The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

Aging Cell, Journal Year: 2023, Volume and Issue: 22(6)

Published: March 8, 2023

Abstract Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers bidirectional information network between microbiota OA, which may provide a new way protect OA. However, role microbiota‐derived metabolites in ferroptosis‐relative remains unclear. The objective this study was analyze protective effect its metabolite capsiate (CAT) on vivo vitro experiments. From June 2021 February 2022, 78 patients were evaluated retrospectively divided into two groups: health group ( n = 39) 40). Iron oxidative stress indicators determined peripheral blood samples. And then experiments, surgically destabilized medial meniscus (DMM) mice model established treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) utilized inhibit SLC2A1 expression. Serum iron increased significantly but total binding capacity decreased than healthy people p < 0.0001). least absolute shrinkage selection operator clinical prediction suggested serum iron, capacity, transferrin, superoxide dismutase all independent predictors 0.001). Bioinformatics results SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript (MALAT1), HIF‐1α (Hypoxia Inducible Factor Alpha)‐related signaling pathways play important homeostasis In addition, 16s sequencing untargeted metabolomics used find negatively correlated Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration 0.0017). Moreover, reduced ferroptosis‐dependent vitro. against could be eliminated by silencing SLC2A1. upregulated levels DMM group. HIF‐1α, MALAT1, apoptosis after knockout chondrocyte cells Finally, downregulation expression Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves vivo. Our findings indicated inhibited HIF‐1a activating

Language: Английский

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Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 91, P. 102035 - 102035

Published: Aug. 23, 2023

Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially Alzheimer's disease (AD), Parkinson's (PD), multiple sclerosis (MS), amyotrophic lateral (ALS), Huntington's (HD), so on. Treating presents opportunities as well challenges for diseases. This review provides a comprehensive overview underlying mechanisms that contribute to occurrence ferroptosis, their implications pathogenesis advancement major disorders. Meanwhile, we summarize interaction between other types diseases contribution corresponding drug development. In addition, specifically recent advances developing therapeutic means targeting these which may guide future approaches effective management devastating medical conditions.

Language: Английский

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METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke

Cell Biology and Toxicology, Journal Year: 2024, Volume and Issue: 40(1)

Published: Feb. 2, 2024

Abstract Background Stroke is a major medical problem, and novel therapeutic targets are urgently needed. This study investigates the protective role potential mechanisms of N6-methyladenosine (m6A) RNA methyltransferase METTL3 against cerebral injury resulting from insufficient blood flow. Methods In this study, we constructed mouse MCAO models HT-22 cell OGD/R to mimic ischemic stroke-induced brain neuronal damage. We generated NEDD4L knockout overexpression validated effects using infarct volume, edema, neurologic scoring. performed qRT-PCR, western blotting, co-immunoprecipitation assess influence on ferroptosis markers TFRC expression. verified effect ubiquitination by detecting half-life ubiquitination. Finally, impact mRNA stability outcomes in both vitro vivo experimental models. Result find expression downregulated Overexpressing inhibits iron carrier protein upregulating E3 ubiquitin ligase NEDD4L, thereby alleviating oxidative damage protect injury. Mechanistic studies show can methylate stabilize mRNA, enhancing As downstream effector, ubiquitinates degrades TFRC, reducing accumulation ferroptosis. Conclusion summary, uncover METTL3-NEDD4L-TFRC axis critical for inhibiting post-ischemic Enhancing pathway may serve as an effective strategy stroke therapy. lays theoretical foundation developing m6A-related therapies

Language: Английский

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Analysis and identification of oxidative stress-ferroptosis related biomarkers in ischemic stroke

