METTL3 upregulates IRF5 to epigenetically regulate inflammation, apoptosis and ferroptosis of IL-1β-induced CHON-001 chondrocytes through CX43

Journal of Orthopaedics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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RGS12 is a target of penehyclidine hydrochloride that enhances oxidative stress and ferroptosis in a model of myocardial ischemia/reperfusion injury by inhibiting the Nrf2 pathway

International Journal of Molecular Medicine, Journal Year: 2025, Volume and Issue: 55(3)

Published: Jan. 24, 2025

Regulator of G‑protein signaling 12 (RGS12) is a regulatory factor that involved in various physiological processes. However, the role RGS12 myocardial ischemia/reperfusion injury (MIRI) currently remains unclear. The present study established mouse model MIRI by ligating left main coronary artery followed reperfusion. In addition, HL‑1 cells were cultured hypoxic and serum‑free medium, reoxygenation to establish an in vitro cell hypoxia/reoxygenation (H/R). Adenoviruses targeting subsequently used either overexpress or silence expression. was highly expressed both tissues mice with subjected H/R. results from experiments demonstrated knockdown reduced oxidative stress under pathological environment, as indicated decreased reactive oxygen species (ROS) levels malondialdehyde activity increased activities superoxide dismutase catalase. Furthermore, underwent H/R stimulation exhibited ferroptosis, whereas reversed these changes. These showed post‑RGS12 silencing Fe²⁺ lipid ROS decreased, expression glutathione peroxidase 4 cystine transporter solute carrier family 7 member 11 mitochondrial structure improved preventing loss crest. Mechanistically, nuclear erythroid 2‑related 2 (Nrf2) pathway anti‑ferroptosis anti‑oxidative capacities activated knockdown. Conversely, overexpression exerted opposite effects vivo vitro. Notably, it penehyclidine hydrochloride (PHC), known block process, vivo vitro, inhibited therapeutic PHC on MIRI. conclusion, RGS12, target PHC, potentially enhanced progression promoting this effect may involve regulation Nrf2 pathway.

Language: Английский

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Relaxin‐2 Alleviated Ferroptosis and Inflammation in TNF‐α‐Treated Chondrocytes via Regulating the Nrf2/NF‐κB Signaling Pathway

Peptide Science, Journal Year: 2025, Volume and Issue: 117(2)

Published: Jan. 25, 2025

ABSTRACT Excessive inflammatory responses and ferroptosis‐associated dysfunction of chondrocytes are significant pathological features osteoarthritis (OA). Relaxin‐2, a well‐known hormone involved in metabolic regulation across various tissues cells, has not been extensively studied the context chondrocyte OA. T/C‐28a2 cells were stimulated with tumor necrosis factor α (TNF‐α) (10 ng/mL) or without recombinant human relaxin‐2 (rh relaxin‐2) (25, 50 nM) for 48 h. Various techniques, including 2′,7′‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining, real‐time PCR, western blot analysis, enzyme‐linked immunosorbent assay (ELISA), luciferase activity assays, employed. We discovered that exposure to TNF‐α decreased expression Relaxin‐2 at both mRNA protein levels. Further investigation revealed treatment rh mitigated lipid peroxidation by reducing levels reactive oxygen species (ROS), malondialdehyde (MDA), 4‐hydroxy‐2‐nonenal (4‐HNE), while increasing superoxide dismutase (SOD) glutathione (GSH) content. Notably, restored iron metabolism balance disrupted decreasing Fe 2+ levels, downregulating transferrin receptor 1 (TFR1) gene expression, upregulating ferritin expression. Additionally, alleviated ferroptosis induced these peroxidase 4 (GPX4) acyl‐CoA synthetase long‐chain family member (ACSL4) lactate dehydrogenase (LDH) release. Rh also inhibited TNF‐α‐induced pro‐inflammatory cytokines, interleukin‐1β (IL‐1β) interleukin‐6 (IL‐6). Interestingly, attenuated degeneration suppressing matrix metalloproteinase‐13 (MMP‐13) preventing degradation collagen type II alpha1 chain (Col2α). Mechanistically, effects found be mediated through nuclear erythroid 2‐related 2 (Nrf2)/NF‐κB signaling pathway. Our findings suggest could potential therapeutic strategy

Language: Английский

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Fraxinellone-mediated targeting of cathepsin B leakage from lysosomes induces ferroptosis in fibroblasts to inhibit hypertrophic scar formation

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 4, 2025

Hypertrophic scar (HS) is a common fibrotic skin disorder characterized by the excessive deposition of extracellular matrix (ECM). Fibroblasts are most important effector cells involved in HS formation. Currently no satisfactory treatment has been developed. The impact fraxinellone (FRA) on proliferation and migration capacity human hypertrophic scar-derived fibroblasts (HSFs) was assessed EdU proliferation, wound healing transwell assays. Quantitative real-time PCR (qRT‒PCR), Western blot (WB), immunofluorescence staining collagen gel contraction assays were performed to evaluate production activation HSFs. Oxford Nanopore Technologies long-read RNA sequencing (ONT RNA-seq) revealed occurrence ferroptosis HSF executioner-cathepsin B (CTSB). mechanisms underlying FRA-induced examined through fluorescence staining, qRT‒PCR, WB molecular docking study. therapeutic efficacy FRA further validated vivo using rabbit ear model. significantly suppressed migration, ONT RNA-seq discovered that modulated expression transcripts related lysosomes. Mechanistically, reduced protein level glutathione peroxidase 4 (GPX4) induced release CTSB from lysosomes into cytoplasm. via spermidine/spermine-N1-acetyltransferase (SAT1)-mediated lipid peroxidation, mitochondrial damage mitogen-activated kinase (MAPK) signalling pathway activation, eventually affecting function Moreover, attenuated formation ears CTSB-mediated ferroptosis. antifibrotic effects abrogated pretreatment with inhibitor (CA-074-me). This study reveals ameliorates inducing leakage lysosomes, causing SAT1-mediated MAPK thus mediating Therefore, could be promising agent for treating HS.

