Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats

Imanishi, Yukihiro; Maeda, Naoto; Otogawa, Kohji; Seki, Shuichi; Matsui, Hiroko; Kawada, Norifumi; Arakawa, Tetsuo

doi:10.1016/j.jhep.2004.04.005

Cited by 68 publications

(60 citation statements)

References 33 publications

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“…Emodin exhibits a wide range of pharmacological effects, including anti-tumor [17] , anti-inflammatory [6] and hepatic and renal protective activities [18] . Huang et al [19] was the first to demonstrate the immunosuppressive effects of emodin, and our previous study also confirmed that emodin treatment attenuated skin allograft rejection and prolonged skin graft survival via stimulating serum IL-2 levels in skin transplantation models [8] .…”

Section: Discussionmentioning

confidence: 99%

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction

Shen

et al. 2013

Acta Pharmacol Sin

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Aim: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L. Methods: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca 2+ . Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers. Results: Emodin (1, 10, and 100 µmol/L) inhibited the growth of human T cells and induced apoptosis in dose-and time-dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca 2+ in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/ GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N-acetylcysteine (NAC, 20 µmol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis. Conclusion: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS-mediated ER stress and mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction

Shen

et al. 2013

Acta Pharmacol Sin

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“…It was reported that emodin could inhibit the expression of TGF-β1 in liver fibrosis model of rats [6] . Imanishi et al [19] found that emodin could modulate the effect of PDGF, which could slow down the progression of fibrosis. In our study, emodintreated groups showed low expression of TGF-β1, especially in high-dose emodin-treated group.…”

Section: Discussionmentioning

confidence: 99%

Effect of emodin on pancreatic fibrosis in rats

Wang

Gao²,

Yu³

et al. 2007

WJG

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AIM:To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis. METHODS:Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was infused into the pancreatic duct to induce chronic pancreatitis in rats (except for normal group). Emodin-treated rats were fed with different doses of emodin (20, 40 and 80 mg/kg body weight) for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factorbeta-1 (TGF-β1) was localized by immunochemistry. RESULTS:In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 ± 19.3 µg/L vs 112.7 ± 26.5 µg/L, P < 0.05; LN 44.3 ± 10.4 µg/L vs 86.2 ± 16.5 µg/L, P < 0.05); the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group (36% ± 5% vs 42% ± 6%, P < 0.05); with the increased doses of emodin, the expression of TGF-β1 was declined, compared with those in control group. CONCLUSION:Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.

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“…In this study, we employed flow cytometry and measured cell cycle related proteins, PDGF-BB-related signalling molecules and apoptosis markers to provide some explanations for molecular mechanisms of Sal A. In addition to this study, there are other reports that herbal extracts such as Inchin-ko-to (TJ-135) and polyphenol epigallocatechin-3-gallate (EGCG) from green tea also inhibit PDGF-activated proliferation in HSCs (Imanishi et al 2004;Sakata et al 2004). Taken together, these studies indicated that the anti-PDGF-BB effects of herbal extracts were partially mediated through reducing PDGFR phosphorylation in HSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Tubulin was used as an internal control for equal protein loading. The protocols of Borkham-Kamphorst et al (2004) and Imanishi et al (2004) were followed to measure phosphorylation of PDGF receptors-(PDGFR-) and Akt.…”

Section: Western Blotting Analysesmentioning

confidence: 99%

Antiproliferative effect of salvianolic acid A on rat hepatic stellate cells

Lin

Lee²,

Huang

et al. 2006

Journal of Pharmacy and Pharmacology

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Suppression of activation or proliferation, or induction of apoptosis in hepatic stellate cells (HSCs) have been proposed as therapeutic strategies against liver fibrosis. Salvia miltiorrhiza has been reported to exert antifibrotic effects in rats with hepatic fibrosis, but its mechanisms of action remain to be clarified. We have investigated the effects of salvianolic acid A (Sal A), an active principle from S. miltiorrhiza, on the proliferation-related biomarkers in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor-BB homodimer (PDGF-BB). DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of Sal A. The results showed that Sal A (1-10 M) concentration-dependently attenuated PDGF-BB-stimulated proliferation (BrdU incorporation) in HSC-T6 cells. Sal A at 10 M induced cell apoptosis in PDGF-BB-incubated HSCs, together with a reduction of Bcl-2 protein expression, induction of cell cycle inhibitory proteins p21 and p27, and down-regulation of cyclins D1 and E, suppression of Akt phosphorylation, reduction in PDGF receptor phosphorylation, and an increase in caspase-3 activity. Sal A exerted no direct cytotoxicity on primary hepatocytes and HSC-T6 cells under experimental concentrations. Our results suggested that Sal A inhibited PDGF-BB-activated HSC proliferation, partially through apoptosis induction.

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Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats

Cited by 68 publications

References 33 publications

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction

Effect of emodin on pancreatic fibrosis in rats

Antiproliferative effect of salvianolic acid A on rat hepatic stellate cells

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