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Rock inhibitor

Katharina Grundler, Raffaela Rotter, Sloane Tilley, Joachim Pircher, Thomas Czermak, Mustaf Yakac, Erik Gaitzsch, Steffen Massberg, Florian Krötz, Hae-Young Sohn, Ulrich Pohl, Hanna Mannell, Bjoern F Kraemer
INTRODUCTION: Platelets possess critical hemostatic functions in the system of thrombosis and hemostasis, which can be affected by a multitude of external factors. Previous research has shown that platelets have the capacity to synthesize proteins de novo and more recently a multicatalytic protein complex, the proteasome, has been discovered in platelets. Due to its vital function for cellular integrity, the proteasome has become a therapeutic target for anti-proliferative drug therapies in cancer...
October 13, 2016: Thrombosis Research
Pieter Uvin, Maarten Albersen, Ine Bollen, Maarten Falter, Emmanuel Weyne, Loes Linsen, Hanna Tinel, Peter Sandner, Trinity J Bivalacqua, Dirk Jmk De Ridder, Frank Van der Aa, Bert Brône, Koenraad Van Renterghem
OBJECTIVES: To evaluate the expression of the Rho/Rho associated protein kinase (ROCK) pathway in corpus cavernosum of patients with severe erectile dysfunction (ED) compared to healthy human corpus cavernosum, and to test the functional effects of two Rho Kinase Inhibitors (RKI) on erectile tissue of patients with severe ED, not responding to phosphodiesterase type 5 inhibitors (PDE5-i). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from individuals undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for qPCR)...
October 20, 2016: BJU International
Anup Arumughan, Yvette Roske, Carolin Barth, Laura Lleras Forero, Kenny Bravo-Rodriguez, Alexandra Redel, Simona Kostova, Erik McShane, Robert Opitz, Katja Faelber, Kirstin Rau, Thorsten Mielke, Oliver Daumke, Matthias Selbach, Elsa Sanchez-Garcia, Oliver Rocks, Daniela Panáková, Udo Heinemann, Erich E Wanker
Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers...
October 20, 2016: Nature Communications
Jason Gien, Nancy Tseng, Gregory J Seedorf, Katherine Kuhn, Steven H Abman
Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through rho-kinase (ROCK) activation, ET-1 impairs endothelial cell function, however, whether ET-1-ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intra-peritoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, non-selective ET receptor blocker (ETRB) (bosentan) or fasudil (ROCK inhibitor)...
October 19, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Anping Cai, Yingqing Feng, Yingling Zhou, Jiyan Chen
OBJECTIVE: To investigate the effects and mechanisms of levorotatory (L)-amlodipine combined fluvastatin treatment on endothelium-mesenchymal transition (EndMT), a process related to hypertension development. DESIGN AND METHOD: Human umbilical vein endothelial cells (HUVECs) were used and divided to six groups based on different therapeutic strategies as follows: Blank Control, angiotensin-II (Ang-II), Ang-II+ rho-associated kinase (ROCK) inhibitor, Ang-II+ L-amlodipine, Ang-II+ fluvastatin, and Ang-II +L-amlodipine + fluvastatin groups...
September 2016: Journal of Hypertension
Nadia Soudani, Crystal M Ghantous, Zein Farhat, Wassim N Shebaby, Kazem Zibara, Asad Zeidan
Background and Aims: Hypertension and obesity are important risk factors of cardiovascular disease. They are both associated with high leptin levels and have been shown to promote vascular hypertrophy, through the RhoA/ROCK and ERK1/2 phosphorylation. Calcineurin/NFAT activation also induces vascular hypertrophy by upregulating various genes. This study aimed to decipher whether a crosstalk exists between the RhoA/ROCK pathway, Ca(2+)/calcineurin/NFAT pathway, and ERK1/2 phosphorylation in the process of mechanical stretch-induced vascular smooth muscle cell (VSMC) hypertrophy and leptin synthesis...
2016: Frontiers in Physiology
Donna N Petersen, Julie Hawkins, Wanida Ruangsiriluk, Kimberly A Stevens, Bruce A Maguire, Thomas N O'Connell, Benjamin N Rocke, Markus Boehm, Roger B Ruggeri, Tim Rolph, David Hepworth, Paula M Loria, Philip A Carpino
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin...
