High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.

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.

Maresin 1 Alleviates Diabetic Kidney Disease via LGR6-Mediated cAMP-SOD2-ROS Pathway.

BACKGROUND: Chronic hyperglycemia-induced inflammation is recognized as the most important pathophysiological process in diabetic kidney disease (DKD). As maresin 1 (MaR1) is an extensive anti-inflammatory lipid mediator, the present study investigated the protective role of MaR1 in the pathogenesis of DKD and its clinical relevance. METHODS: Serum MaR1 concentrations were analyzed in 104 subjects with normal glucose tolerant, type 2 diabetes (T2DM), or DKD. Streptozotocin (STZ) together with high fat diet was used to induce male C57BL/6 J mice into diabetic mice which were treated with MaR1. Human renal tubule epithelial cells (HK-2 cells) were treated by high glucose for glucotoxicity cell model and transfected with LGR6 siRNA for knockdown with MaR1 added，and detected oxidative stress and inflammatory related factors. RESULTS: Serum MaR1 concentrations were significant decreased in T2DM with or without kidney disease compared with normal participant and were lowest in patients with DKD. Serum MaR1 concentrations were negatively correlated with hemoglobin A1c (HbA1c), duration of diabetes, urinary albumin to creatinine ratio (UACR), neutrophil, and neutrophil-lymphocyte ratio and were positively correlated with high-density lipoprotein-cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR). In mouse model, MaR1 injection alleviated hyperglycemia, UACR and the pathological progression of DKD. Interestingly, the renal expression of LGR6 was down-regulated in DKD and high glucose treated HK-2 cells but up-regulated by MaR1 treatment. Mechanistically, MaR1 alleviated inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway in DKD mice and high glucose treated HK-2 cells. CONCLUSIONS: Our study demonstrates that decreased serum MaR1 levels were correlated with the development of DKD. MaR1 could alleviate DKD and glucotoxicity-induced inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway. Thus, our present findings identify MaR1 as a predictor and a potential therapeutic target for DKD.

Innate Immunity in Diabetic Wound Healing: Focus on the Mastermind Hidden in Chronic Inflammatory.

A growing body of evidence suggests that the interaction between immune and metabolic responses is essential for maintaining tissue and organ homeostasis. These interacting disorders contribute to the development of chronic diseases associated with immune-aging such as diabetes, obesity, atherosclerosis, and nonalcoholic fatty liver disease. In Diabetic wound (DW), innate immune cells respond to the Pathogen-associated molecular patterns (PAMAs) and/or Damage-associated molecular patterns (DAMPs), changes from resting to an active phenotype, and play an important role in the triggering and maintenance of inflammation. Furthermore, the abnormal activation of innate immune pathways secondary to immune-aging also plays a key role in DW healing. Here, we review studies of innate immune cellular molecular events that identify metabolic disorders in the local microenvironment of DW and provide a historical perspective. At the same time, we describe some of the recent progress, such as TLR receptor-mediated intracellular signaling pathways that lead to the activation of NF-κB and the production of various pro-inflammatory mediators, NLRP3 inflammatory via pyroptosis, induction of IL-1ß and IL-18, cGAS-STING responds to mitochondrial injury and endoplasmic reticulum stress, links sensing of metabolic stress to activation of pro-inflammatory cascades. Besides, JAK-STAT is also involved in DW healing by mediating the action of various innate immune effectors. Finally, we discuss the great potential of targeting these innate immune pathways and reprogramming innate immune cell phenotypes in DW therapy.

Skipping breakfast is associated with overweight and obesity: A systematic review and meta-analysis.

