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https://www.readbyqxmd.com/read/27879448/rhoa-kinase-inhibition-with-fasudil-versus-simvastatin-in-murine-models-of-cerebral-cavernous-malformations
#1
Robert Shenkar, Changbin Shi, Cecilia Austin, Thomas Moore, Rhonda Lightle, Ying Cao, Lingjiao Zhang, Meijing Wu, Hussein A Zeineddine, Romuald Girard, David A McDonald, Autumn Rorrer, Carol Gallione, Peter Pytel, James K Liao, Douglas A Marchuk, Issam A Awad
BACKGROUND AND PURPOSE: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. METHODS: Two heterozygous murine models, Ccm1(+/-)Msh2(-)(/-) and Ccm2(+/-)Trp53(-/-), were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo...
November 22, 2016: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/27856608/reversal-of-bone-marrow-mobilopathy-and-enhanced-vascular-repair-by-angiotensin-1-7-in-diabetes
#2
Goutham Vasam, Shrinidh Joshi, Sean E Thatcher, Stephen H Bartelmez, Lisa A Cassis, Yagna Pr Jarajapu
Ang-(1-7)/MasR pathway activates vascular repair-relevant functions of bone marrow progenitor cells. We tested the effects of Ang-(1-7) on mobilization and vasoreparative functions of progenitor cells that are impaired in diabetes. Study was carried out in streptozotocin-induced diabetic or db/db mice. Diabetes resulted in decreased number of Lineage(-) Sca-1(+) c-Kit(+) (LSK) cells in the circulation, which was normalized by Ang-(1-7). Diabetes-induced depletion of LSK cells in the bone marrow was reversed by Ang-(1-7)...
November 17, 2016: Diabetes
https://www.readbyqxmd.com/read/27825961/repression-of-microrna-function-mediates-inflammation-associated-colon-tumorigenesis
#3
Takeshi Yoshikawa, Jianfeng Wu, Motoyuki Otsuka, Takahiro Kishikawa, Nobumi Suzuki, Akemi Takata, Motoko Ohno, Rei Ishibashi, Mari Yamagami, Ryo Nakagawa, Naoya Kato, Masaaki Miyazawa, Jiahuai Han, Kazuhiko Koike
BACKGROUND & AIMS: Little is known about the mechanisms by which chronic inflammation contributes to carcinogenesis, such as the development of colon tumors in patients with inflammatory bowel diseases. Specific microRNA (miRNAs) can function as suppressors or oncogenes, and widespread alterations in miRNA expression have been associated with tumorigenesis. We studied whether alterations in miRNA function contribute to inflammation-associated colon carcinogenesis. METHODS: We studied the effects of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 alpha (IL1A), and IL1 beta (IL1B) on miRNA function, measured by activity of reporter constructs containing miRNA-binding sites in their 3' untranslated regions, in human 293T embryonic kidney, Caco-2, HT29, and HCT116 colon carcinoma cells, as well as dicer +/+ and dicer -/- and Apobec3 +/+ and Apobec3 -/- mouse embryonic fibroblasts...
November 5, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27795403/the-andes-virus-nucleocapsid-protein-directs-basal-endothelial-cell-permeability-by-activating-rhoa
#4
Elena E Gorbunova, Matthew J Simons, Irina N Gavrilovskaya, Erich R Mackow
: Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases...
October 25, 2016: MBio
https://www.readbyqxmd.com/read/27791202/fasudil-an-inhibitor-of-rho-associated-coiled-coil-kinase-improves-cognitive-impairments-induced-by-smoke-exposure
#5
Deng Xueyang, Ma Zhanqiang, Ma Chunhua, Hao Kun
The current study was designed to investigate the pathological changes in brain induced by smoke exposure, and explore whether fasudil could alleviate these impairments.Adult C57BL/6 mice were exposed to tobacco smoking for four months, and fasudil was treated from the third months. To investigate lung injuries, the immunohistochemistry of lung tissue, immune cell infiltrations, cytokine productions in bronchoalveolar lavage (BAL) fluid, and seurm inflammatory cytokines were evaluated. To investigate cognitive impairments, Morris water maze test, hippocampal inflammatory cytokines and Rho associated signaling pathways were evaluated...
