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https://www.readbyqxmd.com/read/29169155/rho-kinase-regulates-aortic-vascular-smooth-muscle-cell-stiffness-via-actin-srf-myocardin-in-hypertension
#1
Ning Zhou, Jia-Jye Lee, Shaunrick Stoll, Ben Ma, Kevin D Costa, Hongyu Qiu
BACKGROUND/AIMS: Our previous studies demonstrated that intrinsic aortic smooth muscle cell (VSMC) stiffening plays a pivotal role in aortic stiffening in aging and hypertension. However, the underlying molecular mechanisms remain largely unknown. We here hypothesized that Rho kinase (ROCK) acts as a novel mediator that regulates intrinsic VSMC mechanical properties through the serum response factor (SRF) /myocardin pathway and consequently regulates aortic stiffness and blood pressure in hypertension...
November 23, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29153889/3d-qsar-studies-on-indole-and-7-azoindole-derivatives-as-rock-2-inhibitors-an-integrative-computational-approach
#2
Santhosh Kumar Nagarajan, Sathya Babu, Honglae Sohn, Panneer Devaraju, Thirumurthy Madhavan
Rho Kinases (ROCK) has been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states. In this study, we have performed pharmacophore modeling and 3D QSAR studies on a series of 36 indoles and 7-azoindoles derivatives as ROCK2 inhibitors to elucidate the structural variations with their inhibitory activities...
October 9, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29152648/melatonin-inhibits-colon-cancer-rko-cell-migration-by-downregulating-rho%C3%A2-associated-protein-kinase-expression-via-the-p38-mapk-signaling-pathway
#3
Zhen Liu, Duobing Zou, Xiaoping Yang, Xiaolong Xue, Li Zuo, Qing Zhou, Ruolei Hu, Yuan Wang
Melatonin is predominately produced and secreted by the pineal gland, and inhibits cell growth in various cancer cell lines such as colorectal cancer. However, the precise mechanisms involved have not been fully elucidated. In the present study, the potential molecular mechanism underlying the efficacy of melatonin on migration in RKO colon cancer cells was investigated. The effects of melatonin and H‑1152, a selective inhibitor of Rho‑associated protein kinase (ROCK), on the migration of RKO cells were analyzed by an in vitro wound healing assay...
October 19, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29143227/pdgfr-inhibition-mediated-intracellular-signalling-in-c6-glioma-growth-and-migration-role-of-erk-and-rock-pathway
#4
Juhi Singh, Kedarlal Sharma, Prakash P Pillai
Aberrant PDGFR (Platelet derived growth factor receptor) signalling in brain tumors and gliomas is one of the primary cause of tumor progression. PDGFR stimulation by its ligand and the role of its downstream mediators such as extracellular regulated kinases (ERK1/2), PI3K and ROCK pathways have not been thoroughly investigated. The present study sought to investigate the role of PDGF receptor signalling inhibition on suppression of rat C6 glioma growth and migration. Treatment of C6 cells with PDGFR inhibitor, AG1295 caused a significant reduction in migration and proliferation by regulating the ERK and ROCK signalling...
