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https://www.readbyqxmd.com/read/29305421/fluid-flow-modulates-electrical-activity-in-cardiac-herg-potassium-channels
#1
Samrat Roy, M K Mathew
Fluid movement within the heart generates substantial shear forces, but the effect of this mechanical stress on the electrical activity of the human heart has not been examined. The fast component of the delayed rectifier potassium currents responsible for repolarization of the cardiac action potential, Ikr, is encoded by the hERG channel. Here, we exposed hERG1a channel-expressing HEK293T cells to laminar shear stress (LSS) and observed that this mechanical stress increased the whole-cell current by 30%-40%...
January 5, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29275372/nitric-oxide-dependent-feedback-loop-regulates-transient-receptor-potential-vanilloid-4-trpv4-channel-cooperativity-and-endothelial-function-in-small-pulmonary-arteries
#2
Corina Marziano, Kwangseok Hong, Eric L Cope, Michael I Kotlikoff, Brant E Isakson, Swapnil K Sonkusare
BACKGROUND: Recent studies demonstrate that spatially restricted, local Ca2+ signals are key regulators of endothelium-dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (PAs) and systemic arteries, but the local Ca2+ signals that control endothelium-dependent vasodilation of PAs are not known. Localized, unitary Ca2+ influx events through transient receptor potential vanilloid 4 (TRPV4) channels, termed TRPV4 sparklets, regulate endothelium-dependent vasodilation in resistance-sized mesenteric arteries via activation of Ca2+-dependent K+ channels...
December 23, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29237724/dual-%C3%AE-v%C3%AE-3-and-%C3%AE-v%C3%AE-5-blockade-attenuates-fibrotic-and-vascular-alterations-in-a-murine-model-of-systemic-sclerosis
#3
Gianluca Bagnato, Natasha Irrera, Gabriele Pizzino, Domenico Santoro, William Neal Roberts, Gianfilippo Bagnato, Giovanni Pallio, Mario Vaccaro, Francesco Squadrito, Antonino Saitta, Domenica Altavilla, Alessandra Bitto
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell-integrin interaction are sufficient to initiate pro-fibrotic processes. SSc fibroblasts express both αvβ3 and αvβ5 integrins and their activation induces myofibroblasts differentiation. The aim of this study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis...
December 13, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/29209525/final-results-of-the-large-scale-multinational-trial-profile-1005-efficacy-and-safety-of-crizotinib-in-previously-treated-patients-with-advanced-metastatic-alk-positive-non-small-cell-lung-cancer
#4
Fiona Blackhall, D Ross Camidge, Alice T Shaw, Jean-Charles Soria, Benjamin J Solomon, Tony Mok, Vera Hirsh, Pasi A Jänne, Yuankai Shi, Pan-Chyr Yang, Tommaso De Pas, Toyoaki Hida, Javier De Castro Carpeño, Silvana Lanzalone, Anna Polli, Shrividya Iyer, Arlene Reisman, Keith D Wilner, Dong-Wan Kim
Purpose: Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods: PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease...
2017: ESMO Open
https://www.readbyqxmd.com/read/29181726/the-inhibition-of-polyamine-biosynthesis-weakens-the-drought-tolerance-in-white-clover-trifolium-repens-associated-with-the-alteration-of-extensive-proteins
#5
Zhou Li, Yan Zhang, Dandan Peng, Yan Peng, Xinquan Zhang, Xiao Ma, Linkai Huang, Yanhong Yan
Changes of endogenous polyamine (PA) levels could be a key adaptive response to drought in plants. White clover pretreated with or without dicyclohexylamine (DCHA), an inhibitor of PA biosynthesis, was subjected to drought stress induced by 18% polyethylene glycol 6000 for 8 days in controlled growth chambers. Results showed that drought stress significantly increased endogenous PA content, whereas DCHA significantly decreased PA accumulation under drought stress. The attenuate PA biosynthesis was unfavorable for plant growth and drought tolerance, as reflected by significantly lower relative water content, relative growth rate, instantaneous water use efficiency, and cell membrane stability in leaves in response to drought...
