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Poole Corcoran posted an update 6 months ago
Loss of Cav-1 reduced ATP7A protein, but not mRNA, and this was mediated by ubiquitination of ATP7A and proteasomal degradation. ATP7A bound to Cav-1 and was colocalized with SOD3 in caveolae/lipid rafts or perinucleus in vascular tissues or cells. https://www.selleckchem.com/products/sm-164.html Impaired endothelium-dependent vasorelaxation in Cav-1-/- mice was rescued by gene transfer of SOD3 or by ATP7A-overexpressing transgenic mice. These data reveal an unexpected role of Cav-1 in stabilizing ATP7A protein expression by preventing its ubiquitination and proteasomal degradation, thereby increasing SOD3 activity, which in turn protects against vascular oxidative stress-mediated endothelial dysfunction.The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1-/- mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic β-cell dysfunction.Thrombospondins (TSPs) are a family of five multimeric matricellular proteins. Through a wide range of interactions, TSPs play pleiotropic roles in embryogenesis and in tissue remodeling in adult physiology as well as in pathological conditions, including cancer development and metastasis. TSPs are active in bone remodeling, the process of bone resorption (osteolysis) and deposition (osteogenesis) that maintains bone homeostasis. TSPs are particularly involved in aberrant bone remodeling, including osteolytic and osteoblastic skeletal cancer metastasis, frequent in advanced cancers such as breast and prostate carcinoma. TSPs are major players in the bone metastasis microenvironment, where they finely tune the cross talk between tumor cells and bone resident cells in the metastatic niche. Each TSP family member has different effects on the differentiation and activity of bone cells-including the bone-degrading osteoclasts and the bone-forming osteoblasts-with different outcomes on the development and growth of osteolytic and osteoblastic metastases. Here, we overview the involvement of TSP family members in the bone tissue microenvironment, focusing on their activity on osteoclasts and osteoblasts in bone remodeling, and present the evidence to date of their roles in bone metastasis establishment and growth.Myoblast differentiation is a crucial process for myogenesis. Mitochondria function as an energy-providing machine that is critical to this process, and mitochondrial dysfunction can prevent myoblasts from fusing into myotubes. However, the molecular mechanisms underlying the dynamic regulation of mitochondrial networks remain poorly understood. In the present study, we found that the PTEN induced kinase 1 (PINK1)/Parkin (an E3 ubiquitin-protein ligase) pathway is activated at the early stage of myoblast differentiation. Moreover, downregulation of mitofusin 2 (Mfn2) and increased dynamin-related protein 1 (Drp1) resulted in loosely formed mitochondria during this period. Furthermore, selective knockdown of the mitochondrial matrix protein Lon peptidase-1 (LonP1) at the early stage of myoblast differentiation induced mitochondrial depolarization and suppressed the PINK1/Parkin pathway and reduced Mfn2 and Drp1 levels, which blocked mitochondrial remodeling and myoblast differentiation. Overall, these data demonstrate that LonP1 promotes myoblast differentiation by regulating PINK1/Parkin-mediated mitochondrial remodeling.The actions needed to mitigate the spread of the coronavirus 2019 (COVID-19) have forged rapid paradigm shifts across healthcare delivery. In a time of crisis, continued access to and delivery of medication for opioid use disorder (M-OUD) is essential to save lives. However, prior to COVID-19, large variability in M-OUD adoption existed across the Veteran Health Administration (VHA) and it is unknown whether the COVID-19 pandemic exacerbated this divide. For the past two years, our team worked with eight VHA facilities to enhance adoption of M-OUD through a multi-component implementation intervention. This commentary explores these providers’ responses to COVID-19 and the subsequent impact on their progress toward increasing adoption of M-OUD. Briefly, the loosening of regulatory restrictions fostered accelerated adoption of M-OUD, rapid support for telehealth offered a mechanism to increase M-OUD access, and reevaluation of current practices surrounding M-OUD strengthened adoption. Overall, during the COVID-19 crisis, facilities and providers responded positively to the call for increased access to M-OUD and appropriate care of patients with OUD. The VHA providers’ responses and continued progress in enhancing M-OUD amidst a crisis may, in part, be attributable to their participation in an implementation effort prior to COVID-19 that established resources, expert support, and a community of practice. We anticipate the themes presented are generalizable to other healthcare systems grappling to deliver care to patients with OUD during a crisis. We propose areas of future research and quality improvement to continue to provide access and high quality, life-saving care to patients with OUD.
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