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https://www.readbyqxmd.com/read/29202196/effects-of-dlc1-deficiency-on-endothelial-cell-contact-growth-inhibition-and-angiosarcoma-progression
#1
David Sánchez-Martín, Atsushi Otsuka, Kenji Kabashima, Taekyu Ha, Dunrui Wang, Xiaolan Qian, Douglas R Lowy, Giovanna Tosato
Background: Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene frequently deleted in cancer. However, DLC1 is not known to be deleted in angiosarcoma, an aggressive malignancy of endothelial cell derivation. Additionally, the physiologic functions of DLC1 protein in endothelial cells are poorly defined. Methods: We investigated the effects of shRNA-induced DLC1 depletion in endothelial cells. Cell growth was measured by 3H thymidine incorporation, IncuCyte imaging, and population doublings; cell death by cell cycle analysis; gene expression by Affimetrix arrays and quantitative polymerase chain reaction; NF-κB activity by reporter assays; and protein levels by immunoblotting and immunofluorescence staining...
November 30, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29187752/inhibiting-rho-kinase-promotes-goal-directed-decision-making-and-blocks-habitual-responding-for-cocaine
#2
Andrew M Swanson, Lauren M DePoy, Shannon L Gourley
The prelimbic prefrontal cortex is necessary for associating actions with their consequences, enabling goal-directed decision making. We find that the strength of action-outcome conditioning correlates with dendritic spine density in prelimbic cortex, suggesting that new action-outcome learning involves dendritic spine plasticity. To test this, we inhibited the cytoskeletal regulatory factor Rho kinase. We find that the inhibitor fasudil enhances action-outcome memory, resulting in goal-directed behavior in mice that would otherwise express stimulus-response habits...
November 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/29162447/co-administration-of-liposomal-fasudil-and-tissue-plasminogen-activator-ameliorated-ischemic-brain-damage-in-occlusion-model-rats-prepared-by-photochemically-induced-thrombosis
#3
Tatsuya Fukuta, Yosuke Yanagida, Tomohiro Asai, Naoto Oku
Delivery of neuroprotectants with liposomes has been shown to be effective for the treatment of ischemic stroke. We have recently revealed that intravenous administration of liposomal fasudil (Fasudil-Lip), a Rho-kinase inhibitor, prior to thrombolysis with tissue plasminogen activator (t-PA) can extend the narrow therapeutic time window (TTW) of t-PA. In the present study, we examined the influence of t-PA treatment on liposomal accumulation into the ischemic region and cerebroprotective effect of combined treatment with Fasudil-Lip and t-PA performed at the same timing after the onset of ischemia in middle cerebral artery occlusion (MCAO) prepared by photochemically induced thrombosis...
November 18, 2017: Biochemical and Biophysical Research Communications
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
#4
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/29119680/nicorandil-regulates-the-macrophage-skewing-and-ameliorates-myofibroblasts-by-inhibition-of-rhoa-rho-kinase-signalling-in-infarcted-rats
#5
Tsung-Ming Lee, Shinn-Zong Lin, Nen-Chung Chang
We have demonstrated that ATP-sensitive potassium (KATP ) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti-fibrotic effects of KATP channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA-kinase-dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of KATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction...
November 9, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29099428/neuroprotective-effects-of-fasudil-a-rho-kinase-inhibitor-after-spinal-cord-ischemia-and-reperfusion-in-rats
#6
Masahiko Ohbuchi, Tetsu Kimura, Toshiaki Nishikawa, Takashi Horiguchi, Masayuki Fukuda, Yoko Masaki
BACKGROUND: Excessive Rho/Rho-kinase pathway activation occurs subsequent to stroke. We examined the neuroprotective effects of pre- and posttreatment with fasudil (a Rho-kinase inhibitor) in a rat transient spinal cord ischemia-reperfusion model under normothermic conditions. METHODS: After approval by our animal research committee, male Sprague-Dawley rats were assigned to 1 of 6 groups: pre- and postcontrol (C); pre- and postfasudil (F); and pre- and postsham (S)...
