RESUMEN

BACKGROUND: Abnormal biological behaviour of keratinocytes (KCs) is a critical pathophysiological manifestation of psoriasis. Ferroptosis is programmed cell death induced by the accumulation of lipid reactive oxygen species (ROS) in the presence of increased intracellular iron ions or inhibition of GPX4. OBJECTIVES: The purpose of this study was to investigate the effects of ferroptosis on the biological behaviour of Keratinocytes (KCs) in psoriasis vulgaris and its possible regulatory mechanisms in clinical samples, cells, and mouse models. METHODS: We first examined the differences in the expression of GPX4 and 4-HNE between psoriasis and normal human lesions. And detected KRT6, FLG, and inflammatory cytokines after inducing ferroptosis in animal and cell models by RT-qPCR, Western blot, immunohistochemistry, and flow cytometry. RESULTS: We found that GPX4 was decreased and that the oxidation product 4-hydroxy-2-nonenal (HNE) was increased in the skin lesions of patients with psoriasis vulgaris. The expression level of GPX4 correlates with the severity of skin lesions. Moreover, inducing ferroptosis promoted the expression of FLG and reduced the expression of KRT6 and inflammatory cytokines in vitro, and alleviated the phenotype of skin lesions in vivo. LIMITATIONS: Our study has limitations, notably small sample size. Larger clinical trials are necessary to investigate the association between ferroptosis and disease progression further. More research is necessary to explore how the ferroptosis inducer RSL3 regulates the abnormal biological behaviour of KCs at both cellular and animal levels and establish ferroptosis inhibitors as controls. CONCLUSIONS: This study confirms the existence of ferroptosis in psoriatic lesions, which may be inversely correlated with disease severity. The ferroptosis inducer RSL3 ameliorated psoriatic symptoms by improving the abnormal biological behaviour of KCs.

Asunto(s)

Modelos Animales de Enfermedad , Ferroptosis , Queratinocitos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Psoriasis , Psoriasis/patología , Psoriasis/metabolismo , Psoriasis/inmunología , Ferroptosis/fisiología , Queratinocitos/metabolismo , Queratinocitos/patología , Humanos , Animales , Ratones , Proyectos Piloto , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Aldehídos/metabolismo , Femenino , Masculino , Adulto , Queratina-6/metabolismo , Citocinas/metabolismo , Piel/patología , Piel/metabolismo , Piel/inmunología , Persona de Mediana Edad , Resorcinoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Carbolinas

RESUMEN

Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Asunto(s)

Biología Computacional , Ferroptosis , Insuficiencia Cardíaca , Saponinas , Triterpenos , Animales , Ferroptosis/efectos de los fármacos , Triterpenos/farmacología , Saponinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Ratas , Biología Computacional/métodos , Masculino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Simulación de Dinámica Molecular , Miocardio/metabolismo , Miocardio/patología

RESUMEN

Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene (PHE), are common pollutants found in coastal areas where shrimp farming is developed. Even though PAHs can have adverse effects on physiology, shrimp can detoxify and metabolize toxic compounds and neutralize the reactive oxygen species (ROS) produced during this process. This requires the activation of multiple antioxidant enzymes, including peroxiredoxin 6 (Prx6). Prx6 uses glutathione (GSH) to reduce phospholipid hydroperoxides, a function shared with GSH peroxidase 4 (GPx4). Prx6 has been scarcely studied in crustaceans exposed to pollutants. Herein, we report a novel Prx6 from the shrimp Penaeus vannamei that is abundantly expressed in gills and hepatopancreas. To elucidate the involvement of Prx6 in response to PAHs, we analyzed its expression in the hepatopancreas of shrimp sub-lethally exposed to PHE (3.3 µg/L) and acetone (control) for 24, 48, 72, and 96 h, along with GPx4 expression, GSH-dependent peroxidase activity, and lipid peroxidation (indicated by TBARS). We found that GPx4 expression is not affected by PHE, but Prx6 expression and peroxidase activity decreased during the trial. This might contribute to the rise of TBARS found at 48 h of exposure. However, maintaining GPx4 expression could aid to minimize lipid damage during longer periods of exposure to PHE.

