Metabolic Profiling of Praziquantel-mediated Prevention ofOpisthorchis viverrini-induced Cholangiocyte Transformation in the Hamster Model of Cholangiocarcinoma

Abstract

Background: Opisthorchis viverrini (Ov) infectioninduced cholangiocarcinoma (CCA) is a major public health problem in northeastern Thailand. Praziquantel was shown to prevent CCA development in an Ov-infected hamster model; however, the molecular mechanism remains unknown. Materials and Methods: In this study, we used a hamster model with Ov and N-nitrosodimethylamine-induced CCA to study the mechanisms of praziquantel action. The liver tissues from the hamsters with and without praziquantel treatment were analyzed using 1 H nuclear magnetic resonance spectroscopy. Results: A total of 14 metabolites were found to be significantly different between the two groups. Furthermore, the combination of acetate, inosine and sarcosine was shown to exert an anti-inflammatory effect through interleukin-6 inhibition in a macrophage cell line, suggesting a mechanism by which praziquantel may prevent inflammation caused by Ov, cholangiocyte transformation and further CCA develpoment. Conclusion: These findings might avail the development of a preventive strategy for CCA in high-risk populations.Cholangiocarcinoma (CCA), a malignancy of bile duct epithelial cells, is a major public health problem in Northeast Thailand, which has the highest incidence in the world of this disease (1). A parasitic infection caused by Opisthorchis viverrini (Ov), a liver fluke, was identified as a cause of CCA in 1994 and is associated with CCA development (1). Upon liver fluke infection, CCA genesis is hypothesized to be initially induced via multiple mechanistic pathways, including mechanical damage caused by the fluke suckers, fluke toxic secretory products, and the host immunopathological response, leading to chronic inflammation (2). Moreover, the overproduction of reactive oxygen species and reactive nitrogen species from chronic inflammation results in tissue injury associated with CCA initiation and progression (3). In accordance with the hepatic changes first reported in 1978 in an Ov-infected hamster model, hyperplasia, adenomatous formations and periductal and portal scarring of the bile duct epithelium were also observed at 22 weeks post infection, although bile duct carcinoma was not seen at that time (4). In addition, a previous study showed that alone, Nnitrosodimethylamine (NDMA), a potential carcinogen, did not induce tumor formation in hamsters, but together with Ov infection, CCA was observed in a number of animals (5). Furthermore, histological changes, such as inflammatory reactions, bile duct proliferation, periductal fibrosis and cholangiocarcinoma lesions, were all observed in this cotreatment group (5). At the gene-expression level, we have shown a single down-regulated and 23 up-regulated give transcripts that were involved in Ov-induced CCA development (6). The up-regulated genes include signal 29 This article is freely accessible online.

Curcumin and Its Supramolecular Complex with Disodium Glycyrrhizinate as Potential Drugs for the Liver Fluke Infection Caused by Opisthorchis felineus

“…Doses of PZQ (400 mg/kg) and Cur (50 mg/kg) were chosen according to published data [ 11 , 26 , 35 , 36 ] and by taking into account the possible toxicity of Cur when it is chronically administered [ 25 ]. The dose of the new Cur:Na 2 GA complex was the same as that of Cur, however, the mass content of Cur in it was 3 times lower [ 31 ].…”

“…Additionally, there was a group of non-infected animals (CON hamsters) that were given additional water for 30 days (to mimic chronic stress due to drug administration) (Figure 1). Doses of PZQ (400 mg/kg) and Cur (50 mg/kg) were chosen according to published data [11,26,35,36] and by taking into account the possible toxicity of Cur when it is chronically administered [25]. The dose of the new Cur:Na 2 GA complex was the same as that of Cur, however, the mass content of Cur in it was 3 times lower [31].…”

Quantitative Metabolomics and Lipoprotein Analysis of PDAC Patients Suggests Serum Marker Categories for Pancreatic Function, Pancreatectomy, Cancer Metabolism, and Systemic Disturbances

“…Quantitative biofluid 1 H nuclear magnetic resonance (NMR)-based metabolomics with in vitro diagnostics regulation (IVDr) compliant assays have been recently emerging and exploited to study a large variety of human diseases, such as prostate and ovarian cancer, human immunodeficiency virus infection, coronavirus infection, and Alzheimer’s disease . Such quantitative parameters also allow refinement of the stratification of diseases.…”

Reduction of carcinogens in fermented fish (pla-ra and pla-som) by heating

“…Chinese-style salted fish is classified as a Group 1 carcinogen due to the formation of N -nitroso compounds during the preparation and steaming processes and causes nasopharyngeal cancer in humans [ 18 ]. Hamsters treated with N -nitrosodimethylamine (NDMA) and OV have been used as animal models for CCA studies in Thailand [ 19 , 20 ]. Gas chromatography has revealed high NDMA levels in fermented fish dishes, such as PR and PS, and in mixed fermented vegetables and fermented beef [ 21 ].…”