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Fasudil

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https://www.readbyqxmd.com/read/29909615/paradoxically-most-flexible-ligand-binds-most-entropy-favored-intriguing-impact-of-ligand-flexibility-and-solvation-on-drug-kinase-binding
#1
Barbara Wienen-Schmidt, Hendrik R A Jonker, Tobias Wulsdorf, Hans-Dieter Gerber, Krishna Saxena, Denis Kudlinzki, Sridhar Sreeramulu, Giacomo Parigi, Claudio Luchinat, Andreas Heine, Harald Schwalbe, Gerhard Klebe
Biophysical parameters can accelerate drug development, e.g. rigid ligands may reduce entropic penal-ty and improve binding affinity. We studied systematically the impact of ligand rigidification on ther-modynamics using a series of fasudil derivatives inhibiting protein kinase A by crystallography, iso-thermal titration calorimetry, nuclear magnetic resonance and molecular dynamics simulations. The ligands varied in their internal degrees of freedom but conserve the number of heteroatoms. Counter-intuitively, the most flexible ligand displays the entropically most favored binding...
June 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29904913/mir-128-1-5p-regulates-tight-junction-induced-by-selenium-deficiency-via-targeting-cell-adhesion-molecule-1-in-broilers-vein-endothelial-cells
#2
Tingru Pan, Xueyuan Hu, Tianqi Liu, Zhe Xu, Na Wan, Yiming Zhang, Shu Li
Vein endothelial cells (VECs) constitute an important barrier for macromolecules and circulating cells from the blood to the tissues, stabilizing the colloid osmotic pressure of the blood, regulating the vascular tone, and rapidly changing the intercellular connection, and maintaining normal physiological function. Tight junction has been discovered as an important structural basis of intercellular connection and may play a key role in intercellular connection injuries or vascular diseases and selenium (Se) deficiency symptoms...
June 15, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29901088/fasudil-preserves-lung-endothelial-function-and-reduces-pulmonary-vascular-remodeling-in-a-rat-model-of-end%C3%A2-stage-pulmonary-hypertension-with-left-heart-disease
#3
Rulin Zhuang, Jinfu Wu, Fang Lin, Lu Han, Xiaoting Liang, Qingshu Meng, Yuyu Jiang, Zhulin Wang, Aixue Yue, Yuying Gu, Huimin Fan, Xiaohui Zhou, Zhongmin Liu
Pulmonary hypertension (PH) due to left heart disease (LHD) is a common condition associated with significant morbidity. It contributes to the elevation of pulmonary vascular resistance and mean pulmonary pressure, eventually leading to heart failure and even mortality. The present study aimed to explore the potential efficacy of late and long‑term treatment with a Rho‑kinase (ROCK) signaling inhibitor, namely fasudil, in a rat model of end‑stage PH‑LHD. The PH‑LHD model was established by supracoronary aortic banding, and the effect of fasudil treatment on the progression of PH‑LHD was monitored...
June 13, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29885441/screening-rhoa-rock-inhibitors-for-the-ability-to-prevent-chronic-rejection-of-mouse-cardiac-allografts
#4
Wei Chen, Song Chen, Wenhao Chen, Xian C Li, Rafik M Ghobrial, Malgorzata Kloc
BACKGROUND: Chronic rejection of transplanted organs is a major obstacle in organ transplantation. The main symptoms of chronic rejection are vessel occlusion and tissue fibrosis. Macrophages play a crucial role in chronic rejection. We showed previously that RhoA deletion or RhoA/Rock inhibition using Y27632 inhibitor reorganizes macrophage actin cytoskeleton, prevents macrophage movement to the cardiac allografts, and abrogates chronic rejection in rodent models. Although besides Y27632 there are other RhoA/ROCK inhibitors available commercially, their efficacy in inhibition of chronic rejection remains unknown...
June 6, 2018: Transplant Immunology
https://www.readbyqxmd.com/read/29807069/fasudil-hydrochloride-ameliorates-memory-deficits-in-rat-model-of-streptozotocin-induced-alzheimer-s-disease-involvement-of-pi3-kinase-enos-and-nf%C3%AE%C2%BAb
#5
Manish Kumar, Nitin Bansal
Restoration of PI3-kinase signaling portrays therapeutic potential in Alzheimer's disease (AD). Hyperactive Rho-kinase in AD negatively modulates PI3-kinase pathway, thereby cause cognitive decline. Fasudil is a Rho-kinase inhibitor that has shown therapeutic benefits in brain disorders. The present study is aimed to decipher the role of PI3-kinase pathway in neuroprotective activity of fasudil using STZ-ICV model of AD. MWM and NORT showed that fasudil (300 µg/kg, ICV) averted the STZ-ICV (3 mg/kg) induced memory dysfunctions in rats...
