Mutations in ISDR may be linked to high viremia and virus resistance to IFN-alpha-2b but responsive to PEG-IFN-alpha-2a

Mutation in interferon sensitivity determining region may play role in virus resistance. Genotype 3a patient was subjected to 48 weeks combination therapy of IFN-alpha-2b plus ribavirin but he showed high levels of viremia before, during and after treatment although his ALT level became normal. His IL-8 and TNF-alpha levels werefound quite high before and after IFN-alpha-2 combination therapy. While comparing its ISDR-NS5A with end of treatment responder patient, eight mutations were observed in a 52 amino acid protein residue. Patient was advised for PEG-IFN-alpha-2a combination therapy for 24 weeks, to which he responded well after 4 week and showed sustained virologic response after 06 months of completion of therapy. His IL-8 and TNF-alpha levels also came to lower levels after treatment with PEG-IFN-alpha 2a combination therapy. In phylogenetic tree its genome (NZ1) along with another nonresponder case (NZ2) was placed close to Brazilian isolates. NZI and NZ2 showed 87 % sequence homology with each other while NZ1 had 89% sequence homology with EF208017 and 87% with EF20995. NZ2 showed 91% homology with EF208017 and 98% with EF207995 which is quite interesting. Mutations in ISDR sequence may be the reason for non response to IFN combination therapy of this HCV genotype 3 patient. ISDR of genotype 3 along with IL-8 and TNF-alpha may be screened on larger scale in Pakistani population which may help in deciding a cost effective treatment plan

Synthesis of some potent immunomodulatory and anti-inflammatory metabolites by fungal transformation of anabolic steroid oxymetholone

<p>Abstract</p> <p>Background</p> <p>Biotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures.</p> <p>Results</p> <p>Incubation of oxymetholone (<b>1</b>) with <it>Macrophomina phaseolina</it>, <it>Aspergillus niger</it>, <it>Rhizopus stolonifer</it>, and <it>Fusarium lini</it> produced 17β-hydroxy-2-(hydroxy-methyl)-17α-methyl-5α-androstan-1-en-3-one (<b>2</b>), 2α,17α-di(hydroxyl-methyl)-5α-androstan-3β,17β-diol (<b>3</b>), 17α-methyl-5α-androstan-2α,3β,17β-triol (<b>4</b>), 17β-hydroxy-2-(hydroxymethyl)-17α-methyl-androst-1,4-dien-3-one (<b>5</b>), 17β-hydroxy-2α-(hydroxy-methyl)-17α-methyl-5α-androstan-3-one (<b>6</b>), and 2α-(hydroxymethyl)-17α-methyl-5α-androstan-3β-17β-diol (<b>7</b>). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds <b>2</b>–<b>5</b> were identified as the new metabolites of <b>1</b>. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds <b>1</b>–<b>7</b> were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC₅₀ values between 31.2 to 2.7 μg/mL, while the IC₅₀ values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 μg/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay.</p> <p>Conclusion</p> <p>Microbial transformation of oxymetholone (<b>1</b>) provides an efficient method for structural transformation of <b>1</b>. The transformed products were obtained as a result of <it>de novo</it> stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs.</p

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