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Shahsavari K, Ardekani SS, Ardekani MRS, Esfahani MM, Kazemizadeh H, Jamialahmadi T, Iranshahi M, Khanavi M, Hasanpour M. Are alterations needed in Silybum marianum (Silymarin) administration practices? A novel outlook and meta-analysis on randomized trials targeting liver injury. BMC Complement Med Ther 2025; 25:134. [PMID: 40221681 PMCID: PMC11992775 DOI: 10.1186/s12906-025-04886-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
It is widely believed that Silybum marianum (Silymarin) alleviates liver injury arising from various etiologies with different degrees of damage through its anti-inflammatory and antioxidant activities. This meta-analysis investigated the effects of silymarin administration on serum levels of liver enzymes including AST, ALT and ALP. From inception to November, 2023, a comprehensive literature search was conducted. Inclusion criteria for this study were randomized trials that provided sufficient data for each group at the beginning and end of the follow-up period. Ultimately, 55 studies with a total of 3545 patients were included. Comprehensive Meta-Analysis (CMA) V4 software was used for meta-analysis. Begg's funnel plot symmetry status, Begg's rank correlation, and Egger's weighted regression tests were used to examine potential publication bias. According to the findings of this meta-analysis silymarin administration showed a significant reduction in AST (SMD [95% CI]: - 0.670 [- 0.931, - 0.408], p-value = 0.000), and ALT (SMD [95% CI]: - 0.912 [- 1.177, - 0.646], p-value = 0.000) levels. While it had no statistically significant effect on ALP level (SMD [95% CI]: - 0.236 [- 1.929, 1.458], p-value = 0.159). Meta-regression analysis showed that there is no significant association between dose, age, BMI, treatment duration and hepatoprotective effects of silymarin. In subgroup analysis, a greater reduction in liver enzymes levels was observed in patients under 50 years old. The subgroup analysis was also showed significant decrease in AST and ALT levels for patients with BMI less than 30, while silymarin treatment had no significant effects on AST and ALT levels in patients with BMI ≥ 30. Silymarin at a dose of less than 400 mg and treatment duration ≤ 2 months showed greater decreasing effects on AST and ALT levels compared to its high doses and longer treatment duration. AST and ALT levels significantly decreased in patients with NAFLD and viral hepatitis, while it had no significant hepatoprotective effects in patients with drugs induced liver injury and alcohol-related liver disease. Modifying the dose and treatment duration with silymarin is recommended in patients with various causes of liver damage.
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Affiliation(s)
- Kasra Shahsavari
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Reza Shams Ardekani
- Department of Pharmacognosy, Faculty of Pharmacy, and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, PO Box: 14155 - 6451, Tehran, Iran
| | - Majid Mokaber Esfahani
- Department of Chemistry, Faculty of Science, Gonbad Kavous University, Gonbad Kavous, Iran
| | - Hossein Kazemizadeh
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahnaz Khanavi
- Department of Pharmacognosy, Faculty of Pharmacy, and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, PO Box: 14155 - 6451, Tehran, Iran.
| | - Maede Hasanpour
- Department of Pharmacognosy, Faculty of Pharmacy, and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, PO Box: 14155 - 6451, Tehran, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Schäfer N, Rothhaar P, Heuss C, Neumann-Haefelin C, Thimme R, Dietz J, Sarrazin C, Schnitzler P, Merle U, Pérez-del-Pulgar S, Laketa V, Lohmann V. Detection of Hepatitis C Virus Infection from Patient Sera in Cell Culture Using Semi-Automated Image Analysis. Viruses 2024; 16:1871. [PMID: 39772180 PMCID: PMC11680372 DOI: 10.3390/v16121871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 01/30/2025] Open
Abstract
The study of hepatitis C virus (HCV) replication in cell culture is mainly based on cloned viral isolates requiring adaptation for efficient replication in Huh7 hepatoma cells. The analysis of wild-type (WT) isolates was enabled by the expression of SEC14L2 and by inhibitors targeting deleterious host factors. Here, we aimed to optimize cell culture models to allow infection with HCV from patient sera. We used Huh7-Lunet cells ectopically expressing SEC14L2, CD81, and a GFP reporter with nuclear translocation upon cleavage by the HCV protease to study HCV replication, combined with a drug-based regimen for stimulation of non-modified wild-type isolates. RT-qPCR-based quantification of HCV infections using patient sera suffered from a high background in the daclatasvir-treated controls. We therefore established an automated image analysis pipeline based on imaging of whole wells and iterative training of a machine learning tool, using nuclear GFP localization as a readout for HCV infection. Upon visual validation of hits assigned by the automated image analysis, the method revealed no background in daclatasvir-treated samples. Thereby, infection events were found for 15 of 34 high titer HCV genotype (gt) 1b sera, revealing a significant correlation between serum titer and successful infection. We further show that transfection of viral RNA extracted from sera can be used in this model as well, albeit with so far limited efficiency. Overall, we generated a robust serum infection assay for gt1b isolates using semi-automated image analysis, which was superior to conventional RT-qPCR-based quantification of viral genomes.
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Affiliation(s)
- Noemi Schäfer
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Heidelberg University, 69120 Heidelberg, Germany
| | - Paul Rothhaar
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Heidelberg University, 69120 Heidelberg, Germany
| | - Christian Heuss
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Heidelberg University, 69120 Heidelberg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Julia Dietz
- Department of Internal Medicine 1, University Hospital, Goethe University, 60596 Frankfurt, Germany
- German Center for Infection Research (DZIF), Partner Site Frankfurt, 60596 Frankfurt, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine 1, University Hospital, Goethe University, 60596 Frankfurt, Germany
- German Center for Infection Research (DZIF), Partner Site Frankfurt, 60596 Frankfurt, Germany
- Medizinische Klinik 2, St. Josefs-Hospital, 65189 Wiesbaden, Germany
| | - Paul Schnitzler
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Sofía Pérez-del-Pulgar
- Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, 08036 Barcelona, Spain;
| | - Vibor Laketa
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- German Center for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Heidelberg University, 69120 Heidelberg, Germany
- German Center for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany
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Pereira-Filho JL, Mendes AGG, Campos CDL, Moreira IV, Monteiro CRAV, Soczek SHDS, Fernandes ES, Carvalho RC, Monteiro-Neto V. A Comprehensive Review on the Antibacterial, Antifungal, Antiviral, and Antiparasitic Potential of Silybin. Antibiotics (Basel) 2024; 13:1091. [PMID: 39596784 PMCID: PMC11591437 DOI: 10.3390/antibiotics13111091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
Silybin, a flavonolignan extracted from the seeds of the plant species Silybum marianum (L.) Gaertn., has a variety of pharmacological activities, including antimicrobial activity against several microorganisms of clinical interest. This review analyzes the existing studies on silybin's antimicrobial activity and possible mechanisms of action. Silybin has been shown to inhibit the growth of Gram-positive and Gram-negative bacteria, as well as some fungi, viruses, and protozoa. In general, possible mechanisms of antimicrobial action include the inhibition of efflux pumps, prevention of biofilm formation, reduction of the expression of virulence factors, induction of apoptosis-like effects, and plasma membrane damage, as well as the inhibition of nucleic acid and protein synthesis. Silybin has been shown to have synergistic effects when combined with conventional antibiotics against both drug-sensitive and drug-resistant microorganisms. However, the low bioavailability observed for this flavonolignan has been a challenge to its clinical use. In this context, nanotechnology has been used to increase silybin's bioavailability while enhancing its antimicrobial activity. Furthermore, certain structural modifications have been able to enhance its antimicrobial activity in comparison to that of the natural molecule. Overall, this review provides insights into the scientific understanding of the mechanism of action of silybin and its desired properties for the effective treatment of infections.
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Affiliation(s)
- José Lima Pereira-Filho
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Amanda Graziela Gonçalves Mendes
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Carmem Duarte Lima Campos
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Israel Viegas Moreira
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Cinara Regina Aragão Vieira Monteiro
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Suzany Hellen da Silva Soczek
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.d.S.S.); (E.S.F.)
