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Jason Gien, Nancy Tseng, Gregory J Seedorf, Katherine Kuhn, Steven H Abman
Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through rho-kinase (ROCK) activation, ET-1 impairs endothelial cell function, however, whether ET-1-ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intra-peritoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, non-selective ET receptor blocker (ETRB) (bosentan) or fasudil (ROCK inhibitor)...
October 19, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Wenning Li, Wen Chen, Maowei Xie, Haiyang Huang, Huiluan Su, Hui Han, Daofa Zhang, Ying Zhang, Xiaohong Yang, Wentan Xu, Yan Su, Wei Wu, Yun Huang, Keying Fu, Jiali Wei
Disturbances in hemostasis are common complications of kidney diseases and correlate well with cardiovascular mortality. Little is known about the effects of fasudil on tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression in peripheral blood mononuclear cells (PBMCs) in CAPD patients. PBMCs were isolated from 13 individuals with CAPD and 13 healthy subjects. After 4 h of incubation with or without LPS (10 ng/mL), TF and PAI-1 mRNA of PBMCs were detected by RT-PCR. The levels of TF and PAI-1 in culture supernatants of PBMCs were determined by ELISA...
October 19, 2016: Renal Failure
Josef Zicha, Michal Behuliak, Ivana Vaneckova
OBJECTIVE: Comparing BP response to Ca channel opener BAY K8644 prior and after Rho kinase inhibition we demonstrated lowered calcium sensitization in spontaneously hypertensive rats (SHR), although BP response of intact SHR to Rho kinase inhibitor fasudil was enhanced (Behuliak et al. J Hypertens 31:2025,2013). The aim of the present study was to evaluate calcium sensitization in hypertensive TGR and their normotensive HanSD controls using the same methods. We also tried to elucidate the interference of baroreflex-activated sympathetic activity with BP response to fasudil...
September 2016: Journal of Hypertension
Keiji Ohata, Toyofumi F Chen-Yoshikawa, Toshi Menju, Ei Miyamoto, Satona Tanaka, Mamoru Takahashi, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Hiroshi Date
BACKGROUND: Rho-kinase, an intracellular serine/threonine kinase, is a key regulator of cytoskeletal dynamics. Recent studies have demonstrated that Rho-kinase is involved in the ischemia-reperfusion injury (IRI) pathogenesis of many organs; however, its involvement with lung IRI remains unclear. This study assessed the association of Rho-kinase with lung IRI and evaluated the protective effect of inhaled Rho-kinase inhibitors in lung IRI. METHODS: The study included isolated rat lung perfusion models, divided into three groups: sham, Rho-kinase inhibitor, and warm ischemia (n = 6 each)...
October 12, 2016: Annals of Thoracic Surgery
Quentin Vanhaelen, Polina Mamoshina, Alexander M Aliper, Artem Artemov, Ksenia Lezhnina, Ivan Ozerov, Ivan Labat, Alex Zhavoronkov
Here, we provide a comprehensive overview of the current status of in silico repurposing methods by establishing links between current technological trends, data availability and characteristics of the algorithms used in these methods. Using the case of the computational repurposing of fasudil as an alternative autophagy enhancer, we suggest a generic modular organization of a repurposing workflow. We also review 3D structure-based, similarity-based, inference-based and machine learning (ML)-based methods. We summarize the advantages and disadvantages of these methods to emphasize three current technical challenges...
September 28, 2016: Drug Discovery Today
Xuan Zhang, Hailong An, Junwei Li, Yuanyuan Zhang, Yang Liu, Zhanfeng Jia, Wei Zhang, Li Chu, Hailin Zhang
BACKGROUND AND PURPOSE: Kv7 (Kv7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests a crucial role for Kv7.4/Kv7.5 channels in regulating vascular smooth muscle contractility. Most of the reported Kv7 openers shown poor selectivity across these five subtypes. In this study, fasudil-a drug for cerebral vasospasm-has been found to be a selective opener of Kv7.4/Kv7.5 channels. EXPERIMENTAL APPROACH: A perforated whole-cell patch technique was used to record the currents and membrane potential...
September 28, 2016: British Journal of Pharmacology
Peter R Pellegrino, Alicia M Schiller, Karla K V Haack, Irving H Zucker
Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway...
