RESUMEN
BACKGROUND: Influence on stem cells' angiogenesis and osteogenesis of NAD(P)H Quinone Dehydrogenase 1(NQO1) has been established, but its impact on dental pulp stem cells (DPSCs) is unexplored. An important strategy for the treatment of arteriosclerosis is to inhibit calcium deposition and to promote vascular repair and angiogenesis. This study investigated the function and mechanism of NQO1 on angiogenesis and osteogenesis of DPSCs, so as to provide a new ideal for the treatment of arteriosclerosis. METHODS: Co-culture of human DPSCs and human umbilical vein endothelial cells (HUVECs) was used to detect the angiogenesis ability. Alkaline phosphatase (ALP) activity, alizarin red staining (ARS), and transplantation of HA/tricalcium phosphate with DPSCs were used to detect osteogenesis. RESULTS: NQO1 suppressed in vitro tubule formation, migration, chemotaxis, and in vivo angiogenesis, as evidenced by reduced CD31 expression. It also enhanced ALP activity, ARS, DSPP expression and osteogenesis and boosted mitochondrial function in DPSCs. CoQ10, an electron transport chain activator, counteracted the effects of NQO1 knockdown on these processes. Additionally, NQO1 downregulated MAPK signaling, which was reversed by CoQ10 supplementation in DPSCs-NQO1sh. CONCLUSIONS: NQO1 inhibited angiogenesis and promoted the osteogenesis of DPSCs by suppressing MAPK signaling pathways and enhancing mitochondrial respiration.
Asunto(s)
Pulpa Dental , Células Endoteliales de la Vena Umbilical Humana , Sistema de Señalización de MAP Quinasas , NAD(P)H Deshidrogenasa (Quinona) , Neovascularización Fisiológica , Osteogénesis , Humanos , Osteogénesis/efectos de los fármacos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Neovascularización Fisiológica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Pulpa Dental/citología , Pulpa Dental/metabolismo , Técnicas de Cocultivo , Células Madre/metabolismo , Células Madre/citología , Células Cultivadas , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquinona/metabolismo , Animales , Diferenciación Celular , AngiogénesisRESUMEN
One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.
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Apoptosis , Neuronas Motoras , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Xantonas , Xantonas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones , Animales , Neuronas Motoras/metabolismo , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Transducción de Señal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Humanos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genéticaRESUMEN
The betel nut is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. Arecoline is an active ingredient from the areca nut. It has many pharmacological effects and can affect the central nervous system. In this study, we found that arecoline can relieve fatigue behavior. OBJECTIVE: This research aims to estimate the anti-fatigue effects of arecoline and explore its underlying mechanisms using a murine model of central fatigue precipitated by sleep deprivation (SD). METHODS: Seventy-two male C57BL/6 mice were randomly assigned to six groups: a control group, an SD-induced fatigue model group, a group that received Rhodiola Rosea capsules (2.5 mg/kg), and three arecoline groups, which were administered at low, medium, and high doses (10, 20, and 40 mg/kg, respectively). Following 28 days of continuous administrations, the effects of arecoline on mouse fatigue-related behaviors were assessed by behavioral tests, including grip strength, rotarod performance, and weight-bearing swimming endurance. The release levels of the related biochemical markers were measured by enzyme-linked immunosorbent assays (ELISAs). Western blotting was employed to quantify the expression levels of nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), sequestosome-1 (p62), and NADPH quinone oxidoreductase 1 (NQO1) in the gastrocnemius muscle. RESULTS: Arecoline administration notably enhanced grip strength, delayed the onset of fatigue as evidenced by extended latencies in rotarod tests, and increased the duration of weight-bearing swimming in mice. In the elevated plus maze, arecoline obviously decreased both the number of entries and the total distance traveled in the open arms. Arecoline markedly decreased the contents of creatine kinase, blood urea nitrogen, lactate dehydrogenase, triglycerides, and cholesterol in the serum, while it elevated the levels of total testosterone, lactate dehydrogenase, and immunoglobulin G. Furthermore, it significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase in the gastrocnemius muscle, reduced malondialdehyde levels, augmented hippocampal SOD and CAT activity, and elevated glycogen stores in both liver and muscle tissues. Neurotransmitter levels showed significant increases, cytokine levels were markedly reduced, and the expressions of Nrf2, Keap1, NQO1, p62, and HO-1 in brain tissues were significantly upregulated. CONCLUSIONS: This study demonstrates that arecoline has anti-fatigue activity, and the specific mechanisms are associated with elevating glucose and lipid metabolism levels, relieving oxidative stress damage, inhibiting neuroinflammatory response, and regulating neurotransmitter levels and the Keap1/Nrf2/HO-1 signaling pathway. The research provides a new direction for arecoline's potential in preventing and improving fatigue.
