This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1 ) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1 mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.

Radiotherapy significantly improves the therapeutic outcomes and survival of breast cancer patients. However, the acquired resistance to this therapeutic modality is a major clinical challenge. Here we show that ionizing irradiation (IR)-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) at the Tyr705 residue and the induction of reactive oxygen species (ROS) in wild-type and radioresistant MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines. Comparing with radiosensitive parental TNBC cells, significantly low levels of ROS and higher protein levels of phospho-STAT3 and Bcl-2 were observed in TNBC cells with acquired radioresistance. Moreover, knockdown of STAT3 by shRNA sensitized the TNBC cells to IR. Niclosamide, a potent inhibitor of STAT3, overcame the radioresistance in TNBC cells via inhibition of STAT3 and Bcl-2 and induction of ROS. In combination with radiation, niclosamide treatment resulted in significant increase of ROS generation and induction of apoptosis in parental and radioresistant TNBC cells in vitro and TNBC xenograft tumors in vivo. These findings demonstrate that activation of STAT3 and Bcl-2 and reduction of ROS contribute to the development of radioresistance in TNBC, and niclosamide acts as a potent radiosensitizer via inhibiting STAT3 and Bcl-2 and increasing ROS generation in TNBC cells and xenograft tumors. Our findings suggest that niclosamide in combination with irradiation may offer an effective alternative approach for restoring the sensitivity of radioresistant TNBC cells to IR for improved therapeutic efficacy and outcomes.

Aims Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the ‘right-level’ of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated. Methods and results Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts. Conclusions Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.

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AIM:To investigate the role of subjective global assessment (SGA) in nutritional assessment and outcome prediction of Chinese patients with gastrointestinal cancer.

Abbreviations: endothelial progenitor cells (EPCs); endothelial cells (ECs); mononuclear cells (MNCs); angiotensin II (AngII); angiotensin II type 1 receptor (AT1R); renin-angiotensin system (RAS); nitric oxide (NO); bone marrow (BM); peripheral blood (PB); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); vascular endothelial growth factor receptor-2 (VEGFR-2); 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); endothelial nitric oxide synthase (eNOS); angiotensin converting enzyme inhibitor (ACEI); angiotensin receptor blockers (

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High glucose sensitized cardiomyocytes to ischaemia/reperfusion injury through nitrative Trx-1 inactivation. Interventions restoring Trx-1 activity in the diabetic heart may represent novel therapies attenuating cardiac injury in diabetic patients.