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Profibrotic pathways

Uğur Canpolat
No abstract text is available yet for this article.
October 1, 2016: Clinics
Argyrios Tzouvelekis, Guoying Yu, Christian Lacks Lino Cardenas, Jose D Herazo-Maya, Rong Wang, Tony Woolard, Yi Zhang, Koji Sakamoto, Hojin Lee, Jae-Sung Yi, Giuseppe DeIuliis, Nikolaos Xylourgidis, Farida Ahangari, Patty J Lee, Vassilis Aidinis, Erica L Herzog, Robert Homer, Anton M Bennett, Naftali Kaminski
RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing-tyrosine phosphatase (SHP2) as a therapeutic target has not been studied in IPF Objectives: To determine the expression, mechanistic role and potential therapeutic utility of SHP2 in Pulmonary Fibrosis Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to pro-fibrotic stimuli were analyzed in-vitro in primary human and mouse lung fibroblasts...
October 13, 2016: American Journal of Respiratory and Critical Care Medicine
Steven T Haller, Yanling Yan, Christopher A Drummond, Joe Xie, Jiang Tian, David J Kennedy, Victoria Y Shilova, Zijian Xie, Jiang Liu, Christopher J Cooper, Deepak Malhotra, Joseph I Shapiro, Olga V Fedorova, Alexei Y Bagrov
BACKGROUND: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K-ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K-ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway...
September 30, 2016: Journal of the American Heart Association
Niloufar Kavian, Souad Mehlal, Wioleta Marut, Amélie Servettaz, Caroline Giessner, Christophe Bourges, Carole Nicco, Christiane Chéreau, Hervé Lemaréchal, Marie-Flore Dutilh, Olivier Cerles, Philippe Guilpain, Vincent Vuiblet, Sandrine Chouzenoux, Franck Galland, Isabelle Quere, Bernard Weill, Philippe Naquet, Frédéric Batteux
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting...
September 19, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S Waikar, Helmut Rennke, Benjamin D Humphreys, Joseph V Bonventre, Andreas Herrlich
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis...
August 18, 2016: JCI Insight
Nagla A El-Sherbeeny, Manar A Nader, Ghalia M Attia, Hayam Ateyya
Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates...
September 16, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Li-Juan Liu, Feng-Juan Yao, Gui-Hua Lu, Cheng-Gui Xu, Zhe Xu, Kai Tang, Yun-Jiu Cheng, Xiu-Ren Gao, Su-Hua Wu
OBJECTIVES: To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. METHODS AND RESULTS: A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks...
2016: PloS One
Sarah D Ahadome, Rose Mathew, Nancy J Reyes, Priyatham S Mettu, Scott W Cousins, Virginia L Calder, Daniel R Saban
Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b(+) DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis...
August 4, 2016: JCI Insight
Patricio Araos, David Mondaca, Jorge E Jalil, Cristián Yañez, Ulises Novoa, Italo Mora, María Paz Ocaranza
BACKGROUND: Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats...
September 1, 2016: Therapeutic Advances in Cardiovascular Disease
Joachim Alexandre, Eric Saloux, Mathieu Chequel, Stéphane Allouche, Pierre Ollitrault, Anne-Flore Plane, Damien Legallois, Marc-Olivier Fischer, Vladimir Saplacan, Dimitrios Buklas, Fabien Labombarda, Katrien Blanchart, Joe-Elie Salem, Marie Nowoczyn, Paolo-Emilio Puddu, Alain Manrique, Jean-Jacques Parienti, Paul Milliez
OBJECTIVE: Postoperative atrial fibrillation (POAF) is associated with poor outcomes after coronary artery bypass graft (CABG) surgery. We aimed to assess the additional value of preoperative plasma aldosterone levels, a biomarker promoting proarrhythmic and profibrotic pathways, for predicting POAF after CABG. METHODS: We conducted a prospective cohort study involving consecutive patients with left ventricular ejection fraction (LVEF) more than 50% requiring elective CABG in our university hospital...
August 31, 2016: Journal of Hypertension
A M Saracino, C P Denton, C H Orteu
A number of immunoinflammatory and profibrotic mechanisms are recognised in the pathogenesis of broad sclerotic skin processes, and more specifically, morphoea. However, precise aetiopathogenesis is complex and remains unclear. Morphoea is clinically heterogeneous, with variable anatomical patterning, depth of tissue involvement, and sclerotic, inflammatory, atrophic and dyspigmented morphology. Underlying mechanisms determining these reproducible clinical subsets are poorly understood, but of great clinical and therapeutic relevance...
