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ABSTRACT: BACKGROUND: At present there is no effective and accepted therapy for hepatic fibrosis. Transforming growth factor (TGF)-beta1 singling pathway contributes greatly to hepatic fibrosis. Reducing TGF-beta synthesis or inhibiting components of its complex signaling pathway represent important therapeutic targets. The aim of the study was to investigate the effect of curcumin on liver fibrosis and whether curcumin attenuates the TGF-beta1 singling pathway. METHODS: Sprague--Dawley rat was induced liver fibrosis by carbon tetrachloride (CCl4) for six weeks together with or without curcumin, and hepatic histopathology and collagen content were employed to quantify liver necro-inflammation and fibrosis. Moreover, the mRNA and protein expression levels of TGF-beta1, Smad2, phosphorylated Smad2, Smad3, Smad7 and connective tissue growth factor (CTGF) were determined by quantitative real time-PCR, Western blot, or immunohistochemistry. RESULTS: Rats treated with curcumin improved liver necro-inflammation, and reduced liver fibrosis in association with decreased alpha-smooth muscle actin expression, and decreased collagen deposition. Furthermore, curcumin significantly attenuated expressions of TGFbeta1, Smad2, phosphorylated Smad2, Smad3, and CTGF and inducted expression of the Smad7. CONCLUSIONS: Curcumin significantly attenuated the severity of CCl4-induced liver inflammation and fibrosis through inhibition TGF-beta1/Smad signalling pathway and CTGF expression. These data suggest that curcumin might be an effective antifibrotic drug in the prevention of liver disease progression.
BMC Complementary and Alternative Medicine 09/2012; 12(1):156. · 2.24 Impact Factor
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ABSTRACT: Curcumin has antiviral, antioxidant, and anti-inflammatory properties. However, the hepatoprotective effects and molecular mechanisms of curcumin on acute liver injury have not been carefully examined. The aims of this study were to examine the anti-inflammatory effect of curcumin on Concanavalin A (Con A) induced hepatitis, and to elucidate its underlying molecular mechanisms in mice. Mice received curcumin (200 mg/kg body weight) by gavage before Con A intravenous administration. We found that curcumin pretreatment was able to significantly reduce the elevated plasma aminotransferase levels and liver necrosis in Con A-induced hepatitis. Also, curcumin pretreatment reduced intrahepatic expression of genes encoding pro-inflammatory molecules such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) as compared with the vehicle controls, but augmented anti-inflammatory cytokine interleukin 10 (IL-10) by enzyme linked immunosorbent assay (ELISA). Furthermore, the expression levels of Toll-like receptor (TLR) 2, TLR4 and TLR9 mRNA or protein in liver tissues were significantly lowered by curcumin treatment. Curcumin pretreatment did not affect hepatic Kupffer cell numbers after Con A injection. These results suggest that curcumin pretreatment protects against T cell-mediated hepatitis in mice. The beneficial effect of curcumin may be partly mediated by inhibiting the expression levels of TLR2, TLR4 and TLR9 in the liver.
International immunopharmacology 12/2011; 12(1):151-7. · 2.21 Impact Factor
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ABSTRACT: Fifteen citrinin derivatives (1-4, 6-16), including two unprecedented citrinin trimers tricitrinols A (3) and B (4), were isolated from Penicillium citrinum HGY1-5. The six-membered ring A system is essential for the cytotoxicity of active dimers (1, 2, and 5) and trimers (3 and 4). Tricitrinol B (4) showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC(50) values (1-10 μM) and potential antimultidrug resistance capabilities. Tricitrinol B (4) induced cell apoptosis in HL60 and HCT116 cells via mainly extrinsic pathways and G2/M arrest. Further antitumor mechanism study and computational docking analysis indicated that tricitrinol B (4) works as an intercalating topoisomerase IIα (topo IIα) poison, which inhibits the enzyme activity of topo IIα by interfering predominantly with the topo IIα-mediated poststrand-passage cleavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo IIα-inhibitory skeletons for developing new chemotherapeutic agents.
Journal of Medicinal Chemistry 08/2011; 54(16):5796-810. · 4.80 Impact Factor
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ABSTRACT: The effect of curcumin on liver injury caused by Concanavalin A (Con A) has not been carefully examined. This study was designed to evaluate the protective effect of curcumin on Con A-induced hepatitis in mice. Liver injured mice received curcumin by gavage at a dose of 200 mg/kg body weight before Con A intravenous administration. Curcumin was effective in reducing the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with Con A-injected control group. Enzyme-linked immunosorbent assay (ELISA) showed that curcumin suppressed proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-4 production in Con A-injected mice. The reduced severity of hepatitis in curcumin pretreated mice correlated with decrease in numbers of liver CD4(+) T cells but not CD8(+) T cells by immunohistochemical analysis. Furthermore, the expression levels of intercellular adhesion molecule-1 (ICAM-1) and the interferon-inducible chemokine CXCL10 in hepatic tissue were significantly decreased by curcumin pretreatment. In conclusion, curcumin pretreatment protects against T cell-mediated hepatitis in mice.