May 25, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29791873/rhoa-rock-signaling-regulates-smooth-muscle-phenotypic-modulation-and-vascular-remodeling-via-the-jnk-pathway-and-vimentin-cytoskeleton
#6
Lian Tang, Fan Dai, Yan Liu, Xiaoqiang Yu, Chao Huang, Yuqin Wang, Wenjuan Yao
The RhoA/ROCK signaling pathway regulates cell morphology, adhesion, proliferation, and migration. In this study, we investigated the regulatory role of RhoA/ROCK signaling on PDGF-BB-mediated smooth muscle phenotypic modulation and vascular remodeling and clarified the molecular mechanisms behind these effects. PDGF-BB treatment induced the activation of RhoA, ROCK, PDGF-Rβ, and the expression of PDGF-Rβ in HA-VSMCs (human aortic vascular smooth muscle cells). PDGF-Rβ inhibition and RhoA suppression blocked PDGF-BB-induced RhoA activation and ROCK induction...
May 20, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29787758/tissue-factor-mediates-microvesicles-shedding-from-mda-mb-231-breast-cancer-cells
#7
Araci M da R Rondon, Vitor H de Almeida, Tainá Gomes, Bruno R F Verçoza, Renato S Carvalho, Sandra König, Juliany C F Rodrigues, Claudia Dos S Mermelstein, Henri H Versteeg, Robson Q Monteiro
Extracellular vesicles, such as microvesicles (MVs), were identified as important players in tumor progression and acquisition of an aggressive phenotype. Tissue factor (TF) is a transmembrane protein that initiates the blood coagulation cascade. In tumor cells, TF has been associated with aggressiveness and cancer progression. Previous studies demonstrate that TF is incorporated into MVs secreted by tumor cells; however, it is unknown whether TF is actively involved in the release of MVs. Here, we investigated the influence of TF expression on the release of MVs...
May 19, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29785232/effects-of-fasudil-on-patients-with-pulmonary-hypertension-associated-with-left-ventricular-heart-failure-with-preserved-ejection-fraction-a-prospective-intervention-study
#8
Xiang Zhang, Xueming Zhang, Saihua Wang, Jun Luo, Zhihong Zhao, Changzhu Zheng, Jieyan Shen
Background: Pulmonary hypertension due to left ventricular heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly medical problem. The aim of the study was to evaluate the clinical efficacy of fasudil on PH-HFpEF elderly patients and to figure out the subtype of PH-HFpEF which may be the therapeutic object of fasudil. Method: 58 PH-HFpEF elderly patients were enrolled. Patients were diagnosed with passive pulmonary hypertension (PPH) or reactive pulmonary hypertension (RPH) by right heart catheterization and all receiving Rho kinase inhibitor fasudil for 2 weeks...
2018: Canadian Respiratory Journal: Journal of the Canadian Thoracic Society
https://www.readbyqxmd.com/read/29767392/a-novel-rabbit-model-for-benign-biliary-stricture-formation-and-the-effects-of-medication-infusions-on-stricture-formation
#9
Qin Yang, Junke Wang, Fei Liu, Wenjie Ma, Haijie Hu, Congdun Ran, Fuyu Li, Qiuwei Pan
BACKGROUND: Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS. METHOD: A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy...
May 16, 2018: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29756460/inhaled-fasudil-lacks-pulmonary-selectivity-in-thromboxane-induced-acute-pulmonary-hypertension-in-newborn-lambs
#10
Shawn F L Hanson, Michael H Terry, Dafne T Moretta, Gordon G Power, Sean M Wilson, Farzana Alam, Fakhrul Ahsan, Arlin B Blood, Paresh C Giri
INTRODUCTION: Pulmonary hypertension (PH) is a potentially deadly disease for infants and adults with few existing medical interventions and no cure. In PH, increased blood pressure in the pulmonary artery eventually leads to heart failure. Fasudil, an antagonist of Rho-kinase, causes vasodilation leading to decreased systemic artery pressure and pulmonary artery pressure (PAP). This study compared the effects of fasudil administered as either an intravenous infusion or inhaled aerosol in newborn lambs...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29745021/the-rhoa-rock-pathway-mediates-high-glucose-induced-cardiomyocyte-apoptosis-via-oxidative-stress-jnk-and-p38mapk-pathways-in-neonatal-rats
#11
Hong Zhou, Yonghong Sun, Lihui Zhang, Wenyuan Kang, Na Li, Yongjun Li
AIMS: To understand the roles of the RhoA/ROCK and MAPK pathways in high glucose (HG)-induced apoptosis and oxidative stress in cardiomyocytes. MATERIALS AND METHODS: Neonatal rat cardiomyocytes were cultured in DMEM, supplemented with 5.5 or 30 mmol/L D-glucose, in the presence or absence of fasudil (50 or 100 μM), SB203580, SP600125 or PD98059 (10 μM, respectively). The percentage of early apoptotic cardiomyocytes was evaluated using flow cytometry. The SOD activity and MDA contents in the cellular supernatants were measured...