November 28, 2017: Protoplasma
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#6
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29133150/structure-and-function-of-per-arnt-sim-domains-and-their-possible-role-in-the-life-cycle-biology-of-trypanosoma-cruzi
#7
REVIEW
Maura Rojas-Pirela, Daniel J Rigden, Paul A Michels, Ana J Cáceres, Juan Luis Concepción, Wilfredo Quiñones
Per-ARNT-Sim (PAS) domains of proteins play important roles as modules for signalling and cellular regulation processes in widely diverse organisms such as Archaea, Bacteria, protists, plants, yeasts, insects and vertebrates. These domains are present in many proteins where they are used as sensors of stimuli and modules for protein interactions. Characteristically, they can bind a broad spectrum of molecules. Such binding causes the domain to trigger a specific cellular response or to make the protein containing the domain susceptible to responding to additional physical or chemical signals...
November 10, 2017: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/29070699/inhibition-of-pyruvate-dehydrogenase-kinase-improves-pulmonary-arterial-hypertension-in-genetically-susceptible-patients
#8
Evangelos D Michelakis, Vikram Gurtu, Linda Webster, Gareth Barnes, Geoffrey Watson, Luke Howard, John Cupitt, Ian Paterson, Richard B Thompson, Kelvin Chow, Declan P O'Regan, Lan Zhao, John Wharton, David G Kiely, Adam Kinnaird, Aristeidis E Boukouris, Chris White, Jayan Nagendran, Darren H Freed, Stephen J Wort, J Simon R Gibbs, Martin R Wilkins
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29070458/-receptor-for-advanced-glycation-end-products-upregulates-muc5ac-expression-and-promotes-mucus-overproduction-in-mice-with-toluene-diisocyanate-induced-asthma
#9
Jing Xiong, Wen-Qu Zhao, Guo-Hua Huang, Li-Hong Yao, Hang-Ming Dong, Chang-Hui Yu, Hai-Jin Zhao, Shao-Xi Cai
OBJECTIVE: To explore the role of the receptor for advanced glycation end products (RAGE) in regulating the expression of MUC5AC and mucus production in a mouse model of toluene diisocyanate (TDI)?induced asthma. METHODS: BALB/c mice were randomly divided into control group, vehicle (AOO) group, TDI?induced asthma group and RAGE inhibitor (FPS?ZM1) group. PAS staining, Western blotting, and immunohistochemistry were used to analyze the changes in mucus production and MUC5AC expression in the airway of the mice, and the expression of p?ERK was detected with Western blotting...
October 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29057954/photosensing-and-thermosensing-by-phytochrome-b-require-both-proximal-and-distal-allosteric-features-within-the-dimeric-photoreceptor
#10
E Sethe Burgie, Adam N Bussell, Shu-Hui Lye, Tong Wang, Weiming Hu, Katrice E McLoughlin, Erin L Weber, Huilin Li, Richard D Vierstra
Phytochromes (Phys) encompass a diverse collection of bilin-containing photoreceptors that help plants and microorganisms perceive light through photointerconversion between red light (Pr) and far-red light (Pfr)-absorbing states. In addition, Pfr reverts thermally back to Pr via a highly enthalpic process that enables temperature sensation in plants and possibly other organisms. Through domain analysis of the Arabidopsis PhyB isoform assembled recombinantly, coupled with measurements of solution size, photoconversion, and thermal reversion, we identified both proximal and distal features that influence all three metrics...
October 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29054108/increase-in-pro-apoptotic-activity-of-inhibitory-pas-domain-protein-via-phosphorylation-by-mk2
#11
Shuya Kasai, Mary Jane Elizabeth Richardson, Satoru Torii, Ken-Ichi Yasumoto, Hiroki Shima, Kazuhiko Igarashi, Ken Itoh, Kazuhiro Sogawa, Kazutaka Murayama
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that downregulates hypoxic gene expression and exerts pro-apoptotic activity by preventing pro-survival activity of Bcl-xL and its related factors. Pro-apoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of IPAS at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the pro-apoptotic function of IPAS...