Asunto(s)

Glutatión Peroxidasa , Peroxidación de Lípido , Penaeidae , Peroxiredoxina VI , Fenantrenos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Animales , Fenantrenos/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Penaeidae/metabolismo , Penaeidae/efectos de los fármacos , Penaeidae/genética , Penaeidae/enzimología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Peroxiredoxina VI/metabolismo , Peroxiredoxina VI/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Contaminantes Químicos del Agua/toxicidad , Hepatopáncreas/metabolismo , Hepatopáncreas/efectos de los fármacos , Branquias/metabolismo , Branquias/efectos de los fármacos , Proteínas de Artrópodos/metabolismo , Proteínas de Artrópodos/genética

RESUMEN

OBJECTIVE: To investigate the effect of sanguinarine (SAN) on proliferation and ferroptosis of colorectal cancer cells. METHODS: SW620 and HCT-116 cells treated with different concentrations of SAN were examined for cell viability changes using CCK8 assay to determine the IC50 of SAN in the two cells. The inhibitory effects of SAN on proliferation, invasion and migration of the cells were evaluated using colony-forming assay and Transwell assays. ROS production in the treated cells was analyzed with flow cytometry, and lipid peroxide production was assessed by detecting malondialdehyde (MDA) level. Glutathione (GSH) levels in the cells were detected, and Western blotting was used to detect the expressions of ferroptosis-related proteins STUB1 and GPX4. RESULTS: SAN significantly inhibited the proliferation, invasion and migration of SW620 and HCT-116 cells. SAN treatment significantly promoted ROS production, increased intracellular MDA level, and lowered GSH level in the two cells (P<0.05). Western blotting showed that SAN significantly upregulated the expression of STUB1 and down-regulated the expression of its downstream protein GPX4 (P<0.05). CONCLUSION: SAN induces ferroptosis in colorectal cancer cells by regulating STUB1/GPX4, which may serve as a new therapeutic target for colorectal cancer.

Asunto(s)

Benzofenantridinas , Proliferación Celular , Neoplasias Colorrectales , Ferroptosis , Isoquinolinas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proliferación Celular/efectos de los fármacos , Isoquinolinas/farmacología , Línea Celular Tumoral , Benzofenantridinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Abajo , Células HCT116 , Regulación hacia Arriba/efectos de los fármacos , Movimiento Celular/efectos de los fármacos

RESUMEN

Cis-dichlorodiammineplatinum(II) (CDDP), while widely utilized in tumor therapy, results in toxic side effects that patients find intolerable. The specific mechanism by which CDDP inflicts ovarian damage remains unclear. This study aimed to explore the involvement of ferrostatin-1 (FER-1) and ferroptosis in CDDP-induced ovarian toxicity. This study established models of CDDP-induced injury in granulosa cells (GCs) and rat model of premature ovarian failure (POF). CCK-8 assessed the effects of CDDP and FER-1 on GC viability. FerroOrange and Mito-FerroGreen, DCFH-DA and MitoSox-Red, Rhodamine 123 and Transmission electron microscopy (TEM) measured Fe2+, reactive oxygen species (ROS), mitochondrial membrane potential and the mitochondrial morphology in GC cells, respectively. Serum hormone levels; organ indices; malondialdehyde, superoxide dismutase, and glutathione analyses; and western blotting were performed to examine ferroptosis's role in vitro. Molecular docking simulation was evaluated the interaction between FER-1 and GPX4 or FER-1 and NRF2. Molecular docking simulations were conducted to evaluate the interactions between FER-1 and GPX4, as well as FER-1 and NRF2. The findings revealed that CDDP-induced ovarian toxicity involved iron accumulation, increased ROS accumulation, and mitochondrial dysfunction, leading to endocrine disruption and tissue damage in rats. These changes correlated with NRF2, HO-1, and GPX4 levels. However, FER-1 decreased the extent of ferroptosis. Thus, ferroptosis appears to be a crucial mechanism of CDDP-induced ovarian injury, with GPX4 as potential protective targets.