November 1, 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/29070466/-rhoa-rho-kinase-contributes-to-chronic-pain-following-thoracotomy-by-up-regulating-glutaminase-1-expression-in-rat-spinal-dorsal-cord
#7
Zi-Yan Liu, Hai-Tang Wang, Jing Tang, Zai-Sheng Qin
OBJECTIVE: To investigate whether RhoA/Rho-kinase contributes to the occurrence of chronic post-thoracotomy pain (CPSP) by up regulation of glutaminase 1 (GLS1) expression in the spinal dorsal cord. METHODS: Twenty five male Sprague Dawley (SD) rats were divided into control group (n=5) and model group (n=20). The rats in the model group were randomized into two sub groups (n=10) for observation on day 10 and day 21 after thoracotomy, and each group was further divided into CPSP and non CPSP groups according to the behavioral test results...
October 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
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
#8
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/29055813/amyloid-%C3%AE-synaptotoxicity-is-wnt-pcp-dependent-and-blocked-by-fasudil
#9
Katherine J Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana I Rojo, Heledd H Jarosz-Griffiths, Iain A Watson, Weiming Xia, Mikhail Semenov, Peter Morin, Nigel M Hooper, Rod Porter, Jane Preston, Raya Al-Shawi, George Baillie, Simon Lovestone, Antonio Cuadrado, Michael Harte, Paul Simons, Deepak P Srivastava, Richard Killick
INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. METHODS: We compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway...
October 19, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/29051005/protective-effect-of-a-rho-kinase-inhibitor-on-bladder-dysfunction-in-a-rat-model-of-chronic-bladder-ischemia
#10
Hidenori Akaihata, Masanori Nomiya, Kanako Matsuoka, Tomoyuki Koguchi, Junya Hata, Nobuhiro Haga, Nobuhiro Kushida, Kei Ishibashi, Ken Aikawa, Yoshiyuki Kojima
OBJECTIVES: To investigate the effect of fasudil, a Rho-kinase inhibitor, on chronic ischemia-related bladder dysfunction. METHODS: Male Sprague-Dawley rats (16 weeks old) were divided into control, chronic bladder ischemia (CBI) and CBI with fasudil treatment (CBI/Fa) groups. The CBI and CBI/Fa groups underwent balloon endothelial injury of bilateral iliac arteries and received a 2% cholesterol diet for 8 weeks after the procedure to induce chronic bladder ischemia...
October 16, 2017: Urology
https://www.readbyqxmd.com/read/29048389/discovery-of-novel-n-substituted-prolinamido-indazoles-as-potent-rho-kinase-inhibitors-and-vasorelaxation-agents
#11
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/29033348/design-and-synthesis-of-benzimidazole-based-rho-kinase-inhibitors-for-the-treatment-of-glaucoma
#12
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/29029794/rho-kinase-inhibition-reverses-impaired-ca-2-handling-and-associated-left-ventricular-dysfunction-in-pressure-overload-induced-cardiac-hypertrophy
#13
Yusuf Olgar, Murat Cenk Celen, Bilge Eren Yamasan, Nihal Ozturk, Belma Turan, Semir Ozdemir
Recent studies have implicated a relationship between RhoA/ROCK activity and defective Ca(2+) homeostasis in hypertrophic hearts. This study investigated molecular mechanism underlying ROCK inhibition-mediated cardioprotection against pressure overload-induced cardiac hypertrophy, with a focus on Ca(2+) homeostasis. Cardiac hypertrophy model was established by performing transverse aortic constriction (TAC) in 8-week-old male rats. Groups were assigned as SHAM, TAC and TAC+Fas (rats undergoing TAC and treated with fasudil)...
November 2017: Cell Calcium
https://www.readbyqxmd.com/read/28993291/pak4-crystal-structures-suggest-unusual-kinase-conformational-movements
#14
Eric Y Zhang, Byung Hak Ha, Titus J Boggon
In order for protein kinases to exchange nucleotide they must open and close their catalytic cleft. These motions are associated with rotations of the N-lobe, predominantly around the 'hinge region'. We conducted an analysis of 28 crystal structures of the serine-threonine kinase, p21-activated kinase 4 (PAK4), including three newly determined structures in complex with staurosporine, FRAX486, and fasudil (HA-1077). We find an unusual motion between the N-lobe and C-lobe of PAK4 that manifests as a partial unwinding of helix αC...