Asunto(s)
Arecolina , Fatiga , Ratones Endogámicos C57BL , Privación de Sueño , Animales , Masculino , Arecolina/farmacología , Fatiga/tratamiento farmacológico , Privación de Sueño/complicaciones , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Modelos Animales de Enfermedad , Fuerza de la Mano , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Conducta Animal/efectos de los fármacos , Proteínas de la MembranaRESUMEN
Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.
Asunto(s)
Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Humanos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Línea Celular Tumoral , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Ulcerative colitis (UC), a chronic idiopathic inflammatory bowel disease (IBD), presents with limited current drug treatment options. Consequently, the search for safe and effective drug for UC prevention and treatment is imperative. Our prior studies have demonstrated that the phenolic compound p-Hydroxybenzaldehyde (HD) from Nostoc commune, effectively mitigates intestinal inflammation. However, the mechanisms underlying HD's anti-inflammatory effects remain unclear. PURPOSE: This study delved into the pharmacodynamics of HD and its underlying anti-inflammation mechanisms. METHODS: For in vivo experiments, dextran sodium sulfate (DSS)-induced colitis mouse model was established. In vitro inflammation model was established using lipopolysaccharide (LPS)-induced RAW264.7 and bone marrow-derived macrophages (BMDMs). The protective effect of HD against colitis was determined by monitoring clinical symptoms and histological morphology in mice. The levels of inflammatory factors and oxidative stress markers were subsequently analyzed with enzyme-linked immunosorbent assay (ELISA) and biochemical kits. Furthermore, western blotting (WB), immunofluorescence (IF), luciferase reporter gene, drug affinity reaction target stability (DARTS) assay, molecular docking, and molecular dynamics (MD) simulation were used to determine the potential target and molecular mechanism of HD. RESULTS: Our findings indicate that HD significantly alleviated the clinical symptoms and histological morphology of colitis in mice, and curtailed the production of pro-inflammatory cytokines, including TNF-α, IL-6, IFN-γ, COX-2, and iNOS. Furthermore, HD stimulated the production of SOD, CAT, and GSH-px, enhanced total antioxidant capacity (T-AOC), and reduced MDA levels. Mechanically, HD augmented the expression of Nrf2, HO-1, and NQO-1, while concurrently downregulating the phosphorylation of p65, IκBα, c-Jun, and c-Fos. ML385 and siNrf2 largely attenuated the protective effect of HD in enteritis mice and RAW 264.7 cells, as well as the promotion of HO-1 expression levels. ZnPP-mediated HO-1 knockdown reversed HD-induced inhibition of colonic inflammation. Luciferase reporter assay and IF assay confirmed the transcriptional activation of Nrf2 by HD. DARTS analysis, molecular docking, and MD results showed high binding strength, interaction efficiency and remarkable stability between Nrf2 and HD. CONCLUSION: These outcomes extend our previous research results that HD can combat oxidative stress through the Nrf2/HO-1/NQO-1/NF-κB/AP-1 pathways, effectively alleviating colitis, and propose new targets for HD to protect against intestinal barrier damage.
