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Mechie NC, Goralzcyk AD, Reinhardt L, Mihm S, Amanzada A. Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study. BMC Res Notes 2015; 8:260. [PMID: 26109044 PMCID: PMC4479221 DOI: 10.1186/s13104-015-1248-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/17/2015] [Indexed: 12/18/2022] Open
Abstract
Background Chronic hepatitis C (CHC) is a global health challenge. New therapeutic agents with excellent sustained virological response (SVR) rates are available mainly in developed countries, while the majority of CHC patients live in countries with low health budget. Predictors of therapeutic response are therefore necessary. Vitamin B12 appears to be involved in hepatitis C virus replication. Methods We therefore studied retrospectively the relationship between baseline serum vitamin B12 levels and clinical features in 116 CHC genotype 1 infected patients. Logistic regression models with univariate and multivariate analysis were used in the statistical analysis. Results Baseline serum vitamin B12 levels were found to be positively associated with serum transaminase activities (AST, p = 0.002, ALT, p = 0.04), baseline viral load (p < 0.0001), stage of fibrosis (p = 0.0001) and favorable interferon-λ3/4 (IFNL3/IFNL4) rs12979860 genotypes (p = 0.04), and inversely with SVR (p < 0.001) as well as with rapid virological response (p = 0.001). Patients with baseline serum vitamin B12 levels below a cut-off value of 570 ng/L achieved a SVR rate of 59% with an odds ratio (OR) of 13.4 [confidence interval (CI) 4.3–41.9, p < 0.0001] compared to patients above the cut-off value. By combining serum vitamin B12 levels and IFNL3/IFNL4 rs12979860 genotypes, patients with baseline serum vitamin B12 levels below the cut-off value of 570 ng/L and IFNL3/IFNL4 rs12979860 CC genotype achieved a SVR rate of even 80% with an OR of 54 (CI 9.9–293, p < 0.0001) compared to patients above the cut-off value and non-CC-genotypes. Conclusion Our data suggest baseline serum vitamin B12 levels as useful noninvasive marker for characterizing CHC patients. They might further help to identify responders to a standard treatment.
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Affiliation(s)
- Nicolae-Catalin Mechie
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Armin D Goralzcyk
- Division of Internal Medicine, Clinic of Herzberg and Osterode, Dr Froessel Allee, 37412, Herzberg am Harz, Germany.
| | - Lars Reinhardt
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Sabine Mihm
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
| | - Ahmad Amanzada
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August University Goettingen, Robert Koch Strasse 40, 37075, Göttingen, Germany.
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Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in gastrointestinal diseases. World J Gastroenterol 2015; 21:5191-5209. [PMID: 25954093 PMCID: PMC4419060 DOI: 10.3748/wjg.v21.i17.5191] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases. For instance, most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials, however interventional trials failed to prove a clear beneficial preventive role. On the other hand, more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities. Examples for this include the therapeutic role of vitamin E in patients with non-alcoholic steatohepatitis, the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus, the role of vitamin C in reducing the risk of gallstones, the positive outcome with vitamin B12 in patients with aphthous stomatitis, and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease. Other potential uses are yet to be elaborated, like those on celiac disease, pancreatic cancer, pancreatitis, cholestasis and other potential fields. Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years. Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost, their use should be encouraged in the fields where positive data are available.
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Lee TH, Tillmann HL, Patel K. Individualized therapy for hepatitis C infection: focus on the interleukin-28B polymorphism in directing therapy. Mol Diagn Ther 2014; 18:25-38. [PMID: 24022240 DOI: 10.1007/s40291-013-0053-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
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Abstract
The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism.