- Faculdades Pequeno Príncipe, Curitiba 80250-060, PR, Brazil
| | - Elizabeth Soares Fernandes
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.d.S.S.); (E.S.F.)
- Faculdades Pequeno Príncipe, Curitiba 80250-060, PR, Brazil
| | - Rafael Cardoso Carvalho
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
| | - Valério Monteiro-Neto
- Centro de Ciências da Saúde, Universidade Federal do Maranhão—UFMA, São Luís 65080-805, MA, Brazil; (J.L.P.-F.); (A.G.G.M.); (C.D.L.C.); (I.V.M.); (C.R.A.V.M.); (R.C.C.)
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Selc M, Macova R, Babelova A. Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders. Drug Des Devel Ther 2024; 18:4629-4659. [PMID: 39444787 PMCID: PMC11498047 DOI: 10.2147/dddt.s483140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.
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Affiliation(s)
- Michal Selc
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Radka Macova
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Genetics, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovakia
| | - Andrea Babelova
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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Jayanti S, Vitek L, Verde CD, Llido JP, Sukowati C, Tiribelli C, Gazzin S. Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases. Biomolecules 2024; 14:63. [PMID: 38254662 PMCID: PMC10813662 DOI: 10.3390/biom14010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.
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Affiliation(s)
- Sri Jayanti
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16915, Indonesia
| | - Libor Vitek
- Institute of Medical Biochemistry and Laboratory Diagnostics, and 4th Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, 12000 Prague, Czech Republic;
| | - Camilla Dalla Verde
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Department of Life Sciences, University of Trieste, 34139 Trieste, Italy
| | - John Paul Llido
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Department of Life Sciences, University of Trieste, 34139 Trieste, Italy
- Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig City 1631, Philippines
| | - Caecilia Sukowati
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16915, Indonesia
| | - Claudio Tiribelli
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
| | - Silvia Gazzin
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
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Mandal A, Hazra B. Medicinal plant molecules against hepatitis C virus: Current status and future prospect. Phytother Res 2023; 37:4353-4374. [PMID: 37439007 DOI: 10.1002/ptr.7936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 07/14/2023]
Abstract
Hepatitis C virus (HCV), a global malady, causes acute and chronic hepatitis leading to permanent liver damage, hepatocellular carcinoma, and death. Modern anti-HCV therapies are efficient, but mostly inaccessible for residents of underdeveloped regions. To innovate more effective treatments at affordable cost, medicinal plant-based products need to be explored. The aim of this article is to review plant constituents in the light of putative anti-HCV mechanisms of action, and discuss existing problems, challenges, and future directions for their potential application in therapeutic settings. One hundred sixty literatures were collected by using appropriate search strings via scientific search engines: Google Scholar, PubMed, ScienceDirect, and Scopus. Bibliography was prepared using Mendeley desktop software. We found a substantial number of plants that were reported to inhibit different stages of HCV life cycle. Traditional medicinal plants such as Phyllanthus amarus Schumach. and Thonn., Eclipta alba (L.) Hassk., and Acacia nilotica (L.) Delile exhibited strong anti-HCV activities. Again, several phytochemicals such as epigallocatechin-3-gallate, honokilol, punicalagin, and quercetin have shown broad-spectrum anti-HCV effect. We have presented promising phytochemicals like silymarin, curcumin, glycyrrhizin, and camptothecin for nanoparticle-based hepatocyte-targeted drug delivery. Nevertheless, only a few animal studies have been performed to validate the anti-HCV effect of these plant products. Again, insufficient clinical evaluation of the safety and effectiveness of herbal medications remain a problem. Selected plants products could be developed as novel therapeutics for HCV patients only after scrupulous evaluation of their safety and efficacy in a clinical set-up.
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Affiliation(s)
- Anirban Mandal
- Department of Microbiology, Mrinalini Datta Mahavidyapith, Birati, Kolkata, India
| | - Banasri Hazra
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
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Zarenezhad E, Abdulabbas HT, Kareem AS, Kouhpayeh SA, Barbaresi S, Najafipour S, Mazarzaei A, Sotoudeh M, Ghasemian A. Protective role of flavonoids quercetin and silymarin in the viral-associated inflammatory bowel disease: an updated review. Arch Microbiol 2023; 205:252. [PMID: 37249707 DOI: 10.1007/s00203-023-03590-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/14/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent inflammation of the gastrointestinal tract (GIT). IBD patients are susceptible to various infections such as viral infections due to the long-term consumption of immunosuppressive drugs and biologics. The antiviral and IBD protective traits of flavonoids have not been entirely investigated. This study objective included an overview of the protective role of flavonoids quercetin and silymarin in viral-associated IBD. Several viral agents such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and enteric viruses can be reactivated and thus develop or exacerbate the IBD conditions or eventually facilitate the disease remission. Flavonoids such as quercetin and silymarin are non-toxic and safe bioactive compounds with remarkable anti-oxidant, anti-inflammatory and anti-viral effects. Mechanisms of anti-inflammatory and antiviral effects of silymarin and quercetin mainly include immune modulation and inhibition of caspase enzymes, viral binding and replication, RNA synthesis, viral proteases and viral assembly. In the nutraceutical sector, natural flavonoids low bioavailability and solubility necessitate the application of delivery systems to enhance their efficacy. This review study provided an updated understanding of the protective role of quercetin and silymarin against viral-associated IBD.
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Affiliation(s)
- Elham Zarenezhad
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Hussein T Abdulabbas
- Department of Medical Microbiology, Medical College, Al Muthanna University, Al Muthanna, Iraq
| | - Ahmed Shayaa Kareem
- Department of Medical Laboratories Techniques, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
| | - Seyed Amin Kouhpayeh
- Department of Pharmacology, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Silvia Barbaresi
- Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium
| | - Sohrab Najafipour
- Department of Microbiology, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Abdulbaset Mazarzaei
- Department of Immunology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Mitra Sotoudeh
- Department of Nutrition, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Abdolmajid Ghasemian
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
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Ponticelli M, Bellone ML, Parisi V, Iannuzzi A, Braca A, de Tommasi N, Russo D, Sileo A, Quaranta P, Freer G, Pistello M, Milella L. Specialized metabolites from plants as a source of new multi-target antiviral drugs: a systematic review. PHYTOCHEMISTRY REVIEWS : PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE 2023; 22:1-79. [PMID: 37359711 PMCID: PMC10008214 DOI: 10.1007/s11101-023-09855-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 01/30/2023] [Indexed: 06/28/2023]
Abstract
Viral infections have always been the main global health challenge, as several potentially lethal viruses, including the hepatitis virus, herpes virus, and influenza virus, have affected human health for decades. Unfortunately, most licensed antiviral drugs are characterized by many adverse reactions and, in the long-term therapy, also develop viral resistance; for these reasons, researchers have focused their attention on investigating potential antiviral molecules from plants. Natural resources indeed offer a variety of specialized therapeutic metabolites that have been demonstrated to inhibit viral entry into the host cells and replication through the regulation of viral absorption, cell receptor binding, and competition for the activation of intracellular signaling pathways. Many active phytochemicals, including flavonoids, lignans, terpenoids, coumarins, saponins, alkaloids, etc., have been identified as potential candidates for preventing and treating viral infections. Using a systematic approach, this review summarises the knowledge obtained to date on the in vivo antiviral activity of specialized metabolites extracted from plant matrices by focusing on their mechanism of action.
