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Profibrotic pathways

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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
#1
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
#2
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...
February 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28201843/regression-of-liver-fibrosis
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/28130402/connective-tissue-growth-factor-domain-4-amplifies-fibrotic-kidney-disease-through-activation-of-ldl-receptor-related-protein-6
#7
Bryce G Johnson, Shuyu Ren, Gamze Karaca, Ivan G Gomez, Cécile Fligny, Benjamin Smith, Ayla Ergun, George Locke, Benbo Gao, Sebastian Hayes, Scott MacDonnell, Jeremy S Duffield
Connective tissue growth factor (CTGF), a matrix-associated protein with four distinct cytokine binding domains, has roles in vasculogenesis, wound healing responses, and fibrogenesis and is upregulated in fibroblasts and myofibroblasts in disease. Here, we investigated the role of CTGF in fibrogenic cells. In mice, tissue-specific inducible overexpression of CTGF by kidney pericytes and fibroblasts had no bearing on nephrogenesis or kidney homeostasis but exacerbated inflammation and fibrosis after ureteral obstruction...
January 27, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28102712/bone-morphogenetic-protein-2-and-7-mediate-the-anabolic-function-of-nucleus-pulposus-cells-with-discrete-mechanisms
#8
Victor Yl Leung, Lixiong Zhou, Wai-Kit Tam, Yi Sun, Fengjuan Lv, Guangqian Zhou, Kenneth Mc Cheung
Bone morphogenetic proteins (BMPs) play roles in promoting cell anabolism, especially extracellular matrix production. The difference between BMP members in their capacity to modulate intervertebral disc cell activity is yet to be defined. BMP-7/OP-1 has been shown to retard disc degeneration. We compared the activity of BMP-7 with BMP-2 on nucleus pulposus (NP) cell phenotype and function, and investigated how they differentially affect the gene expression profiles of signaling cascade components in human NP cells under degenerative states...
January 19, 2017: Connective Tissue Research
https://www.readbyqxmd.com/read/28079145/galectin-3-as-a-marker-of-interstitial-atrial-remodelling-involved-in-atrial-fibrillation
#9
Diana Hernández-Romero, Juan Antonio Vílchez, Álvaro Lahoz, Ana I Romero-Aniorte, Eva Jover, Arcadio García-Alberola, Rubén Jara-Rubio, Carlos M Martínez, Mariano Valdés, Francisco Marín
Remodelling in the atria could appear as a result of hypertension, diabetes or ischaemic heart disease. Galectin-3 (Gal-3) is a mediator of profibrotic pathways and a potential biomarker of cardiac remodelling. We prospectively recruited consecutive patients undergoing elective cardiac surgery. Preoperative Gal-3 levels were determined from serum samples, and the presence of fibrosis was assessed from atrial appendage tissue samples obtained during cardiac surgery. We included 100 patients with aortic valve or ischaemic heart diseases and 15 controls with permanent AF...
January 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28077652/exosome-mediated-intercellular-communication-between-hepatitis-c-virus-infected-hepatocytes-and-hepatic-stellate-cells
#10
Pradip B Devhare, Reina Sasaki, Shubham Shrivastava, Adrian M Di Bisceglie, Ranjit Ray, Ratna B Ray
: Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of the non-parenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate cells (LX2) were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo) and the expression of fibrosis related genes was examined...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28073888/selective-targeting-of-lysyl-oxidase-like-2-loxl2-suppresses-hepatic-fibrosis-progression-and-accelerates-its-reversal
#11
Naoki Ikenaga, Zhen-Wei Peng, Kahini A Vaid, Susan B Liu, Shuhei Yoshida, Deanna Y Sverdlov, Amanda Mikels-Vigdal, Victoria Smith, Detlef Schuppan, Yury V Popov
BACKGROUND/AIMS: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. METHODS: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c...
January 10, 2017: Gut
https://www.readbyqxmd.com/read/28051114/novel-therapeutics-identification-for-fibrosis-in-renal-allograft-using-integrative-informatics-approach
#12
Li Li, Ilana Greene, Benjamin Readhead, Madhav C Menon, Brian A Kidd, Andrew V Uzilov, Chengguo Wei, Nimrod Philippe, Bernd Schroppel, John Cijiang He, Rong Chen, Joel T Dudley, Barbara Murphy
Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA...
