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Joon-Ii Jun, Lester F Lau
The expression of Ccn2 (CTGF) has been linked to fibrosis in many tissues and pathologies, although its activities in fibroblastic cells and precise mechanism of action in fibrogenesis are still controversial. Here, we showed that CCN2 can induce cellular senescence in fibroblasts both in vitro and in vivo, whereupon senescent cells express an anti-fibrotic "senescence-associated secretory phenotype" (SASP) that includes upregulation of matrix metalloproteinases and downregulation of collagen. Mechanistically, CCN2 induces fibroblast senescence through integrin α6β1-mediated accumulation of reactive oxygen species, leading to activation of p53 and induction of p16(INK4a)...
October 18, 2016: Journal of Cell Communication and Signaling
Shanfei Ge, Lunli Zhang, Jianping Xie, Fei Liu, Jinni He, Jinwen He, Xiaowei Wang, Tianxing Xiang
:  Background. We previously identified miR-146b as being up-regulated during the development of hepatic fibrosis using deep sequencing technology and gene expression analysis. However, the roles and related mechanisms of miR-146b in hepatic stellate cells (HSCs), which are involved in fibrogenesis and fibrosis, have not been elucidated. RESULTS: We report that miR-146b expression was increased in TGF-ß1-treated HSCs. TGF- ß1 enhanced α-SMA and COL1A1 protein expression in HSCs and stimulated proliferation of these cells compared with cells transfected with inhibitor NC...
November 2016: Annals of Hepatology
Philipp Lohneis, Stephan Wienert, Frederick Klauschen, Ioannis Anagnostopoulos, Korinna Jöhrens
There is evidence from studies on fibrotic diseases that a TH2 polarized immune response, characterized by the production of cytokines like IL-4, IL-5, and IL-13 is important for fibrosis development. Data concerning the role of TH2 polarized immune response for fibrogenesis in lymphomas are scarce. Using immunohistochemistry, we investigated paraffin embedded tissue specimens of 58 follicular lymphomas (FL) grade 1/2 with and without fibrosis. In FL with fibrosis, we detected more interfollicular GATA-3 positive lymphocytes and a shift towards a TH2 immune response...
October 13, 2016: Leukemia & Lymphoma
María José Acuña, Enrique Brandan
CCN2 or connective tissue growth factor (CTGF) is a matricellular protein that regulates several cellular processes. In skeletal muscle, CTGF is a key modulator of fibrogenesis, is increased in pathological conditions such as muscular dystrophies, and plays a major role in the pathology outcome. Overexpression of CTGF in skeletal muscle of wild-type mice results in muscle damage, fibrosis, and reduction of strength. In contrast, a decrease in CTGF in dystrophic mice increases strength and reduces damage and fibrosis...
2017: Methods in Molecular Biology
Hideki Yokoi, Masashi Mukoyama
Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis. Transforming growth factor-β (TGF-β) is postulated to play a central role in the development of both fibrotic processes. Extracellular matrix proteins, particularly type I collagen and fibronectin, accumulate in the tissue during renal fibrogenesis. CCN2, also known as connective tissue growth factor (CTGF), is increased in the setting of fibrosis and modulates a number of downstream signaling pathways involved in the fibrogenic properties of TGF-β...
2017: Methods in Molecular Biology
Puebla Cassini-Vieira, Mariane Felipetto, Leandro Barbosa Prado, Thiago Verano-Braga, Silvia Passos Andrade, Robson A S Santos, Mauro Martins Teixeira, Maria Elena de Lima, Adriano M C Pimenta, Luciola Silva Barcelos
We have previously described a 25mer anti-hypertensive peptide, previously named TsHpt-I (Tityus serrulatus Hypotensin-I), now Ts14, as an agonist of B2 kinin receptor. Bradykinin is known to play physiological roles in angiogenic, inflammatory, and fibrogenic processes, mostly mediated by B2 receptor. Therefore, we investigated whether Ts14 could modulate key events (neovascularization, inflammatory cell recruitment, and extracellular matrix deposition) of the fibrovascular tissue, induced by polyether-polyurethane sponge implants in mice...