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Affiliation(s)
- Maria Ponticelli
- Department of Science, University of Basilicata, Viale Dell’ateneo Lucano 10, 85100 Potenza, Italy
| | - Maria Laura Bellone
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
- Ph.D. Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
| | - Valentina Parisi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
- Ph.D. Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
| | - Annamaria Iannuzzi
- Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy
- Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56100 Pisa, Italy
- Retrovirus Center, Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Alessandra Braca
- Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy
- Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56100 Pisa, Italy
- Retrovirus Center, Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Nunziatina de Tommasi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
| | - Daniela Russo
- Department of Science, University of Basilicata, Viale Dell’ateneo Lucano 10, 85100 Potenza, Italy
| | - Annalisa Sileo
- Department of Science, University of Basilicata, Viale Dell’ateneo Lucano 10, 85100 Potenza, Italy
| | | | - Giulia Freer
- Virology Unit, Pisa University Hospital, Pisa, Italy
| | | | - Luigi Milella
- Department of Science, University of Basilicata, Viale Dell’ateneo Lucano 10, 85100 Potenza, Italy
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9
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Mukherjee S, Sharma D, Sharma AK, Jaiswal S, Sharma N, Borah S, Kaur G. Flavan-based phytoconstituents inhibit Mpro, a SARS-COV-2 molecular target, in silico. J Biomol Struct Dyn 2022; 40:11545-11559. [PMID: 34348081 DOI: 10.1080/07391102.2021.1960196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A well-validated in-silico approach can provide promising drug candidates for the treatment of the ongoing CoVID19 pandemic. In this study, we have screened 32 phytochemical constituents (PCCs) with Mpro binding site (PDB:6W63) based on which we identified three possible candidates that are likely to be effective against CoVID19-viz., licoleafol (binding energy: -8.1 kcal/mol), epicatechin gallate (-8.5 kcal/mol) and silibinin (-8.4 kcal/mol) that result in higher binding affinity than the known inhibitor, X77 (-7.7 kcal/mol). Molecular dynamics (MD) simulations of PCCs-Mpro complex confirmed molecular docking results with high structural and dynamical stability. The selected compounds were found to exhibit low mean squared displacements (licoleafol: 2.25 ± 0.43 Å, epicatechin gallate: 1.93 ± 0.35 Å, and silibinin: 1.39 ± 0.19 Å) and overall low fluctuations of the binding complexes (root mean squared fluctuations below 2 Å). Visualization of the MD trajectories and structural analyses revealed that they remain confined to the initial binding region, with mean fluctuations lower than 3 Å. To access the collective motion of the atoms, we performed principal component analysis demonstrating that the first 10 principal components are the major contributors (approximate contribution of 80%) and are responsible for the overall PCCs motion. Considering that the three selected PCCs share the same flavan backbone and exhibit antiviral activity against hepatitis C, we opine that licoleafol, epi-catechin gallate, and silibinin can be promising anti-CoVID19 drug candidates. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Soham Mukherjee
- School of Pharmaceutical Sciences, Shoolini University, Solan, India.,Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, India
| | - Deepika Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, India
| | - Ajay Kumar Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, India
| | - Shreya Jaiswal
- School of Pharmaceutical Sciences, Shoolini University, Solan, India
| | - Nancy Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, India
| | - Sangkha Borah
- Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Gurjot Kaur
- School of Pharmaceutical Sciences, Shoolini University, Solan, India
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10
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Musazadeh V, Karimi A, Bagheri N, Jafarzadeh J, Sanaie S, Vajdi M, Karimi M, Niazkar HR. The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms. Biomed Pharmacother 2022; 154:113593. [PMID: 36027611 PMCID: PMC9393179 DOI: 10.1016/j.biopha.2022.113593] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 11/11/2022] Open
Abstract
The proceeding pandemic of coronavirus disease 2019 is the latest global challenge. Like most other infectious diseases, inflammation, oxidative stress, and immune system dysfunctions play a pivotal role in the pathogenesis of COVID-19. Furthermore, the quest of finding a potential pharmaceutical therapy for preventing and treating COVID-19 is still ongoing. Silymarin, a mixture of flavonolignans extracted from the milk thistle, has exhibited numerous therapeutic benefits. We reviewed the beneficial effects of silymarin on oxidative stress, inflammation, and the immune system, as primary factors involved in the pathogenesis of COVID-19. We searched PubMed/Medline, Web of Science, Scopus, and Science Direct databases up to April 2022 using the relevant keywords. In summary, the current review indicates that silymarin might exert therapeutic effects against COVID-19 by improving the antioxidant system, attenuating inflammatory response and respiratory distress, and enhancing immune system function. Silymarin can also bind to target proteins of SARS-CoV-2, including main protease, spike glycoprotein, and RNA-dependent RNA-polymerase, leading to the inhibition of viral replication. Although multiple lines of evidence suggest the possible promising impacts of silymarin in COVID-19, further clinical trials are encouraged.
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Affiliation(s)
- Vali Musazadeh
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Karimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Nasim Bagheri
- Department of microbiology Islamic Azad University of medical science, Tehran, Iran
| | - Jaber Jafarzadeh
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mozhde Karimi
- Department of Immunology, Faculty ofMedical Sciences ,Tarbiat Modares University
| | - Hamid Reza Niazkar
- Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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11
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Silybin induces endothelium-dependent vasodilation via TRPV4 channels in mouse mesenteric arteries. Hypertens Res 2022; 45:1954-1963. [PMID: 36056206 DOI: 10.1038/s41440-022-01000-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/08/2022]
Abstract
Silybin is a flavonolignan extracted from the seeds of Silybum marianum that has been used as a dietary supplement for treating hepatic diseases and components of metabolic syndrome such as diabetes, obesity and hypertension. Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+-permeable, nonselective cation channels that regulate vascular endothelial function and blood flow. However, the relationship between silybin and TRPV4 channels in small mesenteric arteries remains unknown. In our study, we carried out a molecular docking experiment by using Discovery Studio v3.5 to predict the binding of silybin to TRPV4. Activation of TRPV4 with silybin was detected via intracellular Ca2+ concentration ([Ca2+]i) measurement and patch clamp experiments. The molecular docking results showed that silybin was likely to bind to the ankyrin repeat domain of TPRV4. [Ca2+]i measurements in mesenteric arterial endothelial cells (MAECs) and TRPV4-overexpressing HEK293 (TRPV4-HEK293) cells demonstrated that silybin induced Ca2+ influx by activating TRPV4 channels. The patch clamp experiments indicated that in TRPV4-HEK293 cells, silybin induced TRPV4-mediated cation currents. In addition, in high-salt-induced hypertensive mice, oral administration of silybin decreased systolic blood pressure (SBP) and significantly improved the arterial dilatory response to acetylcholine. Our findings provide the first evidence that silybin could induce mesenteric endothelium-dependent vasodilation and reduce blood pressure in high-salt-induced hypertensive mice via TRPV4 channels, thereby revealing the potential effect of silybin on preventing endothelial dysfunction-related cardiovascular diseases.
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12
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Mechanistic Insights into the Pharmacological Significance of Silymarin. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165327. [PMID: 36014565 PMCID: PMC9414257 DOI: 10.3390/molecules27165327] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/29/2022]
Abstract
Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70–80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, β-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.
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13
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Ding Y, Zhang S, Sun Z, Tong Z, Ge Y, Zhou L, Xu Q, Zhou H, Wang W. Preclinical validation of silibinin/albumin nanoparticles as an applicable system against acute liver injury. Acta Biomater 2022; 146:385-395. [PMID: 35460909 DOI: 10.1016/j.actbio.2022.04.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Silibinin (SIL) has been extensively studied for its therapeutic effects on various liver diseases. However, its effect on acute liver injury was limited for poor solubility and low bioavailability. Thus, we prepared SIL and bovine serum albumin (SIL/BSA) nanoparticles and further evaluated their therapeutic efficacy against acute liver injury in mouse models. METHODS SIL/BSA nanoparticles were prepared via a nanoprecipitation method. Both in vitro cell culture model and in vivo mouse models of acetaminophen (APAP) and lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury were used to evaluate the therapeutic effect of SIL/BSA nanoparticles and potential mechanisms. RESULTS The SIL/BSA nanoparticles with hydrophilic diameters of 90 ± 29 nm were stably suspended. SIL/BSA nanoparticles presented better biocompatibility and more liver distribution in vivo than SIL microparticles. SIL/BSA nanoparticles significantly alleviated APAP and LPS/D-GalN induced acute liver injury in mice. Similarly, SIL/BSA nanoparticles remarkably enhanced the viability of hepatocytes in vitro against both APAP and LPS/D-GalN induced hepatocyte damage. Moreover, SIL/BSA nanoparticles exhibited antioxidant effects against intracellular oxidative stress via upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway, decreasing ROS and regulating antioxidant enzyme reactivity. And the downstream of mitochondria damage and caspase 9/3 related apoptosis pathway was also inhibited CONCLUSION: SIL/BSA nanoparticles were successfully prepared to enhance the liver availability of SIL. Both in vivo and in vitro, SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer. STATEMENT OF SIGNIFICANCE In our study, we prepared small-size, stable and well-dispersed silibinin/bovine serum albumin (SIL/BSA) nanoparticles via using simple and cost-effective nanoprecipitation techniques. Their physicochemical and pharmacokinetic characteristics were analyzed. We systematically studied the hepatoprotective and antioxidant efficacy of SIL/BSA both in vivo and in vitro, using two acute liver injury models. These findings revealed that SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer.
