RESUMEN
The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.
Asunto(s)
Antioxidantes , Caenorhabditis elegans , Ferroptosis , Neuronas , Vitamina A , Animales , Ferroptosis/efectos de los fármacos , Vitamina A/farmacología , Vitamina A/metabolismo , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Antioxidantes/farmacología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/citología , Ciclohexilaminas/farmacología , Diferenciación Celular/efectos de los fármacos , Vitamina E/farmacología , Receptores de Ácido Retinoico/metabolismo , Receptores de Ácido Retinoico/genética , Tretinoina/farmacología , Organoides/efectos de los fármacos , Organoides/metabolismo , Neurogénesis/efectos de los fármacos , Ratones , Humanos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Transducción de Señal/efectos de los fármacos , FenilendiaminasRESUMEN
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/metabolismoRESUMEN
Spinal cord injury (SCI) results in irreversible neurological impairment. After SCI, Ferritinophagy-induced free iron released from ferritin can lead to extensive lipid peroxidation and aggravate neurological damage. NRF2/HO-1 pathway is to endow cells with a protective effect against oxidative stress, and it plays an important role in the transcriptional activation of a series of antioxidant and detoxification genes. UAMC-3203 is a ferrostatin-1(Fer-1) analogue with better solubility and stability, which can more effectively inhibit ferroptosis after SCI. A rat SCI model was constructed, and the recovery of motor function was observed after treatment with UAMC-3203. ELISA was employed to assess the impact of UAMC-3203 on inflammation-related factors, while immunofluorescence was utilized to investigate the influence of UAMC-3203 on neuronal count as well as the activation of astrocytes and microglia/macrophages. Malondialdehyde (MDA) were detected to reflect the level of oxidation products. Western blot analysis was used to measure the level of ferroptosis markers and the expression of NRF2/HO-1. Our findings demonstrate that UAMC-3203 inhibits the production of reactive oxygen species (ROS) and lipid peroxides, preventing ferroptosis and reducing neuronal degeneration. Additionally, UAMC-3203 suppresses astrocyte proliferation and microglia/macrophage activation, as well as the release of ferroptosis-related inflammatory factors. These combined effects contribute to the preservation of spinal cord tissue and the facilitation of motor function recovery. UAMC-3203 maybe inhibit ferroptosis after SCI to promote functional recovery.
Asunto(s)
Ferroptosis , Factor 2 Relacionado con NF-E2 , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Ferroptosis/efectos de los fármacos , Ratas , Recuperación de la Función/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Masculino , Ciclohexilaminas/farmacología , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/farmacología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)RESUMEN
Osteoarthritis (OA) is a common joint disease associated with the aging of the population, and it reduces the quality of life of patients. It is characterized by the destruction of articular cartilage and the secretion of inflammatory cytokines. Owing to the unclear pathogenesis of OA, current treatment methods have significant limitations. Oxidative stress has been revealed to play an important role in the development of OA. Our experiments indicated that the levels of GSH decreased and the level of MDA increased in chondrocytes, which induced ferroptosis in chondrocytes in OA. We also revealed that ferroptosis was the main mechanism of cartilage destruction caused by the addition of the ferroptosis activator erastin and the ferroptosis inhibitor ferrostatin-1. NOX1 is the main modulator of oxidative stress by increasing the generation of reactive oxidative species (ROS). We suppressed the expression of NOX1 in chondrocytes through cell transfection. The expression of collagen II and MMP13, and the secretion of IL-1ß and TNF-α were reversed. An increase in the mitochondrial membrane potential and a decrease in the level of intracellular ROS indicate an improvement in oxidative damage. Additionally, we determined the effect of the Nrf2/HO-1 pathway on NOX1-mediated chondrocyte injury. We found that NOX1 inhibited the expression of Nrf2/HO-1, but the activation of Nrf2 improved the oxidative damage to chondrocytes in vivo and vitro. This study revealed that NOX1-mediated oxidative stress induces chondrocyte ferroptosis by inhibiting the Nrf2/HO-1 pathway. Our findings contribute to revealing the pathogenesis of OA, providing targets for drug design and optimizing the clinical treatment of OA.
