Hypertension is the leading cause of cardiac remodelling and heart failure. Recent evidence has highlighted the role of the non-hemodynamic function of angiotensin II in hypertension. MyD88 is the canonical adaptor of TLRs and IL-1Rs, which serves as the central node in regulating inflammatory responses. Previous studies reported the opposite roles of MyD88 in hypertension. In this study, we aimed to determine the role of MyD88 and the underlying mechanisms in hypertension. Cardiomyocyte-specific MyD88 knockout mice, macrophage-specific MyD88 knockout mice, and MyD88 inhibitor-treated mice were challenged with Ang II infusion to establish a cardiac remodelling model. An inflammatory cytokine array was used to determine the internal mediators. Our results showed that cardiomyocyte MyD88 deficiency showed little protection, whereas macrophage MyD88 deficiency and pharmacological MyD88 inhibition using LM8 significantly ameliorated Ang II-induced cardiac inflammation, fibrosis, and dysfunction. The cytokine and chemokine array demonstrated that CXCL1 and CCL2 were differentially expressed between cardiomyocyte-specific MyD88 knockout and macrophage-specific MyD88 knockout mice. Deletion of MyD88 in macrophages significantly decreased macrophage infiltration and suppressed the activation of macrophages, which then reduced the conditioned medium-induced cardiomyocyte hypertrophy. Our study demonstrated that targeting myeloid MyD88 could be a potential strategy in treating hypertensive cardiac remodelling.

The three-dimensional structures of proteins are being solved apace, yet this information is often underused in quantitative structure-activity relationship (QSAR) studies. Here, we describe and compare methods for exploiting protein structures to derive 3D-QSARs. These methods can facilitate molecular design and lead optimization and should increasingly become a standard component of the drug designer's repertoire.:

Cardiovascular diseases are the primary cause of mortality in patients with diabetes and obesity. Hyperglycemia and hyperlipidemia in diabetes alters cardiac function, which is associated with broader cellular processes such as aberrant inflammatory signaling. Recent studies have shown that a pattern recognition receptor called Dectin1, expressed on macrophages, mediates pro-inflammatory responses in innate immunity. In the present study, we examined the role of Dectin-1 in the pathogenesis of diabetic cardiomyopathy. We observed increased Dectin-1 expression in heart tissues of diabetic mice and localized the source to macrophages. We then investigated the cardiac function in Dectin-1-deficient mice with STZ-induced type 1 diabetes and high-fat-diet-induced type 2 diabetes. Our results show that Dectin-1 deficient mice are protected against diabetes-induced cardiac dysfunction, cardiomyocyte hypertrophy, tissue fibrosis, and inflammation. Mechanistically, our studies show that Dectin-1 is important for cell activation and induction of inflammatory cytokines in high-concentration glucose and palmitate acid (HG + PA)-challenged macrophages. Deficiency of Dectin-1 generate fewer paracrine inflammatory factors capable of causing cardiomyocyte hypertrophy and fibrotic responses in cardiac fibroblasts. In conclusion, this study provides evidence that Dectin-1 mediates diabetes-induced cardiomyopathy through regulating inflammation. Dectin-1 may be a potential target to combat diabetic cardiomyopathy.

Obesity is an important independent risk factor for cardiovascular diseases, remaining an important health concern worldwide. Evidence shows that saturated fatty acid-induced inflammation in cardiomyocytes contributes to obesity-related cardiomyopathy. Dapagliflozin (Dapa), a selective SGLT2 inhibitor, exerts a favorable preventive activity in heart failure. In this study, we investigated the protective effect of Dapa against cardiomyopathy caused by high fat diet-induced obesity in vitro and in vivo. Cultured rat cardiomyocyte H9c2 cells were pretreated with Dapa (1, 2.5 μM) for 1.5 h, followed by treatment with palmitic acid (PA, 200 μM) for 24 h. We showed that Dapa pretreatment concentration-dependently attenuated PA-induced cell hypertrophy, fibrosis and apoptosis. Transcriptome analysis revealed that inhibition of PA-activated MAPK/AP-1 pathway contributed to the protective effect of Dapa in H9c2 cells, and this was confirmed by anti-p-cJUN fluorescence staining assay. Using surface plasmon resonance analysis we found the direct binding of Dapa with NHE1. Gain and loss of function experiments further demonstrated the role of NHE1 in the protection of Dapa. In vivo experiments were conducted in mice fed a high fat diet for 5 months. The mice were administered Dapa (1 mg·kg−1·d−1, i.g.) in the last 2 months. Dapa administration significantly reduced the body weight and improved the serum lipid profiles. Dapa administration also alleviated HFD-induced cardiac dysfunction and cardiac aberrant remodeling via inhibiting MAPK/AP-1 pathway and ameliorating cardiac inflammation. In conclusion, Dapa exerts a direct protective effect against saturated fatty acid-induced cardiomyocyte injury in addition to the lowering effect on serum lipids. The protective effect results from negative regulating MAPK/AP-1 pathway in a NHE1-dependent way. The current study highlights the potential of clinical use of Dapa in the prevention of obesity-related cardiac dysfunction.

Background: Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link.Methods: C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop ne-phropathy. Mice were treated with small-molecule MyD88 inhibitor LM8. In vitro, MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells.Results: We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-Kappa B (NF-Kappa B), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-Kappa B activation, and elaboration of inflammatory cytokines and fibrosis -associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension.Conclusion: These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease.

目的 通过调查疫情背景下我校2022届护理专科毕业生的职业规划现状以及对就业指导的需求,提出提高护理专科生就业质量的就业指导对策.方法 采用整群抽样法,选取温州医科大学2022届护理专科毕业生作为研究对象,发放自制问卷《疫情背景下护理专科生就业指导需求现状调研问卷》,采用统计工具SPSS 20.0进行统计分析,计数资料以率表示.结果 共收集有效问卷131份.调查显示,超80％的护理专科生认为发生疫情后护理人员的社会认可度有提升,他们希望获取就业信息的途径和方式可以更加多样化、获取就业指导的内容更加丰富,70.32％的护理专科生认为疫情背景下榜样精神的鼓舞对其坚定选择护理职业起到了促进作用.结论 在疫情背景下,我校2022届护理专科毕业生对护理职业的认可度有所提升,但职业规划不清晰等情况仍存在.为提高护理专科学生的就业质量,该文提出了四项就业指导对策.