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Vilahur G, Sutelman P, Mendieta G, Ben-Aicha S, Borrell-Pages M, Peña E, Crespo J, Casaní L, Badimon L. Triglyceride-induced cardiac lipotoxicity is mitigated by Silybum marianum. Atherosclerosis 2021; 324:91-101. [PMID: 33857761 DOI: 10.1016/j.atherosclerosis.2021.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 02/21/2021] [Accepted: 03/10/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND AIMS Silybum marianum (SM) is an herbal product with cytoprotective and antioxidant properties. We have previously demonstrated that SM ameliorates ventricular remodeling and improves cardiac performance. Here, we evaluated whether SM could exert beneficial effects against cardiac lipotoxicity in a pig model of closed-chest myocardial infarction (MI). METHODS Study 1 investigated the effect of SM administration on lipid profile and any potential SM-related adverse effects. Animals received SM or placebo during 10 days and were afterward sacrificed. Study 2 evaluated the effectiveness of SM daily administration in reducing cardiac lipotoxicity in animals subjected to a 1.5h myocardial infarction (MI), who were subsequently reperfused for 2.5h and euthanized or kept under study for three weeks and then sacrificed. RESULTS Animals administered a 10-day SM regime presented a sharp decline in plasma triglyceride levels vs. controls, with no other modifications in lipid profile. The decrease in triglyceride concentration was accompanied by a marked reduction in triglyceride intestinal absorption and glycoprotein-P expression. Three weeks post-MI the triglyceride content in the ischemic myocardium of the SM-treated animals was significantly lower than in the ischemic myocardium of placebo-controls. This effect was associated with an enhanced cardiac expression of PPARγ and triglyceride clearance receptors. This long-term SM-administration induced a lower expression of lipid receptors in subcutaneous adipose tissue. No SM-related side-effects were registered. CONCLUSION SM administration reduces plasma triglyceride levels through attenuation of triglyceride intestinal absorption and modulates cardiac lipotoxicity in the ischemic myocardium, likely contributing to improve ventricular remodeling.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain; CiberCV, Institute Carlos III, Madrid, Spain
| | - Pablo Sutelman
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Guiomar Mendieta
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain; Department of Cardiology, Clinic Hospital, Barcelona, Spain
| | - Soumaya Ben-Aicha
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - María Borrell-Pages
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Esther Peña
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Javier Crespo
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Laura Casaní
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain; CiberCV, Institute Carlos III, Madrid, Spain
| | - Lina Badimon
- Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain; CiberCV, Institute Carlos III, Madrid, Spain; Chair UAB, Barcelona, Spain.
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15
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Ali SI, Sheikh WM, Rather MA, Venkatesalu V, Muzamil Bashir S, Nabi SU. Medicinal plants: Treasure for antiviral drug discovery. Phytother Res 2021; 35:3447-3483. [PMID: 33590931 PMCID: PMC8013762 DOI: 10.1002/ptr.7039] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022]
Abstract
The pandemic of viral diseases like novel coronavirus (2019-nCoV) prompted the scientific world to examine antiviral bioactive compounds rather than nucleic acid analogous, protease inhibitors, or other toxic synthetic molecules. The emerging viral infections significantly associated with 2019-nCoV have challenged humanity's survival. Further, there is a constant emergence of new resistant viral strains that demand novel antiviral agents with fewer side effects and cell toxicity. Despite significant progress made in immunization and regenerative medicine, numerous viruses still lack prophylactic vaccines and specific antiviral treatments that are so often influenced by the generation of viral escape mutants. Of importance, medicinal herbs offer a wide variety of therapeutic antiviral chemotypes that can inhibit viral replication by preventing viral adsorption, adhering to cell receptors, inhibiting virus penetration in the host cell, and competing for pathways of activation of intracellular signals. The present review will comprehensively summarize the promising antiviral activities of medicinal plants and their bioactive molecules. Furthermore, it will elucidate their mechanism of action and possible implications in the treatment/prevention of viral diseases even when their mechanism of action is not fully understood, which could serve as the base for the future development of novel or complementary antiviral treatments.
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Affiliation(s)
- Sofi Imtiyaz Ali
- Biochemistry & Molecular Biology Lab, Division of veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Srinagar, India
| | - Wajid Mohammad Sheikh
- Biochemistry & Molecular Biology Lab, Division of veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Srinagar, India
| | - Muzafar Ahmad Rather
- Biochemistry & Molecular Biology Lab, Division of veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Srinagar, India
| | | | - Showkeen Muzamil Bashir
- Biochemistry & Molecular Biology Lab, Division of veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Srinagar, India
| | - Showkat Ul Nabi
- Large Animal Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Srinagar, India
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16
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Abstract
Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.
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17
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Mailly L, Baumert TF. Hepatitis C virus infection and tight junction proteins: The ties that bind. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183296. [PMID: 32268133 DOI: 10.1016/j.bbamem.2020.183296] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 02/07/2023]
Abstract
The hepatitis C virus (HCV) is a major cause of liver diseases ranging from liver inflammation to advanced liver diseases like cirrhosis and hepatocellular carcinoma (HCC). HCV infection is restricted to the liver, and more specifically to hepatocytes, which represent around 80% of liver cells. The mechanism of HCV entry in human hepatocytes has been extensively investigated since the discovery of the virus 30 years ago. The entry mechanism is a multi-step process relying on several host factors including heparan sulfate proteoglycan (HSPG), low density lipoprotein receptor (LDLR), tetraspanin CD81, Scavenger Receptor class B type I (SR-BI), Epidermal Growth Factor Receptor (EGFR) and Niemann-Pick C1-like 1 (NPC1L1). Moreover, in order to establish a persistent infection, HCV entry is dependent on the presence of tight junction (TJ) proteins Claudin-1 (CLDN1) and Occludin (OCLN). In the liver, tight junction proteins play a role in architecture and homeostasis including sealing the apical pole of adjacent cells to form bile canaliculi and separating the basolateral domain drained by sinusoidal blood flow. In this review, we will highlight the role of liver tight junction proteins in HCV infection, and we will discuss the potential targeted therapeutic approaches to improve virus eradication.
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Affiliation(s)
- Laurent Mailly
- Université de Strasbourg, INSERM, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, F-67000 Strasbourg, France.
| | - Thomas F Baumert
- Université de Strasbourg, INSERM, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, F-67000 Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; Institut Universitaire de France, F-75231 Paris, France.
