The Hypoxia-Adenosine Link during Myocardial Ischemia-Reperfusion Injury

Despite increasing availability and more successful interventional approaches to restore coronary reperfusion, myocardial ischemia-reperfusion injury is a substantial cause of morbidity and mortality worldwide. During myocardial ischemia, the myocardium becomes profoundly hypoxic, thus causing stabilization of hypoxia-inducible transcription factors (HIF). Stabilization of HIF leads to a transcriptional program that promotes adaptation to hypoxia and cellular survival. Transcriptional consequences of HIF stabilization include increases in extracellular production and signaling effects of adenosine. Extracellular adenosine functions as a signaling molecule via the activation of adenosine receptors. Several studies implicated adenosine signaling in cardioprotection, particularly through the activation of the Adora2a and Adora2b receptors. Adenosine receptor activation can lead to metabolic adaptation to enhance ischemia tolerance or dampen myocardial reperfusion injury via signaling events on immune cells. Many studies highlight that clinical strategies to target the hypoxia-adenosine link could be considered for clinical trials. This could be achieved by using pharmacologic HIF activators or by directly enhancing extracellular adenosine production or signaling as a therapy for patients with acute myocardial infarction, or undergoing cardiac surgery

Hif-2α-Dependent Induction of miR-29a Restrains TH1 Activity During T Cell Dependent Colitis

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation

The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwid

Metabolites Produced by the Oral Commensal Bacterium Corynebacterium durum Extend the Lifespan of Caenorhabditis elegans via SIR-2.1 Overexpression

Human microbiota is heavily involved in host health, including the aging process. Based on the hypothesis that the human microbiota manipulates host aging via the production of chemical messengers, lifespan-extending activities of the metabolites produced by the oral commensal bacterium Corynebacterium durum and derivatives thereof were evaluated using the model organism Caenorhabditis elegans. Chemical investigation of the acetone extract of a C. durum culture led to the identification of monoamines and N-acetyl monoamines as major metabolites. Phenethylamine and N-acetylphenethylamine induced a potent and dose-dependent increase of the C. elegans lifespan, up to 21.6% and 19.9%, respectively. A mechanistic study revealed that the induction of SIR-2.1, a highly conserved protein associated with the regulation of lifespan, was responsible for the observed increased longevity

p21‐activated kinase 4 phosphorylates peroxisome proliferator‐activated receptor Υ and suppresses skeletal muscle regeneration

Abstract Background Skeletal muscle regeneration is an adaptive response to injury that is crucial to the maintenance of muscle mass and function. A p21‐activated kinase 4 (PAK4) serine/threonine kinase is critical to the regulation of cytoskeletal changes, cell proliferation, and growth. However, PAK4's role in myoblast differentiation and regenerative myogenesis remains to be determined. Methods We used a mouse model of myotoxin (notexin)‐induced muscle regeneration. In vitro myogenesis was performed in the C2C12 myoblast cell line, primary myoblasts, and primary satellite cells. In vivo overexpression of PAK4 or kinase‐inactive mutant PAK4S474A was conducted in skeletal muscle to examine PAK4's kinase‐dependent effect on muscle regeneration. The regeneration process was evaluated by determining the number and size of multinucleated myofibres and expression patterns of myogenin and eMyHC. To explore whether PAK4 inhibition improves muscle regeneration, mice were injected intramuscularly with siRNA that targeted PAK4 or orally administered with a chemical inhibitor of PAK4. Results p21‐activated kinase 4 was highly expressed during the myoblast stage, but expression gradually and substantially decreased as myoblasts differentiated into myotubes. PAK4 overexpression, but not kinase‐inactive mutant PAK4S474A overexpression, significantly impeded myoblast fusion and MyHC‐positive myotube formation in C2C12 cells, primary myoblasts, and satellite cells (P < 0.01). Conversely, PAK4 silencing led to an 8.7% and a 20.3% increase in the number of multinucleated larger myotubes in C2C12 cells and primary myoblasts. Further, in vivo overexpression of PAK4 by adenovirus injection to mice prior to and after myotoxin‐induced injury led to a 52.6% decrease in the number of eMyHC‐positive myofibres on Day 5 in tibialis anterior muscles as compared with those injected with control adenoviruses (P < 0.01), while Ad‐PAK4S474A showed comparable muscle regeneration parameters. PAK4‐induced repression of muscle regeneration coincided with an increase in phosphatase and tensin homologue (PTEN) expression and a decrease in phosphoinositide 3‐kinase‐Akt signalling. In contrast, PAK4 silencing reduced PTEN expression in mice. Consistent with these findings, prodrug of PAK4 inhibitor CZh‐226 (30 mg/kg) orally administered to mice repressed PTEN expression and accelerated myotube formation. Subsequent mechanistic studies revealed that PAK4 directly phosphorylates PPARγ at S273 to increase its transcription activity, thereby up‐regulating PTEN expression. Importantly, an analysis of the Genotype‐Tissue Expression database showed a positive correlation between PAK4 and PTEN in human skeletal muscle tissues (P < 0.01). Conclusions p1‐activated kinase 4 is a new member of PPARγ kinase, and PAK4 inhibition may have a therapeutic role as an accelerant of muscle regeneration

Incidence and Survival Outcomes of Colorectal Cancer in Long-Term Metformin Users with Diabetes: A Population-Based Cohort Study Using a Common Data Model

Background and aims: Previous studies have reported that metformin use in patients with diabetes mellitus may reduce the risk of colorectal cancer (CRC) incidence and prognosis; however, the evidence is not definite. This population-based cohort study aimed to investigate whether metformin reduces the risk of CRC incidence and prognosis in patients with diabetes mellitus using a common data model of the Korean National Health Insurance Service database from 2002 to 2013. Methods: Patients who used metformin for at least 6 months were defined as metformin users. The primary outcome was CRC incidence, and the secondary outcomes were the all-cause and CRC-specific mortality. Cox proportional hazard model was performed and large-scaled propensity score matching was used to control for potential confounding factors. Results: During the follow-up period of 81,738 person-years, the incidence rates (per 1000 person-years) of CRC were 5.18 and 8.12 in metformin users and non-users, respectively (p = 0.001). In the propensity score matched cohort, the risk of CRC incidence in metformin users was significantly lower than in non-users (hazard ratio (HR), 0.58; 95% CI (confidence interval), 0.47&ndash;0.71). In the sensitivity analysis, the lag period extending to 1 year showed similar results (HR: 0.63, 95% CI: 0.51&ndash;0.79). The all-cause mortality was significantly lower in metformin users than in non-users (HR: 0.71, 95% CI: 0.64&ndash;0.78); CRC-related mortality was also lower among metformin users. However, there was no significant difference (HR: 0.55, 95% CI: 0.26&ndash;1.08). Conclusions: Metformin use was associated with a reduced risk of CRC incidence and improved overall survival