Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

Free fatty acids (FFA) is a key contributor to insulin resistance and endothelial dysfunction. However, the precise mechanism underlying the role of FFA remains elusive. This study aimed to investigate the role of NLRP3 (NOD-like receptor pyrin domain containing-3) inflammasome in FFA induced endothelial dysfunction. HUVECs were transfected with NLRP3 siRNA and then stimulated with LPS and palmitate. C57 BL/6 J mice transfected with NLRP3 Lenti-Virus were fed with a high-fat diet (HFD). The levels of NLRP3 inflammasome, AMPKα (AMP-activated protein kinase), endothelial nitric oxide synthase (eNOS) and the activity of the insulin signal pathway, in endothelial cells were determined via Western blotting. Endothelial function was determined by measuring the level of endothelium-dependent vasodilatation. FFA could activate NLRP3 inflammasome and induce IL-1β release both in vitro. and in vivo. Using siRNA and Lenti-Virus to inhibit NLRP3 abolished palmitate-induced IL-1β release and restored impaired phosphorylation of IRS-1 (Tyr), Akt (Ser473) and eNOS (Ser1177) and ACh-mediated endothelium-dependent vasorelaxation induced by palmitate. AMPKα activator AICAR(5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside) inhibited NLRP3 inflammasome activation and decreased IL-1β release and restored impaired insulin signal pathway induced by palmitate. NLRP3 inflammasome activation via AMPKα inactivation mediated palmitate-induced endothelial dysfunction through involves IL-1β-induced insulin signal pathway.

Myricetin, a major flavonoid found in several foods including berries, grapes and wine, exhibited strong antioxidant potency, yet the effect on atherosclerosis is not fully understood. In this study, we examined the effect of myricetin on lipid accumulation in macrophage and atherosclerosis in atherosclerosis-prone low density lipoprotein receptor-deficient (Ldlr−/−) mice. Ldlr−/− mice were fed an atherogenic diet supplemented with myricetin (0.15% in the diet, v/v) for 8 weeks. Body weight, adipose tissue weight, food intake, serum biochemical parameters were measured. Atherosclerosis lesions and macrophages accumulaton in lesions were analyzed and quantified. Macrophages were exposed to 20 μM of myricetin before incubated with oxidized low-density lipoprotein (ox-LDL) (25μg/mL) or Dil-ox-LDL for the indicated time. Lipid uptake and foam cell formation were evaluated by flow cytometry and microscopy. The intracellular lipids were extracted and measured. mRNA expression and protein of cholesterol metabolism related receptors were analyzed. Myricetin administration reduced the weight, plasma lipid levels but not food intake in Ldlr−/− mice when fed an atherogenic diet. Myceritin-treated Ldlr−/− mice displayed significantly less atherosclerotic areas and macrophages in the cross sections of the aortic root. There were also less lipophilic areas in En face Oil red O staining of aorta from myceritin-treated Ldlr−/− mice. Myceritin treatment also markedly ameliorated ox-LDL-induced cholesterol accumulation in macrophages. The expression of CD36 were decreased in myricetin treated macrophages with ox-LDL incubation, while scavenger receptors class A (SR-A) and scavenger receptors class B (SR-BI) expression was not altered, indicating that these effect of myricetin were dependent on CD36 pathway. Our findings indicated that myricetin suppressed cholesterol accumulation in macrophage foam cells by inhibition of CD36-mediated ox-LDL uptake, and suggested myricetin may have an important therapeutic function for atherosclerosis.

Ubiquitin-specific protease 2 (USP2) is an important member of the deubiquitination system. GEO dataset revealed that USP2 was downregulated in the hearts under pressure overload. However, the cardiomyocyte-specific function of USP2 in the setting of pressure overload is unknown. In the current study, a mouse model of pressure overload was induced by transverse aortic constriction (TAC, 2 weeks). Overexpression of USP2 in the heart was conducted by AAV9 infection. Changes in heart histology were detected by Masson’s trichrome staining and hematoxylin-eosin staining (H&E). Echocardiography was used to assess cardiac function. The size of cardiomyocytes was examined by wheat germ agglutinin (WGA) staining. Cardiac oxidative stress was detected by dihydroethidine staining. Our results showed that USP2 was downregulated in the cardiomyocytes following 2 weeks of TAC. Overexpression of cardiac USP2 preserved ventricular function following 2 weeks of TAC. Overexpression of cardiac USP2 inhibited TAC-induced cardiac remodeling, by suppressing cardiac hypertrophy, inhibiting inflammatory responses and fibrosis, and attenuating oxidative stress. Our findings reveal a previously unrecognized role of USP2 in regulating pressure overload-induced cardiac remodeling.

The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX‐related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX‐induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose‐dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX‐related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX‐related injury in Sirt1‐deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX‐related cardiac injury through activation of the Sirt1 signaling pathway.

Diabetic foot ulcers (DFUs) represent a common and serious complication of diabetes, characterized by impaired wound healing and an increased risk of infection. These infections severely impact patient health, necessitating extensive medical intervention, and increasing the risk of amputation. Vitamin D (VD) plays a critical role in immune regulation and tissue repair. To investigate the effects of VD supplementation on infection rates, wound healing, and immune function in patients with DFUs. A randomized controlled trial was conducted involving 120 patients with DFUs. Participants were randomly assigned to either a control group (n = 60), which received standard care without VD supplementation, or an intervention group (n = 60), which received 2000 IU of oral VD3 (cholecalciferol) daily for 12 weeks. The primary outcomes included the incidence and severity of infections, whereas the secondary outcomes included wound healing rate, serum 25-hydroxyvitamin D level, levels of immune markers (cathelicidin, interleukin-6 and tumor necrosis factor-α), and adverse events, such as hypercalcemia. The incidence of infection was significantly lower in the VD supplementation group (25%) compared with the control group (45%) (P = 0.01). Severe infections requiring systemic antibiotics or hospitalization were also less frequent in the VD supplementation group. Wound healing was notably enhanced in the VD supplementation group, with a 60% reduction in ulcer size compared with a 35% reduction in the control group (P < 0.01). Serum 25(OH)D level significantly increased in the VD supplementation group (from 16.5 ng/mL to 35.2 ng/mL), confirming the efficacy of VD supplementation. Immune function improved, as demonstrated by a 30% rise in cathelicidin level and a 20% decline in levels of pro-inflammatory cytokines. No adverse effects, including hypercalcemia, were reported. The VD supplementation effectively reduced infection rate, promoted wound healing, and strengthened immune responses in patients with DFUs. These findings support the incorporation of VD as a safe and effective adjunctive therapy in the clinical management of DFUs.