Apelin-13对LPS诱导人脐静脉内皮细胞屏障损伤的干预作用*

目的: 探讨Apelin-13对LPS诱导人脐静脉内皮细胞(HUVECs)屏障损伤的影响。方法: 将体外培养的HUVECs分为4组:正常对照组、LPS组、Apelin-13+LPS组、Apelin-13组。用5 μg/ml LPS作用细胞24 h, 复制屏障功能受损模型。1 μmol/L Apelin-13提前30 min给予,再给予LPS作用24 h,确定Apelin-13的影响。通过CCK8法检测Apelin-13对细胞活力的影响;Western blot检测血管内皮细胞钙粘蛋白(VE-cadherin)、纤维状肌动蛋白(F-actin)表达变化;免疫荧光检测VE-cadherin、F-actin的表达变化及核转录因子Kappa B(NF-κB p65)入核情况。结果: 与正常对照组相比,单独给予Apelin-13对细胞活力无明显影响。与正常对照组相比,LPS组细胞活力明显下降(P＜0.01),VE-cadherin蛋白表达下降(P＜0.01)、F-actin蛋白表达升高(P＜0.05),NF-κB p65入核明显增加。与LPS组相比,Apelin-13明显增加细胞活力(P＜0.01),VE-cadherin蛋白表达增加(P＜0.05)、F-actin蛋白表达下降(P＜0.01),蛋白NF-κB p65入核下降明显。结论: Apelin-13可减轻LPS诱导的人脐静脉内皮细胞损伤及屏障受损,其机制可能与抑制炎症相关。     

肺部微生物组通过炎症反应介导慢性阻塞性肺疾病转化为肺癌的研究进展

肺部微生物组存在于呼吸道和实质组织中,通过菌群紊乱、代谢产物、炎症反应、免疫反应、基因毒性等方面介导肺部损伤。随着肺部微生物组的深入研究,发现肺部微生物组的相关活动与慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)和肺癌息息相关,能够促使COPD向肺癌的转变。本文主要介绍了肺部微生物组稳态及其通过炎症反应导致COPD和肺癌,重点探讨了肺部微生物组如何通过炎症反应介导COPD转化为肺癌,以期为COPD和肺癌的临床预防、优化治疗以及新型药物设计提供新的理论依据。     

Molecular docking analysis of stachydrine and sakuranetin with IL-6 and TNF-α in the context of inflammation

Inflammation is a process triggered by pro-inflammatory cytokines and anti-inflammatory molecules. Therefore, it is of interest to document the anti-inflammatory activity of Stachydrine and Sakuranetin against the inflammatory target proteins IL-6 and TNF-α by using molecular docking analysis. Both compounds showed good binding features with the selected target proteins. Compared to Sakuranetin, the Stachydrine have low binding energy and good hydrogen bond interactions. Hence, data show that Stachydrine possessed high and specific inhibitory activity on tumor necrosis factor-α and interleukin-6.     

Site‐specific contribution of Toll‐like receptor 4 to intestinal homeostasis and inflammatory disease

Toll‐like receptor 4 (TLR4) is a highly conserved protein of innate immunity, responsible for the regulation and maintenance of homeostasis, as well as immune recognition of external and internal ligands. TLR4 is expressed on a variety of cell types throughout the gastrointestinal tract, including on epithelial and immune cell populations. In a healthy state, epithelial cell expression of TLR4 greatly assists in homeostasis by shaping the host microbiome, promoting immunoglobulin A production, and regulating follicle‐associated epithelium permeability. In contrast, immune cell expression of TLR4 in healthy states is primarily centred on the maturation of dendritic cells in response to stimuli, as well as adequately priming the adaptive immune system to fight infection and promote immune memory. Hence, in a healthy state, there is a clear distinction in the site‐specific roles of TLR4 expression. Similarly, recent research has indicated the importance of site‐specific TLR4 expression in inflammation and disease, particularly the impact of epithelial‐specific TLR4 on disease progression. However, the majority of evidence still remains ambiguous for cell‐specific observations, with many studies failing to provide the distinction of epithelial versus immune cell expression of TLR4, preventing specific mechanistic insight and greatly impacting the translation of results. The following review provides a critical overview of the current understanding of site‐specific TLR4 activity and its contribution to intestinal/immune homeostasis and inflammatory diseases.     