May 9, 2018: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/29730311/sodium-tanshinone-iia-sulfonate-promotes-endothelial-integrity-via-regulating-ve-cadherin-dynamics-and-rhoa-rock-mediated-cellular-contractility-and-prevents-atorvastatin-induced-intracerebral-hemorrhage-in-zebrafish
#12
Zhong-Yan Zhou, Bin Huang, Shang Li, Xiao-Hui Huang, Jing-Yi Tang, Yiu Wa Kwan, Pui Man Hoi, Simon Ming-Yuen Lee
Impaired vascular integrity leads to serious cerebral vascular diseases such as intracerebral hemorrhage (ICH). In addition, high-dose statin therapy is suggested to cause increased ICH risk due to unclear effects of general inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) on the vascular system. Here we evaluated the protective effects of sodium tanshinone IIA sulfonate (STS), which has high efficacy and safety in clinical studies of ischemic stroke, by using atorvastatin (Ator) induced ICH zebrafish embryos and human umbilical vein endothelial cells (HUVECs)...
May 3, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29722320/the-rho-associated-kinase-inhibitors-y27632-and-fasudil-promote-microglial-migration-in-the-spinal-cord-via-the-erk-signaling-pathway
#13
Pei-Cai Fu, Rong-Hua Tang, Zhi-Yuan Yu, Min-Jie Xie, Wei Wang, Xiang Luo
Rho-associated kinase (ROCK) is a key regulatory protein involved in inflammatory secretion in microglia in the central nervous system. Our previous studies showed that ROCK inhibition enhances phagocytic activity in microglia through the extracellular signal-regulated kinase (ERK) signaling pathway, but its effect on microglial migration was unknown. Therefore, in this study, we investigated the effects of the ROCK inhibitors Y27632 and fasudil on the migratory activity of primary cultured microglia isolated from the spinal cord, and we examined the underlying mechanisms...
April 2018: Neural Regeneration Research
https://www.readbyqxmd.com/read/29678838/rho-associated-protein-kinase-1-mediates-the-regulation-of-inflammatory-markers-in-diabetic-retina-and-in-retinal-m%C3%A3-ller-cells
#14
Ghulam Mohammad, Heba Mowafak AlSharif, Mohammad Mairaj Siddiquei, Ajmal Ahmad, Kaiser Alam, Ahmed M Abu El-Asrar
GOAL: To investigate the effects of blocking Rho kinase pathway on the expression of inflammatory signaling pathways in the retina of diabetic mice and in human retinal Müller glial cells stimulated with high-glucose to replicate hyperglycemia. PROCEDURES: Retinas from diabetic mice and human retinal Müller glial cells (MIO-M1) were studied. Western blot analysis, immunofluorescence, and enzyme-linked immunosorbent assay were utilized to study the effect of the Rho kinase inhibitor fasudil on the expression of Rho-associated protein kinase-1 (ROCK-1), extracellular signal-regulated kinases1&2(ERK ½), phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-κB), inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1/CCL2)...
March 2018: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/29673911/targeting-the-rhoa-rock-pathway-to-regulate-t-cell-homeostasis-in-hypoxia-induced-pulmonary-arterial-hypertension
#15
Cheng Li, Ping-Ping Liu, Dou-Dou Tang, Rong Song, Yi-Qing Zhang, Si Lei, Shang-Jie Wu
BACKGROUND: Hypoxic pulmonary arterial hypertension (PAH) is a crippling disease with limited therapeutic methods. The imbalance of T helper 17 cell (Th17)/regulatory T cell (Treg) plays an important role in the development of Hypoxic PAH. However, whether targeting the ras homolog family member A-Rho kinase (RhoA-ROCK) pathway (activation and inhibition) by lysophosphatidic acid (LPA) and fasudil (FSD) regulate T-cell homeostasis in Hypoxic PAH remain unknown. OBJECTIVE: To examine the effects of LPA and FSD on hypoxic pulmonary vascular remodeling and homeostasis of Th17/Treg cells in Hypoxic PAH...