Asunto(s)
Benzaldehídos , Sulfato de Dextran , Factor 2 Relacionado con NF-E2 , FN-kappa B , Estrés Oxidativo , Factor de Transcripción AP-1 , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Benzaldehídos/farmacología , Estrés Oxidativo/efectos de los fármacos , FN-kappa B/metabolismo , Células RAW 264.7 , Factor de Transcripción AP-1/metabolismo , Masculino , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Modelos Animales de Enfermedad , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Transducción de Señal/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Lipopolisacáridos , Hemo Oxigenasa (Desciclizante)/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
BACKGROUND: Drug resistance to doxorubicin (DOX) significantly limits its therapeutic efficacy in breast cancer (BC) patients. Saikosaponin D (SSD), a triterpene saponin derived from the traditional herb Radix Bupleuri, has shown promise as a chemotherapeutic sensitizer in preclinical studies due to its notable antitumor activity. However, the role and mechanism of SSD in DOX-resistant BC cells remain largely unexplored. PURPOSE: This study aimed to investigate the chemosensitizing effect of SSD on DOX-resistant BC and the underlying molecular mechanisms both in vitro and in vivo. METHODS: In vitro assays, including cell viability, clone formation, three-dimensional tumor spheroid growth, and apoptosis analysis, were conducted to evaluate the synergistic effect of SSD and DOX on resistant BC cells. Reactive oxygen species (ROS), GSH/GSSG, NADPH/NADP+, and NADH/NAD+ detections were employed to assess the impact of SSD on cellular redox homeostasis. Western blotting, cell cycle distribution assay, and DOX uptake assay were performed to further elucidate the possible antineoplastic mechanism of SSD. Finally, a subcutaneous MCF7/DOX cell xenografted model in nude mice was established to identify the in vivo anticarcinogenic effect of SSD combined with DOX. RESULTS: SSD significantly inhibited cell viability, proliferation, and clone formation, enhancing DOX's anticancer efficacy in vitro and in vivo. Mechanistically, SSD reduced STAT1, NQO1, and PGC-1α protein levels, leading to cellular redox imbalance, excessive ROS generation, and depletion of GSH, NADPH, and NADH. SSD induced DNA damage by disrupting redox homeostasis, resulting in G0/G1 phase cell cycle arrest. Additionally, SSD increased DOX accumulation in BC cells via inhibiting P-gp protein expression and efflux activity. CONCLUSION: We demonstrated for the first time that SSD enhances the sensitivity of chemoresistant BC cells to DOX by disrupting cellular redox homeostasis through inactivation of the STAT1/NQO1/PGC-1α signaling pathway. This study provides evidence for SSD as an adjuvant agent in drug-resistant BC treatment.
Asunto(s)
Neoplasias de la Mama , Doxorrubicina , Resistencia a Antineoplásicos , Ratones Desnudos , NAD(P)H Deshidrogenasa (Quinona) , Ácido Oleanólico , Oxidación-Reducción , Especies Reactivas de Oxígeno , Saponinas , Doxorrubicina/farmacología , Saponinas/farmacología , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Sinergismo Farmacológico , Células MCF-7 , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Factor de Transcripción STAT1/metabolismo , Supervivencia Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 µg/mL, 0.14 µg/mL, and 0.2-0.3 µg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 µg/mg) is 10-fold higher than that in normal prostate tissues (0.14 µg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.
Asunto(s)
Peroxirredoxinas , Prebióticos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Animales , Ratones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Peroxirredoxinas/metabolismo , Humanos , Línea Celular Tumoral , Oligosacáridos/farmacología , Oligosacáridos/química , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
BACKGROUND: Ischemic stroke (IS) is a major cause of death and disability worldwide. Genetic factors are important risk factors for the development of IS. The quinone oxidoreductase 1 gene (NQO1) has antioxidant, anti-inflammatory, and cytoprotective properties. Thus, in this study, we investigated the relationship between NQO1 gene polymorphism and the risk of IS. METHODS: Peripheral blood was collected from 143 patients with IS and 124 the control groups in Yunnan, China, and NQO1 rs2917673, rs689455, and rs1800566 were genotyped. Logistic regression was used to analyze the relationship between the three NQO1 loci and IS susceptibility. The difference in the expression levels of NQO1 between the control groups and IS groups was verified using public databases and enzyme-linked immunosorbent assay. RESULTS: The rs2917673 locus increased the risk of IS by 2.375 times in TT genotype carriers under the co-dominance model compared with CC carriers and was statistically associated with the risk of IS (OR = 2.375, 95% CI = 1.017-5.546, P = 0.046). In the recessive model, TT genotype carriers increased IS risk by 2.407 times compared with CC/CT carriers and were statistically associated with the risk of IS (OR = 2.407, 95% CI = 1.073-5.396, P = 0.033). CONCLUSIONS: NQO1 rs2917673 polymorphism is significantly associated with IS. Mutant TT carriers are risk factors for IS.
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Predisposición Genética a la Enfermedad , Accidente Cerebrovascular Isquémico , NAD(P)H Deshidrogenasa (Quinona) , Polimorfismo de Nucleótido Simple , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , China , Pueblos del Este de Asia/genética , Accidente Cerebrovascular Isquémico/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Factores de RiesgoRESUMEN
Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H2O2. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy.
