Involvement of lipid peroxidation and organic peroxides in UVA-induced matrix metalloproteinase-1 expression. Polte Tobias,Tyrrell Rex M Free radical biology & medicine Ultraviolet A (UVA) irradiation causes human skin aging and skin cancer at least partially through the activation of matrix metalloproteinases (MMPs). MMP-1, the interstitial collagenase, is responsible for the degradation of collagen and is involved in tumor progression in human skin. The present study uses human skin fibroblast cells (FEK4) to investigate the involvement of lipid peroxidation and the role of peroxides as possible mediators in MMP-1 activation by UVA. Preincubation with the antioxidants butylated hydroxytoluene and Trolox reduced UVA-dependent MMP-1 upregulation, suggesting that peroxidation of membrane lipids is involved. Blocking the iron-driven generation of lipid peroxides and hydroxyl radicals by different iron chelators led to a decrease in UVA-induced MMP-1 mRNA accumulation. Moreover, modulation of glutathione peroxidase activity by use of the specific inhibitor mercaptosuccinate (MS) or by the depletion of glutathione (using buthionine-S, R-sulfoximine, BSO), enhanced the UVA-dependent MMP-1 response. Finally, UVA irradiation generated a significant increase in intracellular peroxide levels which is augmented by pretreatment of the cells with BSO or MS. Our results demonstrate that lipid peroxidation and the production of peroxides are important events in the signalling pathway of MMP-1 activation by UVA. 10.1016/j.freeradbiomed.2004.04.003

Characterization of PKCα-rutin interactions and their application as a treatment strategy for pulmonary arterial hypertension by inhibiting ferroptosis. Food & function As a common plant-derived dietary flavonoid, rutin receives widespread attention because of its good antioxidant bioactivities. Protein kinase Cα (PKCα) is a serine/threonine kinase that is involved in uncountable cellular processes, among which ferroptosis, a novel form of cell death, is triggered by lipid peroxidation and has been reported to be associated with pulmonary arterial hypertension (PAH). But it is still not well appreciated how rutin inhibits ferroptosis in PAH and what function PKCα has in this process. In this study, we first observed whether rutin could prevent PAH by attenuating ferroptosis with a PAH animal model and pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Mitochondrial metabolomics and network pharmacology were employed to clarify the metabolic alterations and screen target proteins, and the results showed that PKCα was a vital node in rutin regulating mitochondrial metabolism related to ferroptosis in PAH. Based on molecular docking and multispectral analysis, we found that rutin could directly interact with PKCα through hydrogen bonds, which could induce static quenching, and then influence the secondary structure of PKCα. In conclusion, these findings mainly point to a novel mechanism that rutin protects PAH rats by modifying the structure and altering the activity of PKCα, and thus suppressing ferroptosis. This work reveals that the interaction behaviors between small molecules and bio-macromolecules are a critical factor to develop natural biological active ingredients and gives an insight into the potential applications of flavonoids in health and disease. 10.1039/d3fo01306e

Sodium rutin extends lifespan and health span in mice including positive impacts on liver health. British journal of pharmacology BACKGROUND AND PURPOSE:Ageing is associated with progressive metabolic dysregulation. Rutin is a metabolic regulator with a poor solubility. Using soluble sodium rutin we investigating the effect and mechanisms of rutin in ageing process. EXPERIMENTAL APPROACH:Wild type male mice were treated with or without sodium rutin ( 0.2 mg·ml in drinking water from 8-month-old until end of life. Kaplan-Meier survival curve was used for lifespan assay, ageing-related histopathology analysis and metabolic analysis were performed to determine the effects of chronic sodium rutin on the longevity. Serological test, liver tissue metabolomics and transcriptomics were used for liver function assay. SiRNA knockdown Angptl8 and autophagy flux assay in HepG2 cell lines explored the mechanism through which sodium rutin might impact the function of hepatocyte. KEY RESULTS:Sodium rutin treatment extends the lifespan of mice by 10%. Sodium rutin supplementation alleviates ageing-related pathological changes and promotes behaviour performance in ageing mice. Sodium rutin supplementation altered the whole-body metabolism in mice, which exhibited increased energy expenditure and lower respiratory quotient. Transcriptomics analysis showed that Sodium rutin affected the expression of metabolic genes. Metabolomics analysis showed that Sodium rutin reduced liver steatosis through increased lipid β-oxidation. Sodium rutin treatment increased the autophagy level both in vivo and in vitro. The inhibition of autophagy partially abolished the sodium rutin-mediated effect on lipolysis in HepG2 cells. CONCLUSION AND IMPLICATIONS:Sodium rutin treatment extends the lifespan and health span of mice with beneficial effects on metabolism, which were achieved by enhancing the autophagy activity in hepatocytes. LINKED ARTICLES:This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc. 10.1111/bph.15410