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18
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Wang F, Chen S, Ren L, Wang Y, Li Z, Song T, Zhang H, Yang Q. The Effect of Silibinin on Protein Expression Profile in White Adipose Tissue of Obese Mice. Front Pharmacol 2020; 11:55. [PMID: 32184719 PMCID: PMC7059093 DOI: 10.3389/fphar.2020.00055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/20/2020] [Indexed: 01/07/2023] Open
Abstract
Objective To investigate the effect of silibinin on the protein expression profile of white adipose tissue (WAT) in obese mice by using Tandem Mass Tag (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods According to experimental requirements, 36 C57BL/6JC mice were randomly divided into normal diet group (WC group), high fat diet group (WF group), and high fat diet + silibinin group (WS group). WS group was intragastrically administered with 54 mg/kg body weight of silibinin, and the WC group and the WF group were intragastrically administered with equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. IPGTT was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. TMT combined with LC-MS/MS were used to study the expression of WAT, and its cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics. Finally, RT-PCR and LC-MS/MS were used to detect the mRNA and protein expressions of FABP5, Plin4, GPD1, and AGPAT2, respectively. Results Although silibinin did not reduce the mice's weight, it did improve glucose metabolism. In addition, silibinin decreased the concentration of TC, TG, and LDL-C and increased the concentration of HDL-C in the serum of mice. In the WF/WS group, 182 differentially expressed proteins were up-regulated and 159 were down-regulated. While in the WS/WF group, 362 differentially expressed proteins were up-regulated and 176 were down-regulated. Further analysis found that these differential proteins are mainly distributed in the peroxisome proliferation-activated receptor (PPAR), lipolysis of fat cells, metabolism of glycerides, oxidative phosphorylation, and other signaling pathways, and participate in cell processes and lipid metabolism through catalysis and integration functions. Specifically, silibinin reduced the expression of several key factors such as FABP5, Plin4, GPD1, and AGPTA2. Conclusion High fat diet (HFD) can increase the expression of lipid synthesis and transport-related proteins and reduce mitochondrial related proteins, thereby increasing lipid synthesis, reducing energy consumption, and improving lipid metabolism in vivo. Silibinin can reduce lipid synthesis, increase energy consumption, and improve lipid metabolism in mice in vivo.
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Affiliation(s)
- Fei Wang
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Shuchun Chen
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Yichao Wang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.,North China University of Science and Technology, Tangshan, China
| | - Zelin Li
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Tiantian Song
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - He Zhang
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Qiwen Yang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.,Hebei North University, Zhangjiakou, China
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Vrba J, Papoušková B, Lněničková K, Kosina P, Křen V, Ulrichová J. Identification of UDP-glucuronosyltransferases involved in the metabolism of silymarin flavonolignans. J Pharm Biomed Anal 2020; 178:112972. [PMID: 31727359 DOI: 10.1016/j.jpba.2019.112972] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 12/18/2022]
Abstract
Silybum marianum (milk thistle) is a medicinal plant used for producing the hepatoprotective remedy silymarin. Its main bioactive constituents, including silybin and related flavonolignans, can be metabolized directly by phase II conjugation reactions. This study was designed to identify UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of six silymarin flavonolignans, namely silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin. UHPLC-MS analyses showed that all of the tested compounds, both individually and in silymarin, were glucuronidated by human liver microsomes, and that glucuronidation was the main metabolic transformation in human hepatocytes. Further, each compound was glucuronidated by multiple recombinant human UGT enzymes. UGTs 1A1, 1A3, 1A8 and 1A9 were able to conjugate all of the tested flavonolignans, and some of them were also metabolized by UGTs 1A6, 1A7, 1A10, 2B7 and 2B15. In contrast, no glucuronides were produced by UGTs 1A4, 2B4, 2B10 and 2B17. With silymarin, we found that UGT1A1 and, to a lesser extent UGT1A9, were primarily responsible for the glucuronidation of the flavonolignan constituents. It is concluded that the metabolism of silymarin flavonolignans may involve multiple UGT enzymes, of which UGT1A1 appears to play the major role in the glucuronidation. These results may be relevant for future research on the metabolism of flavonolignans in humans.
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Affiliation(s)
- Jiří Vrba
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
| | - Barbora Papoušková
- Regional Centre of Advanced Technologies and Materials, Department of Analytical Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, Olomouc 77146, Czech Republic
| | - Kateřina Lněničková
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic
| | - Pavel Kosina
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic
| | - Vladimír Křen
- Institute of Microbiology of the Czech Academy of Sciences, Laboratory of Biotransformation, Vídeňská 1083, Prague 14220, Czech Republic
| | - Jitka Ulrichová
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic
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Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations? Arch Biochem Biophys 2019; 672:108062. [DOI: 10.1016/j.abb.2019.108062] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/20/2019] [Accepted: 07/01/2019] [Indexed: 11/23/2022]
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Yang XY, Zhang YY, Xie WR, He SH, Wu LH, He XX, Xia HHX. Herbal Medicines for Hepatitis C Virus Infection: The Exploratory Journey from Bench to Bedside Still Has a Long Way to Go. JOURNAL OF EXPLORATORY RESEARCH IN PHARMACOLOGY 2019; 4:9-18. [DOI: 10.14218/jerp.2019.00003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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22
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Antiviral Activities of Silymarin and Derivatives. Molecules 2019; 24:molecules24081552. [PMID: 31010179 PMCID: PMC6514695 DOI: 10.3390/molecules24081552] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 12/22/2022] Open
Abstract
Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development.
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Vitek L, Bellarosa C, Tiribelli C. Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity? Clin Pharmacol Ther 2019; 106:568-575. [PMID: 30588615 DOI: 10.1002/cpt.1341] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/03/2018] [Indexed: 01/04/2023]
Abstract
Observational epidemiological studies showed that mild hyperbilirubinemia has beneficial effects on the prevention of cardiovascular disease, type 2 diabetes mellitus, and metabolic syndrome. In mammals, bilirubin plays a major role as a potent antioxidant. Uridine 5'-diphospho-glucuronosyl transferase (UGT)1A1 variants coding for bilirubin UDP-glucuronosyl transferase resulting in mild hyperbilirubinemia (as in Gilbert syndrome (GS)) may confer a strong genetic advantage. Strategies to boost bioavailability of bilirubin or to mimic GS represent an attractive approach to prevent many oxidative stress and inflammation-mediated diseases. Even a tiny, micromolar increase in serum bilirubin concentrations substantially decreases the risk of oxidative stress-mediated diseases. There are several possible ways to achieve this, including lifestyle changes, changes in dietary patterns, regular physical activities, or use of chemical drug or of specific plant products either in the form of regular food items or nutraceuticals. Further basic and experimental research is required to fully uncover this promising therapeutic field.
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Affiliation(s)
- Libor Vitek
- Institute of Medical Biochemistry and Laboratory Diagnostics and 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Cristina Bellarosa
- Fondazione Italiana Fegato ONLUS, AREA Science Park-Basovizza, Trieste, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park-Basovizza, Trieste, Italy
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Isolated Silymarin Flavonoids Increase Systemic and Hepatic Bilirubin Concentrations and Lower Lipoperoxidation in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6026902. [PMID: 30891115 PMCID: PMC6390243 DOI: 10.1155/2019/6026902] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 10/25/2018] [Accepted: 11/25/2018] [Indexed: 01/27/2023]
Abstract
Bilirubin is considered to be one of the most potent endogenous antioxidants in humans. Its serum concentrations are predominantly affected by the activity of hepatic bilirubin UDP-glucuronosyl transferase (UGT1A1). Our objective was to analyze the potential bilirubin-modulating effects of natural polyphenols from milk thistle (Silybum marianum), a hepatoprotective herb. Human hepatoblastoma HepG2 cells were exposed to major polyphenolic compounds isolated from milk thistle. Based on in vitro studies, 2,3-dehydrosilybins A and B were selected as the most efficient compounds and applied either intraperitoneally or orally for seven days to C57BL/6 mice. After, UGT1A1 mRNA expression, serum, intrahepatic bilirubin concentrations, and lipoperoxidation in the liver tissue were analyzed. All natural polyphenols used increased intracellular concentration of bilirubin in HepG2 cells to a similar extent as atazanavir, a known bilirubinemia-enhancing agent. Intraperitoneal application of 2,3-dehydrosilybins A and B (the most efficient flavonoids from in vitro studies) to mice (50 mg/kg) led to a significant downregulation of UGT1A1 mRNA expression (46 ± 3% of controls, p < 0.005) in the liver and also to a significant increase of the intracellular bilirubin concentration (0.98 ± 0.03vs.1.21 ± 0.02 nmol/mg, p < 0.05). Simultaneously, a significant decrease of lipoperoxidation (61 ± 2% of controls, p < 0.005) was detected in the liver tissue of treated animals, and similar results were also observed after oral treatment. Importantly, both application routes also led to a significant elevation of serum bilirubin concentrations (125 ± 3% and 160 ± 22% of the controls after intraperitoneal and oral administration, respectively, p < 0.005 in both cases). In conclusion, polyphenolic compounds contained in silymarin, in particular 2,3-dehydrosilybins A and B, affect hepatic and serum bilirubin concentrations, as well as lipoperoxidation in the liver. This phenomenon might contribute to the hepatoprotective effects of silymarin.