Asunto(s)
NAD(P)H Deshidrogenasa (Quinona) , Neoplasias , Humanos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Quinonas/farmacología , Quinonas/metabolismo , Terapia Molecular DirigidaRESUMEN
Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.
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Apoptosis , Cromo , Genisteína , Hígado , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Floretina , Transducción de Señal , Sirtuina 1 , Ubiquinona , Animales , Sirtuina 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ratones , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Genisteína/farmacología , Apoptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Cromo/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Floretina/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Arsénico/toxicidad , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo-Oxigenasa 1/metabolismo , Proteínas de la MembranaRESUMEN
Parkinson's disease (PD) is a degenerative neurological disorder defined by the deterioration and loss of dopamine-producing neurons in the substantia nigra, leading to a range of motor impairments and non-motor symptoms. The underlying mechanism of this neurodegeneration remains unclear. This research examined the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in mitigating neuronal damage induced by rotenone via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Using human neuroblastoma SH-SY5Y cells and PD model mice, we found that ECP, rich in the antioxidant polyphenol phlorotannin, boosted the gene expression and functionality of the antioxidant enzyme NAD(P)H quinone oxidoreductase-1. ECP also promoted Nrf2 nuclear translocation and increased p62 expression, suggesting that p62 helps sustain Nrf2 activation via a positive feedback loop. The neuroprotective effect of ECP was significantly reduced by Compound C (CC), an AMP-activated protein kinase (AMPK) inhibitor, which also suppressed Nrf2 nuclear translocation. In PD model mice, ECPs improved motor functions impaired by rotenone, as assessed by the pole test and wire-hanging test, and restored intestinal motor function and colon tissue morphology. Additionally, ECPs increased tyrosine hydroxylase expression in the substantia nigra, indicating a protective effect on dopaminergic neurons. These findings suggest that ECP has a preventative effect on PD.
Asunto(s)
Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Enfermedad de Parkinson , Polifenoles , Rotenona , Animales , Humanos , Masculino , Ratones , Elementos de Respuesta Antioxidante/efectos de los fármacos , Antioxidantes/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Fármacos Neuroprotectores/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/prevención & control , Enfermedad de Parkinson/tratamiento farmacológico , Polifenoles/farmacología , Transducción de Señal/efectos de los fármacos , Kelp/químicaRESUMEN
NAD(P)H: quinone oxidoreductase-1 (NQO1) plays critical roles in antioxidation and abnormally overexpresses in tumors. Developing a fast and sensitive method of monitoring NQO1 will greatly promote cancer diagnosis in clinical practice. This study introduces a transformative colorimetric detection strategy for NQO1, harnessing an innovative competitive substrate mechanism between NQO1 and a new NADH oxidase (NOX) mimic, cobalt-nitrogen-doped carbon nanozyme (CoNC). This method ingeniously exploits the differential consumption of NADH in the presence of NQO1 to modulate the generation of H2O2 from CoNC catalysis, which is then quantified through a secondary, peroxidase-mimetic cascade reaction involving Prussian blue (PB) nanoparticles. This dual-stage reaction framework not only enhances the sensitivity of NQO1 detection, achieving a limit of detection as low as 0.67 µg mL-1, but also enables the differentiation between cancerous and noncancerous cells by their enzymatic activity profiles. Moreover, CoNC exhibits exceptional catalytic efficiency, with a specific activity reaching 5.2 U mg-1, significantly outperforming existing NOX mimics. Beyond mere detection, CoNC serves a dual role, acting as both a robust mimic of cytochrome c reductase (Cyt c) and a cornerstone for enzymatic regeneration, thereby broadening the scope of its biological applications. This study not only marks a significant step forward in the bioanalytical application of nanozymes but also sets the stage for their expanded use in clinical diagnostics and therapeutic monitoring.
