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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.
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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 , CarbolinasRESUMEN
Acute lung injury (ALI) is one of the most deadly and prevalent diseases in the intensive care unit. Ferroptosis and mitophagy are pathological mechanisms of ALI. Ferroptosis aggravates ALI, whereas mitophagy regulates ALI. Ferroptosis and mitophagy are both closely related to reactive oxygen species (ROS). Mitophagy can regulate ferroptosis, but the specific relationship between ferroptosis and mitophagy is still unclear. This study summarizes previous research findings on ferroptosis and mitophagy, revealing their involvement in ALI. Examining the functions of mTOR and NLPR3 helps clarify the connection between ferroptosis and mitophagy in ALI, with the goal of establishing a theoretical foundation for potential therapeutic approaches in the future management of ALI.
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Lesión Pulmonar Aguda , Ferroptosis , Mitofagia , Especies Reactivas de Oxígeno , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Ferroptosis/fisiología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Animales , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management. In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.
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Diabetes Mellitus , Ferroptosis , Hierro , Ferroptosis/fisiología , Humanos , Hierro/metabolismo , Animales , Diabetes Mellitus/metabolismo , Complicaciones de la Diabetes/metabolismo , Peroxidación de LípidoRESUMEN
BACKGROUND: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of ß-1,4-galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. METHODS: Recombinant human B4galt1 (rh-B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh-B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5-triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence-labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. RESULTS: We demonstrated that rh-B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood-brain barrier (BBB) for preventing damage. These findings further illustrated that rh-B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh-B4galt1 could increase the levels of TAZ, Nrf2 and HO-1 after I/R. And TAZ-siRNA and ML385 reversed the neuroprotective effects of rh-B4galt1. CONCLUSIONS: The results indicated that rh-B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO-1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.
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Isquemia Encefálica , Ferroptosis , Galactosiltransferasas , Hemo-Oxigenasa 1 , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Galactosiltransferasas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Infarto de la Arteria Cerebral Media , Proteínas de la Membrana , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration, destruction, and excessive ossification of articular cartilage. The prevalence of OA is rising annually, concomitant with the aging global population and increasing rates of obesity. This condition imposes a substantial and escalating burden on individual health, healthcare systems, and broader social and economic frameworks. The etiology of OA is multifaceted and not fully understood. Current research suggests that the death of chondrocytes, encompassing mechanisms such as cellular apoptosis, pyroptosis, autophagy, ferroptosis and cuproptosis, contributes to both the initiation and progression of the disease. These cell death pathways not only diminish the population of chondrocytes but also exacerbate joint damage through the induction of inflammation and other deleterious processes. This paper delineates the morphological characteristics associated with various modes of cell death and summarizes current research results on the molecular mechanisms of different cell death patterns in OA. The objective is to review the advancements in understanding chondrocyte cell death in OA, thereby offering novel insights for potential clinical interventions.
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Muerte Celular , Condrocitos , Progresión de la Enfermedad , Osteoartritis , Condrocitos/patología , Humanos , Osteoartritis/patología , Osteoartritis/terapia , Muerte Celular/fisiología , Apoptosis/fisiología , Cartílago Articular/patología , Autofagia/fisiología , Animales , Piroptosis/fisiología , Ferroptosis/fisiologíaRESUMEN
