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https://www.readbyqxmd.com/read/29337194/fasudil-ameliorates-the-ischemia-reperfusion-oxidative-injury-in-rat-hearts-through-suppression-of-myosin-regulatory-light-chain-nadph-oxidase-2-pathway
#1
Yi-Shuai Zhang, Li-Jing Tang, Hua Tu, Shi-Jing Wang, Bin Liu, Xiao-Jie Zhang, Nian-Sheng Li, Xiu-Ju Luo, Jun Peng
Fasudil is a potent Rho-kinase (ROCK) inhibitor and can relax smooth muscle or cardiac muscle contraction through decreasing the phosphorylation level of myosin regulatory light chain (p-MLC20 or p-MLC2v), while p-MLC2v can function as a transcription factor to promote the NADPH oxidase 2 (NOX2) expression in rat hearts subjected to ischemia/reperfusion (I/R). This study aims to explore whether fasudil can protect the rat hearts against I/R oxidative injury through suppressing NOX2 expression via reduction of p-MLC2v level...
January 11, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29336470/tnf-%C3%AE-induces-drp1-mediated-mitochondrial-fragmentation-during-inflammatory-cardiomyocyte-injury
#2
Yue-Liang Shen, Ying-Zhou Shi, Gai-Ge Chen, Lin-Lin Wang, Ming-Zhi Zheng, Hong-Feng Jin, Ying-Ying Chen
Dynamin-related peptide 1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes...
January 15, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29314498/design-of-aminobenzothiazole-inhibitors-of-rho-kinases-1-and-2-utilizing-pka-as-a-structure-surrogate
#3
Russell Judge, Victoria Scott, Gricelda Simler, Steve Pratt, Marian Namovic, Brent Putman, Ana Aguirre, Vincent Stoll, Mulugeta Mamo, Steve Swann, Adrian D Hobson
We describe the design, synthesis and SAR of a series of 2-aminobenzothiazole inhibitors of Rho Kinase (ROCK) 1 and 2 which were optimized to low nanomolar potencies using structure-based design. Protein Kinase A was used as a surrogate protein structure to guide compound design. A subset of these molecules also showed robust activity in a myosin phosphatase cell based assay and in a mechanical hyperalgesia in vivo pain model.
January 4, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29310804/the-cytoskeletal-network-regulates-expression-of-the-profibrotic-genes-pai-1-and-ctgf-in-vascular-smooth-muscle-cells
#4
Rohan Samarakoon, Paul J Higgins
Vascular smooth muscle cells (VSMCs) are subject to changing hemodynamic stimuli that alter cytoskeletal dynamics, cellular architecture, and structure-associated signal transduction. Tensional stress, force application, and structural perturbations are sensed by VSMCs and impact the physiological as well as pathophysiological responses of the vasculature. Microtubule-targeting drugs provide useful tools to analyze cytoskeletal-associated signaling pathways and their linkages to pathological outcomes. Architecture-based controls on a subset of profibrotic genes commonly expressed in vascular disease are highlighted by their frequent induction in mechanically manipulated cells and with associated changes in cytoskeletal dynamics...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29306925/calcium-sensitization-mechanisms-in-detrusor-smooth-muscles
#5
REVIEW
Irfan Anjum
The contraction of detrusor smooth muscles depends on the increase in intracellular calcium. The influx of calcium from the plasma membrane calcium channels and calcium release from the sarcoplasmic reticulum give rise to intracellular calcium. Under the pathophysiological conditions, the increased sensitivity of regulatory and contractile proteins to calcium also plays an important role in maintaining the spontaneous detrusor smooth muscle activity. Many proteins have been identified to play a role in calcium sensitization...