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Colorimetría , NAD(P)H Deshidrogenasa (Quinona) , NADH NADPH Oxidorreductasas , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/química , Humanos , NADH NADPH Oxidorreductasas/metabolismo , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Complejos Multienzimáticos/metabolismo , Complejos Multienzimáticos/química , Cobalto/química , Carbono/química , Biomimética , Límite de Detección , Nitrógeno/química , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Ferrocianuros/química , NAD/metabolismo , NAD/químicaRESUMEN
BACKGROUND: Ferroptosis, an emerging nonapoptotic, modulated cell death process characterized by iron accumulation and subsequent lipid peroxidation, has been intimately implicated in the development and progression of ovarian cancer (OC). Daphnetin (Daph), a natural product isolated from Daphne Korean Nakai, exhibits anticancer efficacy against various solid tumors. However, the specific role and potential mechanism underlying Daph-mediated modulation of ferroptosis in OC cells remain elusive. PURPOSE: This study aims to analyze the proferroptotic impacts of Daph on OC cells and to further explore the underlying mechanisms involved. STUDY DESIGN AND METHODS: We used CCK-8, wound healing and Transwell assays to assess whether Daph can inhibit the proliferation and migration of OC cells. Additionally, transmission electron microscopy (TEM), iron measurement, reactive oxygen species (ROS) analysis, lipid peroxidation assays, qRT-PCR and western blotting were utilized to evaluate the impact of Daph on ferroptosis and elucidate the potential underlying mechanism. Furthermore, RNA sequencing analysis, molecular docking analysis, cellular thermal shift assays (CETSAs) and NQO1 activity assays were used to predict and validate the binding and mechanistic interactions between Daph and NQO1. Subcutaneous tumorigenesis models were utilized to examine the effectiveness of Daph (and/or cisplatin) in vivo. RESULTS: Daph exerted antitumor effects by inducing the death and suppressing the migration of A2780 and SKOV3 cells. Further, Daph induced ferroptosis in OC cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), ROS and lipid peroxides, as well as the decreases in the glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio and the expression of ferroptosis indicators (SLC7A11 and GPX4). RNA sequencing and molecular docking analyses revealed that the direct interaction between NQO1 and Daph reduced both the activity and expression of NQO1. Importantly, NQO1 overexpression effectively alleviated the effects of Daph on proliferation, migration, and ferroptosis in vitro and in vivo. Interestingly, we also found that combination treatment with Daph, a negative regulator of NQO1, and cisplatin synergistically induced cytotoxicity in OC cells. CONCLUSION: Our findings are the firstly demonstrated that Daph acts as a novel ferroptosis inducer in OC cells by specifically targeting NQO1 and is thus a promising candidate agent for OC treatment.
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Proliferación Celular , Ferroptosis , Simulación del Acoplamiento Molecular , NAD(P)H Deshidrogenasa (Quinona) , Neoplasias Ováricas , Especies Reactivas de Oxígeno , Umbeliferonas , Ferroptosis/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Femenino , Humanos , Línea Celular Tumoral , Animales , Especies Reactivas de Oxígeno/metabolismo , Umbeliferonas/farmacología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Cisplatino/farmacología , Ratones , Peroxidación de Lípido/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C , Daphne/química , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
Sesamolin, a lignan isolated from sesame oils, has been found to possess neuroprotective, anticancer, and free radical scavenging properties. We hypothesized that sesamolin could stimulate the activity of nuclear factor erythroid-derived 2-like 2 (Nrf2) and inhibit adipocyte differentiation of preadipocytes. The objective of this study was to investigate effects of sesamolin on adipocyte differentiation and its underlying molecular mechanisms. In this study, we determined the effects of treatment with 25 to 100 µM sesamolin on adipogenesis in cell culture systems. Sesamolin inhibited lipid accumulation and suppressed the expression of adipocyte markers during adipocyte differentiation of C3H10T1/2, 3T3-L1, and primary preadipocytes. Mechanism studies revealed that sesamolin increased Nrf2 protein expression without inducing its mRNA, leading to an increase in the expression of Nrf2 target genes such as heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 (Nqo1) in C3H10T1/2 adipocytes and mouse embryonic fibroblasts. These effects were significantly attenuated in Nrf2 knockout (KO) mouse embryonic fibroblasts, indicating that effects of sesamolin were dependent on Nrf2. In H1299 human lung cancer cells with KO of Kelch like-ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, sesamolin failed to further increase Nrf2 protein expression. However, upon reexpressing Keap1 in Keap1 KO cells, the ability of sesamolin to elevate Nrf2 protein expression was restored, highlighting the crucial role of Keap1 in sesamolin-induced Nrf2 activation. Taken together, these findings show that sesamolin can inhibit adipocyte differentiation through Keap1-mediated Nrf2 activation.