Xi-Kun Yuan Pin-Shi Ni Zhen-Hao Yan Zhi Yu Zhuang-Zhi Wang Chen-Kai Zhang Fang-Hui Li Xiao-Ming Yu 1Sports Department, Nanjing University of Science and Technology ZiJin College, Nanjing, China, 2School of Sport Sciences, Nanjing Normal University, Nanjing, China, 3Shanghai Seventh People's Hospital, Shanghai, China To investigate the effects of life-long exercise (LLE) on age-related inflammatory cytokines, apoptosis, oxidative stress, ferroptosis markers, and the NRF2/KAEP 1/Klotho pathway in rats. Eight-month-old female Sprague-Dawley rats were divided into four groups: 1) LLE: 18-month LLE training starting at 8 months of age, 2) Old moderate-intensity continuous training (OMICT): 8 months of moderate-intensity continuous training starting at 18 months of age, 3) Adult sedentary (ASED): 8 month-old adult sedentary control group, and 4) Old sedentary (OSED): a 26-month-old sedentary control group. Hematoxylin eosin staining was performed to observe the pathological changes of kidney tissue injury in rats; Masson's staining to observe the deposition of collagen fibers in rat kidney tissues; and western blotting to detect the expression levels of IL-6, IL 1beta, p53, p21, TNF-alpha, GPX4, KAEP 1, NRF2, SLC7A11, and other proteins in kidney tissues. Results: Compared with the ASED group, the OSED group showed significant morphological changes in renal tubules and glomeruli, which were swollen and deformed, with a small number of inflammatory cells infiltrated in the tubules. Compared with the OSED group, the expression levels of inflammation-related proteins such as IL-1beta, IL-6, TNF alpha, and MMP3 were significantly lower in the LLE group. Quantitative immunofluorescence analysis and western blotting revealed that compared with the ASED group, KAEP 1 protein fluorescence intensity and protein expression levels were significantly enhanced, while Klotho and NRF2 protein fluorescence intensity and protein expression levels were reduced in the OSED group. Compared with the OSED group, KAEP 1 protein fluorescence intensity and protein expression levels were reduced in the LLE and OMICT groups. Klotho and KAEP 1 protein expression levels and immunofluorescence intensity were higher in the LLE group than in the OSED group. The expression levels of GPX4 and SLC7A11, two negative marker proteins associated with ferroptosis, were significantly higher in the LLE group than in the OSED group, while the expression of p53 a cellular senescence-associated protein that negatively regulates SLC7A11, and the downstream protein p21 were significantly decreased. LLE may ameliorated aging-induced oxidative stress, inflammatory response, apoptosis, and ferroptosis by regulating Klotho and synergistically activating the NRF2/KAEP 1 pathway. Keywords: Life-long exercise, Moderate intensity continuous training, Aging, Kidney tissue, Ferroptosis.
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Apoptosis , Ferroptosis , Riñón , Proteínas Klotho , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Femenino , Apoptosis/fisiología , Ratas , Ferroptosis/fisiología , Riñón/metabolismo , Riñón/patología , Condicionamiento Físico Animal/fisiología , Envejecimiento/metabolismo , Envejecimiento/patología , Inflamación/metabolismo , Inflamación/patología , Transducción de Señal/fisiología , Glucuronidasa/metabolismo , Biomarcadores/metabolismoRESUMEN
The mechanisms of secondary injury following spinal cord injury are complicated. The role of ferroptosis, which is a newly discovered form of regulated cell death in the neurovascular unit(NVU), is increasingly important. Ferroptosis inhibitors have been shown to improve neurovascular homeostasis and attenuate secondary spinal cord injury(SCI). This review focuses on the mechanisms of ferroptosis in NVU cells and NVU-targeted therapeutic strategies according to the stages of SCI, and analyzes possible future research directions.
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Ferroptosis , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Ferroptosis/fisiología , Ferroptosis/efectos de los fármacos , Humanos , AnimalesRESUMEN
Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.
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Lesiones Traumáticas del Encéfalo , Ferroptosis , Hierro , Necroptosis , Piroptosis , Piroptosis/fisiología , Humanos , Ferroptosis/fisiología , Hierro/metabolismo , Necroptosis/fisiología , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
This editorial discusses a recently published paper in the World Journal of Gastroenterology. Our research focuses on p53's regulatory mechanism for controlling ferroptosis, as well as the intricate connection between ferroptosis and liver diseases. Ferroptosis is a specific form of programmed cell death that is de-pendent on iron and displays unique features in terms of morphology, biology, and genetics, distinguishing it from other forms of cell death. Ferroptosis can affect the liver, which is a crucial organ responsible for iron storage and meta-bolism. Mounting evidence indicates a robust correlation between ferroptosis and the advancement of liver disorders. P53 has a dual effect on ferroptosis through various distinct signaling pathways. However, additional investigations are required to clarify the regulatory function of p53 metabolic targets in this complex association with ferroptosis. In the future, researchers should clarify the mechanisms by which ferroptosis and other forms of programmed cell death contribute to the progression of liver diseases. Identifying and controlling important regulatory factors associated with ferroptosis present a promising therapeutic strategy for liver disorders.