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Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase. Biochimie 2013; 95:1033-40. [PMID: 23415654 DOI: 10.1016/j.biochi.2013.01.020] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 01/30/2013] [Indexed: 12/16/2022]
Abstract
Vitamin B12 (cobalamin, cbl) is a cofactor of methionine synthase (MTR) in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAM), which is involved in epigenomic regulatory mechanisms. We have established a neuronal cell model with stable expression of a transcobalamin-oleosin chimer and subsequent decreased cellular availability of vitamin B12, which produces reduced proliferation, increased apoptosis and accelerated differentiation through PP2A, NGF and TACE pathways. Anti-transcobalamin antibody or impaired transcobalamin receptor expression produce also impaired proliferation in other cells. Consistently, the transcription, protein expression and activity of MTR are increased in proliferating cells of skin and intestinal epitheliums, in rat intestine crypts and in proliferating CaCo2 cells, while MTR activity correlates with DNA methylation in rat intestine villi. Exposure to nitrous oxide in animal models identified impairment of MTR reaction as the most important metabolic cause of neurological manifestations of B12 deficiency. Early vitamin B12 and folate deprivation during gestation and lactation of a 'dam-progeny' rat model developed in our laboratory is associated with long-lasting disabilities of behavior and memory capacities, with persisting hallmarks related to increased apoptosis, impaired neurogenesis and altered plasticity. We found also an epigenomic deregulation of energy metabolism and fatty acids beta-oxidation in myocardium and liver, through imbalanced methylation/acetylation of PGC-1alpha and decreased expression of SIRT1. These nutrigenomic effects display similarities with the molecular mechanisms of fetal programming. Beside deficiency, B12 loading increases the expression of MTR through internal ribosome entry sites (IRES) and down-regulates MDR-1 gene expression. In conclusion, vitamin B12 influences cell proliferation, differentiation and apoptosis in brain. Vitamin B12 and folate combined deficiency impairs fatty acid oxidation and energy metabolism in liver and heart through epigenomic mechanisms related to imbalanced acetylation/methylation. Some but not all of these effects reflect the upstream role of vitamin B12 in SAM synthesis.
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Tillmann HL. Vitamins? The magic bullet against hepatitis C. Expert Rev Anti Infect Ther 2012; 10:1273-1277. [DOI: 10.1586/eri.12.127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Rosenberg P, Hagen K. Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection. J Viral Hepat 2011; 18:129-34. [PMID: 20196801 DOI: 10.1111/j.1365-2893.2010.01288.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment response (ETR) in patients with chronic HCV. Ninety-nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s-B12) was analysed in samples collected before treatment start. Pretreatment s-B12 levels were correlated to ETR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s-B12 levels ≤ 360 pm, 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s-B12 > 360 pm, one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 360 vs ≤ 360 pm: OR 28.6 CI 2.31-354, P = 0.008. Fibrosis stage 3-4 vs 0-2: OR 0.29 CI 0.074-1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87-83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048-0.91 P = 0.034. Standard interferon vs pegylated-interferon: OR 0.079, CI 0.0091-0.68 P = 0.019. Age and gender were not correlated to ETR. S-B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti-HCV treatment.
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Affiliation(s)
- P Rosenberg
- Department of Medicine, Karolinska Institute, Stockholm, Sweden.
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Solomon LR. Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev 2007; 21:113-30. [DOI: 10.1016/j.blre.2006.05.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Jang SK. Internal initiation: IRES elements of picornaviruses and hepatitis c virus. Virus Res 2005; 119:2-15. [PMID: 16377015 DOI: 10.1016/j.virusres.2005.11.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2005] [Revised: 08/29/2005] [Accepted: 11/02/2005] [Indexed: 02/08/2023]
Abstract
The scanning hypothesis provides an explanation for events preceding the first peptide bond formation during the translation of the vast majority of eukaryotic mRNAs. However, this hypothesis does not explain the translation of eukaryotic mRNAs lacking the cap structure required for scanning. The existence of a group of positive sense RNA viruses lacking cap structures (e.g. picornaviruses) indicates that host cells also contain a 5' cap-independent translation mechanism. This review discusses the translation mechanisms of atypical viral mRNAs such as picornaviruses and hepatitis c virus, and uses these mechanisms to propose a general theme for all translation, including that of both eukaryotic and prokaryotic mRNAs.
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Affiliation(s)
- Sung Key Jang
- NRL, PBC, Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
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Oltean S, Banerjee R. A B12-responsive internal ribosome entry site (IRES) element in human methionine synthase. J Biol Chem 2005; 280:32662-8. [PMID: 16051610 DOI: 10.1074/jbc.m501964200] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Regulation of homocysteine, a sulfur-containing amino acid that is a risk factor for cardiovascular diseases, is poorly understood. Methionine synthase (MS) is a key enzyme that clears intracellular homocysteine, and its activity is induced by its cofactor, vitamin B12, at a translational level. In this study, we demonstrate that translation of MS, which has a long and highly structured 5'-untranslated region, is initiated from an internal ribosome entry site (IRES), which is modulated by B12. The minimal IRES element spans 71 bases immediately upstream of the initiation codon. Electrophoretic mobility shift analysis reveals the presence of a B12 -dependent protein-RNA complex and suggests the possibility that B12-dependent increase of IRES efficiency is mediated via a protein. Modulation of the IRES-dependent translation of an essential gene by the cofactor of the encoded enzyme represents a novel example of a gene-nutrient interaction.
