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Verónica M Negrón-Pérez, Luana Teixeira Rodrigues, Gisele Zoccal Mingoti, Peter J Hansen
Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) are activated by binding to RHO GTPases and phosphorylate a variety of downstream targets including actinomyosin. In the mouse embryo, ROCK signaling acts to promote formation of trophectoderm (TE) and inhibit formation of the inner cell mass (ICM) by polarizing outer cells of the embryo to inactivate Hippo signaling (Kono et al., 2014; Mihajlović and Bruce, 2016). This article is protected by copyright. All rights reserved.
March 15, 2018: Molecular Reproduction and Development
Shigeru Kinoshita, Noriko Koizumi, Morio Ueno, Naoki Okumura, Kojiro Imai, Hiroshi Tanaka, Yuji Yamamoto, Takahiro Nakamura, Tsutomu Inatomi, John Bush, Munetoyo Toda, Michio Hagiya, Isao Yokota, Satoshi Teramukai, Chie Sotozono, Junji Hamuro
BACKGROUND: Corneal endothelial cell (CEC) disorders, such as Fuchs's endothelial corneal dystrophy, induce abnormal corneal hydration and result in corneal haziness and vision loss known as bullous keratopathy. We investigated whether injection of cultured human CECs supplemented with a rho-associated protein kinase (ROCK) inhibitor into the anterior chamber could increase CEC density. METHODS: We performed an uncontrolled, single-group study involving 11 persons who had received a diagnosis of bullous keratopathy and had no detectable CECs...
March 15, 2018: New England Journal of Medicine
Richard T Amison, Shirin Jamshidi, Khondaker M Rahman, Clive P Page, Simon C Pitchford
Platelet P2Y1 receptor signaling via RhoGTPases is necessary for platelet-dependent leukocyte recruitment, where no platelet aggregation is observed. We investigated signaling cascades involved in distinct P2Y1 -dependent platelet activities in vitro, using specific inhibitors for phospholipase C (PLC) (U73122, to inhibit the canonical pathway), and RhoGTPases: Rac1 (NSC23766) and RhoA (ROCK inhibitor GSK429286). Human platelet rich plasma (for platelet aggregation) or isolated washed platelets (for chemotaxis assays) was treated with U73122, GSK429286 or NSC23766 prior to stimulation with adenosine diphosphate (ADP) or the P2Y1 specific agonist MRS2365...
March 10, 2018: European Journal of Pharmacology
T Michael De Silva, Mary L Modrick, Fabrice Dabertrand, Frank M Faraci
Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters of isolated pressurized parenchymal arterioles were similar in adult (4-5 month) and old mice (22±1 month; ≈15±1 µm). Endothelium-dependent dilation was impaired in old mice compared with adults in a pathway-specific manner...
March 12, 2018: Hypertension
Yuan Dai, Weijia Luo, Jiang Chang
Rho kinases (ROCKs) are the first discovered RhoA effectors that are now widely known for their effects on actin organization. Recent studies have shown that ROCKs play important roles in cardiac physiology. Abnormal activation of ROCKs participate in multiple cardiovascular pathological processes, including cardiac hypertrophy, apoptosis, fibrosis, systemic hypertension, and pulmonary hypertension. ROCK inhibitors, fasudil and statins, have shown beneficial cardiovascular effects in many animal studies, clinical trials, and applications...
February 2018: Current Opinion in Physiology
Etsuo Chihara, Galina Dimitrova, Tomoyuki Chihara
PURPOSE: To assess the responses of the superficial peripapillary retinal vessel density (VD) and prelaminar flow index (PLFI) to topical Rho-assisted coiled-coil forming protein kinase (ROCK) inhibitor ripasudil and alpha-2 agonist brimonidine using optical coherence tomography angiography. METHODS: This is a prospective, non-randomized, comparative cohort study. We studied the response of optical coherence tomography angiography (OCTA) parameters to drugs in 24 eyes treated with ripasudil and 23 eyes treated with brimonidine at the Sensho-kai Eye Institute...