Molecular and Cellular Biochemistry 06/2011; 358(1-2):53-60. · 2.06 Impact Factor
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Yi Jiang,
Ze-Hong Miao,
Lei Xu,
Bing Yu,
Jing-Xu Gong,
Lin-Jiang Tong,
Yi Chen,
Zhao-Li Zhou, Hong-Chun Liu,
Yi Wang,
Yue-Wei Guo,
Jian Ding
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ABSTRACT: Hepatocellular carcinoma (HCC) is inherently resistant to the majority of clinical anticancer drugs. To obtain drugs that can circumvent or evade such inherent drug resistance of HCC, we investigated the effect of the marinely derived steroid methyl spongoate (MESP) on HCC cells. MESP displayed potent cell killing against a panel of six HCC cell lines, independent of their expression of drug transporters. MESP did not change the function of the drug transporters, and its cell killing was not impaired in multidrug-resistant cancer cells overexpressing the transporters. The cell killing of MESP was irrelevant to estrogen or androgen signaling and was not associated with cell cycle progression, inhibition of microtubules, and topoisomerases. In contrast, MESP potently induced apoptosis via activation of a proapoptotic caspase cascade and relief of the suppression of antiapoptotic signal transducers and activators of transcription 3 (STAT3) signaling. MESP inhibited the phosphorylation of STAT3, a critical survival signaling factor that reduced the expression of the antiapoptotic protein x-linked inhibitor of apoptosis protein but enhanced the expression of the proapoptotic protein Bax, thus promoting caspase-dependent apoptosis. These data reveal that MESP may well serve as an important candidate drug lead for HCC therapy.
Journal of Biological Chemistry 06/2011; 286(30):26461-9. · 4.77 Impact Factor
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ABSTRACT: Numerous studies have shown that changes in the glycan structures of cells correlate with tumorigenesis, however, a casual link between the altered glycan structures and the abnormal GJIC in cancer cells is rarely studied. In this paper, we investigated the effects of sialic acid on the Cx43 gap junction functions, and clarified its potential mechanisms thereby. Sialidase significantly increased Cx43 gap junction functions in constructed Cx43-Hela cells along with down-regulation of cell surface sialic acid, which is dramatically reversed by sialidase inhibitor NeuAc2en. Further study indicated that sialidase failed to affect Cx43 at either protein or phosphorylation level, instead, it induced a considerable fraction of Triton X-100 insoluble, as compared with the untreated cells. We also found that sialidase treatment reduced the N-cadherin glycosylation and enhanced both Cx43-ZO-1 interaction and N-cadherin-ZO-1 association. Moreover, sialidase promoted the cell-cell adhesion with elevating N-cadherin binding to β-catenin, accompanied by increasing colocalization of Cx43 with microtubules at the cell periphery. Based on live cell microscopy, with the FARP technology in the Cx43-EGFP-Hela cells, we found that Cx43 in the plague recovered more quickly in sialidase treatment group, indicating that sialidase could promote the Cx43 traffic to the plague. Overall, these studies indicate cell surface sialic acid on cancer cells may suppress Cx43 gap junction functions via inhibiting Cx43 traffic to the plague involving in sialylated N-cadherin, a process that likely underlies the intimate association between abnormal GJIC and glycosylation on cancer development.
Molecular and Cellular Biochemistry 11/2010; 344(1-2):241-51. · 2.06 Impact Factor
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Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 09/2009; 17(9):699-700.
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ABSTRACT: To provide evidence that blocking the receptor-interacting protein 2 (Rip2) expression can decrease inflammatory cytokine production by macrophage and protect mice from endotoxin lethality.
Murine Rip2 small interfering RNA (siRNA) plamids were constructed and transfected into macrophages and Rip2 expression was assessed with RT-PCR and Western blot. Cell proliferation was assayed with MTT; TNFalpha concentration was assayed with ELISA and high-mobility group box 1 protein (HMGB1) level with semi quantitative Western blot after lipopolysaccharide (LPS) stimulation. LPS challenge was given after the plasmids were injected into mice and the survival rate was calculated. Rip2 and HMGB1 expression in liver was assessed with Western blot and serum TNFalpha level with ELISA.
Rip2 siRNA plasmids could block the mRNA and protein expression of Rip2 and promote cell proliferation. Blocking of Rip2 could attenuate LPS-induced TNFalpha and HMGB1 production. HMGB1 expression in liver were decreased to (40.21 +/- 11.03) pg/g and serum TNFalpha level was decreased to (300.43 +/- 59.26) ng/L (P < 0.05). The survival rate of endotoxemic mice was also improved (P < 0.05).
The results demonstrate that Rip2 siRNA plasmids can block the expression of Rip2, and decrease the production of TNFalpha and HMGB1, thus protect mice from lethal endotoxemia.
Zhonghua nei ke za zhi [Chinese journal of internal medicine] 09/2007; 46(9):721-4.