Asunto(s)
Condrocitos , Ferroptosis , Hemo-Oxigenasa 1 , NADPH Oxidasa 1 , Factor 2 Relacionado con NF-E2 , Osteoartritis , Estrés Oxidativo , Especies Reactivas de Oxígeno , Transducción de Señal , Condrocitos/metabolismo , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ratones , Osteoartritis/metabolismo , Osteoartritis/patología , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Masculino , Cartílago Articular/metabolismo , Cartílago Articular/patología , Humanos , Proteínas de la Membrana , FenilendiaminasRESUMEN
Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways.
Asunto(s)
Corteza Cerebral , Ferroptosis , Hipotermia , Neuronas , Ferroptosis/genética , Animales , Hipotermia/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Neuronas/metabolismo , Hierro/metabolismo , Peroxidación de Lípido , Masculino , Ratas , Fenilendiaminas/farmacología , CiclohexilaminasRESUMEN
The oil used to fry food is often used multiple times to reduce costs. However, when foods containing sweeteners are processed in this way, the sweeteners may produce substances harmful to the body as a result of repeated frying at high temperatures. This article investigated the stability of sodium cyclamate during deep-frying by HPLC using a pre-column derivatization method. The results showed that cyclohexylamine was a decomposition product of a standard sample of sodium cyclamate when deep-fried at 200°C for 25 min. A pre-column derivatization/HPLC method was established to determine cyclohexylamine, a decomposition product of sodium cyclamate, under these conditions. Dansyl chloride was used as the derivatization reagent, the derivatization temperature was 60°C, the derivatization time was 20 min, the pH of sodium bicarbonate buffer solution was 11, and the concentration of dansyl chloride was 2.0 mg/mL. Detection was carried out by using an Agilent 1260 high-performance liquid chromatograph coupled with an ultraviolet detector. The ultraviolet detection wavelength was 254 nm, and the mobile phase was acetonitrile-1.0 g/L potassium dihydrogen phosphate solution at a flow rate of 1.0 mL/min. Gradient elution was adopted, the peak of the cyclohexylamine derivative appeared at a retention time of 17.75 min, and the peak area response value was the largest. The methodological validation analysis showed that the detection limit of cyclohexylamine was 0.5 mg/kg, the quantification limit was 2.0 mg/kg, and the spiked recoveries were in the range of 99.37-110.16%. The relative standard deviations (RSDs) were in the range of 0.17-1.26%. Four samples were tested and analyzed by the established method, and cyclohexylamine was not detected.
Asunto(s)
Ciclamatos , Cromatografía Líquida de Alta Presión/métodos , Ciclamatos/análisis , Ciclamatos/química , Calor , Ciclohexilaminas/química , Ciclohexilaminas/análisisRESUMEN
Background: Myocardial infarction (MI) is characterized by irreversible cardiomyocyte death resulting from an inadequate supply of oxygenated blood to the myocardium. Recent studies have indicated that ferroptosis, a form of regulated cell death, exacerbates myocardial injury during MI. Concurrently, the upregulation of CD47 on the surface of damaged myocardium following MI impairs the clearance of dead cells by macrophages, thereby hindering efferocytosis. In this context, simultaneously inhibiting ferroptosis and enhancing efferocytosis may represent a promising strategy to mitigate myocardial damage post-MI. Methods: In this study, we engineered platelet membrane-coated hollow mesoporous silicon nanoparticles (HMSN) to serve as a drug delivery system, encapsulating ferroptosis inhibitor, Ferrostatin-1, along with an anti-CD47 antibody. We aimed to assess the potential of these nanoparticles (designated as Fer-aCD47@PHMSN) to specifically target the site of MI and evaluate their efficacy in reducing cardiomyocyte death and inflammation. Results: The platelet membrane coating on the nanoparticles significantly enhanced their ability to successfully target the site of myocardial infarction (MI). Our findings demonstrate that treatment with Fer-aCD47@PHMSN resulted in a 38.5% reduction in cardiomyocyte ferroptosis under hypoxia, indicated by decreased lipid peroxidation and increased in vitro. Additionally, Fer-aCD47@PHMSN improved cardiomyocyte efferocytosis by approximately 15% in vitro. In MI mice treated with Fer-aCD47@PHMSN, we observed a substantial reduction in cardiomyocyte death (nearly 30%), decreased inflammation, and significant improvement in cardiac function. Conclusion: Our results demonstrated that the cooperation between the two agents induced anti-ferroptosis effects and enhanced dead cardiomyocyte clearance by macrophage as well as anti-inflammation effects. Thus, our nanoparticle Fer-aCD47@PHMSN provides a new therapeutic strategy for targeted therapy of MI.
