly
decreased from normal to ADH/FEA, while it was similar in ADH/FEA, DCIS and IBC.
In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER)
status, and LINE-1 hypomethylation was associated with negative ER status, ERBB2
(HER2) amplification and p53 overexpression. Alu and LINE-1 methylation status
was significantly different between breast cancer subtypes, and the HER2
enriched subtype had lowest methylation levels. In survival analyses, low Alu
methylation status tended to be associated with poor disease-free survival of
the patients. Our findings suggest that LINE-1 hypomethylation is an early event
and Alu hypomethylation is probably a late event during breast cancer
progression, and prominent hypomethylation of Alu and LINE-1 in HER2 enriched
subtype may be related to chromosomal instability of this specific subtype.
DOI: 10.1371/journal.pone.0100429
PMCID: PMC4074093
PMID: 24971511 [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/22479188 | 1. PLoS Genet. 2012;8(3):e1002530. doi: 10.1371/journal.pgen.1002530. Epub 2012
Mar 29.
A quantitative, high-throughput reverse genetic screen reveals novel connections
between Pre-mRNA splicing and 5' and 3' end transcript determinants.
Albulescu LO(1), Sabet N, Gudipati M, Stepankiw N, Bergman ZJ, Huffaker TC,
Pleiss JA.
Author information:
(1)Department of Molecular Biology and Genetics, Cornell University, Ithaca, New
York, United States of America.
Here we present the development and implementation of a genome-wide reverse
genetic screen in the budding yeast, Saccharomyces cerevisiae, that couples
high-throughput strain growth, robotic RNA isolation and cDNA synthesis, and
quantitative PCR to allow for a robust determination of the level of nearly any
cellular RNA in the background of ~5,500 different mutants. As an initial test
of this approach, we sought to identify the full complement of factors that
impact pre-mRNA splicing. Increasing lines of evidence suggest a relationship
between pre-mRNA splicing and other cellular pathways including chromatin
remodeling, transcription, and 3' end processing, yet in many cases the specific
proteins responsible for functionally connecting these pathways remain unclear.
Moreover, it is unclear whether all pathways that are coupled to splicing have
been identified. As expected, our approach sensitively detects pre-mRNA
accumulation in the vast majority of strains containing mutations in known
splicing factors. Remarkably, however, several additional candidates were found
to cause increases in pre-mRNA levels similar to that seen for canonical
splicing mutants, none of which had previously been implicated in the splicing
pathway. Instead, several of these factors have been previously implicated to
play roles in chromatin remodeling, 3' end processing, and other novel
categories. Further analysis of these factors using splicing-sensitive
microarrays confirms that deletion of Bdf1, a factor that links transcription
initiation and chromatin remodeling, leads to a global splicing defect,
providing evidence for a novel connection between pre-mRNA splicing and this
component of the SWR1 complex. By contrast, mutations in 3' end processing
factors such as Cft2 and Yth1 also result in pre-mRNA splicing defects, although
only for a subset of transcripts, suggesting that spliceosome assembly in S.
cerevisiae may more closely resemble mammalian models of exon-definition. More
broadly, our work demonstrates the capacity of this approach to identify novel
regulators of various cellular RNAs.
DOI: 10.1371/journal.pgen.1002530
PMCID: PMC3315463
PMID: 22479188 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22551571 | 1. Rev Neurol (Paris). 2012 Dec;168(12):910-8. doi: 10.1016/j.neurol.2011.11.008.
Epub 2012 Apr 30.
Recommendations for the management of facioscapulohumeral muscular dystrophy in
2011.
Attarian S(1), Salort-Campana E, Nguyen K, Behin A, Andoni Urtizberea J.
Author information:
(1)Centre of Reference for neuromuscular diseases and ALS, University Teaching
Hospital, CHU La Timone, 264 rue Saint-Pierre, Marseille, France.
sattarian@ap-hm.fr
Comment in
Rev Neurol (Paris). 2012 Dec;168(12):901. doi: 10.1016/j.neurol.2012.10.002.
Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease,
characterized by an autosomal dominant mode of inheritance, facial involvement,
and selectivity and asymmetry of muscle involvement. In general, FSHD typically
presents before age 20 years. Usually, FSHD muscle involvement starts in the
face and then progresses to the shoulder girdle, the humeral muscles and the
abdominal muscles, and then the anterolateral compartment of the leg. Disease
severity is highly variable and progression is very slow. About 20% of FSHD
patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of
FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named
D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified.
The progressive pattern of FSHD requires that the severity of symptoms as well
as their physical, social and psychological impact be evaluated on a regular
basis. A yearly assessment is recommended. Multidisciplinary management of
FSHD--consisting of a combination of genetic counselling, functional assessment,
an assessment by a physical therapist, prescription of symptomatic therapies and
prevention of known complications of this disease--is required. Prescription of
physical therapy sessions and orthopedic appliances are to be adapted to the
patient's deficiencies and contractures.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.neurol.2011.11.008
PMID: 22551571 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7739631 | 1. Muscle Nerve Suppl. 1995;2:S81-4.
Facioscapulohumeral muscular dystrophy in the Dutch population.
Padberg GW(1), Frants RR, Brouwer OF, Wijmenga C, Bakker E, Sandkuijl LA.
Author information:
(1)Department of Neurology, University Hospital, Nijmegen, The Netherlands.
Extrapolating the figures from a previous study on FSHD in a province of The
Netherlands to the entire Dutch population suggests that at present a nearly
complete overview is obtained of all symptomatic kindred. In 139 families,
dominant inheritance was observed in 97, a pattern compatible with germline
mosaicism in 6, while sporadic cases were found in 36 families. A mutation
frequency of 9.6% was calculated. Mental retardation and severe retinal
vasculopathy were reported in low frequencies (1%). Early onset was seen more
frequently in sporadic cases. Chromosome 4 linkage appeared excluded in 3 of 22
autosomal-dominant families. The clinical pictures in the linked and nonlinked
families were identical.
PMID: 7739631 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22975042 | 1. Biochim Biophys Acta. 2013 Jan;1829(1):134-40. doi:
10.1016/j.bbagrm.2012.08.005. Epub 2012 Sep 7.
Transcriptional elongation and alternative splicing.
Dujardin G(1), Lafaille C, Petrillo E, Buggiano V, Gómez Acuña LI, Fiszbein A,
Godoy Herz MA, Nieto Moreno N, Muñoz MJ, Alló M, Schor IE, Kornblihtt AR.
Author information:
(1)Departamento de Fisiología, Universidad de Buenos Aires, Ciudad
Universitaria, Buenos Aires, Argentina.
Alternative splicing has emerged as a key contributor to proteome diversity,
highlighting the importance of understanding its regulation. In recent years it
became apparent that splicing is predominantly cotranscriptional, allowing for
crosstalk between these two nuclear processes. We discuss some of the links
between transcription and splicing, with special emphasis on the role played by
transcription elongation in the regulation of alternative splicing events and in
particular the kinetic model of alternative splicing regulation. This article is
part of a Special Issue entitled: RNA polymerase II Transcript Elongation.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2012.08.005
PMID: 22975042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16172632 | 1. PLoS Comput Biol. 2005 Sep;1(4):e39. doi: 10.1371/journal.pcbi.0010039. Epub
2005 Sep 16.
Analysis of a splice array experiment elucidates roles of chromatin elongation
factor Spt4-5 in splicing.
Xiao Y(1), Yang YH, Burckin TA, Shiue L, Hartzog GA, Segal MR.
Author information:
(1)Department of Epidemiology and Biostatistics, Center for Bioinformatics and
Molecular Biostatistics, University of California, San Francisco, California,
United States of America.
Splicing is an important process for regulation of gene expression in
eukaryotes, and it has important functional links to other steps of gene
expression. Two examples of these linkages include Ceg1, a component of the mRNA
capping enzyme, and the chromatin elongation factors Spt4-5, both of which have
recently been shown to play a role in the normal splicing of several genes in
the yeast Saccharomyces cerevisiae. Using a genomic approach to characterize the
roles of Spt4-5 in splicing, we used splicing-sensitive DNA microarrays to
identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5
mutants. In the context of a complex, nested, experimental design featuring 22
dye-swap array hybridizations, comprising both biological and technical
replicates, we applied five appropriate statistical models for assessing
differential expression between wild-type and the mutants. To refine selection
of differential expression genes, we then used a robust model-synthesizing
approach, Differential Expression via Distance Synthesis, to integrate all five
models. The resultant list of differentially expressed genes was then further
analyzed with regard to select attributes: we found that highly transcribed
genes with long introns were most sensitive to spt mutations. QPCR confirmation
of differential expression was established for the limited number of genes
evaluated. In this paper, we showcase splicing array technology, as well as
powerful, yet general, statistical methodology for assessing differential
expression, in the context of a real, complex experimental design. Our results
suggest that the Spt4-Spt5 complex may help coordinate splicing with
transcription under conditions that present kinetic challenges to spliceosome
assembly or function.
DOI: 10.1371/journal.pcbi.0010039
PMCID: PMC1214541
PMID: 16172632 [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/15205169 | 1. Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2216-25. doi:
10.1152/ajpheart.00137.2004. Epub 2004 Jun 17.
Age-dependent biochemical and contractile properties in atrium of transgenic
mice overexpressing junctin.
Kirchhefer U(1), Baba HA, Hanske G, Jones LR, Kirchhof P, Schmitz W, Neumann J.
Author information:
(1)Institut für Pharmakologie und Toxikologie, Westfälische
Wilhelms-Universität, Domagkstrasse 12, 48149 Münster, Germany.
kirchhef@uni-muenster.de
Junctin is a transmembrane protein of the cardiac junctional sarcoplasmic
reticulum (SR) that binds to the ryanodine receptor, calsequestrin, and triadin
1. This quaternary protein complex is thought to facilitate SR Ca2+ release. To
improve our understanding of the contribution of junctin to the regulation of SR
function, we examined the age-dependent effects of junctin overexpression in the
atrium of 3-, 6-, and 18-wk-old transgenic mice. The ratio of atrial weight and
body weight was unchanged between junctin-overexpressing (JCN) and wild-type
(WT) mice at all ages investigated (n=6-8). The protein expression of triadin 1
was decreased starting in 3-wk-old JCN atria (by 69%), whereas the expression of
the ryanodine receptor was diminished in 6- (by 48%) and 18-wk-old (by 57%) JCN
atria compared with age-matched WT atria. Force of contraction was decreased by
35% in 18-wk-old JCN compared with age-matched WT left atrial muscle strips,
which was accompanied by a prolonged time of relaxation (48.1 +/- 0.9 vs. 44.2
+/- 0.8 ms, respectively, n=6-8, P <0.05). The spontaneous beating rate of
isolated right atria was higher in 18-wk-old JCN mice compared with age-matched
WT mice (389 +/- 10 vs. 357 +/- 6 beats/min, respectively, n=6-8, P <0.05).
Heart rate was lower by 9% in telemetric ECG recordings in 18-wk-old JCN mice
during stress tests. Three-week-old JCN atria exhibited a higher potentiation of
force of contraction at rest pauses of 30 s (by 13%) and of 300 s (by 35%),
suggesting increased SR Ca2+ content. This was consistent with the higher force
of contraction in 3-wk-old JCN atria (by 29%) compared with age-matched WT atria
(by 10%) under the administration of caffeine. We conclude that in 3-wk-old
atria, junctin overexpression was associated with a reduced expression of
triadin 1 resulting in a higher SR Ca2+ load without changes in contractility or
heart rate. In 6-wk-old JCN atria, the compensatory downregulation of the
ryanodine receptor may offset the effects of junctin overexpression. Finally,
the progressive decrease in ryanodine receptor density may contribute to the
decreased atrial contractility and lower heart rate during stress in 18-wk-old
JCN mice.
DOI: 10.1152/ajpheart.00137.2004
PMID: 15205169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22025663 | 1. J Physiol. 2011 Dec 15;589(Pt 24):6063-80. doi: 10.1113/jphysiol.2011.215988.
Epub 2011 Oct 24.
Dual role of junctin in the regulation of ryanodine receptors and calcium
release in cardiac ventricular myocytes.
Altschafl BA(1), Arvanitis DA, Fuentes O, Yuan Q, Kranias EG, Valdivia HH.
Author information:
(1)Department of Physiology, University of Wisconsin Medical School, Madison, WI
53711, USA.
Junctin, a 26 kDa intra-sarcoplasmic reticulum (SR) protein, forms a quaternary
complex with triadin, calsequestrin and the ryanodine receptor (RyR) at the
junctional SR membrane. The physiological role for junctin in the luminal
regulation of RyR Ca(2+) release remains unresolved, but it appears to be
essential for proper cardiac function since ablation of junctin results in
increased ventricular automaticity. Given that the junctin levels are severely
reduced in human failing hearts, we performed an in-depth study of the
mechanisms affecting intracellular Ca(2+) homeostasis in junctin-deficient
cardiomyocytes. In concurrence with sparks, JCN-KO cardiomyocytes display
increased Ca(2+) transient amplitude, resulting from increased SR [Ca(2+)]
([Ca(2+)](SR)). Junctin ablation appears to affect how RyRs 'sense' SR Ca(2+)
load, resulting in decreased diastolic SR Ca(2+) leak despite an elevated
[Ca(2+)](SR). Surprisingly, the β-adrenergic enhancement of [Ca(2+)](SR)
reverses the decrease in RyR activity and leads to spontaneous Ca(2+) release,
evidenced by the development of spontaneous aftercontractions. Single channel
recordings of RyRs from WT and JCN-KO cardiac SR indicate that the absence of
junctin produces a dual effect on the normally linear response of RyRs to
luminal [Ca(2+)]: at low luminal [Ca(2+)] (<1 mmol l(-1)), junctin-devoid RyR
channels are less responsive to luminal [Ca(2+)]; conversely, high luminal
[Ca(2+)] turns them hypersensitive to this form of channel modulation. Thus,
junctin produces complex effects on Ca(2+) sparks, transients, and leak, but the
luminal [Ca(2+)]-dependent dual response of junctin-devoid RyRs demonstrates
that junctin normally acts as an activator of RyR channels at low luminal
[Ca(2+)], and as an inhibitor at high luminal [Ca(2+)]. Because the crossover
occurs at a [Ca(2+)](SR) that is close to that present in resting cells, it is
possible that the activator-inhibitor role of junctin may be exerted under
periods of prevalent parasympathetic and sympathetic activity, respectively.
DOI: 10.1113/jphysiol.2011.215988
PMCID: PMC3286686
PMID: 22025663 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23394554 | 1. Curr Med Chem. 2013;20(14):1817-23. doi: 10.2174/0929867311320140002.
Ivabradine: the hope for a good treatment of ischemic heart disease.
Riccioni G(1).
Author information:
(1)Intensive Cardiology Care Unit, San Camillo de Lellis Hospital, Manfredonia,
Foggia, Italy. griccioni@hotmail.com
Chronic stable angina pectoris (CSAP) is the most common manifestation of
coronary artery disease (CAD). Angina pectoris occurs as a result of an
imbalance between myocardial perfusion and the demands of the myocardium.
Elevated heart rate (HR) is an important pathophysiological variable that
increases myocardial oxygen demand, and also limits tissue perfusion by reducing
the duration of diastole during which most myocardial perfusion occurs. Elevated
resting HR represents a significant predictor of all-cause and cardiovascular
mortality in the general population and patients with cardiovascular disease
(CVD) because it assists the progression of CVD through the development of
atherosclerosis, plaque destabilization, and initiation of arrhythmias. Since
β-blockers have been found to reduce HR, therefore, they are currently viewed as
the first line therapy for CSAP and are associated with an improved prognosis
after acute myocardial infarction (AMI) or congestive heart failure (CHF). The
classical treatments for HR reduction have shown negative aspects, such as
β-blockers therapy which exerts negative effects on regional myocardial blood
flow and function when HR reduction is eliminated by atrial pacing. Calcium
channel antagonists functionally antagonize coronary vasoconstriction mediated
through α-adrenoreceptors, and are thus devoid of this undesired effect, but the
compounds are nevertheless negative inotrope. Ivabradine (IVA), a pure HR
lowering drug, reduces the demand of myocardial oxygen during exercise,
contributes to the restoration of oxygen balance and is therefore beneficial in
chronic CVD. No relevant negative effects have been observed on cardiac
conduction, contractility, relaxation, repolarization or blood pressure (BP).
Beneficial effects of IVA have been noticed in CSAP and CHF, with optimal
tolerability profile due to selective interaction with I(f) channel of sino
atrial node cells. More recently, IVA has been highly recommended to be used in
patients with CAD in association with β-blockers. This review highlights the
importance of IVA in the treatment of ischemic heart disease.
DOI: 10.2174/0929867311320140002
PMID: 23394554 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19248726 | 1. Ideggyogy Sz. 2009 Jan 30;62(1-2):41-7.
Genetically determined neuromuscular disorders of some Roma families living in
Hungary.
Aranka L(1), Peter M, Jeno K, Katalin R, Gyula T, Emoke E, Agnes H, Tibor H,
Laszlo T, Edit B, Marta K, Janos S, Veronika K.
Author information:
(1)University of Szeged, Albert Szent-Györgyi Medical and Pharmaceutical Centre,
Department of Paediatrics, Szeged. laszloar@pedia.szote.u-szeged.hu
The authors discuss the clinical and molecular genetic aspects of genetically
determined neuromuscular disorders of some Roma families living in Hungary.
Among the autosomal recessively inherited spinal muscular atrophic (SMA) group,
8 Caucasian children had the typical 7-8 exonal deletions of the SMA gene, but
only 2 patients belonged to the Roma population. There was no difference in the
molecular genetic findings among the Caucasian and the Roma SMA patients. All of
them had 7-8 exonal deletions of the SMA gene. We wanted to call attention to
the founder mutation of the Roma population in 7 patients suffering from
congenital myasthenia (CMS) from 3 Roma families. The 1267G deletion for CMS was
detected by molecular genetic method. Clinical onset was pubertal and relatively
slow progression of specific and phenotypic features for this founder mutation
of acetyl-cholin receptor epsylon gene. In 2 patients (sister and brother) the
sarcoglycanopathy 2C type C283Q mutation was proven in one Roma family suffering
from limb-girdle muscular dystrophy (LGMD). Two out of the three
facioscapular-humeral dystrophy (FSHD) Roma families carried 21.8 kb and 18.5 kb
alleles in FSHD A1 gene (D4S139). In one family together with prenatal diagnosis
founder mutation in FSHD A1 gene was detected, according to the autosomal
dominant (AD) inheritance. In (F2) prenatal diagnosis was carried out, 18.5
kb/18.5 kb homozygosity was proven in the fetus, so the pregnancy was
interrupted. In the CMS, LGMD and FSHD Roma patients ancient typical Roma
founder mutations were found.
PMID: 19248726 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20662462 | 1. Cas Lek Cesk. 2009;148(11):544-8.
[Wilson's disease].
[Article in Czech]
Brůha R(1), Marecek Z, Martásek P, Nevsímalová S, Petrtýl J, Urbánek P,
Kalistová H, Pospísilová L.
Author information:
(1)Univerzita Karlova v Praze, 1. lékarská fakulta, IV. interní klinika VFN.
bruha@cesnet.cz
Wilson's disease is an inherited disorder leading to accumulation of copper in
tissues, mainly in the liver and brain. Genetic defect is in the gene coding
ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more
then 500 mutations causing Wilson's disease were described. The most frequent
mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's
disease is usually hepatic or neurologic. Hepatic form is manifested by acute or
chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested
usually after 20 year of age by motor disturbances (tremor, disturbed speech,
problems with writing), which could progress into severe extrapyramidal syndrome
with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is
based on clinical and laboratory examinations (neurologic symptoms, liver
disease, low serum ceruloplasmin levels, elevated free copper concentration in
serum, high urine copper excretion, and presence of Kayser-Fleischer rings).
Confirmation of diagnosis is done by hepatic copper concentration in liver
biopsy or by genetic examination. Untreated disease leads to the death of a
patient. Treatment is based on chelating agents decreasing the copper content by
excretion into urine (D-penicillamine, trientine) or on agents preventing
absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with
asymptomatic Wilson's disease have to be treated as well. In Czech Republic
either penicillamine or zinc are used. Liver transplantation is indicated in
patients with fulminant liver failure or decompensated cirrhosis. Screening in
families of affected patients (all siblings) is obvious.
PMID: 20662462 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22298808 | 1. Circ Res. 2012 Mar 2;110(5):663-8. doi: 10.1161/CIRCRESAHA.111.263939. Epub
2012 Jan 31.
Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural
abnormalities in adult calsequestrin-null mice with inherited arrhythmias.
Denegri M(1), Avelino-Cruz JE, Boncompagni S, De Simone SA, Auricchio A, Villani
L, Volpe P, Protasi F, Napolitano C, Priori SG.
Author information:
(1)Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
RATIONALE: Catecholaminergic polymorphic ventricular tachycardia is an inherited
disease that predisposes to cardiac arrest and sudden death. The disease is
associated with mutations in the genes encoding for the cardiac ryanodine
receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a
major loss of CASQ2 monomers, possibly because of enhanced degradation of the
mutant protein. The decrease of CASQ2 is associated with a reduction in the
levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2
and RyR2, a macromolecular complex devoted to control of calcium release from
the sarcoplasmic reticulum.
OBJECTIVE: We intended to evaluate whether viral gene transfer of wild-type
CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2.
METHODS AND RESULTS: We used an adeno-associated serotype 9 viral vector to
express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after
intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed
normalization of the levels of calsequestrin, triadin, and junctin, rescue of
electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation,
and lack of life-threatening arrhythmias.
CONCLUSIONS: We have proven the concept that induction of CASQ2 expression in
knockout mice reverts the molecular, structural, and electric abnormalities and
prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic
polymorphic ventricular tachycardia mice. These data support the view that
development of CASQ2 viral gene transfer could have clinical application.
