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Profibrotic pathway

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https://www.readbyqxmd.com/read/28294324/blocking-fibrotic-signaling-in-fibroblasts-from-patients-with-carpal-tunnel-syndrome
#1
REVIEW
Yoshiaki Yamanaka, Anne Gingery, Gosuke Oki, Tai-Hua Yang, Chunfeng Zhao, Peter C Amadio
Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor β1 (TGF-β1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF-β receptor type 1 (TβRI), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) or vascular endothelial growth factor receptor (VEGFR)...
March 10, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28284377/treatment-of-renal-fibrosis-turning-challenges-into-opportunities
#2
REVIEW
Barbara M Klinkhammer, Roel Goldschmeding, Jürgen Floege, Peter Boor
Current treatment modalities are not effective in halting the progression of most CKD. Renal fibrosis is a pathological process common to all CKD and thereby represents an excellent treatment target. A large number of molecular pathways involved in renal fibrosis were identified in preclinical studies, some of them being similar among different organs and some with available drugs in various phases of clinical testing. Yet only few clinical trials with antifibrotic drugs are being conducted in CKD patients...
March 2017: Advances in Chronic Kidney Disease
https://www.readbyqxmd.com/read/28283950/caveolin-1-in-the-pathogenesis-of-diabetic-nephropathy-potential-therapeutic-target
#3
REVIEW
Richard Van Krieken, Joan C Krepinsky
PURPOSE OF REVIEW: Diabetic nephropathy, a major microvascular complication of diabetes and the most common cause of end-stage renal disease, is characterized by prominent accumulation of extracellular matrix. The membrane microdomains caveolae, and their integral protein caveolin-1, play critical roles in the regulation of signal transduction. In this review we discuss current knowledge of the contribution of caveolin-1/caveolae to profibrotic signaling and the pathogenesis of diabetic kidney disease, and assess its potential as a therapeutic target...
March 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28282408/the-renal-phenotype-of-allopurinol-treated-hprt-deficient-mouse
#4
Cristina Zennaro, Federica Tonon, Paola Zarattini, Milan Clai, Alessandro Corbelli, Michele Carraro, Marialaura Marchetti, Luca Ronda, Gianluca Paredi, Maria Pia Rastaldi, Riccardo Percudani
Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice...
2017: PloS One
https://www.readbyqxmd.com/read/28274188/extracellular-matrix-remodeling-in-idiopathic-pulmonary-fibrosis-it-is-the-bed-that-counts-and-not-the-sleepers
#5
Ioannis P Tomos, Argyrios Tzouvelekis, Vassilis Aidinis, Effrosyni D Manali, Evangelos Bouros, Demosthenes Bouros, Spyros A Papiris
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible fibrosis. Current disease pathogenesis assumes an aberrant wound healing process in response to repetitive injurious stimuli leading to apoptosis of epithelial cells, activation of fibroblasts and accumulation of extracellular matrix (ECM). Particularly, lung ECM is a highly dynamic structure that lies at the core of several physiological and developmental pathways. The scope of this review article is to summarize current knowledge on the role of ECM in the pathogenesis of IPF, unravel novel mechanistic data and identify future more effective therapeutic targets...
March 8, 2017: Expert Review of Respiratory Medicine
https://www.readbyqxmd.com/read/28271726/molecular-mechanisms-of-atrial-fibrosis-implications-for-the-clinic
#6
Shivshankar Thanigaimani, Dennis H Lau, Thomas Agbaedeng, Adrian D Elliott, Rajiv Mahajan, Prashanthan Sanders
Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking...
March 8, 2017: Expert Review of Cardiovascular Therapy
https://www.readbyqxmd.com/read/28256533/myofibroblast-differentiation-and-its-functional-properties-are-inhibited-by-nicotine-and-e-cigarette-via-mitochondrial-oxphos-complex-iii
#7
Wei Lei, Chad Lerner, Isaac K Sundar, Irfan Rahman
Nicotine is the major stimulant in tobacco products including e-cigarettes. Fibroblast to myofibroblast differentiation is a key process during wound healing and is dysregulated in lung diseases. The role of nicotine and e-cigarette derived nicotine on cellular functions including profibrotic response and other functional aspects is not known. We hypothesized that nicotine and e-cigarettes affect myofibroblast differentiation, gel contraction, and wound healing via mitochondria stress through nicotinic receptor-dependent mechanisms...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28253513/microarray-analysis-reveals-increased-expression-of-matrix-metalloproteases-and-cytokines-of-interleukin-20-subfamily-in-the-kidneys-of-neonate-rats-underwent-unilateral-ureteral-obstruction-a-potential-role-of-il-24-in-the-regulation-of-inflammation-and-tissue
#8
Domonkos Pap, Erna Sziksz, Zoltán Kiss, Réka Rokonay, Apor Veres-Székely, Rita Lippai, István Márton Takács, Éva Kis, Andrea Fekete, György Reusz, Adam Vannay, Attila J Szabó
BACKGROUND/AIMS: Congenital obstructive nephropathy (CON) is the main cause of pediatric chronic kidney diseases leading to renal fibrosis. High morbidity and limited treatment opportunities of CON urge the better understanding of the underlying molecular mechanisms. METHODS: To identify the differentially expressed genes, microarray analysis was performed on the kidney samples of neonatal rats underwent unilateral ureteral obstruction (UUO). Microarray results were then validated by real-time RT-PCR and bioinformatics analysis was carried out to identify the relevant genes, functional groups and pathways involved in the pathomechanism of CON...