Language: Английский

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Epigenetic factors and inflammaging: FOXO3A as a potential biomarker of sarcopenia and upregulation of DNMT3A and SIRT3 in older adults

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

Published: Feb. 17, 2025

Background Epigenetic factors influence inflammaging and geriatric disorders such as sarcopenia frailty. It is necessary to develop a biomarker/panel of biomarkers for fast easy diagnostics. Currently, hard-to-access equipment required diagnose sarcopenia. The development will prevent many older adults from being excluded the diagnostic process. Methods In this study, we analyzed selected gene expression profiles, namely, SIRT1 , SIRT3 SIRT6 DNMT3A FOXO1 FOXO3A ELAVL1 in whole blood. study included 168 subjects divided into five groups: patients hospitalized at Geriatrics Clinic Polyclinic with sarcopenia, frailty syndrome, or without those (geriatric control), non-hospitalized healthy controls (HC) aged 25 30 years over 50 years. Results We revealed lower mRNA level (p<0.001) sarcopenic compared controls. Furthermore, detected upregulation (p=0.003) (p=0.015) HC old Interestingly, observed 2 cluster formations during correlation analysis ( ). also noted correlations clinical parameters levels group, vitamin D (r=0.64, p=0.010), creatine kinase (r=–0.58, p=0.032) (r=–0.59, p=0.026), creatinine (r=0.57, erythrocyte sedimentation rate (ESR) (r=0.69, p=0.004), lactate dehydrogenase (LDH) (r=–0.86, p=0.007). syndrome appendicular skeletal muscle mass (ASMM) (r=0.59, p=0.026) level. controls, serum iron (r=–0.79, p=0.036). Conclusions Our potential biomarker high epigenetic ) adults.

Language: Английский

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KLF9, Epigenetic Silenced by DNMT1, Promotes ERK‐Mediated Ferroptosis of Osteoarthritic Chondrocytes Through Transcriptionally Regulating CYP1B1

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(5)

Published: Feb. 27, 2025

ABSTRACT Ferroptosis plays a crucial role in the pathogenesis of osteoarthritis (OA), and inhibition chondrocyte ferroptosis effectively alleviates OA progression. Krüppel‐like factor 9 (KLF9) is demonstrated to be upregulated OA, but its molecular mechanism remains unclear. The study aimed investigate KLF9 Primary chondrocytes were treated with IL‐1β establish an cell model, showed that was highly expressed IL‐1β‐incubated chondrocytes. Knockdown alleviated IL‐1β‐induced degeneration. In addition, decreased methylation proportion gene promoter. DNA methyltransferase 1 (DNMT1) directly bound promoter, overexpression DNMT1 inhibited expression by promoting promoter Subsequently, shRNA pcDNA‐CYP1B1 individually or altogether transfected into Cytochrome P450 1B1 (CYP1B1) chondrocytes, abrogated inhibitory effect on ferroptosis. Moreover, Ferrostatin‐1 (Fer‐1, inhibitor ferroptosis) reversed promotion Finally, vivo experiments significantly suppressed cartilage tissue damage, ferroptosis, IHC scores CYP1B1 rats. conclusion, our results suggested KLF9, epigenetic silenced DNMT1, promoted extracellular signal‐regulated kinase (ERK)‐mediated through transcriptionally regulating CYP1B1. Thus, expected new target for treatment OA.

Language: Английский

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Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 6, 2025

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease with complex mechanism. Currently, ferroptosis believed to play role in it, but the specific mechanism unknown, especially immune response. In this study, we demonstrated that high expression of major histocompatibility I (MHC-I) molecules RA fibroblast-like synoviocytes (FLSs) an antigen-presenting cell property and closely related increase antigens after citrullination. Moreover, detected higher levels among FLSs from patient than OA patients. Ferroptosis can citrullinated histone H3 (cit-h3) by promoting production peptidyl arginine deiminase 4 (PAD4), which further promotes MHC-I molecules. We cocultured RA-FLSs treated drugs selected CD8 + T cells assess effect on endogenous function RA-FLSs. promoted proliferation release inflammatory factors Tumor necrosis factor-α (TNF-α) Interferon-gamma (IFN-γ), enhanced effect. This phenomenon was also observed collagen-induced (CIA) mouse model. Finally, ferrostatin-1 (fer-1), inhibitor, inhibited above effects reduced factors, indicating may therapeutic providing new ideas for treatment field immunity.

Language: Английский

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Pantothenic acid alleviates osteoarthritis progression by inhibiting inflammatory response and ferroptosis through the SIRT1/Nrf2 signaling pathway

Chemico-Biological Interactions, Journal Year: 2025, Volume and Issue: 413, P. 111494 - 111494

Published: March 29, 2025

Language: Английский

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UVB irradiation induces melanocyte damage through ferroptosis: mechanisms and implications

Photochemical & Photobiological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Language: Английский

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The interplay between autophagy and programmed cell death in osteoarthritis: insights into mechanisms and therapeutic targets

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Language: Английский

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