Bayer AG.

BackgroundEndoplasmic reticulum (ER) stress is considered one of the mechanisms contributing to reactive oxygen species (ROS)- mediated cell apoptosis. In diabetic cardiomyopathy (DCM), cell apoptosis is generally accepted as the etiological factor and closely related to cardiac ROS generation. ER stress is proposed the link between ROS and cell apoptosis; however, the signaling pathways and their roles in participating ER stress- induced apoptosis in DCM are still unclear.MethodsIn this study, we investigated the signaling transductions in ROS- dependent ER stress- induced cardiomocyte apoptosis in animal model of DCM. Moreover, in order to clarify the roles of IRE1 (inositol - requiring enzyme-1), PERK (protein kinase RNA (PKR)- like ER kinase) and ATF6 (activating transcription factor-6) in conducting apoptotic signal in ROS- dependent ER stress- induced cardiomocyte apoptosis, we further investigated apoptosis in high- glucose incubated cardiomyocytes with IRE1, ATF6 and PERK- knocked down respectively.Resultswe demonstrated that the ER stress sensors, referred as PERK, IRE1 and ATF6, were activated in ROS- mediated ER stress- induced cell apoptosis in rat model of DCM which was characterized by cardiac pump and electrical dysfunctions. The deletion of PERK in myocytes exhibited stronger protective effect against apoptosis induced by high- glucose incubation than deletion of ATF6 or IRE in the same myocytes. By subcellular fractionation, rather than ATF6 and IRE1, in primary cardiomyocytes, PERK was found a component of MAMs (mitochondria-associated endoplasmic reticulum membranes) which was the functional and physical contact site between ER and mitochondria.ConclusionsROS- stimulated activation of PERK signaling pathway takes the major responsibility rather than IRE1 or ATF6 signaling pathways in ROS- medicated ER stress- induced myocyte apoptosis in DCM.

Pathogenic mechanisms underlying the development of lung cancer are very complex and not yet entirely clarified. T lymphocytes and their immune-regulatory cytokines play a pivotal role in controlling tumor growth and metastasis. Following activation by unique cytokines, CD4+ T helper cells differentiate into Th1, Th2, Th17, and regulatory T cells (Tregs). Traditionally, research in lung cancer immunity has focused almost exclusively on Th1/Th2 cell balance. Recently, Th17 cells and Tregs represent an intriguing issue to be addressed in lung cancer pathogenesis. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against tumor cells. Th17 cells directly or via other proinflammatory cytokines modulate antitumor immune responses. Notably, there is a close relation between Tregs and Th17 cells. However, the possible interaction between these subsets in lung cancer remains to be elucidated. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent a useful tool for lung cancer treatment in the future. The purpose of this review is to discuss recent findings of the role of these novel populations in lung cancer immunity and to highlight the pleiotropic effects of these subsets on the development and regulation of lung cancer.

Background Coronavirus disease 2019 (COVID-19) has killed over 2.5 million people worldwide, but effective care and therapy have yet to be discovered. We conducted this analysis to better understand tocilizumab treatment for COVID-19 patients. Main text We searched major databases for manuscripts reporting the effects of tocilizumab on COVID-19 patients. A total of 25 publications were analyzed with Revman 5.3 and R for the meta-analysis. Significant better clinical outcomes were found in the tocilizumab treatment group when compared to the standard care group [odds ratio (OR) = 0.70, 95% confidential interval (C): 0.54–0.90, P = 0.007]. Tocilizumab treatment showed a stronger correlation with good prognosis among COVID-19 patients that needed mechanical ventilation (OR = 0.59, 95% CI, 0.37–0.93, P = 0.02). Among stratified analyses, reduction of overall mortality correlates with tocilizumab treatment in patients less than 65 years old (OR = 0.68, 95% CI: 0.60–0.77, P < 0.00001), and with intensive care unit patients (OR = 0.62, 95% CI: 0.55–0.70, P < 0.00001). Pooled estimates of hazard ratio showed that tocilizumab treatment predicts better overall survival in COVID-19 patients (HR = 0.45, 95% CI: 0.24–0.84, P = 0.01), especially in severe cases (HR = 0.58, 95% CI 0.49–0.68, P < 0.00001). Conclusions Our study shows that tocilizumab treatment is associated with a lower risk of mortality and mechanical ventilation requirement among COVID-19 patients. Tocilizumab may have substantial effectiveness in reducing mortality among COVID-19 patients, especially among critical cases. This systematic review provides an up-to-date evidence of potential therapeutic role of tocilizumab in COVID-19 management. Graphical abstract

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