February 28, 2017: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/28249987/trpv4-ion-channel-is-a-novel-regulator-of-dermal-myofibroblast-differentiation
#9
Shweta Sharma, Rishov Goswami, Michael Merth, Jonathan Cohen, Kai Y Lei, David X Zhang, Shaik O Rahaman
Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts...
March 1, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28245135/connexin43-controls-the-myofibroblastic-differentiation-of-bronchial-fibroblasts-from-asthmatic-patients
#10
Milena Paw, Izabela Borek, Dawid Wnuk, Damian Ryszawy, Katarzyna Piwowarczyk, Katarzyna Kmiotek, Katarzyna A Wójcik-Pszczoła, Małgorzata Pierzchalska, Zbigniew Madeja, Marek Sanak, Przemysław Błyszczuk, Marta Michalik, Jarosław Czyż
Pathologic accumulation of myofibroblasts in asthmatic bronchi is regulated by extrinsic stimuli and by the intrinsic susceptibility of bronchial fibroblasts to transforming growth factor-β (TGF-β). The specific function of gap junctions and connexins in this process remained unknown. Here, we investigated the role of connexin (Cx)43 in TGF-β-induced myofibroblastic differentiation of fibroblasts derived from bronchoscopic biopsies of asthmatic patients and non-asthmatic donors. Asthmatic fibroblasts expressed considerably higher levels of Cx43 and were more susceptible to TGF-β1-induced myofibroblastic differentiation than their non-asthmatic counterparts...
February 28, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28240316/p53-induces-mir199a-3p-to-suppress-socs7-for-stat3-activation-and-renal-fibrosis-in-uuo
#11
Ruhao Yang, Xuan Xu, Huiling Li, Jinwen Chen, Xudong Xiang, Zheng Dong, Dongshan Zhang
The role of p53 in renal fibrosis has recently been suggested, however, its function remains controversial and the underlying mechanism is unclear. Here, we show that pharmacological and genetic blockade of p53 attenuated renal interstitial fibrosis, apoptosis, and inflammation in mice with unilateral urethral obstruction (UUO). Interestingly, p53 blockade was associated with the suppression of miR-215-5p, miR-199a-5p&3p, and STAT3. In cultured human kidney tubular epithelial cells (HK-2), TGF-β1 treatment induced fibrotic changes, including collagen I and vimentin expression, being associated with p53 accumulation, p53 Ser15 phosphorylation, and miR-199a-3p expression...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28229819/dabigatran-aggravates-topoisomerase-i-peptide-loaded-dendritic-cells-induced-lung-and-skin-fibrosis
#12
Heena Mehta, Shunya Mashiko, Philippe-Olivier Goulet, Jade Desjardins, Gemma Pérez, Martial Koenig, Jean-Luc Senécal, Marika Sarfati
OBJECTIVES: Dysregulated coagulation cascade has been implicated in development of fibrosis in systemic sclerosis (SSc). Thrombin, a key mediator of the coagulation pathway, has both proinflammatory and procoagulant properties. Here, we evaluated the efficacy of oral dabigatran, a direct thrombin inhibitor, on topoisomerase I dendritic cells (TOPOIA DCs)-induced lung and skin fibrosis, an experimental model of SSc. METHODS: Mice were repeatedly immunized with TOPOIA DCs...
February 8, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28225655/mnte-2-pyp-treatment-or-nox4-inhibition-protects-against-radiation-induced-damage-in-mouse-primary-prostate-fibroblasts-by-inhibiting-the-tgf-beta-1-signaling-pathway
#13
Arpita Chatterjee, Elizabeth A Kosmacek, Rebecca E Oberley-Deegan
Prostate cancer patients who undergo radiotherapy frequently suffer from side effects caused by radiation-induced damage to normal tissues adjacent to the tumor. Exposure of these normal cells during radiation treatment can result in tissue fibrosis and cellular senescence, which ultimately leads to postirradiation-related chronic complications including urinary urgency and frequency, erectile dysfunction, urethral stricture and incontinence. Radiation-induced reactive oxygen species (ROS) have been reported as the most potent causative factor for radiation damage to normal tissue...