蛹虫草菌粉胶囊抑制肺部炎症及缓解肺纤维化的研究

传统中药可治疗肺炎。新型急性呼吸综合征冠状病毒2型（SARS-CoV-2）外部囊膜上的S蛋白是决定病毒毒力的关键因素及主要抗原。本研究利用SARS-CoV-2病毒的S蛋白和细菌脂多糖（LPS）诱导的肺炎模型,初步探索了蛹虫草菌粉对肺炎模型的促炎性因子、单核/巨噬细胞和髓源抑制性细胞（MDSCs）以及纤维化的调节作用。研究发现蛹虫草菌粉可降低SARS-CoV-2病毒的S蛋白组和LPS组小鼠血清中TNF-α、IL-6和IL-10的表达,并降低肺组织、肺泡灌洗液和外周血中巨噬细胞的比例,降低外周血和脾脏中MDSC的数量。进一步研究发现,蛹虫草还可降低SARS-CoV-2病毒的S蛋白组和LPS组小鼠肺组织羟基脯氨酸的表达和成纤维细胞的分布,进而减轻小鼠的肺纤维化水平。qRT-PCR实验发现蛹虫草菌粉处理不仅可以降低SARS-CoV-2病毒的S蛋白组小鼠肺组织中TGF-β R1水平,还降低SARS-CoV-2病毒的S蛋白组和LPS组肺组织中smad2的表达。因此认为蛹虫草菌粉可缓解SARS-CoV-2病毒的S蛋白和LPS诱导的肺部炎症和纤维化症状,且纤维化缓解作用可能与TGF-β R1/smad2信号通路相关。     

Synthetic glycolipid-based TLR4 antagonists negatively regulate TRIF-dependent TLR4 signalling in human macrophages

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.     

Macrophage migration inhibitory factor regulates joint capsule fibrosis by promoting TGF-β1 production in fibroblasts

Joint capsule fibrosis caused by excessive inflammation results in post-traumatic joint contracture (PTJC). Transforming growth factor (TGF)-β1 plays a key role in PTJC by regulating fibroblast functions, however, cytokine-induced TGF-β1 expression in specific cell types remains poorly characterized. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology. In this study, we investigated whether MIF can facilitate TGF-β1 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that MIF and TGF-β1 significantly increased in fibroblasts of injured rat posterior joint capsules. Treatment the lesion sites with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP) reduced TGF-β1 production and relieved joint capsule inflammation and fibrosis. In vitro, MIF facilitated TGF-β1 expression in primary joint capsule fibroblasts by activating mitogen-activated protein kinase (MAPK) (P38, ERK) signaling through coupling with membrane surface receptor CD74, which in turn affected fibroblast functions and promoted MIF production. Our results reveal a novel function of trauma-induced MIF in the occurrence and development of joint capsule fibrosis. Further investigation of the underlying mechanism may provide potential therapeutic targets for PTJC.     

Metabolipidomic profiling reveals an age‐related deficiency of skeletal muscle pro‐resolving mediators that contributes to maladaptive tissue remodeling

Specialized pro‐resolving mediators actively limit inflammation and support tissue regeneration, but their role in age‐related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography‐tandem mass spectrometry and tested whether treatment with the pro‐resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro‐resolving mediators 8‐oxo‐RvD1, resolvin E3, and maresin 1, as well as many anti‐inflammatory cytochrome P450‐derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro‐inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E₂) and 12‐lipoxygenase (e.g., 12‐hydroxy‐eicosatetraenoic acid), but aged mice produced fewer markers of pro‐resolving mediators including the lipoxins (15‐hydroxy‐eicosatetraenoic acid), D‐resolvins/protectins (17‐hydroxy‐docosahexaenoic acid), E‐resolvins (18‐hydroxy‐eicosapentaenoic acid), and maresins (14‐hydroxy‐docosahexaenoic acid). Similar absences of downstream pro‐resolving mediators including lipoxin A₄, resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro‐resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non‐steroidal anti‐inflammatory drugs.