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Células 3T3-L1 , Adipocitos , Adipogénesis , Diferenciación Celular , Proteína 1 Asociada A ECH Tipo Kelch , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Animales , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Dioxoles/farmacología , Ratones Noqueados , Lignanos/farmacología , Humanos , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of ß-amyloid (Aß) plaques and neurofibrillary tangles composed of tau protein in the brain. These neuropathological hallmarks contribute to cognitive impairment by inducing neuronal loss in the cerebral cortex and hippocampus. Unfortunately, current therapeutic approaches only target symptomatic relief and do not impede disease progression. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising candidate for the treatment of age-related neurodegenerative disorders. NMN supplementation could restore NAD+ levels, thereby alleviating neuronal damage and slowing the progression of AD and other aging-associated diseases. AD is closely associated with autophagic impairment and oxidative stress. Our in vivo experiments demonstrated that NMN could ameliorate pathological and behavioral impairments in AD mice. Specifically, NMN enhanced autophagy and promoted p-tau clearance. Meanwhile, NMN could activate the Nrf2/Keap1/NQO1 pathway, thereby reducing the oxidative stress. Immunofluorescence results demonstrated that NMN could alleviate neuronal damage in AD mice. Furthermore, in vitro results showed that the p-tau clearance and antioxidant stress effects of NMN were suppressed by autophagy inhibitor, chloroquine (CQ) or bafilomycin A1 (BafA1), in Aß-induced PC12 cells. Lastly, when Nrf2 was knocked down, the antioxidant stress, autophagy enhancement, and p-tau clearance effects of NMN were all inhibited. In conclusion, our research indicates that NMN exerts therapeutic effect against AD by activating autophagy and the Nrf2/Keap1/NQO1 pathway through a mutual regulating mechanism of autophagy and antioxidative stress. These findings highlight the promising potential of NMN for the treatment of AD.
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Enfermedad de Alzheimer , Autofagia , Factor 2 Relacionado con NF-E2 , Mononucleótido de Nicotinamida , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Autofagia/efectos de los fármacos , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/uso terapéutico , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Proteínas tau/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones Transgénicos , Masculino , Modelos Animales de Enfermedad , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Células PC12 , Ratas , Péptidos beta-Amiloides/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
Chronic Kidney Disease (CKD), closely linked to environmental factors, poses a significant public health challenge. This study, based on 529 triple-repeated measures from key national environmental pollution area and multiple gene-related public databases, employs various epidemiological and bioinformatics models to assess the impact of combined heavy metal exposure (Chromium [Cr], Cadmium [Cd], and Lead [Pb]) on early renal injury and CKD in the elderly. Introducing the novel Enviro-Target Mendelian Randomization method, our research explores the causal relationship between metals and CKD. The findings indicate a positive correlation between increased levels of metal and renal injury, with combined exposure caused renal damage more significantly than individual exposure. The study reveals that metals primarily influence CKD development through oxidative stress and metal ion resistance pathways, focusing on three related genes (SOD2, MPO, NQO1) and a transcription factor (NFE2L2). Metals were found to regulate oxidative stress levels in the body by increasing the expression of SOD2, MPO, NQO1, and decreasing NFE2L2, leading to CKD onset. Our research establishes a new causal inference framework linking environmental pollutants-pathways-genes-CKD, assessing the impact and mechanisms of metal exposure on CKD. Future studies with more extensive in vitro evidence and larger population are needed to validate.
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Cadmio , Contaminantes Ambientales , Análisis de la Aleatorización Mendeliana , Metales Pesados , Estrés Oxidativo , Insuficiencia Renal Crónica , Humanos , Metales Pesados/toxicidad , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/epidemiología , Estrés Oxidativo/efectos de los fármacos , Anciano , Cadmio/toxicidad , Contaminantes Ambientales/toxicidad , Plomo/toxicidad , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Factor 2 Relacionado con NF-E2/genética , Exposición a Riesgos Ambientales/efectos adversos , Masculino , Femenino , Cromo/toxicidad , Riñón/efectos de los fármacosRESUMEN
Chemodynamic therapy (CDT), employing metal ions to transform endogenous H2O2 into lethal hydroxyl radicals (â¢OH), has emerged as an effective approach for tumor treatment. Yet, its efficacy is diminished by glutathione (GSH), commonly overexpressed in tumors. Herein, a breakthrough strategy involving extracellular vesicle (EV) mimetic nanovesicles (NVs) encapsulating iron oxide nanoparticles (IONPs) and ß-Lapachone (Lapa) was developed to amplify intracellular oxidative stress. The combination, NV-IONP-Lapa, created through a serial extrusion from ovarian epithelial cells showed excellent biocompatibility and leveraged magnetic guidance to enhance endocytosis in ovarian cancer cells, resulting in selective H2O2 generation through Lapa catalysis by NADPH quinone oxidoreductase 1 (NQO1). Meanwhile, the iron released from IONPs ionization under acidic conditions triggered the conversion of H2O2 into â¢OH by the Fenton reaction. Additionally, the catalysis process of Lapa eliminated GSH in tumor, further amplifying oxidative stress. The designed NV-IONP-Lapa demonstrated exceptional tumor targeting, facilitating MR imaging, and enhanced tumor suppression without significant side effects. This study presents a promising NV-based drug delivery system for exploiting CDT against NQO1-overexpressing tumors by augmenting intratumoral oxidative stress.