Rutin as a Mediator of Lipid Metabolism and Cellular Signaling Pathways Interactions in Fibroblasts Altered by UVA and UVB Radiation. Gęgotek Agnieszka,Rybałtowska-Kawałko Paula,Skrzydlewska Elżbieta Oxidative medicine and cellular longevity Rutin is a natural nutraceutical that is a promising compound for the prevention of UV-induced metabolic changes in skin cells. The aim of this study was to examine the effects of rutin on redox and endocannabinoid systems, as well as proinflammatory and proapoptotic processes, in UV-irradiated fibroblasts. Fibroblasts exposed to UVA and UVB radiation were treated with rutin. The activities and levels of oxidants/antioxidants and endocannabinoid system components, as well as lipid, DNA, and protein oxidation products, and the proinflammatory and pro/antiapoptotic proteins expression were measured. Rutin reduced UV-induced proinflammatory response and ROS generation and enhanced the activity/levels of antioxidants (SOD, GSH-Px, vitamin E, GSH, and Trx). Rutin also normalized UV-induced Nrf2 expression. Its biological activity prevented changes in the levels of the lipid mediators: MDA, 4-HNE, and endocannabinoids, as well as the endocannabinoid receptors CB1/2, VR1, and GPR55 expression. Furthermore, rutin prevented the protein modifications (tyrosine derivatives formation in particular) and decreased the levels of the proapoptotic markers-caspase-3 and cytochrome c. Rutin prevents UV-induced inflammation and redox imbalance at protein and transcriptional level which favors lipid, protein, and DNA protection. In consequence rutin regulates endocannabinoid system and apoptotic balance. 10.1155/2017/4721352

Rutin ameliorates HCD-induced cholesterol metabolism disorder in zebrafish larvae revealed by transcriptome and metabolome analysis. Phytomedicine : international journal of phytotherapy and phytopharmacology Changes in modern lifestyles have led to an increase in obesity rates. Excessive lipid accumulation leads to abnormal cholesterol metabolism, and maintaining a balanced cholesterol metabolism is essential for the normal functioning of cells and the body. Rutin belongs to the group of flavonoids with hypolipidemic, anti-inflammatory and antioxidant effects. The aim of this study was to investigate the role of rutin in cholesterol metabolism disorders induced by a high cholesterol diet in zebrafish larvae. The trial was divided into five groups: Normal diet (ND), 5 % high cholesterol diet (HCD), 5 % high cholesterol diet with 80 μg/g ezetimibe diet (EZE), 5 % high cholesterol diet with 5 % rutin diet (RL-HCD), and 5 % high cholesterol diet with 10 % rutin diet (RH-HCD). Zebrafish larvae at 5 dpf were randomly divided into five groups and continuously fed different diets for 10 days, after 10 days zebrafish samples were collected for subsequent experiments. Body length, body width, oil red O, and Nile red staining were measured to detect biochemical indexes, analyze inflammatory response and lipid accumulation. Vascular endothelial injury was assessed by stereofluorescence microscopy and ELISA. In order to study the protective effect of rutin in zebrafish with cholesterol metabolism disorder induced by HCD, RNA-seq and LC-MS/MS nontargeted metabolomics were employed. The results indicate that HCD led to an increase in the body length and width of zebrafish. The HCD group induced an increase in body length and width, lipid accumulation, and exacerbated inflammation. Additionally, vascular damage and abnormal expression of endothelial cell markers were observed. Rutin lowered lipid levels in zebrafish fed an HCD, reduced inflammation, and protected endothelial cells. The RNA-seq and metabolomic analysis combined demonstrated that rutin effectively ameliorates the disorder of cholesterol metabolism in vivo by reducing cholesterol synthesis and promoting cholesterol transport. 10.1016/j.phymed.2024.156058