October 13, 2016: Cell Chemical Biology
Xinjian Mao, Zhe Chen, Qing Luo, Bingyu Zhang, Guanbin Song
Exposure to microgravity during space flight affects almost all human physiological systems. Migration, proliferation, and differentiation of stem cells are crucial for tissues repair and regeneration. However, the effect of microgravity on the migration potentials of bone marrow mesenchymal stem cells (BMSCs) is unclear, which are important progenitor and supporting cells. Here, we utilized a clinostat to model simulated microgravity (SMG) and found that SMG obviously inhibited migration of rat BMSCs. We detected significant reorganization of F-actin filaments and increased Young's modulus of BMSCs after exposure to SMG...
October 15, 2016: Cytotechnology
Thomas Broggini, Lisa Schnell, Ali Ghoochani, José María Mateos, Michael Buchfelder, Kurt Wiendieck, Michael K Schäfer, Ilker Y Eyupoglu, Nicolai E Savaskan
The Plasticity Related Gene family covers five, brain-specific, transmembrane proteins (PRG1-5, also termed LPPR1-5) that operate in neuronal plasticity during development, aging and brain trauma. Here we investigated the role of the PRG family on axonal and filopodia outgrowth. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons...
October 15, 2016: Aging
Priscila de Souza, Karla Lorena Guarido, Karin Scheschowitsch, Luísa Mota da Silva, Maria Fernanda Werner, Jamil Assreuy, José Eduardo da Silva-Santos
We investigated long-lasting changes in endothelial and vascular function in adult rat survivors of severe sepsis induced by cecal ligation and puncture (CLP) model. For this, male Wistar rats (200-350g) had their cecum punctured once (non-transfixing hole) with a 14-gauge needle. Performed in this way, a mortality rate around 30% was achieved in the first 72h. The survivors, together with age-matched control rats (not subjected to CLP), were maintained in our holding room for 60 days (S60 group) and had the descending thoracic aorta processed for functional, histological, biochemical or molecular analyses...
September 30, 2016: Redox Biology
Shaofeng Yan, Hao Xue, Ping Zhang, Xiao Han, Xing Guo, Guang Yuan, Lin Deng, Gang Li
Matrix metalloproteinases (MMPs) play the important role in the process of glioblastoma cell invasion through 3D matrices. However, the effects of MMP inhibitors used in the treatment of malignant gliomas are unsatisfactory. The aim of this study was to explore the reason and mechanism by which cells move through the dense extracellular matrix without proteolysis. The results showed that MMP inhibitor (MMPI), Ilomastat, induced glioma cells to have an amoeboid-like morphology with invasive ability. Moreover, the RhoA/Rho kinase (ROCK)/myosin light chain (MLC) signal is involved in the MMPI-induced movement mode switch, and RhoA activation is dependent on P115RhoGEF...
October 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Jiangwei Yao, Megan E Ericson, Matthew W Frank, Charles O Rock
Enoyl-acyl carrier protein reductase catalyzes the last step in each elongation cycle of type II bacterial fatty acid synthesis and is a key regulatory protein in bacterial fatty acid synthesis. The facultative intracellular pathogen Listeria monocytogenes encodes two functional enoyl-ACP isoforms based on their ability to complement the temperature-sensitive growth phenotype of E. coli strain JP1111 (fabI(Ts)). The FabI isoform was inactivated by the FabI selective inhibitor AFN-1252, but the FabK isoform was not affected by the drug as expected...
October 10, 2016: Infection and Immunity
Michael J Susienka, Benjamin T Wilks, Jeffrey R Morgan
Tissue fusion, whereby two or more spheroids coalesce, is a process that is fundamental to biofabrication. We have designed a quantitative, high-throughput platform to investigate the fusion of multicellular spheroids using agarose micro-molds. Spheroids of primary human chondrocytes (HCH) or human breast cancer cells (MCF-7) were self-assembled for 24 h and then brought together to form an array comprised of two spheroids (one doublet) per well. To quantify spheroid fusogenicity, we developed two assays: (1) an initial tack assay, defined as the minimum amount of time for two spheroids to form a mechanically stable tissue complex or doublet, and (2) a fusion assay, in which we defined and tracked key morphological parameters of the doublets as a function of time using wide-field fluorescence microscopy over a 24 h time-lapse...
