Vaccarin Ameliorates Renal Fibrosis by Inhibiting Ferroptosis via Nrf2/SLC7A11/GPX4 Signaling Pathway

Drug Design Development and Therapy, Journal Year: 2025, Volume and Issue: Volume 19, P. 1609 - 1626

Published: March 1, 2025

Purpose: Vaccarin is a natural flavonoid glycoside with anti-inflammatory, antioxidant and nephroprotective effects. However, the effects of vaccarin on renal fibrosis (RF) its molecular mechanisms remain unclear. This study aimed to investigate RF mechanisms. Methods: Network pharmacology was used analyze effect RF, docking dynamics simulations were performed assess binding nuclear factor erythroid 2-related 2 (Nrf2) vaccarin. A mouse model unilateral ureteral obstruction (UUO) established in vivo, human tubular epithelial (HK2) cells induced transforming growth factor-β (TGF-β) RSL3, respectively, as an vitro model. The anti-fibrotic observed by histopathological staining determination fibrous markers. Changes oxidative stress ferroptosis-related markers detected kits, Western blot (WB), qRT-PCR immunofluorescence (IF). Finally, Nrf2 inhibitors added observe ferroptosis. Results: cross genes are enriched for stress. binds stably Both vivo experiments showed that treatment reduced expression markers, decreased levels reactive oxygen species (ROS), malondialdehyde (MDA), lipid peroxidation (LPO) Fe 2+ , increased glutathione (GSH) secretion. In addition, down-regulated Long-chain acyl-CoA synthetase 4 (ACSL4), prostaglandin-endoperoxide synthase (PTGS2) NADPH oxidase 1 (NOX1), up-regulated downstream solute transport family 7 member 11 (SLC7A11) peroxidase (GPX4) expression. Mechanistic studies indicated activated Nrf2/SLC7A11/GPX4 pathway inhibit ferroptosis, this inhibition effectively reversed inhibitor. Conclusion: ameliorates inhibiting ferroptosis via pathway. Keywords: vaccarin, fibrosis, pathway, stress, network

Language: Английский

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Prioritization of prognostic biomarkers regulated by calorie restriction in colon cancer through integrated biosignature analysis

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 20, 2025

Colorectal cancer (CRC) remains a critical global health challenge, ranking second in cancer-related mortality and third incidence as of 2018, with risk increasing age. Addressing its rising burden requires early diagnosis, prognostic biomarkers, effective therapeutic strategies. Emerging evidence suggests that calorie restriction may mitigate aging-related functional decline influence CRC progression, yet the molecular markers mechanisms remain poorly understood. In this study, we analyzed GSE24432 dataset, using multiple computational databases to screen differentially expressed genes (DEGs) associated CRC. Functional annotations, including Gene Ontology (GO), KEGG pathway analysis, gene set enrichment analysis (GSEA), were undertaken explore potential underlying pathways pathogenesis. Kaplan Meier Cox proportional hazards regression analyses conducted establish diagnostic significance hub genes. The validation test was via databases. Our investigation identified 50 DEGs, cutoff criteria, p. adj < 0.05, |log2FC|> 0.3. GO results revealed extensive crosstalk cellular components mRNA ribosome biogenesis, AMPK signaling, p53 signaling following restriction. To understand how these DEGs drive biological reactions, sorted according score > 3 term obtained 14 most relevant terms. Further CHORD showed are enriched biogenesis protein synthesis. (GSEA) involvement several hallmarks, such tissue invasion metastasis (p 0.001), tumor-promoting inflammation resisting cell death 0.01), replicative immortality 0.05). Survival higher expression 7 genes, CDKN2A 0.05), RPL9 0.02), TUBB6 RPS15A lower CDKN1B NPM1 RALA correlated shorter survival colon cancer. However, cross-reference decreased expressions while increased Several tests from high is overall rates, indicating target could serve more reliable biomarker for prognosis. These findings potentially facilitate development precision-based energy interventions management, offering promising prospects targeted strategies patients.

Language: Английский

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Magnolia kobus DC. Alleviates adenine-induced chronic kidney disease by regulating ferroptosis in C57BL/6 mice

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 29, 2025

Magnolia kobus DC. (MO) is a medicinal plant that reportedly possesses various bioactive properties, including anti-hyperplastic, anti-inflammatory, and anti-cancer effects. Chronic kidney disease (CKD) progressive disorder characterized by inflammation, fibrosis, oxidative stress, which leads to renal dysfunction. This study aimed evaluate the renoprotective effects of MO against adenine-induced CKD in C57BL/6 mice. significantly attenuated injury reducing blood urea nitrogen level morphological change. Additionally, effectively reduced inflammation inhibiting expression tumor necrosis factor-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, F4/80, intercellular adhesion molecule-1, vascular cell molecule-1. also considerably ameliorated fibrosis regulating suppressor mothers decapentaplegic/matrix metalloproteinase signaling. Furthermore, protected senescence protein p53, p16, p21 induced CKD. supplementation suppressed CKD-induced ferroptosis ferritinophagy SLC7A11 glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, human palmitoyl-CoA ligase, NADPH oxidase 4-hydroxynonenal, transferrin receptor, heme oxygenase-1, nuclear receptor coactivator beclin-1, microtubule-associated proteins 1A/1B light chain 3B, kallikrein-related peptidase 4. In conclusion, this suggests may be potential functional food, pharmaceutical, or can help regulate mechanisms associated with health.

Language: Английский

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TGF-β1 induces ROS to activate ferroptosis via the ERK1/2-WISP1 pathway to promote the progression of renal tubular epithelial cell fibrosis

Cytotechnology, Journal Year: 2025, Volume and Issue: 77(2)

Published: Feb. 14, 2025

Language: Английский

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Ferroptosis and renal fibrosis: mechanistic insights and emerging therapeutic targets

Renal Failure, Journal Year: 2025, Volume and Issue: 47(1)

Published: May 6, 2025

Ferroptosis is a regulated, iron-dependent form of cell death driven by lipid peroxidation and distinct from apoptosis, necroptosis, pyroptosis. Recent studies implicate ferroptosis as central contributor to the pathogenesis renal fibrosis, hallmark chronic kidney disease associated with high morbidity progression end-stage failure. This review synthesizes current evidence linking ferroptotic signaling fibrotic remodeling in kidney, focusing on iron metabolism dysregulation, glutathione peroxidase 4 (GPX4) inactivation, peroxide accumulation, ferroptosis-regulatory pathways such FSP1-CoQ10-NAD(P)H GCH1-BH4. We detail how tubular epithelial cells modulates pro-fibrotic cytokine release, macrophage recruitment, TGF-β1-driven extracellular matrix deposition. Moreover, we explore therapeutic vulnerability highlighting promising agents including chelators, GPX4 activators, anti-lipid peroxidants, exosome-based gene delivery systems. By consolidating emerging preclinical data, this provides comprehensive mechanistic framework identifies translational opportunities for targeting disease.

Language: Английский

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