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1.
Ecotoxicol Environ Saf ; 281: 116680, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38964057

RESUMO

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/6 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.


Assuntos
Ferroptose , Guanidinas , Peroxidação de Lipídeos , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fibrose Pulmonar , Animais , Ferroptose/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Camundongos , Peroxidação de Lipídeos/efeitos dos fármacos , Linhagem Celular , Guanidinas/toxicidade , Guanidinas/farmacologia , Masculino , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Cicloexilaminas/farmacologia , Fenilenodiaminas , Quinoxalinas , Compostos de Espiro
2.
Cell Death Dis ; 15(7): 481, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965216

RESUMO

Autoimmune diseases commonly affect various systems, but their etiology and pathogenesis remain unclear. Currently, increasing research has highlighted the role of ferroptosis in immune regulation, with immune cells being a crucial component of the body's immune system. This review provides an overview and discusses the relationship between ferroptosis, programmed cell death in immune cells, and autoimmune diseases. Additionally, it summarizes the role of various key targets of ferroptosis, such as GPX4 and TFR, in immune cell immune responses. Furthermore, the release of multiple molecules, including damage-associated molecular patterns (DAMPs), following cell death by ferroptosis, is examined, as these molecules further influence the differentiation and function of immune cells, thereby affecting the occurrence and progression of autoimmune diseases. Moreover, immune cells secrete immune factors or their metabolites, which also impact the occurrence of ferroptosis in target organs and tissues involved in autoimmune diseases. Iron chelators, chloroquine and its derivatives, antioxidants, chloroquine derivatives, and calreticulin have been demonstrated to be effective in animal studies for certain autoimmune diseases, exerting anti-inflammatory and immunomodulatory effects. Finally, a brief summary and future perspectives on the research of autoimmune diseases are provided, aiming to guide disease treatment strategies.


Assuntos
Doenças Autoimunes , Ferroptose , Ferro , Humanos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Ferro/metabolismo , Animais , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia
3.
Sci Rep ; 14(1): 15107, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956066

RESUMO

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos , Ferroptose , Flavonoides , Espécies Reativas de Oxigênio , Ferroptose/efeitos dos fármacos , Animais , Flavonoides/farmacologia , Ratos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Linhagem Celular Tumoral , Ferro/metabolismo , alfa-Sinucleína/metabolismo , Ratos Sprague-Dawley , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo
4.
Cell Death Dis ; 15(7): 474, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38956060

RESUMO

Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.


Assuntos
Neoplasias Colorretais , Ferroptose , Lipogênese , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1 , Serina-Treonina Quinases TOR , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Camundongos , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Linhagem Celular Tumoral , Mutação/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
5.
Sci Rep ; 14(1): 15246, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956068

RESUMO

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.


Assuntos
Proteínas 14-3-3 , Ferroptose , Traumatismo por Reperfusão Miocárdica , PPAR alfa , Ferroptose/efeitos dos fármacos , Animais , PPAR alfa/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas 14-3-3/metabolismo , Camundongos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Linhagem Celular , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Camundongos Endogâmicos C57BL , Ratos , Modelos Animais de Doenças
6.
Int J Mol Med ; 54(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38994772

RESUMO

It is considered that the etiology of endometriosis is retrograde menstruation of endometrial tissue. Although shed endometrial cells are constantly exposed to a challenging environment with iron overload, oxidative stress and hypoxia, a few cells are able to survive and continue to proliferate and invade. Ferroptosis, an iron­dependent form of non­apoptotic cell death, is known to play a major role in the development and course of endometriosis. However, few papers have concentrated on the dynamic interaction between autophagy and ferroptosis throughout the progression of diseases. The present review summarized the current understanding of the mechanisms underlying autophagy and ferroptosis in endometriosis and discuss their role in disease development and progression. For the present narrative review electronic databases including PubMed and Google Scholar were searched for literature published up to the October 31, 2023. Autophagy and ferroptosis may be activated at early stages in endometriosis development. On the other hand, excessive activation of intrinsic pathways (e.g., estrogen and mechanistic target of rapamycin) may promote disease progression through autophagy inhibition. Furthermore, suppression of ferroptosis may cause further progression of endometriotic lesions. In conclusion, the autophagy and ferroptosis pathways may play a dual role in disease initiation and progression. The present review discussed the temporal transition of non­apoptotic cell death regulation during disease progression from retrograde endometrium to early lesions to established lesions.