Asunto(s)

Cisplatino , Ciclohexilaminas , Ferroptosis , Simulación del Acoplamiento Molecular , Fenilendiaminas , Especies Reactivas de Oxígeno , Animales , Femenino , Ferroptosis/efectos de los fármacos , Ciclohexilaminas/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/efectos adversos , Fenilendiaminas/farmacología , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo

RESUMEN

Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIPPCPO) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIPPCPO is found to boost lysosomal Fe2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIPPCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIPPCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIPPCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIPPCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.

Asunto(s)

Neoplasias de la Mama , Ferroptosis , Liposomas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ferroptosis/efectos de los fármacos , Animales , Humanos , Femenino , Línea Celular Tumoral , Ratones , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Liposomas/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Artesunato/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Fosfatidilcolinas/metabolismo , Fosfatidilcolinas/química , Hierro/metabolismo , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Ratones Desnudos , Glutatión/metabolismo , Ratones Endogámicos BALB C

RESUMEN

This study aims to investigate the role of ferroptosis, an iron-dependent form of regulated cell death, in male infertility. The motivation behind this research stems from the increasing recognition of oxidative stress and iron metabolism dysregulation as critical factors in male reproductive health. In this study, 28 infertile patients (grouped by the presence of urogenital infections or varicocele) and 19 fertile men were selected. Spermiograms were performed by light microscopy (WHO, 2021). Testosterone, ferritin, transferrin-bound iron, transferrin, and F2-isoprostanes (F2-IsoPs) were detected in seminal plasma. Glutathione peroxidase 4 (GPX4) and acyl coenzyme A synthetase long chain family member 4 (ACSL4) were also assessed in sperm cells using enzyme-linked immunosorbent assays (ELISA). All the variables were correlated (statistically significant Spearman's rank correlations) in the whole population, and then the comparison between variables of the different groups of men were carried out. Seminal ferritin and transferrin positively correlated with seminal F2-IsoPs, which had positive correlations with ACSL4 detected in sperm cells. Ferritin and ACSL4 negatively correlated with the seminal parameters. No correlation was detected for GPX4. Comparing the variables in the three examined groups, elevated levels of ACSL4 were observed in infertile patients with urogenital infections and varicocele; GPX4 levels were similar in the three groups. These results suggested a mechanism of ferroptosis, identified by increased ACSL4 levels and the occurrence of lipid peroxidation. Such events appear to be GPX4-independent in reproductive pathologies such as varicocele and urogenital infections.

Asunto(s)

Biomarcadores , Ferroptosis , Infertilidad Masculina , Semen , Humanos , Masculino , Semen/metabolismo , Adulto , Biomarcadores/metabolismo , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Coenzima A Ligasas/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fertilidad , Espermatozoides/metabolismo , Espermatozoides/patología

RESUMEN

Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.

Asunto(s)

Biomarcadores de Tumor , Ferroptosis , Peroxidación de Lípido , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Humanos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Pronóstico , Femenino , Masculino , Biomarcadores de Tumor/metabolismo , Anciano , Persona de Mediana Edad , Ferroptosis/efectos de los fármacos , Línea Celular Tumoral , Aldehídos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética

