Adenosine 2 receptor regulates autophagy and apoptosis to alleviate ischemia reperfusion injury in type 2 diabetes via IRE-1 signaling.

PURPOSE: This study aimed to determine the effect and mechanism of action of adenosine 2 receptor (A2R) activation on myocardial ischemia reperfusion injury (MIRI) under diabetic conditions. METHODS: MIRI type 2 diabetic rats and H9C2 cardiomyocytes were treated with A2R agonist and then subjected to hypoxia for 6 h and reoxygenation for 18 h. Myocardial damage, and infarct size were determined by cardiac ultrasound. Indicators of cardiomyocyte injury, creatine kinase-MB and cardiac troponin I were detected by Enzyme Linked Immunosorbent Assay. Endoplasmic reticulum stress (ERS) was determined through measuring the expression levels of ERS related genes GRP78, p-IRE1/IRE1, and p-JNKJNK. The mechanism of A2R cardio protection in MIRI through regulating ERS induced autophagy was determined by investigating the ER resident protein IRE-1. The ER-stress inducer Tunicamycin, and the IRE-1 inhibitor STF in combination with the A2R agonist NECA were used, and the cellular responses were assessed through autophagy proteins expression Beclin-1, p62, LC3 and apoptosis. RESULTS: NECA improved left ventricular function post MIRI, limited myocardial infarct size, reduced myocardial damage, decreased cardiomyocytes apoptosis, and attenuated ERS induced autophagy through regulating the IRE-XBP1s-CHOP pathway. These actions resulted into overall protection of the myocardium against MIRI. CONCLUSION: In summary, A2R activation by NECA prior to ischemia attenuates apoptosis, reduces ERS induced autophagy and restores left ventricular function. This protective effect occurs through regulating the IRE1-XBPs-CHOP related mechanisms. NECA is thus a potential target for the treatment of MIRI in patient with type 2 diabetes.

Optimum cycles of induction chemotherapy in concurrent chemo-radiotherapy management of unresectable stage III non-small cell lung cancer: Results from a single institutional database.

Induction chemotherapy (IC) prior to concurrent chemo-radiotherapy is the recommended treatment for unresectable stage III non-small cell lung cancer (NSCLC). However, the optimum number of IC cycles for improved survival outcomes is still not known. Here, we assessed the efficacy of 2 or more cycles of IC for unresectable stage III NSCLC patients from our hospital. Data on unresectable stage III NSCLC patients treated with IC + concurrent chemo-radiotherapy at our hospital between 2018 and 2022 were retrieved and analyzed, and survival outcomes compared between IC = 2 and IC > 2 patients. Univariate and multivariate Cox regression, and Chi-square or Fisher exact test were used to assess prognosis and acute toxicity profiles. One hundred twenty-six patients were recruited; 90 for IC = 2 and 36 for IC > 2. Median follow-up time was 26 months [IQR 16-38]. Three-year overall survival was not statistically significant between the 2 groups (77.8% vs 75.0%, P = .453). Distant metastasis free survival, loco-regional recurrence free survival and progression free survival were also not significant, (90.0% vs 86.1%, P = .068), 97.8% vs 97.2%, P = .056), and (73.3% vs 66.7%, P = .446) respectively. Univariate and multivariate Cox regression analysis revealed smoking, T_stage, N_stage, and IC_regimen as independent prognostic factor for overall survival, while drinking and T_stage were risk factors for progression free survival. In summary, 2 cycles of platinum-based IC was effective for stage III unresectable NSCLC and adding more than 2 cycles did not offer extra survival benefits.