Assuntos
Autofagia , Endometriose , Ferroptose , Humanos , Endometriose/metabolismo , Endometriose/patologia , Autofagia/fisiologia , Feminino , Animais , Cistos/patologia , Cistos/metabolismo , Endométrio/metabolismo , Endométrio/patologia
7.
Theranostics ; 14(10): 4090-4106, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994016

RESUMO

Purpose: Due to intrinsic defensive response, ferroptosis-activating targeted therapy fails to achieve satisfactory clinical benefits. Though p62-Keap1-Nrf2 axis is activated to form a negative feedback loop during ferroptosis induction, how p62 is activated remains largely unknown. Methods: MTS assay was applied to measure cell growth. Lipid ROS was detected with C11-BODIPY reagent by flow cytometer. Quantitative real-time PCR (qPCR) and western blotting were performed to determine mRNA and protein level. Immunofluorescence (IF) was performed to examine the distribution of proteins. Fluorescence recovery after photobleaching (FRAP) was adopted to evaluate p62 phase separation. Immunoprecipitation (IP), co-IP and Proximal ligation assay (PLA) were performed to detected protein posttranslational modifications and protein-protein interactions. Tumor xenograft model was employed to inspect in vivo growth of pancreatic cancer cells. Results: Upon ferroptosis induction, Nuclear Factor E2 Related Factor 2 (Nrf2) protein and its downstream genes such as HMOX1 and NQO1 were upregulated. Knockdown of p62 significantly reversed Nrf2 upregulation and Keap1 decrease after ferroptosis induction. Knockdown of either p62 or Nrf2 remarkably sensitized ferroptosis induction. Due to augmented p62 phase separation, formation of p62 bodies were increased to recruit Keap1 after ferroptosis induction. Protein arginine methyltransferase 6 (PRMT6) mediated asymmetric dimethylarginine (ADMA) of p62 to increase its oligomerization, promoting p62 phase separation and p62 body formation. Knockdown of p62 or PRMT6 notably sensitized pancreatic cancer cells to ferroptosis both in vitro and in vivo through suppressing Nrf2 signaling. Conclusion: During ferroptosis induction, PRMT6 mediated p62 ADMA to promote its phase separation, sequestering Keap1 to activate Nrf2 signaling and inhibit ferroptosis. Therefore, targeting PRMT6-mediated p62 ADMA could be a new option to sensitize ferroptosis for cancer treatment.


Assuntos
Arginina , Ferroptose , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Humanos , Animais , Arginina/metabolismo , Arginina/análogos & derivados , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Linhagem Celular Tumoral , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Retroalimentação Fisiológica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Camundongos Nus , Transdução de Sinais , Separação de Fases , Proteínas de Ligação a RNA
8.
Front Immunol ; 15: 1440309, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994366

RESUMO

Ferroptosis, a new type of programmed cell death proposed in recent years, is characterized mainly by reactive oxygen species and iron-mediated lipid peroxidation and differs from programmed cell death, such as apoptosis, necrosis, and autophagy. Ferroptosis is associated with a variety of physiological and pathophysiological processes. Recent studies have shown that ferroptosis can aggravate or reduce the occurrence and development of diseases by targeting metabolic pathways and signaling pathways in tumors, ischemic organ damage, and other degenerative diseases related to lipid peroxidation. Increasing evidence suggests that ferroptosis is closely linked to the onset and progression of various ophthalmic conditions, including corneal injury, glaucoma, age-related macular degeneration, diabetic retinopathy, retinal detachment, and retinoblastoma. Our review of the current research on ferroptosis in ophthalmic diseases reveals significant advancements in our understanding of the pathogenesis, aetiology, and treatment of these conditions.