January 8, 2018: Journal of Basic and Clinical Physiology and Pharmacology
https://www.readbyqxmd.com/read/29288243/rho-rock-pathway-regulates-migration-and-invasion-of-esophageal-squamous-cell-carcinoma-by-regulating-caveolin-1
#6
Zhaohui Liu, Jing Yu, Ruinuan Wu, Shengxin Tang, Xiaoman Cai, Guanghua Guo, Suzuan Chen
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. Caveolin-1 (Cav1) and Rho/ROCK pathway play important roles in tumor metastasis, separately. However, less research was focused on the relationship between Cav1 and Rho/ROCK in ECSS metastasis. Therefore, we investigated the relationship between Cav1 and Rho/ROCK pathway in ESCC metastasis. MATERIAL AND METHODS Cav1 and phosphorylated Cav1 (PY14Cav1) were examined in ESCC and in adjacent and non-tumorous tissues from ESCC patients by immunohistochemistry (IHC)...
December 30, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29280033/a-combined-fisher-and-laplacian-score-for-feature-selection-in-qsar-based-drug-design-using-compounds-with-known-and-unknown-activities
#7
Mohammad Amin Valizade Hasanloei, Razieh Sheikhpour, Mehdi Agha Sarram, Elnaz Sheikhpour, Hamdollah Sharifi
Quantitative structure-activity relationship (QSAR) is an effective computational technique for drug design that relates the chemical structures of compounds to their biological activities. Feature selection is an important step in QSAR based drug design to select the most relevant descriptors. One of the most popular feature selection methods for classification problems is Fisher score which aim is to minimize the within-class distance and maximize the between-class distance. In this study, the properties of Fisher criterion were extended for QSAR models to define the new distance metrics based on the continuous activity values of compounds with known activities...
December 26, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29277889/rhoa-stimulated-intra-capillary-morphology-switch-facilitates-the-arrest-of-individual-circulating-tumor-cells
#8
Xi Huang, Yu Yang, Yuwei Zhao, Cao Dan, Xiaolin Ai, Anqi Zeng, Maling Gou, Lulu Cai, Hanshuo Yang, Chengjian Zhao
Metastasis is the primary cause of death for most cancer patients. Hematogenous arrest of circulating tumor cells (CTCs) is an essential prerequisite for metastases formation. Using transparent transgenic zebrafish (kdrl:eGFP; Casper), together with resonant laser scanning confocal microscopy, we tracked the fate of CTCs in vivo in the blood circulation for days. We found the intra-capillary morphology-switch (ICMS) of individual CTCs from strip to sphere was necessary for their intravascular arrests. Further genetic and pharmacological inhibition experiments indicated that the RhoA signaling was necessary for ICMS and the arrest of CTCs...
December 26, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29259896/involvement-of-rho-associated-coiled-coil-kinase-signaling-inhibition-in-tgf-%C3%AE-1-smad2-3-signal-transduction-in-vitro
#9
Zhao-Hui Feng, Xiao-Hui Zhang, Jia-Qi Zhao, Jun-Ze Ma
AIM: To research the effect of Y-27632, a selective Rho-associated coiled-coil kinase (ROCK) inhibitor, on TGF-β1/Smad2, 3 signal transduction in ocular Tenon's capsule fibroblasts (OTFs). METHODS: Primary ocular Tenon's capsule fibroblasts had been cultured in vitro. The effect of Y27632 on proliferation of OTF stimulated by lysophosphatidic acid (LPA) was evaluated by MTT colorimetric assay so as to sift out the proper concentrations range of Y-27632 for the next experiment...
2017: International Journal of Ophthalmology
https://www.readbyqxmd.com/read/29246246/rho-gtpases-as-therapeutic-targets-in-alzheimer-s-disease
#10
REVIEW
Byron J Aguilar, Yi Zhu, Qun Lu
The progress we have made in understanding Alzheimer's disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD...