October 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27760762/endothelin-1-rho-kinase-interactions-impair-lung-structure-and-cause-pulmonary-hypertension-after-bleomycin-exposure-in-neonatal-rat-pups
#6
Jason Gien, Nancy Tseng, Gregory 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 intraperitoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor)...
December 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27756191/fasudil-inhibits-tissue-factor-and-plasminogen-activator-inhibitor-1-secretion-by-peripheral-blood-mononuclear-cells-in-capd-patients
#7
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
https://www.readbyqxmd.com/read/27753928/os-05-03-decreased-rho-kinase-based-calcium-sensitization-in-hypertensive-ren-2-transgenic-rats-tgr
#8
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
https://www.readbyqxmd.com/read/27743639/protective-effect-of-inhaled-rho-kinase-inhibitor-on-lung-ischemia-reperfusion-injury
#9
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
https://www.readbyqxmd.com/read/27693712/design-of-efficient-computational-workflows-for-in-silico-drug-repurposing
#10
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
https://www.readbyqxmd.com/read/27677924/selective-activation-of-vascular-kv-7-4-kv-7-5-k-channels-by-fasudil-contributes-to-its-vasorelaxant-effect
#11
Xuan Zhang, Hailong An, Junwei Li, Yuanyuan Zhang, Yang Liu, Zhanfeng Jia, Wei Zhang, Li Chu, Hailin Zhang
BACKGROUND AND PURPOSE: Kv 7 (Kv 7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests Kv 7.4/Kv 7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported Kv 7 openers have shown poor selectivity across these five subtypes. In this study, fasudil - a drug used for cerebral vasospasm - has been found to be a selective opener of Kv 7.4/Kv 7.5 channels...
December 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27672026/central-angiotensin-ii-increases-blood-pressure-and-sympathetic-outflow-via-rho-kinase-activation-in-conscious-rabbits
#12
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
https://www.readbyqxmd.com/read/27671802/endothelial-repair-in-stented-arteries-is-accelerated-by-inhibition-of-rho-associated-protein-kinase
#13
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
https://www.readbyqxmd.com/read/27643321/os-05-03-decreased-rho-kinase-based-calcium-sensitization-in-hypertensive-ren-2-transgenic-rats-tgr
#14
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
https://www.readbyqxmd.com/read/27590141/fasudil-enhances-therapeutic-efficacy-of-neural-stem-cells-in-the-mouse-model-of-mptp-induced-parkinson-s-disease
#15
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
https://www.readbyqxmd.com/read/27587602/diuretics-prevent-rho-kinase-activation-and-expression-of-profibrotic-oxidative-genes-in-the-hypertensive-aortic-wall
#16
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
https://www.readbyqxmd.com/read/27576917/the-rho-kinase-inhibitor-fasudil-ameliorates-diabetes-induced-cardiac-dysfunction-by-improving-calcium-clearance-and-actin-remodeling
#17
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"
https://www.readbyqxmd.com/read/27574422/aptamer-functionalized-peptide-h3cr5c-as-a-novel-nanovehicle-for-codelivery-of-fasudil-and-mirna-195-targeting-hepatocellular-carcinoma
#18
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
https://www.readbyqxmd.com/read/27573128/synergistic-and-superimposed-effect-of-bone-marrow-derived-mesenchymal-stem-cells-combined-with-fasudil-in-experimental-autoimmune-encephalomyelitis
#19
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
https://www.readbyqxmd.com/read/27566106/inhibition-of-rho-associated-kinase-1-2-attenuates-tumor-growth-in-murine-gastric-cancer
#20
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
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