Asunto(s)
Antígeno CD47 , Ferroptosis , Infarto del Miocardio , Miocitos Cardíacos , Nanopartículas , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Ferroptosis/efectos de los fármacos , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nanopartículas/química , Ratones , Antígeno CD47/metabolismo , Fagocitosis/efectos de los fármacos , Ciclohexilaminas/farmacología , Ciclohexilaminas/química , Masculino , Fenilendiaminas/farmacología , Fenilendiaminas/química , Macrófagos/efectos de los fármacos , Plaquetas/efectos de los fármacos , Ratones Endogámicos C57BL , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Portadores de Fármacos/química , Humanos , EferocitosisRESUMEN
OBJECTIVE: To investigate the effects of Xiongcan Yishen Formula (XYF) on ferroptosis in mouse TM3 Leydig cells after oxidative stress injury (OSI) induced by H2O2.ãMethods: An oxidative stress injury model was established in mouse TM3 Leydig cells using H2O2 induction. The modeled TM3 cells were randomly divided into OSI group, XYF group, the ferroptosis inhibitor Ferrostatin-1 (F-1) group, and F-1+XYF group, which were respectively intervened with blank serum, 20% drug-containing serum, 2µmol/L F-1, and 2µmol/L F-1+ 20% drug-containing serum. A control group (normal TM3 cells + blank serum) was also set up. The morphology of cells in each group was observed, and the levels of testosterone, superoxide dismutase (SOD), reactive oxygen species (ROS), malondialdehyde (MDA), ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), glutathione peroxidase 4 (GPX4), fatty acid CoA ligase 4 (FACL4), total iron ions, and ferrous ions were detected. RESULTS: Compared with the model group, the control group showed significantly decreased expression of ROS, MDA, FACL4, total iron, and ferrous ions (P<0.05), and significantly increased levels of testosterone, SOD, GSH, FTH1, SLC7A11, and GPX4 (P<0.05). The male silkworm kidney-tonifying formula group significantly promoted testosterone secretion by TM3 cells and upregulated the expression of FTH1, SLC7A11, GPX4, GSH, and SOD in TM3 cells (P<0.05), while significantly downregulating ROS, MDA, FACL4, total iron ions, and ferrous ions (P<0.05). CONCLUSION: Following H2O2 exposure, oxidative stress can induce ferroptosis in mouse TM3 Leydig cells. XYF can antagonize OSI and ferroptosis in TM3 cells by activating the SLC7A11/GSH/GPX4 axis, which may underlie the mechanism of XYF in the treatment of male late-onset hypogonadism.
