Lingyu Zhang, Zhihao Jiang, Shaozhen Hu, Haojie Ni, Yijing Zhao, Xiaoqin Tan, Yi Lang, Risong Na, Yanwu Li, Qun Du, Qing X Li, Yan Dong
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And the protection on barrier function was observed in in vitro blood-brain barrier (BBB) model of mouse brain microvascular endothelial cells (bEnd.3). The results show that TFGF-18 and ISO improved cognitive function in SCOP-induced mice, and inhibited cholinergic system disorders and inflammation in the brain and intestine, decreased the level of lipopolysaccharides (LPS) in serum and intestine, protected the diversity and balance of intestinal microbiome, increased the expressions of tight junction protein (ZO-1, occludin), brain derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the mouse brain and intestine. In addition, TFGF-18 and ISO protected against barrier damage in LPS-stimulated BBB model of bEnd.3 cells in vitro. TFGF-18 and ISO increased the ratio of p-GSK3β/GSK3β, suppressed toll-like receptors 4 (TLR-4) expression and nuclear factor kappa-B (NF-κB) activation in vivo and in vitro, and increased the expressions of β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in vitro. In conclusion, The GSK3β inhibitors TFGF-18 and ISO modulate the gut homeostasis and barrier function to inhibit neuroinflammation and attenuate cognitive impairment by regulating NF-κB, β-catenin and Nrf2/HO-1 pathways.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"GSK3β Substrate-competitive Inhibitors Regulate the gut Homeostasis and Barrier Function to Inhibit Neuroinflammation in Scopolamine-induced Alzheimer's Disease Model Mice.\",\"authors\":\"Lingyu Zhang, Zhihao Jiang, Shaozhen Hu, Haojie Ni, Yijing Zhao, Xiaoqin Tan, Yi Lang, Risong Na, Yanwu Li, Qun Du, Qing X Li, Yan Dong\",\"doi\":\"10.1007/s10753-024-02133-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by cognitive impairment. 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The results show that TFGF-18 and ISO improved cognitive function in SCOP-induced mice, and inhibited cholinergic system disorders and inflammation in the brain and intestine, decreased the level of lipopolysaccharides (LPS) in serum and intestine, protected the diversity and balance of intestinal microbiome, increased the expressions of tight junction protein (ZO-1, occludin), brain derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the mouse brain and intestine. In addition, TFGF-18 and ISO protected against barrier damage in LPS-stimulated BBB model of bEnd.3 cells in vitro. TFGF-18 and ISO increased the ratio of p-GSK3β/GSK3β, suppressed toll-like receptors 4 (TLR-4) expression and nuclear factor kappa-B (NF-κB) activation in vivo and in vitro, and increased the expressions of β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in vitro. 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引用次数: 0
摘要
阿尔茨海默病（AD）是一种以认知障碍为主要特征的神经退行性疾病。糖原合酶激酶3（GSK3β）是一种潜在的抗阿尔茨海默病治疗靶点。异连蛋白（ISO）是一种GSK3β底物竞争性抑制剂，在体外和体内AD模型中发挥抗AD作用。TFGF-18是ISO的合成类似物，具有更好的效力，但其在体内的神经保护作用仍有待阐明，GSK3β抑制剂抗AD的内在机制也有待明确。本研究探讨了TFGF-18和ISO对东莨菪碱（SCOP）诱导的AD小鼠肠道稳态和神经炎症的影响。并在体外血脑屏障（BBB）模型小鼠脑微血管内皮细胞（bEnd.3）中观察了其对屏障功能的保护作用。结果表明，TFGF-18和ISO能改善SCOP诱导小鼠的认知功能，抑制胆碱能系统紊乱和脑肠炎症，降低血清和肠道中脂多糖（LPS）的水平、保护肠道微生物群的多样性和平衡，增加小鼠大脑和肠道中紧密连接蛋白（ZO-1、occludin）、脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）的表达。此外，TFGF-18 和 ISO 还能保护体外 bEnd.3 细胞在 LPS 刺激的 BBB 模型中免受屏障损伤。TFGF-18和ISO提高了p-GSK3β/GSK3β的比率，抑制了体内和体外toll样受体4（TLR-4）的表达和核因子卡巴-B（NF-κB）的激活，并提高了体外β-catenin、核因子红细胞2相关因子2（Nrf2）和血红素加氧酶1（HO-1）的表达。总之，GSK3β抑制剂TFGF-18和ISO通过调节NF-κB、β-catenin和Nrf2/HO-1通路，调节肠道稳态和屏障功能，从而抑制神经炎症并减轻认知障碍。
GSK3β Substrate-competitive Inhibitors Regulate the gut Homeostasis and Barrier Function to Inhibit Neuroinflammation in Scopolamine-induced Alzheimer's Disease Model Mice.
Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by cognitive impairment. Glycogen synthase kinase 3 (GSK3β) is a potential therapeutic target against AD. Isoorientin (ISO), a GSK3β substrate competitive inhibitor, plays anti-AD effects in in vitro and in vivo AD model. TFGF-18 is an ISO synthetic analog with improved potency, but its neuroprotective effect in vivo remains to be elucidated, and the underlying mechanisms of GSK3β inhibitor against AD need to be clarified. This study investigated the TFGF-18 and ISO effects on gut homeostasis and neuroinflammation in scopolamine (SCOP)-induced AD mice. And the protection on barrier function was observed in in vitro blood-brain barrier (BBB) model of mouse brain microvascular endothelial cells (bEnd.3). The results show that TFGF-18 and ISO improved cognitive function in SCOP-induced mice, and inhibited cholinergic system disorders and inflammation in the brain and intestine, decreased the level of lipopolysaccharides (LPS) in serum and intestine, protected the diversity and balance of intestinal microbiome, increased the expressions of tight junction protein (ZO-1, occludin), brain derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the mouse brain and intestine. In addition, TFGF-18 and ISO protected against barrier damage in LPS-stimulated BBB model of bEnd.3 cells in vitro. TFGF-18 and ISO increased the ratio of p-GSK3β/GSK3β, suppressed toll-like receptors 4 (TLR-4) expression and nuclear factor kappa-B (NF-κB) activation in vivo and in vitro, and increased the expressions of β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in vitro. In conclusion, The GSK3β inhibitors TFGF-18 and ISO modulate the gut homeostasis and barrier function to inhibit neuroinflammation and attenuate cognitive impairment by regulating NF-κB, β-catenin and Nrf2/HO-1 pathways.
期刊介绍：
Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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