November 2016: Hypertension
Sarah T Hsiao, Tim Spencer, Luke Boldock, Svenja Dannewitz Prosseda, Ioannis Xanthis, Francesco J Tovar-Lopez, Heleen van Buesekamp, Ramzi Y Khamis, Nicolas Foin, Neil Bowden, Adil Hussain, Alex Rothman, Victoria Ridger, Ian Halliday, Cecile Perrault, Julian Gunn, Paul C Evans
AIMS: Stent deployment causes endothelial cell (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow pertubation on EC injury and repair are incompletely understood. By studying the effects of stent struts on flow and EC migration we identified an intervention that promotes endothelial repair in stented arteries. METHODS AND RESULTS: In vitro and in vivo models were developed to monitor endothelialization under flow and the influence of stent struts...
September 26, 2016: Cardiovascular Research
Josef Zicha, Michal Behuliak, Ivana Vaneckova
OBJECTIVE: Comparing BP response to Ca channel opener BAY K8644 prior and after Rho kinase inhibition we demonstrated lowered calcium sensitization in spontaneously hypertensive rats (SHR), although BP response of intact SHR to Rho kinase inhibitor fasudil was enhanced (Behuliak et al. J Hypertens 31:2025,2013). The aim of the present study was to evaluate calcium sensitization in hypertensive TGR and their normotensive HanSD controls using the same methods. We also tried to elucidate the interference of baroreflex-activated sympathetic activity with BP response to fasudil...
September 2016: Journal of Hypertension
Yan-Hua Li, Jing-Wen Yu, Jian-Yin Xi, Wen-Bo Yu, Jian-Chun Liu, Qing Wang, Li-Juan Song, Ling Feng, Ya-Ping Yan, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma
Bone marrow-derived neural stem cells (NSCs) are ideal cells for cellular therapy because of their therapeutic potential for repairing and regenerating damaged neurons. However, the optimization of implanted cells and the improvement of microenvironment in the central nervous system (CNS) are still two critical elements for enhancing therapeutic effect. In the current study, we observed the combined therapeutic effect of NSCs with fasudil in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model and explored the possible cellular and molecular mechanisms...
September 2, 2016: Molecular Neurobiology
Patricio Araos, David Mondaca, Jorge E Jalil, Cristián Yañez, Ulises Novoa, Italo Mora, María Paz Ocaranza
BACKGROUND: Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats...
September 1, 2016: Therapeutic Advances in Cardiovascular Disease
Dongwu Lai, Jing Gao, Xukun Bi, Hong He, Xiaolu Shi, Shaoxiang Weng, Yu Chen, Ying Yang, Yang Ye, Guosheng Fu
: Previous study showed inhibition of RhoA and Rho kinase (ROCK) activity with fasudil could alleviate diabetes-induced cardiac dysfunction partially due to improvement of myocardial fibrosis. However, the effect of fasudil on intracellular calcium cycling and actin remodeling, both of which are important to regulate excitation-contract coupling, is still not fully elucidated. In this study, a diabetic cardiomyopathy model was induced by a single intraperitoneal injection of streptozotocin (STZ) in male Sprague Dawley rats...
August 30, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Ying Liu, Xin Wu, Yuan Gao, Jigang Zhang, Dandan Zhang, Shengying Gu, Guanhua Zhu, Gaolin Liu, Xiaoyu Li
Liver cancer is the fifth most commonly diagnosed malignancy, of which hepatocellular carcinoma (HCC) represents the dominating histological subtype. Antiangiogenic therapy aimed at vascular endothelial growth factor (VEGF) has shown promising but deficient clinical prospects on account of vasculogenic mimicry, a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel, which may function as blood supply networks occurring in aggressive tumors including HCC. In this study, we used a new cationic peptide, disulfide cross-linked stearylated polyarginine peptide modified with histidine (H3R5), as a reducible vector, cell penetrating peptide-modified aptamer (ST21) with specific binding to HCC cells to conjugate to peptide H3R5 as the targeting probe, miRNA-195 (miR195) as a powerful gene drug to inhibit VEGF, and fasudil to suppress vasculogenic mimicry by blocking ROCK2, all of which were simultaneously encapsulated in the same nanoparticles...