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Affiliation(s)
- Sebastian Oltean
- Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664, USA
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Li D, Lott WB, Martyn J, Haqshenas G, Gowans EJ. Differential effects on the hepatitis C virus (HCV) internal ribosome entry site by vitamin B12 and the HCV core protein. J Virol 2004; 78:12075-81. [PMID: 15479850 PMCID: PMC523236 DOI: 10.1128/jvi.78.21.12075-12081.2004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
To investigate the role of the hepatitis C virus internal ribosome entry site (HCV IRES) domain IV in translation initiation and regulation, two chimeric IRES elements were constructed to contain the reciprocal domain IV in the otherwise HCV and classical swine fever virus IRES elements. This permitted an examination of the role of domain IV in the control of HCV translation. A specific inhibitor of the HCV IRES, vitamin B(12), was shown to inhibit translation directed by all IRES elements which contained domain IV from the HCV and the GB virus B IRES elements, whereas the HCV core protein could only suppress translation from the wild-type HCV IRES. Thus, the mechanisms of translation inhibition by vitamin B(12) and the core protein differ, and they target different regions of the IRES.
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Affiliation(s)
- Dongsheng Li
- Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, VIC 3001, Australia
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12
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Abstract
Functional RNAs such as ribosomal RNA and structured domains of mRNA are targets for small molecule ligands that can act as modulators of the RNA biological activity. Natural ligands for RNA display a bewildering structural and chemical complexity that has yet to be matched by synthetic RNA binders. Comparison of natural and artificial ligands for RNA may help to direct future approaches to design and synthesize potent novel scaffolds for specific recognition of RNA targets.
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Affiliation(s)
- Thomas Hermann
- Department of Computational Chemistry & Structure, Anadys Parmaceuticals, Inc., 9050 Camino Santa Fe, San Diego, CA 92121, USA.
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13
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Oltean S, Banerjee R. Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J Biol Chem 2003; 278:20778-84. [PMID: 12670934 DOI: 10.1074/jbc.m300845200] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Vitamins B12, B6, and folic acid converge at the homocysteine metabolic junction where they support the activities of two key enzymes involved in intracellular homocysteine management, methionine synthase (MS) and cystathionine beta-synthase. The molecular mechanism for the regulation of homocysteine metabolism by B12 supplementation has been investigated in this study. B12 supplementation does not alter mRNA or protein turnover rates but induces translational up-regulation of MS by shifting the mRNA from the ribonucleoprotein to the polysome pool. The B12-responsive element has been localized by deletion analysis using a reporter gene assay to a 70-bp region located at the 3' end of the 5'-untranslated region of the MS mRNA. The cellular consequence of the B12 response is a 2- and 3.5-fold increase in the flux of homocysteine through the MS-dependent transmethylation pathway in HepG2 and 293 cells, respectively. It is speculated that B12-induced up-regulation of MS may have evolved as an adaptive strategy for rapidly sequestering an essential and rare nutrient whose availability may have been limited in the evolutionary history of mammals, a problem that is exacerbated by the absence of this vitamin from the plant kingdom.
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Affiliation(s)
- Sebastian Oltean
- Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664, USA
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Abstract
The base of knowledge concerning RNA structure and function has been expanding rapidly in recent years. Simultaneously, an increasing awareness of the pivotal role RNA plays in viral diseases has prompted many researchers to apply new technologies in high-throughput screening and molecular modelling to the design of antiviral drugs that target RNA. While the two RNA viruses with the greatest unmet medical need, HIV and HCV, have been most actively pursued, the approaches discussed in this review are relevant to all virus infections. Both traditional small-molecule and large-molecule therapeutics, such as antisense, ribozymes and interfering dsRNAs have been described, and several molecules are under development for commercialization. The purpose of this review is to summarize the current state of the art in this field and to postulate new directions in the future.
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MESH Headings
- Antiviral Agents/therapeutic use
- Base Sequence
- Drug Design
- Humans
- Models, Molecular
- Molecular Sequence Data
- Nucleic Acid Conformation
- Oligonucleotides, Antisense/genetics
- Oligonucleotides, Antisense/therapeutic use
- RNA, Antisense/genetics
- RNA, Antisense/therapeutic use
- RNA, Catalytic/genetics
- RNA, Catalytic/therapeutic use
- RNA, Viral/chemistry
- RNA, Viral/drug effects
- RNA, Viral/genetics
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Affiliation(s)
- Kevin L McKnight
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind., USA.
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