Search results for "Rho Kinase"
showing 8 items of 8 documents
The antifibrotic potential of a sustained release formulation of a PDGF beta-receptor targeted rho kinase inhibitor
2019
Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGF beta-receptor, using the drug carrier pPB-MSA. This carrier consists of mou…
Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway
2010
Migration and proliferation of endothelial cells are involved in re-endothelialization and angiogenesis, two important cardiovascular processes that are increased in response to estrogens. RhoA, a small GTPase which controls multiple cellular processes, is involved in the control of cell migration and proliferation. Our aim was to study the role of RhoA on estradiol-induced migration and proliferation and its dependence on estrogen receptors activity. Human umbilical vein endothelial cells were stimulated with estradiol, in the presence or absence of ICI 182780 (estrogen receptors antagonist) and Y-27632 (Rho kinase inhibitor). Estradiol increased Rho GEF-1 gene expression and RhoA (gene an…
Bradykinin Contracts Rat Urinary Bladder Largely Independently of Phospholipase C
2014
Several receptor systems in the bladder causing detrusor smooth muscle contraction stimulate phospholipase C (PLC). PLC inhibition abolishes bladder contraction via P2Y6 but not that via M3 muscarinic receptors, indicating a receptor-dependent role of PLC. Therefore, we explored the role of PLC in rat bladder contraction by bradykinin. The PLC inhibitor U 73,122 [1-(6-[([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-pyrrole-2,5-dione] did not affect the bradykinin response to a significantly greater degree than its inactive analog U 73,343 [10 μM each; 1-(6-[-([17β]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-2,5-pyrrolidinedione], whereas the phospholipase D inhibitor b…
Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-Dependent Manner
2012
Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors a…
Reduction of tumor necrosis factor-alpha (TNF-α) related nuclear factor-kappaB (NF-κB) translocation but not inhibitor kappa-B (Iκ-B)-degradation by …
2002
Degradation of inhibitor kappa-B (Ikappa-B) followed by translocation of nuclear factor-kappaB (NF-kappaB) into the nucleus and activation of gene expression is essential in tumor necrosis factor-alpha (TNF-alpha)-signaling. In order to analyze the role of Rho proteins in TNF-alpha-induced NF-kappaB-activation in human umbilical cord vein endothelial cells (HUVEC) we used Clostridium difficile toxin B-10463 (TcdB-10463) which inactivates RhoA/Rac1/Cdc42 by glucosylation and Clostridium botulinum C3-toxin which inhibits RhoA/B/C by ADP-ribosylation. Exposure of HUVEC to 10 ng/mL TcdB-10463 or 2.5 microg/mL C3-toxin inhibited TNF-alpha (100 ng/mL)-induced expression of a NF-kappaB-dependent r…
The development of benzimidazoles as selective rho kinase inhibitors
2010
Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA).
Inhibition of intracellular Ca2+ release by a Rho-kinase inhibitor for the treatment of ischemic damage in primary cultured rat hippocampal neurons.
2008
The effects of hydroxy fasudil, a specific Rho-kinase inhibitor, on behavior and brain neuronal activity in animal studies have been described previously. However, whether a Rho-kinase inhibitor can directly protect neurons against ischemic damage and the molecular mechanisms underlying these effects are poorly understood. The present work was designed to investigate the effect of hydroxy fasudil against oxygen-glucose deprivation (OGD) induced acute neuronal injury and the underlying mechanisms in vitro. Pretreatment with hydroxy fasudil at 5 and 10 microM could concentration-dependently improve cell viability and decrease Lactate dehydrogenase (LDH) level in extracellular solution of neur…
Antiproliferative effects of drugs affecting different signalling pathways on rat and human pulmonary artery smooth muscle cells
2015
Current treatments for pulmonary arterial hypertension (PAH) include pulmonary vasodilators which may also inhibit PASMC proliferation. The aim of this study was to compare the antiproliferative effects of multiple drugs on rat and human PASMC (rPASMC and hPMASC, respectively) in vitro. rPASMCs and hPASMC were starved for 24 h, then treated with different inhibitors and incubated for 48 h in 1% foetal calf serum plus endothelin-1, 5-HT and U46619. Cell number was estimated by the MTT test. Viable cells increased by 160-180% in 48 h. Activation of the cGMP pathway with the soluble guanylyl cyclase activators riociguat and YC-1 (≤ 10 µM) or the cAMP pathway by the adenylyl cyclase activator f…