Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.

Mortality of Escalation and Modulation Antithrombotic Therapy in Coronary Artery Disease Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The net clinical benefit of antithrombotic therapy (ATT) reflects the concomitant effects of bleeding and ischemic events. OBJECTIVES: We sought to assess the overall effect of the modulation or escalation of ATT on all-cause mortality as well as ischemic and bleeding events. METHODS: We performed a meta-analysis of randomized controlled trials comparing escalation or modulation of ATT versus standard ATT in patients with coronary artery disease. A total of 32 studies with 160,659 subjects were enrolled in this analysis. RESULTS: Neither escalation nor modulation of ATT has significant effect on all-cause mortality (escalation: relative risk [RR]: 0.94, 95% confidence interval [CI]: 0.85-1.04; modulation: RR: 0.90; 95% CI: 0.81-1.01). Compared with standard ATT therapy, escalation of ATT was associated with lower risk of myocardial infarction (MI; RR: 0.84, 95% CI: 0.76-0.94), but had a higher risk of major or minor bleeding (RR: 1.38, 95% CI: 1.15-1.66). Modulation of ATT was associated with a similar risk of MI (RR: 1.07, 95% CI: 0.96-1.19), but a reduced risk for major or minor bleeding (RR: 0.58, 95% CI: 0.51-0.66). Meta-regression combining both escalation and modulation studies found that the heterogeneity of all-cause mortality was mainly attributed to the heterogeneity of major or minor bleeding (adjusted R-squared = 100.00%, p = 0.004), but not to MI. CONCLUSION: Either escalation or modulation of ATT has little benefit in all-cause mortality. The variability of the treatment effects on all-cause mortality was mainly attributed to the variability of major or minor bleeding, but not to MI.

Prognostic significance of multiple triglycerides-derived metabolic indices in patients with acute coronary syndrome.

BACKGROUND: Triglyceride (TG) and its related metabolic indices, all recognized as surrogates of insulin resistance, have been demonstrated to be relevant to clinical prognosis. However, the relative value of these TG-related indices for predicting cardiovascular events among patients with acute coronary syndrome (ACS) has not been examined. METHODS: The TG, the triglyceride-glucose (TyG) index, the atherogenic index of plasma, TG to high-density lipoprotein cholesterol ratio, and the lipoprotein combine index were assessed in 1694 ACS patients undergoing percutaneous coronary intervention. The primary endpoint was major adverse cardiovascular event (MACE), which was the composite of all-cause mortality, stroke, myocardial infarction, or unplanned repeat revascularization. RESULTS: During a median follow-up of 31 months, 345 patients (20.4%) had MACE. The risk of the MACE was increased with higher TG and the four TG-derived metabolic indices [TG-adjusted hazard ratio (HR) = 1.002, 95% CI: 1.001-1.003; TyG index-adjusted HR = 1.736, 95% CI: 1.398-2.156; atherogenic index of plasma-adjusted HR = 2.513, 95% CI: 1.562-4.043; TG to high-density lipoprotein cholesterol ratio-adjusted HR = 1.148, 95% CI: 1.048-1.258; and lipoprotein combine index-adjusted HR = 1.009, 95% CI: 1.004-1.014; P < 0.001 for all indices]. TG and all the four indices significantly improved the predictive ability for MACE in addition to the baseline model. Among them, TyG index showed the best ability for predicting MACE compared with the other three indices from all the three measurements ( P < 0.05 for all comparison). CONCLUSIONS: TG and TG-derived metabolic indices were all strongly associated with MACE among ACS patients undergoing percutaneous coronary intervention. Among all the indices, TyG index showed the best ability to predict the risk of MACE.

Monoterpenoid indole alkaloids with potential neuroprotective activities from the stems and leaves of Melodinus cochinchinensis.

