Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12‐deficient mice exhibit high‐fat diet (HFD)–induced and high‐fat high‐cholesterol diet–induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD‐induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal‐regulating kinase 1 (ASK1), which mediates the mitogen‐activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1‐related proteins, JUN N‐terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high‐fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.

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.

Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Although Panax notoginseng saponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stress and its associated cell apoptosis along with the related mechanism in cardiac myocytes. PNS compounds were identified via high-performance liquid chromatograph (HPLC) assay. PNS-pretreated H9c2 cells, HL-1 cells, and primary cultured neonatal rat cardiomyocytes were stimulated with thapsigargin (TG) to induce ER stress response and apoptosis. ER stress response was tested by immunofluorescence or immunoblot of the ER protein chaperones—calnexin, binding immunoglobulin protein (BiP) and the C/EBP homologous protein (CHOP). Cell viability was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was detected by immunoblot of Cleaved caspase-3 and flow cytometry analysis of Annexin V/propidium iodide (PI) staining. Cytosolic, mitochondrial, and ER calcium dynamics were investigated by calcium imaging. Moreover, a ryanodine receptor type-2 (RyR₂) overexpression stable cell line was generated to verify the mechanism of RyR₂ involved in PNS in the inhibition of ER stress and cell apoptosis. We demonstrate here that PNS protected cardiac myocytes from ER stress response and associated cell death in a concentration-dependent manner. Importantly, PNS reduced the elevation of cytosolic calcium, mitochondria calcium, as well as ER calcium in response to either TG or histamine treatment. PNS protection in ER stress was regulated by RyR₂ expression. In summary, PNS protection against TG-induced ER stress response and its associated cell apoptosis in cardiac myocytes is calcium dependent. Through the regulation of ER calcium release mediated by RyR₂, a novel mechanism for PNS in the prevention of cardiovascular diseases is thereby identified.

Background: Ovarian hyper stimulation syndrome (OHSS) is an iatrogenic complication associated with fertility drugs. It is characterized by increased vascular permeability and substantial fluid shift with accumulation in the body cavity. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. Results: Using western blot and short-circuit current (Isc) techniques, we investigate the potential coactions of analysis in cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin 1 (AQP1) on the hyper permeability of body cavity peritoneal epithelial cells in the pathogenesis of OHSS. The rats develop OHSS symptoms, with the up regulation of both CFTR and AQP1 expression and enhanced CFTR channel activity in peritoneal epithelial cells, can also be mimicked by administration of estrogen, alone in ovariectomized rats. Administration of progesterone suppresses CFTR activity, OHSS symptoms as well as CFTR and AQP1 expression. Besides, AQP1 inhibitor, HgCl₂, can suppress CFTR channel activity. Therefore, antisera against CFTR or AQP1 to OHSS animals may result in alleviation of the symptom. Conclusion: This study confirms the coactions of CFTR and AQP1 play a critical role in the development and progression of increased peritoneal epithelial permeability in severe OHSS. These findings may provide grounds for ameliorating assisted reproduction treatment strategy to reduce the risk of OHSS in in vitro fertilization (IVF).

Fine particulate matter (PM_2.5) and ozone (O₃) are key air pollutants linked to a higher risk of cardiovascular diseases. However, the effects of combined PM_2.5 and O₃ exposure on cardiovascular health remain unclear. In this study, C57BL/6 J mice were exposed to PM_2.5 suspension (6 mg/kg body weight) and/or O₃ (1.00 ppm) for 8 weeks, resulting in abnormal myocardial enzyme profiles. Sirius Red and Masson's trichrome staining confirmed myocardial fibrosis and collagen deposition in the mice. Further experiments demonstrated that PM_2.5 and O₃ subchronic co-exposure increased cardiac inflammatory factors, phosphorylation of p38, ERK1/2, and JNK, as well as cardiomyocyte apoptosis. Subsequently, an atherosclerosis model was established using ApoE-/- mice, which were exposed to PM_2.5 suspension (6 mg/kg b.w.) and O₃ (1.00 ppm) for 8 consecutive weeks. During this period, the mice were treated with quercetin, a flavonoid antioxidant derived from plants. Our findings demonstrated that PM_2.5 and O₃ co-exposure promoted the progression of atherosclerosis. In contrast, administration of quercetin in PM_2.5- and O₃-exposed ApoE-/- mice significantly reduced cardiac enzyme markers, myocardial fibrosis, collagen deposition, cardiomyocyte apoptosis, and activation of the MAPK signaling pathway. Omics results revealed that quercetin primarily exerted its protective effects in atherosclerotic mice by modulating phosphatidylcholine, phosphatidylethanolamine, as well as the inflammatory signaling pathways. In summary, subchronic exposure to PM_2.5 and O₃ contributes to cardiac injury and accelerates the progression of atherosclerosis in mice and this detrimental effect can be mitigated by the administration of quercetin. Our study presents novel strategies aimed at mitigating the cardiovascular health impacts of air pollution.