Assuntos
Oftalmopatias , Ferroptose , Humanos , Oftalmopatias/metabolismo , Oftalmopatias/patologia , Animais , Espécies Reativas de Oxigênio/metabolismo , Peroxidação de Lipídeos , Transdução de Sinais , Morte Celular , Ferro/metabolismo
9.
BMC Cardiovasc Disord ; 24(1): 351, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987672

RESUMO

Diabetic cardiomyopathy (DCM) is a chronic disease caused by diabetes mellitus, which is recognized as a worldwide challenging disease. This study aimed to investigate the role and the potential mechanism of knocking down the NACHT-, LRR- and PYD domains-containing protein 3 (NLRP3), an inflammasome associated with onset and progression of various diseases, on high glucose or diabetes -induced cardiac cells pyroptosis and ferroptosis, two regulated non-necrosis cell death modalities discovered recent years. In the present study, both in vivo and in vitro studies were conducted simultaneously. Diabetic rats were induced by 55 mg/kg intraperitoneal injection of streptozotocin (STZ). Following the intraperitoneal injection of MCC950 (10 mg/kg), On the other hand, the DCM model in H9C2 cardiac cells was simulated with 35 mmol/L glucose and a short hairpin RNA vector of NLRP3 were transfected to cells. The results showed that in vivo study, myocardial fibers were loosely arranged and showed inflammatory cell infiltration, mitochondrial cristae were broken and the GSDMD-NT expression was found notably increased in the DM group, while the protein expressions of xCT and GPX4 was significantly decreased, both of which were reversed by MCC950. High glucose reduced the cell viability and ATP level in vitro, accompanied by an increase in LDH release. All of the above indicators were reversed after NLRP3 knockdown compared with the HG treated alone. Moreover, the protein expressions of pyroptosis- and ferroptosis-related fators were significantly decreased or increased, consistent with the results shown by immunofluorescence. Furthermore, the protective effects of NLRP3 knockdown against HG were reversed following the mtROS agonist rotenone (ROT) treatment. In conclusion, inhibition of NLRP3 suppressed DM-induced myocardial injury. Promotion of mitochondrial ROS abolished the protective effect of knockdown NLRP3, and induced the happening of pyroptosis and ferroptosis. These findings may present a novel therapeutic underlying mechanism for clinical diabetes-induced myocardial injury treatment.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Ferroptose , Técnicas de Silenciamento de Genes , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Animais , Ferroptose/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Linhagem Celular , Ratos Sprague-Dawley , Ratos , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Inflamassomos/metabolismo , Sulfonamidas/farmacologia , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Gasderminas
10.
BMC Cardiovasc Disord ; 24(1): 350, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987722

RESUMO

BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.


Assuntos
Cardiotoxicidade , Ferroptose , Simulação de Acoplamento Molecular , Estresse Oxidativo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/genética , Redes Reguladoras de Genes , Fatores de Tempo , Transcriptoma , Epirubicina/efeitos adversos , Doxorrubicina , Antibióticos Antineoplásicos/efeitos adversos , Estudos de Casos e Controles , Idarubicina , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Perfilação da Expressão Gênica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estudos Longitudinais , Antraciclinas/efeitos adversos , Regulação da Expressão Gênica , Transdução de Sinais
11.
BMC Oral Health ; 24(1): 773, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987730

RESUMO

OBJECTIVE: Resveratrol (Res) is a natural phytoestrogen with antitumor activity. This study sought to investigate the role of Res in ferroptosis in oral squamous cell carcinoma (OSCC). METHODS: Normal human oral keratinocyte (HOK)/oral OSCC (CAL-27/SCC-9) cell lines were treated with different doses of Res. Res toxicity was determined by MTT assay, with half maximal inhibitory concentration values of Res on CAL-27 and SCC-9 cells calculated. Cell viability/colony formation efficiency/migration/invasion/cycle were assessed by CCK-8/colony formation assay/transwell assay/flow cytometry. The expression of p53 protein in the nucleus and cytoplasm, glutathione peroxidase 4 (GPX4) expression, and SLC7A11 messenger RNA (mRNA) and protein expression levels were determined by Western blot and RT-qPCR. Fe2+ content, reactive oxygen species (ROS) level, reduced glutathione (GSH), and lactate dehydrogenase (LDH) release were assessed. RESULTS: Medium- to low-dose Res had no toxic effect on HOK cells, while high-dose Res markedly reduced HOK cell viability. Res significantly suppressed the viability of OSCC cells (CAL-27 and SCC-9). Res inhibited OSCC cell colony formation/migration/invasion, and induced G1 phase arrest. Res caused the translocation of p53 protein to the nucleus, obviously increased Fe2+ content, ROS level and LDH release, decreased GSH content and GPX4 protein expression, and induced ferroptosis. Down-regulation of p53 partially reversed the inhibitory effects of Res on CAL-27 cell malignant behaviors. Res inhibited SLC7A11 transcription by promoting p53 entry into the nucleus. SLC7A11 overexpression negated the the regulatory effects of p53 knockout on the role of Res in OSCC cell malignant behaviors and ferroptosis. CONCLUSION: Res accelerated ferroptosis and inhibited malignant behaviors in OSCC cells by regulating p53/SLC7A11.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Carcinoma de Células Escamosas , Ferroptose , Neoplasias Bucais , Resveratrol , Proteína Supressora de Tumor p53 , Humanos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Ferroptose/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
12.
Front Immunol ; 15: 1428920, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39015566