RESUMEN

Nasopharyngeal carcinoma (NPC) originates from the nasopharynx epithelium, and luteolin is recognized as an important anti-cancer agent. This study investigated the effects of luteolin on ferroptosis in NPC cells. NPC cells were cultured and exposed to varying concentrations of luteolin. Cell viability, malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, glutathione (GSH) levels, Fe2+ concentration, and glutathione peroxidase 4 (GPX4) protein level were assessed. Additionally, SRY-related high-mobility-group box 4 (SOX4) expression was measured. Subsequently, the binding of SOX4 to the growth differentiation factor-15 (GDF15) promoter and GDF15 mRNA levels were evaluated. The impact of the SOX4/GDF15 axis on luteolin-induced ferroptosis in NPC cells was assayed. Luteolin treatment induced cell ferroptosis, evidenced by decreased cell viability, increased MDA and Fe2+ levels, and reduced SOD, GSH, and GPX4 levels. Furthermore, luteolin downregulated SOX4 expression, while overexpression of SOX4 reversed luteolin's pro-ferroptotic effects in NPC cells. SOX4 was found to up-regulate GDF15 transcription by directly binding to its promoter. Conversely, overexpression of GDF15 mitigated the ferroptotic effects induced by luteolin in NPC cells. Therefore, luteolin induces ferroptosis in NPC cells via modulation of the SOX4/GDF15 axis. In conclusion, luteolin reduces the binding of SOX4 to the GDF15 promoter by suppressing SOX4 expression, thereby down-regulating GDF15 transcription levels and inducing ferroptosis in NPC cells.

Asunto(s)

Supervivencia Celular , Ferroptosis , Factor 15 de Diferenciación de Crecimiento , Luteolina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Luteolina/farmacología , Humanos , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Malondialdehído/metabolismo , Antineoplásicos/farmacología , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Regiones Promotoras Genéticas/genética

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease worldwide. Spermidine (SPD), a naturally occurring polyamine, has shown potential in alleviating the accumulation of hepatic lipids and reducing NAFLD symptoms in overweight mice. Nonetheless, the specific mechanisms through which SPD exerts its effects remain largely unknown. This study seeks to explore the protective effects of SPD on NAFLD and to clarify the underlying mechanisms. An in vitro model of NAFLD was established by inducing steatosis in AML-12 cells through the use of free fatty acids (FFAs). Our experimental results demonstrate that SPD significantly reduces NAFLD development induced by FFAs. This reduction is primarily achieved through the inhibition of cellular ferroptosis, as evidenced by decreased levels of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS). Additionally, SPD was found to enhance cellular activity and ameliorate mitochondrial dysfunction and oxidative stress caused by FFA exposure. Further mechanistic studies have revealed that SPD upregulates the expression of solute transporter family 7a member 11 (SLC7A11), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase (GPX4). This upregulation is mediated by the activation of activating transcription factor 4 (ATF4). Knockdown experiments of ATF4 confirmed that its inhibition reverses the upregulation of SLC7A11, GCLM, and GPX4, thereby negating the protective effects of SPD. In conclusion, our findings suggest that SPD mitigates NAFLD by modulating the ATF4/SLC7A11/GCLM/GPX4 signaling pathway, resulting in the suppression of ferroptosis and the improvement of cellular health. These insights provide a novel molecular mechanism and identify potential therapeutic targets for the treatment of NAFLD.

Asunto(s)

Factor de Transcripción Activador 4 , Sistema de Transporte de Aminoácidos y+ , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Transducción de Señal , Espermidina , Ferroptosis/efectos de los fármacos , Espermidina/farmacología , Espermidina/metabolismo , Animales , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Ratones , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Transducción de Señal/efectos de los fármacos , Ácidos Grasos no Esterificados/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Glutamato-Cisteína Ligasa/metabolismo , Glutamato-Cisteína Ligasa/genética , Línea Celular , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal ferroptosis and cognitive impairment.

Asunto(s)

Arsénico , Disfunción Cognitiva , Ácido Elágico , Ferroptosis , Factor 2 Relacionado con NF-E2 , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ratas Wistar , Transducción de Señal , Animales , Ácido Elágico/farmacología , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Arsénico/toxicidad , Transducción de Señal/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología

RESUMEN

Deoxynivalenol (DON), one of the most common mycotoxins in food and feed, can cause acute and chronic liver injury, posing a serious health risk to humans and animals. One of the important manifestations of DON-induced hepatotoxicity is ferroptosis. It has been reported that CYP2E1 can mediated ferroptosis, but the role of DON-induced CYP2E1 in DON-induced ferroptosis in hepatocytes is unknown. In the present study, we observed that DON significantly increased the expression of CYP2E1 and decreased the expression of the ferroptosis inhibitory proteins GPX4 and SLC7A11, as well as GCLC and NQO1. This resulted in an increase in the levels of cell lipid ROS and FeII, 4-HNE, which ultimately led to cell ferroptosis. Notably, knockdown of CYP2E1 resulted in an increase in DON-induced low levels of GPX4 and SLC7A11, a decrease in DON-induced high levels of lipid ROS, FeII and cell secreted 4-HNE, thus ameliorating cell ferroptosis. Moreover, the ferroptosis inhibitor ferrostatin-1 was observed to antagonise the cell growth inhibitory toxicity induced by DON exposure. This was achieved by blocking the increase in lipid ROS and FeII overload, which in turn reduced the extent of ferroptosis and increased IGF-1 protein expression. In conclusion, the present study demonstrated that CYP2E1 played a regulatory role in DON-induced ferroptosis in hepatocytes. Targeting ferroptosis may prove an effective strategy for alleviating DON-induced cell growth retardation toxicity. These findings provided a potential target and strategies to mitigate DON hepatotoxicity in the future.

Asunto(s)

Citocromo P-450 CYP2E1 , Ferroptosis , Hepatocitos , Especies Reactivas de Oxígeno , Tricotecenos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Ferroptosis/efectos de los fármacos , Tricotecenos/toxicidad , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/genética , Especies Reactivas de Oxígeno/metabolismo , Humanos , Animales , Células Hep G2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum torvum Sw. (ST) is used to clear heat toxins, promote blood circulation, and alleviate blood stasis. Therefore, this plant has traditionally been used as an ethnomedicine for common cold, chronic gastritis, and tumors. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which ST induces ferroptosis in hepatocellular carcinoma (HCC), the combination effect with lenvatinib, and the impact on lenvatinib-resistant cells. MATERIALS AND METHODS: Cell viability assays were performed using different hepatoma cell lines treated with ST. Lipid peroxidation and iron assays were performed using flow cytometry. Molecules involved in the ferroptosis pathway were detected by Western blotting. Finally, a lenvatinib-resistant cell line was established to evaluate the antiproliferative effects of ST. RESULTS: ST ethanol extract inhibited the growth of various hepatoma cell lines. A significant reduction in glutathione peroxidase 4 (GPX4) expression was observed following ST treatment, which was accompanied by increased lipid peroxidation and Fe2+ accumulation. ST induced ferroptosis mainly through heme oxygenase-1 (HO-1) expression. HO-1 knockdown reduced ST-induced lipid peroxidation and reversed GPX4 suppression. Acyl-CoA synthetase long-chain family member 4 (ACSL4) also participated in ST-induced ferroptosis. ST and lenvatinib combination showed an additive effect, and ST retained its potential anti-HCC efficacy in a lenvatinib-resistant cell line. CONCLUSION: This study demonstrated that the ethanol extract of ST inhibits hepatoma cell growth by inducing ferroptosis. ST displayed an additive effect with lenvatinib in Hep 3B cells and showed remarkable anti-HCC activity in lenvatinib-resistant Hep 3B cells. Collectively, the study shows that ST might have the potential to reduce lenvatinib use in clinical practice and salvage cases of lenvatinib resistance.

Asunto(s)

Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Extractos Vegetales , Quinolinas , Solanum , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Solanum/química , Extractos Vegetales/farmacología , Línea Celular Tumoral , Quinolinas/farmacología , Compuestos de Fenilurea/farmacología , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo

