Capsaicin induces de-differentiation of activated hepatic stellate cell

2012 ◽  
Vol 90 (6) ◽  
pp. 683-690 ◽  
Author(s):  
Shanna Bitencourt ◽  
Fernanda C. de Mesquita ◽  
Eduardo Caberlon ◽  
Gabriela V. da Silva ◽  
Bruno S. Basso ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Type I Collagen ◽  
Stellate Cell ◽  
Type I ◽  
Collagen Mrna ◽  
Collagen Secretion ◽  
Liver Fibrogenesis ◽  
In Vitro Effects ◽  
Tgf Β1

Hepatic stellate cells (HSC) play a key role in liver fibrogenesis. Activation of PPARγ and inhibition of fibrogenic molecules are potential strategies to block HSC activation and differentiation. A number of natural products have been suggested to have antifibrotic effects for the de-activation and de-differentiation of HSCs. The purpose of this study was to investigate the in vitro effects of capsaicin on HSC de-activation and de-differentiation. The results demonstrated that capsaicin induced quiescent phenotype in GRX via PPARγ activation. Significant decrease in COX-2 and type I collagen mRNA expression was observed in the first 24 h of treatment. These events preceded the reduction of TGF-β1 and total collagen secretion. Thus, capsaicin promoted down-regulation of HSC activation by its antifibrotic and anti-inflammatory actions. These findings demonstrate that capsaicin may have potential as a novel therapeutic agent for the treatment of liver fibrosis.

scholarly journals Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Min Liu ◽  
Youwei Xu ◽  
Xu Han ◽  
Lianhong Yin ◽  
Lina Xu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Pyrrolidine Dithiocarbamate ◽  
Type I ◽  
Tgf Β1

Abstract The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future.

Mechanical stretch modulates TGF-β1 and α1(I) collagen expression in fetal human intestinal smooth muscle cells

1999 ◽  
Vol 277 (5) ◽  
pp. G1074-G1080 ◽  
Author(s):  
Jorge A. Gutierrez ◽  
Hilary A. Perr
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Type I Collagen ◽  
Intestinal Smooth Muscle ◽  
Type I ◽  
Collagen Mrna ◽  
Collagen Expression ◽  
Collagen Protein ◽  
Mrna Content ◽  
Tgf Β1

Intestinal muscle undergoes stretch intermittently during peristalsis and persistently proximal to obstruction. The influence of this pervasive biomechanical force on developing smooth muscle cell function remains unknown. We adapted a novel in vitro system to study whether stretch modulates transforming growth factor-β1 (TGF-β1) and type I collagen protein and component α1 chain [α1(I) collagen] expression in fetal human intestinal smooth muscle cells. Primary confluent cells at 20-wk gestation, cultured on flexible silicone membranes, were subjected to two brief stretches or to 18 h tonic stretch. Nonstretched cultures served as controls. TGF-β1 protein was measured by ELISA and type I collagen protein was assayed by Western blot. TGF-β1 and α1(I) collagen mRNA abundance was determined by Northern blot analysis, quantitated by phosphorimaging, and normalized to 18S rRNA. Transcription was examined by nuclear run-on assay. Tonic stretch increased TGF-β1 protein 40%, type I collagen protein 100%, TGF-β1 mRNA content 2.16-fold, and α1(I) collagen mRNA 3.80-fold and enhanced transcription of TGF-β1 and α1(I) collagen by 3.1- and 4.25-fold, respectively. Brief stretch stimulated a 50% increase in TGF-β1 mRNA content but no change in α1(I) collagen. Neutralizing anti-TGF-β1 ablated stretch-mediated effects on α1(I) collagen. Therefore, stretch upregulates transcription for TGF-β1, which stimulates α1(I) collagen gene expression in smooth muscle from developing gut.

Posttranslational inhibition of Ito cell type I collagen production by triiodothyronine

1993 ◽  
Vol 264 (6) ◽  
pp. G1090-G1095
Author(s):  
T. W. Lissoos ◽  
D. W. Beno ◽  
B. H. Davis
Keyword(s):  
Type I Collagen ◽  
Suppressive Effect ◽  
Type I ◽  
Ito Cell ◽  
Ito Cells ◽  
Collagen Production ◽  
Fold Reduction ◽  
Liver Fibrogenesis

Increased Ito cell collagen production occurs during in vivo liver fibrogenesis. Regulation of the overproduction of collagen was studied in cultured rat hepatic Ito cells, which resemble the myofibroblast associated with liver fibrosis. Previous studies suggest that the steroid hormones, retinoic acid, and glucocorticoids may have antifibrogenic properties in vitro and in vivo when used at pharmacological doses. Their potential roles at physiological levels are not well understood. The current study examined the potential regulation of the overproduction of type I collagen in cultured rat hepatic Ito cells by another steroid hormone, 3,5,3'-triiodo-L-thyronine (T3). T3 induced a 3.4-fold reduction in type I collagen production. The effect was dose dependent and was maximal with physiological levels of T3 (10(-9) M). The effect of T3 was independent of any suppression in total protein synthesis. The mechanism of the suppressive effect of T3 on collagen production was explored and was found to be at a posttranslational level. This study suggests that the inhibitory effects of T3 on type I collagen production are likely caused by enhanced intracellular turnover of type I collagen.

