Diabetic nephropathy (DN) is a chronic low-grade inflammatory disease. Oxidative stress and nuclear factor kappa B (NF-κB) signaling play an important role in the pathogenesis of DN. Short-chain fatty acids (SCFAs) produced from carbohydrate fermentation in the gastrointestinal tract exert positive regulatory effects on inflammation and kidney injuries. However, it is unclear whether SCFAs can prevent and ameliorate DN. In the present study, we evaluated the role and mechanism of the three main SCFAs (acetate, propionate, and butyrate) in high-fat diet (HFD) and streptozotocin- (STZ-) induced type2 diabetes (T2D) and DN mouse models and in high glucose-induced mouse glomerular mesangial cells (GMCs), to explore novel therapeutic strategies and molecular targets for DN. We found that exogenous SCFAs, especially butyrate, improved hyperglycemia and insulin resistance; prevented the formation of proteinuria and an increase in serum creatinine, urea nitrogen, and cystatin C; inhibited mesangial matrix accumulation and renal fibrosis; and blocked NF-κB activation in mice. SCFAs also inhibited high glucose-induced oxidative stress and NF-κB activation and enhanced the interaction between β-arrestin-2 and I-κBα in GMCs. Specifically, the beneficial effects of SCFAs were significantly facilitated by the overexpression GPR43 or imitated by a GPR43 agonist but were inhibited by siRNA-GPR43 in GMCs. These results support the conclusion that SCFAs, especially butyrate, partially improve T2D-induced kidney injury via GPR43-mediated inhibition of oxidative stress and NF-κB signaling, suggesting SCFAs may be potential therapeutic agents in the prevention and treatment of DN.

Diabetic wound (DW) is characterized by elevated pro-inflammatory cytokines and cellular dysfunction consistent with elevated reactive oxygen species (ROS) levels. Recent advances in immunology have dissected molecular pathways involved in the innate immune system where cytoplasmic DNA can trigger STING-dependent inflammatory responses and play an important role in metabolic-related diseases. We investigated whether STING regulates inflammation and cellular dysfunction in DW healing. We found that STING and M1 macrophages were increased in wound tissues from DW in patients and mice and delayed the wound closure. We also noticed that the massively released ROS in the High glucose (HG) environment activated STING signaling by inducing the escape of mtDNA to the cytoplasm, inducing macrophage polarization into a pro-inflammatory phenotype, releasing pro-inflammatory cytokines, and exacerbating endothelial cell dysfunction. In Conclusion, mtDNA-cGAS-STING pathway activation under diabetic metabolic stress is an important mechanism of DW refractory healing. While using STING gene-edited macrophages for wound treatment by cell therapy can induce the polarization of wound macrophages from pro-inflammatory M1 to anti-inflammatory M2, promote angiogenesis, and collagen deposition to accelerate DW healing. STING may be a promising therapeutic target for DW.

Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.

Chronic high‐dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol‐induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment‐induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin‐1 (Nec‐1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N‐acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol‐induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high‐dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol‐induced osteopenia.

Pyroptosis is an inflammatory form of programmed cell death that is dependent on inflammatory caspases, leading to the cleavage of gasdermin D (GSDMD) and increased secretion of interleukin (IL)-1β and IL-18. Recent studies have reported that hyperglycemia-induced cellular stress stimulates pyroptosis, and different signaling pathways have been shown to play crucial roles in regulating pyroptosis. This review summarized and discussed the molecular mechanisms, regulation, and cellular effects of pyroptosis in diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. In addition, this review aimed to provide new insights into identifying better treatments for diabetic microvascular complications.