黄芩苷对代谢性炎症及肠道菌群的调节作用探讨

【目的】探讨黄芩苷对高脂血症模型代谢性炎症及肠道菌群的调节作用。【方法】选取32只C57BL/6J雄性小鼠随机平均分为正常组、模型组、黄芩苷高剂量组(剂量为50 mg·kg-1·d-1)、黄芩苷低剂量组(剂量为25 mg·kg-1·d-1)。高脂饲料喂养3周后,2个黄芩苷用药组分别给予不同浓度黄芩苷灌胃5周。采用酶联免疫吸附法检测各组小鼠血清血脂水平以及肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)及内毒素水平,采用Miseq平台对小鼠肠道粪便微生物进行基因测序。【结果】与正常组比较,模型组总胆固醇及低密度脂蛋白水平显著升高(P0.01),高密度脂蛋白水平显著降低(P0.01),血清TNF-α、IL-6和内毒素水平显著升高(P0.01);黄芩苷高剂量组的TNF-α、IL-6、内毒素水平均较模型组显著降低(P0.05或P0.01),黄芩苷低剂量组内毒素水平亦较模型组显著降低(P0.01)。测序生物信息学分析发现,在门的水平,模型组脱铁杆菌门和变形杆菌门数目较正常组显著增多,疣微菌门数目较正常组显著减少。在属的水平,模型组Christensenella、uncultured_Peptococcaceae、脱硫弧菌属数目较正常组显著增多,而粪球菌属、Akkermansia及uncultured_Lachnospiraceae数目较正常组显著减少;黄芩苷高、低剂量组脱硫弧菌属丰度均较模型组降低。各组革兰氏阴性菌与革兰氏阳性菌数目之比,模型组较正常组显著升高(P0.05),黄芩苷低剂量组较模型组显著降低(P0.05)。【结论】黄芩苷能治疗高脂饮食引起的代谢性炎症,这可能与黄芩苷能调节肠道菌群的结构有关。     

Toll样受体4在棕榈酸诱导RAW264.7巨噬细胞 炎症反应中的作用及机制

目的 探讨 Toll 样受体 4（TLR4）在棕榈酸诱导 RAW264.7 巨噬细胞炎症反应中的作用及可能机制。方 法 观察正常对照组（正常饮食）和高脂饲料组（高脂饮食诱导肥胖小鼠模型）C57BL/6J 小鼠血清自由脂肪酸（FFA） 水平及内脏脂肪组织炎症细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和单核细胞趋化蛋白-1（MCP- 1）的表达;采用棕榈酸（150 μmol/L 组和 300 μmol/L 组）刺激小鼠 RAW264.7 巨噬细胞,观察这 2 组和空白对照 （Control）组、无 FFA 牛血清白蛋白（BSA）组的 TNF-α、IL-6 和 MCP-1 的表达和分泌,同时检测 TLR4 的蛋白表达和 核因子-κB（NF-κB）的激活情况;利用 siRNA 干扰实验抑制 TLR4,观察在 Control 组、BSA 组、棕榈酸（300 μmol/L） 组、棕榈酸（300 μmol/L）+Control siRNA 组、棕榈酸（300 μmol/L）+TLR4 siRNA 组中棕榈酸诱导巨噬细胞炎症因子的 表达和分泌。结果 高脂饲料组体质量和 Lee’s 指数高于正常对照组,血清中 FFA 水平升高,内脏脂肪组织中 TNF-α、IL-6 和 MCP-1 的表达明显增加（P＜0.05）。与 BSA 组比较,棕榈酸 150 μmol/L 组和棕榈酸 300 μmol/L 组 炎症因子 TNF-α、IL-6 和 MCP-1 的表达和分泌均明显增加,TLR4 和 NF-κB p65 磷酸化蛋白水平均增加（P＜0.05）。 与 BSA 组比较,棕榈酸 300 μmol/L 组 NF-κB p65 的核转运水平和细胞内水平明显升高（P＜0.05）。TLR4 被抑制 后,棕榈酸+TLR4 siRNA 组的 TLR4、TNF-α、IL-6 和 MCP-1 的 mRNA 表达和分泌水平明显低于棕榈酸组（P＜ 0.05）。结论 TLR4 可能参与棕榈酸诱导的 RAW264.7 巨噬细胞炎症反应,诱导炎症因子 TNF-α、IL-6 和 MCP-1 的释放,且其介导的炎症反应与 NF-κB 的激活有关。     

Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB–mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.

