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https://www.readbyqxmd.com/read/28639365/vascular-calcification-vitamin-k-and-warfarin-therapy-possible-or-plausible-connection
#1
Aino Siltari, Heikki Vapaatalo
Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone...
June 21, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28638346/micrornas-in-muscle-characterizing-the-powerlifter-phenotype
#2
Randall F D'Souza, Thomas Bjørnsen, Nina Zeng, Kirsten M M Aasen, Truls Raastad, David Cameron-Smith, Cameron J Mitchell
Powerlifters are the epitome of muscular adaptation and are able to generate extreme forces. The molecular mechanisms underpinning the significant capacity for force generation and hypertrophy are not fully elucidated. MicroRNAs (miRs) are short non-coding RNA sequences that control gene expression via promotion of transcript breakdown and/or translational inhibition. Differences in basal miR expression may partially account for phenotypic differences in muscle mass and function between powerlifters and untrained age-matched controls...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28637335/astrocyte-produced-mir-146a-as-a-mediator-of-motor-neuron-loss-in-spinal-muscular-atrophy
#3
Samantha L Sison, Teresa N Patitucci, Emily R Seminary, Eric Villalon, Christian L Lorson, Allison D Ebert
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28623958/knockdown-of-subunit-3-of-the-cop9-signalosome-inhibits-c2c12-myoblast-differentiation-via-nf-kappab-signaling-pathway
#4
Mariam A Ba, Jeffrey Surina, Cherie A Singer, Maria L Valencik
BACKGROUND: The COP9 signalosome (CSN) is a conserved protein complex composed of 8 subunits designated CSN1-CSN8. CSN3 represents the third subunit of the CSN and maintains the integrity of the complex. CSN3 binds to the striated muscle-specific β1D integrin tail, and its subcellular localization is altered in differentiated skeletal muscle cells. However, the role of CSN3 in skeletal muscle differentiation is unknown. The main goal of this study was to identify whether CSN3 participates in myoblast differentiation and the signalling mechanisms involved using C2C12 cells as a skeletal muscle cell model...
June 17, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28615015/the-gastroprotective-effect-of-ethyl-acetate-fraction-of-hot-water-extract-of-trichosanthes-cucumerina-linn-and-its-underlying-mechanisms
#5
Ramani Karunakaran, M Ira Thabrew, G Mayuri Thammitiyagodage, B Prasanna Galhena, L D A Menuka Arawwawala
BACKGROUND: Antacids, anticholinergic drugs, histamine H2- receptor antagonists and irreversible proton pump inhibitors have been used for the treatment of gastric ulcers. However, prolonged use of these drugs may lead to series of adverse effects such as diarrhea, headache, rash, hypertension, muscular and joint pain. Therefore, there is an urgent need of more effective and safer treatments with fewer side effects. The aim of the present study was to scientifically evaluate the gastroprotective activity of fractions of the hot water extract of Trichosanthes cucumerina Linn (Family: Cucurbitaceae) aerial parts with a view to identifying the fraction with the best gastroprotective activity and the possible mechanism/s by which this fraction exert gastroprotection...
June 14, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28608457/potential-therapeutic-interventions-for-chronic-kidney-disease-associated-sarcopenia-via-indoxyl-sulfate-induced-mitochondrial-dysfunction
#6
Yuki Enoki, Hiroshi Watanabe, Riho Arake, Rui Fujimura, Kana Ishiodori, Tadashi Imafuku, Kento Nishida, Ryusei Sugimoto, Saori Nagao, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
BACKGROUND: Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice...
June 12, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/28607086/specific-targeting-of-tgf-%C3%AE-family-ligands-demonstrates-distinct-roles-in-the-regulation-of-muscle-mass-in-health-and-disease
#7
Justin L Chen, Kelly L Walton, Adam Hagg, Timothy D Colgan, Katharine Johnson, Hongwei Qian, Paul Gregorevic, Craig A Harrison
The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (∼20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth...
June 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28591280/keratoconus-progression-is-not-inhibited-by-reducing-eyelid-muscular-force-with-botulinum-toxin-a-treatment-a-randomized-trial
#8
Adimara da Candelaria Renesto, Teissy Hentona Osaki, Midori Hentona Osaki, Flávio E Hirai, Mauro Campos
Purpose: To evaluate whether reducing eyelid muscular force through the administration of botulinum toxin type A (BTX-A) to the orbicularis oculi muscles of patients with keratoconus affected corneal parameters indicative of disease progression. Methods: In this prospective parallel randomized clinical trial, 40 eyes of 40 patients with keratoconus were randomized into equally sized control and BTX-A groups. Patients in the BTX-A group received subcutaneous BTX-A injections into the orbicularis muscle...