DOI: 10.1161/CIRCRESAHA.111.263939
PMID: 22298808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15919200 | 1. Eur J Cancer. 2005 Jul;41(10):1467-73. doi: 10.1016/j.ejca.2005.03.021.
Gefitinib-trastuzumab combination on hormone-refractory prostate cancer
xenograft.
Formento P(1), Hannoun-Levi JM, Gérard F, Mazeau C, Fischel JL, Etienne-Grimaldi
MC, Gugenheim J, Milano G.
Author information:
(1)Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France.
New drugs and new combinations of drugs have recently shown promising clinical
activity in hormone refractory prostate cancer. We studied the association of
gefitinib with trastuzumab on the androgen-refractory prostate cancer cell line
DU145 expressing both epidermal growth factor receptor (EGFR) and HER-2. Drug
combinations with radiotherapy (RT) were considered along with the analysis of
factors linked to cell proliferation and apoptosis. The antitumour effects of
gefitinib were more pronounced than those observed with trastuzumab. In mice
receiving the gefitinib-trastuzumab combination, reduction in tumour volume was
inferior to that predicted by the observed impact of the agents alone. The
presence of trastuzumab markedly attenuated the relative increase on p27
expression and the Bax:Bcl2 ratio induced by gefitinib. The combination
gefitinib-RT had similar antitumour effects as those predicted by the impact of
the individual treatments, whereas the effect of the trastuzumab-RT combination
was inferior to that predicted by the individual effects. The present data
should be borne in mind when designing new clinical schedules for treatment of
hormone-refractory prostate cancer including the use of HER inhibitors.
DOI: 10.1016/j.ejca.2005.03.021
PMID: 15919200 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17142577 | 1. J Clin Pathol. 2006 Dec;59(12):1327-30. doi: 10.1136/jcp.2005.035147.
Adenoid cystic/basal cell carcinoma of the prostate strongly expresses
HER-2/neu.
Iczkowski KA(1), Montironi R.
Author information:
(1)Pathology and Laboratory Medicine Service, Veterans Administration Medical
Center, Gainesville, Florida 32608-1197, USA. iczkoka@patholog.ufl.edu
Adenoid cystic/basal cell carcinoma (ACBCC) is a rare neoplasm in the prostate.
Definitive treatment is warranted, as among 19 patients previously reported by
us, 5 had extraprostatic extension and 4 were metastatic. The HER-2/neu
(c-erbB-2) gene has been reportedly overexpressed in adenoid cystic carcinomas
in other organs, but its status in prostatic ACBCC was uncertain.
Immunohistochemical staining and in situ hybridisation were carried out in 13
patients with ACBCC (11 from transurethral resection, 2 prostatectomy). One
patient had metastasis to the lung. Citrate buffer and steam heat were used for
antigen retrieval. Ten acinar adenocarcinomas of varying grades were also
immunostained as controls. Protein and mRNA expression were 2+ to 3+ (of 3+) in
all patients with ACBCC, compared to a breast cancer control with strong
reactivity, whereas protein expression was noted in only one acinar carcinoma
and mRNA expression was absent in all acinar carcinomas. Benign acini expressed
HER-2/neu only in the basal layer. The finding of strong, consistent HER-2/neu
expression in ACBCC suggests that treatment with Herceptin (trastuzumab) may be
effective in patients with this rare tumour.
DOI: 10.1136/jcp.2005.035147
PMCID: PMC1860524
PMID: 17142577 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/11069905 | 1. J Biol Chem. 2001 Feb 9;276(6):4142-9. doi: 10.1074/jbc.M006443200. Epub 2000
Nov 7.
Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing
triadin 1.
Kirchhefer U(1), Neumann J, Baba HA, Begrow F, Kobayashi YM, Reinke U, Schmitz
W, Jones LR.
Author information:
(1)Institut für Pharmakologie und Toxikologie, Gerhard-Domagk-Institut für
Pathologie, Westfälische Wilhelms-Universität, 48149 Münster, Germany.
kirchhef@uni-muenster.de
Triadin 1 is a major transmembrane protein in cardiac junctional sarcoplasmic
reticulum (SR), which forms a quaternary complex with the ryanodine receptor
(Ca(2+) release channel), junctin, and calsequestrin. To better understand the
role of triadin 1 in excitation-contraction coupling in the heart, we generated
transgenic mice with targeted overexpression of triadin 1 to mouse atrium and
ventricle, employing the alpha-myosin heavy chain promoter to drive protein
expression. The protein was overexpressed 5-fold in mouse ventricles, and
overexpression was accompanied by cardiac hypertrophy. The levels of two other
junctional SR proteins, the ryanodine receptor and junctin, were reduced by 55%
and 73%, respectively, in association with triadin 1 overexpression, whereas the
levels of calsequestrin, the Ca(2+)-binding protein of junctional SR, and of
phospholamban and SERCA2a, Ca(2+)-handling proteins of the free SR, were
unchanged. Cardiac myocytes from triadin 1-overexpressing mice exhibited
depressed contractility; Ca(2+) transients decayed at a slower rate, and cell
shortening and relengthening were diminished. The extent of depression of cell
shortening of triadin 1-overexpressing cardiomyocytes was rate-dependent, being
more depressed under low stimulation frequencies (0.5 Hz), but reaching
comparable levels at higher frequencies of stimulation (5 Hz). Spontaneously
beating, isolated work-performing heart preparations overexpressing triadin 1
also relaxed at a slower rate than control hearts, and failed to adapt to
increased afterload appropriately. The fast time inactivation constant, tau(1),
of the l-type Ca(2+) channel was prolonged in transgenic cardiomyocytes. Our
results provide evidence for the coordinated regulation of junctional SR protein
expression in heart independent of free SR protein expression, and furthermore
suggest an important role for triadin 1 in regulating the contractile properties
of the heart during excitation-contraction coupling.
DOI: 10.1074/jbc.M006443200
PMID: 11069905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22946920 | 1. Bioanalysis. 2012 Aug;4(16):2049-58. doi: 10.4155/bio.12.162.
Utilization of hydrophilic-interaction LC to minimize matrix effects caused by
phospholipids.
Tan B(1), Negahban A, McDonald T, Zhang Y, Holliman C.
Author information:
(1)Dynamics & Metabolism Department, Pfizer Global Research & Development,
Groton, CT 06340, USA. beijing.tan@pfizer.com
BACKGROUND: In bioanalysis, phospholipids may affect the precision and accuracy
of LC-MS/MS methods and compromise the quality of the results, especially when
samples in complex biomatrices are extracted by protein precipitation
techniques.
RESULTS: It was found that the retentive behavior of both common pharmaceuticals
and physiologically relevant phospholipids under bare silica
hydrophilic-interaction LC (HILIC) is more predictable than under reversed-phase
conditions. In particular, the retention time of phospholipids was not
significantly affected by varying the salt and acid modifiers in the mobile
phases, but common pharmaceuticals can be shifted away from these phospholipid
interferences through mobile phase modifiers. Several mass spectrometric
techniques were applied to confirm this finding.
CONCLUSION: HILIC chromatography is a valued tool in the development of robust
bioanalytical assays with minimal and predictable phospholipid interferences.
Furthermore, addition of a small amount of ion-pairing additives can reliably
move pharmaceutical compounds away from these suppressive regions.
DOI: 10.4155/bio.12.162
PMID: 22946920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23073287 | 1. J Chromatogr A. 2012 Nov 16;1264:31-9. doi: 10.1016/j.chroma.2012.09.059. Epub
2012 Sep 26.
Evaluation of hydrophilic interaction chromatography (HILIC) versus C₁₈
reversed-phase chromatography for targeted quantification of peptides by mass
spectrometry.
Simon R(1), Enjalbert Q, Biarc J, Lemoine J, Salvador A.
Author information:
(1)UMR 5280, Institut des Sciences Analytiques, Université de Lyon, Lyon 1,
France.
Hydrophilic-interaction liquid chromatography (HILIC) is a widely used technique
for small polar molecule analysis and offers the advantage of improved
sensitivity in mass spectrometry. Although HILIC is today frequently employed as
an orthogonal fractionation method for peptides during the proteomic discovery
phase, it is still seldom considered for quantification. In this study, the
performances in terms of peak capacity and sensitivity of 3 HILIC columns were
compared to traditional reversed phase liquid C(18) column in the context of
targeted quantification of proteotypic peptides using selected reaction
monitoring mode (SRM). The results showed that the maximum sensitivity in HILIC
chromatography was achieved by using an amide column without salt buffer and
that the signal increased compared to classic reversed phase chromatography.
However, the intensity improvement is quite low compared to the one obtained for
small molecules. This is due on one hand to a higher matrix effect in HILIC and
on the other hand to a change of charge states of peptides in organic solvent
(doubly charged to monocharged). The doubly charged ions can be more readily
dissociated than singly charged ions, making them ideal for SRM peptide
quantification. As a result "supercharging" reagents are added to the mobile
phase to shift from predominant singly charged ions to the more favorable doubly
charged species. Using such optimized conditions, peptide signal is improved by
a factor of between two and ten for 88% of the peptides of the 81 peptides
investigated.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.chroma.2012.09.059
PMID: 23073287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18206802 | 1. Trends Cardiovasc Med. 2008 Jan;18(1):1-5. doi: 10.1016/j.tcm.2007.10.002.
Regulatory roles of junctin in sarcoplasmic reticulum calcium cycling and
myocardial function.
Fan GC(1), Yuan Q, Kranias EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati
College of Medicine, Cincinnati, OH 45267-0575, USA.
Junctin (JCN), a 26-kd sarcoplasmic reticulum (SR) transmembrane protein, forms
a quaternary protein complex with the ryanodine receptor, calsequestrin, and
triadin in the SR lumen of cardiac muscle. Within this complex, calsequestrin,
triadin, and JCN appear to be critical for normal regulation of ryanodine
receptor-mediated calcium (Ca) release. Junctin and triadin exhibit 60% to 70%
amino acid homology in their transmembrane domains, including repeated KEKE
motifs important for macromolecular protein-protein interactions within their SR
luminal tails. Recent studies have uncovered functional roles of both JCN and
triadin in the mouse heart, using transgenic overexpression strategies, which
exhibit varying phenotypes including mild SR structural alterations,
prolongation of Ca transient decay, impaired relaxation, and cardiac hypertrophy
and/or heart failure. More specifically, both in vitro adenoviral gene transfer
and in vivo gene-targeting techniques to manipulate JCN expression levels have
shown that JCN is an essential factor in maintaining normal cardiac Ca handling
and cardiac function. This article reviews the new findings on the regulatory
roles of JCN in cardiac SR Ca cycling and contractility, with special emphasis
on the effects of JCN ablation on delayed after depolarization-induced
arrhythmias and premature mortality in mouse models.
DOI: 10.1016/j.tcm.2007.10.002
PMCID: PMC2593792
PMID: 18206802 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14638677 | 1. J Biol Chem. 2004 Feb 20;279(8):6994-7000. doi: 10.1074/jbc.M312446200. Epub
2003 Nov 24.
Negatively charged amino acids within the intraluminal loop of ryanodine
receptor are involved in the interaction with triadin.
Lee JM(1), Rho SH, Shin DW, Cho C, Park WJ, Eom SH, Ma J, Kim DH.
Author information:
(1)Department of Life Science, Kwangju Institute of Science & Technology,
Gwangju, 500-712, Korea.
In mammalian striated muscles, ryanodine receptor (RyR), triadin, junctin, and
calsequestrin form a quaternary complex in the lumen of sarcoplasmic reticulum.
Such intermolecular interactions contribute not only to the passive buffering of
sarcoplasmic reticulum luminal Ca2+, but also to the active Ca2+ release process
during excitation-contraction coupling. Here we tested the hypothesis that
specific charged amino acids within the luminal portion of RyR mediate its
direct interaction with triadin. Using in vitro binding assay and site-directed
mutagenesis, we found that the second intraluminal loop of the skeletal muscle
RyR1 (amino acids 4860-4917), but not the first intraluminal loop of RyR1 (amino
acids 4581-4640) could bind triadin. Specifically, three negatively charged
residues Asp4878, Asp4907, and Glu4908 appear to be critical for the association
with triadin. Using deletional approaches, we showed that a KEKE motif of
triadin (amino acids 200-232) is essential for the binding to RyR1. Because the
second intraluminal loop of RyR has been previously shown to contain the
ion-conducting pore as well as the selectivity filter of the Ca2+ release
channel, and Asp4878, Asp4907, and Glu4908 residues are predicted to locate at
the periphery of the pore assembly of the channel, our data suggest that a
physical interaction between RyR1 and triadin could play an active role in the
overall Ca2+ release process of excitation-contraction coupling in muscle cells.
DOI: 10.1074/jbc.M312446200
PMID: 14638677 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21238772 | 1. Talanta. 2011 Feb 15;83(5):1707-10. doi: 10.1016/j.talanta.2010.11.073. Epub
2010 Dec 4.
Determination of uric acid and creatinine in human urine using hydrophilic
interaction chromatography.
Zuo Y(1), Yang Y, Zhu Z, He W, Aydin Z.
Author information:
(1)Department of Chemistry and Biochemistry, University of Massachusetts
Dartmouth, North Dartmouth, MA 02747, USA. yzuo@umassd.edu
Uric acid is the end-product of purine metabolism and a major antioxidant in
humans. The concentrations of uric acid in plasma and urine are associated with
various diseases and routinely measured in clinical and biomedical laboratories
using enzymatic conversion and colorimetric measurement. In this study a
hydrophilic interaction chromatographic (HILIC) method was developed for
simultaneous determination of uric acid and creatinine, a biomarker of urine
dilution and renal function, in human urine. Urine samples were pretreated by
dilution, protein precipitation, centrifugation and filtration. Uric acid and
creatinine were separated from other components in urine samples and quantified
using HILIC chromatography. A linear relationship between the ratio of the peak
area of the standards to that of the internal standard and the concentration of
the standards was obtained for both uric acid and creatinine with the square of
correlation coefficients >0.999 for both analytes. The detection limits were
0.04 μg/mL for creatinine and 0.06 μg/mL for uric acid. The described HILIC
method has proved to be simple, accurate, robust and reliable.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.talanta.2010.11.073
PMID: 21238772 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15731387 | 1. Biophys J. 2005 May;88(5):3444-54. doi: 10.1529/biophysj.104.051441. Epub 2005
Feb 24.
Regulation of ryanodine receptors by calsequestrin: effect of high luminal Ca2+
and phosphorylation.
Beard NA(1), Casarotto MG, Wei L, Varsányi M, Laver DR, Dulhunty AF.
Author information:
(1)John Curtin School of Medical Research, Australian Capital Territory,
Australia. nicole.beard@anu.edu.au
Calsequestrin, the major calcium sequestering protein in the sarcoplasmic
reticulum of muscle, forms a quaternary complex with the ryanodine receptor
calcium release channel and the intrinsic membrane proteins triadin and junctin.
We have investigated the possibility that calsequestrin is a luminal calcium
concentration sensor for the ryanodine receptor. We measured the luminal calcium
concentration at which calsequestrin dissociates from the ryanodine receptor and
the effect of calsequestrin on the response of the ryanodine receptor to changes
in luminal calcium. We provide electrophysiological and biochemical evidence
that: 1), luminal calcium concentration of >/=4 mM dissociates calsequestrin
from junctional face membrane, whereas in the range of 1-3 mM calsequestrin
remains attached; 2), the association with calsequestrin inhibits ryanodine
receptor activity, but amplifies its response to changes in luminal calcium
concentration; and 3), under physiological calcium conditions (1 mM),
phosphorylation of calsequestrin does not alter its ability to inhibit native
ryanodine receptor activity when the anchoring proteins triadin and junctin are
present. These data suggest that the quaternary complex is intact in vivo, and
provides further evidence that calsequestrin is involved in the sarcoplasmic
reticulum calcium signaling pathway and has a role as a luminal calcium sensor
for the ryanodine receptor.
DOI: 10.1529/biophysj.104.051441
PMCID: PMC1305491
PMID: 15731387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18620751 | 1. Cell Calcium. 2009 Jan;45(1):29-37. doi: 10.1016/j.ceca.2008.05.006. Epub 2008
Jul 11.
Altered stored calcium release in skeletal myotubes deficient of triadin and
junctin.
Wang Y(1), Li X, Duan H, Fulton TR, Eu JP, Meissner G.
Author information:
(1)Department of Biochemistry and Biophysics, University of North Carolina,
Chapel Hill, NC 27599-7260, United States.
Triadin and junctin are integral sarcoplasmic reticulum membrane proteins that
form a macromolecular complex with the skeletal muscle ryanodine receptor (RyR1)
but their roles in skeletal muscle calcium homeostasis remain incompletely
understood. Here we report that delivery of siRNAs specific for triadin or
junctin into C2C12 skeletal myoblasts reduced the expression of triadin and
junctin in 8-day-old myotubes by 80 and 100%, respectively. Knocking down either
triadin or junctin in these cells reduced Ca2+ release induced by depolarization
(10mM KCl) by 20-25%. Unlike triadin knockdown myotubes, junctin knockdown and
junctin/triadin double knockdown myotubes also had reduced Ca2+ release induced
by 400 microM 4-chloro-m-cresol, 10mM caffeine, 400 microM UTP, or 1 microM
thapsigargin. Thus, knocking down junctin compromised the Ca2+ stores in the
sarcoplasmic reticulum of these cells. Our subsequent studies showed that in
junctin knockdown myotubes at least two sarcoplasmic reticulum proteins (RyR1
and skeletal muscle calsequestrin) were down-regulated while these proteins'
mRNA expression was not affected. The results suggest that triadin has a role in
facilitating KCl depolarization-induced Ca2+ release in contrast to junctin
which has a role in maintaining sarcoplasmic reticulum Ca2+ store size in C2C12
myotubes.
DOI: 10.1016/j.ceca.2008.05.006
PMCID: PMC2626147
PMID: 18620751 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/23143600 | 1. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11.
Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele
causes facioscapulohumeral muscular dystrophy type 2.
Lemmers RJ(1), Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van
der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen
JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC,
Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN,
Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM.
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, Leiden, The
Netherlands.
Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of
the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded
DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is
caused by contraction of the D4Z4 array, whereas the genetic determinants and
inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we
show that mutations in SMCHD1 (encoding structural maintenance of chromosomes
flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein
levels and segregate with genome-wide D4Z4 CpG hypomethylation in human
kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and
a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4
expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4
contraction-independent DUX4 expression. Our study identifies SMCHD1 as an
epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic
determinant of FSHD2 and possibly other human diseases subject to epigenetic
regulation.
DOI: 10.1038/ng.2454
PMCID: PMC3671095
PMID: 23143600 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1611701 | 1. Circ Shock. 1992 Mar;36(3):169-73.
Cardiovascular mechanisms of thyrotropin-releasing hormone against experimental
hemorrhagic shock.
Zheng D(1), Chen HS, Hu DY.
Author information:
(1)Center of Traumatic Surgery, 43rd Hospital, Kunming Yunnan, People's Republic
of China.
Thyrotropin-releasing hormone (TRH) improved mean arterial pressure (MAP) and
myocardial contractility (dp/dtmax, -dp/dtmax, Vpm, and Vmax) and increased
plasma epinephrine levels significantly at 10 min after TRH treatment in rabbits
following shock, but the effects of TRH on MAP and myocardial contractility
disappeared in reserpinized rabbits (4 mg/kg, 24 hr pre-treatment, iv). TRH had
no effect on myocardial contractility and MAP at 20 and 30 min post-treatment in
rabbits pre-treated with the beta adrenergic blocker propranolol (1 mg/kg, 1 hr
before TRH treatment, iv), but the alpha adrenergic blocker phenoxybenzamine did
not affect these responses to TRH. Experiments in vitro show that although TRH
(10(-3) to 10(-8) M) had no direct effects on the isolated heart, left atrium,
and aortic strip, it did potentiate the inotropic effects of isoprenaline and
dopamine on the left atrium. These results suggest that the antishock effects of
TRH are related to adrenergic systems, perhaps acting on the sympathomedullary
system to secrete epinephrine and sensitize the beta receptors, but not alpha
receptors. Thus, TRH improves cardiac contractility, cardiac output, and
hemodynamics during hemorrhagic shock. The sensitization of the beta adrenergic
and dopamine receptors may play an important role in the direct peripheral
cardiovascular mechanism of TRH effects.
PMID: 1611701 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15905409 | 1. Genes Dev. 2005 May 15;19(10):1211-26. doi: 10.1101/gad.1291705.
A human splicing factor, SKIP, associates with P-TEFb and enhances transcription
elongation by HIV-1 Tat.
Brès V(1), Gomes N, Pickle L, Jones KA.
Author information:
(1)Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La
Jolla, California 92037, USA.
HIV-1 Tat binds human CyclinT1 and recruits the CDK9/P-TEFb complex to the viral
TAR RNA in a step that links RNA polymerase II (RNAPII) C-terminal domain (CTD)
Ser 2 phosphorylation with transcription elongation. Previous studies have
suggested a connection between Tat and pre-mRNA splicing factors. Here we show
that the splicing-associated c-Ski-interacting protein, SKIP, is required for
Tat transactivation in vivo and stimulates HIV-1 transcription elongation, but
not initiation, in vitro. SKIP associates with CycT1:CDK9/P-TEFb and Tat:P-TEFb
complexes in nuclear extracts and interacts with recombinant Tat:P-TEFb:TAR RNA
complexes in vitro, indicating that it may act through nascent RNA to overcome
pausing by RNAPII. SKIP also associates with U5snRNP proteins and tri-snRNP110K
in nuclear extracts, and facilitates recognition of an alternative Tat-specific
splice site in vivo. The effects of SKIP on transcription elongation, binding to
P-TEFb, and splicing are mediated through the SNW domain. HIV-1 Tat
transactivation is accompanied by the recruitment of P-TEFb, SKIP, and
tri-snRNP110K to the integrated HIV-1 promoter in vivo, whereas the U5snRNPs
associate only with the transcribed coding region. These findings suggest that
SKIP plays independent roles in transcription elongation and pre-mRNA splicing.