November 15, 2017: Cytotechnology
https://www.readbyqxmd.com/read/29142175/macrophage-differentiation-induced-by-pma-is-mediated-by-activation-of-rhoa-rock-signaling
#5
Lifeng Yang, Fan Dai, Lian Tang, Yulan Le, Wenjuan Yao
In order to investigate the effects of RhoA/ROCK signaling in macrophage differentiation, we used 100 ng/mL PMA to induce macrophage differentiation from U937 cells in vitro. The observation of cell morphology and the expression of CD68 and SR-A were performed to confirm the differentiation induced by PMA. Western blot analysis showed that the expression of ROCK1 and ROCK2 and the phosphorylation of MYPT1 were significantly increased after PMA treatment. Pulldown assay showed that the activation of RhoA was obviously enhanced when U937 cells were treated with PMA...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/29135354/depression-following-traumatic-brain-injury-in-mice-is-associated-with-down-regulation-of-hippocampal-astrocyte-glutamate-transporters-by-thrombin
#6
Chun-Shu Piao, Ashley L Holloway, Sue Hong-Routson, Mark S Wainwright
Depression after traumatic brain injury (TBI) is common but the mechanisms by which TBI causes depression are unknown. TBI decreases glutamate transporters GLT-1 and GLAST and allows extravasation of thrombin. We examined the effects of thrombin on transporter expression in primary hippocampal astrocytes. Application of a PAR-1 agonist caused down-regulation of GLT-1, which was prevented by inhibition of Rho kinase (ROCK). To confirm these mechanisms in vivo, we subjected mice to closed-skull TBI. Thrombin activity in the hippocampus increased one day following TBI...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29125705/m-tuberculosis-mce3c-promotes-mycobacteria-entry-into-macrophages-through-activation-of-%C3%AE-2-integrin-mediated-signaling-pathway
#7
Yong Zhang, Jie Li, Bingxi Li, Jing Wang, Cui Hua Liu
Establishment of infection by facultative intracellular pathogen Mycobacterium tuberculosis (Mtb) requires adherence to and internalization by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalization of mycobacteria into mammalian cells. Here we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif-dependent manner...
November 10, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/29122888/tnf-stimulated-gene-6-promotes-formation-of-hyaluronan-inter-%C3%AE-inhibitor-heavy-chain-complexes-necessary-for-ozone-induced-airway-hyperresponsiveness
#8
Vandy P Stober, Collin G Johnson, Alana Majors, Mark E Lauer, Valbona Cali, Ronald J Midura, Hans-Georg Wisniewski, Mark A Aronica, Stavros Garantziotis
Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-α-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptors binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological HA-HC matrix. However, the role of TSG-6 in acute airway inflammation is not well understood. Here, we hypothesized that TSG-6 is essential for the development of HA- and ozone-induced AHR...
November 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29115372/inhibition-of-rho-kinase-protects-against-colitis-in-mice-by-attenuating-intestinal-epithelial-barrier-dysfunction-via-mlc-and-the-nf-%C3%AE%C2%BAb-pathway
#9
Yanting Zou, Lili Ma, Yuan Zhao, Shuncai Zhang, Chaohui Zhou, Yu Cai
The aim of the present study was to investigate the role of Rho kinase (also known as ROCK) inhibitor in 2,4,6-trinitrobenzene sulfonic acid induced mouse colitis; and to elucidate the underlying mechanism of ROCK1/ROCK2 inhibition in enhancing intestinal epithelial barrier (IEB) function. A specific inhibitor of ROCK, Y-27632, was used to examine the role of ROCK in mouse colitis models. ROCK1 and ROCK2 were silenced respectively using RNA interference in Caco-2 cells. The expression of tight junction proteins and the downstream molecules of ROCK were assessed...
October 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29098568/the-signaling-of-protease-activated-receptor-2-activating-peptide-induced-contraction-in-cat-esophageal-smooth-muscle-cells
#10
Hyun Su Ha, Se Eun Lee, Hyun Seok Lee, Gil Hyung Kim, Chan Jong Yoon, Jong Soo Han, Ji-Yun Lee, Uy Dong Sohn
Protease-activated receptors (PARs) are a family of G protein-coupled receptors with a unique activation mechanism involving proteolytic cleavage of the extracellular N-terminal domain of the receptor. PAR2 has a contractile effect on esophageal smooth muscle. We investigate the signaling pathways of the PAR2-activating peptide (PAR2-AP) induced contraction in cat esophageal smooth muscle cells. The length of freshly isolated smooth muscle cells and permeabilized cells from feline esophagus were measured by scanning micrometry, and by confirming molecular basis via western blot analysis...
November 2, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29091102/mechanical-mismatch-between-ras-transformed-and-untransformed-epithelial-cells
#11
Corinne Gullekson, Gheorghe Cojoc, Mirjam Schürmann, Jochen Guck, Andrew Pelling
The organization of the actin cytoskeleton plays a key role in regulating cell mechanics. It is fundamentally altered during transformation, affecting how cells interact with their environment. We investigated mechanical properties of cells expressing constitutively active, oncogenic Ras (Ras(V12)) in adherent and suspended states. To do this, we utilized atomic force microscopy and a microfluidic optical stretcher. We found that adherent cells stiffen and suspended cells soften with the expression of constitutively active Ras...