2016: International Journal of Nanomedicine
Jing-Wen Yu, Yan-Hua Li, Guo-Bin Song, Jie-Zhong Yu, Chun-Yun Liu, Jian-Chun Liu, Hai-Fei Zhang, Wan-Fang Yang, Qing Wang, Ya-Ping Yan, Bao-Guo Xiao, Cun-Gen Ma
Bone marrow-derived mesenchymal stem cells (MSCs) are the ideal transplanted cells of cellular therapy for promoting neuroprotection and neurorestoration. However, the optimization of transplanted cells and the improvement of microenvironment around implanted cells are still two critical challenges for enhancing therapeutic effect. In the current study, we observed the therapeutic potential of MSCs combined with Fasudil in mouse model of experimental autoimmune encephalomyelitis (EAE) and explored possible mechanisms of action...
August 30, 2016: Journal of Molecular Neuroscience: MN
Isabel Hinsenkamp, Sandra Schulz, Mareike Roscher, Anne-Maria Suhr, Björn Meyer, Bogdan Munteanu, Jens Fuchser, Stefan O Schoenberg, Matthias P A Ebert, Björn Wängler, Carsten Hopf, Elke Burgermeister
Gastric cancer (GC) remains a malignant disease with high mortality. Patients are frequently diagnosed in advanced stages where survival prognosis is poor. Thus, there is high medical need to find novel drug targets and treatment strategies. Recently, the comprehensive molecular characterization of GC subtypes revealed mutations in the small GTPase RHOA as a hallmark of diffuse-type GC. RHOA activates RHO-associated protein kinases (ROCK1/2) which regulate cell contractility, migration and growth and thus may play a role in cancer...
August 2016: Neoplasia: An International Journal for Oncology Research
Sebastián Castillo-Galán, Sebastián Quezada, Fernando A Moraga, Germán Ebensperger, Emilio A Herrera, Felipe Beñaldo, Ismael Hernandez, Renato Ebensperger, Santiago Ramirez, Anibal J Llanos, Roberto V Reyes
Calcium signaling through store operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, 6 of them received a 2-APB treatment and the other 6 received vehicle treatment, for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge...
August 19, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Sara Basbous, Anaïs Levescot, Nathalie Piccirilli, Françoise Brizard, François Guilhot, Lydia Roy, Nicolas Bourmeyster, Jean-Marc Gombert, André Herbelin
CD1d-restricted iNKT cells are believed to play a key role in cancer immune surveillance and are functionally deficient in chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker...
August 11, 2016: Journal of Pathology
L Calo', U Vertolli, E Pagnin, V Ravarotto, E Naso, G Maiolino, A Naso
OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human model opposite to hypertension such as Bartter's/Gitelman's syndromes patients, its downregulation associates with lack of CV remodeling...
September 2016: Journal of Hypertension
Shu Hasegawa, Yu Hasegawa, Masaki Miura
BACKGROUND: Cerebral vasospasm (CVS) is well known as a major complication in subarachnoid hemorrhage (SAH) patients, and research has long been focused on improving morbidity and mortality. As CVS commonly develops from day 4 to day 14 after SAH onset, SAH patients require therapies with drugs for preventing CVS after surgical treatment for the source of hemorrhage, mostly ruptured intracranial aneurysms. It is thought that the pathogenesis of CVS is initiated by prolonged smooth muscle contraction, and the subsequent hypoperfusion and cytotoxic responses induce cerebral ischemia...
August 8, 2016: Current Drug Delivery
Magdalena Jasińska-Stroschein, Jacek Owczarek, Urszula Sołtysiak, Daria Orszulak-Michalak
INTRODUCTION: It remains controversial whether statins have a beneficial effect on pulmonary arterial hypertension (PAH). This study is intended to evaluate whether statin, co-administered with Rho-kinase inhibitor, could enhance its efficacy. Although Rho-kinase inhibitors, including fasudil, have been reported to improve pulmonary hypertension in experimental and clinical studies, the combination of these agents has not been tested in the treatment of pulmonary hypertension (PH). MATERIAL AND METHODS: The effects of such a regimen on hemodynamics, right ventricle hypertrophy, and Rho-associated protein kinase (ROCK) activity in experimental monocrotaline (MCT)-induced pulmonary hypertension were examined...
August 1, 2016: Archives of Medical Science: AMS
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