TGF-β1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k

2004 ◽  
Vol 287 (5) ◽  
pp. G974-G987 ◽  
Author(s):  
Carmen G. Lechuga ◽  
Zamira H. Hernández-Nazara ◽  
José-Alfredo Domínguez Rosales ◽  
Elena R. Morris ◽  
Ana Rosa Rincón ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
De Novo ◽  
Stellate Cells ◽  
Type I ◽  
Collagen Mrna ◽  
Matrix Metalloproteinase 13 ◽  
De Novo Protein Synthesis ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-β1 induces a transient elevation of α1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the α1(I) collagen mRNA. In the present study, we report that TGF-β1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of α1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-β1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70S6k. Altogether, our data suggest that regulation of MMP-13 by TGF-β1 is a complex process involving transcriptional and posttranscriptional mechanisms.

Relationships between mesangial cell proliferation and types I and IV collagen mRNA levels in vitro

1995 ◽  
Vol 269 (3) ◽  
pp. C554-C562 ◽  
Author(s):  
C. J. He ◽  
L. J. Striker ◽  
M. Tsokos ◽  
C. W. Yang ◽  
E. P. Peten ◽  
...  
Keyword(s):  
Type I Collagen ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Methyl Cellulose ◽  
Collagen Gel ◽  
Type I ◽  
Mrna Levels ◽  
Collagen Mrna ◽  
Type Iv

Changes in the composition of the mesangial extracellular matrix (ECM) and cell turnover are present in glomerular disease. To determine if ECM changes play a role in perpetuating mesangial cell dysfunction, we examined a line of mouse mesangial cells cultured on films or gels of several ECM components and also on methyl cellulose, an inert substrate that prevents attachment. Cells on films of fibronectin or type IV or I collagen had persistently high growth rates and high levels of alpha 1-I and alpha 1-IV collagen mRNAs. In contrast, on gels of type IV or I collagen or matrigel, the growth rate was low. The alpha 1-IV collagen mRNA levels were low on type IV collagen gel or matrigel, whereas the alpha 1-I collagen mRNA levels remained high. In contrast, the alpha 1-I collagen mRNA levels were low on type I collagen gel, and the alpha 1-IV collagen mRNA levels were high. Cells on methyl cellulose formed floating aggregates, did not proliferate, and had a 5- to 10-fold decrease in both alpha 1-I and alpha 1-IV collagen mRNA levels. These phenotypic changes were largely reversible. Finally, when matrigel was layered over cells on fibronectin films, alpha 1-IV collagen mRNA levels decreased, but alpha 1-I collagen mRNA levels and proliferation remained high. Thus proliferation and alpha 1-I and alpha 1-IV collagen mRNA levels in mesangial cells were independently regulated and depended on attachment and the nature of the adjacent matrix.

Fibroblast-Like Cells from Tendons Differ from Skin Fibroblasts in their Ability to form Three-Dimensional Structures in Vitro

1998 ◽  
Vol 23 (5) ◽  
pp. 633-641 ◽  
Author(s):  
C. E. EVANS ◽  
I. A. TRAIL
Keyword(s):  
Immunohistochemical Staining ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Three Dimensional ◽  
Skin Fibroblasts ◽  
Type I ◽  
Type Iii ◽  
Collagen Secretion ◽  
Histological Staining

Tendon samples cultured in vitro produced cells (TC) with fibroblast-like morphology and confluence occurred within 5 weeks. Histological staining demonstrated proteoglycan and collagen secretion by TC. Immunohistochemical staining revealed type I collagen but no type III. Assay of total collagen demonstrated a rapid increase in synthesis with time in culture. Cultures allowed to become ‘superconfluent’ spontaneously formed three-dimensional structures after about 4 weeks, which became macroscopic, tendon-like structures (TLS). Cells within TLS seemed under cell-generated tension. Haematoxylin and eosin staining of sections of tendon, of TLS and of TC cultures demonstrated similarities in morphology. These studies were performed using human and rabbit cells and findings were similar for the two species, but with some differences in cell metabolism. Skin fibroblasts were also cultured as a comparison.