A chemical study on the stems and leaves of Melodinus cochinchinensis resulted in the isolation and identification of a new monoterpenoid indole alkaloid, melodicochine A (1), together with seven known monoterpenoid indole alkaloids (2-8). The chemical structure of 1 was elucidated on the basis of extensive spectral data analyses and the known compounds were identified by comparing their experimental spectral data with the reported data in the literature. All isolated indole alkaloids were evaluated for their neuroprotective effects against 6-hydroxydopamine induced cell death in human neuroblastoma SH-SY5Y cells in vitro. Monoterpenoid indole alkaloids 1-8 exhibited notable neuroprotective effects with EC50 values in range of 0.72 ± 0.06 to 17.89 ± 0.16 µM.[Formula: see text].

Association of serum complement C1q with cardiovascular outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention.

OBJECTIVE: To determine the association of serum complement C1q levels with cardiovascular outcomes among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), and evaluate the value of C1q modified by high-sensitivity C-reactive protein (hs-CRP) levels as an independent predictor. METHODS: As a single-center prospective observational study, we analyzed 1701 patients who had received primary or elective PCI for ACS at Beijing Anzhen Hospital, Capital Medical University, Beijing, China between June 1, 2016 and November 30, 2017. The associations of C1q modified by hs-CRP with major adverse cardiovascular events (MACE) were determined in survival analysis. RESULTS: Patients with the lowest C1q tertile had the highest cumulative risk of MACE (log-rank P = 0.007). In fully adjusted Cox regression models, stratifying the total population according to hs-CRP dichotomy, C1q was significantly associated with MACE in patients with hs-CRP levels less than 2 mg/L but not in those with 2 mg/L or more (P interaction = 0.02). In patients with hs-CRP levels less than 2 mg/L, with the lowest C1q tertile as reference, the risk of MACE was reduced by 40.0% in the middle C1q tertile [hazard ratio (HR) = 0.600, 95% CI: 0.423-0.852, P = 0.004] and by 43.9% in the highest C1q tertile (HR = 0.561, 95% CI: 0.375-0.840, P = 0.005). CONCLUSIONS: Serum complement C1q is significantly associated with cardiovascular outcomes in patients with ACS undergoing PCI, only when hs-CRP levels are less than 2 mg/L. This finding implicates the usefulness of C1q for the risk stratification in ACS patients with reduced systemic inflammation.

GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses.

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.

GLP-1 and Underlying Beneficial Actions in Alzheimer's Disease, Hypertension, and NASH.

GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.

Nutritional Risk Index Improves the GRACE Score Prediction of Clinical Outcomes in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Background: Malnutrition has been shown to be associated with adverse cardiovascular outcomes in many patient populations. Aims: To investigate the prognostic significance of malnutrition as defined by nutritional risk index (NRI) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and whether NRI could improve the GRACE score based prognostic models. Methods: This study applied NRI among 1,718 patients with ACS undergoing PCI. Patients were divided into three nutritional risk groups according to their baseline NRI: no nutritional risk (NRI ≥ 100), mild nutritional risk (97.5 ≤ NRI <100), and moderate-to-severe nutritional risk (NRI <97.5). The primary endpoint was the composite of major adverse cardiovascular events (MACE), including all-cause death, non-fatal stroke, non-fatal myocardial infarction, or unplanned repeat revascularization. Results: During a median follow-up of 927 days, 354 patients developed MACE. In the overall population, compared with normal nutritional status, malnutrition was associated with increased risk for MACE [adjusted HR for mild and moderate-to-severe nutritional risk, respectively: 1.368 (95%CI 1.004-1.871) and 1.473 (95%CI 1.064-2.041)], and NRI significantly improved the predictive ability of the GRACE score for MACE (cNRI: 0.070, P = 0.010; IDI: 0.005, P < 0.001). In the diabetes subgroup, malnutrition was associated with nearly 2-fold high adjusted risk of MACE, and the GRACE score combined with NRI appeared to have better predictive ability than that in the overall population. Conclusion: Malnutrition as defined by NRI was independently associated with MACE in ACS patients who underwent PCI, especially in individuals with diabetes, and improved the predictive ability of the GRACE score based prognostic models.