Asunto(s)
Medicamentos Herbarios Chinos , Ferroptosis , Células Intersticiales del Testículo , Estrés Oxidativo , Animales , Ferroptosis/efectos de los fármacos , Masculino , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno , Superóxido Dismutasa/metabolismo , Malondialdehído/metabolismo , Testosterona , Glutatión/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Ciclohexilaminas , FenilendiaminasRESUMEN
Atherosclerosis is a leading cause of cardiovascular diseases (CVDs), often resulting in major adverse cardiovascular events (MACEs), such as myocardial infarction and stroke due to the rupture or erosion of vulnerable plaques. Ferroptosis, an iron-dependent form of cell death, has been implicated in the development of atherosclerosis. Despite its involvement in CVDs, the specific role of ferroptosis in atherosclerotic plaque stability remains unclear. In this study, we confirmed the presence of ferroptosis in unstable atherosclerotic plaques and demonstrated that the ferroptosis inhibitor ferrostatin-1 (Fer-1) stabilizes atherosclerotic plaques in apolipoprotein E knockout (Apoe-/-) mice. Using bioinformatic analysis combining RNA sequencing (RNA-seq) with single-cell RNA sequencing (scRNA-seq), we identified Yes-associated protein 1 (YAP1) as a potential key regulator of ferroptosis in vascular smooth muscle cells (VSMCs) of unstable plaques. In vitro, we found that YAP1 protects against oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in VSMCs. Mechanistically, YAP1 exerts its anti-ferroptosis effects by regulating the expression of glutaminase 1 (GLS1) to promote the synthesis of glutamate (Glu) and glutathione (GSH). These findings establish a novel mechanism where the inhibition of ferroptosis promotes the stabilization of atherosclerotic plaques through the YAP1/GLS1 axis, attenuating VSMC ferroptosis. Thus, targeting the YAP1/GLS1 axis to suppress VSMC ferroptosis may represent a novel strategy for preventing and treating unstable atherosclerotic plaques.
Asunto(s)
Ferroptosis , Músculo Liso Vascular , Placa Aterosclerótica , Proteínas Señalizadoras YAP , Animales , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Proteínas Señalizadoras YAP/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Masculino , Ratones Endogámicos C57BL , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Ratones Noqueados , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Fenilendiaminas/farmacología , Ciclohexilaminas/farmacología , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genéticaRESUMEN
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
Asunto(s)
Autofagia , Modelos Animales de Enfermedad , Ferroptosis , Peroxidación de Lípido , Pancreatitis , Ratas Sprague-Dawley , Animales , Pancreatitis/metabolismo , Pancreatitis/patología , Ratas , Masculino , Adenina/análogos & derivados , Adenina/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ácido Taurocólico , Ciclohexilaminas/farmacología , Páncreas/patología , Páncreas/metabolismo , Fenilendiaminas/farmacología , Malondialdehído/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedad Aguda , Glutatión/metabolismo , Hierro/metabolismoRESUMEN
Liver injury caused by acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. The mode of APAP-induced cell death has been controversially discussed with ferroptosis emerging as a more recent hypothesis. Ferroptosis is characterized by ferrous iron-catalyzed lipid peroxidation (LPO) causing cell death, which can be prevented by the lipophilic antioxidants ferrostatin-1 and UAMC-3203. To assess the efficacy of these ferroptosis inhibitors, we used two murine models of APAP hepatotoxicity, APAP overdose alone or in combination with FeSO4 in fasted male C57BL/6J mice. APAP triggered severe liver injury in the absence of LPO measured as hepatic malondialdehyde (MDA) levels. In contrast, ferrous iron co-treatment aggravated APAP-induced liver injury and caused extensive LPO. Standard doses of ferrostatin-1 did not affect MDA levels or the injury in both models. In contrast, UAMC-3203 partially protected in both models and reduced LPO in the presence of ferrous iron. However, UAMC-3203 attenuated the translocation of phospho-JNK through downregulation of the mitochondrial anchor protein Sab resulting in reduced mitochondrial dysfunction and liver injury. Thus, APAP toxicity does not involve ferroptosis under normal conditions. The lack of effects of ferroptosis inhibitors in the pathophysiology indicates that ferroptosis signaling pathways are not relevant therapeutic targets.
Asunto(s)
Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Modelos Animales de Enfermedad , Ferroptosis , Ratones Endogámicos C57BL , Animales , Acetaminofén/efectos adversos , Acetaminofén/toxicidad , Ferroptosis/efectos de los fármacos , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ratones , Ciclohexilaminas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Fenilendiaminas/farmacologíaRESUMEN
BACKGROUND: Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. RESULTS: Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. CONCLUSION: Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.
Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Antibacterianos , Ferroptosis , Gentamicinas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Transducción de Señal , Proteína p53 Supresora de Tumor , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Gentamicinas/toxicidad , Gentamicinas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Sistema de Transporte de Aminoácidos y+/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/toxicidad , Línea Celular , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Glutatión Peroxidasa/metabolismo , FenilendiaminasRESUMEN
Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6â¯J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.
Asunto(s)
Ferroptosis , Guanidinas , Peroxidación de Lípido , Ratones Endogámicos C57BL , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Fibrosis Pulmonar , Animales , Ferroptosis/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Ratones , Peroxidación de Lípido/efectos de los fármacos , Línea Celular , Guanidinas/toxicidad , Guanidinas/farmacología , Masculino , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patología , Ciclohexilaminas/farmacología , Fenilendiaminas , Quinoxalinas , Compuestos de EspiroRESUMEN
Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.
Asunto(s)
Lesión Pulmonar Aguda , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Coenzima A Ligasas , Ferroptosis , Inflamación , Macrófagos , Animales , Masculino , Ratones , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Ciclohexilaminas , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Lipopolisacáridos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones Endogámicos C57BL , Fenilendiaminas/farmacología , Células RAW 264.7RESUMEN
Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.
Asunto(s)
Modelos Animales de Enfermedad , Ferroptosis , Sobrecarga de Hierro , Ratones Endogámicos C57BL , Miocitos Cardíacos , Dióxido de Silicio , Silicosis , Animales , Ferroptosis/efectos de los fármacos , Masculino , Ratones , Sobrecarga de Hierro/metabolismo , Dióxido de Silicio/toxicidad , Silicosis/metabolismo , Silicosis/tratamiento farmacológico , Silicosis/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Deferoxamina/farmacología , Fenilendiaminas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Hierro/metabolismo , Ciclohexilaminas/farmacologíaRESUMEN
The physiological parameters such as growth, Chl a content, and photosynthetic performance of the experimental cyanobacterium Anabaenopsis circularis HKAR-22 were estimated to evaluate the cumulative effects of photosynthetically active radiation (PAR) and ultraviolet (UV) radiation. Maximum induction of UV-screening molecules, MAAs, was observed under the treatment condition of PAR + UV-A + UV-B (PAB) radiations. UV/VIS absorption spectroscopy and HPLC-PDA detection primarily confirmed the presence of MAA-shinorine (SN) having absorption maxima (λmax) at 332.3 nm and retention time (RT) of 1.47 min. For further validation of the presence of SN, HRMS, FTIR and NMR were utilized. UV-stress elevated the in vivo ROS scavenging and in vitro enzymatic antioxidant capabilities. SN exhibited substantial and concentration-dependent antioxidant capabilities which was determined utilizing 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate (ABTS), ferric reducing power (FRAP) and superoxide radical scavenging assay (SRSA). The density functional theory (DFT) method using B3LYP energy model and 6-311G++(d,p) basis set was implied to perform the quantum chemical calculation to systematically investigate the antioxidant nature of SN. The principal pathways involved in the antioxidant reactions along with the basic molecular descriptors affecting the antioxidant potentials of a compound were also studied. The results favor the potential of SN as an active ingredient to be used in cosmeceutical formulations.