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 15, 2024

Abstract Studies have shown that a series of molecular events caused by oxidative stress is associated with ferroptosis and oxidation after ischemic stroke (IS). Differential analysis was performed to identify differentially expressed mRNA (DEmRNAs) between IS control groups. Critical module genes were identified using weighted gene co-expression network (WGCNA). DEmRNAs, critical genes, stress-related (ORGs), ferroptosis-related (FRGs) crossed screen for intersection mRNAs. Candidate mRNAs screened based on the protein–protein interaction (PPI) MCODE plug-in. Biomarkers two types machine learning algorithms, obtained. Functional items related pathways biomarkers set enrichment (GSEA). Finally, single-sample GSEA (ssGSEA) Wilcoxon tests used differential immune cells. An miRNA-mRNA-TF created. Quantitative real-time polymerase chain reaction (qRT-PCR) verify expression levels in There 8287 DE The turquoise selected as IS. Thirty intersecting overlaps. Seventeen candidate also identified. Four (CDKN1A, GPX4, PRDX1, PRDX6) machine-learning algorithms. results indicated steroid biosynthesis. Nine cells (activated B neutrophils) markedly different We 3747 regulatory pairs network, including hsa-miR-4469-CDKN1A-BACH2 hsa-miR-188-3p-GPX4-ATF2. CDKN1A, PRDX6 upregulated samples compared samples. This study suggests four are significantly provides new reference diagnosis treatment

Language: Английский

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Iron dyshomeostasis and ferroptosis in Alzheimer’s disease: Molecular mechanisms of cell death and novel therapeutic drugs and targets for AD

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 16, 2022

Alzheimer’s disease (AD) is a degenerative of the central nervous system that most common type senile dementia. Ferroptosis new iron-dependent programmed cell death identified in recent years different from other forms. induced by excessive accumulation lipid peroxides and reactive oxygen species (ROS) cells. In years, it has been found ferroptosis plays an important role pathological process AD. Iron dyshomeostasis contribute to plaques (SP) deposition neurofibrillary tangles (NFTs). metabolism imbalance brain dysfunction endogenous antioxidant systems including Xc- glutathione peroxidase (GPX) are closely related etiopathogenesis Dysfunction nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy can accelerates addition, NRF2, through regulating expression considerable number genes ferroptosis, iron metabolism, development Here, we review potential interaction between AD major pathways We also active natural synthetic compounds such as chelators, peroxidation inhibitors antioxidants available treat alleviating preventing mice models provide valuable information for future treatment prevention

Language: Английский

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Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease

Antioxidants and Redox Signaling, Journal Year: 2023, Volume and Issue: 39(1-3), P. 141 - 161

Published: May 22, 2023

Significance: The lack of disease-modifying treatments for Alzheimer’s disease (AD) that substantially alter the course highlights need new biological models progression and neurodegeneration. Oxidation macromolecules within brain, including lipids, proteins, DNA, is believed to contribute AD pathophysiology, concomitant with dysregulation redox-active metals, such as iron. Creating a unified model pathogenesis underpinned by iron redox in could lead therapeutic targets potential. Recent Advances: Ferroptosis, which was named 2012, necrotic form regulated cell death depends on both lipid peroxidation. While it distinct from other types death, ferroptosis regarded being mechanistically synonymous oxytosis. paradigm has great explanatory potential describing how neurons degenerate die AD. At molecular level, executed lethal accumulation phospholipid hydroperoxides generated iron-dependent peroxidation polyunsaturated fatty acids, while major defensive protein against selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding network protective proteins pathways have also been identified complement GPX4 protection cells ferroptosis, central role emerging nuclear factor erythroid 2-related 2 (NRF2). Critical Issues: In this review, we provide critical overview utility NRF2 dysfunction understanding iron- peroxide-associated neurodegeneration Future Directions: Finally, discuss providing spectrum targets. Antioxid. Redox Signal. 39, 141–161.

Language: Английский

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Identification of Novel Biomarkers for Alzheimer’s Disease and Related Dementias Using Unbiased Plasma Proteomics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 8, 2024

