At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole‐body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.

The endosteum of the bone marrow provides a specialized hypoxic niche that may serve to preserve the integrity, pluripotency, longevity and stemness of resident mesenchymal stem cells (MSCs). To explore the molecular genetic consequences of such a niche we subjected human (h) MSCs to a pO₂ of 4 mmHg and analyzed global gene expression and alternative splicing (AS) by genome-exon microarray and RT-qPCR, and phenotype by western blot and immunostaining. Out of 446 genes differentially regulated by >2.5-fold, down-regulated genes outnumbered up-regulated genes by 243:203. Exon analyses revealed 60 hypoxia-regulated AS events with splice indices (SI) >1.0 from 53 genes and a correlation between high SI and degree of transcript regulation. Parallel analyses of a publicly available AS study on human umbilical vein endothelial cells (HUVECs) showed that there was a strong cell-specific component with only 11 genes commonly regulated in hMSCs and HUVECs and 17 common differentially spliced genes. Only 3 genes were differentially responsive to hypoxia at the gene (>2.0) and AS levels in both cell types. Functional assignments revealed unique profiles of gene expression with complex regulation of differentiation, extracellular matrix, intermediate filament and metabolic marker genes. Antioxidant genes, striated muscle genes and insulin/IGF-1 signaling intermediates were down-regulated. There was a coordinate induction of 9 out of 12 acidic keratins that along with other epithelial and cell adhesion markers implies a partial mesenchymal to epithelial transition. We conclude that severe hypoxia confers a quiescent phenotype in hMSCs that is reflected by both the transcriptome profile and gene-specific changes of splicosome actions. The results reveal that severe hypoxia imposes markedly different patterns of gene regulation of MSCs compared with more moderate hypoxia. This is the first study to report hypoxia-regulation of AS in stem/progenitor cells and the first molecular genetic characterization of MSC in a hypoxia-induced quiescent immobile state.

Hongjingtian injection (HJT) has been widely used in the clinic to treat coronary heart disease in China. However, the underlying mechanisms of therapies still need to be illustrated. The present study aims to determine whether HJT protects against myocardial ischemia reperfusion injury via Reactive Oxygen Species (ROS)-induced autophagic flux and apoptosis and, if so, to explore the underlying mechanisms. In vivo myocardial protection and autophagy regulation of HJT in myocardial ischemia reperfusion injury in C57BL/6 J and CAG-RFP-EGFP-LC3 transgenic C57BL/6 J mice were investigated. In vitro, the effects of HJT on apoptosis, autophagic flux, oxidative stress and mitochondrial function were observed in H₂O₂-induced H9c2 cells. In addition, apoptosis-related proteins and autophagy-related proteins were assessed to explore the underlying mechanisms. HJT significantly decreased the infarct area and cell apoptosis after myocardial ischemia reperfusion injury in C57BL/6 J mice. Autophagic flux was reduced by HJT treatment after myocardial ischemia reperfusion injury in CAG-RFP-EGFP-LC3 transgenic C57BL/6 J mice. HJT inhibited H₂O₂-induced cell apoptosis by significantly decreasing the levels of cleaved caspase 3 and increasing the Bcl-2/Bax ratio. HJT inhibited autophagic flux after H₂O₂ stimulation by significantly decreasing LC3-Ⅱ and p-AMPK expression and increasing p-mTOR. HJT inhibited ROS production and improved mitochondrial function in H₂O₂-induced cells by significantly increasing the mitochondrial membrane potential, intracellular ATP contents and oxygen consumption. The beneficial effects of HJT in treating myocardial ischemia reperfusion are partially due to improved mitochondrial function and regulated autophagy to inhibit cell apoptosis through the AMPK/mTOR pathway.

Deep insights into the metabolic remodelling effects on the immune microenvironment of oesophageal squamous cell carcinoma (ESCC) are crucial for advancing precision immunotherapies and targeted therapies. This study aimed to provide novel insights into the molecular landscape of ESCC and identify clinically actionable targets associated with immunosuppression driven by metabolic changes. We performed metabolomic and proteomic analyses combined with previous genomic and transcriptomic data, identified multi-omics-linked molecular features, and constructed metabolic-immune interaction-based ESCC classifiers in a discovery cohort and an independent validation cohort. We further verified the molecular characteristics and related mechanisms of ESCC subtypes. Our integrated multi-omics analysis revealed dysregulated proteins and metabolic imbalances characterizing ESCC, with significant alterations in metabolites and proteins linked to genetic traits. Importantly, ESCC patients were stratified into three subtypes (S1, S2, and S3) on the basis of integrated metabolomic and proteomic data. A robust subtype prediction model was developed and validated across two independent cohorts. Notably, patients classified under the poorest prognosis subtype (S3 subtype) exhibited a significant immunosuppressive microenvironment. We identified key metabolism-related biomarkers for the S3 subtype, specifically creatine and hexokinase 3 (HK3). Creatine accumulation and HK3 protein deficiency synergistically reprogrammed macrophage metabolism, driving M2-like TAM polarization. This metabolic shift fostered an immunosuppressive microenvironment that accelerated tumour progression. These results highlight the potential of targeting creatine metabolism to improve the efficacy of immunotherapy and targeted therapy for ESCC. Our analysis reveals molecular variation in multi-omics linkages and identifies targets that reverse the immunosuppressive microenvironment through metabolic remodelling improving immunotherapy and targeted therapy for ESCC.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Natural compounds extracted from medicinal plants characterized by diverse biological activities and low toxicity or side effects, are increasingly taking center stage in the search for new drugs. Currently, preclinical evaluation of natural products relies mainly on the use of immortalized cell lines of human origin or animal models. Increasing evidence indicates that cardiomyopathy models based on immortalized cell lines do not recapitulate pathogenic phenotypes accurately and a substantial physiological discrepancy between animals and humans casts doubt on the clinical relevance of animal models for these studies. The newly developed human induced pluripotent stem cell (hiPSC) technology in combination with highly-efficient cardiomyocyte differentiation methods provides an ideal tool for modeling human cardiomyopathies in vitro. Screening of drugs, especially screening of natural products, based on these models has been widely used and has shown that evaluation in such models can recapitulate important aspects of the physiological properties of drugs. The purpose of this review is to provide information on the latest developments in this area of research and to help researchers perform screening of natural products using the hiPSC-CM platform.