December 15, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29226331/a-novel-pathway-activated-by-somatostatin-receptor-type-2-sst2-inhibition-of-pituitary-tumor-cell-migration-and-invasion-through-cytoskeleton-protein-recruitment
#11
E Peverelli, E Giardino, D Treppiedi, R Catalano, F Mangili, M Locatelli, A G Lania, M Arosio, A Spada, G Mantovani
The pharmacological therapy of GH-secreting pituitary tumors is based on somatostatin (SS) analogs that reduce GH secretion and cell proliferation by binding mainly SS receptors type 2 (SST2). Antimigratory effects of SS have been demonstrated in different cell models, but no data on pituitary tumors are available. Aims of our study were to evaluate SST2 effects on migration and invasion of human and rat tumoral somatotrophs, and to elucidate the molecular mechanism involved focusing on the role of cofilin and filamin A (FLNA)...
December 11, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29220720/induction-of-thymic-stromal-lymphopoietin-by-a-steroid-alkaloid-derivative-in-mouse-keratinocytes
#12
Yan Weng, Natsumi Mizuno, Jiangxu Dong, Ryosuke Segawa, Takayuki Yonezawa, Byung Yoon Cha, Je-Tae Woo, Takahiro Moriya, Masahiro Hiratsuka, Noriyasu Hirasawa
Thymic stromal lymphopoietin (TSLP) plays critical roles in inducing and exacerbating allergic diseases. Chemical compounds that induce TSLP production can enhance sensitization to antigens and exacerbate allergic inflammation. Hence, identifying such chemicals will be important to prevent an increase in allergic diseases. In the present study, we found, for the first time, that a steroid alkaloid derivative, code no. 02F04, concentration and time dependently induced mRNA expression and production of TSLP in a mouse keratinocyte cell line, PAM212...
December 5, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29211497/the-rho-kinase-isoforms-rock1-and-rock2-each-contribute-to-the-development-of-experimental-pulmonary-fibrosis
#13
Rachel S Knipe, Clemens K Probst, David Lagares, Alicia Franklin, Jillian J Spinney, Patricia L Brazee, Paula Grasberger, Linlin Zhang, Katharine E Black, Norihiko Sakai, Barry S Shea, James K Liao, Benjamin D Medoff, Andrew M Tager
Pulmonary fibrosis is thought to result from dysregulated wound repair after repetitive lung injury. Many cellular responses to injury involve rearrangements of the actin cytoskeleton mediated by the two isoforms of the Rho-associated coiled coil forming protein kinase, ROCK1 and ROCK2. Additionally, profibrotic mediators such as transforming growth factor-beta (TGF-β), thrombin and lysophosphatidic acid (LPA) act through receptors that activate ROCK. Inhibition of ROCK activation may be a potent therapeutic strategy for human pulmonary fibrosis...
December 6, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29201898/small-molecule-supplements-improve-cultured-megakaryocyte-polyploidization-by-modulating-multiple-cell-cycle-regulators
#14
Xiaojing Zou, Mingyi Qu, Fang Fang, Zeng Fan, Lin Chen, Wen Yue, Xiaoyan Xie, Xuetao Pei
Platelets (PLTs) are produced by megakaryocytes (MKs) that completed differentiation and endomitosis. Endomitosis is an important process in which the cell replicates its DNA without cytokinesis and develops highly polyploid MK. In this study, to gain a better PLTs production, four small molecules (Rho-Rock inhibitor (RRI), nicotinamide (NIC), Src inhibitor (SI), and Aurora B inhibitor (ABI)) and their combinations were surveyed as MK culture supplements for promoting polyploidization. Three leukemia cell lines as well as primary mononuclear cells were chosen in the function and mechanism studies of the small molecules...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29201057/crosstalk-between-substrates-and-rho-associated-kinase-inhibitors-in-cryopreservation-of-tissue-engineered-constructs
#15
REVIEW
Arindam Bit, Awanish Kumar, Abhishek Kumar Singh, Albert A Rizvanov, Andrey P Kiassov, Pradeep Kumar Patra, Munish Kumar, Akalabya Bissoyi
It is documented that human mesenchymal stem cells (hMSCs) can be differentiated into various types of cells to present a tool for tissue engineering and regenerative medicine. Thus, the preservation of stem cells is a crucial factor for their effective long-term storage that further facilitates their continuous supply and transportation for application in regenerative medicine. Cryopreservation is the most important, practicable, and the only established mechanism for long-term preservation of cells, tissues, and organs, and engineered tissues; thus, it is the key step for the improvement of tissue engineering...