October 7, 2017: Biochimica et Biophysica Acta
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
#15
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
https://www.readbyqxmd.com/read/28972449/targeting-rock-activity-to-disrupt-and-prime-pancreatic-cancer-for-chemotherapy
#16
Claire Vennin, Nicola Rath, Marina Pajic, Michael F Olson, Paul Timpson
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease; the identification of novel targets and development of effective treatment strategies are urgently needed to improve patient outcomes. Remodeling of the pancreatic stroma occurs during PDAC development, which drives disease progression and impairs responses to therapy. The actomyosin regulatory ROCK1 and ROCK2 kinases govern cell motility and contractility, and have been suggested to be potential targets for cancer therapy, particularly to reduce the metastatic spread of tumor cells...
October 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/28968596/resveratrol-inhibits-the-epidermal-growth-factor-induced-migration-of-osteoblasts-the-suppression-of-sapk-jnk-and-akt
#17
Tetsu Kawabata, Haruhiko Tokuda, Kazuhiko Fujita, Shingo Kainuma, Go Sakai, Rie Matsushima-Nishiwaki, Osamu Kozawa, Takanobu Otsuka
BACKGROUND/AIMS: Resveratrol is a polyphenol enriched in the skins of grapes and berries, that shows various beneficial effects for human health. In the present study, we investigated the mechanism behind the epidermal growth factor (EGF)-induced migration of osteoblast-like MC3T3-E1 cells, and the effect of resveratrol on this cell migration. METHODS: The cell migration was examined using Boyden chamber, and phosphorylation of each kinase was analyzed by Western blotting...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28963443/fasudil-alleviates-lps-induced-lung-injury-by-restoring-aquaporin-5-expression-and-inhibiting-inflammation-in-lungs
#18
Jing-Jing Wang, Hui Kong, Jian Xu, Yan-Li Wang, Hong Wang, Wei-Ping Xie
Fasudil, a selective rho kinase (ROCK) inhibitor, has been reported to play a beneficial role in systemic?inflammation?in acute?lung injury, but its mechanism for ameliorating pulmonary edema and inflammation remains unclear. Using hematoxylin-and-eosin (HE) staining, immunohistochemistry, enzyme-linked immunosorbent assay, quantitative real time PCR and Western blotting, we found that fasudil attenuated LPS-induced lung injury, decreased lung edema, and suppressed inflammatory responses including leukocyte infiltration and IL-6 production...
September 30, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28957641/a-screening-system-for-evaluating-cell-extension-formation-collagen-compaction-and-degradation-in-drug-discovery
#19
Asuka Yuda, Christopher A McCulloch
The generation of cell extensions is critical for matrix remodeling in tissue invasion by cancer cells, but current methods for identifying molecules that regulate cell extension formation and matrix remodeling are not well adapted for screening purposes. We applied a grid-supported, floating collagen gel system (~100 Pa stiffness) to examine cell extension formation, collagen compaction, and collagen degradation in a single assay. With the use of cultured diploid fibroblasts, a fibroblast cell line, and two cancer cell lines, we found that compared with attached collagen gels (~2800 Pa), the mean number and length of cell extensions were respectively greater in the floating gels...
September 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28929640/rho-kinase-inhibitor-fasudil-attenuates-contrast-induced-acute-kidney-injury
#20
Yiming Wang, Hao Zhang, Zhijian Yang, Dengshun Miao, Dingguo Zhang
In this study, we tested the hypothesis that fasudil, a Rho kinase inhibitor, would protect against contrast-induced acute kidney injury (CI-AKI) in a mouse model and attempted to elucidate the mechanism involved. Mice subjected to unilateral ligation of the left anterior renal pedicle were divided into four groups: (1) control group, (2) CI-AKI induced by contrast media (CM group), (3) CI-AKI plus low-dose fasudil (LD group) and (4) CI-AKI plus high-dose fasudil (HD group). Animals from groups 2-4 received iodixanol (4...
September 19, 2017: Basic & Clinical Pharmacology & Toxicology
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