College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
Phytomedicine. 2022 Nov;106:154404. doi: 10.1016/j.phymed.2022.154404. Epub 2022 Aug 27.
Metabolic hypertension (MH) is characterized by elevated blood pressure accompanied by metabolic abnormalities, with the gut-derived lipopolysaccharide/toll like receptor 4 (LPS/TLR4) pathway an important triggering mechanism. The conventional Chinese plant Polygonatum sibiricum Red. is traditionally used as a medicinal and edible food source. Currently, several studies have examined its anti-obesity and anti-diabetic actions, with potential roles for MH treatment; however, specific P. sibiricum Red. roles in MH and associated mechanisms remain unclear.
Our purpose was to identify the effects and mechanisms of P. sibiricum Red. superfine powder (PSP) in a MH rat model triggered by high sugar and high fat compounds in an excessive alcohol diet (ACHSFDs).
A MH rat model was induced by ACHSFDs, and PSP was administered daily at 0.5 and 1.0 g/kg doses, respectively. Firstly, the effects of PSP on MH were assessed using blood pressure, serum lipid, and lipid deposition assays in the liver. Changes in intestinal flora were detected by high-throughput 16S rRNA sequencing, while metabolite short-chain fatty acids (SCFAs) and LPS levels were quantified by gas chromatography (GC) and enzyme-linked immunosorbent assay (ELISA), respectively. Hematoxylin & eosin (H&E) staining and transmission electron microscopy (TEM) were performed to evaluate histopathological changes in the rat colon. d-lactic acid (d-LA) levels and tight junction proteins (TJPs) expression were also measured to assess intestinal barrier function. Also, aortic endothelial microstructures, serum endothelin 1 (ET-1), and nitric oxide (NO) levels were investigated to determine vascular endothelial function. Finally, the TLR4/MyD88 signaling pathway in the aorta and gut was evaluated by western blotting, immunohistochemistry (IHC), and quantitative real-time polymerase chain reaction (qRT-PCR).
Blood pressure and blood lipid metabolism disorders induced by ACHSFDs in MH rats were improved by PSP administration. Intestinal flora analyses revealed decreased SCFAs and LPS levels following PSP administration, which was accompanied by increased Streptococcus species levels and decreased Desulfobacter and Desulfovibrio species levels. PSP increased SCFAs levels, and the expression of SCFAs receptors GPCR41 and GPCR43 in the colon. Meanwhile, the expression of tight junction proteins (TJPs) such as Claudin-1, occludin were upregulated in the ileum and colon, while TLR4 and MyD88 were downregulated, thereby strengthening intestinal barrier integrity and reducing serum LPS levels. Additionally, PSP treatment improved vascular endothelial function by inhibiting the TLR4/MyD88 pathway in vessels, improving vascular endothelial cell shedding, and regulating the NO and ET-1 balance.
We demonstrated the beneficial effects and potential mechanisms of PSP in our MH rat model. Based on gut microbiota structure modulation and intestinal barrier improvements, PSP inhibited LPS-induced vascular TLR4/MyD88 signaling activation to improve vascular endothelial function, which in turn reduced blood pressure. Our study provides valuable insights on PSP therapy for MH.
代谢性高血压（MH）的特点是血压升高伴有代谢异常，肠道来源的脂多糖/ toll 样受体 4（LPS/TLR4）途径是重要的触发机制。传统中药黄精是一种药食同源的植物。目前，已有多项研究探讨了其抗肥胖和抗糖尿病作用，可能对 MH 治疗有作用；然而，黄精红在 MH 中的具体作用及其相关机制尚不清楚。
本研究旨在探讨黄精红超细粉（PSP）对高糖高脂复合酒精过量饮食（ACHSFDs）诱导的 MH 大鼠模型的作用及机制。
采用 ACHSFDs 诱导 MH 大鼠模型，PSP 分别以 0.5 和 1.0 g/kg 剂量灌胃。首先，通过血压、血清脂质和肝脏脂质沉积检测评估 PSP 对 MH 的影响。采用高通量 16S rRNA 测序检测肠道菌群变化，采用气相色谱（GC）和酶联免疫吸附试验（ELISA）分别检测短链脂肪酸（SCFAs）和 LPS 水平。采用苏木精和伊红（H&E）染色和透射电子显微镜（TEM）观察大鼠结肠的组织病理学变化。还测量了 d-乳酸（d-LA）水平和紧密连接蛋白（TJPs）的表达，以评估肠道屏障功能。此外，通过检测主动脉内皮的超微结构、血清内皮素 1（ET-1）和一氧化氮（NO）水平来评估血管内皮功能。最后，通过 Western blot、免疫组化（IHC）和实时定量聚合酶链反应（qRT-PCR）评估主动脉和肠道中 TLR4/MyD88 信号通路。
ACHSFDs 诱导的 MH 大鼠血压和血脂代谢紊乱经 PSP 给药后得到改善。肠道菌群分析显示，PSP 给药后 SCFAs 和 LPS 水平降低，同时链球菌属水平升高，脱硫弧菌属和脱硫肠状菌属水平降低。PSP 增加了 SCFAs 水平，并增加了结肠中 SCFAs 受体 GPCR41 和 GPCR43 的表达。同时，回肠和结肠中紧密连接蛋白（TJPs）如 Claudin-1、occludin 的表达上调，而 TLR4 和 MyD88 表达下调，从而增强了肠道屏障的完整性，降低了血清 LPS 水平。此外，PSP 通过抑制血管中 TLR4/MyD88 通路、改善血管内皮细胞脱落以及调节 NO 和 ET-1 平衡，改善了血管内皮功能。
本研究在 MH 大鼠模型中证实了 PSP 的有益作用和潜在机制。基于肠道微生物群结构的调节和肠道屏障的改善，PSP 抑制了 LPS 诱导的血管 TLR4/MyD88 信号激活，从而改善了血管内皮功能，降低了血压。本研究为 PSP 治疗 MH 提供了有价值的见解。