June 2018: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29660902/effect-of-rho-kinase-inhibitor-fasudil-on-the-expression-et-1-and-no-in-rats-with-hypoxic-pulmonary-hypertension
#16
Xing-Zhen Sun, Shu-Yan Li, Xiang-Yang Tian, Ze Hong, Jia-Xin Li
OBJECTIVE: This study aims to study the effect of Rho kinase inhibitor fasudil on the expression endothelin-1 (ET-1) and nitric oxide (NO) in rats with hypoxic pulmonary hypertension (HPH). METHODS: Twenty-four male SD rats were randomly divided into three groups: control group, model group (HPH group) and HPH+fasudil group. The rat HPH model was established by intermittent hypoxia (IH) at atmospheric pressure. Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI), ET-1 and NO levels, and pulmonary vascular structural changes were observed in all groups...
April 12, 2018: Clinical Hemorheology and Microcirculation
https://www.readbyqxmd.com/read/29599137/afadin-facilitates-vascular-endothelial-growth-factor-induced-network-formation-and-migration-of-vascular-endothelial-cells-by-inactivating-rho-associated-kinase-through-arhgap29
#17
Toru Tagashira, Terunobu Fukuda, Muneaki Miyata, Kazuha Nakamura, Hidenobu Fujita, Yoshimi Takai, Ken-Ichi Hirata, Yoshiyuki Rikitake
OBJECTIVE: We previously reported that afadin, an actin filament-binding protein, regulated vascular endothelial growth factor-induced angiogenesis. However, the underlying molecular mechanisms are poorly understood. Here, we investigated the mechanisms of how Rho-associated kinase is activated in afadin-knockdown human umbilical vein endothelial cells (HUVECs) and how its activation is involved in defects of vascular endothelial growth factor-induced network formation and migration of the cells...
May 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29581852/rhoa-rho-kinase-triggers-epithelial-mesenchymal-transition-in-mesothelial-cells-and-contributes-to-the-pathogenesis-of-dialysis-related-peritoneal-fibrosis
#18
Qinglian Wang, Xiaowei Yang, Ying Xu, Zhenwei Shen, Hongxia Cheng, Fajuan Cheng, Xiang Liu, Rong Wang
Peritoneal fibrosis (PF) with associated peritoneal dysfunction is almost invariably observed in long-term peritoneal dialysis (PD) patients. Advanced glycation end products (AGEs) are pro-oxidant compounds produced in excess during the metabolism of glucose and are present in high levels in standard PD solutions. The GTPase RhoA has been implicated in PF, but its specific role remains poorly understood. Here, we studied the effects of RhoA/Rho-kinase signaling in AGEs-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs), and evaluated morphological and molecular changes in a rat model of PD-related PF...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29581784/autophagy-inhibition-stimulates-apoptosis-in-oesophageal-squamous-cell-carcinoma-treated-with-fasudil
#19
Fa-Jun Xie, Qiu-Qing Zheng, Jing Qin, Ling-Ling Zhang, Na Han, Wei-Min Mao
Fasudil has been proven to be a promising chemotherapeutic drug for various malignancies. However, the potential anticancer effects of fasudil in oesophageal squamous cell carcinoma (ESCC) remain to be established. We confirmed the RhoA activity is inhibited by fasudil in ESCC cells. Then measured the effects of fasudil on apoptosis and autophagy in ESCC. Our study showed fasudil could both induce ESCCs apoptosis and autophagy, and when fasudil-induced autophagy was inhibited by knockdown of the essential autophagy genes (Beclin 1 or ATG7), and pharmacologic agent (chloroquine) treatment, both treatments also significantly sensitized ESCC to fasudil-induced apoptosis, reducing cell viability in vitro...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29554661/alkannin-inhibited-hepatic-inflammation-in-diabetic-db-db-mice
#20
Wenhua Xue, Zhirui Fan, Yuanzhe Li, Lifeng Li, Tengfei Zhang, Jingli Lu, Bingjun Ma, Zijia Zhu, Jingyao Lian, Chaoqi Zhang, Xiaoqin Song, Dongxu Sun, Yunkai Zhai, Ruitai Fan, Yang Cao, Xiaoming Deng, Jie Zhao
BACKGROUND/AIMS: The current study was designed to investigate the protective role of alkannin (ALK) on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. METHODS: An oral glucose tolerance test (OGTT) was performed. The levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were determined by ELISA...
2018: Cellular Physiology and Biochemistry
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