Metaflammation defines a chronic inflammatory state in response to prolonged excessive nutrient intake and is characterized by low-grade inflammation of metabolic tissues (1). Macrophage reprogramming toward an inflammatory phenotype plays a critical role in obesity-induced metaflammation (2, 3). In lean individuals, macrophages in metabolic tissues maintain tissue homeostasis and insulin sensitivity, potentially through secreting anti-inflammatory cytokines, for example, TGF-β and IL-10 (1). In metaflammation, however, macrophages in adipose tissue and liver are activated through proinflammatory factors in their microenvironment, such as high levels of saturated free fatty acids (FA) and IFN-γ. Consequently, these macrophages produce high amounts of tumor necrosis factor (TNF), which directly inhibits canonical insulin signaling (4), leading to ectopic fat deposition in the liver and in skeletal muscles (5). Additionally, activation of Kupffer cells (KCs), the liver-resident macrophages, promotes recruitment and activation of inflammatory monocytes, which contribute to hepatic insulin resistance and steatosis (6–8).The MR (also termed CD206) is a type I transmembrane protein belonging to the C-type lectin family, which is mainly expressed by subpopulations of macrophages, dendritic cells, and endothelial cells (9, 10). The MR consists of a cysteine-rich region, a fibronectin type II domain, eight C-type lectin-like domains (CTLDs), a transmembrane region, and a short cytosolic tail. Due to its high affinity for glycosylated antigens, the MR plays an important role in antigen uptake and presentation (11, 12). In addition to its functions as a transmembrane protein, the extracellular part of the MR can be shed by metalloproteases and released into the extracellular space (13, 14). Hence, soluble MR (sMR) can be detected in murine and human serum, and its level was found to be increased in patients with a variety of inflammatory diseases (15–20), correlating with severity of disease and even mortality. However, a physiological role of the sMR has not been studied yet, and it remains unclear whether the sMR can actively trigger inflammation.Here, we report that sMR enhances macrophage proinflammatory activation, both in vitro and in vivo, and promotes metaflammation. We demonstrate that the sMR directly interacts with CD45 on the surface of macrophages and inhibits its phosphatase activity, leading to Src/Akt/NF-κB–mediated cellular reprogramming toward an inflammatory phenotype. Additionally, we found enhanced sMR serum levels in obese mice and humans and show that sMR-induced activation of macrophages triggers metaflammation in vivo.     

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代谢异常巳成为我国高血压患病率升高的主要原因,代谢性高血压巳成为高血压的主要临床类型,其发病机制除涉及经典血压调控途径外,尚与免疫炎症关系密切。另外,血压调控器官的代谢性损害也是血压升高的重要原因。目前的高血压药物治疗对高血压合并代谢异常的控制有一定局限性,探索新的治疗策略是面临的新挑战。     

Dysregulation of maternal serum adiponectin in preterm labor

Objective. Intra-amniotic and systemic infection/inflammation have been causally linked to preterm parturition and fetal injury. An emerging theme is that adipose tissue can orchestrate a metabolic response to insults, but also an inflammatory response via the production of adipocytokines, and that these two phenomenons are interrelated. Adiponectin, an insulin-sensitising, anti-inflammatory adipocytokine, circulates in multimeric complexes including low-molecular weight (LMW) trimers, medium-molecular weight (MMW) hexamers and high-molecular weight (HMW) isoforms. Each of these complexes can exert differential biological effects. The aim of this study was to determine whether spontaneous preterm labor (PTL) with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal serum circulating adiponectin multimers.

Study design. This cross-sectional study included patients in the following groups: (1) normal pregnant women (n = 158); (2) patients with an episode of preterm labor and intact membranes without IAI who delivered at term (n = 41); (3) preterm labor without IAI who delivered preterm (n = 27); and (4) preterm labor with IAI who delivered preterm (n = 36). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.

Results. (1) Preterm labor leading to preterm delivery or an episode of preterm labor that does not lead to preterm delivery was associated with a lower median maternal serum concentration of total and HMW adiponectin, a lower median HMW/total adiponectin ratio and a higher median LMW/total adiponectin ratio than normal pregnancy; (2) among patients with preterm labor, those with IAI had the lowest median concentration of total and HMW adiponectin, as well as the lowest median HMW/total adiponectin ratio; (3) the changes in maternal adiponectin and adiponectin multimers remained significant after adjusting for confounding factors such as maternal age, BMI, gestational age at sampling and parity.

Conclusion. (1) Preterm labor is characterised by a change in the profile of adiponectin multimers concentrations and their relative isoforms. These changes were observed in patients with an episode of preterm labor not leading to preterm delivery, in patients with intra-amniotic inflammation, or in those without evidence of intra-amniotic inflammation. (2) The changes in adiponectin multimer concentrations reported in preterm labor are different from those previously reported in spontaneous labor at term, suggesting that there is a fundamental difference between preterm labor and labor at term. (3) The findings reported herein provide the first evidence for the participation of adiponectin multimer in preterm parturition. We propose that adiponectins and adipokines in general provide a mechanism to organise the metabolic demands generated by the process of preterm parturition regardless of the nature of the insult (intra-amniotic inflammation or not).     

脂源性外泌体与肥胖诱导的代谢性炎症研究进展

越来越多的研究结果显示，肥胖引起的代谢性炎症是导致胰岛素抵抗和一系列并发症的主要原因。脂肪组织作为代谢性炎症启动和发生的主要场所，其分泌的外泌体不仅是脂肪组织与其他组织、器官间通信的重要媒介，也是机体代谢性炎症的重要调节者。本文在介绍脂源性外泌体的成分及生物学功能的基础上，重点综述了脂源性外泌体在肥胖引起的代谢性炎症发生、发展中的作用及具体的作用机制。