October 9, 2016: Peptides
Chongxiang Xiong, Monica V Masucci, Xiaoxu Zhou, Na Liu, Xiujuan Zang, Evelyn Tolbert, Ting C Zhao, Shougang Zhuang
Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively inhibit tumorgenesis and ameliorate pulmonary fibrosis by targeting bromodomain proteins that bind acetylated chromatin markers. However, their pharmacological effects in renal fibrosis remain unclear. In this study, we examined the effect of I-BET151, a selective and potent BET inhibitor, on renal fibroblast activation and renal fibrosis. In cultured renal interstitial fibroblasts, exposure of cells to I-BET151, or silencing of bromodoma in-containing protein 4 (Brd4), a key BET protein isoform, significantly reduced their activation as indicated by decreased expression of α-smooth muscle actin, collagen 1 and fibronectin...
October 6, 2016: Oncotarget
Bo Zhu, Yumei Chen, Xiaolu Shen, Xishi Liu, Sun-Wei Guo
BACKGROUND: Recently emerging evidence indicates that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR), and platelets induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), leading ultimately to fibrosis. Due to the commonality of cyclic bleeding as in endometriosis, adenomyotic lesions are also wounds that undergo ReTIAR, and we have recently provided evidence corroborating platelet-induced EMT, FMT and fibrogenesis in adenomyosis...
October 10, 2016: Reproductive Biology and Endocrinology: RB&E
Zakaria Ezzoukhry, Elodie Henriet, Léo Piquet, Kevin Boyé, Paulette Bioulac-Sage, Charles Balabaud, Gabrielle Couchy, Jessica Zucman-Rossi, Violaine Moreau, Frédéric Saltel
Transforming growth factor-β1 (TGF-β1) is an important player in chronic liver diseases inducing fibrogenesis and hepatocellular carcinoma (HCC) development. TGF-β1 promotes pleiotropic modifications at the cellular and matrix microenvironment levels. TGF-β1 was described to enhance production of type I collagen and its associated cross-linking enzyme, the lysyl oxidase-like2 (LOXL2). In addition, TGF-β1 and type I collagen are potent inducers of invadosomes. Indeed, type I collagen fibers induce the formation of active linear invadosomes through the discoidin domain receptor 1 (DDR1)...
October 4, 2016: European Journal of Cell Biology
Marina B Klein, Jürgen K Rockstroh, Linda Wittkop
PURPOSE OF REVIEW: Hepatitis C virus (HCV) coinfection is a common and an important comorbidity in HIV infection. We review current trends in mortality and the potential for early combination antiretroviral therapy (cART) and HCV therapy to improve survival in coinfected patients. RECENT FINDINGS: HIV/HCV coinfection increases risk of death from all causes, and from liver disease and harmful drug use in particular. There is growing evidence for a direct role of HIV in liver fibrogenesis and for cART to decrease the risk of dying from liver disease in coinfected persons...
September 2016: Current Opinion in HIV and AIDS
Zannis Almpanis, Maria Demonakou, Dina Tiniakos
Hepatic fibrogenesis may gradually result to cirrhosis due to the accumulation of extracellular matrix components as a response to liver injury. Thus, therapeutic decisions in chronic liver disease, regardless of the cause, should first and foremost be guided by an accurate quantification of hepatic fibrosis. Detection and assessment of the extent of hepatic fibrosis represent a challenge in modern Hepatology. Although traditional histological staging systems remain the "best standard", they are not able to quantify liver fibrosis as a dynamic process and may not accurately substage cirrhosis...
October 2016: Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology
Martin L Decaris, Kelvin W Li, Claire L Emson, Michelle Gatmaitan, Shanshan Liu, Yenny Wang, Edna Nyangau, Marc Colangelo, Thomas E Angel, Carine Beysen, Jeffrey Cui, Carolyn Hernandez, Len Lazaro, David A Brenner, Scott M Turner, Marc K Hellerstein, Rohit Loomba
: Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and non-invasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water ((2) H2 O, 50 ml aliquots) 2-3 times daily for 3 to 5 weeks prior to a clinically indicated liver-biopsy...
