Rationale: Among all the diabetic complications, diabetic cardiomyopathy, which is characterized by myocyte loss and myocardial fibrosis, is the leading cause of mortality and morbidity in diabetic patients. Tissue kallikrein-related peptidases (KLKs) are secreted serine proteases, that have distinct and overlapping roles in the pathogenesis of cardiovascular diseases. However, whether KLKs are involved in the development of diabetic cardiomyopathy remains unknown.The present study aimed to determine the role of a specific KLK in the initiation of endothelial-to-mesenchymal transition (EndMT) during the pathogenesis of diabetic cardiomyopathy. Methods and Results- By screening gene expression profiles of KLKs, it was found that KLK8 was highly induced in the myocardium of mice with streptozotocin-induced diabetes. KLK8 deficiency attenuated diabetic cardiac fibrosis, and rescued the impaired cardiac function in diabetic mice. Small interfering RNA (siRNA)-mediated KLK8 knockdown significantly attenuated high glucose-induced endothelial damage and EndMT in human coronary artery endothelial cells (HCAECs). Diabetes-induced endothelial injury and cardiac EndMT were significantly alleviated in KLK8-deficient mice. In addition, transgenic overexpression of KLK8 led to interstitial and perivascular cardiac fibrosis, endothelial injury and EndMT in the heart. Adenovirus-mediated overexpression of KLK8 (Ad-KLK8) resulted in increases in endothelial cell damage, permeability and transforming growth factor (TGF)-β1 release in HCAECs. KLK8 overexpression also induced EndMT in HCAECs, which was alleviated by a TGF-β1-neutralizing antibody. A specificity protein-1 (Sp-1) consensus site was identified in the human KLK8 promoter and was found to mediate the high glucose-induced KLK8 expression. Mechanistically, it was identified that the vascular endothelial (VE)-cadherin/plakoglobin complex may associate with KLK8 in HCAECs. KLK8 cleaved the VE-cadherin extracellular domain, thus promoting plakoglobin nuclear translocation. Plakoglobin was required for KLK8-induced EndMT by cooperating with p53. KLK8 overexpression led to plakoglobin-dependent association of p53 with hypoxia inducible factor (HIF)-1α, which further enhanced the transactivation effect of HIF-1α on the TGF-β1 promoter. KLK8 also induced the binding of p53 with Smad3, subsequently promoting pro-EndMT reprogramming via the TGF-β1/Smad signaling pathway in HCAECs. The in vitro and in vivo findings further demonstrated that high glucose may promote plakoglobin-dependent cooperation of p53 with HIF-1α and Smad3, subsequently increasing the expression of TGF-β1 and the pro-EndMT target genes of the TGF-β1/Smad signaling pathway in a KLK8-dependent manner. Conclusions: The present findings uncovered a novel pro-EndMT mechanism during the pathogenesis of diabetic cardiac fibrosis via the upregulation of KLK8, and may contribute to the development of future KL...

Exercise training exerts protective effects against diabetic nephropathy. This study aimed to investigate whether exercise training could attenuate diabetic renal injury via regulating endogenous hydrogen sulfide (H2S) production. First, C57BL/6 mice were allocated into the control, diabetes, exercise, and diabetes + exercise groups. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ). Treadmill exercise continued for four weeks. Second, mice was allocated into the control, diabetes, H2S and diabetes + H2S groups. H2S donor sodium hydrosulfide (NaHS) was intraperitoneally injected once daily for four weeks. STZ‐induced diabetic mice exhibited glomerular hypertrophy, tissue fibrosis and increased urine albumin levels, urine protein‐ and albumin‐to‐creatinine ratios, which were relieved by exercise training. Diabetic renal injury was associated with apoptotic cell death, as evidenced by the enhanced caspase‐3 activity, the increased TdT‐mediated dUTP nick‐end labeling ‐positive cells and the reduced expression of anti‐apoptotic proteins, all of which were attenuated by exercise training. Exercise training enhanced renal sirtuin 1 (SIRT1) expression in diabetic mice, accompanied by an inhibition of the p53‐#ediated pro‐apoptotic pathway. Furthermore, exercise training restored the STZ‐mediated downregulation of cystathionine‐β‐synthase (CBS) and cystathionine‐γ‐lyase (CSE) and the reduced renal H2S production. NaHS treatment restored SIRT1 expression, inhibited the p53‐mediated pro‐apoptotic pathway and attenuated diabetes‐associated apoptosis and renal injury. In high glucose‐treated MPC5 podocytes, NaHS treatment inhibited the p53‐mediated pro‐apoptotic pathway and podocyte apoptosis in a SIRT1‐dependent manner. Collectively, exercise training upregulated CBS/CSE expression and enhanced the endogenous H2S production in renal tissues, thereby contributing to the modulation of the SIRT1/p53 apoptosis pathway and improvement of diabetic nephropathy.

BackgroundThis research focused on evaluating the correlation between platelet count and sepsis prognosis, and even the dose-response relationship, in a cohort of American adults.MethodPlatelet counts were recorded retrospectively after hospitalization for patients admitted to Beth Israel Deaconess Medical Center’s intensive care unit between 2008 and 2019. On admission to the intensive care unit, sepsis patients were divided into four categories based on platelet counts (very low < 50 × 109/L, intermediate-low 50 × 109–100 × 109/L, low 100 × 109–150 × 109/L, and normal ≥ 150 × 109/L). A multivariate Cox proportional risk model was used to calculate the 28-day risk of mortality in sepsis based on baseline platelet counts, and a two-piece linear regression model was used to calculate the threshold effect.ResultsThe risk of 28-day septic mortality was nearly 2-fold higher in the platelet very low group when compared to the low group (hazard ratios [HRs], 2.24; 95% confidence interval [CI], 1.92–2.6). Further analysis revealed a curvilinear association between platelets and the sepsis risk of death, with a saturation effect predicted at 100 × 109/L. When platelet counts were below 100 × 109/L, the risk of sepsis 28-day death decreased significantly with increasing platelet count levels (HR, 0.875; 95% CI, 0.84–0.90).ConclusionWhen platelet count was less than 100 × 109/L, it was a strong predictor of the potential risk of sepsis death, which is declined by 13% for every 10 × 109/L growth in platelets. When platelet counts reach up to 100 × 109/L, the probability of dying to sepsis within 28 days climbs by 1% for every 10 × 109/L increase in platelet count.

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Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.