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Naftoquinonas , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Animales , Ratones , Naftoquinonas/química , Naftoquinonas/farmacología , Línea Celular Tumoral , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Peróxido de Hidrógeno/química , Nanopartículas Magnéticas de Óxido de Hierro/química , Estrés Oxidativo/efectos de los fármacos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Glutatión/metabolismo , Glutatión/química , Sistemas de Liberación de MedicamentosRESUMEN
Accurate prediction of Drug-Target Interactions (DTI) is crucial for drug development. Current state-of-the-art deep learning methods have significantly advanced the field; however, these methods exhibit limitations in predictive performance and the propensity for false negatives. Therefore, we propose EADTN, a simple and efficient ensemble model. We have designed an innovative feature adaptation technique to automatically extract local weights of drugs and targets, and we utilize clustering-enhanced parameter fine-tuning to overcome the issue of false negatives, thereby enhancing its reliability in drug discovery. Based on EADTN, we also propose a Shapley value-based method for identifying key drug substructures, effectively enhancing the model's interpretability. Additionally, we utilized EADTN to reveal potential interactions between NQO1 targets and the drugs SIRT-IN-1 and LY2183240, which were subsequently validated through wet-lab experiments. Experimental evidence demonstrates that EADTN consistently outperforms existing best-performing models across various data sets, promising significant benefits in fields such as drug repositioning.
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Aprendizaje Profundo , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Sirtuina 1/metabolismo , Descubrimiento de Drogas , HumanosRESUMEN
Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II-IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II-IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.
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Antígeno B7-H1 , Linfocitos T CD8-positivos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Microambiente Tumoral , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Antígeno B7-H1/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Masculino , Femenino , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/metabolismo , Persona de Mediana Edad , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Adulto , Estadificación de Neoplasias , Linfocitos Infiltrantes de Tumor/patología , Linfocitos Infiltrantes de Tumor/inmunología , Pronóstico , InmunohistoquímicaRESUMEN
The aim of the present study was to evaluate the cardiotoxic effects of alcohol and its potential toxic mechanism on ferroptosis in mice and H9c2 cells. Mice were intragastrically treated with three different concentrations of alcohol, 7, 14, and 28%, each day for 14 days. Body weight and electrocardiography (ECG) were recorded over the 14 day period. Serum creatine kinase (CK), lactic dehydrogenase (LDH), MDA, tissue iron, and GSH levels were measured. Cardiac tissues were examined histologically, and ferroptosis was assessed. In H9c2 cardiomyocytes, cell viability, reactive oxygen species (ROS), labile iron pool (LIP), and mitochondrial membrane potential (MMP) were measured. The proteins of ferroptosis were evaluated by the western blot technique in vivo and in vitro. The results showed that serum CK, LDH, MDA, and tissue iron levels significantly increased in the alcohol treatment group in a dose-dependent manner. The content of GSH decreased after alcohol treatment. ECG and histological examinations showed that alcohol impaired cardiac function and structure. In addition, the levels of ROS and LIP increased, and MMP levels decreased after alcohol treatment. Ferrostatin-1 (Fer-1) protected cells from lipid peroxidation. Western blotting analysis showed that alcohol downregulated the expression of Nrf2, NQO1, HO-1, and GPX4. The expressions of P53 and TfR were upregulated in vivo and in vitro. Fer-1 significantly alleviated alcohol-induced ferroptosis. In conclusion, the study showed that Nrf2/NQO1-dependent ferroptosis played a vital role in the cardiotoxicity induced by alcohol.