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    • Bosch et al performed frequent sampling of the nasopharyngea

    2018-11-14

    Bosch et al. performed frequent sampling of the nasopharyngeal microbiome during the first 6months of life, a period not well-covered by previous studies (). Thus, this study captured for the first time the most dynamic changes that occur within the first two months of life, and also showed that the observed patterns of microbiome evolution were independent of breastfeeding, a potential confounder during this early period. They further demonstrated that a transient abundance of species was associated with (parental-reported) respiratory symptoms suggestive of infection, in accordance to previous studies ().
    Remote preconditioning (RPC) occurs when short periods of induced ischemia of an organ or limb confer protective effects to other distant organs and tissues (). RPC has shown promise in clinical trials as a strategy to protect against potentially injurious exposures, including the prevention of radiographic contrast-induced kidney damage, a serious clinical problem (). Though an intriguing phenomenon, the mechanisms mediating RPC are not well-understood. In this issue of , Wang et al. report that the 37kDa protein renalase mediates RPC-induced protection against contrast-induced nephropathy (CIN) in a rat model, and that siRNA knockdown of renalase expression in the kidney abolishes this protection (). The authors find that renalase expression in the kidney is upregulated by RPC, and present evidence that this is mediated by circulating TNFα released into the bloodstream during RPC. These data add to a growing number of studies showing that renalase has a powerful cytoprotective function, including recent studies showing that this function of renalase is exploited by malignant Senexin B as a survival strategy (). Renalase, named for its discovery as a protein secreted by the kidney, exhibits fascinating biology (). It is an intracellular and extracellular flavoprotein, circulates in blood at a concentration of approximately 5μg/ml, and functions both as a flavoenzyme and as a cytokine. Its intracellular role has remained unclear, although it has been assumed that its enzyme function is likely important there. Recently an enzymatic role in converting dihydro forms of ßNAD(P)H to metabolically available ßNAD(P)H was described, and it is postulated that intracellular renalase has a metabolic role (). Whether this role relates specifically to renalase cytoprotective effects remains unknown, and indeed the relative contributions of intracellular versus extracellular renalase to its cytoprotective function are also unclear. Extracellular renalase does, however, confer marked cytoprotection, and it has now been established in multiple studies that specific short renalase-derived peptides, devoid of enzyme activity, can confer the same cytoprotection as does full-length renalase (). Strong evidence links this to the ability of renalase, and specific renalase-derived peptides, to activate outside-in signal transduction pathways, including STAT3, MAPK, and AKT. Recently, the plasma membrane Ca-ATPase PMCA4b was defined as a receptor for renalase and for the bioactive renalase-derived peptides (). PMCA4b is a low-capacity calcium pump thought to function primarily as part of a signaling complex. Genetic knockdown of PMCA4b, or specific pharmacological inhibition, abolishes renalase and renalase peptide-induced signaling and concomitantly their cytoprotective effects, thus establishing a crucial role of PMCA4b in a receptor-mediated extracellular renalase function. In the study by Wang et al., RPC-induced renalase expression in the kidney was attributed to NFkB signaling induced by TNFα, and was blocked by a TNFα inhibitor. This is of significant interest in that a role for renalase in modulation of inflammation and immune surveillance has been postulated, potentially as a mechanism whereby tumors escape the immune system (). Indeed, Wang et al. show that RPC reduced MCP-1 expression and macrophage infiltration of the kidney after contrast exposure, and that siRNA knockdown of renalase abolished this anti-inflammatory effect of RPC. The regulation of renalase expression is an area of active investigation, and it has been shown that STAT3 induces renalase transcription. As such, a role for extracellular renalase, signaling via STAT3, in upregulating intracellular renalase expression in a positive feedback manner has been postulated, and fits with data demonstrating that intracellular renalase levels vary in the same direction as extracellular renalase (). Whether extracellular renalase acting via receptor-mediated signaling alters other aspects of intracellular renalase biology, influencing post-translational modifications, enzyme activity, cellular location, or even secretion, is also unknown and of significant interest.