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Ou Q, Weng Y, Wang S, Zhao Y, Zhang F, Zhou J, Wu X. Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-κB Pathway. Dig Dis Sci 2018; 63:3398-3408. [PMID: 30191499 DOI: 10.1007/s10620-018-5268-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Silybin is the major biologically active compound of silymarin, the standardized extract of the milk thistle (Silybum marianum). Increasing numbers of studies have shown that silybin can improve nonalcoholic steatohepatitis (NASH) in animal models and patients; however, the mechanisms underlying silybin's actions remain unclear. METHODS Male C57BL/6 mice were fed a methionine-choline deficient (MCD) diet for 8 weeks to induce the NASH model, and silybin was orally administered to the NASH mice. The effects of silybin on lipid accumulation, hepatic fibrosis, oxidative stress, inflammation-related gene expression and nuclear factor kappa B (NF-κB) activities were evaluated by biochemical analysis, immunohistochemistry, immunofluorescence, quantitative real-time PCR and western blot. RESULTS Silybin treatment significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NASH mice. Moreover, silybin inhibited HSC activation and hepatic apoptosis and prevented the formation of MDBs in the NASH liver. Additionally, silybin partly reversed the abnormal expression of lipid metabolism-related genes in NASH. Further study showed that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway played important roles in the silybin-derived antioxidant effect, as evidenced by the upregulation of Nrf2 target genes in the silybin treatment group. In addition, silybin significantly downregulated the expression of inflammation-related genes and suppressed the activity of NF-κB signaling. CONCLUSIONS Silybin was effective in preventing the MCD-induced increases in hepatic steatosis, fibrosis and inflammation. The effect was related to alteration of lipid metabolism-related gene expression, activation of the Nrf2 pathway and inhibition of the NF-κB signaling pathway in the NASH liver.
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Affiliation(s)
- Qiang Ou
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China
| | - Yuanyuan Weng
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China
| | - Siwei Wang
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China
| | - Yajuan Zhao
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China
| | - Feng Zhang
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.
| | - Jianhua Zhou
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China. .,The Central Laboratory of the Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 201508, China.
| | - Xiaolin Wu
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China. .,The Central Laboratory of the Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 201508, China.
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Crouchet E, Wrensch F, Schuster C, Zeisel MB, Baumert TF. Host-targeting therapies for hepatitis C virus infection: current developments and future applications. Therap Adv Gastroenterol 2018; 11:1756284818759483. [PMID: 29619090 PMCID: PMC5871046 DOI: 10.1177/1756284818759483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/15/2018] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) worldwide. In the past few years, anti-HCV therapies have undergone a revolution with the approval of multiple direct-acting antivirals (DAAs), which enable interferon-free treatments with considerable improvement of sustained virologic response in patients. Today, DAAs have become the standard of care for HCV therapy. However, several limitations remain, which include access to therapy, treatment failure in a subset of patients and persistent risk of HCC development following cure in patients with advanced fibrosis. By targeting conserved host proteins involved in the HCV life cycle, host-targeting agents (HTAs) offer opportunities for pan-genotypic antiviral approaches with a high barrier to drug resistance. Moreover, when applied in combination with DAAs, HTAs could improve the management of difficult-to-treat patients by acting through a complementary mechanism of action. In this review, we summarize the different HTAs evaluated in preclinical and clinical development and discuss their potential role for anti-HCV therapies.
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Affiliation(s)
- Emilie Crouchet
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Florian Wrensch
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Mirjam B. Zeisel
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
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Liu CH, Lin CC, Hsu WC, Chung CY, Lin CC, Jassey A, Chang SP, Tai CJ, Tai CJ, Shields J, Richardson CD, Yen MH, Tyrrell DLJ, Lin LT. Highly bioavailable silibinin nanoparticles inhibit HCV infection. Gut 2017; 66:1853-1861. [PMID: 27436270 DOI: 10.1136/gutjnl-2016-312019] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/12/2016] [Accepted: 06/23/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Silibinin is a flavonolignan that is well established for its robust antiviral activity against HCV infection and has undergone several clinical trials for the management of hepatitis C. Despite its potency, silibinin suffers from poor solubility and bioavailability, restricting its clinical use. To overcome this limitation, we developed highly bioavailable silibinin nanoparticles (SB-NPs) and evaluated their efficiency against HCV infection. DESIGN SB-NPs were prepared using a nanoemulsification technique and were physicochemically characterised. Infectious HCV culture systems were used to evaluate the influence of SB-NP on the virus life cycle and examine their antioxidant activity against HCV-induced oxidative stress. The safety profiles of SB-NP, in vivo pharmacokinetic studies and antiviral activity against infection of primary human hepatocytes were also assessed. RESULTS SB-NP consisted of nanoscale spherical particles (<200 nm) encapsulating amorphous silibinin at >97% efficiency and increasing the compound's solubility by >75%. Treatment with SB-NP efficiently restricted HCV cell-to-cell transmission, suggesting that they retained silibinin's robust anti-HCV activity. In addition, SB-NP exerted an antioxidant effect via their free radical scavenging function. Oral administration of SB-NP in rodents produced no apparent in vivo toxicity, and pharmacokinetic studies revealed an enhanced serum level and superior biodistribution to the liver compared with non-modified silibinin. Finally, SB-NP efficiently reduced HCV infection of primary human hepatocytes. CONCLUSIONS Due to SB-NP's enhanced bioavailability, effective anti-HCV activity and an overall hepatoprotective effect, we suggest that SB-NP may be a cost-effective anti-HCV agent that merits further evaluation for the treatment of hepatitis C.
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Affiliation(s)
- Ching-Hsuan Liu
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Ching Lin
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Chan Hsu
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chueh-Yao Chung
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Chan Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Alagie Jassey
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shun-Pang Chang
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chen-Jei Tai
- Department of Chinese Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Jeng Tai
- Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Justin Shields
- Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada
| | - Christopher D Richardson
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pediatrics and Canadian Center for Vaccinology, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada
| | - Ming-Hong Yen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Anti-hepatitis C virus strategy targeting host entry factor claudin-1. Uirusu 2017; 65:245-254. [PMID: 27760923 DOI: 10.2222/jsv.65.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is a major threat to global public health, because it is significantly correlated with the development of severe liver diseases including cirrhosis and hepatocellular carcinomas. Host molecules as well as viral factors are promising targets for anti-HCV preventive and therapeutic strategies. Multiple host factors such as CD81, SRBI, claudin-1, and occludin are involved in HCV entry into hepatocytes. In this paper, I first introduce our anti-HCV strategy targeting for host tight junction protein claudin-1. And this review also summarizes developments of other entry inhibitors to prevent initiation of HCV infection and spread. Entry inhibitors might be useful in blocking primary infections, such those as after liver transplantation, and in combination therapies with other anti-HCV agents such as direct-acting antivirals.
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DebRoy S, Hiraga N, Imamura M, Hayes CN, Akamatsu S, Canini L, Perelson AS, Pohl RT, Persiani S, Uprichard SL, Tateno C, Dahari H, Chayama K. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. J Viral Hepat 2016; 23:708-17. [PMID: 27272497 PMCID: PMC4974116 DOI: 10.1111/jvh.12551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 04/04/2016] [Indexed: 12/15/2022]
Abstract
Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle (Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes.