February 22, 2017: Radiation Research
https://www.readbyqxmd.com/read/28220029/a-novel-inhibitor-of-homeodomain-interacting-protein-kinase-2-mitigates-kidney-fibrosis-through-inhibition-of-the-tgf-%C3%AE-1-smad3-pathway
#14
Ruijie Liu, Bhaskar Das, Wenzhen Xiao, Zhengzhe Li, Huilin Li, Kyung Lee, John Cijiang He
Homeodomain interacting protein kinase 2 (HIPK2) is a critical regulator of multiple profibrotic pathways, including that of TGF-β1/Smad3. Genetic ablation of HIPK2 was shown previously to significantly reduce renal fibrosis in the experimental unilateral ureteral obstruction model and Tg26 mice, a model of HIV-associated nephropathy. To develop specific pharmacologic inhibitors of HIPK2 for antifibrotic therapy, we designed and synthesized small molecule inhibitor compounds on the basis of the predicted structure of HIPK2...
February 20, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28209920/effect-of-captopril-on-radiation-induced-tgf-%C3%AE-1-secretion-in-ea-hy926-human-umbilical-vein-endothelial-cells
#15
Jingni Wei, Hui Xu, Yinyin Liu, Baiyu Li, Fuxiang Zhou
The pathophysiological mechanism involved in the sustained endothelial secretion of cytokines that leads to fibrosis 6-16 months after radiotherapy remains unclear. Angiotensin II (Ang II) is produced by the endothelium in response to stressing stimuli, like radiation, and may induce the synthesis of TGF-β, a profibrotic cytokine. In this study we tested the hypothesis that captopril, an angiotensin-converting enzyme (ACE) inhibitor, inhibits or attenuates radiation-induced endothelial TGF-β1 secretion. The human endothelial hybrid cell line EA...
February 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28202417/triptolide-attenuates-pressure-overload-induced-myocardial-remodeling-in-mice-via-the-inhibition-of-nlrp3-inflammasome-expression
#16
Rujun Li, Kuiying Lu, Yao Wang, Mingxing Chen, Fengyu Zhang, Hui Shen, Deshan Yao, Kaizheng Gong, Zhengang Zhang
Triptolide is the predominant active component of the Chinese herb Tripterygium wilfordii Hook F (TwHF) that has been widely used to treat several chronic inflammatory diseases due to its immunosuppressive, anti-inflammatory, and anti-proliferative properties. In the present study, we elucidated the cardioprotective effects of triptolide against cardiac dysfunction and myocardial remodeling in chronic pressure-overloaded hearts. Furthermore, the potential mechanisms of triptolide were investigated. For this purpose, C57/BL6 mice were anesthetized and subjected to transverse aortic constriction (TAC) or sham operation...
March 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28201843/regression-of-liver-fibrosis
#17
Lara Campana, John P Iredale
Liver fibrosis is the final common pathway of chronic or iterative liver damage. Advanced chronic fibrosis is described as cirrhosis with a loss of architecture and attendant functional failure and the development of life-threatening complications. However, compelling evidence from rodent models and human studies indicates that if the injury is removed liver fibrosis is reversible. Hepatocytes, activated hepatic stellate cells, endothelial and immune cells, particularly macrophages, cooperate in the establishment and resolution of liver fibrosis...
February 2017: Seminars in Liver Disease
https://www.readbyqxmd.com/read/28148567/critical-role-of-the-camp-pka-pathway-in-hyperglycemia-induced-epigenetic-activation-of-fibrogenic-program-in-the-kidney
#18
Dilip K Deb, Riyue Bao, Yan Chun Li
Hyperglycemia is a major pathogenic factor that promotes diabetic nephropathy, but the underlying mechanism remains incompletely understood. Here, we show that high glucose induced cAMP response element-binding protein (CREB)-binding protein (CBP)-mediated H3K9/14 hyperacetylation in approximately 5000 gene promoters in glomerular mesangial cells, including those of Tgfb1, Tgfb3, and Ctgf, the major profibrotic factors that are known to drive diabetic renal fibrogenesis. In these promoters, H3K9/14 hyperacetylation was closely associated with NF-κB or CREB motifs...
February 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28148565/pirfenidone-exerts-antifibrotic-effects-through-inhibition-of-gli-transcription-factors
#19
Miroslava Didiasova, Rajeev Singh, Jochen Wilhelm, Grazyna Kwapiszewska, Lukasz Wujak, Dariusz Zakrzewicz, Liliana Schaefer, Philipp Markart, Werner Seeger, Matthias Lauth, Malgorzata Wygrecka
Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients suffering from idiopathic pulmonary fibrosis (IPF). Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown. Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway. We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription...
February 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28135282/mesenchymal-cell-reprogramming-in-experimental-mplw515l-mouse-model-of-myelofibrosis
#20
Ying Han, Lanzhu Yue, Max Wei, Xiubao Ren, Zonghong Shao, Ling Zhang, Ross L Levine, Pearlie K Epling-Burnette
Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo...
2017: PloS One
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