March 8, 2018: Graefe's Archive for Clinical and Experimental Ophthalmology
Paul A Turner, Michael R Garrett, Sean P Didion, Amol V Janorkar
This study highlights functional differences between 2-D monolayer and 3-D spheroid 3T3-L1 adipocyte culture models and explores the underlying genomic mechanisms responsible for the different phenotypes present. The spheroids showed higher triglyceride accumulation than the monolayer culture and further increase with larger spheroid size. Whole transcriptome analysis indicated significant differential expression of genes related to adipogenesis, including adipocytokine signaling, fatty acid metabolism, and PPAR-γ signaling...
March 2, 2018: Annals of Biomedical Engineering
Ajay Vikram Singh, Timotheus Jahnke, Vimal Kishore, Byung-Wook Park, Madu Batuwangala, Joachim Bill, Metin Sitti
Cancer cells have the capacity to synthesize nanoparticles (NPs). The detailed mechanism of this process is not very well documented. We report the mechanism of biomineralization of aqueous gold chloride into NPs and microplates in the breast-cancer cell line MCF7. Spherical gold NPs are synthesized in these cells in the presence of serum in the culture media by the reduction of HAuCl4 . In the absence of serum, the cells exhibit gold microplate formation through seed-mediate growth albeit slower reduction...
February 27, 2018: Acta Biomaterialia
Victor S C Wong, Cristina Picci, Michelle Swift, Max Levinson, Dianna Willis, Brett Langley
Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule α-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons...
January 2018: ENeuro
Yongqing Chen, Fangju Su, Juanping Han, Piqi Jiao, Wenyun Guo
To study the expression of Rho kinase (Rho associated coil forming protein kinase-1, ROCK-1) and its substrate myosin phosphatase target subunit 1 (myosin phosphatase target subunit-1, MYPT-1), connexin 40 (Cx40) and connexin 43 (Cx43) in the left atrial appendage of patients with atrial fibrillation, and explore the role of ROCK signaling pathway in patients with atrial fibrillation and its underlying mechanism. Methods: 40 patients undergoing open heart surgery were divided into two groups; atrial fibrillation group (AF group) and sinus rhythm group (SR group)...
February 19, 2018: Heart Surgery Forum
Jingjing Wang, Jian Xu, Xinyun Zhao, Weiping Xie, Hong Wang, Hui Kong
Regulation of leukocyte-endothelial cell interactions and of vascular permeability plays a critical role in the maintenance of functional pulmonary microvascular barriers. Little is yet known about the effect of the Rho-associated protein kinase (ROCK) inhibitor fasudil on leukocyte-endothelial cell interactions or the underlying mechanism. In the present study, as evaluated using co-culture systems of neutrophils and human pulmonary microvascular endothelial cells (HPMECs), fasudil dose-dependently suppressed neutrophil chemotaxis by decreasing the production of chemotactic factors in lipopolysaccharide (LPS)-treated HPMECs...
February 23, 2018: Experimental Cell Research
Sung-Yup Cho, Chang Ohk Sung, Jeesoo Chae, Jieun Lee, Deukchae Na, Wonyoung Kang, Jinjoo Kang, Seoyeon Min, Ahra Lee, Eunhye Kwak, Jooyoung Kim, Boram Choi, Hyunsoo Kim, Jeffrey H Chuang, Hyo-Kyung Pak, Chan-Sik Park, Sanghui Park, Young Hyeh Ko, Dakeun Lee, Jin Roh, Min-Sun Cho, Seongyeol Park, Young Seok Ju, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, James Keck, Jacques Banchereau, Edison T Liu, Woo-Ho Kim, Hansoo Park, Han-Kwang Yang, Jong-Il Kim, Charles Lee
Epstein-Barr virus (EBV)-positive diffuse large B cell lymphomas (EBV+ -DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+ -DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+ -DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+ -DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2 , and Rho pathway transcriptomic activation...