November 22, 2017: Soft Matter
https://www.readbyqxmd.com/read/29084331/the-anti-inflammatory-effect-of-ripasudil-k-115-a-rho-kinase-rock-inhibitor-on-endotoxin-induced-uveitis-in-rats
#12
Takatoshi Uchida, Megumi Honjo, Reiko Yamagishi, Makoto Aihara
Purpose: To investigate the anti-inflammatory properties of ripasudil, a Rho kinase (ROCK) inhibitor, using endotoxin-induced uveitis (EIU) in rats. Methods: Endotoxin-induced uveitis was induced by footpad injection of lipopolysaccharide (LPS). Ripasudil was administered intraperitoneally 1 hour before and after LPS injection. The aqueous humor was collected 24 hours after injection, and the infiltrating cells, protein concentration, and levels of monocyte chemotactic protein-1 (MCP-1) were determined...
October 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29075304/effects-of-gualou-guizhi-decoction-aqueous-extract-on-axonal-regeneration-in-organotypic-cortical-slice-culture-after-oxygen-glucose-deprivation
#13
Lihong Nan, Lan Yang, Yanfang Zheng, Yibo He, Qingqing Xie, Zheming Chen, Huang Li, Mei Huang
Gualou Guizhi decoction (GLGZD) is effective for the clinical treatment of limb spasms caused by ischemic stroke, but its underlying mechanism is unclear. Propidium iodide (PI) fluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), immunohistochemistry, western blot, and real-time qPCR were used to observe the axonal regeneration and neuroprotective effects of GLGZD aqueous extract on organotypic cortical slices exposed to oxygen-glucose deprivation (OGD) and further elucidate the potential mechanisms...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29057980/rock-inhibition-with-fasudil-induces-beta-catenin-nuclear-translocation-and-inhibits-cell-migration-of-mda-mb-231-human-breast-cancer-cells
#14
Fabiana Sélos Guerra, Ramon Guerra de Oliveira, Carlos Alberto Manssour Fraga, Claudia Dos Santos Mermelstein, Patricia Dias Fernandes
Tumor aggressiveness is usually associated with metastasis. MDA-MB 231, a triple-negative breast cancer (TNBC), is an aggressive type of breast cancer and associated with early metastasis. The Rho/ROCK pathway is a key regulator of cell motility involving cytoskeleton regulation through stabilization of actin filaments and stress fiber formation. In this study we show that Fasudil, a ROCK inhibitor, inhibited the migration of MDA-MB 231 and A549 cells, without altering the viability of these cells at the concentration of 10 μM, modified tumor cell morphology, with disorganization of stress fibers and promotes activation of the canonical-Wnt/beta-catenin pathway...
October 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29057688/rock-as-a-therapeutic-target-for-ischemic-stroke
#15
Nikola Sladojevic, Brian Yu, James K Liao
Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology...
October 30, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/29054429/surface-chemistry-induces-mitochondria-mediated-apoptosis-of-breast-cancer-cells-via-pten-pi3k-akt-signaling-pathway
#16
Jing Zhang, Li Li, Yueting Peng, Yu Chen, Xiaoying Lv, Shun Li, Xiang Qin, Hong Yang, Chunhui Wu, Yiyao Liu
Tumor cell can be significantly influenced by various chemical groups of the extracellular matrix proteins. However, the underlying molecular mechanisms involved in the interaction between cancer cells and functional groups in the extracellular matrix remain unknown. Using chemically modified surfaces with biological functional groups (CH3, NH2, OH), it was found that hydrophobic surfaces modified with CH3 and NH2 suppressed cell proliferation and induced the number of apoptotic cells. Mitochondrial dysfunction, cytochrome c release, Bax upregulation, cleaved caspase-3 and PARP, and Bcl-2 downregulation indicated that hydrophobic surfaces with CH3 and NH2 triggered the activation of intrinsic apoptotic signaling pathway...