DOI: 10.1101/gad.1291705
PMCID: PMC1132007
PMID: 15905409 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23217321 | 1. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Dec 12;911:170-9. doi:
10.1016/j.jchromb.2012.10.038. Epub 2012 Nov 3.
Validation of an LC-MS/MS method for the quantification of choline-related
compounds and phospholipids in foods and tissues.
Xiong Y(1), Zhao YY, Goruk S, Oilund K, Field CJ, Jacobs RL, Curtis JM.
Author information:
(1)Department of Agricultural, Food and Nutritional Sciences, University of
Alberta, Edmonton, Canada T6G 2P5.
A hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC
LC-MS/MS) method was developed and validated to simultaneously quantify six
aqueous choline-related compounds and eight major phospholipids classes in a
single run. HILIC chromatography was coupled to positive ion electrospray mass
spectrometry. A combination of multiple scan modes including precursor ion scan,
neutral loss scan and multiple reaction monitoring was optimized for the
determination of each compound or class in a single LC/MS run. This work
developed a simplified extraction scheme in which both free choline and related
compounds along with phospholipids were extracted into a homogenized phase using
chloroform/methanol/water (1:2:0.8) and diluted into methanol for the analysis
of target compounds in a variety of sample matrices. The analyte recoveries were
evaluated by spiking tissues and food samples with two isotope-labeled internal
standards, PC-d(3) and Cho-d(3). Recoveries of between 90% and 115% were
obtained by spiking a range of sample matrices with authentic standards
containing all 14 of the target analytes. The precision of the analysis ranged
from 1.6% to 13%. Accuracy and precision was comparable to that obtained by
quantification of selected phospholipid classes using (31)P NMR. A variety of
sample matrices including egg yolks, human diets and animal tissues were
analyzed using the validated method. The measurements of total choline in
selected foods were found to be in good agreement with values obtained from the
USDA choline database.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jchromb.2012.10.038
PMID: 23217321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28315371 | 1. J Biotechnol. 2017 Apr 20;248:43-47. doi: 10.1016/j.jbiotec.2017.03.010. Epub
2017 Mar 14.
Complete genome sequence of Arthrobacter sp. ZXY-2 associated with effective
atrazine degradation and salt adaptation.
Zhao X(1), Ma F(2), Feng C(3), Bai S(2), Yang J(4), Wang L(5).
Author information:
(1)State Key Laboratory of Urban Water Resource and Environment, Harbin
Institute of Technology, 150090, Harbin, China; Section of Sanitary Engineering,
Department of Water Management, Delft University of Technology, 2628CN, Delft,
The Netherlands.
(2)State Key Laboratory of Urban Water Resource and Environment, Harbin
Institute of Technology, 150090, Harbin, China.
(3)Section of Sanitary Engineering, Department of Water Management, Delft
University of Technology, 2628CN, Delft, The Netherlands.
(4)State Key Laboratory of Urban Water Resource and Environment, Harbin
Institute of Technology, 150090, Harbin, China. Electronic address:
yangxj@hit.edu.cn.
(5)State Key Laboratory of Urban Water Resource and Environment, Harbin
Institute of Technology, 150090, Harbin, China. Electronic address:
wli@hit.edu.cn.
An atrazine-degrading strain Arthrobacter sp. ZXY-2 was originally isolated from
Jilin Pesticide Plant (China). Strain ZXY-2 demonstrated excellent atrazine
degradation performance and saline tolerance. Here we report the complete genome
sequence of strain ZXY-2 contained a circular chromosome and five circular
plasmids encoding for the mechanism of salt adaptation and pollutant
degradation.
Copyright © 2017 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jbiotec.2017.03.010
PMID: 28315371 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9225129 | 1. Endocrine. 1997 Apr;6(2):153-8. doi: 10.1007/BF02738958.
Serotonin (5-HT) stimulates thyrotropin-releasing hormone (TRH) gene
transcription in rat embryonic cardiomyocytes.
Shi ZX(1), Xu W, Selmanoff MK, Wilber JF.
Author information:
(1)Department of Medicine, University of Maryland, School of Medicine at
Baltimore 21201, USA. zshi@umabnet.ab.umd.edu
Thyrotropin-releasing hormone (TRH) and its mRNA have been identified in the rat
heart, and TRH can enhance cardiomyocyte contractility in vivo. At present,
little is known about cardiac TRH gene transcriptional regulation in the heart.
Hormones and neurotransmitters, including thyroid hormone (T3), glucocorticoids,
testosterone, and 5-HT initiate effects not only in the cardiovascular system,
but also in the regulation of hypothalamic TRH. To clarify the potential roles
of these modulators upon the cardiac TRH gene transcription, rat TRH promoter
activity was assessed in rat embryonic myocyte cells (H9C2) by transient
transfection assays. TRH promoter activity was stimulated significantly by
dexamethasone (10(-4) M) and testosterone (10(-5) M), and was inhibited by T3
(10(-7) M). Interestingly, the neurotransmitter 5-HT stimulated TRH promoter
activity in H9C2 cells, but not in HTB-11 cells. To further clarify this
selective role of 5-HT on TRH promoter transcriptional activity in cardiac
cells, 5-HT receptor antagonists and agonists were tested. A selective 5-HT2
receptor antagonist blocked 5-HT stimulation, whereas 5-HT agonist analogs
caused augmentative effects when combined with 5-HT. Neither 5-HT nor any
antagonists or agonists influenced H9C2 cell growth or morphology. These data
suggest that 5-HT is an important transcriptional regulator of the cardiac TRH
gene.
DOI: 10.1007/BF02738958
PMID: 9225129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1979356 | 1. J Tongji Med Univ. 1990;10(3):187-92. doi: 10.1007/BF02986460.
Action of thyrotropin-releasing hormone in experimental hemorrhagic
shock--cardiovascular mechanism.
Zheng D(1), Chen HS, Hu DY.
Author information:
(1)Trauma Research Center, 43rd Hospital, Kunming, Yunnan.
Thyrotropin-releasing hormone (TRH) could improve mean arterial pressure (MAP),
myocardial contractile parameters (+/- dp/dtmax, Vpm and Vmax) and increase
plasma epinephrine level significantly at 10 min after TRH administration in
hemorrhagic shock rabbits, but the action of TRH on MAP and the myocardial
contractility did not appear in rabbits pre-treated with reserpine (4 mg/kg, 24
h pre-treatment, i.v.). TRH had no effects on myocardial contractility and MAP
at 20 and 30 min after administration to rabbits pre-treated with
beta-adrenergic blocker propranolol (1 mg/kg, 1 h before TRH injection i.v.),
but it did exert effects on these parameters in rabbits pre-treated with
alpha-adrenergic blocker phenoxybenzamine. Experiments in vitro showed that,
although TRH (10(-4) M/L) had no direct effect on heart, left atrium and aortic
strip, it did potentiate the inotropic effects of isoprenaline and dopamine on
the left atrium. These results suggested that antishock effect of TRH is related
to adrenergic system. TRH stimulates sympathomedullary system to secrete
epinephrine and sensitize the beta-receptors, but not alpha-receptors. Thus, TRH
improves cardiac contractility, cardiac output and hemodynamics during
hemorrhagic shock. The sensitization of the beta- and dopamine receptors played
an important role in producing direct peripheral actions of TRH.
DOI: 10.1007/BF02986460
PMID: 1979356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28642378 | 1. Genome Announc. 2017 Jun 22;5(25):e00565-17. doi: 10.1128/genomeA.00565-17.
New Genome Sequence of an Echinaceapurpurea Endophyte, Arthrobacter sp. Strain
EpSL27, Able To Inhibit Human-Opportunistic Pathogens.
Miceli E(1), Presta L(1), Maggini V(1)(2)(3), Fondi M(1), Bosi E(1), Chiellini
C(1), Fagorzi C(1), Bogani P(1), Di Pilato V(4), Rossolini GM(5), Mengoni A(1),
Firenzuoli F(3), Perrin E(1), Fani R(6).
Author information:
(1)Department of Biology, University of Florence, Florence, Italy.
(2)Department of Experimental and Clinical Medicine, University of Florence,
Florence, Italy.
(3)Center for Integrative Medicine, Careggi University Hospital, University of
Florence, Florence, Italy.
(4)Department of Surgery and Translational Medicine, University of Florence,
Florence, Italy.
(5)Clinical Microbiology and Virology Unit, Careggi University Hospital,
Florence, Italy.
(6)Department of Biology, University of Florence, Florence, Italy
renato.fani@unifi.it.
We announce here the draft genome sequence of Arthrobacter sp. strain EpSL27,
isolated from the stem and leaves of the medicinal plant Echinacea purpurea and
able to inhibit human-pathogenic bacterial strains. The genome sequencing of
this strain may lead to the identification of genes involved in the production
of antimicrobial molecules.
Copyright © 2017 Miceli et al.
DOI: 10.1128/genomeA.00565-17
PMCID: PMC5481584
PMID: 28642378 |
http://www.ncbi.nlm.nih.gov/pubmed/18621770 | 1. Eur Heart J. 2008 Sep;29(18):2265-75. doi: 10.1093/eurheartj/ehn337. Epub 2008
Jul 10.
Improvement of regional myocardial blood flow and function and reduction of
infarct size with ivabradine: protection beyond heart rate reduction.
Heusch G(1), Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R.
Author information:
(1)Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
gerd.heusch@uk-essen.de
Erratum in
Eur Heart J. 2008 Dec;29(23):2949.
AIMS: Effects of the bradycardic agent ivabradine on regional blood flow,
contractile function, and infarct size were studied in a pig model of myocardial
ischaemia/reperfusion. Heart rate reduction by beta-blockade is associated with
negative inotropism and unmasked alpha-adrenergic coronary vasoconstriction.
Ivabradine is the only available bradycardic agent for clinical use.
METHODS AND RESULTS: Anaesthetized pigs were subjected to 90 min controlled left
anterior descending coronary artery hypoperfusion and 120 min reperfusion.
Regional blood flow was measured with microspheres, regional function with
sonomicrometry, and infarct size with triphenyl tetrazolium chloride staining.
Pigs received placebo or ivabradine (0.6 mg/kg i.v.) before or during ischaemia
or before reperfusion, respectively. Pre-treatment with ivabradine reduced
infarct size from 35 +/- 4 (SEM) to 19 +/- 4% of area at risk (AAR). Ivabradine
15-20 min after the onset of ischaemia increased regional myocardial blood flow
from 2.12 +/- 0.31 to 3.55 +/- 0.56 microL/beat/g and systolic wall thickening
from 6.7 +/- 1.0 to 16.3 +/- 3.0%; infarct size was reduced from 12 +/- 4 to 2
+/- 1% of AAR. Ivabradine 5 min before reperfusion still reduced infarct size
from 36 +/- 4 to 21 +/- 5% of AAR. The benefit of ivabradine on flow and
function was eliminated by atrial pacing, but part of the reduction of infarct
size by ivabradine was not.
CONCLUSION: Ivabradine's protection goes beyond heart rate reduction.
DOI: 10.1093/eurheartj/ehn337
PMID: 18621770 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23039946 | 1. BMC Genomics. 2012 Oct 6;13:534. doi: 10.1186/1471-2164-13-534.
Complete genome sequence and metabolic potential of the quinaldine-degrading
bacterium Arthrobacter sp. Rue61a.
Niewerth H(1), Schuldes J, Parschat K, Kiefer P, Vorholt JA, Daniel R, Fetzner
S.
Author information:
(1)Institute of Molecular Microbiology and Biotechnology, University of Münster,
Corrensstrasse 3, 48149, Münster, Germany.
BACKGROUND: Bacteria of the genus Arthrobacter are ubiquitous in soil
environments and can be considered as true survivalists. Arthrobacter sp. strain
Rue61a is an isolate from sewage sludge able to utilize quinaldine
(2-methylquinoline) as sole carbon and energy source. The genome provides
insight into the molecular basis of the versatility and robustness of this
environmental Arthrobacter strain.
RESULTS: The genome of Arthrobacter sp. Rue61a consists of a single circular
chromosome of 4,736,495 bp with an average G + C content of 62.32%, the circular
231,551-bp plasmid pARUE232, and the linear 112,992-bp plasmid pARUE113 that was
already published. Plasmid pARUE232 is proposed to contribute to the resistance
of Arthrobacter sp. Rue61a to arsenate and Pb2+, whereas the linear plasmid
confers the ability to convert quinaldine to anthranilate. Remarkably,
degradation of anthranilate exclusively proceeds via a CoA-thioester pathway.
Apart from quinaldine utilization, strain Rue61a has a limited set of aromatic
degradation pathways, enabling the utilization of 4-hydroxy-substituted aromatic
carboxylic acids, which are characteristic products of lignin depolymerization,
via ortho cleavage of protocatechuate. However, 4-hydroxyphenylacetate
degradation likely proceeds via meta cleavage of homoprotocatechuate. The genome
of strain Rue61a contains numerous genes associated with osmoprotection, and a
high number of genes coding for transporters. It encodes a broad spectrum of
enzymes for the uptake and utilization of various sugars and organic nitrogen
compounds. A. aurescens TC-1 is the closest sequenced relative of strain Rue61a.
CONCLUSIONS: The genome of Arthrobacter sp. Rue61a reflects the saprophytic
lifestyle and nutritional versatility of the organism and a strong adaptive
potential to environmental stress. The circular plasmid pARUE232 and the linear
plasmid pARUE113 contribute to heavy metal resistance and to the ability to
degrade quinaldine, respectively.
DOI: 10.1186/1471-2164-13-534
PMCID: PMC3534580
PMID: 23039946 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21316059 | 1. J Chromatogr A. 2011 Sep 2;1218(35):5964-74. doi:
10.1016/j.chroma.2011.01.075. Epub 2011 Jan 31.
Application of hydrophilic interaction chromatography for the analysis of polar
contaminants in food and environmental samples.
van Nuijs AL(1), Tarcomnicu I, Covaci A.
Author information:
(1)Toxicological Center, University of Antwerp, Antwerp, Belgium.
For the analysis of highly hydrophilic and polar compounds, Hydrophilic
Interaction Chromatography (HILIC) has been established as a valuable
complementary approach to reversed-phase liquid chromatography (RPLC). Moreover,
the use of mobile phases with a high percentage of organic solvent in HILIC
separation is beneficial for mass spectrometric (MS) detection, because of
enhanced ionization which results in an increased sensitivity. In this review,
various applications of HILIC are described for a number of environmental and
food contaminants together with detailed methodological descriptions and the
advantages or drawbacks of HILIC compared to other LC methods are critically
discussed. In the first part of the review, an overview is given of the work
that has been carried out with HILIC for the analysis of pharmaceuticals and
pesticides in environmental samples. HILIC has shown its applicability for polar
pharmaceuticals, such as antibiotics, estrogens and their metabolites, drugs of
abuse, cytostatics, metformin and contrast agents. In the pesticide group, HILIC
chromatography was helpful for polar phenylurea and organophosphorus pesticides.
The second part of the review focuses on the analysis of antibiotic residues in
food and feed with HILIC, while in the pesticide group, HILIC experiments have
been reported for dithiocarbamates and quaternary ammonium compounds. The last
chapter gives an overview of the analysis by HILIC of miscellaneous analytes in
aquatic and food/feed samples.
Copyright © 2011 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.chroma.2011.01.075
PMID: 21316059 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15096458 | 1. Circulation. 2004 May 11;109(18):2240-5. doi:
10.1161/01.CIR.0000127951.13380.B4. Epub 2004 Apr 19.
Thyrotropin-releasing hormone is induced in the left ventricle of rats with
heart failure and can provide inotropic support to the failing heart.
Jin H(1), Fedorowicz G, Yang R, Ogasawara A, Peale F, Pham T, Paoni NF.
Author information:
(1)Genentech, Inc, 1 DNA Way, South San Francisco, Calif 94080, USA.
hkj@gene.com
BACKGROUND: We reported previously that left ventricular gene expression for
thyrotropin-releasing hormone (TRH) precursor was increased in rats with heart
failure 8 weeks after myocardial infarction (MI) and that early ACE inhibition
tended to cause further myocardial induction of this gene.
METHODS AND RESULTS: Here, we show that after MI, the expression of pro-TRH is
induced in the heart coordinately with the protease PC1, an important enzyme in
TRH biosynthesis. Pro-TRH gene expression was induced in cardiac interstitial
cells after MI, and this effect was restricted to the heart, because no increase
in TRH mRNA abundance was observed in the hypothalamus, kidney, or lung.
Transcript abundance of pro-TRH can be increased in cultured cardiac fibroblasts
by several adrenergic agonists, indicating that the adrenergic axis may play a
regulatory role in cardiac TRH production. Acute intravenous administration of
TRH to rats with ischemic cardiomyopathy caused a significant increase in heart
rate, mean arterial pressure, cardiac output, stroke volume, and cardiac
contractility.
CONCLUSIONS: Taken together, these results indicate that TRH is specifically
induced in the heart after MI and that it can increase cardiac performance in
rats with ischemic cardiomyopathy. Thus, in addition to catecholamine and
angiotensin II, pro-TRH/TRH may be another important axis that affects
hemodynamics and cardiac function in heart failure.
DOI: 10.1161/01.CIR.0000127951.13380.B4
PMID: 15096458 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26150028 | 1. Arch Ital Urol Androl. 2015 Jul 7;87(2):121-9. doi: 10.4081/aiua.2015.2.121.
Efficacy and safety of second-line agents for treatment of metastatic
castration-resistant prostate cancer progressing after docetaxel. A systematic
review and meta-analysis.
Perletti G(1), Monti E, Marras E, Cleves A, Magri V, Trinchieri A, Rennie PS.
Author information:
(1)Biomedical Research Division, Dept. of Theoretical and Applied Sciences,
Università degli Studi dell'Insubria, Busto Arsizio, Italy; Department of Basic
Medical Sciences, Ghent University, Ghent. gianpaolo.perletti@uninsubria.it.
Comment in
Arch Ital Urol Androl. 2016 Mar 31;88(1):72-3. doi: 10.4081/aiua.2016.1.72.
Arch Ital Urol Androl. 2016 Mar 31;88(1):74-5. doi: 10.4081/aiua.2016.1.74.
OBJECTIVE: We performed a systematic review of the literature to assess the
efficacy and the safety of second-line agents targeting metastatic
castration-resistant prostate cancer (mCRPC) that has progressed after
docetaxel. Pooled-analysis was also performed, to assess the effectiveness of
agents targeting the androgen axis via identical mechanisms of action
(abiraterone acetate, orteronel).
MATERIALS AND METHODS: We included phase III randomized controlled trials that
enrolled patients with mCRPC progressing during or after first-line docetaxel
treatment. Trials were identified by electronic database searching. The primary
outcome of the review was overall survival. Secondary outcomes were radiographic
progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).
RESULTS: Ten articles met the inclusion criteria for the review. These articles
reported the results of five clinical trials, enrolling in total 5047 patients.
The experimental interventions tested in these studies were enzalutamide,
ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control
cohorts (active drug-treated or placebo-treated), the significant overall
survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for
death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for
abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P <
0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs.
mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis
of androgen synthesis inhibitors orteronel and abiraterone resulted in
significantly increased overall and progression-free survival for anti-androgen
agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87,
P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77,
P < 0.00001). Androgen synthesis inhibitors induced significant increases in
risk ratios for adverse effects linked to elevated mineralocorticoid secretion,
compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P =
0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).
CONCLUSIONS: In docetaxel-pretreated patients enzalutamide,
abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival
of patients, compared to placebo or to best of care at the time of study
(mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide,
abiraterone, orteronel) significantly prolonged rPFS, compared to placebo.
Further investigation is warranted to evaluate the benefit of combination or
sequential administration of these agents. Large-scale studies are also
necessary to evaluate the impact of relevant toxic effects observed in a limited
number of patients (e.g., enzalutamide-induced seizures, orteronel-induced
pancreatitis, and others).
DOI: 10.4081/aiua.2015.2.121
PMID: 26150028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28450506 | 1. Genome Announc. 2017 Apr 27;5(17):e00217-17. doi: 10.1128/genomeA.00217-17.
Draft Genome Sequence of the Nylon Oligomer-Degrading Bacterium Arthrobacter sp.
Strain KI72.
Takehara I(1), Kato DI(2), Takeo M(1), Negoro S(3).
Author information:
(1)Department of Applied Chemistry, Graduate School of Engineering, University
of Hyogo, Himeji, Hyogo, Japan.
(2)Graduate School of Science and Engineering, Kagoshima University, Korimoto,
Kagoshima, Japan.
(3)Department of Applied Chemistry, Graduate School of Engineering, University
of Hyogo, Himeji, Hyogo, Japan negoro@eng.uhyogo.ac.jp.
We report here the 4.6-Mb genome sequence of a nylon oligomer-degrading
bacterium, Arthrobacter sp. strain KI72. The draft genome sequence of strain
KI72 consists of 4,568,574 bp, with a G+C content of 63.47%, 4,372 coding
sequences (CDSs), 54 tRNAs, and six rRNAs.
Copyright © 2017 Takehara et al.
DOI: 10.1128/genomeA.00217-17
PMCID: PMC5408104
PMID: 28450506 |
http://www.ncbi.nlm.nih.gov/pubmed/11236029 | 1. Semin Oncol. 2000 Dec;27(6 Suppl 11):53-63; discussion 92-100.
HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate
cancer, and ovarian cancer.
