No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: The ATRACTION study, a phase II randomised trial

Schuchmann, Marcus; Kittner, Jens M.; Schlaak, Joerg F.; Klass, Dietmar M.; Eisenbach, Christoph; Berg, Thomas; Günther, Rainer; Zeuzem, Stefan; Gösseringer, Roger; Ehrlich, A.; Neumann, Konrad; Wachtlin, Daniel; Sprinzl, Martin; Zimmermann, Tim; Böcher, Wulf O.; Galle, Peter R.

doi:10.1016/j.dld.2012.11.006

Cited by 5 publications

(3 citation statements)

References 34 publications

(44 reference statements)

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“…Hence, restoration of GI‐GPx has been considered as a therapeutic target to overcome HCV infection, and considering the fact that Tp80 is more potent in both GI‐GPx restoration and anti‐HCV activity than ATRA (Fig. B and C), it is expected that Tp80 will improve anti‐HCV activity of ATRA shown in the past clinical trials . Transcription of GI‐GPx was previously shown to be directly regulated by ATRA/RAR complex, through a tandem RAR‐binding elements within GI‐GPx promoter region, and ATRA treatment could recover GI‐GPx expression level in HCV replicon‐harboring Huh7 cells .…”

Section: Discussionmentioning

confidence: 99%

Retinoid derivative Tp80 exhibits anti‐hepatitis C virus activity through restoration of GI‐GPx expression

Nguyen

Okuno

Ajiro

et al. 2017

Journal of Medical Virology

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Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus with an estimated infection in ∼180 million people worldwide, and its chronic infection leads to development of cirrhosis and hepatocellular carcinoma. Although recent development of direct acting antiviral (DAA) compounds improved anti-HCV regimens, alternative therapeutic compounds are still demanded due to an expected emergence of escape mutants for those DAAs. In order to identify novel anti-HCV agents, we conducted chemical library screening for 2086 compounds using HCV Rep-Feo reporter replicon in Huh7 hepatoma cells. Our screening identified retinoid derivative Tp80, which inhibits replication of HCV Rep-Feo (genotype 1b) and JFH1 HCV (genotype 2a) with 0.62 μM and 1.0 μM, respectively, of 50% effective concentration (EC ), at which cytotoxicity is not evident for host hepatocytes. Subsequent transcriptome profiling revealed Tp80 exhibits anti-HCV activity through restoration of gastrointestinal glutathione peroxidase (GI-GPx), suppression of which is responsible for HCV-induced oxidative stress to facilitate HCV replication. Furthermore, comparison of Tp80 with other retinoid derivatives revealed Tp80 shows best potency in both GI-GPx restoration and anti-HCV activity among compounds we examined. In conclusion, our current study provides Tp80 as a promising candidate of anti-HCV compound, suppressing host cellular oxidative stress through a restoration of GI-GPx.

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Section: Discussionmentioning

confidence: 99%

Retinoid derivative Tp80 exhibits anti‐hepatitis C virus activity through restoration of GI‐GPx expression

Nguyen

Okuno

Ajiro

et al. 2017

Journal of Medical Virology

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“…Unfortunately, this result could not be duplicated in a controlled trial. (8) Alcohol induces the depletion of retinoid stores, and in cirrhosis there is profound loss of hepatic vitamin A storage as a result of stellate cell activation. Retinoids also appear to play a role in clearance of other viruses through up-regulation of RIG-I, (9) expression of type I IFN receptor, and up-regulation of ISGs in uninfected bystander cells.…”

mentioning

confidence: 99%

“…Vitamin A levels are low in chronic hepatitis C patients, and pilot studies have suggested that retinoic acid supplementation improves viral clearance. Unfortunately, this result could not be duplicated in a controlled trial . Alcohol induces the depletion of retinoid stores, and in cirrhosis there is profound loss of hepatic vitamin A storage as a result of stellate cell activation.…”

mentioning

confidence: 99%

Retinoids: The Link Between Alcohol and Interferon?

Weinman

Tikhanovich

2016

Hepatology

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O ne of the greatest accomplishments in the history of the field of hepatology is the 25-year effort that led from the discovery of the hepatitis C virus (HCV) to the understanding of its life cycle and ultimately the development of highly effective targeted therapy. Perhaps less well appreciated is the extent to which the global scientific effort against HCV has transformed our knowledge of liver disease, host-viral interactions, and antiviral immune responses. Among these insights are the understanding of the reversibility of cirrhosis, the prognostic interpretation of liver histology, and the genesis of hepatocellular carcinoma. However, of all the scientific fruits of HCV research, none have been as significant as the profound insights gained into the nature of the antiviral interferon (IFN) pathway and the factors that determine its efficacy in different individuals. Although the development of new anti-HCV drugs has reached a state of maturity, basic scientific understandings of the nature of the livervirus interaction continue to emerge.One of the central issues that remain unresolved is the relationship between HCV and alcohol consumption. It is well documented that HCV and alcohol each exacerbate liver injury caused by the other, but even more profound is the observation that alcohol consumption leads to a more than seven-fold increase in the rate of virological failure of IFN treatment. (1) In spite of these strong clinical data, the mechanisms responsible for this effect are poorly understood-and their relevance, if any, to IFN-free treatment regimens is unknown.Interferons generated by hepatocytes in response to viral infection both clear virus from infected cells and make uninfected cells resistant to infection. In the case of HCV, the viral RNA is recognized by the pattern receptor and RNA helicase, RIG-I, and this triggers a signaling cascade involving the adapter protein MAVS, the downstream kinases TBK1 and IKKe, and the transcription factors IRF3 and IRF7. In hepatocytes, this results in the secretion of IFN-b. This process engages the effector arm of the IFN pathway where type 1 IFN binding to the receptors INFAR1 and IFNAR2 results in activation of the receptor-bound kinases TYK2 and JAK1. These in turn cause tyrosine phosphorylation of STAT1 and STAT2, which then form a heterotrimeric complex of pSTAT1, pSTAT2, and IRF9. This IFN-stimulated gene factor 3 is the active transcription factor that binds many IFN-sensitive response elements (ISREs) inducing IFN-stimulated genes (ISGs) that suppress viral replication by multiple mechanisms. Prior to the development of direct-activing antivirals, HCV therapy was almost wholly based on trying to activate this endogenous method to clear the virus. Endogenous IFN responses still determine the outcome of acute infections and may even play some role in direct-activing antiviral efficacy.Initially, there was little understanding of how alcohol affected IFN responses, but as replicon and in vitro infectious virus models of HCV became available, multiple e...

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Dermatological drugs, topical agents, and cosmetics

Choulis

2012

A Worldwide Yearly Survey of New Data in Adverse Drug Reactions and Interactions

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No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: The ATRACTION study, a phase II randomised trial

Cited by 5 publications

References 34 publications

Retinoid derivative Tp80 exhibits anti‐hepatitis C virus activity through restoration of GI‐GPx expression

Retinoid derivative Tp80 exhibits anti‐hepatitis C virus activity through restoration of GI‐GPx expression

Retinoids: The Link Between Alcohol and Interferon?

Dermatological drugs, topical agents, and cosmetics

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