RESUMO

Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Ferroptose , Mitocôndrias , Neoplasias , Espécies Reativas de Oxigênio , Ferroptose/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Mitocôndrias/metabolismo , Animais , Metástase Neoplásica
13.
Zhen Ci Yan Jiu ; 49(7): 678-685, 2024 Jul 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-39020485

RESUMO

OBJECTIVES: To investigate the impact of combined treatment of colorectal cancer (CRC) with electroacupuncture (EA) and capeOX (combined administration of fluorouracil, oxaliplatin and capecitabine) on the tumor volume, weight, spleen coefficient, apoptosis and ferroptosis of tumor tissue, and liver and kidney functions in nude mice with CRC, so as to explore its mechanisms underlying inhibiting CRC and alleviating toxic reactions of capeOX. METHODS: Female Balb/c nude mice were randomly assigned to 3 groups:model, capeOX, and EA+capeOX, with 8 nude mice in each group. The CRC model was established by subcutaneous injection of colon cancer cells at the right inguinal region. Nude mice of the capeOX group received intraperitoneal injection of oxaliplatin for 1 day and gavage of capecitabine from day 2 to day 7. EA (1 mA, 2 Hz/100 Hz) was applied to bilateral "Zusanli" (ST36) for 20 min, once daily for 7 days. During the interven-tion, the tumor volume and weight were measured every day, and at the end of intervention, the weight of the tumor tissue and spleen were measured, with tumor volume difference and spleen coefficient calculated. The proportion of apoptotic cells was measured by flow cytometry, and the contents of serum malondialdehyde (MDA), alanine aninotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were detected using ELISA. The expression level of glutathione peroxidase 4 (GPX4, a key regulator for ferroptosis) protein of the tumor tissue was determined using Western blot. RESULTS: Compared to the model group, both the capeOX group and EA+capeOX group showed a decrease in the tumor volume (on day 3 and 4 in the capeOX group, and from day 2 to 7 in the EA+capeOX group) and body weight (P<0.05, on day 3 to 7 in the EA+capeOX group and on day 2 to 7 in the capeOX group), being evidently lower in the tumor volume on day 7 in the EA+capeOX than in the capeOX group (P<0.05), and evidently higher in the body weight on day 6 and 7 in the EA+capeOX group than in the capeOX group (P<0.05). In comparison with the model group, the tumor volume difference, tumor weight and spleen coefficient in both capeOX and EA+capeOX groups were significantly decreased (P<0.05), and MDA content in EA+capeOX group was significantly decreased (P<0.05), while the contents of ALT, BUN and Cr in the capeOX group, the proportion of apoptotic cells in both capeOX and EA+capeOX groups, and the GPX4 expression level in the EA+capeOX group were all significantly increased (P<0.05). The tumor volume difference, tumor weight, and contents of MDA, ALT, AST, BUN and Cr in the EA+capeOX group were markedly lower than in the capeOX group (P<0.05), while the spleen coefficient, proportion of apoptotic cells and GPX4 expression level in the EA+capeOX group were markedly higher than those in the capeOX group (P<0.05). CONCLUSIONS: EA of ST36 can enhance the effect of capeOX in inhibiting colorectal cancer growth in nude mice with CRC, which may be related with its functions in promoting tumor cell apoptosis, inhibiting ferroptosis, and modulating immune tolerance. In addition, EA can lower the side effects of capeOX in hematopoietic and immune, liver, and kidney functions.