RESUMEN

ABSTRACT: Lipopolysaccharide (LPS) plays an important role in Raw264.7 macrophage ferroptosis and inflammation. Purine-rich element-binding protein B (Purb) influences cellular processes by regulating gene expression as a transcription factor. However, the effect and molecular mechanism of Purb in regulating Raw264.7 macrophage ferroptosis is still unknown. In this study, we used malondialdehyde, glutathione (GSH) assays, Fe 2+ fluorescence, reactive oxygen species staining, and western blotting to determine the effect of Purb on LPS-induced Raw264.7 macrophage ferroptosis. Pharmacological inhibitor of ferroptosis was utilized to explore its potential effects for inflammation by reverse transcription-quantitative polymerase chain reaction analysis. Meanwhile, chromatin immunoprecipitation was performed to verify the binding of Purb and the GSH-dependent peroxidase 4 (Gpx4). The results showed that LPS-induced inflammation in Raw264.7 macrophages was inhibited by ferroptosis inhibitor Fer-1 treatment. LPS inhibited the expression of Purb in Raw264.7 macrophages. In addition, Purb overexpression relieved the ferroptosis, and inflammatory response of Raw264.7 macrophages induced by LPS. Mechanistically, the binding of Purb to the Gpx4 promoter was decreased after LPS stimulation. Therefore, we concluded for the first time that Purb played a critical role in LPS-induced ferroptosis and inflammatory response by regulating the transcription of Gpx4. These results provide a theoretical basis for further research on the macrophage ferroptosis and inflammation.

Asunto(s)

Ferroptosis , Inflamación , Lipopolisacáridos , Macrófagos , Animales , Ferroptosis/efectos de los fármacos , Ratones , Lipopolisacáridos/farmacología , Células RAW 264.7 , Inflamación/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2's anti-lipid peroxidation effect, ultimately leading to ferroptosis.

Asunto(s)

Mal de Altura , Ferroptosis , Hipocampo , Hipoxia , Animales , Ferroptosis/fisiología , Hipocampo/metabolismo , Ratones , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Peroxidación de Lípido , Receptores de Transferrina/metabolismo , Altitud , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Glutatión/metabolismo , Malondialdehído/metabolismo , Hierro/metabolismo , Proteínas de Transporte de Catión/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética

RESUMEN

Glioblastoma-derived exosomes (GDEs), containing nucleic acids, proteins, fatty acids and other substances, perform multiple important functions in glioblastoma microenvironment. Tumor-derived exosomes serve as carriers of fatty acids and induce a shift in metabolism towards oxidative phosphorylation, thus driving immune dysfunction of dendritic cells (DCs). Lipid peroxidation is an important characteristic of ferroptosis. Nevertheless, it remains unclear whether GDEs can induce lipid accumulation and lipid oxidation to trigger ferroptosis in DCs. In our study, we investigate the impact of GDEs on lipid accumulation and oxidation in DCs by inhibiting GDEs secretion through knocking down the expression of Rab27a using a rat orthotopic glioblastoma model. The results show that inhibiting the secretion of GDEs can reduce lipid accumulation in infiltrating DCs in the brain and decrease mature dendritic cells (mDCs) lipid peroxidation levels, thereby suppressing glioblastoma growth. Mechanistically, we employed in vitro treatments of bone marrow-derived dendritic cells (BMDCs) with GDEs. The results indicate that GDEs decrease the viability of mDCs compared to immature dendritic cells (imDCs) and trigger ferroptosis in mDCs via the NRF2/GPX4 pathway. Overall, these findings provide new insights into the development of immune-suppressive glioblastoma microenvironment through the interaction of GDEs with DCs.

Asunto(s)

Neoplasias Encefálicas , Células Dendríticas , Exosomas , Ferroptosis , Glioblastoma , Metabolismo de los Lípidos , Factor 2 Relacionado con NF-E2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ferroptosis/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Exosomas/metabolismo , Glioblastoma/inmunología , Glioblastoma/metabolismo , Glioblastoma/patología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Transducción de Señal , Humanos , Microambiente Tumoral/inmunología , Línea Celular Tumoral , Masculino , Peroxidación de Lípido