August 24, 2016: British Journal of Dermatology
Shadi Salloum, Jacinta A Holmes, Rohit Jindal, Shyam S Bale, Cynthia Brisac, Nadia Alatrakchi, Anna Lidofsky, Annie J Kruger, Dahlene N Fusco, Jay Luther, Esperance A Schaefer, Wenyu Lin, Martin L Yarmush, Raymond T Chung
: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection accelerates progressive liver fibrosis; however, the mechanisms remain poorly understood. HCV and HIV independently induce profibrogenic markers transforming growth factor beta-1 (TGFβ1) (mediated by reactive oxygen species [ROS]) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in hepatocytes and hepatic stellate cells in monoculture; however, they do not account for cellular crosstalk that naturally occurs...
August 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Resat Cinar, Malliga R Iyer, Ziyi Liu, Zongxian Cao, Tony Jourdan, Katalin Erdelyi, Grzegorz Godlewski, Gergő Szanda, Jie Liu, Joshua K Park, Bani Mukhopadhyay, Avi Z Rosenberg, Jeih-San Liow, Robin G Lorenz, Pal Pacher, Robert B Innis, George Kunos
Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases...
July 21, 2016: JCI Insight
Giovanni Musso, Franco De Michieli, Daria Bongiovanni, Renato Parente, Luciana Framarin, Nicola Leone, Mara Berrutti, Roberto Gambino, Maurizio Cassader, Solomon Cohney, Elena Paschetta
Epidemiological data set an association between the prevalence and severity of NAFLD and the incidence and stage of chronic kidney disease(CKD); furthermore, NASH-related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver-kidney transplantation(SLKT) and a poorer renal outcome than cirrhosis of other etiologies even after SLKT. These data suggest NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are incompletely targeted by current treatments...
August 10, 2016: Clinical Gastroenterology and Hepatology
Patrick F Wilkinson, Francis X Farrell, Diane Morel, William Law, Suzanne Murphy
Interstitial renal fibrosis is a major pathophysiological manifestation of patients diagnosed with Chronic Kidney Disease (CKD), Diabetic Nephropathy (DN) and other inflammatory diseases. Adenosine signaling is an innate autocrine and paracrine cellular signaling pathway involving several key mediators that are elevated in the blood and kidneys of patients with DN. In these studies, we hypothesized that extracellular adenosine signals through one or more functional adenosine GPCRs on renal fibroblasts which increases profibrotic and proinflammatory mediators by inducing an activated fibroblast phenotype...
July 2016: Annals of Clinical and Laboratory Science
Yung-Chien Hsu, Pey-Jium Chang, Cheng Ho, Yu-Ting Huang, Ya-Hsueh Shih, Ching-Jen Wang, Chun-Liang Lin
Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/β-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/β-catenin signaling were concomitantly detected in glomeruli of streptozotocin-induced diabetic mice. Gain of miR-29a function in diabetic mice substantially increased the expression of β-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-β1 and fibronectin, in glomerular mesangium...
2016: Scientific Reports
Xiang Huang, Weicheng Wang, Huaqin Yuan, Jing Sun, Lele Li, Xingxin Wu, Jinhua Luo, Yanhong Gu
Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis...
2016: Tohoku Journal of Experimental Medicine
Tetsuhiro Tanaka
Renal fibrosis is characterized by tubular cell atrophy and accumulation of extracellular matrix. Fibroblast activation becomes evident in areas surrounding atrophic tubules, with rarefaction of peritubular capillaries. Tubulointerstitial hypoxia is the final common pathway in progressive kidney disease. Hypoxia suppresses tubular epithelial growth and leads to failure of remodeling by facilitating dedifferentiation and apoptosis. Profibrotic factors such as transforming growth factor-β (TGF-β) mediate fibroblast activation, and recruited leukocytes, which appear in hypoxic areas, contribute to fibrosis...
July 20, 2016: Medical Molecular Morphology
Moisés Selman, Carlos López-Otín, Annie Pardo
Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that IPF represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated...
August 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
X R Tian, X L Tian, H F Wang, Q Chang, R J Huo, D L Ying, G P Zheng
OBJECTIVE: To investigate the regulation effect of β-catenin pathway on transforming growth factor beta1 (TGF-β1) induced pulmonary pro-fibrosis. METHODS: The rat alveolar typeⅡ cells (RLE-6TN) were divided into four groups: A1.control group; B1.TGF-β1 group was treated with 5 μg/L TGF-β1; C1.pcDNA+ TGF-β1 group was transiently transfected with eukaryotic expression vector pcDNA3.0 (pcDNA) and followed by TGF-β1 treatment (5 μg/L); D1.F-(β-TrCP)-Ecad+ TGF-β1 group was transiently transfected with β-catenin protein knockout vector [F-(β-TrCP)-Ecad] and followed by TGF-β1 treatment (5 μg/L)...
June 28, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
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