No abstract

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and δ2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and δ2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective δ OR antagonist TIPP(ψ) (30 nmol/l), the selective δ1 OR antagonist BNTX (1 nmol/l), the selective δ2 OR antagonist naltriben (1 nmol/l), the selective peptide μ OR antagonist CTAP (100 nmol/l) and the selective κ OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activity in coronary effluent and cardiac contractile function were monitored to assess cardiac injury and functional impairment. Additionally, cardiac tissue was collected to measure ATP and to isolate mitochondria to measure respiration rate and calcium retention capacity. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the postischemic recovery of contractile function. Additionally, CNH improved mitochondrial state 3 and uncoupled respiration rates, ADP/O, mitochondrial transmembrane potential and calcium retention capacity and myocardial ATP level during reperfusion compared to the normoxic group. These protective effects were completely abolished by naloxone, TIPP(ψ), naltriben, CTAP but not BNTX or nor-binaltorphimine. These results suggest that cardioprotection associated with adaptation to CNH is mediated by µ and δ2 opioid receptors activation and preservation of mitochondrial function.

No abstract

No abstract

The tissues and plasma of patients taking EGFR-TKIs were used to examine the correlation between the drug's efficacy and IL-22 level. We identified IL-22-induced EGFR-TKIs resistance and the effect of IL-22 on EGFR/AKT/ERK pathways in NSCLC PC-9 and HCC827 cells by CCK-8 assay, flow cytometric analysis, and western blotting. Then, we established the PC-9 xenograft model with IL-22 exposure and used gefitinib combined with vehicle or IL-22 to treat mice. Result: We confirmed that IL-22 can inhibit the effect of gefitinib on NSCLC cells and determined the effects of IL-22 on EGFR/ AKT/ERK pathways. Then, we showed that IL-22 exposures could promote tumor growth and induce resistance to gefitinib in the PC-9 xenograft model. Conclusion: These results suggest that IL-22 contributes to tumor progression and EGFR-TKIs resistance in NSCLC. Therefore, IL-22 is a potential therapeutic target for EGFR-TKIs resistance.