curcumin and Opisthorchiasis

Comorbidity of Opisthorchis viverrini (OV) infection and nonalcoholic fatty-liver disease (NAFLD) enhances NAFLD progression to nonalcoholic steatohepatitis (NASH) by promoting severe liver inflammation and fibrosis. Here, we investigated the effect of supplementation with curcumin-loaded nanocomplexes (CNCs) on the severity of NASH in hamsters.. Hamsters were placed in experimental groups as follows: fed standard chow diet (normal control, NC); fed only high-fat and high-fructose (HFF) diet; O. viverrini-infected and fed HFF diet (HFFOV); group fed with blank nanocomplexes (HFFOV+BNCs); groups fed different doses of CNCs (25, 50 and 100 mg/kg body weight: HFFOV+CNCs25; HFFOV+CNCs50; HFFOV+CNCs100, respectively) and a group given native curcumin (HFFOV+CUR). All treatment were for three months.. The HFF group revealed NAFLD as evidenced by hepatic fat accumulation, ballooning, mild inflammation and little or no fibrosis. These changes were more obvious in the HFFOV group, indicating development of NASH. In contrast, in the HFFOV+CNCs50 group, histopathological features indicated that hepatic fat accumulation, cell ballooning, cell inflammation and fibrosis were lower than in other treatment groups. Relevantly, the expression of lipid-uptake genes, including fatty-acid uptake (cluster of differentiation 36), was reduced, which was associated with the lowering of alanine aminotransferase, total cholesterol and triglyceride (TG) levels. Reduced expression of an inflammation marker (high-mobility group box protein 1) and a fibrosis marker (alpha smooth-muscle actin) were also observed in the HFFOV+CNCs50 group.. CNCs treatment attenuates the severity of NASH by decreasing hepatic steatosis, inflammation, and fibrosis as well as TG synthesis. CNCs mitigate the severity of NASH in this preclinical study, which indicates promise for future use in patients.

Topics: Actins; Alanine Transaminase; Animals; Cholesterol; Cricetinae; Curcumin; Diet, High-Fat; Disease Models, Animal; Fructose; Humans; Inflammation; Lipids; Liver; Non-alcoholic Fatty Liver Disease; Opisthorchiasis; Opisthorchis; Triglycerides

Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.

Topics: 14-3-3 Proteins; Animals; Bile Duct Neoplasms; Chemoprevention; Cholangiocarcinoma; Cricetinae; Curcumin; Disease Models, Animal; Fasciola hepatica; Gene Expression Regulation; Humans; Liver; Lumican; Membrane Glycoproteins; Microfilament Proteins; Opisthorchiasis; Opisthorchis; Proteomics; S100 Calcium Binding Protein A6; Vimentin

This study investigated the effects of nanoencapsulated curcumin (NEC) and praziquantel (PZQ) treatment on the resolution of periductal fibrosis (PDF) and bile canalicular (BC) abnormalities in Opisthorchis viverrini infected hamsters. Chronic O. viverrini infection (OV) was initially treated with either PZQ (OP) and subsequently treated with NEC (OP+NEC), curcumin (OP+Cur) or unloaded carriers (OP+carrier) daily for one month. OP+NEC treatment reduced the PDF by suppression of fibrotic markers (hydroxyproline content, α-SMA, CTGF, fibronectin, collagen I and III), cytokines (TGF-β and TNF-α) and TIMP-1, 2, 3 expression and upregulation of MMP-7, 13 genes. Higher activity of NEC in reducing fibrosis compared to curcumin was also demonstrated in in vitro studies. Moreover, OP+NEC also prevented BC abnormalities and upregulated several genes involved in bile acid metabolism. These results demonstrate that NEC and PZQ treatment reduces PDF and attenuates BC defect in experimental opisthorchiasis. From the Clinical Editor: Infection by Opisthorchis viverrini leads to liver fibrosis and affects population in SE Asia. Currently, praziquantel (PZQ) is the drug of choice but this drug has significant side effects. In this study, the authors combined curcumin (NEC) and praziquantel in a nanocarrier to test the anti-oxidative effect of curcumin in an animal model. The encouraging results may pave a way for better treatment in the future.

Topics: Animals; Anthelmintics; Anti-Inflammatory Agents, Non-Steroidal; Bile Canaliculi; Cricetinae; Curcumin; Diffusion; Drug Combinations; Fibrosis; Nanocapsules; Opisthorchiasis; Praziquantel; Treatment Outcome