Agus DB(1), Bunn PA Jr, Franklin W, Garcia M, Ozols RF.
Author information:
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY,
USA.
HER-2/neu is overexpressed in most epithelial malignancies. Lung cancer,
prostate cancer, and ovarian cancer are common epithelial tumors in which
clinical trials are currently in progress to explore the potential therapeutic
role for monoclonal antibodies to HER-2/neu (trastuzumab [Herceptin; Genentech,
Inc, South San Francisco, CA]). In preclinical studies with tumor cell lines,
trastuzumab was found to have additive and synergistic effects with some
chemotherapeutic agents. Clinical trials investigating combination chemotherapy
with trastuzumab and a variety of chemotherapeutic agents are already in
progress in lung cancer.
PMID: 11236029 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10365964 | 1. Nature. 1999 Jun 3;399(6735):491-6. doi: 10.1038/20974.
Structure and ligand of a histone acetyltransferase bromodomain.
Dhalluin C(1), Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM.
Author information:
(1)Structural Biology Program, Department of Physiology and Biophysics, Mount
Sinai School of Medicine, New York, New York 10029-6574, USA.
Histone acetylation is important in chromatin remodelling and gene activation.
Nearly all known histone-acetyltransferase (HAT)-associated transcriptional
co-activators contain bromodomains, which are approximately 110-amino-acid
modules found in many chromatin-associated proteins. Despite the wide occurrence
of these bromodomains, their three-dimensional structure and binding partners
remain unknown. Here we report the solution structure of the bromodomain of the
HAT co-activator P/CAF (p300/CBP-associated factor). The structure reveals an
unusual left-handed up-and-down four-helix bundle. In addition, we show by a
combination of structural and site-directed mutagenesis studies that
bromodomains can interact specifically with acetylated lysine, making them the
first known protein modules to do so. The nature of the recognition of
acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by
histone acetyltransferase. Thus, the bromodomain is functionally linked to the
HAT activity of co-activators in the regulation of gene transcription.
DOI: 10.1038/20974
PMID: 10365964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19074674 | 1. Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H435-41. doi:
10.1152/ajpheart.00591.2008. Epub 2008 Dec 12.
Beneficial effects of delayed ivabradine treatment on cardiac anatomical and
electrical remodeling in rat severe chronic heart failure.
Milliez P(1), Messaoudi S, Nehme J, Rodriguez C, Samuel JL, Delcayre C.
Author information:
(1)INSERM U942, Cardiovascular Research Center INSERM Lariboisière, Paris,
France. paulmilliez@hotmail.com
We tested the hypothesis that heart rate (HR) reduction, induced by the
selective hyperpolarization-activated current inhibitor ivabradine (Iva), might
improve left ventricular (LV) function, structure, and electrical remodeling in
severe post-myocardial infarction (MI) chronic heart failure (HF). MI was
produced in adult male Wistar rats. After 2 mo, echocardiography was performed
before the randomization into MI and MI + Iva (10 mg x kg(-1) x day(-1)) groups.
After 3 mo of treatment, echocardiography and 24-h telemetry were recorded.
Cardiac collagen, mRNA, and protein expressions of angiotensin-converting enzyme
(ACE) and ANG II type 1 (AT(1)) receptor were quantified. As a result, at 2 mo
post-MI, all rats displayed severe congestive HF signs (ejection fraction <
30%). At 5 mo post-MI, body and heart weights were similar in the MI and MI +
Iva groups. LV ejection fraction and LV end-diastolic pressure were worsened in
the MI group, whereas both were improved with Iva. Iva reduced HR by 10.4% (P <
0.03 vs. MI) and ventricular premature complexes by 89% (P < 0.03) and improved
HR variability (standard deviation of the RR interval) by 22% (P < 0.05). There
were no effects of Iva on PR, QRS, and QT durations. Interstitial fibrosis in
the MI-remote LV was markedly reduced by Iva (4.0 +/- 0.1 vs. 1.8 +/- 0.1%, P <
0.005). Increases in ventricular gene and protein expressions of ACE and AT(1)
receptor in MI were completely blunted by Iva. In conclusion, these data
indicated that HR reduction by Iva prevents the worsening of LV dysfunction and
remodeling that may be related to a downregulation of cardiac
renin-angiotensin-aldosterone system transcripts. Such beneficial effects of Iva
on cardiac remodeling open new clinical perspectives for the treatment of severe
HF.
DOI: 10.1152/ajpheart.00591.2008
PMID: 19074674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11007230 | 1. RETRACTED ARTICLE
Am J Gastroenterol. 2000 Sep;95(9):2285-95. doi:
10.1111/j.1572-0241.2000.03248.x.
Enterocolitis in children with developmental disorders.
Wakefield AJ(1), Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S,
O'Leary JJ, Berelowitz M, Walker-Smith JA.
Author information:
(1)University Department of Medicine, Royal Free and University College Medical
School, London, United Kingdom.
Retraction in
Am J Gastroenterol. 2010 May;105(5):1214. doi: 10.1038/ajg.2010.149.
Comment in
Am J Gastroenterol. 2000 Sep;95(9):2154-6. doi:
10.1111/j.1572-0241.2000.03247.x.
Histopathology. 2007 May;50(6):794. doi: 10.1111/j.1365-2559.2007.02668.x.
OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia
(LNH) and mucosal inflammation, has been described in children with
developmental disorders. This study describes some of the endoscopic and
pathological characteristics in a group of children with developmental disorders
(affected children) that are associated with behavioral regression and bowel
symptoms, and compares them with pediatric controls.
METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children
(median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50
patients), Asperger's syndrome (five), disintegrative disorder (two), attention
deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia
(one). Severity of ileal LNH was graded (0-3) in both affected children and 37
developmentally normal controls (median age 11 yr, range 2-13 yr) who were
investigated for possible inflammatory bowel disease (IBD). Tissue sections were
reviewed by three pathologists and scored on a standard proforma. Data were
compared with ileocolonic biopsies from 22 histologically normal children
(controls) and 20 children with ulcerative colitis (UC), scored in an identical
manner. Gut pathogens were sought routinely.
RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five
of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%)
affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically,
reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies
from affected children and in four of 14 (29%) with UC, but not in non-IBD
controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected
children but not in controls. Chronic colitis was identified in 53 of 60 (88%)
affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%)
with UC. Scores of frequency and severity of inflammation were significantly
greater in both affected children and those with UC, compared with controls (p <
0.001).
CONCLUSIONS: A new variant of inflammatory bowel disease is present in this
group of children with developmental disorders.
DOI: 10.1111/j.1572-0241.2000.03248.x
PMID: 11007230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9088928 | 1. Gen Physiol Biophys. 1996 Aug;15(4):309-16.
Positive inotropic effect of thyrotropin-releasing hormone on isolated rat
hearts.
Socci R(1), Kolbeck RC, Mészáros LG.
Author information:
(1)Medical College of Georgia, Department of Physiology and Endocrinology,
Augusta 30912, USA.
The effects of thyrotropin releasing hormone (TRH) on the contractility of
electrically stimulated and perfused isolated rat hearts were investigated. TRH
in the range of 0.1-10 mumol/l was found to exert a positive inotropic effect on
cardiac contractility, which however qualitatively differed at lower vs. higher
concentrations of the hormone: at 1 mumol/l, TRH was found to significantly
enhance the rate of contraction as well as that of relaxation (by 23.2 +/- 3.7
and 27.8 +/- 7.7%, respectively), which culminated in an increased peak
contractile force. However, at 10 mumol/l, the positive inotropic effect of TRH
(i.e. the increase in peak contractile force) was smaller than at 1 mumol/l,
which apparently was due to both a reduced TRH-induced elevation in the rate of
contraction (12.4 +/- 3.2%) and a TRH-induced decrease in relaxation rate (11.1
+/- 8.1%). Since TRH is expressed in the heart, the above findings suggest that,
in addition to its CNS-mediated cardiovascular effects, TRH modulates cardiac
contractility as an autocrine regulator in a concentration-dependent manner,
which likely involves more than one TRH receptor and associated signaling
pathway.
PMID: 9088928 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9585670 | 1. J Assoc Acad Minor Phys. 1998;9(1):9-15.
Improved social and language skills after secretin administration in patients
with autistic spectrum disorders.
Horvath K(1), Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT.
Author information:
(1)Department of Pediatrics, University of Maryland School of Medicine,
Maryland, USA.
We report three children with autistic spectrum disorders who underwent upper
gastrointestinal endoscopy and intravenous administration of secretin to
stimulate pancreaticobiliary secretion. All three had an increased
pancreaticobiliary secretory response when compared with nonautistic patients
(7.5 to 10 mL/min versus 1 to 2 mL/min). Within 5 weeks of the secretin
infusion, a significant amelioration of the children's gastrointestinal symptoms
was observed, as was a dramatic improvement in their behavior, manifested by
improved eye contact, alertness, and expansion of expressive language. These
clinical observations suggest an association between gastrointestinal and brain
function in patients with autistic behavior.
PMID: 9585670 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2848686 | 1. Endocrinology. 1988 Dec;123(6):2805-11. doi: 10.1210/endo-123-6-2805.
Inotropic effect of thyrotropin-releasing hormone on the guinea pig myocardium.
Hasegawa J(1), Hirai S, Kotake H, Hisatome I, Mashiba H.
Author information:
(1)Department of Internal Medicine, Tottori University School of Medicine,
Yonago, Japan.
The inotropic effect of the physiological level of TRH on isolated guinea pig
cardiac muscle was studied using a force transducer and standard microelectrode
techniques. TRH increased the contractile force of muscles dose-dependently
without changing the time course of contraction in normal Tyrode and a high K+
(27 mM) solution. The positive inotropic effect of TRH was associated with an
augmentation of slow action potentials in high K+ solution and was reduced in
the presence of diltiazem, verapamil, and manganese. TRH potentiated the
response of contractile force to increasing extracellular Ca2+ concentration.
The inotropic effect of TRH was suppressed by metoclopramide, phentolamine, and
cimetidine, but was not affected by propranolol. TRH increased the contractile
force even in the myocardium of reserpinized guinea pig. It is suggested that
TRH has a positive inotropic effect at least partly due to an increase in the
slow inward Ca2+ current.
DOI: 10.1210/endo-123-6-2805
PMID: 2848686 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17694091 | 1. Oncogene. 2007 Aug 13;26(37):5521-7. doi: 10.1038/sj.onc.1210618.
Structure and acetyl-lysine recognition of the bromodomain.
Mujtaba S(1), Zeng L, Zhou MM.
Author information:
(1)Department of Structural and Chemical Biology, Mount Sinai School of
Medicine, New York, NY 10029, USA.
Histone lysine acetylation is central to epigenetic control of gene
transcription. The bromodomain, found in chromatin-associated proteins and
histone acetyltranferases, functions as the sole protein module known to bind
acetyl-lysine motifs. Recent structural and functional analyses of bromodomains'
recognition of lysine-acetylated peptides derived from major acetylation sites
in histones and cellular proteins provide new insights into differences in
ligand binding selectivity as well as unifying features of histone recognition
by the bromodomains. These new findings highlight the functional importance of
bromodomain/acetyl-lysine binding as a pivotal mechanism for regulating
protein-protein interactions in histone-directed chromatin remodeling and gene
transcription. These new studies also support the notion that functional
diversity of a conserved bromodomain structural fold is achieved by evolutionary
changes of structurally flexible amino-acid sequences in the ligand binding site
such as the ZA and BC loops.
DOI: 10.1038/sj.onc.1210618
PMID: 17694091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22607127 | 1. Dis Esophagus. 2013 Apr;26(3):237-40. doi: 10.1111/j.1442-2050.2012.01358.x.
Epub 2012 May 18.
Autism and esophageal achalasia in childhood: a possible correlation? Report on
three cases.
Betalli P(1), Carretto E, Cananzi M, Zanatta L, Salvador R, Galeazzi F, Guariso
G, Gamba P, Costantini M.
Author information:
(1)Department of Pediatrics, Pediatric Surgery Department of Surgical and
Gastroenterological Sciences, Clinica Chirurgica 1 Department of Surgical and
Gastroenterological Sciences, Gastroenterology Department of Pediatrics,
Pediatric Gastroenterology, University of Padua, Padua, Italy.
Chronic gastrointestinal symptoms are commonly reported in autistic patients.
Dysphagia is often present, and it is generally related to behavioral eating
disorders. The association between autism and esophageal achalasia has not been
described in literature yet. We report our experience with three cases of
autistic children we recently treated for esophageal achalasia. In the first
case (a 14-year-old male), achalasia was diagnosed with barium swallow and
esophageal manometry and was successfully treated with three pneumatic
endoscopic dilatations (follow-up: 3 years). In the second case (a 12-year-old
female), achalasia was diagnosed with barium swallow and esophageal manometry
and was treated with Heller myotomy after two unsuccessful pneumatic endoscopic
attempts (follow-up: 3 months). In the last case, a 15-year-old male underwent
barium swallow and endoscopy that confirmed achalasia. He was treated with
Heller myotomy, and he is asymptomatic at a 6-month follow-up. To our knowledge,
this is the first report of a possible association between autism and esophageal
achalasia. Because of the rarity of both diseases, their association in the same
patient is unlikely to be casual even if speculation on their common etiology is
impossible at present. This finding needs further confirmation, but it is
sufficient, in our opinion, to indicate proper evaluation with barium swallow
and/or manometry in any autistic children with eating difficulty.
© 2012 Copyright the Authors. Journal compilation © 2012, Wiley Periodicals,
Inc. and the International Society for Diseases of the Esophagus.
DOI: 10.1111/j.1442-2050.2012.01358.x
PMID: 22607127 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23541665 | 1. Can J Cardiol. 2013 May;29(5):636-8. doi: 10.1016/j.cjca.2013.02.019. Epub
2013 Mar 29.
Renal sympathetic denervation for resistant hypertension.
Froeschl M(1), Hadziomerovic A, Ruzicka M.
Author information:
(1)Division of Cardiology, Department of Medicine, University of Ottawa Heart
Institute, University of Ottawa, Ottawa, Ontario, Canada.
mfroeschl@ottawaheart.ca
Resistant hypertension is an increasingly prevalent health problem associated
with important adverse cardiovascular outcomes. The pathophysiology that
underlies this condition involves increased function of both the sympathetic
nervous system and the renin-angiotensin II-aldosterone system. A crucial link
between these 2 systems is the web of sympathetic fibres that course within the
adventitia of the renal arteries. These nerves can be targeted by applying
radiofrequency energy from the lumen of the renal arteries to renal artery walls
(percutaneous renal sympathetic denervation [RSD]), an approach that has
attracted great interest. This paper critically reviews the evidence supporting
the use of RSD. Small studies suggest that RSD can produce dramatic blood
pressure reductions: In the randomized Symplicity HTN-2 trial of 106 patients,
the mean fall in blood pressure at 6 months in patients who received the
treatment was 32/12 mm Hg. However, there are limitations to the evidence for
RSD in the treatment of resistant hypertension. These include the small number
of patients studied; the lack of any placebo-controlled evidence; the fact that
blood pressure outcomes were based on office assessments, as opposed to 24-hour
ambulatory monitoring; the lack of longer-term efficacy data; and the lack of
long-term safety data. Some of these concerns are being addressed in the ongoing
Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-3)
trial. The first percutaneous RSD system was approved by Health Canada in the
spring of 2012. But until more and better-quality data are available, this
procedure should generally be reserved for those patients whose resistant
hypertension is truly uncontrolled.
Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.cjca.2013.02.019
PMID: 23541665 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23514712 | 1. Circ J. 2013;77(4):857-63. doi: 10.1253/circj.cj-13-0297. Epub 2013 Mar 19.
Renal sympathetic denervation for treating resistant hypertension.
Polimeni A(1), Curcio A, Indolfi C.
Author information:
(1)Division of Cardiology, Laboratory of Molecular and Cellular Cardiology,
Department of Medical and Surgical Sciences, Catanzaro, Italy.
Systemic hypertension represents a significant global concern, because it
contributes to vascular and renal morbidity, cardiovascular mortality, and
economic burden, hence the impact of hypertension is a major issue in public
health worldwide. Improving high blood pressure management is therefore
fundamental to influencing clinical outcomes. Despite adherence to multiple
available medical therapies, a significant proportion of patients has persistent
blood pressure elevation, a condition termed "resistant hypertension". Renal
sympathetic innervations contribute to lack of response of anti-hypertensive
drugs through an imbalance of regulatory mechanisms. Renal afferent nerve fibers
are responsible for sympathetic activation and contribute to blood pressure
homeostasis while afferent signals from the kidneys are integrated at the
central nervous system and enhance sympathetic nerve discharge. In this regard,
a novel strategy that selectively removes these hypertensive contributors
represents a new therapeutic opportunity. Recently, a catheter-based method to
induce renal sympathetic denervation has been introduced into daily practice.
Clinical evaluation of selective renal sympathetic denervation demonstrated a
decrease of renal norepinephrine spillover and renin activity, an increase of
renal plasma flow, and has confirmed clinically significant, sustained
reductions in blood pressure in patients with resistant hypertension. This
review summarizes the available data on the role of sympathetic activation in
the pathophysiology of hypertension and the current concepts in transcatheter
renal artery ablation with radiofrequency delivery for systemic hypertension.
Suggestions regarding targets for future systemic hypertension management are
also described.
DOI: 10.1253/circj.cj-13-0297
PMID: 23514712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23819768 | 1. Br J Clin Pharmacol. 2013 Oct;76(4):495-503. doi: 10.1111/bcp.12171.
Renal sympathetic nerve ablation for treatment-resistant hypertension.
Krum H(1), Schlaich M, Sobotka P.
Author information:
(1)Centre of Cardiovascular Research & Education (CCRE) in Therapeutics, Monash
University/Alfred Hospital, Melbourne, Australia.
Hypertension is a major risk factor for increased cardiovascular events with
accelerated sympathetic nerve activity implicated in the pathogenesis and
progression of disease. Blood pressure is not adequately controlled in many
patients, despite the availability of effective pharmacotherapy. Novel
procedure- as well as device-based strategies, such as percutaneous renal
sympathetic nerve denervation, have been developed to improve blood pressure in
these refractory patients. Renal sympathetic denervation not only reduces blood
pressure but also renal as well as systemic sympathetic nerve activity in such
patients. The reduction in blood pressure appears to be sustained over 3 years
after the procedure, which suggests absence of re-innervation of renal
sympathetic nerves. Safety appears to be adequate. This approach may also have
potential in other disorders associated with enhanced sympathetic nerve activity
such as congestive heart failure, chronic kidney disease and metabolic syndrome.
This review will focus on the current status of percutaneous renal sympathetic
nerve denervation, clinical efficacy and safety outcomes and prospects beyond
refractory hypertension.
© 2013 The British Pharmacological Society.
DOI: 10.1111/bcp.12171
PMCID: PMC3791973
PMID: 23819768 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10547242 | 1. J Pediatr. 1999 Nov;135(5):559-63. doi: 10.1016/s0022-3476(99)70052-1.
Gastrointestinal abnormalities in children with autistic disorder.
Horvath K(1), Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT.
Author information:
(1)Department of Pediatrics, University of Maryland School of Medicine,
Baltimore, USA.
Comment in
J Pediatr. 1999 Nov;135(5):533-5. doi: 10.1016/s0022-3476(99)70045-4.
OBJECTIVES: Our aim was to evaluate the structure and function of the upper
gastrointestinal tract in a group of patients with autism who had
gastrointestinal symptoms.
STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with
autistic disorder underwent upper gastrointestinal endoscopy with biopsies,
intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures.
The most frequent gastrointestinal complaints were chronic diarrhea,
gaseousness, and abdominal discomfort and distension.
RESULTS: Histologic examination in these 36 children revealed grade I or II
reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic
duodenitis in 24. The number of Paneth's cells in the duodenal crypts was
significantly elevated in autistic children compared with non-autistic control
subjects. Low intestinal carbohydrate digestive enzyme activity was reported in
21 children (58.3%), although there was no abnormality found in pancreatic
function. Seventy-five percent of the autistic children (27/36) had an increased
pancreatico-biliary fluid output after intravenous secretin administration.
Nineteen of the 21 patients with diarrhea had significantly higher fluid output
than those without diarrhea.
CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux
esophagitis and disaccharide malabsorption, may contribute to the behavioral
problems of the non-verbal autistic patients. The observed increase in
pancreatico-biliary secretion after secretin infusion suggests an upregulation
of secretin receptors in the pancreas and liver. Further studies are required to
determine the possible association between the brain and gastrointestinal
dysfunctions in children with autistic disorder.
DOI: 10.1016/s0022-3476(99)70052-1
PMID: 10547242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21247927 | 1. Eur Heart J. 2011 Mar;32(5):537-44. doi: 10.1093/eurheartj/ehq457. Epub 2011
Jan 18.
Novel procedure- and device-based strategies in the management of systemic
hypertension.
Krum H(1), Schlaich M, Sobotka P, Scheffers I, Kroon AA, de Leeuw PW.
Author information:
(1)Monash Centre of Cardiovascular Research & Education in Therapeutics, School
of Public Health and Preventive Medicine, Monash University/Alfred Hospital,
Melbourne, VIC 3004, Australia. henry.krum@med.monash.edu.au
Despite the considerable advances in the treatment of hypertension that have
been made over the past few decades, adequate management and control of this
condition remains poor, and efforts are ongoing to develop new strategies to
improve related outcomes. Novel therapeutic approaches to the management of
systemic hypertension fall into two major categories: (i) those that seek to
improve blood pressure-lowering efficacy using new therapeutic strategies in
addition to standard non-pharmacological and pharmacological approaches and (ii)
novel ways to optimize and improve the efficacy and utility of existing
therapies. Novel procedure- and device-based strategies to control hypertension
include renal sympathetic denervation and baroreflex sensitization. These two
techniques will be the focus of the present review.