scholarly journals Ligustrazine Inhibits Cartilage Endplate Hypertrophy via Suppression of TGF-β1

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Shufen Liu ◽  
Bizeng Zhao ◽  
Huipeng Shi ◽  
Qianqian Liang ◽  
Yishan Fu ◽  
...  
Keyword(s):  
Intervertebral Disc Degeneration ◽  
Cellular Proliferation ◽  
Type I Collagen ◽  
Positive Staining ◽  
Type I ◽  
Fusion Surgery ◽  
Cartilage Endplate ◽  
Tgf Β1

CEP hypertrophy is one of the characteristics of intervertebral disc degeneration (IDD). LIG exerts a protective effect on IDD in animal model. The effect of LIG on CEP hypertrophy is further investigated in the present study. Cells were isolated from hypertrophic samples obtained from patients during vertebral fusion surgery. Cellular proliferation and the expression of type I collagen (Col I) and TGF-β1 were tested. In the bipedal rats, the edges of the CEP and the sizes of noncartilaginous outgrowth, as well as the expression of osteogenic markers, Col1a, ALP, Runx2, and TGF-β1, were detected. Within two passages, the condensed hypertrophic CEP cells exhibited osteogenic capacity by bony-like nodules and ALP positive staining, along with increased expression of Col I and TGF-β1. LIG inhibited proliferation of CEP cells and downregulated the expression of Col I and TGF-β1in vitro. Furthermore, LIG attenuated CEP hypertrophy on the lumbar spine of bipedal rats by reducing Col1a, ALP, Runx2, and TGF-β1 mRNA expression and TGF-β1 distributionin vivo. We concluded LIG exerted a preventive effect on CEP hypertrophy via suppression of TGF-β1 levels. This information could be used to develop alternative therapeutic methods to treat spinal CEP hypertrophy.

scholarly journals High Glucose Stimulates Proliferation and Collagen Type I Synthesis in Renal Cortical Fibroblasts

1999 ◽  
Vol 10 (9) ◽  
pp. 1891-1899 ◽  
Author(s):  
DONG CHEOL HAN ◽  
MOTOHIDE ISONO ◽  
BRENDA B. HOFFMAN ◽  
FUAD N. ZIYADEH
Keyword(s):  
High Glucose ◽  
Type I Collagen ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Thymidine Incorporation ◽  
Collagen Type I ◽  
Type I ◽  
Dependent Manner ◽  
Collagen Mrna ◽  
Tgf Β1

Abstract. Renal tubular epithelial cells and interstitial fibroblasts are active participants in tubulointerstitial fibrosis, the best correlate of decreased glomerular filtration in diabetic nephropathy. It was reported previously that high ambient glucose stimulates transforming growth factor-β (TGF-β) mRNA and bioactivity, promotes cellular hypertrophy, and increases collagen synthesis in proximal tubular cells. This study evaluates the effects of high glucose and TGF-β on the behavior of murine renal cortical fibroblasts (TFB) in culture. High glucose (450 mg/dl) significantly increased [3H]-thymidine incorporation (by 60 to 80% after 24 to 72 h) and cell number, without significantly increasing cell death when compared with normal glucose (100 mg/dl). There also was a transient increase in the mRNA of the c-mycandegr-1early-response genes. Exogenous TGF-β1 was promitogenic rather than antiproliferative in contrast to other renal cell types. Northern blot analysis demonstrated constitutive expression of TGF-β1, -β2, and -β3 transcripts. Exposure to high glucose increased all three TGF-β isoforms in a time-dependent manner. High glucose as well as exogenous TGF-β1 also increased [3H]-proline incorporation, α2(I) collagen mRNA, and type I collagen protein (measured by immunoassay). Treatment with a neutralizing pan-selective monoclonal anti-TGF-β antibody markedly attenuated the stimulation by high ambient glucose of thymidine incorporation, TGF-β1 mRNA, and type I collagen mRNA and protein levels. It is concluded that high ambient glucose and exogenous TGF-β1 share similar actions on renal fibroblasts. Moreover, the stimulation of cell proliferation and collagen type I synthesis in these cells by high ambient glucose are mediated by activation of an autocrine TGF-β system.

scholarly journals Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

2020 ◽  
Vol 117 (7) ◽  
pp. 3748-3758 ◽  
Author(s):  
Gaofeng Xiong ◽  
Jie Chen ◽  
Guoying Zhang ◽  
Shike Wang ◽  
Kunito Kawasaki ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cancer Metastasis ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Type I ◽  
Sequencing Data ◽  
Mesenchymal Transition ◽  
Collagen Secretion ◽  
Cell Colonization

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.

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