Promising Anti-Hepatitis C Virus Compounds from Natural Reseurcees

Hepatitis C virus (HCV) infection is a major worldwide problem, which involves approximately 170 million people. High morbidity of patients is caused by chronic infection, which leads to liver cirrhosis, hepatocellular carcinoma and other HCV-related diseases. The sustained virological response (SVR) has been markedly improved to be >90% by the current standard interferon (IFN)-free treatment regimens with a combination of direct-acting antiviral agents (DAAs) targeting the viral NS3 protease, NS5A multi-function protein and NS5B RNA-dependent RNA polymerase, compared with 50–70% of SVR rates achieved by the previous standard IFN-based treatment regimens with or without an NS3 protease inhibitor. However, the emergence of DAA-resistant HCV strains and the limited access to the DAAs due to their high cost could be major concerns. Also, the long-term prognosis of patients treated with DAAs, such as the possible development of hepatocellular carcinoma, still needs to be further evaluated. Natural resources are considered to be good candidates to develop anti-HCV agents. Here, we summarize anti-HCV compounds obtained from natural resources, including medicinal plant extracts, their isolated compounds and some of their derivatives that possess high antiviral potency against HC

Anti-viral activity of Phyllanthus niruri against hepatitis C virus

Hepatitis C virus (HCV) infection is a global problem that causes liver disease and hepatocellular carcinoma. Although the current standard treatment provided a significant improvement on response rate with sustain virology response more than 90%, however, the high cost was remaining limited access to this therapy, resistance emergence and serious side effects which provide the necessities to find the new anti-HCV agents. The current study, we evaluated the ethanol extract of Phyllanthus niruri for its anti-HCV activities. Anti-HCV activity was determined by in vitro culture cells of Huh 7it. Anti-HCV activity of P. niruri extract revealed strong inhibition against HCV with IC50 values of 4.14 µg/mL and yield stronger activity in the entry step of the HCV life cycle. Moreover, the P. niruri extract enhanced anti-HCV activity of simeprevir (NS3 protease inhibitor) with increase the activity up to 4-fold compared to a single treatment of simeprevir. Docking analysis was performed to predict the interaction phyllanthin and hypophyllantin, known compounds of P. niruri against HCV receptor. Both of phyllantin and hypophyllantin were mediated a strong interaction with 4GAG, a protein that involved in entry step of HCV. These results suggested that the ethanol extract of P. niruri may be good candidates for the development of anti-HCV drugs

Aktivitas Sitotoksisitas Ekstrak Metanol Daun Sirsak (Annona muricata L.) terhadap Karsinoma Hepatoseluler Strain HUH7IT-1 Cell Line

ABSTRAKLatar Belakang: Karsinoma hepatoseluler (HCC) merupakan tumor ganas hati primer dengan prognosis pada umumnya dapat menyebabkan kematian. Studi awal penelitian antiviral hepatitis C pada tumbuhan Sirsak (Annona muricata L.) pada konsentrasi 20 μg/mL memperlihatkan toksisitas yang sangat tinggi terhadap Huh7it-1 cell line, yang diindikasi memiliki potensi anti kanker terhadap sel hati, sehingga penelitian ini bertujuan menguji beberapa konsentrasi lebih rendah pada ekstrak metanol daun Annona muricata L. (EMDAM) terhadap Karsinoma Hepatoseluler strain Huh7it-1 cell line.Metode: Sel diuji dengan konsentrasi 20, 10, 5, 2.5, 1.25, 0.6, 0.3 μg/mL selama 48 jam. Sitotoksisitas EMDAM terhadap Huh7it-1 dilihat dengan mikrokop inverted dan selanjutnya diukur dengan metode MTT [3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].Hasil: Hasil uji menunjukkan sel memperlihatkan bentuk tidak monolayer pada mikroskop inverted dengan sitotoksisitas hingga konsentrasi terendah pada 0.3 μg/mL mencapai 84,7%, sehingga konsentrasi 50% Sitotoksisitas (CC50) < 0.3 μg/mL.Simpulan: Hasil uji mengindikasi bahwa EMDAM memiliki potential terhadap aktivitas anti kanker hati. Studi lebih lanjut diperlukan untuk purifikasi untuk senyawa aktif sebagai antikanker atau target mekanisme terhadap aktivitas anti kanker hati.Kata kunci: Karsinoma Hepatoseluler, Huh7it-1, Sitotoksisitas, Annona muricataABSTRACTBackground: Hepatocellular carcinoma (HCC) is a malignant tumor of liver cells with prognosis can cause death within 2-3 months. Previous studies of Annona muricata L. on anti-HCV studies at concentrations of 20 μg / mL showed very high toxicity to Huh7it-1 cell line, it was indicated to have anti-cancer potential of liver cells, so this study tested the potency of anticancer activity extract methanol leaf Annona muricata L. (EMDAM) against Hepatocellular Carcinoma Huh7it-1 strain cell line with low dose.Methods: Cells were tested with concentrations of 20, 10, 5, 2.5, 1.25, 0.6, 0.3 μg / mL for 48 hours. The EMDAM cytotoxicity of Huh7it-1 was seen with an inverted microcomputer and then measured with MTT assay [3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].Results: The results showed that the cells presented non-monolayer form in an inverted microscope with cytotoxicity until the lowest concentration of 0.3 μg / mL reached 84.7%, thus concentrating 50% cytotoxicity (CC50) <0.3 μg / mL.Conclusion: The results indicate that EMDAM has the potential for anti-liver cancer activity. Further studies are needed for purification for active compounds as anticancer or target mechanisms against anti-liver cancer activity.Keywords: Hepatocellular carcinoma, Huh7it-1, Cytotoxicity, Annona muricat