DOI: 10.1093/eurheartj/ehq457
PMID: 21247927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17498659 | 1. Biochem Biophys Res Commun. 2007 Jun 29;358(2):435-41. doi:
10.1016/j.bbrc.2007.04.139. Epub 2007 May 2.
Solution structure of BRD7 bromodomain and its interaction with acetylated
peptides from histone H3 and H4.
Sun H(1), Liu J, Zhang J, Shen W, Huang H, Xu C, Dai H, Wu J, Shi Y.
Author information:
(1)Hefei National Laboratory for Physical Sciences at Microscale and School of
Life Sciences, University of Science and Technology of China, Hefei, Anhui, PR
China.
BRD7 is an important protein tightly associated with Nasopharyngeal carcinoma
(NPC). Overexpression of BRD7 inhibits NPC cell growth and cell cycle by
transcriptionally regulating the cell cycle related genes. BRD7 contains a
bromodomain that is found in many chromatin-associated proteins and in nearly
all known nuclear histone acetyltransferases (HATs) and plays an important role
in chromatin remodeling and transcriptional activation. Here, we report the
solution structure of BRD7 bromodomain determined by NMR spectroscopy, and its
binding specificity revealed by NMR titration with several acetylated histone
peptides. We find that BRD7 bromodomain contains the typical left-handed
four-helix bundle topology, and can bind with weak affinity to lysine-acetylated
peptides derived from histone H3 with K9 or K14 acetylated and from histone H4
with K8, K12 or K16 acetylated. Our results show that BRD7 bromodomain lacks
inherent binding specificity when binding to histones in vitro.
DOI: 10.1016/j.bbrc.2007.04.139
PMID: 17498659 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16003132 | 1. Eur J Gastroenterol Hepatol. 2005 Aug;17(8):827-36. doi:
10.1097/00042737-200508000-00009.
The significance of ileo-colonic lymphoid nodular hyperplasia in children with
autistic spectrum disorder.
Wakefield AJ(1), Ashwood P, Limb K, Anthony A.
Author information:
(1)Thoughtful House Center for Children, Austin, Texas 78746, USA.
Wakersa@aol.com
Expression of concern in
Eur J Gastroenterol Hepatol. 2011 Nov;23(11):1082. doi:
10.1097/MEG.0b013e328349d184.
Comment in
Eur J Gastroenterol Hepatol. 2005 Aug;17(8):821-2. doi:
10.1097/00042737-200508000-00007.
Eur J Gastroenterol Hepatol. 2006 May;18(5):569-71; author reply 571-3. doi:
10.1097/00042737-200605000-00023.
BACKGROUND: Intestinal mucosal pathology, characterized by ileo-colonic lymphoid
nodular hyperplasia (LNH) and mild acute and chronic inflammation of the
colorectum, small bowel and stomach, has been reported in children with autistic
spectrum disorder (ASD).
AIM: To assess ileo-colonic LNH in ASD and control children and to test the
hypothesis that there is an association between ileo-colonic LNH and ASD in
children.
PATIENTS AND METHODS: One hundred and forty-eight consecutive children with ASD
(median age 6 years; range 2-16; 127 male) with gastrointestinal symptoms were
investigated by ileo-colonoscopy. Macroscopic and histological features were
scored and compared with 30 developmentally normal (non-inflammatory bowel
disease, non-coeliac disease) controls (median age 7 years; range 1-11; 25 male)
showing mild non-specific colitis in 16 cases (13 male) and normal colonic
histology in 14 cases (12 male). Seventy-four ASD children and 23 controls also
underwent upper gastrointestinal endoscopy. The influence on ileal LNH of
dietary restriction, age at colonoscopy, and co-existent LNH elsewhere in the
intestine, was examined.
RESULTS: The prevalence of LNH was significantly greater in ASD children
compared with controls in the ileum (129/144 (90%) vs. 8/27 (30%), P < 0.0001)
and colon (88/148 (59%) vs. 7/30 (23%), P = 0.0003), whether or not controls had
co-existent colonic inflammation. The severity of ileal LNH was significantly
greater in ASD children compared with controls, with moderate to severe ileal
LNH present in 98 of 144 (68%) ASD children versus 4 of 27 (15%) controls (P <
0.0001). Severe ileal LNH was associated with co-existent colonic LNH in ASD
children (P = 0.01). The presence and severity of ileal LNH was not influenced
by either diet or age at colonoscopy (P = 0.2). Isolated ileal LNH without
evidence of pathology elsewhere in the intestine was a rare event, occurring in
less than 3% of children overall. On histopathological examination, hyperplastic
lymphoid follicles are significantly more prevalent in the ileum of ASD children
(84/138; 61%) compared with controls (2/23; 9%, P = 0.0001).
CONCLUSION: Ileo-colonic LNH is a characteristic pathological finding in
children with ASD and gastrointestinal symptoms, and is associated with mucosal
inflammation. Differences in age at colonoscopy and diet do not account for
these changes. The data support the hypothesis that LNH is a significant
pathological finding in ASD children.
DOI: 10.1097/00042737-200508000-00009
PMID: 16003132 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17148447 | 1. J Biol Chem. 2007 Feb 9;282(6):4193-201. doi: 10.1074/jbc.M605971200. Epub
2006 Dec 5.
Crystal structure of the human BRD2 bromodomain: insights into dimerization and
recognition of acetylated histone H4.
Nakamura Y(1), Umehara T, Nakano K, Jang MK, Shirouzu M, Morita S, Uda-Tochio H,
Hamana H, Terada T, Adachi N, Matsumoto T, Tanaka A, Horikoshi M, Ozato K,
Padmanabhan B, Yokoyama S.
Author information:
(1)RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama
230-0045, Japan.
The BET (bromodomains and extra terminal domain) family proteins recognize
acetylated chromatin through their bromodomain and act as transcriptional
activators. One of the BET proteins, BRD2, associates with the transcription
factor E2F, the mediator components CDK8 and TRAP220, and RNA polymerase II, as
well as with acetylated chromatin during mitosis. BRD2 contains two bromodomains
(BD1 and BD2), which are considered to be responsible for binding to acetylated
chromatin. The BRD2 protein specifically recognizes the histone H4 tail
acetylated at Lys12. Here, we report the crystal structure of the N-terminal
bromodomain (BD1, residues 74-194) of human BRD2. Strikingly, the BRD2 BD1
protein forms an intact dimer in the crystal. This is the first observation of a
homodimer among the known bromodomain structures, through the buried hydrophobic
core region at the interface. Biochemical studies also demonstrated BRD2 BD1
dimer formation in solution. The two acetyllysine-binding pockets and a
negatively charged secondary binding pocket, produced at the dimer interface in
BRD2 BD1, may be the unique features that allow BRD2 BD1 to selectively bind to
the acetylated H4 tail.
DOI: 10.1074/jbc.M605971200
PMID: 17148447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24300195 | 1. Chem Biol Interact. 2014 Feb 25;209:25-34. doi: 10.1016/j.cbi.2013.11.014.
Epub 2013 Dec 1.
A novel compound RY10-4 induces apoptosis and inhibits invasion via inhibiting
STAT3 through ERK-, p38-dependent pathways in human lung adenocarcinoma A549
cells.
Xue P(1), Zhao Y(1), Liu Y(2), Yuan Q(3), Xiong C(1), Ruan J(4).
Author information:
(1)Key Laboratory of Natural Medicinal Chemistry and Resources Evaluation of
Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University
of Science and Technology, 13# Hangkong Road, Wuhan 430030, PR China.
(2)School of Life Science, Wuchang University of Technology, Wuhan 430223, PR
China.
(3)Department of Pharmacology, Yale Medical School, New Haven, CT 06510, USA.
(4)Key Laboratory of Natural Medicinal Chemistry and Resources Evaluation of
Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University
of Science and Technology, 13# Hangkong Road, Wuhan 430030, PR China. Electronic
address: jinlan8152@163.com.
Previous reports suggested that protoapigenone showed remarkable antitumor
activities against a broad spectrum of human cancer cell lines, but had no
effect on human lung adenocarcinoma A549 cell. The lack of effective remedies
had necessitated the application of new therapeutic scheme. A novel compound
RY10-4 which has the similar structure close to protoapigenone showed better
antitumor activity. Treatment with RY10-4 inhibited the expression of
pro-caspase-3, pro-caspase-9, Bcl-2 as well as phosphorylation of signal
transducer and activator of transcription-3 (p-STAT3). It also reduced the
expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9
(MMP-9) and increases the expressions of reversion-inducing cysteine-rich
protein with kazal motifs (RECK), as well as tissue inhibitor of
metalloproteinase (TIMP) via inhibiting STAT3 by activating the
mitogen-activated protein (MAP) kinases (the c-Jun N-terminal kinase (JNK), the
p38 and extracellular signal-regulated kinase (ERK)) in A549 cells treated with
RY10-4. Moreover, the cytotoxic effect of RY10-4 was induction of apoptosis in
A549 cells by enhancing production of reactive oxygen species (ROS). Taken
together, the observations suggested that RY10-4 had affected Bcl-2 family
members, caspases, MMPs, TIMPs expressions and ROS production via inhibiting
STAT3 activities through ERK and p38 pathways in A549 cells.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.cbi.2013.11.014
PMID: 24300195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24291243 | 1. Mol Immunol. 2014 Mar;58(1):32-7. doi: 10.1016/j.molimm.2013.11.003. Epub 2013
Nov 26.
Jellyfish collagen stimulates production of TNF-α and IL-6 by J774.1 cells
through activation of NF-κB and JNK via TLR4 signaling pathway.
Putra AB(1), Nishi K(1), Shiraishi R(2), Doi M(2), Sugahara T(3).
Author information:
(1)Faculty of Agriculture, Ehime University, Matsuyama, Ehime 790-8566, Japan.
(2)Marutomo Co., Ltd., Iyo, Ehime 799-3192, Japan.
(3)Faculty of Agriculture, Ehime University, Matsuyama, Ehime 790-8566, Japan;
South Ehime Fisheries Research Center, Ehime University, Ainan, Ehime 798-4205,
Japan; Food and Health Sciences Research Center, Ehime University, Matsuyama,
Ehime 790-8566, Japan. Electronic address: mars95@agr.ehime-u.ac.jp.
We previously reported that jellyfish collagen stimulates both the acquired and
innate immune responses. In the acquired immune response, jellyfish collagen
enhanced immunoglobulin production by lymphocytes in vitro and in vivo.
Meanwhile, in the innate immune response jellyfish collagen promoted cytokine
production and phagocytotic activity of macrophages. The facts that jellyfish
collagen plays several potential roles in stimulating cytokine production by
macrophages have further attracted us to uncover its mechanisms. We herein
describe that the cytokine production-stimulating activity of jellyfish collagen
was canceled by a Toll-like receptor 4 (TLR4) inhibitor. Moreover, jellyfish
collagen stimulated phosphorylation of inhibitor of κBα (IκBα), promoted the
translocation of nucleus factor-κB (NF-κB), and activated c-Jun N-terminal
kinase (JNK). A JNK inhibitor also abrogated the cytokine production-stimulating
activity of jellyfish collagen. These results suggest that jellyfish collagen
may facilitate cytokine production by macrophages through activation of NF-κB
and JNK via the TLR4 signaling pathways.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.molimm.2013.11.003
PMID: 24291243 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15228586 | 1. J Neurochem. 2004 Jul;90(2):297-308. doi: 10.1111/j.1471-4159.2004.02487.x.
Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and
interferon-beta.
Kim MO(1), Suh HS, Brosnan CF, Lee SC.
Author information:
(1)Department of Pathology, Albert Einstein College of Medicine, Bronx, New York
10461, USA.
In the CNS, astrocytes are significant sources of RANTES/CCL5 (regulated upon
activation, normal T cell expressed and secreted), a CC-chemokine with important
biological function. Astrocyte RANTES/CCL5 has been shown to be induced by
interleukin-1 (IL-1), with interferon-gamma (IFNgamma) as a primer, but whether
type I interferons play any role in the expression of RANTES/CCL5 is not known.
In this report, we studied the detailed mechanism of RANTES/CCL5 induction in
primary human astrocytes activated with IL-1 and IFNbeta. Ribonuclease
protection assay and ELISA showed that IFNbeta, although not effective alone,
increased IL-1-induced RANTES/CCL5 expression, but did not antagonize IFNgamma.
IL-1 or IL-1/IFNbeta-induced RANTES/CCL5 expression was inhibited by the
super-repressor IkappaBalpha or inhibitors of p38 or c-Jun N-terminal kinase
(JNK) MAPKs (mitogen-activated protein kinases), but not by extracellular signal
regulated kinases (ERK) inhibitors. IFNbeta enhanced IL-1-induced
phosphorylation of p38 MAPK, but was not effective alone. Transfection with
mutated RANTES/CCL5 promoter-reporter constructs revealed that kappaB,
interferon-stimulated response element (ISRE) and CAATT-enhancer binding
protein-beta (C/EBPbeta) sites all contributed to IL-1/IFNbeta-induced
RANTES/CCL5 transcription. IFNbeta synergized with IL-1 to induce nuclear
accumulation of C/EBPbeta protein. They also synergized to form nuclear ISRE
complexes with Stat1, Stat2 and interferon regulatory factor-1 (IRF-1) proteins.
Together, our results demonstrate that IFNbeta plays a positive regulatory role
in the expression of RANTES/CCL5 in human astrocytes through several distinct
mechanisms.
DOI: 10.1111/j.1471-4159.2004.02487.x
PMID: 15228586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10827952 | 1. Science. 2000 May 26;288(5470):1422-5. doi: 10.1126/science.288.5470.1422.
Structure and function of a human TAFII250 double bromodomain module.
Jacobson RH(1), Ladurner AG, King DS, Tjian R.
Author information:
(1)Howard Hughes Medical Institute and Department of Molecular and Cell Biology,
401 Barker Hall, University of California, Berkeley, CA 94720-3204, USA.
Comment in
Science. 2000 May 26;288(5470):1372-3. doi: 10.1126/science.288.5470.1372.
TFIID is a large multiprotein complex that initiates assembly of the
transcription machinery. It is unclear how TFIID recognizes promoters in vivo
when templates are nucleosome-bound. Here, it is shown that TAFII250, the
largest subunit of TFIID, contains two tandem bromodomain modules that bind
selectively to multiply acetylated histone H4 peptides. The 2.1 angstrom crystal
structure of the double bromodomain reveals two side-by-side, four-helix bundles
with a highly polarized surface charge distribution. Each bundle contains an
Nepsilon-acetyllysine binding pocket at its center, which results in a structure
ideally suited for recognition of diacetylated histone H4 tails. Thus, TFIID may
be targeted to specific chromatin-bound promoters and may play a role in
chromatin recognition.
DOI: 10.1126/science.288.5470.1422
PMID: 10827952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24321566 | 1. Cell Immunol. 2013 Nov-Dec;286(1-2):53-8. doi: 10.1016/j.cellimm.2013.11.004.
Epub 2013 Nov 21.
Estrogen attenuates lipopolysaccharide-induced nitric oxide production in
macrophages partially via the nongenomic pathway.
Liu L(1), Wang Z(2).
Author information:
(1)Departments of Pathology and Pathophysiology, Medical College of Soochow
University, Suzhou 215123, Jiangsu, China.
(2)Department of Forensic Medicine, Medical College of Soochow University,
Suzhou 215123, Jiangsu, China. Electronic address: zufengwang@suda.edu.cn.
Steroid hormones exert genotropic effects through members of the nuclear hormone
receptor family. In the present study, we examined the effects of 17β-estradiol
(E2) on nitric oxide (NO) production following lipopolysaccharide (LPS)
stimulation and investigated the mechanisms in mouse bone marrow-derived
macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2
inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2
conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic
effects of estrogen, we found that the increase in NO production induced by LPS
was also attenuated. In addition, the intracellular estrogen receptor blocker,
ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated
NO production capacity. E2 also attenuated the LPS activation of p38
mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated
protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This
attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB
203580, greatly reduced the LPS-induced NO production, and the remaining NO
levels were no longer regulated by E2. Additionally, E2-BSA inhibited
LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover,
E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB)
and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially
antagonized by ICI 182780. Taken together, these results suggest that E2 has an
inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38
MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects
are mediated at least in part via a nongenomic pathway.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cellimm.2013.11.004
PMID: 24321566 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24113186 | 1. Cell Death Dis. 2013 Oct 10;4(10):e852. doi: 10.1038/cddis.2013.381.
Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of
c-Jun pro-apoptotic activity in cerebellar granule neurons.
Reddy CE(1), Albanito L, De Marco P, Aiello D, Maggiolini M, Napoli A, Musti AM.
Author information:
(1)Institute for Clinical Neurobiology, University of Würzburg, Würzburg,
Germany.
Cerebellar granule cell (CGC) apoptosis by trophic/potassium (TK) deprivation is
a model of election to study the interplay of pro-apoptotic and pro-survival
signaling pathways in neuronal cell death. In this model, the c-Jun N-terminal
kinase (JNK) induces pro-apoptotic genes through the c-Jun/activator protein 1
(AP-1) transcription factor. On the other side, a survival pathway initiated by
lithium leads to repression of pro-apoptotic c-Jun/AP-1 target genes without
interfering with JNK activity. Yet, the mechanism by which lithium inhibits
c-Jun activity remains to be elucidated. Here, we used this model system to
study the regulation and function of site-specific c-Jun phosphorylation at the
S63 and T91/T93 JNK sites in neuronal cell death. We found that TK-deprivation
led to c-Jun multiphosphorylation at all three JNK sites. However,
immunofluorescence analysis of c-Jun phosphorylation at single cell level
revealed that the S63 site was phosphorylated in all c-Jun-expressing cells,
whereas the response of T91/T93 phosphorylation was more sensitive, mirroring
the switch-like apoptotic response of CGCs. Conversely, lithium prevented T91T93
phosphorylation and cell death without affecting the S63 site, suggesting that
T91T93 phosphorylation triggers c-Jun pro-apoptotic activity. Accordingly, a
c-Jun mutant lacking the T95 priming site for T91/93 phosphorylation protected
CGCs from apoptosis, whereas it was able to induce neurite outgrowth in PC12
cells. Vice versa, a c-Jun mutant bearing aspartate substitution of T95
overwhelmed lithium-mediate protection of CGCs from TK-deprivation, validating
that inhibition of T91/T93/T95 phosphorylation underlies the effect of lithium
on cell death. Mass spectrometry analysis confirmed multiphosphorylation of
c-Jun at T91/T93/T95 in cells. Moreover, JNK phosphorylated recombinant c-Jun at
T91/T93 in a T95-dependent manner. On the basis of our results, we propose that
T91/T93/T95 multiphosphorylation of c-Jun functions as a sensitivity amplifier
of the JNK cascade, setting the threshold for c-Jun pro-apoptotic activity in
neuronal cells.
DOI: 10.1038/cddis.2013.381
PMCID: PMC3824690
PMID: 24113186 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12907332 | 1. Am J Gastroenterol. 2003 Aug;98(8):1777-82. doi:
10.1111/j.1572-0241.2003.07593.x.
Intestinal cytokines in children with pervasive developmental disorders.
DeFelice ML(1), Ruchelli ED, Markowitz JE, Strogatz M, Reddy KP, Kadivar K,
Mulberg AE, Brown KA.
Author information:
(1)Division of Gastroenterology and Nutrition, The Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
OBJECTIVES: A relationship between autism and gastrointestinal (GI) immune
dysregulation has been postulated based on incidence of GI complaints as well as
macroscopically observed lymphonodular hyperplasia and microscopically
determined enterocolitis in pediatric patients with autism. To evaluate GI
immunity, we quantitatively assessed levels of proinflammatory cytokines,
interleukin (IL)-6, IL-8, and IL-1beta, produced by intestinal biopsies of
children with pervasive developmental disorders.
METHODS: Fifteen patients, six with pervasive developmental disorders and nine
age-matched controls, presenting for diagnostic colonoscopy were enrolled.
Endoscopic biopsies were organ cultured, supernatants were harvested, and IL-6,
IL-8, and IL-1beta levels were quantified by ELISA. Tissue histology was
evaluated by blinded pathologists.
RESULTS: Concentrations of IL-6 from intestinal organ culture supernatants of
patients with pervasive developmental disorders (median 318.5 pg/ml,
interquartile range 282.0-393.0 pg/ml) when compared with controls (median 436.9
pg/ml, interquartile range 312.6-602.5 pg/ml) were not significantly different
(p = 0.0987). Concentrations of IL-8 (median 84,000 pg/ml, interquartile range
16,000-143,000 pg/ml) when compared with controls (median 177,000 pg/ml,
interquartile range 114,000-244,000 pg/ml) were not significantly different (p =
0.0707). Concentrations of IL-1beta (median 0.0 pg/ml, interquartile range
0.0-94.7 pg/ml) when compared with controls (median 0.0 pg/ml, interquartile
range 0.0-60.2 pg/ml) were not significantly different (p = 0.8826). Tissue
histology was nonpathological for all patients.
CONCLUSIONS: We have demonstrated no significant difference in production of
IL-6, IL-8, and IL-1beta between patients with pervasive developmental disorders
and age-matched controls. In general, intestinal levels of IL-6 and IL-8 were
lower in patients with pervasive developmental disorders than in age-matched
controls. These data fail to support an association between autism and GI
inflammation.
DOI: 10.1111/j.1572-0241.2003.07593.x
PMID: 12907332 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22573363 | 1. Clin Cardiol. 2012 Sep;35(9):528-35. doi: 10.1002/clc.22008. Epub 2012 May 9.
Catheter-based renal denervation for resistant hypertension: rationale and
design of the SYMPLICITY HTN-3 Trial.