October 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28983630/rebamipide-upregulates-mucin-secretion-of-intestinal-goblet-cells-via-akt-phosphorylation
#12
Yuriko Yasuda-Onozawa, Osamu Handa, Yuji Naito, Chihiro Ushiroda, Yosuke Suyama, Yuki Toyokawa, Takaaki Murakami, Tomoyo Yasuda, Tomohiro Ueda, Atsushi Majima, Yuma Hotta, Toshifumi Doi, Makoto Tanaka, Yusuke Horii, Yasuki Higashimura, Katsura Mizushima, Mayuko Morita, Yukiko Uehara, Hideki Horie, Akifumi Fukui, Osamu Dohi, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiro Katada, Kazuhiko Uchiyama, Takeshi Ishikawa, Tomohisa Takagi, Hideyuki Konishi, Yoshito Itoh
Mucin is produced and secreted by epithelial goblet cells and is a key component of the innate immune system, acting as a barrier in the intestinal tract. However, no studies have been conducted investigating the increase in mucin secretion to enhance the intestinal barrier function. The present study investigated whether rebamipide (Reb) acts as a secretagogue of intestinal mucin and the underlying mechanisms involved, thereby focusing on the effect on goblet cells. The LS174T cell line was used as goblet cell‑like cells...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28973340/therapeutic-effect-of-mk2-inhibitor-on-experimental-murine-dry-eye
#13
Yang Wu, Jinghua Bu, Yiran Yang, Xiang Lin, Xiaoxin Cai, Caihong Huang, Xiaoxiang Zheng, Weijie Ouyang, Wei Li, Xiaobo Zhang, Zuguo Liu
Purpose: To investigate the role of mitogen-activated protein kinase-activated protein kinase-2 (MK2) in ocular surface damage of dry eye. Methods: MK2 inhibition was performed in mice subjected to desiccating stress (DS) by topical application of MK2 inhibitor (MK2i) or vehicle eye drops. The total and phosphorylated MK2 in conjunctiva were detected by Western blot. The phenol red cotton test was used to measure tear production, and Oregon green dextran staining was performed to assess corneal epithelial barrier function...
September 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28900144/structural-and-functional-insights-into-the-periplasmic-detector-domain-of-the-gacs-histidine-kinase-controlling-biofilm-formation-in-pseudomonas-aeruginosa
#14
Ahmad Ali-Ahmad, Firas Fadel, Corinne Sebban-Kreuzer, Moly Ba, Gauthier Dangla Pélissier, Olivier Bornet, Françoise Guerlesquin, Yves Bourne, Christophe Bordi, Florence Vincent
Pseudomonas aeruginosa is an opportunistic pathogenic bacterium responsible for both acute and chronic infections and has developed resistance mechanisms due to its ability to promote biofilm formation and evade host adaptive immune responses. Here, we investigate the functional role of the periplasmic detector domain (GacSPD) from the membrane-bound GacS histidine kinase, which is one of the key players for biofilm formation and coordination of bacterial lifestyles. A gacS mutant devoid of the periplasmic detector domain is severely defective in biofilm formation...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28891712/molecular-and-clinical-features-of-second-generation-anaplastic-lymphoma-kinase-inhibitors-ceritinib
#15
Tommaso De Pas, Laura Pala, Chiara Catania, Fabio Conforti
The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib...
