curcumin and Hepatitis-B

Hepatitis B virus (HBV) infection is a worldwide health problem, and chronic infection can cause many diseases ranging from liver fibrosis to hepatocellular carcinoma (HCC) by complicated mechanisms. Currently, the treatment of HBV infection mainly depends on interferons (IFNs) and nucleotide analogues (NAs); however, both have some limitations. In 2012, sodium taurocholate cotransporting polypeptide (NTCP) was identified as the entry receptor of HBV. Based upon this groundbreaking discovery, a series of molecules have been gradually developed and evaluated to discover novel entry inhibitors targeting NTCP. However, only two macromolecules have been used for potential clinical applications so far. In this Perspective, we focus on summarizing the structural features that convey the biological functions of NTCP, as well as further discuss the anti-HBV activity and selectivity of inhibitors in HBV-related diseases, which should provide clues in the future for the discovery of drug candidates targeting NTCP.

Topics: Carcinoma, Hepatocellular; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Hepatocytes; Humans; Interferons; Liver Neoplasms; Nucleotides; Organic Anion Transporters, Sodium-Dependent; Symporters; Virus Internalization

Hepatitis B virus (HBV) has been implicated in hepatitis and hepatocellular carcinoma. Current agents (nucleos(t)ide analogs and interferons) could only attenuate HBV infection. A combination of agents targeting different stages of viral life cycle (e.g., entry, replication, and cccDNA stability) was expected to eradicate the infection. Curcumin (CCM) was investigated for inhibitory action toward HBV attachment and internalization. Immortalized hepatocyte-like cells (imHCs), HepaRG and non-hepatic cells served as host cells for binding study with CCM. CCM decreased viral load, HBeAg, HBcAg (infectivity), intracellular HBV DNA, and cccDNA levels. The CCM-induced suppression of HBV entry was directly correlated with the density of sodium-taurocholate co-transporting polypeptide (NTCP), a known host receptor for HBV entry. The site of action of CCM was confirmed using TCA uptake assay. The affinity between CCM and NTCP was measured using isothermal titration calorimetry (ITC). These results demonstrated that CCM interrupted HBV entry and would therefore suppress HBV re-infection.

Topics: Curcumin; DNA, Viral; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Organic Anion Transporters, Sodium-Dependent; Reinfection; Symporters; Viral Envelope Proteins; Virus Internalization

Hepatitis B virus (HBV) infects the liver and uses its cell host for gene expression and propagation. Therefore, targeting host factors essential for HBV gene expression is a potential anti-viral strategy. Here we show that treating HBV expressing cells with the natural phenolic compound curcumin inhibits HBV gene expression and replication. This inhibition is mediated via down-regulation of PGC-1alpha, a starvation-induced protein that initiates the gluconeogenesis cascade and that has been shown to robustly coactivate HBV transcription. We suggest curcumin as a host targeted therapy for HBV infection that may complement current virus-specific therapies.

Topics: Antiviral Agents; Biochemical Phenomena; Curcumin; Down-Regulation; Gene Expression; Gluconeogenesis; Hepatitis B; Hepatitis B virus; Humans; Liver; Pepsin A

Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR(-/y)). HBV-L-AR(-/y) mice that received a low dose of the carcinogen N'-N'-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less alpha-fetoprotein HCC marker than do their wild-type HBV-AR(+/y) littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR(+/y) mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Base Sequence; Carcinoma, Hepatocellular; Cell Transformation, Viral; Curcumin; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; Receptors, Androgen; RNA, Viral; Time Factors; Transcription, Genetic; Transfection; Tumor Burden; Viral Load

A medicinal herb Curcuma longa Linn has been used for treating various liver diseases caused by hepatitis B virus (HBV) in Asia.. The study was performed in order to investigate the antiviral activity of Curcuma longa Linn against HBV replication in liver cells.. Aqueous extract of Curcuma longa Linn (CLL) was prepared and used to analyze its antiviral activity against HBV replication in HepG 2.2.15 cells, which contain HBV genomes. The inhibitory effect of CLL on HBV replication was examined by testing the levels of secreted HBV surface antigens (HBsAg), HBV DNAs, and HBV RNAs in HepG 2.2.15 cells using ELISA, Southern blot, and Northern blot analyses. Cytotoxic activities of CLL extract on various liver cells were analyzed by MTT assay. To dissect the inhibitory mechanism of CLL extract on HBV replication, the levels of p53 protein and p53 mRNAs were analyzed by Western blot and RT-PCR in HepG 2.2.15 cells. The repression of CLL extract on HBV transcription was analyzed by RT-PCR and CAT assay.. CLL extract repressed the secretion of HBsAg from HepG 2.2.15 cells. CLL extract also suppressed the production of HBV particles and the level of intracellular HBV RNAs in HepG 2.2.15 cells, suggesting that CLL extract inhibits HBV replication. We found that the anti-HBV activity of CLL extract is mediated through enhancing the cellular accumulation of p53 protein by transactivating the transcription of p53 gene as well as increasing the stability of p53 protein. It turned out that CLL extract repressed the transcription of HBx gene by suppressing HBV enhancer I and X promoter through p53 protein. In addition, CLL extract did not have any cytotoxic effects on liver cells.. These data showed that CLL extract represses HBV replication through enhancing the level of p53 protein. CLL extract can be used as a safe and specific drug for patients with liver diseases caused by HBV infection.

Topics: Antiviral Agents; Cell Line; Curcuma; DNA, Viral; Enhancer Elements, Genetic; Gene Expression; Genome, Viral; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Liver; Phytotherapy; Plant Extracts; Promoter Regions, Genetic; RNA, Messenger; RNA, Viral; Tumor Suppressor Protein p53; Virus Replication