The pharmacological activities of herbal extracts can be enhanced by complex formation. In this study, we manipulated cyanidin and delphinidin-rich extracts to form an anthocyanin complex (AC) with turmeric and evaluated activity against inflammation and periductal fibrosis in Opisthorchis viverrini-infected hamsters. The AC was prepared from anthocyanins extracted from cobs of purple waxy corn (70%), petals of blue butterfly pea (20%) and turmeric extract (10%), resulting in an enhanced free-radical scavenging capacity. Oral administration of AC (175 and 700 mg/kg body weight) every day for 1 month to O. viverrini-infected hamsters resulted in reduced inflammatory cells and periductal fibrosis. Fourier transform infrared spectroscopy and partial least square discriminant analysis suggested nucleic acid changes in the O. viverrini-infected liver samples, which were partially prevented by the AC treatment. AC reduced 8-oxodG formation, an oxidative DNA damage marker, significantly decreased levels of nitrite in the plasma and alanine aminotransferase activity and increased the ferric reducing ability of plasma. AC also decreased the expression of oxidant-related genes (NF-κB and iNOS) and increased the expression of antioxidant-related genes (CAT, SOD, and GPx). Thus, AC increases free-radical scavenging capacity, decreases inflammation, suppresses oxidative/nitrative stress, and reduces liver injury and periductal fibrosis in O. viverrini-infected hamsters.

Topics: Animals; Anthocyanins; Anti-Inflammatory Agents; Antioxidants; Cricetinae; Curcuma; DNA Damage; Gene Expression; Liver Cirrhosis; Male; Mesocricetus; Opisthorchiasis; Opisthorchis; Phenols; Pisum sativum; Plant Extracts; Zea mays

Opisthorchis viverrini infection causes inflammation and liver injury leading to periductal fibrosis. Little is known about the pathological alterations in bile canaliculi in opisthorchiasis. This study aimed to investigate bile canalicular alterations in O. viverrini-infected hamsters and to examine the chemopreventive effects of curcumin on such changes. Hamsters were infected with O. viverrini and one group of animals was fed with 1% dietary curcumin supplement. Animals were examined during the acute infection phase, days 21 and 30 post-infection (PI) and chronic infection phase (day 90 PI). Scanning electron microscopy revealed that in the infected group fed with a normal diet, bile canaliculi became slightly tortuous by 30 day PI and more tortuous at day 90 PI. Transmission electron microscopy showed a reduction in microvilli density of canaliculi starting at day 30 PI, with a marked loss of microvilli at day 90 PI. These ultrastructral changes were slightly seen at day 21 PI, which was similar to that found in infected animals fed with 1% curcumin-supplemented diet. Notably, curcumin treatment prevented the reduction of microvilli density, reduced the dilation of bile canaliculi, and decreased the tortuosity of the bile canaliculi relative to non-infected animals on a normal diet at days 30 and 90 PI. These results suggest that curcumin reduces alteration of bile canaliculi and may be a promising agent to prevent the onset of bile duct abnormalities induced by O. viverrini infection.

Topics: Animals; Anthelmintics; Bile Canaliculi; Chemoprevention; Cricetinae; Curcumin; Disease Models, Animal; Electrons; Liver; Male; Mesocricetus; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Opisthorchiasis; Opisthorchis

The present study revealed the indirect effect of a turmeric (TUR) diet on the histopathological changes and proliferating cell nuclear antigen staining in Syrian hamsters with partial obstruction by liver fluke (Opisthorchis viverrini) infection and inflammation by N-nitrosodimethylamine (NDMA) administration. The result of the analysis of histopathological changes shows that a TUR diet has an anti-inflammatory property in the case of a single condition of NDMA administration or O. viverrini infection, as has been reported previously. Unfortunately, an adverse indirect effect of TUR was observed in the combination of infection with O. viverrini and administration of NDMA, with a 30-50% increase in new bile duct formation, correlated with an increase in proliferating cell nuclear antigen. Our present result suggests that the properties of curcumin are anti-inflammation and antioxidant including enhancing biliary contraction and bile flow. Thus, a combination of factors (treated with O. viverrini, NDMA, and TUR diet) result in an increasing bile duct proliferation which may cause from biliary homeostasis.

Topics: Animals; Anti-Inflammatory Agents; Bile Ducts; Cholestasis; Cricetinae; Curcuma; Diet; Dimethylnitrosamine; Fasciola hepatica; Inflammation; Mesocricetus; Opisthorchiasis; Opisthorchis

Chronic infection with the liver fluke, Opisthorchis viverrini, induces advanced periductal fibrosis and is a relative risk factor for cholangiocarcinoma in Southeastern Asia. We examined the reducing effect of curcumin on hepatobiliary fibrosis using O. viverrini-infected hamsters supplemented with dietary 1% curcumin (w/w) as an animal model. The expression profile of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), cytokines, and collagens was assessed in relation to liver fibrosis. Histopathological studies revealed that curcumin had no effect on fibrosis at the short-term infection (21 days and 1 month); however, peribiliary fibrosis was significantly reduced after the long-term curcumin treatment for 3 months, compared to the untreated group. Expression of alpha-smooth muscle actin was associated with the reduction of liver fibrosis. A decrease in hepatic hydroxyproline level and mRNA expression of collagen I and III supported the reduction of fibrosis. The expression of TIMP-1, TIMP-2, and tumor necrosis factor-alpha genes was also decreased after curcumin treatment. In contrast, curcumin increased mRNA expression of MMP-13, MMP-7 (at 6 months), interleukin-1 beta, and transforming growth factor beta, implying that increased MMPs activity contributes to extracellular matrix degradation. These results suggest that curcumin reduces periductal fibrosis after long-term treatment by tissue resorption via inhibition of TIMPs expression and enhancement of MMPs expression mediated by cytokines. In conclusion, curcumin may serve as a promising nutraceutical agent exerting antifibrotic effect in O. viverrini-infected patients and contribute to cholangiocarcinoma prevention.