September 11, 2017: Future Oncology
https://www.readbyqxmd.com/read/28882814/opsin-3-and-4-mediate-light-induced-pulmonary-vasorelaxation-that-is-potentiated-by-g-protein-receptor-kinase-2-inhibition
#16
Sebastian Barreto Ortiz, Daijiro Hori, Yohei Nomura, Xin Yun, Haiyang Jiang, Hwanmee Yong, James Chen, Sam Paek, Deepesh Pandey, Gautam Sikka, Anil Bhatta, Andrew Gillard, Jochen Steppan, Jae Hyung Kim, Hideo Adachi, Viachaslau Barodka, Lewis Romer, Steven S An, Larissa A Shimoda, Lakshmi Santhanam, Dan E Berkowitz
We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the non-visual G protein-coupled receptor (GPCR) melanopsin (opsin 4; Opn4). Here we tested the hypothesis that non-visual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G-protein coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2 as demonstrated with a proximity ligation assay...
September 7, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28815778/mapk8-regulates-chicken-male-germ-cell-differentiation-through-jnk-signaling-pathway
#17
Yingjie Wang, Yulin Bi, Qisheng Zuo, Wenhui Zhang, Dong Li, Na-Na He, Shaoze Cheng, Ya-Ni Zhang, Bichun Li
The study aims to analyze the key signaling pathways in regulating the process of embryonic stem cells (ESCs) differentiation into spermatogonial stem cells (SSCs). We explored the specific regulating mechanisms of C-Jun amino-terminal kinase (JNK) signaling in this process. Interference/overexpression of MAPK8 allows the JNK signaling pathway to be blocked/activated. In Retinoic acid (RA) induced in vitro differentiation assays, the expression of germ cell marker genes, cvh, c-kit, integrin α6 and integrin β1, was observed to upregulate while activating JNK signaling significantly...
August 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28679058/pharmacological-inhibition-of-mtor-kinase-reverses-right-ventricle-remodeling-and-improves-right-ventricle-structure-and-function-in-rats
#18
Andressa Pena, Ahasanul Kobir, Dmitry Goncharov, Akiko Goda, Tatiana V Kudryashova, Arnab Ray, Rebecca Vanderpool, Jeffrey Baust, Baojun Chang, Ana L Mora, John Gorcsan, Elena A Goncharova
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery (PA) pressure, right-heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival, and pulmonary vascular remodeling via two functionally distinct mTOR complexes (mTORCs)-1 (supports cell growth) and -2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces pulmonary arterial hypertension PA vascular smooth muscle cell apoptosis and reverses pulmonary vascular remodeling...
November 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28674068/structural-and-functional-analysis-of-the-escherichia-coli-acid-sensing-histidine-kinase-evgs
#19
Hrishiraj Sen, Nikhil Aggarwal, Chibueze Ishionwu, Nosheen Hussain, Chandni Parmar, Mohammed Jamshad, Vassiliy N Bavro, Peter A Lund
The EvgS/EvgA two-component system of Escherichia coli is activated in response to low pH and alkali metals and regulates many genes, including those for the glutamate-dependent acid resistance system and a number of efflux pumps. EvgS, the sensor kinase, is one of five unconventional histidine kinases (HKs) in E. coli and has a large periplasmic domain and a cytoplasmic PAS domain in addition to phospho-acceptor, HK and dimerization, internal receiver, and phosphotransfer domains. Mutations that constitutively activate the protein at pH 7 map to the PAS domain...
September 15, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28656209/hydrogen-sulfide-reduced-renal-tissue-fibrosis-by-regulating-autophagy-in-diabetic-rats
#20
Lin Li, Ting Xiao, Fang Li, Yan Li, Ou Zeng, Maojun Liu, Biao Liang, Zining Li, Chun Chu, Jun Yang
The present study aimed to explore the effect of hydrogen sulfide (H2S) on renal tissue fibrosis and its mechanism in diabetic rats. Rats were randomly divided into four groups (n=13/group): Control group; induced diabetes mellitus group (STZ); induced diabetes mellitus treated with H2S group (STZ + H2S); normal rats treated with H2S group (H2S). The diabetic model was induced by intraperitoneal (i.p.) injections of 40 mg/kg body weight streptozotocin (STZ); the control group was treated with saline every day (i...
August 2017: Molecular Medicine Reports
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