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HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

ABSTRACT: Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action.CD(+)4CD45RB(high) T cells were transferred into Rag1(-/-) mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression.Mice treated with MC developed colitis within 4-7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-?), interleukin (IL)-1?, interferon-gamma (IFN-?), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4(+) T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4(+), and IL-17(+), and IFN-? T(+) cells. Furthermore, HMPL-004 inhibited the proliferation of CD4 T cells and differentiation into TH1/TH17 cells in vitro.HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH(1)/TH(17) responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.

SUBMITTER: Michelsen KS

PROVIDER: S-EPMC4465822 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

Michelsen Kathrin S KS Wong Michelle H MH Ko Brian B Thomas Lisa S LS Dhall Deepti D Targan Stephan R SR

Inflammatory bowel diseases 20130101 1

<h4>Background</h4>Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define ...[more]

PMID: 23292349

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Project description:This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from the reduction of thioacetamide-induced toxicity, normalizing reactive oxygen species levels, inhibiting cellular proliferation, and inducing apoptosis in HepG2 cells.

Dataset Information

HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

Publications

HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

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