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Affiliation(s)
- Swati DebRoy
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA,Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC, USA
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Sakura Akamatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Laetitia Canini
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA,Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
| | - Alan S. Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Ralf T. Pohl
- German Association of Phytotherapy, Nachtigallenweg 46, Speyer 67346, Germany
| | | | - Susan L. Uprichard
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | | | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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30
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Wahyuni TS, Utsubo CA, Hotta H. Promising Anti-Hepatitis C Virus Compounds from Natural Resources. Nat Prod Commun 2016. [DOI: 10.1177/1934578x1601100840] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
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 HCV.
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Affiliation(s)
- Tutik Sri Wahyuni
- Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Jl. Dharmawangsa Dalam, Surabaya 60286, Indonesia
| | - Chie Aoki Utsubo
- Department of International Health, Kobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe 654-0142, Japan
| | - Hak Hotta
- Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
- Department of Oral Vaccine and Drug Development, Kobe University Graduate School of Health Sciences, 1-5-6 Minatojima-minamimachi, Chou-ku, Kobe 650-0047, Japan
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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection. Viruses 2015; 7:5659-85. [PMID: 26540069 PMCID: PMC4664971 DOI: 10.3390/v7112898] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 09/25/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.
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Mastron JK, Siveen KS, Sethi G, Bishayee A. Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review. Anticancer Drugs 2015; 26:475-86. [PMID: 25603021 DOI: 10.1097/cad.0000000000000211] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The blessed milk thistle (Silybum marianum L.), a flowering plant native to Mediterranean Europe, has been consumed and extensively used as a cure for various chronic liver ailments over several centuries. Milk thistle extract, known as silymarin, is a complex mixture of seven major flavonolignans and one flavonoid. The phytoconstituents of silymarin owe their therapeutic and hepatoprotective effects to their strong antioxidant and anti-inflammatory properties. Primary liver cancer, also known as hepatocellular carcinoma (HCC), occurs in a milieu of oxidative stress and inflammation. The etiology of HCC includes chronic infection with hepatitis B and C viruses, cirrhosis, and exposure to dietary and environmental hepatocarcinogens. Current therapeutic options for HCC, including surgical resection and liver transplantation, have limited benefits and are essentially ineffective. Chemoprevention, using phytochemicals with potent antioxidant and anti-inflammatory properties, represents a fascinating strategy, which has been a subject of intense investigation in the recent years. In this review, we explore the potential role of silymarin as a chemopreventive and therapeutic agent for HCC. The review systematically evaluates the preclinical in-vitro and in-vivo studies investigating the effects of silymarin and its constituents on HCC. The biochemical mechanisms involved in the anti-liver-cancer effects of silymarin have been presented. The current status of clinical studies evaluating the potential of role of silymarin in liver cancer, especially that caused by hepatitis C virus, has also been examined. Potential challenges and future directions of research involved in the 'bench-to-bedside' transition of silymarin phytoconstituents for the chemoprevention and treatment of HCC have also been discussed.
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Affiliation(s)
- Jeanetta K Mastron
- aAmerican University of Health Sciences, Signal Hill bDepartment of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, California, USA cDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore dInterim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
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Hsu WC, Chang SP, Lin LC, Li CL, Richardson CD, Lin CC, Lin LT. Limonium sinense and gallic acid suppress hepatitis C virus infection by blocking early viral entry. Antiviral Res 2015; 118:139-47. [DOI: 10.1016/j.antiviral.2015.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 03/31/2015] [Accepted: 04/06/2015] [Indexed: 12/18/2022]
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Fagiuoli S, Ravasio R, Lucà MG, Baldan A, Pecere S, Vitale A, Pasulo L. Management of hepatitis C infection before and after liver transplantation. World J Gastroenterol 2015; 21:4447-56. [PMID: 25914454 PMCID: PMC4402292 DOI: 10.3748/wjg.v21.i15.4447] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/11/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.
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Wang H, Yan T, Xie Y, Zhao M, Che Y, Zhang J, Liu H, Cao L, Cheng X, Xie Y, Li F, Qi Q, Wang G, Hao H. Mechanism-based inhibitory and peroxisome proliferator-activated receptor α-dependent modulating effects of silybin on principal hepatic drug-metabolizing enzymes. Drug Metab Dispos 2015; 43:444-54. [PMID: 25587127 DOI: 10.1124/dmd.114.061622] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)α, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARα by fenofibrate, characterized with significantly repressed expression of PPARα targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPARα agonists via the repression of PPARα activation in a competitive mode.
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Affiliation(s)
- Hong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Tingting Yan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Yuan Xie
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Min Zhao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Yuan Che
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Jun Zhang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Huiying Liu
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Lijuan Cao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Xuefang Cheng
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Yang Xie
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Feiyan Li
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Qu Qi
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
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Xiao F, Fofana I, Thumann C, Mailly L, Alles R, Robinet E, Meyer N, Schaeffer M, Habersetzer F, Doffoël M, Leyssen P, Neyts J, Zeisel MB, Baumert TF. Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C. Gut 2015; 64:483-94. [PMID: 24848265 PMCID: PMC4345833 DOI: 10.1136/gutjnl-2013-306155] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. DESIGN Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. RESULTS Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. CONCLUSIONS Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.
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Affiliation(s)
- Fei Xiao
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Isabel Fofana
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Christine Thumann
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Laurent Mailly
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Roxane Alles
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France,Inserm, U977, Strasbourg, France
| | - Eric Robinet
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Nicolas Meyer
- Pôle de Santé Publique, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
| | - Mickaël Schaeffer
- Pôle de Santé Publique, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France
| | - François Habersetzer
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France,Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Michel Doffoël
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France,Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Pieter Leyssen
- Rega Institute for Medical Research, KULeuven, Leuven, Belgium
| | - Johan Neyts
- Rega Institute for Medical Research, KULeuven, Leuven, Belgium
| | - Mirjam B Zeisel
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Strasbourg, France,Université de Strasbourg, Strasbourg, France,Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France,Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA
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Dahari H, Shteingart S, Gafanovich I, Cotler SJ, D'Amato M, Pohl RT, Weiss G, Ashkenazi YJ, Tichler T, Goldin E, Lurie Y. Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics. Liver Int 2015; 35:289-94. [PMID: 25251042 PMCID: PMC4304917 DOI: 10.1111/liv.12692] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 09/15/2014] [Accepted: 09/18/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.
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Affiliation(s)
- Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA,Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA,To whom correspondence and questions regarding mathematical modeling should be addressed: Harel Dahari, Address: Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA; Fax: +1-708-216-6299; Tel: +1-708-216-4682;
| | - Shimon Shteingart
- Digestive Disease Institute, Share'e Zedek Medical Center, Jerusalem, Israel
| | - Inna Gafanovich
- Liver Unit, Digestive Disease Institute, Share'e Zedek Medical Center, Jerusalem, Israel
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | | | | | - Gali Weiss
- Nursing Division, Share'e Zedek Medical Center, Jerusalem, Israel
| | | | - Thomas Tichler
- Internal medicine, Share'e Zedek Medical Center, Jerusalem, Israel
| | - Eran Goldin
- Digestive Disease Institute, Share'e Zedek Medical Center, Jerusalem, Israel
| | - Yoav Lurie
- Liver Unit, Digestive Disease Institute, Share'e Zedek Medical Center, Jerusalem, Israel,To whom correspondence and questions regarding mathematical modeling should be addressed: Harel Dahari, Address: Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA; Fax: +1-708-216-6299; Tel: +1-708-216-4682;
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Yang Z, Zhuang L, Lu Y, Xu Q, Chen X. Effects and tolerance of silymarin (milk thistle) in chronic hepatitis C virus infection patients: a meta-analysis of randomized controlled trials. BIOMED RESEARCH INTERNATIONAL 2014; 2014:941085. [PMID: 25247194 PMCID: PMC4163440 DOI: 10.1155/2014/941085] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 08/06/2014] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of silymarin on chronic hepatitis C virus- (HCV-) infected patients. METHODS Randomized controlled trials (RCTs) of silymarin in chronic HCV-infected patients up to April 1, 2014 were systematically identified in PubMed, Ovid, Web of Science, and Cochrane Library databases. RESULTS A total of 222 and 167 patients in five RCTs were randomly treated with silymarin (or intravenous silibinin) and placebo, respectively. Serum HCV RNA relatively decreased in patients treated with silymarin compared with those administered with placebo, but no significance was found (P = 0.09). Meta-analysis of patients orally treated with silymarin indicated that the changes of HCV RNA are similar in the two groups (P = 0.19). The effect on alanine aminotransferase (ALT) of oral silymarin is not different from that of placebo (P = 0.45). Improvements in quality-of-life (Short Form-36) in both silymarin and placebo recipients were impressive but relatively identical (P = 0.09). CONCLUSION Silymarin is well tolerated in chronic HCV-infected patients. However, no evidence of salutary effects of oral silymarin has yet been reported based on intermediate endpoints (ALT and HCV RNA) in this population. Moreover, intravenous administration of silymarin should be further studied.