Assuntos
Pontos de Acupuntura , Apoptose , Neoplasias Colorretais , Eletroacupuntura , Ferroptose , Camundongos Endogâmicos BALB C , Camundongos Nus , Animais , Camundongos , Ferroptose/efeitos dos fármacos , Humanos , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Feminino , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética
14.
Zhen Ci Yan Jiu ; 49(7): 736-742, 2024 Jul 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-39020492

RESUMO

OBJECTIVES: To explore the effect of moxibustion on the expression of sorting nexin 5 (SNX5), glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1) in the corpus striatum in mice with Parkinson's disease (PD), so as to explore its mechanisms underlying improvement of PD by ameliorating ferroptosis in the substantia nigra striatum. METHODS: C57BL/6J mice were randomly divided into normal, sham operation, model, and moxibustion groups, with 10 mice in each group. The PD model was established by unilateral injection of 6-hydroxydopamine (3.5 µL) into the right medial forebrain bundle (AP=-1.2 mm, ML=-1.3 mm, DV=-4.75 mm). The mice in the moxibustion group received moxibustion at "Baihui"(GV20) and "Sishencong"(EX-HN1) for 20 min each time, once a day, 6 times a week for 4 weeks. After the intervention, mice received apomorphine rotation behavior detection and pole climbing test. The expression of tyrosine hydroxylase (TH) in the substantia nigra was detected by immunofluorescence, the contents of Fe2+, malondialdehyde (MDA), the ratio of glutathione/oxidized glutathione (GSH/GSSG) in the corpus striatum were detected by using photocolorimetric method, and the expression levels of SNX5 (endocytosomal protein), GPX4 (one of the key targets for inhibiting ferroptosis) and FTH1 proteins and mRNAs in the corpus striatum were detected by Western blot and qPCR, respectively. RESULTS: Behavior tests showed that the pole climbing time and number of body rotation were significantly increased in the model group relevant to the sham operation group (P<0.01), and strikingly decreased in the moxibustion group relevant to the model group (P<0.01). The immunofluorescence intensity of TH in the substantia nigra, the ratio of GSH/GSSG, and the expression levels of GPX4 and FTH1 mRNAs and proteins in the corpus striatum were markedly decreased (P<0.01, P<0.05), while the contents of Fe2+ and MDA and the expression levels of SNX5 mRNA and protein in the corpus striatum significantly increased in the model group relevant to the sham operation group (P<0.01, P<0.05). Compared with the model group, the decreased immunofluorescence intensity of TH, GSH/GSSH, and the expression levels of GPX4 and FTH1 mRNAs and proteins, and the increased contents of Fe2+ and MDA and the expression levels of SNX5 mRNA and protein were reversed in the moxibustion group relevant to the model group (P<0.01, P<0.05). CONCLUSIONS: Moxibustion may improve motor dysfunction in PD mice, which may be related to its effects in down-regulating the expression of SNX5, promoting the synthesis of GSH, decreasing the contents of Fe2+ and MDA, up-regulating the ratio of GSH/GSSG and the expression of GPX4 and FTH1 mRNAs and proteins in the corpus striatum, and inhibiting the occurrence of ferroptosis.


Assuntos
Corpo Estriado , Ferroptose , Camundongos Endogâmicos C57BL , Moxibustão , Neurônios , Doença de Parkinson , Animais , Ferroptose/genética , Camundongos , Corpo Estriado/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Masculino , Humanos , Neurônios/metabolismo , Nexinas de Classificação/metabolismo , Nexinas de Classificação/genética , Regulação para Baixo , Atividade Motora , Modelos Animais de Doenças
15.
Mol Med ; 30(1): 102, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009982

RESUMO

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.


Assuntos
Ferroptose , Necroptose , Humanos , Células THP-1 , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Piperazinas/farmacologia , Acrilamidas , Sulfonamidas , Proteínas de Ligação a RNA , Complexo de Proteínas Formadoras de Poros Nucleares
16.
Mycopathologia ; 189(4): 65, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38990436

RESUMO

Candida auris is an emerging multi-drug resistant yeast that can cause life-threatening infections. A recent report clarified the ability of C. auris to form a biofilm with enhanced drug resistance properties in the host skin's deep layers. The formed biofilm may initiate further bloodstream spread and immune escape. Therefore, we propose that secreted chemicals from the biofilm may facilitate fungal pathogenesis. In response to this interaction, the host skin may develop potential defensive mechanisms. Comparative transcriptomics was performed on the host dermal cells in response to indirect interaction with C. auris biofilm through Transwell inserts compared to planktonic cells. Furthermore, the effect of antifungals including caspofungin and fluconazole was studied. The obtained data showed that the dermal cells exhibited different transcriptional responses. Kyoto Encyclopedia of Genes and Genomes and Reactome analyses identified potential defensive responses employed by the dermal cells and potential toxicity induced by C. auris. Additionally, our data indicated that the dominating toxic effect was mediated by ferroptosis; which was validated by qRT-PCR, cytotoxicity assay, and flow cytometry. On the other hand, the viability of C. auris biofilm was enhanced and accompanied by upregulation of MDR1, and KRE6 upon interaction with dermal cells; both genes play significant roles in drug resistance and biofilm maturation, respectively. This study for the first-time shed light on the dominating defensive responses of human dermal cells, microbe colonization site, to C. auris biofilm and its toxic effects. Further, it demonstrates how C. auris biofilm responds to the defensive mechanisms developed by the human dermal cells.