Potent PPARα Activator Derived from Tomato Juice, 13-oxo-9,11-Octadecadienoic Acid, Decreases Plasma and Hepatic Triglyceride in Obese Diabetic Mice

Dyslipidemia is a major risk factor for development of several obesity-related diseases. The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates energy metabolism. Previously, we reported that 9-oxo-10,12-octadecadienoic acid (9-oxo-ODA) is presented in fresh tomato fruits and acts as a PPARα agonist. In addition to 9-oxo-ODA, we developed that 13-oxo-9,11-octadecadienoic acid (13-oxo-ODA), which is an isomer of 9-oxo-ODA, is present only in tomato juice. In this study, we explored the possibility that 13-oxo-ODA acts as a PPARα agonist in vitro and whether its effect ameliorates dyslipidemia and hepatic steatosis in vivo. In vitro luciferase assay experiments revealed that 13-oxo-ODA significantly induced PPARα activation; moreover, the luciferase activity of 13-oxo-ODA was stronger than that of 9-oxo-ODA and conjugated linoleic acid (CLA), which is a precursor of 13-oxo-ODA and is well-known as a potent PPARα activator. In addition to in vitro experiment, treatment with 13-oxo-ODA decreased the levels of plasma and hepatic triglycerides in obese KK-Ay mice fed a high-fat diet. In conclusion, our findings indicate that 13-oxo-ODA act as a potent PPARα agonist, suggesting a possibility to improve obesity-induced dyslipidemia and hepatic steatosis

AntiHepatitis C Virus Activity of Alectryon serratus Leaves Extract

Hepatitis C Virus (HCV) has infected approximately 2-3% (130-170 million) of the world's population. No vaccine is available to prevent HCV infection. Investigation of anti-HCV agent is thus deemed necessary. Various plants have been explored for their anti-HCV activity. A. serratus is a member of Sapindaceae family, which fruit and seed were traditionally used as insecticide. Anti-HCV activity tested on A.serratus leaves extract has been done. The result showed that leaves extract exhibited anti-HCV with IC50 value of 14.9 μg/ml and 9.8 μg/ml against HCV J6/JFH1 and JFH1a, respectively. The cytotoxicity assay results showed that A.serratus leaves extract was not toxic and has CC50 >100 μg/ml. Mode of action experiment results suggested that A.serratus extract inhibited HCV at the post-entry step. Further fractionation of leaves extract by open column chromatography resulted in 4 fractions. Only Fraction 1 (AP-5F.1) exhibited anti-HCV with IC50 value of 1.2 μg/ml against HCV JFH1a. Separation of AP-5F.1 by open column chromatography resulted in 15 fractions. Fraction number 13 (AP-5F.1.13) exhibited anti-HCV with IC50 value of 0.43 μg/ml against HCV JFH1a. Separation of AP-5F.1.13 by semi preparative-HPLC resulted in isolate identified by TLC and LC-MS method as chlorophyll derivate. There was a possibility that chlorophyll derivate has participated in performing the anti-HCV activity of fractions and extract besides the other compounds contained. In this study, we concluded that A. serratus leaves extract, AP-5F.1, and AP-5F.1.13 exhibited anti-HCV activity against JFH1a virus

ANTIHEPATITIS C VIRUS ACTIVITY OF INDONESIAN MAHOGANY (TOONA SURENI)

