Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines

BACKGROUND: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation. METHODS: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed. RESULTS: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells. CONCLUSION: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease

Genetic diversity of the African malaria vector Anopheles gambiae

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease1. To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations

Age-Related Changes of Myelin Basic Protein in Mouse and Human Auditory Nerve

Age-related hearing loss (presbyacusis) is the most common type of hearing impairment. One of the most consistent pathological changes seen in presbyacusis is the loss of spiral ganglion neurons (SGNs). Defining the cellular and molecular basis of SGN degeneration in the human inner ear is critical to gaining a better understanding of the pathophysiology of presbyacusis. However, information on age-related cellular and molecular alterations in the human spiral ganglion remains scant, owing to the very limited availably of human specimens suitable for high resolution morphological and molecular analysis. This study aimed at defining age-related alterations in the auditory nerve in human temporal bones and determining if immunostaining for myelin basic protein (MBP) can be used as an alternative approach to electron microscopy for evaluating myelin degeneration. For comparative purposes, we evaluated ultrastructural alternations and changes in MBP immunostaining in aging CBA/CaJ mice. We then examined 13 temporal bones from 10 human donors, including 4 adults aged 38–46 years (middle-aged group) and 6 adults aged 63–91 years (older group). Similar to the mouse, intense immunostaining of MBP was present throughout the auditory nerve of the middle-aged human donors. Significant declines in MBP immunoreactivity and losses of MBP+ auditory nerve fibers were observed in the spiral ganglia of both the older human and aged mouse ears. This study demonstrates that immunostaining for MBP in combination with confocal microscopy provides a sensitive, reliable, and efficient method for assessing alterations of myelin sheaths in the auditory nerve. The results also suggest that myelin degeneration may play a critical role in the SGN loss and the subsequent decline of the auditory nerve function in presbyacusis

Liver-targeted cyclosporine A-encapsulated poly (lactic-co-glycolic) acid nanoparticles inhibit hepatitis C virus replication

KR Jyothi,1 Jagadish Beloor,2 Ara Jo,1 Minh Nam Nguyen,1 Tae Gyu Choi,1 Jin-Hwan Kim,1 Salima Akter,1 Sang-Kyung Lee,2 Chi Hoon Maeng,3 Hyung Hwan Baik,1 Insug Kang,1 Joohun Ha,1 Sung Soo Kim1 1Department of Biochemistry and Molecular Biology, School of&nbsp;Medicine, Kyung Hee University, Seoul, Republic of Korea; 2Department of Bioengineering and Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea; 3Department of&nbsp;Medical Oncology and Hematology, Kyung Hee University Hospital, Seoul, Republic of Korea Abstract: Therapeutic options for hepatitis C virus (HCV) infection have been limited by drug resistance and adverse side effects. Targeting the host factor cyclophilin A (CypA), which is essential for HCV replication, offers a promising strategy for antiviral therapy. However, due to its immunosuppressive activity and severe side effects, clinical application of cyclosporine A (CsA) has been limited as an antiviral agent. To overcome these drawbacks, we have successfully developed a liver-specific, sustained drug delivery system by conjugating the liver-targeting peptide (LTP) to PEGylated CsA-encapsulated poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA. Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model. As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.Keywords: HCV, liver-targeting peptide, targeted drug deliver