Assuntos
Antifúngicos , Biofilmes , Candida auris , Ferroptose , Perfilação da Expressão Gênica , Humanos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida auris/genética , Candida auris/efeitos dos fármacos , Antifúngicos/farmacologia , Ferroptose/efeitos dos fármacos , Fluconazol/farmacologia , Caspofungina/farmacologia , Pele/microbiologia , Interações Hospedeiro-Patógeno
17.
Int J Med Sci ; 21(9): 1629-1639, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006843

RESUMO

The complete molecular mechanism underlying doxorubicin-induced cardiomyopathy remains incompletely elucidated. In this investigation, we engineered mice with cardiomyocyte-specific sorting nexin 3 knockout (SNX3Cko ) to probe the potential protective effects of SNX3 ablation on doxorubicin-triggered myocardial injury, focusing on GPX4-dependent ferroptosis. Our findings indicate that SNX3 deletion normalized heart contractile/relaxation function and thwarted the escalation of cardiac injury biomarkers following doxorubicin exposure. Additionally, SNX3 deletion in the heart mitigated the inflammatory response and oxidative stress in the presence of doxorubicin. At the molecular level, the detrimental effects of doxorubicin-induced cell death, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction were alleviated by SNX3 deficiency. Molecular analysis revealed the activation of GPX4-mediated ferroptosis by doxorubicin, whereas loss of SNX3 prevented the initiation of GPX4-dependent ferroptosis. Furthermore, treatment with erastin, a ferroptosis inducer, markedly reduced cell viability, exacerbated ER stress, and induced mitochondrial dysfunction in SNX3-depleted cardiomyocytes upon doxorubicin exposure. In summary, our results demonstrate that SNX3 deficiency shielded the heart from doxorubicin-induced myocardial dysfunction by modulating GPX4-associated ferroptosis.


Assuntos
Cardiomiopatias , Doxorrubicina , Ferroptose , Camundongos Knockout , Miócitos Cardíacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Nexinas de Classificação , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Cardiomiopatias/genética , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos
18.
Int J Mol Sci ; 25(13)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-39000568

RESUMO

Osteoarthritis (OA) is the most common joint disease, causing symptoms such as joint pain, swelling, and deformity, which severely affect patients' quality of life. Despite advances in medical treatment, OA management remains challenging, necessitating the development of safe and effective drugs. Quercetin (QUE), a natural flavonoid widely found in fruits and vegetables, shows promise due to its broad range of pharmacological effects, particularly in various degenerative diseases. However, its role in preventing OA progression and its underlying mechanisms remain unclear. In this study, we demonstrated that QUE has a protective effect against OA development both in vivo and in vitro, and we elucidated the underlying molecular mechanisms. In vitro, QUE inhibited the expression of IL-1ß-induced chondrocyte matrix metalloproteinases (MMP3 and MMP13) and inflammatory mediators such as INOS and COX-2. It also promoted the expression of collagen II, thereby preventing the extracellular matrix (ECM). Mechanistically, QUE exerts its protective effect on chondrocytes by activating the SIRT1/Nrf-2/HO-1 and inhibiting chondrocyte ferroptosis. Similarly, in an OA rat model induced by anterior cruciate ligament transection (ACLT), QUE treatment improved articular cartilage damage, reduced joint pain, and normalized abnormal subchondral bone remodeling. QUE also reduced serum IL-1ß, TNF-α, MMP3, CTX-II, and COMP, thereby slowing the progression of OA. QUE exerts chondroprotective effects by inhibiting chondrocyte oxidative damage and ferroptosis through the SIRT1/Nrf-2/HO-1 pathway, effectively alleviating OA progression in rats.