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Ferroptosis , Hierro , Hepatopatías , Hígado , Transducción de Señal , Proteína p53 Supresora de Tumor , Ferroptosis/fisiología , Humanos , Hepatopatías/metabolismo , Hepatopatías/patología , Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Animales , Progresión de la EnfermedadRESUMEN
Ferritinophagy is a regulatory pathway of iron homeostasis. It is a process in which nuclear receptor coactivator 4 (NCOA4) carries ferritin to autophagolysosomes for degradation. After ferritin is degraded by autophagy, iron ions are released, which promotes the labile iron pool (LIP) to drive the Fenton reaction to cause lipid peroxidation. Furthermore, ferroptosis promoted by the accumulation of lipid reactive oxygen species (ROS) induced by ferritinophagy can cause a variety of systemic diseases. In clinical studies, targeting the genes regulating ferritinophagy can prevent and treat such diseases. This article describes the key regulatory factors of ferritinophagy and the mechanism of ferritinophagy involved in ferroptosis. It also reviews the damage of ferritinophagy to the body, providing a theoretical basis for further finding clinical treatment methods.
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Autofagia , Ferritinas , Ferroptosis , Humanos , Ferritinas/metabolismo , Autofagia/fisiología , Ferroptosis/fisiología , Hierro/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Animales , Especies Reactivas de Oxígeno/metabolismo , Homeostasis/fisiología , Peroxidación de Lípido/fisiologíaRESUMEN
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.
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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+/genéticaRESUMEN
Ferroptosis represents a novel mode of programmed cell death characterized by the intracellular accumulation of iron and lipid peroxidation, culminating in oxidative stress and subsequent cell demise. Mounting evidence demonstrates that ferroptosis contributes significantly to the onset and progression of diverse pathological conditions and diseases, including infections, neurodegenerative disorders, tissue ischemia-reperfusion injury, and immune dysregulation. Recent investigations have underscored the pivotal role of ferroptosis in the pathogenesis of rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and asthma. This review provides a comprehensive overview of the current understanding of the regulatory mechanisms governing ferroptosis, particularly its interplay with iron, lipid, and amino acid metabolism. Furthermore, we explore the implications of ferroptosis in autoimmune diseases and deliberate on its potential as a promising therapeutic target for diverse autoimmune disorders.
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Enfermedades Autoinmunes , Ferroptosis , Ferroptosis/fisiología , Humanos , Enfermedades Autoinmunes/inmunología , Animales , Hierro/metabolismo , Peroxidación de Lípido , Estrés OxidativoRESUMEN
BACKGROUD: Bronchopulmonary dysplasia (BPD) is one of the most important complications plaguing neonates and can lead to a variety of sequelae. the ability of the HIF-1α/VEGF signaling pathway to promote angiogenesis has an important role in neonatal lung development. METHOD: Newborn rats were exposed to 85% oxygen. The effects of hyperoxia exposure on Pleomorphic Adenoma Gene like-2 (PLAGL2) and the HIF-1α/VEGF pathway in rats lung tissue were assessed through immunofluorescence and Western Blot analysis. In cell experiments, PLAGL2 was upregulated, and the effects of hyperoxia and PLAGL2 on cell viability were evaluated using scratch assays, CCK-8 assays, and EDU staining. The role of upregulated PLAGL2 in the HIF-1α/VEGF pathway was determined by Western Blot and RT-PCR. Apoptosis and ferroptosis effects were determined through flow cytometry and viability assays. RESULTS: Compared with the control group, the expression levels of PLAGL2, HIF-1α, VEGF, and SPC in lung tissues after 3, 7, and 14 days of hyperoxia exposure were all decreased. Furthermore, hyperoxia also inhibited the proliferation and motility of type II alveolar epithelial cells (AECII) and induced apoptosis in AECII. Upregulation of PLAGL2 restored the proliferation and motility of AECII and suppressed cell apoptosis and ferroptosis, while the HIF-1α/VEGF signaling pathway was also revived. CONCLUSIONS: We confirmed the positive role of PLAGL2 and HIF-1α/VEGF signaling pathway in promoting BPD in hyperoxia conditions, and provided a promising therapeutic targets.