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28040859/myofibroblast-repair-mechanisms-post-inflammatory-response-a-fibrotic-perspective
#13
REVIEW
Casimiro Gerarduzzi, John A Di Battista
INTRODUCTION: Fibrosis is a complex chronic disease characterized by a persistent repair response. Its pathogenesis is poorly understood but it is typically the result of chronic inflammation and maintained with the required activity of transforming growth factor-β (TGFβ) and extracellular matrix (ECM) tension, both of which drive fibroblasts to transition into a myofibroblast phenotype. FINDINGS: As the effector cells of repair, myofibroblasts migrate to the site of injury to deposit excessive amounts of matrix proteins and stimulate high levels of contraction...
December 31, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28009003/acetyl-11-keto-%C3%AE-boswellic-acid-attenuates-prooxidant-and-profibrotic-mechanisms-involving-transforming-growth-factor-%C3%AE-1-and-improves-vascular-remodeling-in-spontaneously-hypertensive-rats
#14
Peijin Shang, Wenxing Liu, Tianlong Liu, Yikai Zhang, Fei Mu, Zhihui Zhu, Lingfei Liang, Xiaohu Zhai, Yi Ding, Yuwen Li, Aidong Wen
Vascular remodeling is an important complication of hypertension with oxidative stress-related profibrotic pathways involved. The transforming growth factor β1 (TGF-β1) has been shown to be a potential target of vasoprotection, and has multiple roles in vascular remodeling. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is one of the active principles of Boswellic acids, and shows antioxidant activity in many diseases. The study is to determine effects of AKBA on systemic oxidative stress of hypertension and vascular remodeling...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27990121/targeting-mechanotransduction-at-the-transcriptional-level-yap-and-brd4-are-novel-therapeutic-targets-for-the-reversal-of-liver-fibrosis
#15
REVIEW
Altynbek Zhubanchaliyev, Aibar Temirbekuly, Kuralay Kongrtay, Leah C Wanshura, Jeannette Kunz
Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27983601/transcriptome-of-cultured-lung-fibroblasts-in-idiopathic-pulmonary-fibrosis-meta-analysis-of-publically-available-microarray-datasets-reveals-repression-of-inflammation-and-immunity-pathways
#16
Laurent Plantier, Hélène Renaud, Renaud Respaud, Sylvain Marchand-Adam, Bruno Crestani
Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%...
December 13, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27956794/galectin-3-and-il-33-st2-axis-roles-and-interplay-in-diet-induced-steatohepatitis
#17
REVIEW
Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic
Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death...
November 28, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27942594/mir-323a-3p-regulates-lung-fibrosis-by-targeting-multiple-profibrotic-pathways
#18
Lingyin Ge, David M Habiel, Phil M Hansbro, Richard Y Kim, Sina A Gharib, Jeffery D Edelman, Melanie Königshoff, Tanyalak Parimon, Rena Brauer, Ying Huang, Jenieke Allen, Dianhua Jiang, Adrianne A Kurkciyan, Takako Mizuno, Barry R Stripp, Paul W Noble, Cory M Hogaboam, Peter Chen
Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking. Here, we identified miR-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome (BOS) after lung transplantation, idiopathic pulmonary fibrosis (IPF), and murine bleomycin-induced fibrosis...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27927780/genomic-analysis-of-kidney-allograft-injury-identifies-hematopoietic-cell-kinase-as-a-key-driver-of-renal-fibrosis
#19
Chengguo Wei, Li Li, Madhav C Menon, Weijia Zhang, Jia Fu, Brian Kidd, Karen L Keung, Christopher Woytovich, Ilana Greene, Wenzhen Xiao, Fadi Salem, Zhengzi Yi, John Cijiang He, Joel T Dudley, Barbara Murphy
Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an Src family tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently binds Hck with high selectivity...
December 7, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27927603/lysophosphatidic-acid-signaling-through-its-receptor-initiates-profibrotic-epithelial-cell-fibroblast-communication-mediated-by-epithelial-cell-derived-connective-tissue-growth-factor
#20
Norihiko Sakai, Jerold Chun, Jeremy S Duffield, David Lagares, Takashi Wada, Andrew D Luster, Andrew M Tager
The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1 expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1 signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1(-/-)) or -sufficient (LPA1(+/+)) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I procollagen promoter (Col-GFP) to identify fibroblasts...
March 2017: Kidney International
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