October 10, 2016: Biofabrication
Yiyuan Duan, Jiaoyue Long, Jun Chen, Xuemei Jiang, Jian Zhu, Yang Jin, Feng Lin, Jun Zhong, Rong Xu, Lizheng Mao, Linhong Deng
A disintegrin and metalloproteinase 33 (ADAM33) has been identified as a susceptibility gene for asthma, but details of the causality are not fully understood. we hypothesize that soluble ADAM33 (sADAM33) overexpression can alter the mechanical behaviors of airway smooth muscle cells (ASMCs) via regulation of the cell's contractile phenotype, and thus contributes to airway hyperresponsiveness (AHR) in asthma. To test this hypothesis, we either overexpressed or knocked down the sADAM33 level in rat ASMCs by transfecting the cells with sADAM33 or a small interfering RNA (siRNA) that specifically targets the ADAM33 disintegrin domain, and subsequently assessed the cells for stiffness, contractility and traction force, together with the expression level of contractile and proliferative phenotype markers...
October 5, 2016: Experimental Cell Research
Rebecca L Eccles, Maciej T Czajkowski, Carolin Barth, Paul Markus Müller, Erik McShane, Stephan Grunwald, Patrick Beaudette, Nora Mecklenburg, Rudolf Volkmer, Kerstin Zühlke, Gunnar Dittmar, Matthias Selbach, Annette Hammes, Oliver Daumke, Enno Klussmann, Sylvie Urbé, Oliver Rocks
Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors...
October 7, 2016: Nature Communications
Anna Korol, Aftab Taiyab, Judith A West-Mays
Transforming growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) leads to the formation of ocular fibrotic pathologies, such as anterior subcapsular cataract and posterior capsule opacification. Remodeling of the actin cytoskeleton, mediated by the Rho family of GTPases, plays a key role in EMT, however, how actin dynamics affect downstream markers of EMT has not been fully determined. Our previous work suggests that myocardin related transcription factor A (MRTF-A), an actin-binding protein, might be an important mediator of TGFβ-induced EMT in lens epithelial cells...
September 29, 2016: Molecular Medicine
Krishnakumar Kizhatil, Arthur Chlebowski, Nicholas G Tolman, Nelson F Freeburg, Margaret M Ryan, Nicholas N Shaw, Alexander D M Kokini, Jeffrey K Marchant, Simon W M John
Purpose: The molecular mechanisms controlling aqueous humor (AQH) outflow and IOP need much further definition. The mouse is a powerful system for characterizing the mechanistic basis of AQH outflow. To enhance outflow studies in mice, we developed a perfusion system that is based on human anterior chamber perfusion culture systems. Our mouse system permits previously impractical experiments. Methods: We engineered a computer-controlled, pump-based perfusion system with a platform for mounting whole dissected mouse eyes (minus lens and iris, ∼45% of drainage tissue is perfused)...
October 1, 2016: Investigative Ophthalmology & Visual Science
Diana Santander-García, Maria Cristina Ortega, Silvia Benito-Martínez, Susana Barroso, Ignacio Jiménez-Alfaro, Jaime Millán
Correct corneal endothelial barrier function is essential for maintaining corneal transparency. However, research on cell signaling pathways mediating corneal endothelial barrier dysfunction has progressed more slowly than that involving other cellular barriers because of the lack of human corneal endothelial cell models. Here we have optimized the culture of the human corneal endothelial cell (HCEC) line B4G12 as a model for studying paracellular permeability. We show that B4G12-HCECs form confluent monolayers with stable cell-cell junctions when cultured on plastic, but not glass, surfaces precoated with various extracellular matrix components...
September 30, 2016: Experimental Eye Research
Mathew J Wong, Crystal Kantores, Julijana Ivanovska, Amish Jain, Robert P Jankov
Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity...
September 30, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Xueer Wang, Pei Tang, Fukun Guo, Min Zhang, Yinghua Chen, Yuan Yan, Zhihui Tian, Pengcheng Xu, Lei Zhang, Lu Zhang, Lin Zhang
BACKGROUND: In our previous study, Activin B induced actin stress fiber formation and cell migration in Bone marrow-derived mesenchymal stem cells (BMSCs) in vitro. However, the underlying molecular mechanisms are not well studied. RhoA is recognized to play a critical role in the regulation of actomyosin cytoskeletal organization and cell migration. METHODS: Pull-down assay was performed to investigate the activity of RhoA. The dominant-negative mutants of RhoA (RhoA(N19)) was used to determine whether RhoA has a role in Activin B-induced cytoskeleton organization and cell migration in BMSCs...
September 28, 2016: Biochimica et Biophysica Acta
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