OBJECTIVE: In recent years, many original studies have shown that skipping breakfast has been associated with overweight and obesity; however, the results of different studies are inconsistent. Therefore, we conducted a systematic review and meta-analysis of observational studies to synthesize the associations between skipping breakfast and the risk of overweight/ obesity. METHODS: We did a systematic search using Pubmed, and Ovid searched up to August 2019. Observational studies (cohort studies and cross-sectional studies) reporting adjusted Odds Ratio or Risk Ratio estimates for the association between breakfast skipping and overweight/obesity (including abdominal obesity). Summary odds ratio (or Risk Ratio) and 95% confidence intervals calculated with a random-effects model. RESULTS: 45 observational studies (36 cross-sectional studies and 9 cohort studies) were included in this meta-analysis. In cross-sectional studies, The ORs of low frequency breakfast intake per week versus high frequency were 1.48 (95% CI 1.40-1.57; I2=54.0%; P=0.002) for overweight/obesity, 1.31 (95% CI 1.17-1.47; I2=43.0%; P=0.15) for abdominal obesity. In cohort studies, The RR of low-frequency breakfast intake per week versus high frequency was 1.44 (95% CI 1.25-1.66; I2=61%; P=0.009) for overweight/obesity. CONCLUSIONS: This meta-analysis confirmed that skipping breakfast is associated with overweight/obesity, and skipping breakfast increases the risk of overweight/obesity. The results of cohort studies and cross-sectional studies are consistent. There is no significant difference in these results among different ages, gender, regions, and economic conditions.

The efficacy and safety of combinations of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of type 2 diabetes or obese adults: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM) or obese adults. METHODS: A meta-analysis was conducted of trials by searching in PubMed, Embase, CENTRAL, Web of Science, and Scopus. RESULTS: A total of five randomized controlled trials (RCTs) and six nonrandomized controlled trials (NCTs) enrolled 1604 participants were identified for meta-analysis. Compared with control/placebo, the combination therapy group had significantly reduced fasting plasma glucose level and 2 h postprandial glucose by 1.28 mmol/L (95% confidence interval [CI]: -1.39, -1.16; p < 0.001) and 1.34 mmol/L (95% CI: -1.47, -1.21; p < 0.001); glycosylated hemoglobin (HbA1c) by 1.32% (95% CI: -1.43, -1.20; p < 0.001); body weight by 0.93 kg (95% CI: -1.04, -0.83; p < 0.001), and systolic blood pressure (SBP) by 1.05 mmHg (95% CI: -1.17, -0.93; p < 0.001). The incidence of genital mycotic infections and urinary infections did not significantly differ from those in the control group, with relative risks (RRs) of 1.67 (95% CI: 0.85, 3.27; p = 0.651) and 1.25 (95% CI: 0.73, 2.15; p = 0.905), respectively. A decreased incidence of cardiovascular events was seen in the combination therapy group (RR = 0.19; 95% CI: 0.04, 0.96; p = 0.403), while an incidence of hypoglycemia was reported (RR = 2.22; 95% CI: 1.20, 4.10; p = 0.71). CONCLUSIONS: SGLT2 inhibitors and GLP-1 agonists combination treatment improved glycemic control, reduced body weight, and decreased SBP without an increase in total adverse events or genital and urinary infections in patients with T2DM or obesity.

Adherence to Teriparatide Treatment and Risk of Fracture: A Systematic Review and Meta-Analysis.

To conduct a retrospective systematic review and meta-analysis of studies investigating the fracture risk among adherence versus non-adherence patients to treatment for osteoporosis. Cohort studies involving adherence to specifically Teriparatide treatment and the risk of fracture, published from inception to June 10 2019, were identified through PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus database of Systematic Reviews. Five eligible cohort studies were included for analysis. Overall, adherence, compared with nonadherence, had a significant 28% reduction in the risk of all fractures, an 49% reduction in the risk of hip fracture and an 26% reduction in the risk of non-vertebral fracture. Subgroup analyses showed that treatment compliant North American patients had a lower incidence of fracture than treatment compliant Asian patients. The effect size associated with adherence showed no difference with non-adherence when the analysis was limited to a small sample size (<10 000 patients). The findings of this retrospective review indicate that high compliance of Teriparatide treatment result in a decreased risk of fracture, particularly in North American treatment adherence, compared with Asian treatment adherence. Improvement of treatment adherence in patients with osteoporosis should be considered through various means in clinical practice.