{"title":"天然 AhR 拮抗剂黄酮能抑制硫酸吲哚啶诱导的体外炎症基因表达和体内肾脏病理损伤。","authors":"Tomomi Iwashima, Yui Takemura, Yoshimi Kishimoto, Chihiro Ono, Ayano Watanabe, Kaoruko Iida","doi":"10.29219/fnr.v68.10032","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR.</p><p><strong>Objective: </strong>This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells <i>in vitro</i> and renal failure <i>in vivo</i>.</p><p><strong>Design: </strong>Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks.</p><p><strong>Results: </strong>In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes (<i>CYP1A1</i> and <i>AhRR</i>), and genes involved in inflammation (<i>NOX4</i>, <i>MCP-1</i>, <i>IL-6,</i> and <i>COX2</i>) and monocyte invasion/adhesion (<i>ICAM1</i>). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of <i>in-vivo</i> experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS.</p><p><strong>Conclusions: </strong>Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR-STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. These flavonoids could be a therapeutic strategy for vascular inflammation in CKD.</p>","PeriodicalId":12119,"journal":{"name":"Food & Nutrition Research","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11305152/pdf/","citationCount":"0","resultStr":"{\"title\":\"Natural antagonistic flavones for AhR inhibit indoxyl sulfate-induced inflammatory gene expression <i>in vitro</i> and renal pathological damages <i>in vivo</i>.\",\"authors\":\"Tomomi Iwashima, Yui Takemura, Yoshimi Kishimoto, Chihiro Ono, Ayano Watanabe, Kaoruko Iida\",\"doi\":\"10.29219/fnr.v68.10032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR.</p><p><strong>Objective: </strong>This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells <i>in vitro</i> and renal failure <i>in vivo</i>.</p><p><strong>Design: </strong>Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks.</p><p><strong>Results: </strong>In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes (<i>CYP1A1</i> and <i>AhRR</i>), and genes involved in inflammation (<i>NOX4</i>, <i>MCP-1</i>, <i>IL-6,</i> and <i>COX2</i>) and monocyte invasion/adhesion (<i>ICAM1</i>). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of <i>in-vivo</i> experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS.</p><p><strong>Conclusions: </strong>Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR-STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. 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引用次数: 0
摘要
背景:尿毒症毒素硫酸吲哚酯(IS)会诱发血管炎症,这是导致肾功能衰竭和慢性肾脏病(CKD)患者血管并发症的关键因素。在内皮细胞中,IS部分通过激活芳基烃受体(AhR)来增加炎症细胞因子的产生,有报道称几种食物黄酮类化合物可作为AhR的拮抗剂:本研究旨在探讨拮抗类黄酮是否能减轻体外血管内皮细胞和体内肾衰竭由 IS 引起的炎症反应:用黄酮类化合物芹菜素、菊黄素或木犀草素预处理的人脐静脉内皮细胞(HUVECs)受到IS刺激。分析参与 AhR 信号转导、炎症细胞因子产生和活性氧(ROS)产生的基因的表达水平。给未切除肾脏的小鼠口服金丝桃素,每天腹腔注射 IS,持续 4 周:结果:在 HUVECs 中,IS 上调了 AhR 靶向基因(CYP1A1 和 AhRR)、炎症相关基因(NOX4、MCP-1、IL-6 和 COX2)和单核细胞侵袭/粘附基因(ICAM1)的 mRNA 表达。所有这三种黄酮都减轻了 IS 诱导的这些 mRNA 表达的增加。它们还抑制了 IS 诱导的 AhR 核转位和细胞内 ROS 的产生。此外,这些黄酮还抑制了 IS 诱导的信号转导和转录激活因子 3(STAT3)的磷酸化。体内实验结果表明,无论小鼠血清中的IS水平是否较高,服用菊黄素都能减轻小鼠血尿素氮水平和AhR靶基因表达的升高以及肾组织的病理损伤:结论:拮抗AhR的天然食物黄酮通过抑制HUVECs中的AhR-STAT3通路,对IS诱导的炎症具有保护作用。此外,在小鼠慢性肾脏病模型中,菊黄素还能改善IS诱导的肾功能障碍。这些黄酮类化合物可能是治疗 CKD 血管炎症的一种策略。
Natural antagonistic flavones for AhR inhibit indoxyl sulfate-induced inflammatory gene expression in vitro and renal pathological damages in vivo.
Background: Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR.
Objective: This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells in vitro and renal failure in vivo.
Design: Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks.
Results: In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes (CYP1A1 and AhRR), and genes involved in inflammation (NOX4, MCP-1, IL-6, and COX2) and monocyte invasion/adhesion (ICAM1). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of in-vivo experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS.
Conclusions: Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR-STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. These flavonoids could be a therapeutic strategy for vascular inflammation in CKD.
期刊介绍:
Food & Nutrition Research is a peer-reviewed journal that presents the latest scientific research in various fields focusing on human nutrition. The journal publishes both quantitative and qualitative research papers.
Through an Open Access publishing model, Food & Nutrition Research opens an important forum for researchers from academic and private arenas to exchange the latest results from research on human nutrition in a broad sense, both original papers and reviews, including:
* Associations and effects of foods and nutrients on health
* Dietary patterns and health
* Molecular nutrition
* Health claims on foods
* Nutrition and cognitive functions
* Nutritional effects of food composition and processing
* Nutrition in developing countries
* Animal and in vitro models with clear relevance for human nutrition
* Nutrition and the Environment
* Food and Nutrition Education
* Nutrition and Economics
Research papers on food chemistry (focus on chemical composition and analysis of foods) are generally not considered eligible, unless the results have a clear impact on human nutrition.
The journal focuses on the different aspects of nutrition for people involved in nutrition research such as Dentists, Dieticians, Medical doctors, Nutritionists, Teachers, Journalists and Manufacturers in the food and pharmaceutical industries.