October 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jeffery M Venner, Konrad S Famulski, Jeff Reeve, Jessica Chang, Philip F Halloran
BACKGROUND: Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression. METHODS: Expression microarrays from 681 kidney transplant indication biopsies taken either early (n = 282, <1 year) or late (n = 399, >1 year) after transplant were used to analyze the molecular landscape of fibrosis in relationship to histologic fibrosis and diseases...
January 21, 2016: JCI Insight
Justin D Schumacher, Grace L Guo
Fibroblast growth factors (FGFs) are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis, angiogenesis, wound healing, and endocrine functions. In the liver, several FGFs are produced basally by hepatocytes and hepatic stellate cells (HSCs). Upon insult to the liver, expression of FGFs in HSCs is greatly upregulated, stimulating hepatocyte regeneration and growth. Various FGF isoforms have also been shown to directly induce HSC proliferation and activation thereby enabling autocrine and paracrine regulation of HSC function...
2016: BioMed Research International
Hedyeh Ebrahimi, Mohammadreza Naderian, Amir Ali Sohrabpour
Liver fibrosis is a potentially reversible response to hepatic insults, triggered by different chronic diseases most importantly viral hepatitis, alcoholic, and nonalcoholic fatty liver disease. In the course of the chronic liver disease, hepatic fibrogenesis may develop, which is attributed to various types of cells, molecules, and pathways. Activated hepatic stellate cell (HSC), the primary source of extracellular matrix (ECM), is fundamental in pathophysiology of fibrogenesis, and thus is the most attractable target for reversing liver fibrosis...
July 2016: Middle East Journal of Digestive Diseases
Chao Li, Sitong Du, Yiping Lu, Xiaowei Lu, Fangwei Liu, Ying Chen, Dong Weng, Jie Chen
Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis...
2016: Theranostics
Hsiang-Han Su, Hsin-Ting Lin, Jau-Ling Suen, Chau Chyun Sheu, Kazunari K Yokoyama, Shau-Ku Huang, Chih Mei Cheng
Pulmonary fibroblast migration and differentiation are critical events in fibrogenesis; meanwhile, fibrosis characterizes the pathology of many respiratory diseases. The role of aryl hydrocarbon receptor (AhR), a unique cellular chemical sensor, has been suggested in tissue fibrosis, but the mechanisms through which the AhR-ligand axis influences the fibrotic process remain undefined. In this study, the potential impact of the AhR-ligand axis on pulmonary fibroblast migration and differentiation was analyzed using human primary lung fibroblasts HFL-1 and CCL-202 cells...
September 30, 2016: Toxicology
M J Nielsen, M A Karsdal, K Kazankov, H Grønbaek, A Krag, D J Leeming, D Schuppan, J George
BACKGROUND: While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical. AIM: To investigate whether differences in extracellular matrix (ECM) composition of the liver during fibrogenesis in two seemingly similar types of viral hepatitis could be reflected by differences in ECM turnover...
October 3, 2016: Alimentary Pharmacology & Therapeutics
Ya Wang, Ying Le, Jun-Yu Xue, Zong-Ji Zheng, Yao-Ming Xue
TGF-β1-induced epithelial to mesenchymal transition (EMT) process of tubular epithelial cells plays a leading role in the occurrence and progression of renal fibrosis as seen in diabetic nephropathy (DN). High mobility group AT-hook 2 (HMGA2) is considered to be involved in TGF-β1-mediated EMT via multifactorial mechanisms. Specific microRNAs (miRNAs) are closely associated with EMT, and here we focused on let-7d miRNA as a regulator of HMGA2. This study aims to investigate the effects of HMGA2 on EMT process induced by TGF-β1 using small interfering RNA (siRNA) technique in vitro, and further explore the potential role of let-7d miRNA during renal fibrosis in DN...
October 28, 2016: Biochemical and Biophysical Research Communications
Cheri L Lamb, Giovan N Cholico, Xinzhu Pu, Gerald D Hagler, Kenneth A Cornell, Kristen A Mitchell
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro...
September 28, 2016: Toxicology and Applied Pharmacology
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