Topics: Actins; Animals; Collagen; Cricetinae; Curcumin; Drug Administration Schedule; Gene Expression Regulation; Hydroxyproline; Inflammation; Interleukin-1beta; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Matrix Metalloproteinases; Opisthorchiasis; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The curcumin compound from turmeric is effective in the treatment of many inflammatory diseases. The aim of our present study was to evaluate the efficacy of turmeric on reducing the histopathological changes of hamster opisthorchiasis. Hamsters were infected with Opisthorchis viverrini and then administered turmeric. Using light microscopic observation, liver function tests for alanine transaminase (ALT), alkaline phosphatase, and direct bilirubin were investigated. The resulting histopathological changes show that turmeric has anti-inflammatory properties--during both N-nitrosodimethylamine administration and O. viverrini infection--by reducing the aggregation of inflammatory cells surrounding the hepatic bile ducts, which correlates with a decreased serum ALT level. The decrease in direct bilirubin levels in the hamsters treated with turmeric suggests that turmeric may enhance biliary contraction. The present study found that turmeric clearly reduces the inflammatory cells in hamster opisthorchiasis at an early stage. This finding may be connected with a reduction in the risk factors of cholangiocarcinoma development.

Topics: Animals; Anti-Inflammatory Agents; Cricetinae; Curcuma; Curcumin; Liver; Liver Function Tests; Mesocricetus; Opisthorchiasis; Opisthorchis

Opisthorchis viverrini (OV) infection is endemic in northeastern Thailand. We have previously reported that OV infection induces oxidative and nitrative DNA damage via chronic inflammation, which contributes to the disease and cholangiocarcinogenesis. Here, we examined the effect of curcumin, an antioxidant, on pathogenesis in OV-infected hamsters. DNA lesions were detected by double immunofluorescence and the hepatic expression of oxidant-generating and antioxidant genes was assessed by quantitative RT-PCR analysis. Dietary 1.0% curcumin significantly decreased OV-induced accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative DNA lesion, and 8-nitroguanine, a nitrative DNA lesion, in the nucleus of bile duct epithelial and inflammatory cells. Expression of oxidant-generating genes (inducible nitric oxide synthase; iNOS, its nuclear transcriptional factor, NF-kappaB, and cyclooxygenase-2), and plasma levels of nitrate, malondialdehyde, and alanine aminotransferase, were also decreased in curcumin-treated group. In contrast, curcumin increased the mRNA expression of antioxidant enzymes (Mn-superoxide dismutase and catalase), and ferric-reducing anti-oxidant power in the plasma. In conclusion, curcumin reduced oxidative and nitrative DNA damage by suppression of oxidant-generating genes and enhancement of antioxidant genes, leading to inhibition of oxidative and nitrative stress. Therefore, curcumin may be used as a chemopreventive agent to reduce the severity of OV-associated diseases and the risk of cholangiocarcinoma (CCA).

Topics: Animals; Antimutagenic Agents; Catalase; Cricetinae; Curcumin; Cyclooxygenase 2; DNA Damage; Dose-Response Relationship, Drug; Gene Expression; Liver; Malondialdehyde; Mesocricetus; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Opisthorchiasis; Opisthorchis; Oxidative Stress; Parasite Egg Count; Proliferating Cell Nuclear Antigen; Superoxide Dismutase

The present study investigated the effect of curcumin, a phenolic compound with yellow color from Curcuma longa L., on the expression of the apoptosis-related genes [BAX (Bcl-2 associated protein X), PKB, p53, MDM2 (mouse double minute 2), caspase 9, c-Ski, smad1 and smad4] in hamster opisthorchiasis. On Opisthorchis viverrini infection treated with dietary curcumin apoptosis-related gene expression profiles were similar to O. viverrini-infected group, but the expression levels seemed lower. Light microscopic observation revealed that aggregation of inflammatory cells surrounding the hepatic bile ducts in the groups infected with O. viverrini and treated with dietary curcumin was lower than in infected group. The intensity of the response is correlated with expression of the genes studied. The results suggest that curcumin reduces pathogenesis in hamster-opisthorchiasis by controlling apoptosis-related gene expression.

Topics: Animals; Apoptosis; Cricetinae; Curcumin; Gene Expression; Male; Opisthorchiasis; Reverse Transcriptase Polymerase Chain Reaction