Kandzari DE(1), Bhatt DL, Sobotka PA, O'Neill WW, Esler M, Flack JM, Katzen BT,
Leon MB, Massaro JM, Negoita M, Oparil S, Rocha-Singh K, Straley C, Townsend RR,
Bakris G.
Author information:
(1)Piedmont Heart Institute, Atlanta, GA, USA. david.kandzari@piedmont.org
Hypertension represents a significant global public health concern, contributing
to vascular and renal morbidity, cardiovascular mortality, and economic burden.
The opportunity to influence clinical outcomes through hypertension management
is therefore paramount. Despite adherence to multiple available medical
therapies, a significant proportion of patients have persistent blood pressure
elevation, a condition termed resistant hypertension. Recent recognition of the
importance of the renal sympathetic and somatic nerves in modulating blood
pressure and the development of a novel procedure that selectively removes these
contributors to resistant hypertension represents an opportunity to provide
clinically meaningful benefit across wide and varied patient populations. Early
clinical evaluation with catheter-based, selective renal sympathetic denervation
in patients with resistant hypertension has mechanistically correlated
sympathetic efferent denervation with decreased renal norepinephrine spillover
and renin activity, increased renal plasma flow, and has demonstrated clinically
significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial
is a pivotal study designed as a prospective, randomized, masked procedure,
single-blind trial evaluating the safety and effectiveness of catheter-based
bilateral renal denervation for the treatment of uncontrolled hypertension
despite compliance with at least 3 antihypertensive medications of different
classes (at least one of which is a diuretic) at maximal tolerable doses. The
primary effectiveness endpoint is measured as the change in office-based
systolic blood pressure from baseline to 6 months. This manuscript describes the
design and methodology of a regulatory trial of selective renal denervation for
the treatment of hypertension among patients who have failed pharmacologic
therapy.
© 2012 Wiley Periodicals, Inc.
DOI: 10.1002/clc.22008
PMCID: PMC6652693
PMID: 22573363 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23176687 | 1. Future Cardiol. 2012 Nov;8(6):837-46. doi: 10.2217/fca.12.66.
Identifying patients with resistant hypertension and options for clinical
management.
Tsang Cheung T(1), Man Yung Cheung B.
Author information:
(1)Division of Clinical Pharmacology & Therapeutics, Department of Medicine, Li
Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital,
Hong Kong SAR, China.
In addition to the increasing prevalence of hypertension, the number of patients
with treatment-resistant hypertension is also rising. It is important to
identify these patients in order to improve the treatment outcomes and to screen
for potential secondary causes. Clinical characteristics of patients with
resistant hypertension include advanced age, male gender, obesity, high salt
intake and alcohol consumption. Those with high baseline blood pressure,
diabetes, chronic kidney disease or obstructive sleep apnea are also prone to
developing resistant hypertension. Physicians should initiate close monitoring
and aggressive treatment for those patients, as resistant hypertension is
associated with a higher risk of cardiovascular morbidities, regardless of the
control of blood pressure. However, treatment of resistant hypertension is
currently a great challenge in clinical practice as all of these patients are
already taking multiple antihypertensive medications, including the first-line
treatments advocated in guidelines. In patients who have been presented multiple
drugs, the room for further titration is often limited. Spironolactone has been
demonstrated to be effective as an add-on therapy for patients with resistant
hypertension. In addition to drug treatment, baroreceptor stimulation therapy
and renal sympathetic denervation are promising new approaches in this group of
patients. Further studies on the pathogenesis and the treatment of resistant
hypertension would help to improve the outcome of this patient subgroup.
DOI: 10.2217/fca.12.66
PMID: 23176687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24144051 | 1. Can J Physiol Pharmacol. 2013 Oct;91(10):804-11. doi: 10.1139/cjpp-2013-0005.
Epub 2013 May 30.
Involvement of cardiomyocyte apoptosis in myocardial injury of hereditary
epileptic rats.
Chen F(1), Cao YG, Qi HP, Li L, Huang W, Wang Y, Sun HL.
Author information:
(1)a Department of Pharmacology, Harbin Medical University - Daqing, Daqing,
Heilongjiang 163319, China.
Many clinical cases have been reported where epilepsy profoundly influenced the
pathophysiological function of the heart; however, the underlying mechanisms
were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy
to investigate the potential mechanisms of myocardial injury. Cardiac functions
were assessed by arrhythmia score, heart rate, heart:body mass ratio, and
hemodynamic parameters including left ventricular systolic pressure (LVSP), left
ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular
pressure rise and fall (+dp/dtmax and -dp/dtmax). Catecholamine level was
detected by HPLC. Apoptotic index was estimated by TUNEL assay. The expressions
of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK),
c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western
blot. The results indicated that there existed cardiac dysfunction and
cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM
rats. Further investigation revealed that apoptosis was mediated by reducing
Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments
demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were
up-regulated. Our results suggest that the sympathetic nervous system activation
and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats.
The mechanisms of apoptosis might be associated with the activation of the
mitochondria-initiated and the mitogen-activated protein kinase pathways.
DOI: 10.1139/cjpp-2013-0005
PMID: 24144051 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24272171 | 1. Inflammation. 2014 Apr;37(2):621-31. doi: 10.1007/s10753-013-9778-9.
Lipopolysaccharide (LPS) induces the apoptosis and inhibits osteoblast
differentiation through JNK pathway in MC3T3-E1 cells.
Guo C(1), Yuan L, Wang JG, Wang F, Yang XK, Zhang FH, Song JL, Ma XY, Cheng Q,
Song GH.
Author information:
(1)Luohe Medical College, 148 Daxue Road, Luohe, 462002, Henan, People's
Republic of China, guospring@126.com.
Bone degradation is a serious complication of chronic inflammatory diseases such
as septic arthritis, osteomyelitis, and infected orthopedic implant failure. Up
to date, effective therapeutic treatments for bacteria-caused bone destruction
are limited. In our previous study, we found that LPS promoted osteoclast
differentiation and activity through activation of mitogen-activated protein
kinases (MAPKs) pathway such as c-Jun N-terminal kinases (JNK) and extracellular
signal regulated kinase (ERK1/2). The current study was to evaluate the
mechanism of LPS on the apoptosis and osteoblast differentiation in MC3T3-E1
cells. MC3T3-E1 osteoblasts were non-treated, treated with LPS. After treatment,
the cell viability, the activity of alkaline phosphatase (ALP) and caspase-3
were measured. The expressions of osteoblast-specific genes and Bax, Bcl-2, and
caspase-3 were determined by real-time quantitative polymerase chain reaction
(qPCR). Protein levels of Bax, Bcl-2, caspase-3, and phosphorylation of MAPKs
were measured using Western blotting assays. The MAPK signaling pathway was
blocked by pretreatment with JNK inhibitor SP600125. LPS treatment induced a
significant decrease in cell metabolism, viability, and ALP activity in MC3T3-E1
cells. LPS also significantly decreased mRNA expressions of osteoblast-related
genes in MC3T3-E1 cells. On the other hand, LPS significantly upregulated mRNA
expressions and protein levels of Bax and caspase-3 as well as activation of
caspase-3, whereas decreased Bcl-2 expression in MC3T3-E1 cells. Furthermore,
LPS significantly promoted MAPK pathway including the phosphorylation of JNK and
the phosphorylation of ERK1/2; moreover, pretreatment with JNK inhibitor not
only attenuated both of phosphorylation-JNK and ERK1/2 enhanced by LPS in
MC3T3-E1 cells, but also reversed the downregulated expressions of
osteoblast-specific genes including ALP and BSP induced by LPS. In conclusion,
LPS could induce osteoblast apoptosis and inhibit osteoblast differentiation via
activation of JNK pathway.
DOI: 10.1007/s10753-013-9778-9
PMID: 24272171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8607977 | 1. Mol Reprod Dev. 1995 Dec;42(4):459-67. doi: 10.1002/mrd.1080420414.
Transcriptional regulation by MAP kinases.
Davis RJ(1).
Author information:
(1)Department of Biochemistry and Molecular Biology, Howard Hughes Medical
Institute, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
Tyrosine kinase growth factor receptors activate MAP kinase by a complex
mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras.
The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase
cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases
have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate
Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP
kinase. Subsequently, the activated MAP kinase translocates into the nucleus
where many of the physiological targets of the MAP kinase signal transduction
pathway are located. These substrates include transcription factors that are
regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and
C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of
signal transduction by growth factor receptors from the cell surface to the
nucleus that results in the regulation of gene expression. Three MAP kinase
homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP
kinases that are similar to the rat Erk kinases have also been identified by
molecular cloning. The human Erk1 protein kinase has been shown to be widely
expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is
a 41-kDa protein that is expressed ubiquitously. In contrast, a human
Erk3-related protein kinase has been found to be expressed at a high level only
in heart muscle and brain. The loci of these MAP kinase genes are widely
distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and
ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase
gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together,
these kinases are a more diverse group than the human erks that have been
identified. Thus the erks are likely to represent only one subgroup of a larger
human MAP kinase gene family. A candidate for this extended family of MAP
kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and
phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and
Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative
of the MAP kinase group that is activated by dual phosphorylation at Tyr and
Thr.
DOI: 10.1002/mrd.1080420414
PMID: 8607977 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23147205 | 1. Protein Expr Purif. 2013 Feb;87(2):87-99. doi: 10.1016/j.pep.2012.10.010. Epub
2012 Nov 10.
High yield purification of JNK1β1 and activation by in vitro reconstitution of
the MEKK1→MKK4→JNK MAPK phosphorylation cascade.
Owen GR(1), Achilonu I, Dirr HW.
Author information:
(1)Protein Structure-Function Research Unit, School of Molecular and Cell
Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
The c-Jun N-terminal kinase (JNK) pathway forms part of the mitogen-activated
protein kinase (MAPK) signaling pathways comprising a sequential three-tiered
kinase cascade. Here, an upstream MAP3K (MEKK1) phosphorylates and activates a
MAP2K (MKK4 and MKK7), which in turn phosphorylates and activates the MAPK, JNK.
The C-terminal kinase domain of MEKK1 (MEKK-C) is constitutively active, while
MKK4/7 and JNK are both activated by dual phosphorylation of S/Y, and T/Y
residues within their activation loops, respectively. While improvements in the
purification of large quantities of active JNKs have recently been made,
inadequacies in their yield, purity, and the efficiency of their phosphorylation
still exist. We describe a novel and robust method that further improves upon
the purification of large yields of highly pure, phosphorylated JNK1β1, which is
most suitable for biochemical and biophysical characterization. Codon
harmonization of the JNK1β1 gene was used as a precautionary measure toward
increasing the soluble overexpression of the kinase. While JNK1β1 and its
substrate ATF2 were both purified to >99% purity as GST fusion proteins using
GSH-agarose affinity chromatography and each cleaved from GST using thrombin,
constitutively-active MEKK-C and inactive MKK4 were separately expressed in E.
coli as thioredoxin-His(6)-tagged proteins and purified using urea refolding and
Ni(2+)-IMAC, respectively. Activation of JNK1β1 was then achieved by
successfully reconstituting the JNK MAPK activation cascade in vitro; MEKK-C was
used to activate MKK4, which in turn was used to efficiently phosphorylate and
activate large quantities of JNK1β1. Activated JNK1β1 was thereafter able to
phosphorylate ATF2 with high catalytic efficiency.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pep.2012.10.010
PMID: 23147205 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22577022 | 1. Proteomics. 2012 Apr;12(8):1207-16. doi: 10.1002/pmic.201100430.
Qualitative improvement and quantitative assessment of N-terminomics.
Guryča V(1), Lamerz J, Ducret A, Cutler P.
Author information:
(1)Translational Research Sciences, F. Hoffmann-La Roche AG, Basel, Switzerland.
Proteolysis represents one of the most tightly controlled physiological
processes, as proteases create events that will typically commit pathways in an
irreversible manner. Despite their implication in nearly all biological systems,
our understanding of the role of proteases in disease pathology is often
limited. Several approaches to studying proteolytic activity as it relates to
biology, pathophysiology, and drug therapy have been published, including the
recently described terminal amine isotopic labeling of substrates (TAILS)
strategy by Kleifeld and colleagues. Here, we investigate TAILS as a methodology
based on targeted enrichment and mass spectrometric detection of endogenous
N-terminal peptides from clinically relevant biological samples and its
potential to provide quantitative information on proteolysis and elucidation of
the protease cleavage sites. While optimizing the most current protocol, by
switching to a streamlined one-tube format and simplifying the reagents' removal
steps, we demonstrate the advantages over previously published methods and
provide solutions to some of the technical challenges presented in the Kleifeld
publication. We also identify some of the current and unresolved limitations. We
use human plasma as a model system to provide data, which illustrates some of
the key analytical parameters of the modified TAILS procedure, including
specificity, sensitivity, quantitative precision, and accuracy.
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/pmic.201100430
PMID: 22577022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23334667 | 1. Nat Genet. 2013 Mar;45(3):285-9. doi: 10.1038/ng.2526. Epub 2013 Jan 20.
Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.
Brastianos PK(1), Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, Ligon
KL, Palescandolo E, Van Hummelen P, Ducar MD, Raza A, Sunkavalli A, Macconaill
LE, Stemmer-Rachamimov AO, Louis DN, Hahn WC, Dunn IF, Beroukhim R.
Author information:
(1)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts, USA.
Comment in
Nat Rev Neurol. 2013 Mar;9(3):121. doi: 10.1038/nrneurol.2013.16.
Cancer Discov. 2013 Mar;3(3):OF13. doi: 10.1158/2159-8290.CD-RW2013-028.
Meningiomas are the most common primary nervous system tumor. The tumor
suppressor NF2 is disrupted in approximately half of all meningiomas, but the
complete spectrum of genetic changes remains undefined. We performed
whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing
on an additional 48 tumors to identify and validate somatic genetic alterations.
Most meningiomas had simple genomes, with fewer mutations, rearrangements and
copy-number alterations than reported in other tumors in adults. However,
several meningiomas harbored more complex patterns of copy-number changes and
rearrangements, including one tumor with chromothripsis. We confirmed focal NF2
inactivation in 43% of tumors and found alterations in epigenetic modifiers in
an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations
harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO
(p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these
pathways. These mutations were present in therapeutically challenging tumors of
the skull base and higher grade. These results begin to define the spectrum of
genetic alterations in meningiomas and identify potential therapeutic targets.
DOI: 10.1038/ng.2526
PMCID: PMC3739288
PMID: 23334667 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24252081 | 1. Clin Exp Dermatol. 2013 Dec;38(8):890-6. doi: 10.1111/ced.12102.
Role of c-Jun N-terminal kinase isoforms in the cellular activity of melanoma
cell lines.
Kogushi-Nishi H(1), Jinnin M, Kobayashi Y, Muchemwa FC, Hirano A, Makino T,
Fukushima S, Masuguchi S, Ishihara T, Inoue Y, Ihn H.
Author information:
(1)Department of Dermatology and Plastic Surgery, Faculty of Life Sciences,
Kumamoto University, Kumamoto, Japan.
BACKGROUND: The c-Jun N-terminal kinase (JNK) is thought to be involved in
inflammation, proliferation and apoptosis.
AIM: To examine the role of JNK isoforms in metastasis, proliferation, migration
and invasion of the malignant melanoma (MM) cell lines SK-MEL-28, SK-MEL-3 and
WM164, using a kinase-specific inhibitor or isoform-specific small interfering
(si)RNAs.
RESULTS: SK-MEL-3, a cell line established from metastatic MM, showed slightly
increased phosphorylation of both JNK1 and JNK2, whereas WM164, a cell line
derived from primary MM, showed significant phosphorylation of JNK1. A JNK
inhibitor, SP600125, inhibited cell proliferation of SK-MEL-3 but not SK-MEL-28
or WM164. Transfection of JNK1-specific siRNA reduced the migratory activity of
WM164 cells, while silencing of either JNK1 or JNK2 strongly suppressed the
invasive activity of SK-MEL-3.
CONCLUSIONS: Our study suggests that JNK isoforms have different roles in MM.
Metastasis of MM may be regulated by JNK2, while invasion is regulated by both
JNK1 and JNK2. JNK1 and JNK2 respectively mediate cell migration and cell
proliferation. Further understanding of the specific roles of JNK isoforms in
the pathogenesis of MM may lead to the development of therapies targeting
specific isoforms.
© 2013 British Association of Dermatologists.
DOI: 10.1111/ced.12102
PMID: 24252081 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15637069 | 1. J Biol Chem. 2005 Mar 18;280(11):9913-20. doi: 10.1074/jbc.M412165200. Epub
2005 Jan 6.
Identification of a specific domain responsible for JNK2alpha2
autophosphorylation.
Cui J(1), Holgado-Madruga M, Su W, Tsuiki H, Wedegaertner P, Wong AJ.
Author information:
(1)Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas
Jefferson University, 233 S. 10th St., Philadelphia, Pennsylvania 19107, USA.
c-Jun N-terminal kinases (JNKs) are a group of mitogen-activated protein kinase
family members that are important in regulating cell growth, proliferation, and
apoptosis. Activation of the JNK pathway has been implicated in the formation of
several human tumors. We have previously demonstrated that a 55-kDa JNK isoform
is constitutively activated in 86% of human brain tumors and more recently
demonstrated that this isoform is either JNK2alpha2 or JNK2beta2. Importantly,
we have also found that among the 10 known JNK isoforms, the JNK2 isoforms are
unique in their ability to autophosphorylate in vitro and in vivo. This does not
require the participation of any upstream kinases and also leads to substrate
kinase activity in vitro and in vivo. To clarify the mechanism of JNK2alpha2
autoactivation, we have generated a series of chimeric cDNAs joining portions of
JNK1alpha2, which does not have detectable autophosphorylation activity, with
portions of JNK2alpha2, which has the strongest autophosphorylation activity.
Through in vivo and in vitro kinase assays, we were able to define a domain
ranging from amino acids 218 to 226 within JNK2alpha2 that is required for its
autophosphorylation. Mutation of JNK2alpha2 to its counterpart of JNK1alpha2 in
this region abrogated the autophosphorylation activity and c-Jun substrate
kinase activity in vivo and in vitro. Notably, switching of JNK1alpha2 to
JNK2alpha2 at this 9-amino acid site enabled JNK1alpha2 to gain the
autophosphorylation activity in vivo and in vitro. We also found two other
functional sites that participate in JNK2alpha2 activity. One site ranging from
amino acids 363 to 382 of JNK2alpha2 is required for efficient c-Jun binding in
vitro, and a site ranging from amino acids 383 to 424 enhances
autophosphorylation intensity, although it is not required for triggering the
autophosphorylation in vitro. These findings have uncovered the regions required
for JNK2alpha2 autophosphorylation, and this information could be used as
potential targets to block JNK2alpha2 activation.
DOI: 10.1074/jbc.M412165200
PMID: 15637069 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23028407 | 1. Open Rheumatol J. 2012;6:220-31. doi: 10.2174/1874312901206010220. Epub 2012
Sep 7.
c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases.
Guma M(1), Firestein GS.
Author information:
(1)Division of Rheumatology, Allergy and Immunology, UC San Diego School of
Medicine, La Jolla, CA, USA.
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein
kinase (MAPK) family and are activated by environmental stress. JNK is also
activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like
receptor ligands. This pathway, therefore, can act as a critical convergence
point in immune system signaling for both adaptive and innate responses. Like
other MAPKs, the JNKs are activated via the sequential activation of protein
kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7)
and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be
deactivated by a specialized group of phosphatases, called MAP kinase
phosphatases. JNK phosphorylates and regulates the activity of transcription
factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and
non-transcription factors, such as members of the Bcl-2 family. The pathway
plays a critical role in cell proliferation, apoptosis, angiogenesis and
migration. In this review, an overview of the functions that are related to
rheumatic diseases is presented. In addition, some diseases in which JNK
participates will be highlighted.
DOI: 10.2174/1874312901206010220
PMCID: PMC3460413
PMID: 23028407 |
http://www.ncbi.nlm.nih.gov/pubmed/24321066 | 1. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2013 Dec;29(12):1251-3.
[Immune regulatory effect of citalopram on microglial cells].
[Article in Chinese]
Wang S(1), Chen H, Xie H.
Author information:
(1)Department of Neurology, Nanlou Clinical Division, PLA General Hospital,
Beijing 100853, China.
OBJECTIVE: To investigate the effects of antidepressant citalopram on the gene
expressions of tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta
(IL-1β), and to discuss the impacts of citalopram on p38 and c-jun N-terminal
kinase (JNK) of mitogen-activated protein kinase (MAPK) family in microglial
cells.
METHODS: BV2 cells were induced by lipopolysaccharide (LPS) to produce TNF-α and
IL-1β. After pretreatment with citalopram (20 μmol/L) for 4 h, the mRNA levels
of TNF-α and IL-1β were measured by quantitative real-time PCR (qRT-PCR); after
pretreatment for 24 h, the protein levels of TNF-α and IL-1β were analyzed by
ELISA; the effects of citalopram on the phosphorylation of p38MAPK and JNK were
observed after pretreatment for 30 min.
RESULTS: Citalopram significantly inhibited the mRNA and protein expressions of
TNF-α and IL-1β, and the phosphorylation of p38MAPK and JNK.
CONCLUSION: Citalopram may play the anti-inflammatory role by inhibiting MAPK
pathway in microglial cells.
PMID: 24321066 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24096618 | 1. Acta Neuropathol. 2013 Nov;126(5):757-62. doi: 10.1007/s00401-013-1187-5. Epub
2013 Oct 6.
AKT1E17K mutations cluster with meningothelial and transitional meningiomas and
can be detected by SFRP1 immunohistochemistry.