October 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29048389/discovery-of-novel-n-substituted-prolinamido-indazoles-as-potent-rho-kinase-inhibitors-and-vasorelaxation-agents
#17
Yangyang Yao, Renze Li, Xiaoyu Liu, Feilong Yang, Ying Yang, Xiaoyu Li, Xiang Shi, Tianyi Yuan, Lianhua Fang, Guanhua Du, Xiaozhen Jiao, Ping Xie
Inhibitors of Rho kinase (ROCK) have potential therapeutic applicability in a wide range of diseases, such as hypertension, stroke, asthma and glaucoma. In a previous article, we described the lead discovery of DL0805, a new ROCK I inhibitor, showing potent inhibitory activity (IC50 6.7 μM). Herein, we present the lead optimization of compound DL0805, resulting in the discovery of 24- and 39-fold more-active analogues 4a (IC50 0.27 μM) and 4b (IC50 0.17 μM), among other active analogues. Moreover, ex-vivo studies demonstrated that 4a and 4b exhibited comparable vasorelaxant activity to the approved drug fasudil in rat aortic rings...
October 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29033935/cannabinoid-receptor-1-participates-in-liver-inflammation-by-promoting-m1-macrophage-polarization-via-rhoa-nf-%C3%AE%C2%BAb-p65-and-erk1-2-pathways-respectively-in-mouse-liver-fibrogenesis
#18
Lei Tian, Weiyang Li, Le Yang, Na Chang, Xiaoting Fan, Xiaofang Ji, Jieshi Xie, Lin Yang, Liying Li
Macrophage M1/M2 polarization mediates tissue damage and inflammatory responses. Cannabinoid receptor (CB) 1 participated in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophages (BMMs) activation. However, the knowledge of whether CB1 is involved in the polarization of BMMs remains limited. Here, we found M1 gene signatures (including CD86, MIP-1β, tumor necrosis factor, IL-6, and inducible nitric oxide synthase) and the amount of M1 macrophages (CD86(+) cells, gated by F4/80) were significantly elevated in carbon tetrachloride (CCl4)-induced mouse injured livers, while that of M2 type macrophages had little change by RT-qPCR and fluorescence-activated cell sorting (FACS)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29033348/design-and-synthesis-of-benzimidazole-based-rho-kinase-inhibitors-for-the-treatment-of-glaucoma
#19
Vasudha Abbhi, Lovneet Saini, Srishti Mishra, Gautam Sethi, Alan Prem Kumar, Poonam Piplani
Rho kinase inhibitors (ROCK II) play a key role in glaucoma management attributed to their IOP lowering ability and neuroprotective effects. In the present study, a series of novel benzimidazole derivatives (9a-m) has been synthesized and evaluated for their IOP lowering, Rho kinase inhibitory and antioxidant properties. The synthesized compounds were found to be lipophilic and showed a significant IOP lowering effect both in the treated and the contralateral eye comparable to the reference standard fasudil...
November 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28989085/ferulic-acid-relaxed-rat-aortic-small-mesenteric-and-coronary-arteries-by-blocking-voltage-gated-calcium-channel-and-calcium-desensitization-via-dephosphorylation-of-erk1-2-and-mypt1
#20
Zhong-Yan Zhou, Jia-Qi Xu, Wai-Rong Zhao, Xin-Lin Chen, Yu Jin, Nuo Tang, Jing-Yi Tang
Ferulic acid, a natural ingredient presents in several Chinese Materia Medica such as Radix Angelicae Sinensis, has been identified as an important multifunctional and physiologically active small molecule. However, its pharmacological activity in different blood vessel types and underlying mechanisms are unclear. The present study was to investigate the vascular reactivity and the possible action mechanism of FA on aorta, small mesenteric arteries and coronary arteries isolated from Wistar rats. We found FA dose-dependently relieved the contraction of aorta, small mesenteric arteries and coronary arteries induced by different contractors, U46619, phenylephrine (Phe) and KCl...
November 15, 2017: European Journal of Pharmacology
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