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Lijun Du, John J Kim, Jinhua Shen, Ning Dai
The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn's disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability...
2016: Gastroenterology Research and Practice
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
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
Cody Kime, Masayo Sakaki-Yumoto, Leeanne Goodrich, Yohei Hayashi, Salma Sami, Rik Derynck, Michio Asahi, Barbara Panning, Shinya Yamanaka, Kiichiro Tomoda
Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion...
October 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zhijun Sun, Xing Wu, Weiping Li, Hui Peng, Xuhua Shen, Lu Ma, Huirong Liu, Hongwei Li
BACKGROUND: Diabetes-induced vascular dysfunction may arise from reduced nitric oxide (NO) availability, following interaction with superoxide to form peroxynitrite. Peroxynitrite can induce formation of 3-nitrotyrosine-modified proteins. RhoA/ROCK signaling is also involved in diabetes-induced vascular dysfunction. The study aimed to investigate possible links between Rho/ROCK signaling, hyperglycemia, and peroxynitrite in small coronary arteries. METHODS: Rat small coronary arteries were exposed to normal (NG; 5...
October 11, 2016: BMC Cardiovascular Disorders
David R Myers, Yongzhi Qiu, Meredith E Fay, Michael Tennenbaum, Daniel Chester, Jonas Cuadrado, Yumiko Sakurai, Jong Baek, Reginald Tran, Jordan C Ciciliano, Byungwook Ahn, Robert G Mannino, Silvia T Bunting, Carolyn Bennett, Michael Briones, Alberto Fernandez-Nieves, Michael L Smith, Ashley C Brown, Todd Sulchek, Wilbur A Lam
Haemostasis occurs at sites of vascular injury, where flowing blood forms a clot, a dynamic and heterogeneous fibrin-based biomaterial. Paramount in the clot's capability to stem haemorrhage are its changing mechanical properties, the major drivers of which are the contractile forces exerted by platelets against the fibrin scaffold. However, how platelets transduce microenvironmental cues to mediate contraction and alter clot mechanics is unknown. This is clinically relevant, as overly softened and stiffened clots are associated with bleeding and thrombotic disorders...
October 10, 2016: Nature Materials
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
Beatriz Galan-Rodriguez, Elodie Martin, Emmanuel Brouillet, Nicole Déglon, Sandrine Betuing, Jocelyne Caboche
Huntington's Disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin -mediated toxicity...
September 26, 2016: European Journal of Neuroscience
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
Wen-Tao Gai, Da-Peng Yu, Xin-Sheng Wang, Pei-Tao Wang
Ursolic acid is a type of pentacyclic triterpene compound with multiple pharmacological activities including cancer resistance, protection from liver injury, antisepsis, anti-inflammation and antiviral activity. The present study aimed to investigate the anticancer effect of ursolic acid. Ursolic acid activates cell apoptosis and its pro-apoptotic mechanism remains to be fully elucidated. Cell Counting kit-8 assays, flow cytometric analysis and analysis of caspase-3 and caspase-9 activity were used to estimate the anticancer effect of ursolic acid on DU145 prostate cancer cells...
October 2016: Oncology Letters
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
Ryoko Tsukahara, Hiroshi Ueda
Lysophosphatidic acid (LPA) initiates demyelination following peripheral nerve injury, which causes neuropathic pain. Our previous in vivo and ex vivo studies using mice have demonstrated that LPA-induced demyelination of spinal dorsal roots is attributed by the LPA1-type receptor-mediated down-regulation of myelin-related molecules, such as MBP and MPZ. In this study using S16 mature-type Schwann cells, we found that LPA-induced down-regulation of myelin-related genes is attributed by the activation of LPA1 receptor, Rho kinase, and p300, leading to an acetylation of NFκB, which down-regulates the transcription of Sox10, MBP and MPZ genes...
September 12, 2016: Journal of Pharmacological Sciences
Martin A Bewley, Kylie B R Belchamber, Kirandeep K Chana, Richard C Budd, Gavin Donaldson, Jadwiga A Wedzicha, Christopher E Brightling, Iain Kilty, Louise E Donnelly, Peter J Barnes, Dave Singh, Moira K B Whyte, David H Dockrell
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects...
2016: PloS One
Sarah T Hsiao, Tim Spencer, Luke Boldock, Svenja Dannewitz Prosseda, Ioannis Xanthis, Francesco J Tovar-Lopez, Heleen van Buesekamp, Ramzi Y Khamis, Nicolas Foin, Neil Bowden, Adil Hussain, Alex Rothman, Victoria Ridger, Ian Halliday, Cecile Perrault, Julian Gunn, Paul C Evans
AIMS: Stent deployment causes endothelial cell (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow pertubation on EC injury and repair are incompletely understood. By studying the effects of stent struts on flow and EC migration we identified an intervention that promotes endothelial repair in stented arteries. METHODS AND RESULTS: In vitro and in vivo models were developed to monitor endothelialization under flow and the influence of stent struts...
September 26, 2016: Cardiovascular Research
S R Frank, C P Köllmann, J F van Lidth de Jeude, J R Thiagarajah, L H Engelholm, M Frödin, S H Hansen
DOCK proteins are guanine nucleotide exchange factors for Rac and Cdc42 GTPases. DOCK1 is the founding member of the family and acts downstream of integrins via the canonical Crk-p130Cas complex to activate Rac GTPases in numerous contexts. In contrast, DOCK5, which possesses the greatest similarity to DOCK1, remains sparingly studied. Here we establish that DOCK5 has a non-redundant role in regulating motile and invasive capacities of epithelial cells. DOCK1 is constitutively associated with sites of integrin attachment termed focal adhesions (FAs)...
September 26, 2016: Oncogene
Shugang Xu, Xing Guo, Xiao Gao, Hao Xue, Jinsen Zhang, Xiaofan Guo, Wei Qiu, Ping Zhang, Gang Li
Macrophage migration inhibitory factor (MIF) is highly expressed in glioblastoma, promoting malignant progression and suppresses immune surveillance. However, the mechanism underlying its biological roles in human glioblastoma and the capability of MIF to escape dendritic cell (DC) surveillance remain poorly understood. In the present study, we found that recombinant human MIF (rhMIF) activated the RhoA‑ROCK1 pathway and simultaneously upregulated F‑actin fibre formation. Additionally, we showed that rhMIF increased autophagy in glioblastoma cells, and knockdown of endogenic MIF suppressed autophagy...
September 23, 2016: International Journal of Oncology
Tingting Qin, Fang Fang, Meiting Song, Ruipeng Li, Zhanqiang Ma, Shiping Ma
There is increasing evidence that major depressive disorder (MDD) is also a progressive neurodegeneration disorder and neuronal damage is the major pathology of MDD. Umbelliferone, a coumarin derivative, was found in a range of plants with proved anti-oxidative, anti-inflammatory and neuroprotective effects. The primary purpose of this investigation was to evaluate whether umbelliferone could confer an antidepressant-like effect on the depressive model in rats developed by chronic unpredictable mild stress (CUMS) and explore the possible mechanism involved in its neuroprotective effects...
September 16, 2016: Behavioural Brain Research
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