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) could induce multiple forms of cell death, ferroptosis, a novel form of cell death distinct from apoptosis and autophagy, plays an important role in disease progression in TBI. Therapies targeting ferroptosis are beneficial for recovery from TBI. Paeoniflorin (Pae) is a water-soluble monoterpene glycoside and the active ingredient of Paeonia lactiflora pall. It has been shown to exert anti-inflammatory and antioxidant effects. However The effects and mechanisms of paeoniflorin on secondary injury after TBI are unknown. PURPOSE: To investigate the mechanism by which Pae regulates ferroptosis after TBI. METHODS: The TBI mouse model and cortical primary neurons were utilized to study the protective effect of paeoniflorin on the brain tissue after TBI. The neuronal cell ferroptosis model was established by treating cortical primary neurons with erastin. Liproxstatin-1(Lip-1) was used as a positive control drug. Immunofluorescence staining, Nissl staining, biochemical analyses, pharmacological analyses, and western blot were used to evaluate the effects of paeoniflorin on TBI. RESULTS: Pae significantly ameliorated neuronal damage after TBI, inhibited mitochondrial damage, increased glutathione peroxidase 4 (GPX4) activity, decreased malondialdehyde (MDA) production, restored neurological function and inhibited cerebral edema. Pae promotes the degradation of P53 in the form of proteasome, promotes its ubiquitination, and reduces the stability of P53 by inhibiting its acetylation, thus alleviating the P53-mediated inhibition of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) by P53. CONCLUSION: Pae inhibits ferroptosis by promoting P53 ubiquitination out of the nucleus, inhibiting P53 acetylation, and modulating the SLC7A11-GPX4 pathway.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Ferroptosis , Glucósidos , Monoterpenos , Proteína p53 Supresora de Tumor , Glucósidos/farmacología , Ferroptosis/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Animales , Monoterpenos/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Acetilación , Ratones , Masculino , Neuronas/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Paeonia/química , Fármacos Neuroprotectores/farmacología

RESUMEN

Inflammatory bowel disease (IBD) has high prevalence in Western counties. The high fat content in Western diets is one of the leading causes for this prevalence; however, the underlying mechanisms have not been fully defined. Here, we find that high-fat diet (HFD) induces ferroptosis of intestinal regulatory T (Treg) cells, which might be the key initiating step for the disruption of immunotolerance and the development of colitis. Compared with effector T cells, Treg cells favor lipid metabolism and prefer polyunsaturated fatty acids (PUFAs) for the synthesis of membrane phospholipids. Therefore, consumption of HFD, which has high content of PUFAs such as arachidonic acid, cultivates vulnerable Tregs that are fragile to lipid peroxidation and ferroptosis. Treg-cell-specific deficiency of GPX4, the key enzyme in maintaining cellular redox homeostasis and preventing ferroptosis, dramatically aggravates the pathogenesis of HFD-induced IBD. Taken together, these studies expand our understanding of IBD etiology.

Asunto(s)

Colitis , Dieta Alta en Grasa , Ácidos Grasos Insaturados , Ferroptosis , Ratones Endogámicos C57BL , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Linfocitos T Reguladores , Animales , Dieta Alta en Grasa/efectos adversos , Ferroptosis/efectos de los fármacos , Colitis/patología , Colitis/metabolismo , Colitis/inducido químicamente , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ácidos Grasos Insaturados/metabolismo , Ratones , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Masculino , Peroxidación de Lípido/efectos de los fármacos

RESUMEN

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.

Asunto(s)

Ferroptosis , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Estrés Oxidativo , Daño por Reperfusión , Tionas , Tiofenos , Animales , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Tionas/farmacología , Tionas/uso terapéutico , Células PC12 , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Ratas , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Modelos Animales de Enfermedad , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Pirazinas

RESUMEN

BACKGROUND: The notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissues，contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells. METHODS: To investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine's Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage. RESULTS: The diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4. CONCLUSION: In the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.

Asunto(s)

Enterocolitis Necrotizante , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Linfocitos T Reguladores , Vitamina E , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Vitamina E/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratones , Enterocolitis Necrotizante/metabolismo , Enterocolitis Necrotizante/patología , Enterocolitis Necrotizante/tratamiento farmacológico , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/patología , Humanos , Ratones Noqueados , Intestinos/patología