 Objective: Toona sureni (Indonesian mahogany) is a member of Meliaceae family and locally known as suren. Previous study reported that T. sureni leaves extract exhibited antiviral activity with 50% inhibitory concentration (IC50) value of 13.9 ± 1.6 μg/ml against hepatitis C virus (HCV) J6/JFH1. Cytotoxicity analysis of T. sureni leaves extract did not reveal any cytotoxicity effect; therefore, further study was taken to investigate the active substances from the extract.Methods: Bioassay-guided isolation of anti-HCV was conducted using Huh-7.5 cells infected with HCV J6/JFH1 in the presence of extracts, fractions, or compounds from the plant.Results: Ethyl acetate fraction (Fr E) exhibited high anti-HCV activity with IC50 value of 1.7 μg/ml. Further, separation of Fr E by open column chromatography resulted in nine sub-fractions (sub-Fr E1-E9). Sub-Fr E3 and E4 have IC50 value of 29.90 μg/ml and 7.68 μg/ml, respectively. Polyphenols compounds have been isolated from sub-Fr E3 and E4. The structures have been determined to be ethyl gallate (1), methyl gallate (2), catechin (3), gallic acid (4), and quercetin 3-O-rhamnoside (5). Among the isolated compounds, gallic acid showed to possess strong anti-HCV activity with IC50 value of 15.9 μg/ml.Conclusion: T. sureni and its isolated compound, gallic acid, may be good candidates to develop for alternative and/or complementary agents of anti-HCV infection

Antiviral activities of curcuma genus against hepatitis C virus

Hepatitis C virus (HCV) infection is one of the major public health problems in the world. Even though the new agents are shown to increase the sustained virology response, however, there are still many people who cannot access the therapy due to the high cost. Moreover, the emergence of resistance and side effects presented the necessity to develop alternative treatment agents for HCV infection. Plants of the genus of curcuma are popular among traditional medicines in the world, including Indonesia. They have been used for many herb remedies and reported to possess many biological activities. Several plants from the curcuma genus were known as treatment agents in liver disease and jaundice. Our current study determines antiviral activities of Curcuma domestica, Curcuma xanthorrhiza, and Curcuma heyneana against HCV and further examines the mechanism of actions. Antiviral activity was performed by in vitro culture cells using Huh 7.5it cells and treated with the mixture of extract and virus JFH1. The effects of extracts in HCV life cycle were determined by mode of action analysis to examine the action of substances in the entry or post entry steps. The results revealed that ethanol extract of C. domestica, C. xanthorrhiza, and C. heyneana showed strong anti-HCV activities with IC50 values of 1.68 ± 0.05, 4.93 ± 0.42 and 5.49 ± 0.59 µg/mL, respectively without any cytotoxicity effect. Mode of action analysis demonstrated that of C. domestica and C. heyneana exhibit HCV in the entry step, while C. xanthorrhiza inhibit in the entry and post entry steps of HCV life cycle. Docking analysis to predict the interaction of curcumin, the main compound of curcuma genus, revealed a strong interaction between curcumin and 4GAG receptor, a protein involved in the entry step of HCV infection. Moreover, it was also reported to possess good interaction with 4EAW, an HCV NS5B, which plays an important role in HCV replication. These results suggested that C. domestica, C. xanthorrhiza, and C. Heyneana possessed strong inhibition against hepatitis C virus, therefore they may be good candidates for anti-HCV agents

Antiviral Activities of Indonesian Medicinal Plants in the East Java Region Against Hepatitis C Virus

Background Hepatitis C virus (HCV) is a major cause of liver disease and a potential cause of substantial morbidity and mortality worldwide. The overall prevalence of HCV infection is 2%, representing 120 million people worldwide. Current standard treatment using pegylated interferon and ribavirin is effective in only 50% of the patients infected with HCV genotype 1, and is associated with significant side effects. Therefore, it is still of importance to develop new drugs for treatment of HCV. Antiviral substances obtained from natural products, including medicinal plants, are potentially good targets to study. In this study, we evaluated Indonesian medicinal plants for their anti-HCV activities. Methods Ethanol extracts of 21 samples derived from 17 species of medicinal plants explored in the East Java region were tested. Anti-HCV activities were determined by a cell culture method using Huh7.5 cells and HCV strains of 9 different genotypes (1a to 7a, 1b and 2b). Results Four of the 21 samples tested showed antiviral activities against HCV: Toona sureni leaves (TSL) with 50% inhibitory concentrations (IC50) of 13.9 and 2.0 μg/ml against the HCV J6/JFH1-P47 and -P1 strains, respectively, Melicope latifolia leaves (MLL) with IC50 of 3.5 and 2.1 μg/ml, respectively, Melanolepis multiglandulosa stem (MMS) with IC50 of 17.1 and 6.2 μg/ml, respectively, and Ficus fistulosa leaves (FFL) with IC50 of 15.0 and 5.7 μg/ml, respectively. Time-of-addition experiments revealed that TSL and MLL inhibited both at the entry and post-entry steps while MMS and FFL principally at the entry step. TSL and MLL inhibited all of 11 HCV strains of all the genotypes tested to the same extent. On the other hand, FFL showed significantly weaker inhibitory activities against the HCV genotype 1a strain, and MMS against the HCV strains of genotypes 2b and 7a to a lesser extent, compared to the other HCV genotypes. Conclusions Ethanol extracts of TSL, MLL, MMS and FFL showed antiviral activities against all the HCV genotypes tested with the exception that some genotype(s) showed significant resistance to FFL and to MMS to a lesser extent. These plant extracts may be good candidates for the development of anti-HCV drug

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