March 2017: Arquivos Brasileiros de Oftalmologia
https://www.readbyqxmd.com/read/28588757/identification-of-neuron-selective-androgen-receptor-inhibitors
#9
Maya Otto-Duessel, Ben Yi Tew, Steven Vonderfecht, Roger Moore, Jeremy O Jones
AIM: To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS: Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors...
May 26, 2017: World Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28581498/dystrophin-glycoprotein-complex-sequesters-yap-to-inhibit-cardiomyocyte-proliferation
#10
Yuka Morikawa, Todd Heallen, John Leach, Yang Xiao, James F Martin
The regenerative capacity of the adult mammalian heart is limited because of the reduced ability of cardiomyocytes (CMs) to progress through mitosis(1). The regenerative capacity of endogenous CMs exists at birth but is lost postnatally, with subsequent organ growth occurring through CM hypertrophy(2,3). The Hippo pathway, a conserved kinase cascade, inhibits CM proliferation in the developing heart to control heart size and in the adult heart to prevent regeneration(4,5). The dystrophin glycoprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for CM homeostasis...
June 5, 2017: Nature
https://www.readbyqxmd.com/read/28576407/rp5063-a-novel-multimodal-serotonin-receptor-modulator-prevents-sugen-5416-hypoxia-induced-pulmonary-arterial-hypertension-in-rats
#11
Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G Reddy, Seema R Bhat, Charles E Laurent, Annie Bouchard, Marzena Biernat, Dany Salvail
RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx)-induced PAH model was used to evaluate twice-daily (b...
May 31, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28576350/cannabinoids-in-attention-deficit-hyperactivity-disorder-a-randomised-controlled-trial
#12
Ruth E Cooper, Emma Williams, Seth Seegobin, Charlotte Tye, Jonna Kuntsi, Philip Asherson
Adults with ADHD describe self-medicating with cannabis, with some reporting a preference for cannabis over ADHD medications. A small number of psychiatrists in the US prescribe cannabis medication for ADHD, despite there being no evidence from randomised controlled studies. The EMA-C trial (Experimental Medicine in ADHD-Cannabinoids) was a pilot randomised placebo-controlled experimental study of a cannabinoid medication, Sativex Oromucosal Spray, in 30 adults with ADHD. The primary outcome was cognitive performance and activity level using the QbTest...
May 30, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28572004/%C3%AE-dystroglycan-hypoglycosylation-affects-cell-migration-by-influencing-%C3%AE-dystroglycan-membrane-clustering-and-filopodia-length-a-multiscale-confocal-microscopy-analysis
#13
V Palmieri, M Bozzi, G Signorino, M Papi, M De Spirito, A Brancaccio, G Maulucci, F Sciandra
Dystroglycan (DG) serves as an adhesion complex linking the actin cytoskeleton to the extracellular matrix. DG is encoded by a single gene as a precursor, which is constitutively cleaved to form the α- and β-DG subunits. α-DG is a peripheral protein characterized by an extensive glycosylation that is essential to bind laminin and other extracellular matrix proteins, while β-DG binds the cytoskeleton proteins. The functional properties of DG depend on the correct glycosylation of α-DG and on the cross-talk between the two subunits...
May 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28555643/development-of-an-orally-available-inhibitor-of-clk1-for-skipping-a-mutated-dystrophin-exon-in-duchenne-muscular-dystrophy
#14
Yukiya Sako, Kensuke Ninomiya, Yukiko Okuno, Masayasu Toyomoto, Atsushi Nishida, Yuka Koike, Kenji Ohe, Isao Kii, Suguru Yoshida, Naohiro Hashimoto, Takamitsu Hosoya, Masafumi Matsuo, Masatoshi Hagiwara
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein...
May 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28549178/rhoa-rock-inhibition-improves-the-beneficial-effects-of-glucocorticoid-treatment-in-dystrophic-muscle-implications-for-stem-cell-depletion
#15
Xiaodong Mu, Ying Tang, Koji Takayama, Wanqun Chen, Aiping Lu, Bing Wang, Kurt Weiss, Johnny Huard
Glucocorticoid treatment represents a standard palliative treatment for Duchenne muscular dystrophy (DMD) patients, but various adverse effects have limited this treatment. In an effort to understand the mechanism(s) by which glucocorticoids impart their effects on the dystrophic muscle, and potentially reduce the adverse effects, we have studied the effect of prednisolone treatment in dystrophin/utrophin double knockout (dKO) mice, which exhibit a severe dystrophic phenotype due to rapid muscle stem cell depletion...