Assuntos
Cartilagem Articular , Condrócitos , Modelos Animais de Doenças , Ferroptose , Fator 2 Relacionado a NF-E2 , Osteoartrite , Quercetina , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ferroptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Interleucina-1beta/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo
19.
FASEB J ; 38(14): e23805, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39003630

RESUMO

Iron homeostasis is of critical importance to living organisms. Drosophila melanogaster has emerged as an excellent model to study iron homeostasis, while the regulatory mechanism of iron metabolism remains poorly understood. Herein, we accidently found that knockdown of juvenile hormone (JH) acid methyltransferase (Jhamt) specifically in the fat body, a key rate-limiting enzyme for JH synthesis, led to iron accumulation locally, resulting in serious loss and dysfunction of fat body. Jhamt knockdown-induced phenotypes were mitigated by iron deprivation, antioxidant and Ferrostatin-1, a well-known inhibitor of ferroptosis, suggesting ferroptosis was involved in Jhamt knockdown-induced defects in the fat body. Further study demonstrated that upregulation of Tsf1 and Malvolio (Mvl, homolog of mammalian DMT1), two iron importers, accounted for Jhamt knockdown-induced iron accumulation and dysfunction of the fat body. Mechanistically, Kr-h1, a key transcription factor of JH, acts downstream of Jhamt inhibiting Tsf1 and Mvl transcriptionally. In summary, the findings indicated that fat body-derived Jhamt is required for the development of Drosophila by maintaining iron homeostasis in the fat body, providing unique insight into the regulatory mechanisms of iron metabolism in Drosophila.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Corpo Adiposo , Homeostase , Ferro , Metiltransferases , Animais , Drosophila melanogaster/metabolismo , Ferro/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Corpo Adiposo/metabolismo , Metiltransferases/metabolismo , Metiltransferases/genética , Hormônios Juvenis/metabolismo , Ferroptose/fisiologia , Fatores de Transcrição Kruppel-Like
20.
Mol Med ; 30(1): 100, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992588

RESUMO

BACKGROUND: Diabetes mellitus (DM)-induced testicular damage is associated with sexual dysfunction and male infertility in DM patients. However, the pathogenesis of DM-induced testicular damage remains largely undefined. METHODS: A streptozotocin (STZ)-induced diabetic model and high glucose (HG)-treated in vitro diabetic model were established. The histological changes of testes were assessed by H&E staining. Serum testosterone, iron, MDA and GSH levels were detected using commercial kits. Cell viability and lipid peroxidation was monitored by MTT assay and BODIPY 581/591 C11 staining, respectively. qRT-PCR, immunohistochemistry (IHC) or Western blotting were employed to detect the levels of BRD7, Clusterin, EZH2 and AMPK signaling molecules. The associations among BRD7, EZH2 and DNMT3a were detected by co-IP, and the transcriptional regulation of Clusterin was monitored by methylation-specific PCR (MSP) and ChIP assay. RESULTS: Ferroptosis was associated with DM-induced testicular damage in STZ mice and HG-treated GC-1spg cells, and this was accompanied with the upregulation of BRD7. Knockdown of BRD7 suppressed HG-induced ferroptosis, as well as HG-induced Clusterin promoter methylation and HG-inactivated AMPK signaling in GC-1spg cells. Mechanistical studies revealed that BRD7 directly bound to EZH2 and regulated Clusterin promoter methylation via recruiting DNMT3a. Knockdown of Clusterin or inactivation of AMPK signaling reverses BRD7 silencing-suppressed ferroptosis in GC-1spg cells. In vivo findings showed that lack of BRD7 protected against diabetes-induced testicular damage and ferroptosis via increasing Clusterin expression and activating AMPK signaling. CONCLUSION: BRD7 suppressed Clusterin expression via modulating Clusterin promoter hypermethylation in an EZH2 dependent manner, thereby suppressing AMPK signaling to facilitate ferroptosis and induce diabetes-associated testicular damage.


Assuntos
Proteínas Quinases Ativadas por AMP , Clusterina , Metilação de DNA , Diabetes Mellitus Experimental , Ferroptose , Regiões Promotoras Genéticas , Transdução de Sinais , Testículo , Animais , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular , Clusterina/genética , Clusterina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/complicações , DNA Metiltransferase 3A/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Ferroptose/genética , Camundongos Endogâmicos C57BL , Testículo/metabolismo , Testículo/patologia
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