Abstract Alzheimer’s disease (AD) and related dementias (ADRD) is a complex with multiple pathophysiological drivers that determine clinical symptomology progression. These diseases develop insidiously over time, through many pathways mechanisms continue to have huge societal impact for affected individuals their families. While emerging blood-based biomarkers, such as plasma p-tau181 p-tau217, accurately detect Alzheimer neuropthology are associated faster cognitive decline, the full extension of proteomic changes in ADRD remains unknown. Earlier detection better classification different subtypes may provide opportunities earlier, more targeted interventions, perhaps higher likelihood successful therapeutic development. In this study, we aim leverage unbiased mass spectrometry proteomics identify novel, biomarkers decline. 1,786 samples from 1,005 patients were collected 12 years partcipants Massachusetts Disease Research Center Longitudinal Cohort Study. Patient metadata includes demographics, final diagnoses, dementia rating (CDR) scores taken concurrently. The Proteograph TM Product Suite (Seer, Inc.) liquid-chromatography mass-spectrometry (LC-MS) analysis used process cohort generate data. Data-independent acquisition (DIA) results yielded 36,259 peptides 4,007 protein groups. Linear mixed effects models revealed 138 differentially abundant proteins between AD healthy controls. Machine learning diagnosis identified potential candidate including MBP, BGLAP, APoD. Cox regression created association progression suggest CLNS1A, CRISPLD2, GOLPH3 targets further investigation biomarkers. workflow provided deep, coverage proteome at speed enabled study almost 1,800 samples, which largest, conducted date.

Language: Английский

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Revealing the novel ferroptosis-related therapeutic targets for diabetic foot ulcer based on the machine learning

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 26, 2022

Objectives: DFU is a serious chronic disease with high disability and fatality rates, yet there no completely effective therapy. While ferroptosis integrated to inflammation infection, its involvement in still unclear. The study aimed identify ferroptosis-related genes DFU, providing potential therapeutic targets. Methods: In the GEO database, two microarray datasets (GSE147890 GSE80178) were collected. WGCNA was conducted modular most involved DFU. Subsequently, enrichment analysis PPI performed. To yield DFU-associated ferroposis genes, retrieved from FerrDb database overlapped genes. Eventually, an optimal prediction model created by combining multiple machine learning algorithms (LASSO, SVM-RFE, Boruta, XGBoost) detect closely associated accuracy of verified utilizing external (GSE7014) based on ROC curves. Results: yielded seven modules all, 1223 DFU-related identified. GO revealed that inflammatory response, decidualization, protein binding highly enriched terms. These module also ErbB signaling, IL-17 MAPK growth hormone synthesis, secretion action, tight junction KEGG pathways. Twenty-five obtained cross-linking which could distinguish patients controls. Ultimately, well established, AUC values (0.79 LASSO, 0.80 SVM, 0.75 0.70 XGBoost). MAFG MAPK3 identified as ferroposis-genes Furthermore, dataset (GSE29221) validation (AUC = 0.81) had superior than 0.62). Conclusion: As related ferroptosis-genes may be employed targets for patients. Moreover, MAPK3, higher accuracy, more biomarker further experimental validation.

Language: Английский

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Network pharmacology reveals that Berberine may function against Alzheimer’s disease via the AKT signaling pathway

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: May 4, 2023

Objective To investigate the mechanism underlying effects of berberine (BBR) in treatment Alzheimer’s disease (AD). Methods 3 × Tg AD mice were treated with BBR for months, then open field test (OFT), novel object recognition (NOR) and Morris water maze (MWM) performed to assess behavioral performance. Hematoxylin–eosin (HE) staining, Nissl staining used examine histopathological changes. The pharmacological molecular properties obtained from TCMSP database. BBR-associated targets identified using PharmMapper (PM), comparative toxicogenomics database (CTD), DisGeNet human gene (GeneCards). Core networks PPI network functional enrichment analyses. AutoDock software was model interaction between potential targets. Finally, RT-qPCR, western blotting validate expression core Results Behavioral experiments, HE have shown that can improve memory task performance neuronal damage hippocampus mice. 117 identified, 43 genes downstream analysis combination results protein–protein (PPI) analysis. 2,230 biological processes (BP) terms, 67 cell components (CC) 243 function (MF) terms 118 KEGG identified. ALB , EGFR CASP3 five PI3K-AKT signaling pathway including AKT1 HSP90AA1 SRC HRAS IGF1 selected by analysis, validated docking RT-q PCR as further Akt1 mRNA levels significantly decreased increased after ( p &lt; 0.05). Besides, AKT ERK phosphorylation group, their levels. Conclusion AD. may exert a neuroprotective effect modulating pathways.

Language: Английский

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Ferroptosis at the crossroads of manganese-induced neurotoxicity: A retrospective study

Toxicology, Journal Year: 2024, Volume and Issue: 502, P. 153727 - 153727

Published: Jan. 10, 2024

Language: Английский

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