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Antioxidantes , Cianobacterias , Teoría Funcional de la Densidad , Rayos Ultravioleta , Antioxidantes/química , Cianobacterias/química , Cianobacterias/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Ciclohexanonas/química , Fotosíntesis , Especies Reactivas de Oxígeno/metabolismo , Clorofila A/química , Clorofila A/metabolismo , Compuestos de Bifenilo/química , Picratos/antagonistas & inhibidores , Picratos/química , Depuradores de Radicales Libres/química , Ciclohexilaminas , Glicina/análogos & derivados , Ácidos Sulfónicos , BenzotiazolesRESUMEN
BACKGROUND: Levosimendan (Levo) is a drug commonly used to treat heart failure. Recent studies have suggested that Levo may have neuroprotective effects, but it is still unknown how exactly it contributes to hypoxia-induced brain damage. Thus, the aim of this study was to investigate how Levo affects hypoxia-induced brain damage and to clarify any possible underlying mechanisms. METHODS: One group of rats (Levo group) was pretreated with Levo via oral force-feeding for four weeks. Another group (Ferrostatin-1 (Fer-1) group) was pretreated with intraperitoneal injections of Fer-1 for four weeks. A rat model of chronic hypoxia was created by treating rats with 13% O2 for 14 days in a closed hypoxia chamber. For each group (Control, Model, Levo, Fer-1), we evaluated learning and memory capacity and the morphology and structure of neurons in the rats' brain tissue. Other measurements included tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6); malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); Fe2+; apoptosis; cleaved caspase-3, caspase-3; phosphatase and tensin homolog (PTEN), protein kinase B (Akt), phosphorylated Akt (p-Akt); and ferroptosis-related proteins Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). RESULTS: The Model group rats had considerably fewer neurons than the Control group, with loosely arranged cells, and markedly impaired learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Model group were significantly intensified, accompanied by a substantial increase in neuronal apoptosis (p < 0.05). PTEN protein, Fe2+ concentration, and cleaved caspase-3 expression were all significantly upregulated, whereas p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically downregulated (p < 0.05). Both the Levo and Fer-1 groups demonstrated significantly more neurons and closely arranged cells than the Model group, along with a notable improvement in learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Levo and Fer-1 groups were markedly alleviated, and neuronal apoptosis was suppressed (p < 0.05). p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically upregulated, whereas the expression of cleaved caspase-3, PTEN protein, and Fe2+ content was considerably downregulated (p < 0.05). CONCLUSIONS: Levo effectively mitigates brain injury in rats with chronic hypoxia, likely by regulating ferroptosis via the PTEN/Akt signaling pathway.
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Ferroptosis , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Simendán , Animales , Fosfohidrolasa PTEN/metabolismo , Ratas , Ferroptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Simendán/farmacología , Simendán/uso terapéutico , Ratas Sprague-Dawley , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Ciclohexilaminas , FenilendiaminasRESUMEN
Cerebral ischemic stroke is a serious disease with high mortality and disability rates. However, few neuroprotective drugs have been used for ischemic stroke in the clinic. Two main reasons may be responsible for this failure: difficulty in penetrating the blood-brain barrier (BBB) and easily inactivated in the blood circulation. Ferroptosis, a lipid oxidation-related cell death, plays significant roles in cerebral ischemia-reperfusion injury. We utilized RVG29, a peptide derived from Rabies virus glycoprotein, to obtain BBB-targeted lipid nanoparticles (T-LNPs) in order to investigate whether T-LNPs improved the neuroprotective effects of Ferrostatin-1 (Fer1, an inhibitor of ferroptosis) against cerebral ischemic damage. T-LNPs significantly increased BBB penetration following oxygen/glucose deprivation exposure in an in vitro BBB model and enhanced the fluorescence distribution in brain tissues at 6 h post-administration in a cerebral ischemic murine model. Moreover, T-LNPs encapsulated Fer1 (T-LNPs-Fer1) significantly enhanced the inhibitory effects of Fer1 on ferroptosis by maintaining the homeostasis of NADPH oxidase 4 (NOX4) and glutathione peroxidase 4 (GPX4) signals in neuronal cells after cerebral ischemia. T-LNPs-Fer1 significantly suppressed oxidative stress [heme oxygenase-1 expression and malondialdehyde (the product of lipid ROS reaction)] in neurons and alleviated ischemia-induced neuronal cell death, compared to Fer1 alone without encapsulation. Furthermore, T-LNPs-Fer1 significantly reduced cerebral infarction and improved behavior functions compared to Fer1-treated cerebral ischemic mice after 45-min ischemia/24-h reperfusion. These findings showed that the T-LNPs helped Fer1 penetrate the BBB and improved the neuroprotection of Fer1 against cerebral ischemic damage in experimental stroke, providing a feasible translational strategy for the development of clinical drugs for the treatment of ischemic stroke.