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Affiliation(s)
- Zongguo Yang
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Liping Zhuang
- Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunfei Lu
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Qingnian Xu
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Xiaorong Chen
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
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Abstract
Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines.
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Affiliation(s)
- Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wen-Chan Hsu
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Ching Lin
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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40
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Canini L, DebRoy S, Mariño Z, Conway JM, Crespo G, Navasa M, D’Amato M, Ferenci P, Cotler SJ, Forns X, Perelson AS, Dahari H. Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy. Antivir Ther 2014; 20:149-155. [PMID: 24912382 PMCID: PMC4262731 DOI: 10.3851/imp2806] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND HCV kinetic analysis and modelling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in three groups of patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. METHODS Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to final effectiveness [εmax]) was fitted to viral kinetic data. RESULTS Baseline viral load and age were significantly associated with the severity of liver disease (P<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline in patients with less severe liver disease. The εmax was significantly (P≤0.032) associated with increasing severity of liver disease (non-cirrhotic εmax [se]=0.86 [0.05], compensated cirrhotic εmax=0.69 [0.06] and decompensated cirrhotic εmax=0.59 [0.1]). The second phase decline slope was not significantly different among groups (mean 1.88 ±0.15 log10 IU/ml/week, P=0.75) as was the rate of change of SIL effectiveness (k=2.12/day [se=0.18/day]). HCV-infected cell loss rate (δ [se]=0.62/day [0.05/day]) was high and similar among groups. CONCLUSIONS The high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.
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Affiliation(s)
- Laetitia Canini
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Swati DebRoy
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
- Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC, USA
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Jessica M Conway
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Gonzalo Crespo
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | | | - Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Scott J Cotler
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Xavier Forns
- Liver Unit, Hospital Clinic, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Alan S Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Harel Dahari
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
- Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
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Rendina M, D'Amato M, Castellaneta A, Castellaneta NM, Brambilla N, Giacovelli G, Rovati L, Rizzi SF, Zappimbulso M, Bringiotti RS, Di Leo A. Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial. Transpl Int 2014; 27:696-704. [PMID: 24673819 DOI: 10.1111/tri.12324] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/17/2014] [Accepted: 03/24/2014] [Indexed: 12/30/2022]
Abstract
Response to interferon-based therapies in HCV recurrence after liver transplantation (LT) is unsatisfactory, and major safety issues aroused in preliminary experience with boceprevir and telaprevir. As transplant community identified HCV viral clearance as a critical matter, efficacious and safe anti-HCV therapies are awaited. The aim of this study was to assess efficacy and safety of intravenous silibinin monotherapy in patients with established HCV recurrence after LT, nonresponders to pegylated interferon and ribavirin. This is a single center, prospective, randomized, parallel-group, double-blind, placebo-controlled, phase 2 trial including 20 patients randomly assigned (3:1) to receive daily 20 mg/kg of intravenous silibinin or saline as placebo, for 14 consecutive days. On day 14 of treatment, viral load decreased by 2.30 ± 1.32 in silibinin group versus no change in the placebo group (P = 0.0002). Sixteen days after the end of the treatment, viral load mean values were similar to baseline. Treatment resulted well tolerated apart from a transient and reversible increase in bilirubin. Neither changes in immunosuppressant through levels nor dosage adjustments were necessary. Silibinin monotherapy has a significant antiviral activity in patients with established HCV recurrence on the graft not responding to standard therapy and confirms safety and tolerability without interaction with immunosuppressive drugs (ClinicalTrials.gov number: NCT01518933).
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Affiliation(s)
- Maria Rendina
- Department of Emergency and Organ Transplantation, Section of Gastroenterology, University Hospital, Bari, Italy
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Fofana I, Jilg N, Chung RT, Baumert TF. Entry inhibitors and future treatment of hepatitis C. Antiviral Res 2014; 104:136-42. [PMID: 24525381 DOI: 10.1016/j.antiviral.2014.02.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/29/2014] [Accepted: 02/02/2014] [Indexed: 12/25/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Furthermore, HCV-induced liver disease is the leading indication for liver transplantation. The recent introduction of direct-acting antivirals (DAAs) has revolutionized HCV treatment by making possible the cure of the majority of patients. However, their efficacy and safety in difficult-to-treat patients such as patients receiving immunosuppression, those with advanced liver disease, co-morbidity and HIV/HCV-co-infection remain to be determined. Furthermore, prevention of liver graft infection remains a pressing issue. HCV entry inhibitors target the very first step of the HCV life cycle and efficiently inhibit cell-cell transmission - a key prerequisite for viral spread. Because of their unique mechanism of action on cell-cell transmission they may provide a promising and simple perspective for prevention of liver graft infection. A high genetic barrier to resistance and complementary mechanism of action compared to DAAs makes entry inhibitors attractive as a new strategy for treatment of multi-resistant or difficult-to-treat patients. Clinical studies are needed to determine the future role of entry inhibitors in the arsenal of antivirals to combat HCV infection. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Isabel Fofana
- Inserm U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - Nikolaus Jilg
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Raymond T Chung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Thomas F Baumert
- Inserm U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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Wlcek K, Koller F, Ferenci P, Stieger B. Hepatocellular organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are inhibited by silibinin. Drug Metab Dispos 2013; 41:1522-1528. [PMID: 23695864 DOI: 10.1124/dmd.113.051037] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na(+)-taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17β-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinin-induced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.
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Affiliation(s)
- Katrin Wlcek
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
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Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology 2013; 57:1262-1271. [PMID: 23213025 PMCID: PMC3594650 DOI: 10.1002/hep.26179] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/05/2012] [Indexed: 12/21/2022]
Affiliation(s)
- Stephen J Polyak
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98104, USA.
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Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements. Antioxidants (Basel) 2013; 2:23-36. [PMID: 26787620 PMCID: PMC4665399 DOI: 10.3390/antiox2010023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 12/27/2012] [Accepted: 01/25/2013] [Indexed: 01/22/2023] Open
Abstract
Milk thistle dietary supplements that contain silymarin are widely marketed and used in the USA and other countries for liver enhancement and recovery. More recently, silymarin has also been identified as a possible antiviral for the treatment of hepatitis C virus (HCV) infection. To assess different brands of commercially sold silymarin, 45 products were collected from local stores and analyzed for their silymarin content, antioxidant activities, and antiviral activity against HCV. Antioxidant activity was measured as radical scavenging activity using DPPH and by estimating their antioxidant capacity as trolox equivalent. Anti-HCV activity was measured in an HCV genotype 1b replication inhibition assay. Samples were found to vary widely in their silymarin content, with some samples having none or very low concentrations while silymarin represented higher than 80% of other samples. Both antioxidant and anti-HCV activity correlated with the overall level of silymarin.
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