2017: Stem Cells International
https://www.readbyqxmd.com/read/29199510/regulation-of-rhoa-gtpase-and-novel-target-proteins-for-rock
#16
Eun-Kyoung Choi, Jae-Gyu Kim, Hee-Jun Kim, Jung-Yoon Cho, Hwalrim Jeong, Yohan Park, Rokibul Islam, Cuong Kim Cap, Jae-Bong Park
Rho GTPases play significant roles in cellular function and their activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), providing activation and inactivation of these GTPases, respectively. Active GTP-bound form of RhoA activates its effector proteins while the inactive GDP-bound form of RhoA exists in a RhoA-RhoGDI (guanine nucleotide dissociation inhibitor) complex in the cytosol. In particular, IκB kinase γ IKKγ/NF-κB essential modulator (NEMO) plays a role as a GDI displacement factor (GDF) for RhoA activation through binding to RhoA-RhoGDI complex...
December 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/29198469/novel-small-molecule-inhibitors-of-protein-kinase%C3%A2-c-epsilon-reduce-ethanol-consumption-in%C3%A2-mice
#17
Angelo Blasio, Jingyi Wang, Dan Wang, Florence P Varodayan, Matthew B Pomrenze, Jacklyn Miller, Anna M Lee, Thomas McMahon, Sandeep Gyawali, Hua-Yu Wang, Marisa Roberto, Stanton McHardy, Michael A Pleiss, Robert O Messing
BACKGROUND: Despite the high cost and widespread prevalence of alcohol use disorders, treatment options are limited, underscoring the need for new, effective medications. Previous results using protein kinase C epsilon (PKCε) knockout mice, RNA interference against PKCε, and peptide inhibitors of PKCε predict that small-molecule inhibitors of PKCε should reduce alcohol consumption in humans. METHODS: We designed a new class of PKCε inhibitors based on the Rho-associated protein kinase (ROCK) inhibitor Y-27632...
December 1, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29190494/fus-chop-promotes-invasion-in-myxoid-liposarcoma-through-a-src-fak-rho-rock-dependent-pathway
#18
Juan Tornin, Francisco Hermida-Prado, Ranjit Singh Padda, M Victoria Gonzalez, Carlos Alvarez-Fernandez, Veronica Rey, Lucia Martinez-Cruzado, Oscar Estupiñan, Sofia T Menendez, Lucia Fernandez-Nevado, Aurora Astudillo, Juan P Rodrigo, Fabrice Lucien, Yohan Kim, Hon S Leong, Juana Maria Garcia-Pedrero, Rene Rodriguez
Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches...
November 27, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29184140/induced-cortical-tension-restores-functional-junctions-in-adhesion-defective-carcinoma-cells
#19
Shoko Ito, Satoru Okuda, Masako Abe, Mari Fujimoto, Tetsuo Onuki, Tamako Nishimura, Masatoshi Takeichi
Normal epithelial cells are stably connected to each other via the apical junctional complex (AJC). AJCs, however, tend to be disrupted during tumor progression, and this process is implicated in cancer dissemination. Here, using colon carcinoma cells that fail to form AJCs, we investigated molecular defects behind this failure through a search for chemical compounds that could restore AJCs, and found that microtubule-polymerization inhibitors (MTIs) were effective. MTIs activated GEF-H1/RhoA signaling, causing actomyosin contraction at the apical cortex...
November 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/29169155/rho-kinase-regulates-aortic-vascular-smooth-muscle-cell-stiffness-via-actin-srf-myocardin-in-hypertension
#20
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
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