February 23, 2018: Blood
Şenay Aydin, Cengiz Özdemir, Cem Ismail Küçükali, Sinem Nedime Sökücü, Murat Giriş, Uğur Akcan, Erdem Tüzün
BACKGROUND/AIM: Obstructive sleep apnea syndrome (OSAS) is associated with intermittent episodes of hypoxia, endothelial dysfunction and associated cardiovascular problems. Our aim was to investigate whether OSAS-related hypoxia alters the expression of rho-associated protein kinase (ROCK), a marker of chronic hypoxia and endothelial dysfunction. MATERIALS AND METHODS: ROCK1 and ROCK2 levels were measured by immunoblotting in peripheral blood mononuclear cells (PBMC) of 47 OSAS patients and 17 healthy controls...
March 2018: In Vivo
Joon Tae Park, Hyun Tae Kang, Chi Hyun Park, Young-Sam Lee, Kyung A Cho, Sang Chul Park
In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells...
February 20, 2018: Experimental Gerontology
Sarah T Boyle, Jasreen Kular, Max Nobis, Andrew Ruszkiewicz, Paul Timpson, Michael S Samuel
The ability to rapidly respond to applied force underpins cell/tissue homeostasis. This response is mediated by mechanotransduction pathways that regulate remodeling and tension of the actomyosin cytoskeleton to counterbalance external forces. Enhanced extracellular matrix tension hyper-activates mechanotransduction and characterizes diseased states such as cancer, but is also required for normal epidermal regeneration. While the impact of extracellular matrix tension on signaling and cell biology are well appreciated, that of acute compressive force is under-studied...
February 17, 2018: Small GTPases
Leyla Sahın, Ozge Selin Cevık, Dilan Deniz Koyuncu, Kansu Buyukafsar
AIMS: Rho/Rho-kinase (ROCK) signaling has extensively been shown to take part in mammalian smooth muscle contractions in response to diverse agents yet its role in the contraction of amphibian smooth muscle has not been investigated. Therefore, we aimed to explore any role of this pathway in the contractions of frog stomach smooth. MAIN METHODS: The strips were prepared and suspended in organ baths filled with Ringer solution. Changes in the circular strips of the frog stomach muscle length were recorded isotonically with a force transducer in organ baths...
February 15, 2018: Life Sciences
T V Povysheva, Y O Mukhamedshina, A A Rizvanov, Y A Chelyshev
The role of the Rho/ROCK/PTEN signaling pathway in the regulation of astrocyte function for consolidation/stabilization of the synapse has not been thoroughly studied. In this study, the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in GFAP-positive astrocytic processes in the ventral horns (VH) of the rat spinal cord has been evaluated in the normal condition and in a delayed period (30 days) after dosed contusion spinal cord injury (SCI) in caudal thoracic segments. In intact rats and at 30 days post-injury (dpi), semi-quantitative immunohistochemical analysis showed that there is approximately 2 folds less synaptophysin reactivity in the motoneuron perikarya than outside the perikarya, i...
February 15, 2018: Molecular and Cellular Neurosciences
Zhongwei Liu, Raouf A Khalil
Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca 2+ has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined...
February 13, 2018: Biochemical Pharmacology
Zubair Ahmed Nizamudeen, Lisa Chakrabarti, Virginie Sottile
Fasudil is a clinically approved Rho-associated protein kinase (ROCK) inhibitor that has been used widely to treat cerebral consequences of subarachnoid hemorrhage. It is known to have a positive effect on animal models of neurological disorders including Parkinson's disease and stroke. However, its cellular effect on progenitor populations and differentiation is not clearly understood. While recent studies suggest that fasudil promotes the mobilization of neural stem cells (NSCs) from the subventricular zone in vivo and promotes the differentiation of the C17...
February 6, 2018: Stem Cell Research
Megumi Honjo, Hidenobu Tanihara
Rho-associated protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aqueous humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) production...
February 14, 2018: Japanese Journal of Ophthalmology
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