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Barrera Hematoencefálica , Ciclohexilaminas , Nanopartículas , Fármacos Neuroprotectores , Fenilendiaminas , Animales , Ratones , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Fármacos Neuroprotectores/farmacología , Nanopartículas/administración & dosificación , Masculino , Ciclohexilaminas/farmacología , Fenilendiaminas/farmacología , Fenilendiaminas/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/patología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Glicoproteínas , Liposomas , Fragmentos de Péptidos , Proteínas ViralesRESUMEN
The toxicity of silica nanoparticles (SiNPs) to lung is known. We previously demonstrated that exposure to SiNPs promoted pulmonary impairments, but the precise pathogenesis remains elucidated. Ferroptosis has now been identified as a unique form of oxidative cell death, but whether it participated in SiNPs-induced lung injury remains unclear. In this work, we established a rat model with sub-chronic inhalation exposure of SiNPs via intratracheal instillation, and conducted histopathological examination, iron detection, and ferroptosis-related lipid peroxidation and protein assays. Moreover, we evaluated the effect of SiNPs on epithelial ferroptosis, possible mechanisms using in vitro-cultured human bronchial epithelial cells (16HBE), and also assessed the ensuing impact on fibroblast activation for fibrogenesis. Consequently, fibrotic lesions occurred in the rat lungs, concomitantly by enhanced lipid peroxidation, iron overload, and ferroptosis. Consistently, the in vitro data showed SiNPs triggered oxidative stress and caused the accumulation of lipid peroxides, resulting in ferroptosis. Importantly, the mechanistic investigation revealed miR-21-5p as a key player in the epithelial ferroptotic process induced by SiNPs via targeting GCLM for GSH depletion. Of note, ferrostatin-1 could greatly suppress ferroptosis and alleviate epithelial injury and ensuing fibroblast activation by SiNPs. In conclusion, our findings first revealed SiNPs triggered epithelial ferroptosis through miR-21-5p/GCLM signaling and thereby promoted fibroblast activation for fibrotic lesions, and highlighted the therapeutic potential of inhibiting ferroptosis against lung impairments upon SiNPs exposure.
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Células Epiteliales , Ferroptosis , Pulmón , MicroARNs , Nanopartículas , Transducción de Señal , Dióxido de Silicio , Ferroptosis/efectos de los fármacos , Animales , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Ratas , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Masculino , Glutamato-Cisteína Ligasa/metabolismo , Glutamato-Cisteína Ligasa/genética , Línea Celular , Ratas Sprague-Dawley , Estrés Oxidativo/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Glutatión/metabolismo , Ciclohexilaminas/farmacología , FenilendiaminasRESUMEN
1,4-cyclohexanedimethylamine (1,4-BAC) is an important monomer for bio-based materials, it finds wide applications in various fields including organic synthesis, medicine, chemical industry, and materials. At present, its synthesis primarily relies on chemical method, which suffer from issues such as expensive metal catalyst, harsh reaction conditions, and safety risks. Therefore, it is necessary to explore greener alternatives for its synthesis. In this study, a two-bacterium three-enzyme cascade conversion pathway was successfully developed to convert 1,4-cyclohexanedicarboxaldehyde to 1,4-cyclohexanedimethylamine. This pathway used Escherichia coli derived aminotransferase (EcTA), Saccharomyces cerevisiae derived glutamate dehydrogenase (ScGlu-DH), and Candida boidinii derived formate dehydrogenase (CbFDH). Through structure-guided protein engineering, a beneficial mutant, EcTAF91Y, was obtained, exhibiting a 2.2-fold increase in specific activity and a 1.9-fold increase in kcat/Km compared to that of the wild type. By constructing recombinant strains and optimizing reaction conditions, it was found that under the optimal conditions, a substrate concentration of 40 g/L could produce (27.4±0.9) g/L of the product, corresponding to a molar conversion rate of 67.5%±2.1%.