May 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28548834/subtly-modulating-glycogen-synthase-kinase-3-%C3%AE-allosteric-inhibitor-development-and-their-potential-for-the-treatment-of-chronic-diseases
#16
Valle Palomo, Daniel I Perez, Carlos Roca, Cara Anderson, Natalia Rodríguez-Muela, Concepción Perez, Jose A Morales-Garcia, Julio A Reyes, Nuria E Campillo, Ana M Perez-Castillo, Lee L Rubin, Lubov Timchenko, Carmen Gil, Ana Martinez
Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated with strong GSK-3β inhibition...
June 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28547925/blockade-of-the-dissociation-of-nmmhc-iia-from-tnfr2-by-d39-a-saponin-from-liriope-muscari-suppresses-tissue-factor-expression-and-venous-thrombosis
#17
Ke-Feng Zhai, Jin-Rong Zheng, You-Mei Tang, Fang Li, Yan-Ni Lv, Yuan-Yuan Zhang, Zhen Gao, Jin Qi, Bo-Yang Yu, Jun-Ping Kou
BACKGROUND AND PURPOSE: Non-muscular myosin heavy chain IIA (NMMHC IIA) has been demonstrated to play a key role in tissue factor (TF) expression and venous thrombosis. However, whether natural products could inhibit thrombosis via NMMHC IIA remains unclear. In this study, we identified that a representative natural saponin D39 from Liriope muscari showed anti-thrombotic activity by targeting NMMHC IIA. EXPERIMENTAL APPROACH: TF expression and activity in endothelial cells were analysed in vitro by western blot and simplified chromogenic assays...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28546788/dmd-transcripts-in-crl-2061-rhabdomyosarcoma-cells-show-high-levels-of-intron-retention-by-intron-specific-pcr-amplification
#18
Emma Tabe Eko Niba, Ryo Yamanaka, Abdul Qawee Mahyoob Rani, Hiroyuki Awano, Masaaki Matsumoto, Hisahide Nishio, Masafumi Matsuo
BACKGROUND: The DMD gene encoding dystrophin is mutated in Duchenne muscular dystrophy, a fatal progressive muscle wasting disease. DMD has also been shown to act as a tumor suppressor gene. Rhabdomyosarcoma (RMS) is a mesodermal sarcoma that shares characteristics of skeletal muscle precursors. Products of the DMD gene in RMS have not yet been fully clarified. Here, DMD products were analyzed in CRL-2061 cells established from alveolar RMS. METHODS: The 14-kb long DMD cDNA was PCR amplified as 20 separated fragments, as were nine short intron regions...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28531801/ace-2-ang1-7-mas-cascade-mediates-ace-inhibitor-captopril-protective-effects-in-estrogen-deficient-osteoporotic-rats
#19
Hatem M Abuohashish, Mohammed M Ahmed, Dina Sabry, Mahmoud M Khattab, Salim S Al-Rejaie
The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis...
May 19, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28498863/notch-ligands-regulate-the-muscle-stem-like-state-ex-vivo-but-are-not-sufficient-for-retaining-regenerative-capacity
#20
Hiroshi Sakai, Sumiaki Fukuda, Miki Nakamura, Akiyoshi Uezumi, Yu-Taro Noguchi, Takahiko Sato, Mitsuhiro Morita, Harumoto Yamada, Kunihiro Tsuchida, Shahragim Tajbakhsh, So-Ichiro Fukada
Myogenic stem cells are a promising avenue for the treatment of muscular disorders. Freshly isolated muscle stem cells have a remarkable engraftment ability in vivo, but their cell number is limited. Current conventional culture conditions do not allow muscle stem cells to expand in vitro with their bona fide engraftment efficiency, requiring the improvement of culture procedures for achieving successful cell-therapy for muscle disorders. Here we expanded mouse muscle stem cells and human myoblasts with Notch ligands, DLL1, DLL4, and JAG1 to activate Notch signaling in vitro and to investigate whether these cells could retain their engraftment efficiency...
2017: PloS One
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