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Células Epiteliales Alveolares , Animales Recién Nacidos , Apoptosis , Ferroptosis , Hiperoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Animales , Ratas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Células Epiteliales Alveolares/metabolismo , Ferroptosis/fisiología , Hiperoxia/metabolismo , Ratas Sprague-Dawley , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación hacia Abajo , Humanos , Proliferación CelularRESUMEN
Invariant NKT (iNKT) cells are a group of innate-like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared with CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of phospholipid hydroperoxidase glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell-specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFN-γ-producing NKT1 subset. RNA-sequencing analysis revealed that IFN-γ signaling, cell cycle regulation, and mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial reactive oxygen species in Gpx4 knockout iNKT cells. Ferroptosis inhibitors, iron chelators, vitamin E, and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Last, vitamin E rescues iNKT cell population in Gpx4 knockout mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
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Ferroptosis , Homeostasis , Peroxidación de Lípido , Ratones Noqueados , Células T Asesinas Naturales , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ferroptosis/inmunología , Ferroptosis/fisiología , Animales , Peroxidación de Lípido/inmunología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratones , Homeostasis/inmunología , Humanos , Células T Asesinas Naturales/inmunología , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Masculino , Femenino , Mitocondrias/metabolismo , Interferón gamma/metabolismoRESUMEN
Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant widely utilized in industrial manufacturing and daily life, leading to significant environmental accumulation and various public health issues. This study aims to characterize spliceosome-associated protein 130 (SAP130) as a key mediator of crosstalk between hepatocytes and macrophages, elucidating its role in PFOS-induced liver inflammation. The data demonstrate that PFOS exposure induces ferroptosis in mouse liver and AML12 cells. During ferroptosis, SAP130 is released from injured hepatocytes into the microenvironment, binding to macrophage-inducible C-type lectin (Mincle) and activating the Mincle/Syk signaling pathway in macrophages, ultimately promoting M1 polarization and exacerbating liver injury. Treatment with the ferroptosis inhibitor Ferrostatin-1 reduces SAP130 release, inhibits Mincle/Syk signaling activation, and mitigates inflammatory response. Furthermore, siSAP130 suppresses the activation of the Mincle signaling pathway and M1 polarization in BMDM cells. Conversely, treatment with the ferroptosis agonist Erastin enhances paracrine secretion of SAP130 and exacerbates inflammation. These findings emphasize the significance of hepatocyte-macrophage crosstalk as a critical pathway for PFOS-induced liver injury in mice while highlighting SAP130 as a pivotal regulator of ferroptosis and inflammation, thereby elucidating the potential mechanism of PFOS-induced liver injury.
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Ácidos Alcanesulfónicos , Ferroptosis , Fluorocarburos , Hepatocitos , Macrófagos , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Animales , Fluorocarburos/toxicidad , Ratones , Hepatocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ácidos Alcanesulfónicos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Contaminantes Ambientales/toxicidad , Transducción de Señal/efectos de los fármacosRESUMEN
Polycystic ovarian syndrome (PCOS) is a common heterogeneous reproductive endocrine metabolic disorder in women of reproductive age characterized by clinical and biochemical hyperandrogenemia, ovulation disorders, and polycystic ovarian morphology. Ferroptosis is a novel type of cell death driven by iron accumulation and lipid peroxidation. Ferroptosis plays a role in maintaining redox balance, iron metabolism, lipid metabolism, amino acid metabolism, mitochondrial activity, and many other signaling pathways linked to diseases. Iron overload is closely related to insulin resistance, decreased glucose tolerance, and the occurrence of diabetes mellitus. There is limited research on the role of ferroptosis in PCOS. Patients with PCOS have elevated levels of ferritin and increased reactive oxygen species in ovarian GCs. Studying ferroptosis in PCOS patients is highly important for achieving personalized treatment. This article reviews the progress of research on ferroptosis in PCOS, introduces the potential connections between iron metabolism abnormalities and oxidative stress-mediated PCOS, and provides a theoretical basis for diagnosing and treating PCOS.
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Ferroptosis , Hierro , Estrés Oxidativo , Síndrome del Ovario Poliquístico , Humanos , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Ferroptosis/fisiología , Femenino , Hierro/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Resistencia a la Insulina/fisiología , Animales , Peroxidación de LípidoRESUMEN
Porcine reproductive and respiratory syndrome virus (PRRSV) is a severe disease with substantial economic consequences for the swine industry. The DEAD-box helicase 3 (DDX3X) is an RNA helicase that plays a crucial role in regulating RNA metabolism, immunological response, and even RNA virus infection. However, it is unclear whether it contributes to PRRSV infection. Recent studies have found that the expression of DDX3X considerably increases in Marc-145 cells when infected with live PRRSV strains Ch-1R and SD16; however, it was observed that inactivated viruses did not lead to any changes. By using the RK-33 inhibitor or DDX3X-specific siRNAs to reduce DDX3X expression, there was a significant decrease in the production of PRRSV progenies. In contrast, the overexpression of DDX3X in host cells substantially increased the proliferation of PRRSV. A combination of transcriptomics and metabolomics investigations revealed that in PRRSV-infected cells, DDX3X gene silencing severely affected biological processes such as ferroptosis, the FoxO signalling pathway, and glutathione metabolism. The subsequent transmission electron microscopy (TEM) imaging displayed the typical ferroptosis features in PRRSV-infected cells, such as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and cytoplasmic membrane rupture. Conversely, the mitochondrial morphology was unchanged in DDX3X-inhibited cells. Furthermore, silencing of the DDX3X gene changed the expression of ferroptosis-related genes and inhibited the virus proliferation, while the drug-induced ferroptosis inversely promoted PRRSV replication. In summary, these results present an updated perspective of how PRRSV infection uses DDX3X for self-replication, potentially leading to ferroptosis via various mechanisms that promote PRRSV replication.
