Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein.

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.

The effect of high doses of ω-3 fatty acid on the structure of the gastrocnemius muscle and on the lipidic profile of Wistar rats submitted to swimming.

OBJECTIVES: Evidence suggests that ω-3 fatty acids (FA) may have an anabolic effect on skeletal muscle. However, questions about dosage, frequency, combined protein supplementation, or different physical exercises remain unanswered. The aim of this study was to quantify by stereology whether supplementation with high dosages of ω-3 FA combined with swimming has an anabolic effect on the skeletal musculature and on the lipid profile of rats. METHODS: Sixty male Wistar rats were divided into four groups: placebo sedentary (PS), ω-3 FA sedentary (ω-3 S), placebo exercise (PE), and ω-3 FA exercise (ω-3 E). The animals in the PE and ω-3 E groups were submitted to swimming 5 d/wk, with an overload of 15% of body weight. The animals received ω-3 FA or olive oil (placebo) by gavage. After sacrifice, blood samples and the gastrocnemius muscle were collected for analysis. RESULTS: Results from this study did not show a difference in the cross-sectional areas of the gastrocnemius muscle between groups. The administration of high doses of ω-3 FA reduced plasmatic concentrations of low-density lipoprotein. Additionally, an interaction effect was observed between physical exercise and supplementation with ω-3 on levels of high-density lipoprotein. Therefore, the association between these two treatments increased high-density lipoprotein levels. CONCLUSIONS: The administration of high doses of ω-3 associated with physical activity may be beneficial in the treatment of dyslipidemia. High doses of ω-3 FA do not cause muscle mass alteration.

Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs.

In order to identify novel nonnucleoside inhibitors of HIV-1 reverse transcriptase two series of amide-containing uracil derivatives were designed as hybrids of two scaffolds of previously reported inhibitors. Subsequent biological evaluation confirmed acetamide uracil derivatives 15a-k as selective micromolar NNRTIs with a first generation-like resistance profile. Molecular modeling of the most active compounds 15c and 15i was employed to provide insight on their inhibitory properties and direct future design efforts.