Sahm F(1), Bissel J, Koelsche C, Schweizer L, Capper D, Reuss D, Böhmer K, Lass
U, Göck T, Kalis K, Meyer J, Habel A, Brehmer S, Mittelbronn M, Jones DT,
Schittenhelm J, Urbschat S, Ketter R, Heim S, Mawrin C, Hainfellner JA, Berghoff
AS, Preusser M, Becker A, Herold-Mende C, Unterberg A, Hartmann C, Kickingereder
P, Collins VP, Pfister SM, von Deimling A.
Author information:
(1)Department of Neuropathology, Institute of Pathology,
Ruprecht-Karls-University Heidelberg, INF 224, 69120, Heidelberg, Germany.
The activating E17K mutation in the AKT1 gene has been detected in several tumor
entities. Currently several clinical studies with specific AKT1 inhibitors are
under way. To determine whether AKT1 mutations are involved in human tumors of
the nervous system, we examined a series of 1,437 tumors including 391 primary
intracranial brain tumors and 1,046 tumors of the coverings of the central and
peripheral nervous system. AKT1E17K mutations were exclusively seen in
meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance
was seen in the variant of meningothelial meningioma WHO grade I of basal and
spinal localization. In contrast, AKT1E17K mutations were rare in WHO grade II
and absent in WHO grade III meningiomas. In order to more effectively detect
this mutation, we tested for immunohistochemical markers associated with this
alteration. We observed strong up-regulation of SFRP1 expression in all
meningiomas with AKT1E17K mutation and in HEK293 cells after transfection with
mutant AKT1E17K, but not in meningiomas and HEK293 cells lacking this mutation.
DOI: 10.1007/s00401-013-1187-5
PMID: 24096618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20305284 | 1. Mol Cell Proteomics. 2010 May;9(5):894-911. doi: 10.1074/mcp.M000050-MCP201.
Epub 2010 Mar 20.
Multiplex N-terminome analysis of MMP-2 and MMP-9 substrate degradomes by
iTRAQ-TAILS quantitative proteomics.
Prudova A(1), auf dem Keller U, Butler GS, Overall CM.
Author information:
(1)Department of Biochemistry and Molecular Biology, Centre for Blood Research,
University of British Columbia, 4.401 Life Sciences Institute, 2350 Health
Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Proteolysis is a major protein posttranslational modification that, by altering
protein structure, affects protein function and, by truncating the protein
sequence, alters peptide signatures of proteins analyzed by proteomics. To
identify such modified and shortened protease-generated neo-N-termini on a
proteome-wide basis, we developed a whole protein isobaric tag for relative and
absolute quantitation (iTRAQ) labeling method that simultaneously labels and
blocks all primary amines including protein N- termini and lysine side chains.
Blocking lysines limits trypsin cleavage to arginine, which effectively
elongates the proteolytically truncated peptides for improved MS/MS analysis and
peptide identification. Incorporating iTRAQ whole protein labeling with terminal
amine isotopic labeling of substrates (iTRAQ-TAILS) to enrich the N-terminome by
negative selection of the blocked mature original N-termini and neo-N-termini
has many advantages. It enables simultaneous characterization of the natural
N-termini of proteins, their N-terminal modifications, and proteolysis product
and cleavage site identification. Furthermore, iTRAQ-TAILS also enables
multiplex N-terminomics analysis of up to eight samples and allows for
quantification in MS2 mode, thus preventing an increase in spectral complexity
and extending proteome coverage by signal amplification of low abundance
proteins. We compared the substrate degradomes of two closely related matrix
metalloproteinases, MMP-2 (gelatinase A) and MMP-9 (gelatinase B), in fibroblast
secreted proteins. Among 3,152 unique N-terminal peptides identified
corresponding to 1,054 proteins, we detected 201 cleavage products for MMP-2 and
unexpectedly only 19 for the homologous MMP-9 under identical conditions. Novel
substrates identified and biochemically validated include insulin-like growth
factor binding protein-4, complement C1r component A, galectin-1,
dickkopf-related protein-3, and thrombospondin-2. Hence, N-terminomics analyses
using iTRAQ-TAILS links gelatinases with new mechanisms of action in
angiogenesis and reveals unpredicted restrictions in substrate repertoires for
these two very similar proteases.
DOI: 10.1074/mcp.M000050-MCP201
PMCID: PMC2871422
PMID: 20305284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21604129 | 1. Methods Mol Biol. 2011;753:273-87. doi: 10.1007/978-1-61779-148-2_18.
Identification of proteolytic products and natural protein N-termini by Terminal
Amine Isotopic Labeling of Substrates (TAILS).
Doucet A(1), Kleifeld O, Kizhakkedathu JN, Overall CM.
Author information:
(1)Department of Pathology and Laboratory Medecine, Centre for Blood Research,
University of British Columbia, Vancouver, BC, Canada. adouce2@uottawa.ca
Determining the sequence of protein N-termini and their modifications
functionally annotates proteins since translation isoforms, posttranslational
modifications, and proteolytic truncations direct localization, activity, and
the half-life of most proteins. Here we present in detail the steps required to
perform our recently described approach we call Terminal Amine Isotopic Labeling
of Substrates (TAILS), a combined N-terminomics and protease substrate discovery
degradomics platform for the simultaneous quantitative and global analysis of
the N-terminome and proteolysis in one MS/MS experiment. By a 3-day procedure
with flexible α- and ɛ-amine labeling and blocking options, TAILS removes
internal tryptic and C-terminal peptides by binding to a dendritic polyglycerol
aldehyde polymer. Therefore, by negative selection, this enriches for both the
N-terminal-labeled peptides and all forms of naturally blocked N-terminal
peptides. In addition to providing valuable proteome annotation, the
simultaneous analysis of the original mature N-terminal peptides enables these
peptides to be used for higher confidence protein substrate identification by
two or more different and unique peptides. Second, the analysis of the
N-terminal peptides forms a statistical classifier to determine valid isotope
ratio cutoffs in order to identify with high-confidence protease-generated
neo-N-terminal peptides. Third, quantifying the loss of acetylated or cyclized
N-terminal peptides that have been cleaved extends overall substrate coverage.
Hence, TAILS allows for the global analysis of the N-terminome and determination
of cleavage site motifs and substrates for protease including those with unknown
or broad specificity.
DOI: 10.1007/978-1-61779-148-2_18
PMID: 21604129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24139673 | 1. J Nutr Biochem. 2013 Dec;24(12):2127-37. doi: 10.1016/j.jnutbio.2013.08.004.
Epub 2013 Oct 15.
Docosahexaenoic acid reduces cellular inflammatory response following permanent
focal cerebral ischemia in rats.
Chang CY(1), Kuan YH, Li JR, Chen WY, Ou YC, Pan HC, Liao SL, Raung SL, Chang
CJ, Chen CJ.
Author information:
(1)Department of Surgery, Fong Yuan Hospital, Taichung 420, Taiwan.
Cellular inflammatory response plays an important role in ischemic brain injury
and anti-inflammatory treatments in stroke are beneficial. Dietary
supplementation with docosahexaenoic acid (DHA) shows anti-inflammatory and
neuroprotective effects against ischemic stroke. However, its effectiveness and
its precise modes of neuroprotective action remain incompletely understood. This
study provides evidence of an alternative target for DHA and sheds light on the
mechanism of its physiological benefits. We report a global inhibitory effect of
3 consecutive days of DHA preadministration on circulating and intracerebral
cellular inflammatory responses in a rat model of permanent cerebral ischemia.
DHA exhibited a neuroprotective effect against ischemic deficits by reduction of
behavioral disturbance, brain infarction, edema and blood-brain barrier
disruption. The results of enzymatic assay, Western blot, real-time reverse
transcriptase polymerase chain reaction and flow cytometric analysis revealed
that DHA reduced central macrophages/microglia activation, leukocyte
infiltration and pro-inflammatory cytokine expression and peripheral leukocyte
activation after cerebral ischemia. In parallel with these immunosuppressive
phenomena, DHA attenuated post-stroke oxidative stress, c-Jun N-terminal kinase
(JNK) phosphorylation, c-Jun phosphorylation and activating protein-1 (AP-1)
activation but further elevated ischemia-induced NF-E2-related factor-2 (Nrf2)
and heme oxygenase-1 (HO-1) expression. DHA treatment also had an
immunosuppressive effect in lipopolysaccharide/interferon-γ-stimulated glial
cultures by attenuating JNK phosphorylation, c-Jun phosphorylation and AP-1
activation and augmenting Nrf2 and HO-1 expression. In summary, we have shown
that DHA exhibited neuroprotective and anti-inflammatory effects against
ischemic brain injury and these effects were accompanied by decreased oxidative
stress and JNK/AP-1 signaling as well as enhanced Nrf2/HO-1 expression.
© 2013.
DOI: 10.1016/j.jnutbio.2013.08.004
PMID: 24139673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21604127 | 1. Methods Mol Biol. 2011;753:243-55. doi: 10.1007/978-1-61779-148-2_16.
N-terminomics: a high-content screen for protease substrates and their cleavage
sites.
Timmer JC(1), Salvesen GS.
Author information:
(1)Department of Pharmacology, University of California San Diego, La Jolla, CA
92037, USA.
Proteases play vital roles in many cellular processes and signaling cascades
through specific limited cleavage of their targets. It is important to identify
what proteins are substrates of proteases and where their cleavage sites are so
as to reveal the molecular mechanisms and specificity of signaling. We have
developed a method to achieve this goal using a strategy that chemically tags
the substrate's alpha amine generated by proteolysis, enriches for tagged
peptides, and identifies them using liquid chromatography-coupled tandem mass
spectrometry (LC-MS/MS). Peptide MS/MS data are searched against a database to
reveal what proteins are cleaved, whereby peptide N-termini demarcate sites of
protease cleavage.
DOI: 10.1007/978-1-61779-148-2_16
PMID: 21604127 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24270002 | 1. Mol Cell Neurosci. 2014 Jan;58:29-39. doi: 10.1016/j.mcn.2013.11.001. Epub
2013 Nov 21.
Proteasome inhibition induces stress kinase dependent transport
deficits--implications for Alzheimer's disease.
Agholme L(1), Nath S(1), Domert J(1), Marcusson J(2), Kågedal K(1), Hallbeck
M(3).
Author information:
(1)Experimental Pathology, Department of Clinical and Experimental Medicine,
Faculty of Health Sciences, Linköping University, Linköping, Sweden.
(2)Geriatric, Department of Clinical and Experimental Medicine, Faculty of
Health Sciences, Linköping University, Linköping, Sweden.
(3)Experimental Pathology, Department of Clinical and Experimental Medicine,
Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department
of Clinical Pathology, County Council of Östergötland, Linköping, Sweden.
Electronic address: martin.hallbeck@liu.se.
Alzheimer's disease (AD) is characterized by accumulation of two misfolded and
aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular
systems responsible for clearance of misfolded and aggregated proteins, the
lysosomal and the proteasomal, have been shown to be malfunctioning in the aged
brain and more so in patients with neurodegenerative diseases, including AD.
This malfunction could be contributing to β-amyloid and tau accumulation,
eventually aggregating in plaques and tangles. We have investigated the impact
of decreased proteasome activity on tau phosphorylation as well as on
microtubule stability and transport. To do this, we used our recently developed
neuronal model where human SH-SY5Y cells obtain neuronal morphology and function
through differentiation. We found that exposure to low doses of the proteasome
inhibitor MG-115 caused tau phosphorylation, microtubule destabilization and
disturbed neuritic transport. Furthermore, reduced proteasome activity activated
several proteins implicated in tau phosphorylation and AD pathology, including
c-Jun N-terminal kinase, c-Jun and extracellular signal-regulated protein kinase
(ERK) 1/2. Restoration of the microtubule transport was achieved by inhibiting
ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun
reversed the proteasome inhibition-induced tau phosphorylation. Taken together,
this study suggests that a decrease in proteasome activity can, through
activation of c-Jun and ERK 1/2, result in several events related to
neurodegenerative diseases. Restoration of proteasome activity or modulation of
ERK 1/2 and c-Jun function can open new treatment possibilities against
neurodegenerative diseases such as AD.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.mcn.2013.11.001
PMID: 24270002 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16206264 | 1. Int J Cancer. 2006 Mar 15;118(6):1381-9. doi: 10.1002/ijc.21578.
The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and
is highly expressed in Ewing tumors.
Mendiola M(1), Carrillo J, García E, Lalli E, Hernández T, de Alava E, Tirode F,
Delattre O, García-Miguel P, López-Barea F, Pestaña A, Alonso J.
Author information:
(1)Departamento de Biología Molecular y Celular del Cáncer, Instituto de
Investigaciones Biomédicas A. Sols CSIC-UAM, 28029 Madrid, Spain.
The Ewing family of tumors harbors chromosomal translocations that join the
N-terminal region of the EWS gene with the C-terminal region of several
transcription factors of the ETS family, mainly FLI1, resulting in chimeric
transcription factors that play a pivotal role in the pathogenesis of Ewing
tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we
established 293 cells expressing constitutively either the chimeric EWS/FLI1 or
wild type FLI1 proteins and used cDNA arrays to identify genes differentially
regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved
in gonadal development, sex determination and steroidogenesis, showed a
consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1.
Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell
systems with inducible expression of EWS/FLI1. We also analyzed the expression
of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated
small round cell tumors. DAX1 was expressed in all Ewing tumor specimens
analyzed, and in seven out of eight Ewing tumor cell lines, but not in any
neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1
by RNA interference in a Ewing tumor cell line markedly reduced the levels of
DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon
EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its
potent transcriptional repressor activity suggest that the oncogenic effect of
EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1
expression.
DOI: 10.1002/ijc.21578
PMID: 16206264 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17461888 | 1. CNS Drug Rev. 2007 Spring;13(1):21-42. doi: 10.1111/j.1527-3458.2007.00001.x.
Lacosamide: a review of preclinical properties.
Beyreuther BK(1), Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T.
Author information:
(1)SCHWARZ BIOSCIENCES, Department of Pharmacology/Toxicology, GmbH, Monheim,
Germany. bettina.beyreuther@schwarzpharma.com
Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide,
previously referred to as harkoseride or ADD 234037) is a member of a series of
functionalized amino acids that were specifically synthesized as anticonvulsive
drug candidates. LCM has demonstrated antiepileptic effectiveness in different
rodent seizure models and antinociceptive potential in experimental animal
models that reflect distinct types and symptoms of neuropathic as well as
chronic inflammatory pain. Recent results suggest that LCM has a dual mode of
action underlying its anticonvulsant and analgesic activity. It was found that
LCM selectively enhances slow inactivation of voltage-gated sodium channels
without affecting fast inactivation. Furthermore, employing proteomic
affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2
alias DRP-2) was identified as a binding partner. Follow-up experiments
confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not
inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic
concentrations. In safety pharmacology and toxicology studies conducted in mice,
rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side
effects were observed in safety studies involving the central nervous,
respiratory, gastrointestinal, and renal systems and there is no indication of
abuse liability. Repeated dose toxicity studies demonstrated that after either
intravenous or oral administration of LCM the adverse events were reversible and
consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic
or carcinogenic effects were observed in vivo, and LCM showed a favorable
profile in reproductive and developmental animal studies. Currently, LCM is in a
late stage of clinical development as an adjunctive treatment for patients with
uncontrolled partial-onset seizures, and it is being assessed as monotherapy in
patients with painful diabetic neuropathy. Further trials to identify LCM's
potential in pain and for other indications have been initiated.
DOI: 10.1111/j.1527-3458.2007.00001.x
PMCID: PMC6494128
PMID: 17461888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23288091 | 1. Ther Drug Monit. 2013 Feb;35(1):4-29. doi: 10.1097/FTD.0b013e31827c11e7.
Therapeutic drug monitoring of antiepileptic drugs by use of saliva.
Patsalos PN(1), Berry DJ.
Author information:
(1)Pharmacology and Therapeutics Unit, Department of Clinical and Experimental
Epilepsy, UCL-Institute of Neurology, London, United Kingdom.
p.patsalos@ucl.ac.uk
Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM)
has proven to be an invaluable surrogate marker for individualizing and
optimizing the drug management of patients with epilepsy. Since 1989, there has
been an exponential increase in AEDs with 23 currently licensed for clinical
use, and recently, there has been renewed and extensive interest in the use of
saliva as an alternative matrix for AED TDM. The advantages of saliva include
the fact that for many AEDs it reflects the free (pharmacologically active)
concentration in serum; it is readily sampled, can be sampled repetitively, and
sampling is noninvasive; does not require the expertise of a phlebotomist; and
is preferred by many patients, particularly children and the elderly. For each
AED, this review summarizes the key pharmacokinetic characteristics relevant to
the practice of TDM, discusses the use of other biological matrices with
particular emphasis on saliva and the evidence that saliva concentration
reflects those in serum. Also discussed are the indications for salivary AED
TDM, the key factors to consider when saliva sampling is to be undertaken, and
finally, a practical protocol is described so as to enable AED TDM to be applied
optimally and effectively in the clinical setting. Overall, there is compelling
evidence that salivary TDM can be usefully applied so as to optimize the
treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin,
lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin,
primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably
not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate,
pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the
data are sparse or nonexistent.
DOI: 10.1097/FTD.0b013e31827c11e7
PMID: 23288091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20677583 | 1. Neurosciences (Riyadh). 2010 Jan;15(1):3-6.
Lacosamide, a newer antiepileptic.
Patyar S(1), Medhi B.
Author information:
(1)Department of Pharmacology, Postgraduate Institute of Medical Education &
Research, Chandigarh, India.
Lacosamide (LCM) is a newer antiepileptic drug with a dual mode of action. It
selectively enhances slow inactivation of voltage-gated sodium channels without
affecting fast inactivation, and modulates collapsing response mediator protein
2 (CRMP-2). It has a high oral bioavailability of approximately 100%. It has
shown potent and broad neuroprotective effects in vitro and in vivo animal
models making it a potential candidate for long term treatment of epilepsy. In
addition to this, it has demonstrated analgesic activity in various animal
models. Apart from this, LCM has demonstrated potent effects in animal models
for a variety of CNS disorders like schizophrenia and stress induced anxiety.
Various safety pharmacology and toxicology studies have shown that LCM is well
tolerated. Clinical trials have also suggested that LCM is a safe, effective,
and well tolerated adjunctive treatment for reduction of seizure frequency in
patients with highly refractory, partial seizures. Other potential indications
of LCM are being investigated.
PMID: 20677583 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18256529 | 1. Cell Cycle. 2008 Jan 15;7(2):250-6. doi: 10.4161/cc.7.2.5229. Epub 2007 Oct
30.
A transcriptional profiling meta-analysis reveals a core EWS-FLI gene expression
signature.
Hancock JD(1), Lessnick SL.
Author information:
(1)The Division of Pediatric Hematology/Oncology and The Center for Children,
Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake
City, Utah, USA.
Ewing's sarcomas are characterized by recurrent chromosomal translocations
expressing EWS-ETS fusion proteins, the most common of which is EWS-FLI.(1-5)
EWS-FLI is an oncogenic transcription factor that regulates genes involved in
tumorigenesis.(6,7) Because the Ewing's sarcoma cell of origin remains unknown,
a variety of model systems have been developed to study EWS-FLI fusions,(8-14)
and multiple microarray experiments describing potential EWS-FLI target genes
have been reported.(8,10,11,13,15-21) Each model has potential benefits and
drawbacks, but a large-scale comparison of these has not been reported. Herein
we report a meta-analysis of the genes that are dysregulated by EWS-FLI in
Ewing's sarcoma model systems. In general, EWS-FLI gain- and loss-of-function
models in human cell types were well correlated to patient-derived tumor
samples, while murine models were not. Using frequency analysis of dysregulated
genes across multiple model systems, we identified a conserved "core" EWS-FLI
transcriptional signature. This signature contained many of the genes known to
be involved in the tumorigenic phenotype of Ewing's sarcoma, and also contained
genes that have not been previously reported. Comparisons between the core
EWS-FLI signature and published mesenchymal stem cell data support the recent
assertion that mesenchymal stem cells are likely the Ewing's sarcoma precursor
cell.(15) These results demonstrate the utility of using comparative analysis to
validate model systems and emphasize the unique potential of this approach to
identify both oncogenic and background cell signatures.
DOI: 10.4161/cc.7.2.5229
PMID: 18256529 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21861814 | 1. Curr Med Chem. 2011;18(28):4344-58. doi: 10.2174/092986711797200408.
Evaluation of anticonvulsants for possible use in neuropathic pain.
Waszkielewicz AM(1), Gunia A, Słoczyńska K, Marona H.
Author information:
(1)Department of Bioorganic Chemistry, Jagiellonian University Medical College,
30-688 Krakow, Poland. awaszkie@cm-uj.krakow.pl
Neuropathic pain is a kind of pain related with functional abnormality of
neurons. Despite large progress in pharmacotherapy, neuropathic pain is still
considered an unmet need. Nowadays, there are few drugs registered for this
condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and
lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known
antiepileptic drugs. Among the group of new antiepileptic drugs, which are
addressed to 1% of human world population suffering from seizures, it turned out
that 30% of the seizures resistant to pharmacotherapy has not enough market to
justify the costs of drug development. Therefore, it is already a phenomenon
that researchers turn their projects toward a larger market, related with
possible similar mechanism. Anticonvulsant mechanism of action is in the first
place among primary indications for drugs revealing potential analgesic
activity. Therefore, many drug candidates for epilepsy, still in preclinical
stage, are being evaluated for activity in neuropathic pain. This review is
focusing on antiepileptic drugs, which are evaluated for their analgesic
activity in major tests related with neuropathic pain. Relation between
structure, mechanism of action and result in tests such as the Chung model
(spinal nerve ligation SNL), the Bennett model (chronic constriction injury of
sciatic nerve CCI) and other tests are considered. The first examples are
carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy
market as well as drug candidates such as valnoctamide, and other valproic acid
derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical
efficacy related with listed animal models has been discussed.