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ARN Helicasas DEAD-box , Ferroptosis , Virus del Síndrome Respiratorio y Reproductivo Porcino , Replicación Viral , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Animales , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Ferroptosis/fisiología , Porcinos , Síndrome Respiratorio y de la Reproducción Porcina/virología , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Línea CelularRESUMEN
Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.
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Ferroptosis , Hierro , Enfermedades Neurodegenerativas , Ferroptosis/fisiología , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Hierro/metabolismo , Animales , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
The newly identified estrogen receptor, G protein-coupled receptor 30 (GPR30), is prevalent in the brain and has been shown to provide significant neuroprotection. Recent studies have linked ferroptosis, a newly characterized form of programmed cell death, closely with cerebral ischemia-reperfusion injury (CIRI), highlighting it as a major contributing factor. Consequently, our research aimed to explore the potential of GPR30 targeting in controlling neuronal ferroptosis and lessening CIRI impacts. Results indicated that GPR30 activation not only improved neurological outcomes and decreased infarct size in a mouse model but also lessened iron accumulation and malondialdehyde formation post-middle cerebral artery occlusion (MCAO). This protective effect extended to increased levels of Nrf2 and GPX4 proteins. Similar protective results were replicated in PC12 cells subjected to Oxygen Glucose Deprivation and Reoxygenation (OGD/R) using the GPR30-specific agonist G1. Importantly, inhibition of Nrf2 with ML385 curtailed the neuroprotective effects of GPR30 activation, suggesting that GPR30 mitigates CIRI primarily through inhibition of neuronal ferroptosis via upregulation of Nrf2 and GPX4.
Asunto(s)
Ferroptosis , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Daño por Reperfusión , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Transducción de Señal/efectos de los fármacos , Ratones , Células PC12 , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Masculino , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Modelos Animales de EnfermedadRESUMEN
Intracerebral hemorrhage (ICH) is a severe hemorrhagic stroke and induces severe secondary neurological injury. However, its pathogenesis remains to be explored. The present work investigates the role of glutathione S-transferase omega 2 (GSTO2) in ICH and the underlying mechanism. Human neuroblastoma cells (SK-N-SH) were stimulated using hemin to mimic ICH-like injury. Protein expression levels of GSTO2 and glutathione peroxidase 4 (GPX4) were detected by western blot analysis assay. Cell viability was assessed by cell counting kit-8 assay. Cell proliferation was investigated by 5-ethynyl-2'-deoxyuridine assay. Cell apoptosis was analyzed by flow cytometry. Interleukin-6 and tumor necrosis factor-α levels were quantified by enzyme-linked immunosorbent assays. Fe2+ colorimetric assay kit was used to detect Fe2+ level. A cellular reactive oxygen species (ROS) assay kit was used to detect ROS levels. Malondialdehyde (MDA) level was assessed using the MDA content assay kit. GSH level was quantified using the GSH assay kit. Co-immunoprecipitation assay was performed to identify the association between GSTO2 and GPX4. Hemin stimulation suppressed SK-N-SH cell proliferation and promoted cell apoptosis, cell inflammation, ferroptosis, and oxidative stress. GSTO2 expression was downregulated in hemin-treated SK-N-SH cells in comparison with the control group. In addition, ectopic GSTO2 expression counteracted hemin-induced inhibitory effect on cell proliferation and promoting effects on cell apoptosis, inflammation, ferroptosis, and oxidative stress. Moreover, GSTO2 was associated with GPX4 in SK-N-SH cells. GPX4 silencing attenuated GSTO2 overexpression-induced effects on hemin-stimulated SK-N-SH cell injury. GSTO2 ameliorated SK-N-SH cell apoptosis, inflammation, ferroptosis, and oxidative stress by upregulating GPX4 expression in ICH, providing a therapeutic strategy for ICH.