DOI: 10.2174/092986711797200408
PMID: 21861814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22367194 | 1. J Biol Chem. 2012 Apr 13;287(16):13382-95. doi: 10.1074/jbc.M111.314179. Epub
2012 Feb 24.
Biochemical characterization and N-terminomics analysis of leukolysin, the
membrane-type 6 matrix metalloprotease (MMP25): chemokine and vimentin cleavages
enhance cell migration and macrophage phagocytic activities.
Starr AE(1), Bellac CL, Dufour A, Goebeler V, Overall CM.
Author information:
(1)Centre for Blood Research, University of British Columbia, Vancouver, British
Columbia V6T 1Z3, Canada.
The neutrophil-specific protease membrane-type 6 matrix metalloproteinase
(MT6-MMP)/MMP-25/leukolysin is implicated in multiple sclerosis and cancer yet
remains poorly characterized. To characterize the biological roles of MT6-MMP,
it is critical to identify its substrates for which only seven are currently
known. Here, we biochemically characterized MT6-MMP, profiled its tissue
inhibitor of metalloproteinase inhibitory spectrum, performed degradomics
analyses, and screened 26 chemokines for cleavage using matrix-assisted laser
desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. MT6-MMP
processes seven each of the CXC and CC chemokine subfamilies. Notably, cleavage
of the neutrophil chemoattractant CXCL5 activates the chemokine, thereby
increasing its agonist activity, indicating a feed-forward mechanism for
neutrophil recruitment. Likewise, cleavage also activated CCL15 and CCL23 to
increase monocyte recruitment. Utilizing the proteomics approach proteomic
identification of cleavage site specificity (PICS), we identified 286 peptidic
cleavage sites spanning from P6 to P6' from which an unusual glutamate
preference in P1 was identified. The degradomics screen terminal amine isotopic
labeling of substrates (TAILS), which enriches for neo-N-terminal peptides of
cleaved substrates, was used to identify 58 new native substrates in fibroblast
secretomes after incubation with MT6-MMP. Vimentin, cystatin C, galectin-1,
IGFBP-7, and secreted protein, acidic and rich in cysteine (SPARC) were among
those substrates we biochemically confirmed. An extracellular "moonlighting"
form of vimentin is a chemoattractant for THP-1 cells, but MT6-MMP cleavage
abolished monocyte recruitment. Unexpectedly, the MT6-MMP-cleaved vimentin
potently stimulated phagocytosis, which was not a property of the full-length
protein. Hence, MT6-MMP regulates neutrophil and monocyte chemotaxis and by
generating "eat-me" signals upon vimentin cleavage potentially increases
phagocytic removal of neutrophils to resolve inflammation.
DOI: 10.1074/jbc.M111.314179
PMCID: PMC3339980
PMID: 22367194 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23667905 | 1. Biol Chem. 2012 Dec;393(12):1477-83. doi: 10.1515/hsz-2012-0269.
CLIPPER: an add-on to the Trans-Proteomic Pipeline for the automated analysis of
TAILS N-terminomics data.
auf dem Keller U(1), Overall CM.
Author information:
(1)Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,
CH-8093 Zurich, Switzerland. ulrich.aufdemkeller@biol.ethz.ch
Data analysis in proteomics is complex and with the extra challenges involved in
the interpretation of data from N-terminomics experiments, this can be
daunting.Therefore, we have devised a rational pipeline of steps to approach
N-terminomics data analysis in a statistically based and valid manner. We have
automated these steps in CLIPPER, an add-on to the Trans-Proteomic
Pipeline(TPP). Applying CLIPPER to the analysis of N- terminomics data generated
by terminal amine isotopic labeling of substrates (TAILS) enables high
confidence peptide to protein assignment, protein N-terminal characterization
and annotation, and for protease analysis readily allows protease substrate
discovery with high confidence.
DOI: 10.1515/hsz-2012-0269
PMID: 23667905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23648276 | 1. Epilepsy Behav. 2013 Jul;28(1):22-5. doi: 10.1016/j.yebeh.2013.03.030. Epub
2013 May 4.
Network analysis reveals patterns of antiepileptic drug use in children with
medically intractable epilepsy.
Ibrahim GM(1), Rutka JT, Snead OC 3rd.
Author information:
(1)Division of Neurosurgery, Hospital for Sick Children, Department of Surgery,
University of Toronto, Toronto, Ontario, Canada. george.m.ibrahim@gmail.com
Network analysis is an emerging tool for the study of complex systems.
Antiepileptic drug (AED) polytherapy in children with medically intractable
epilepsy may be considered a complex system, given the heterogeneity of drug
combinations that are frequently modified according to clinical indications. The
current article presents a concise review of network theory and its application
to the characterization of AED use in children with refractory epilepsy. Current
and previous AEDs prescribed to 27 children with refractory,
localization-related epilepsy were recorded, and network theory was applied to
identify patterns of drug administration. Of the fifteen unique AEDs prescribed,
levetiracetam possessed the highest betweenness centrality within the network.
Furthermore, first generation AEDs were often discontinued, while lacosamide and
topiramate were most likely to be initiated. We also identified three
subnetworks of AEDs that were commonly coadministered. We conclude that network
analysis is an effective method to characterize the complexity of AED
administration patterns in children with epilepsy with many promising future
applications.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yebeh.2013.03.030
PMID: 23648276 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25483190 | 1. Cell Cycle. 2014;13(15):2391-9. doi: 10.4161/cc.29337.
Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B
kinase to the midzone.
Park H(1), Turkalo TK, Nelson K, Folmsbee SS, Robb C, Roper B, Azuma M.
Author information:
(1)a Department of Molecular Biosciences; University of Kansas; Lawrence, KS
USA.
Ewing sarcoma is a malignant bone cancer that primarily occurs in children and
adolescents. Eighty-five percent of Ewing sarcoma is characterized by the
presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we
demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the
inhibition of EWS activity and mitotic dysfunction. Although defective mitosis
is considered to be a critical step in cancer initiation, it is unknown how
interference with EWS contributes to Ewing sarcoma formation. Here, we
demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of
defects in the midzone, a midline structure located between segregating
chromatids during anaphase. Defects in the midzone can lead to the failure of
cytokinesis and can result in the induction of aneuploidy. The similarity among
the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the
inhibition of EWS as the key mechanism for the induction of midzone defects.
Supporting this observation, the ectopic expression of EWS rescues the high
incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered
that EWS interacts with Aurora B kinase, and that EWS is also required for
recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in
the RGG3 domain of EWS is essential for both Aurora B interaction and the
recruitment of Aurora B to the midzone. Here, we propose that the impairment of
EWS-dependent midzone formation via the recruitment of Aurora B is a potential
mechanism of Ewing sarcoma development.
DOI: 10.4161/cc.29337
PMCID: PMC4128884
PMID: 25483190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18485618 | 1. Pathol Biol (Paris). 2008 Jul;56(5):257-9. doi: 10.1016/j.patbio.2008.03.005.
Epub 2008 May 15.
[Ewing's tumours, genetic and cellular aspects].
[Article in French]
Delattre O.
Ewing's tumour is the second most frequent primary tumour of bone. It is
associated in 85% of cases with a specific and recurrent chromosome
translocation, a t(11; 22)(q24; q12) which generates a fusion gene between the
5' part of EWS and the 3' part of FLI-1, a member of the ETS family. Less
frequently, this gene fusion involves EWS and another member of the ETS family
which can be: ERG, ETV1, E1AF or FEV depending on the cases. The EWS-ETS fusion
is causative in the development of Ewing's tumour. Its mechanism of action
mainly relies on the abnormal transcription regulation of key target genes which
are involved in the regulation of cell cycle, signal transduction, migration.
The cellular context within which EWS-FLI-1 exerts its oncogenic action is a
long standing matter of debate. Recent data converge to suggest that the Ewing
cell origin is a mesenchymal stem cell.
DOI: 10.1016/j.patbio.2008.03.005
PMID: 18485618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18976161 | 1. Antioxid Redox Signal. 2009 Jan;11(1):59-98. doi: 10.1089/ars.2008.2104.
Cellular senescence: molecular mechanisms, in vivo significance, and redox
considerations.
Muller M(1).
Author information:
(1)Centre for Education and Research on Ageing, ANZAC Research Institute,
University of Sydney, Concord RG Hospital, Concord, Sydney, Australia.
mmuller@med.usyd.edu.au
Cellular senescence is recognized as a critical cellular response to prolonged
rounds of replication and environmental stresses. Its defining characteristics
are arrested cell-cycle progression and the development of aberrant gene
expression with proinflammatory behavior. Whereas the mechanistic events
associated with senescence are generally well understood at the molecular level,
the impact of senescence in vivo remains to be fully determined. In addition to
the role of senescence as an antitumor mechanism, this review examines cellular
senescence as a factor in organismal aging and age-related diseases, with
particular emphasis on aberrant gene expression and abnormal paracrine
signaling. Senescence as an emerging factor in tissue remodeling, wound repair,
and infection is considered. In addition, the role of oxidative stress as a
major mediator of senescence and the role of NAD(P)H oxidases and changes to
intracellular GSH/GSSG status are reviewed. Recent findings indicate that
senescence and the behavior of senescent cells are amenable to therapeutic
intervention. As the in vivo significance of senescence becomes clearer, the
challenge will be to modulate the adverse effects of senescence without
increasing the risks of other diseases, such as cancer. The uncoupled relation
between cell-cycle arrest and the senescent phenotype suggests that this is an
achievable outcome.
DOI: 10.1089/ars.2008.2104
PMID: 18976161 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25432018 | 1. J Med Chem. 2014 Dec 26;57(24):10290-303. doi: 10.1021/jm501372p. Epub 2014
Dec 12.
Synthesis and structure-activity relationship studies of small molecule
disruptors of EWS-FLI1 interactions in Ewing's sarcoma.
Tosso PN(1), Kong Y, Scher L, Cummins R, Schneider J, Rahim S, Holman KT,
Toretsky J, Wang K, Üren A, Brown ML.
Author information:
(1)Center for Drug Discovery, Georgetown University Medical Center , New
Research Building EP07, 3970 Reservoir Road, NW, Washington, D.C. 20057, United
States.
EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's
sarcoma family tumors (ESFT). Using our previously reported lead compound 2
(YK-4-279), we designed and synthesized a focused library of analogues. The
functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1
reporter luciferase assay and a paired cell screening approach measuring effects
on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and
control PANC1 cell lines devoid of the oncoprotein. Our data revealed that
substitution of electron donating groups at the para-position on the phenyl ring
was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u
(with a dimethylamino substitution) was the most active inhibitor with GI50 =
0.26 ± 0.1 μM. Further, a correlation of growth inhibition (EWS-FLI1 expressing
TC32 cells) and the luciferase reporter activity was established (R(2) = 0.84).
Finally, we designed and synthesized a biotinylated analogue and determined the
binding affinity for recombinant EWS-FLI1 (Kd = 4.8 ± 2.6 μM).
DOI: 10.1021/jm501372p
PMCID: PMC4281097
PMID: 25432018 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21271304 | 1. Mol Neurobiol. 2011 Jun;43(3):180-91. doi: 10.1007/s12035-011-8166-4. Epub
2011 Jan 28.
Collapsin response mediator protein-2: an emerging pathologic feature and
therapeutic target for neurodisease indications.
Hensley K(1), Venkova K, Christov A, Gunning W, Park J.
Author information:
(1)Department of Pathology, University of Toledo Health Science Center, Toledo,
OH 43614, USA. Kenneth.hensley@utoledo.edu
Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional
adaptor protein within the central nervous system. In the developing brain or
cell cultures, CRMP2 performs structural and regulatory functions related to
cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2
functions in adult brain are still being elucidated. CRMP2 has been associated
with several neuropathologic or psychiatric conditions including Alzheimer's
disease (AD) and schizophrenia, either at the level of genetic polymorphisms;
protein expression; post-translational modifications; or protein/protein
interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3β
(GSK3β) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act
on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated
CRMP2 collects in NFTs in association with the synaptic structure-regulating
SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family
verprolin-homologous protein-1) complex. This phenomenon could plausibly
contribute to deficits in neural and synaptic structure that have been well
documented in AD. This review discusses the essential biology of CRMP2 in the
context of nascent data implicating CRMP2 perturbations as either a correlate
of, or plausible contributor to, diverse neuropathologies. A discussion is made
of recent findings that the atypical antidepressant tianeptine increases CRMP2
expression, whereas other, neuroactive small molecules including the epilepsy
drug lacosamide and the natural brain metabolite lanthionine ketimine appear to
bind CRMP2 directly with concomitant affects on neural structure. These findings
constitute proofs-of-concept that pharmacological manipulation of CRMP2 is
possible and hence, may offer new opportunities for therapy development against
certain neurological diseases.
DOI: 10.1007/s12035-011-8166-4
PMID: 21271304 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22723308 | 1. Mol Cancer Res. 2012 Aug;10(8):1098-108. doi: 10.1158/1541-7786.MCR-12-0086.
Epub 2012 Jun 20.
EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting
in increased cell survival and chemoresistance.
Robin TP(1), Smith A, McKinsey E, Reaves L, Jedlicka P, Ford HL.
Author information:
(1)Department of Pharmacology, University of Colorado School of Medicine,
Aurora, CO 80045, USA.
Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in
which patients whose tumors have a poor histologic response to initial
chemotherapy have a poor overall prognosis. Therefore, it is important to
identify molecules involved in resistance to chemotherapy. Herein, we show that
the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed
in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem
cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by
the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1
mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets
the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter
directly. Importantly, we show that high levels of EYA3 significantly correlate
with low levels of miR-708 in Ewing sarcoma samples, suggesting that this
miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because
EYA proteins are important for cell survival during development, we examine, and
show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most
importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to
DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as
expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA
damage less effectively than their control counterparts. These studies identify
EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the
molecular mechanisms of both EYA3 overexpression and of EYA3-mediated
chemoresistance.
DOI: 10.1158/1541-7786.MCR-12-0086
PMCID: PMC3432289
PMID: 22723308 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19718047 | 1. Oncogene. 2009 Nov 19;28(46):4126-32. doi: 10.1038/onc.2009.262. Epub 2009 Aug
31.
GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma
oncogenesis and therapeutic resistance.
Luo W(1), Gangwal K, Sankar S, Boucher KM, Thomas D, Lessnick SL.
Author information:
(1)Department of Oncological Sciences, University of Utah School of Medicine,
Salt Lake City, UT, USA.
Ewing's sarcoma is a malignant bone-associated tumor of children and young
adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein.
EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the
master regulator of Ewing's sarcoma-transformed phenotype. We recently showed
that EWS/FLI regulates one of its key targets, NR0B1, through a
GGAA-microsatellite in its promoter. Whether other critical EWS/FLI targets are
also regulated by GGAA-microsatellites was unknown. In this study, we combined
transcriptional analysis, whole genome localization data, and RNA interference
knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI
target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4
promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its
promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation.
Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's
sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in
drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma
whose tumors had higher levels of GSTM4 expression had worse outcomes than those
with lower expression levels. These data show that GSTM4 contributes to the
cancerous behavior of Ewing's sarcoma and define a wider role for
GGAA-microsatellites in EWS/FLI function than previously appreciated. These data
also suggest a novel therapeutic resistance mechanism, in which the central
oncogenic abnormality directly regulates a resistance gene.
DOI: 10.1038/onc.2009.262
PMID: 19718047 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25162919 | 1. Expert Opin Ther Targets. 2014 Nov;18(11):1315-28. doi:
10.1517/14728222.2014.947963. Epub 2014 Aug 27.
Blocking the road, stopping the engine or killing the driver? Advances in
targeting EWS/FLI-1 fusion in Ewing sarcoma as novel therapy.
Kovar H(1).
Author information:
(1)Children´s Cancer Research Institute, St. Anna Kinderkrebsforschung, and
Medical University Vienna, Department of Pediatrics , Zimmermannplatz 10, A1090
Vienna , Austria +43 1 40470 4092 ; +43 1 40470 64092 ; heinrich.kovar@ccri.at.
INTRODUCTION: Ewing sarcoma (ES) represents the paradigm of an aberrant
E-twenty-six (ETS) oncogene-driven cancer. It is characterized by specific
rearrangements of one of five alternative ETS family member genes with EWSR1.
There is experimental evidence that the resulting fusion proteins act as
aberrant transcription factors driving ES pathogenesis. The transcriptional gene
regulatory network driven by EWS-ETS proteins provides the oncogenic engine to
the tumor. Therefore, EWS-ETS and their downstream machinery are considered
ideal tumor-specific therapeutic targets.
AREAS COVERED: This review critically discusses the literature on the
development of EWS-ETS-directed ES targeting strategies considering current
knowledge of EWS-ETS biology and cellular context. It focuses on determinants of
EWS-FLI1 function with an emphasis on interactions with chromatin structure. We
speculate about the relevance of poorly investigated aspects in ES research such
as chromatin remodeling and DNA damage repair for the development of targeted
therapies.
EXPERT OPINION: This review questions the specificity of signature-based
screening approaches to the identification of EWS-FLI1-targeted compounds. It
challenges the view that targeting the downstream gene regulatory network
carries potential for therapeutic breakthroughs because of resistance-inducing
network rewiring. Instead, we propose to combine targeting of the fusion protein
with epigenetic therapy as a future treatment strategy in ES.
DOI: 10.1517/14728222.2014.947963
PMID: 25162919 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17250957 | 1. Cancer Lett. 2007 Aug 28;254(1):1-10. doi: 10.1016/j.canlet.2006.12.009. Epub
2007 Jan 23.
The Biology of Ewing sarcoma.
Riggi N(1), Stamenkovic I.
Author information:
(1)Division of Experimental Pathology, Institute of Pathology, University of
Lausanne, Switzerland.
Sarcomas account for less than 10% of all human malignancies that are believed
to originate from as yet poorly defined mesenchymal progenitor cells. They
constitute some of the most aggressive adult and childhood cancers in that they
have a high metastatic proclivity and are typically refractory to conventional
chemo- and radiation therapy. Ewing's sarcoma is a member of Ewing's family
tumors (ESFT) and the second most common solid bone and soft tissue malignancy
of children and young adults. It is associated in 85% of cases with the
t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5'
segment of the EWS gene with the 3' segment of the ETS family gene FLI-1. The
resulting EWS-FLI-1 fusion protein is believed to behave as an aberrant
transcriptional activator that contributes to ESFT development by altering the
expression of its target genes in a permissive cellular environment. Although
ESFTs are among the best studied sarcomas, the mechanisms involved in
EWS-FLI-1-induced transformation require further elucidation and the primary
cells from which ESFTs originate need to be identified. This review will
highlight some of the most recent discoveries in the field of Ewing sarcoma
biology and origins.
DOI: 10.1016/j.canlet.2006.12.009
PMID: 17250957 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25857641 | 1. Cancer Genet. 2015 Apr;208(4):107-14. doi: 10.1016/j.cancergen.2015.02.003.
Epub 2015 Feb 19.
Germline and somatic mutations in meningiomas.
Smith MJ(1).
Author information:
(1)Manchester Centre for Genomic Medicine, St Mary's Hospital, University of
Manchester, Manchester, UK. Electronic address: miriam.smith@manchester.ac.uk.
Meningiomas arise from the arachnoid layer of the meninges that surround the
brain and spine. They account for over one third of all primary central nervous
system tumors in adults and confer a significant risk of location-dependent
morbidity due to compression or displacement. A significant increase in risk of
meningiomas is associated with neurofibromatosis type 2 (NF2) disease through
mutation of the NF2 gene. In addition, approximately 5% of individuals with
schwannomatosis disease develop meningiomas, through mutation of the SWI/SNF
chromatin remodeling complex subunit, SMARCB1. Recently, a second SWI/SNF
complex subunit, SMARCE1, was identified as a cause of clear cell meningiomas,
indicating a wider role for this complex in meningioma disease. The sonic
hedgehog (SHH)-GLI1 signaling pathway gene, SUFU, has also been identified as
the cause of hereditary multiple meningiomas in a large Finnish family. The
recent identification of somatic mutations in components of the SHH-GLI1 and
AKT1-MTOR signaling pathways indicates the potential for cross talk of these
pathways in the development of meningiomas. This review describes the known
meningioma predisposition genes and their links to the recently identified
somatic mutations.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cancergen.2015.02.003
PMID: 25857641 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23894528 | 1. PLoS One. 2013 Jul 22;8(7):e69714. doi: 10.1371/journal.pone.0069714. Print
2013.
Differential disruption of EWS-FLI1 binding by DNA-binding agents.
Chen C(1), Wonsey DR, Lemieux ME, Kung AL.
Author information:
(1)Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston
Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an
aberrant gene expression program responsible for the development of Ewing
sarcoma. We used a homogenous proximity assay to screen for compounds that
disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of
DNA-binding chemotherapeutic agents were found to non-specifically disrupt
protein binding to DNA. In contrast, actinomycin D was found to preferentially
disrupt EWS-FLI1 binding by comparison to p53 binding to their respective
cognate DNA targets in vitro. In cell-based assays, low concentrations of
actinomycin D preferentially blocked EWS-FLI1 binding to chromatin, and
disrupted EWS-FLI1-mediated gene expression. Higher concentrations of
actinomycin D globally repressed transcription. These results demonstrate that
actinomycin D preferentially disrupts EWS-FLI1 binding to DNA at selected
concentrations. Although the window between this preferential effect and global
suppression is too narrow to exploit in a therapeutic manner, these results
suggest that base-preferences may be exploited to find DNA-binding compounds
that preferentially disrupt subclasses of transcription factors.
DOI: 10.1371/journal.pone.0069714
PMCID: PMC3718762
PMID: 23894528 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |