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1.
文章 在 英语 | WPRIM | ID: wpr-1010594

摘要

Cardiovascular diseases (CVDs) are a leading factor driving mortality worldwide. Iron, an essential trace mineral, is important in numerous biological processes, and its role in CVDs has raised broad discussion for decades. Iron-mediated cell death, namely ferroptosis, has attracted much attention due to its critical role in cardiomyocyte damage and CVDs. Furthermore, ferritinophagy is the upstream mechanism that induces ferroptosis, and is closely related to CVDs. This review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy, and the regulatory pathways and molecular targets involved in ferritinophagy, and to determine their roles in CVDs. Furthermore, we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating CVDs. Collectively, this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.


Subject(s)
Humans , Cardiovascular Diseases , Ferroptosis , Iron , Trace Elements
2.
Rev. cuba. med ; 62(2)jun. 2023.
文章 在 西班牙语 | LILACS, CUMED | ID: biblio-1530123

摘要

Introducción: La ferroptosis es un proceso no apoptótico de muerte celular regulada que depende de la presencia de iones hierro en el medio intracelular. Se caracterizada por la acumulación de especies reactivas de lípidos oxidados y radicales libres en las membranas celulares. Los inductores e inhibidores de este proceso inciden de manera circunstancial en él, con cuya respuesta celular se trabaja en función de elaborar modelos para el tratamiento del cáncer. Objetivo: Profundizar en el proceso de ferroptosis con un enfoque hacia los inductores e inhibidores, el establecimiento de modelos biofisicoquímicos y las estrategias terapéuticas para el tratamiento del cáncer. Métodos: Se realizó una revisión de los estudios más significativos sobre el tema, publicados en la Web of Science, PubMed, EBSCO, y Scopus. Resultados: Gracias al novedoso descubrimiento de la ferroptosis como impulsor de la muerte de células tumorales para tratar el cáncer, se han comenzado a desarrollar modelos teóricos que simulan el comportamiento de estas células y la complejidad en sistemas biológicos; que permiten encontrar procedimientos alternativos y menos invasivos contra esta y otras enfermedades. Conclusiones: Los inductores e inhibidores tienen una función primordial a la hora de predecir la influencia en la sensibilidad a la ferroptosis; por lo que se indagó en los mecanismos de funcionamiento de estos, que facilitará la forma de inducir en mayor o menor grado la muerte celular y disminuir la población de células cancerígenas(AU)


Introduction: Ferroptosis is a non-apoptotic process of regulated cell death that depends on the presence of iron ions in the intracellular medium. It is characterized by the accumulation of reactive species of oxidized lipids and free radicals in cell membranes. The inducers and inhibitors of this process circumstantially affect it, whose cellular response is used to develop models for cancer treatment. Objective: To deepen the ferroptosis process focusing on inducers and inhibitors, the establishment of biophysiochemical models and therapeutic strategies for cancer treatment. Methods: A review was carried out of the most significant studies on the subject, published in the Web of Science, PubMed, EBSCO and Scopus. Results: Thanks to the novel discovery of ferroptosis as a conductor of tumor cell death to treat cancer, theoretical models have begun to be developed that simulate the behavior of these cells and the complexity in biological systems; that allow finding alternative and less invasive procedures against this and other diseases. Conclusions: Inductors and inhibitors have a primary role in predicting the influence on sensitivity to ferroptosis; therefore, the mechanisms of operation of these were investigated, which will facilitate the way to induce cell death to a greater or lesser degree and reduce the population of cancer cells(AU)


Subject(s)
Humans , Male , Female , Ferroptosis , Neoplasms/drug therapy
3.
Chinese Journal of Hepatology ; (12): 345-348, 2023.
文章 在 中文 | WPRIM | ID: wpr-986140

摘要

Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.


Subject(s)
Humans , Biomarkers/metabolism , Chemical and Drug Induced Liver Injury , Ferroptosis , Iron/metabolism , Lipid Peroxidation/physiology
4.
文章 在 中文 | WPRIM | ID: wpr-985517

摘要

To explore whether PPARA is involved in the process of ferroptosis in hepatoma cells, peroxisome proliferator activated receptor (PPARA) was comprehensively analyzed in hepatocellular carcinoma (HCC) through public database and experimental data, including the expression, the functions and the potential roles of tumor progression. The research design is experimental research,data analysis based on bioinformatics and cell experiment. From January 2022 to August 2022, relevant cell experiments were conducted in the Basic Medical Laboratory of the General Hospital of the Southern Theatre of the Chinese People's Liberation Army. The expression and the correlation with clinicopathologic features of PPARA in HCC were analyzed by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To study the protein expression of PPARA in HCC and normal tissues through the Human Protein Atlas (HPA). The protein-protein interaction (PPI) network between PPARA and the core factor of ferroptosis was constructed based on Search Tool for the Retrival of Interacting Genes/Protein (STRING) database, then, the correlation between PPARA and the core gene Glutamate-cysteine Ligase Catalytic Subunit (GCLC) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Assessed the expression of PPARA in HCC cell lines SK-HEP-1, SMMC-7721, MHCC-97H, BEL-7402 and normal liver cell L02 by Western Blot (WB) and the changes of PPARA expression after 48h treatment with ferroptosis inducer Erastin were observed. Single factor analysis of variance was used to compare the expression of PPARA between groups in GEPIA database. The expression of PPARA in GSE25097 and GSE112790 data was compared by rank sum test. Survival analysis was performed using time series test method. The difference of PPARA expression between clinical and pathological features was compared using the Kruskal-Wallis test. The correlation between the expression of GCLC and PPARA was compared by the method of Spearman correlation. The expression of PPARA in cell lines was compared by paired T test. The results showed that the RNA and protein expression of PPARA in HCC was lower than that in normal tissues (P<0.05). PPARA alterations were correlated with patient clinicopathological features and prognosis (P<0.05). The PPI constructed by STRING database suggests that PPARA interact with the key factors of ferroptosis, such as NFE2 like bZIP transcription factor 2 (NFE2L2), Heme Oxygenase 1 (HMOX1), Tumor Protein P53 (TP53), GCLC, Dipeptidyl Peptidase 4 (DPP4), Citrate Synthase (CS), Arachidonate 15-Lipoxygenase (ALOX15) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4). Furthermore, the PPARA was significantly associated with GCLC validated via GEPIA database(R=0.6, P<0.05). The expression of PPARA increased after treatment with ferroptosis inducer Erastin for 48 h by WB. In conclusion, the expression of PPARA is lower in HCC with a poor prognosis. PPARA interacts with GCLC in regulating ferroptosis in HCC.


Subject(s)
Humans , Carcinoma, Hepatocellular/pathology , Ferroptosis , Liver Neoplasms/pathology , Peroxisome Proliferator-Activated Receptors/genetics
5.
文章 在 中文 | WPRIM | ID: wpr-1009448

摘要

Objective To investigate the effects of YAP on the occurrence and progression of acute liver failure by regulating the ferroptosis pathway and its underlying mechanism. Methods A total of 20 8-week-old C57BL/6 mice were randomly divided into four groups: a control group, an acute liver failure model group, a YAP agonist XMU-MP-1 treatment group and a YAP inhibitor verteporfin treatment group, five mice for each group. HE staining was used to observe the pathological changes of hepatic inflammation and necrosis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by liver biochemistry. Iron (Fe), malondialdehyde (MDA), glutathione (GSH) determination kits were used to measure their levels in liver tissues of each group. The changes of hepatocyte mitochondrial in each group were observed by electron microscopy. Real time PCR and Western blot analysis were used to detect the mRNA and protein expressions of YAP, glutathione peroxidase 4 (GPX4) and 5-lipoxygenase (5-LOX). Results Compared with the control group, mice in the acute liver failure model group and the YAP inhibitor verteporfin treatment group showed severe liver tissue congestion with inflammatory cell infiltration and structural damage to hepatic lobules. Liver injury was alleviated in the XMU-MP-1 treatment group. With the occurrence of liver failure, plasma ALT and AST levels significantly increased, and liver function was improved in XMU-MP-1 treatment group. Electron microscopy showed that mitochondria in hepatocytes of mice with liver failure became smaller and bilayer membrane density increased, while mitochondria changes in the XMU-MP-1 group were alleviated. In addition, the acute liver failure model group showed an increase in Fe and MDA contents, decreased protein expressions of GPX4, and enhanced expression of 5-LOX, suggesting that ferroptosis was involved in acute liver failure in C57BL/6 mice. Ferroptosis was inhibited by activation of YAP. Conclusion Activation of YAP may ameliorate liver injury by inhibiting ferroptosis.


Subject(s)
Animals , Mice , Ferroptosis , Glutathione , Liver Failure , Liver Failure, Acute/drug therapy , Mice, Inbred C57BL , Verteporfin , YAP-Signaling Proteins/metabolism
6.
文章 在 中文 | WPRIM | ID: wpr-1008731

摘要

This study aims to explore the effects of Shenqi Dihuang Decoction on high-glucose induced ferroptosis and the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/glutathione peroxidase 4(GPX4) axis in human renal tubular epithelial cells(HK-2) and to clarify the underlying mechanism. The cell injury model was established by exposing HK-2 to high glucose, and the Shenqi Dihuang Decoction-medicated serum was prepared. The optimal concentration and intervention time of Shenqi Dihuang Decoction were determined. HK-2 were divided into normal, high glucose, and low-, medium-, and high-dose Shenqi Dihuang Decoction groups. After interventions, the cell proliferation rate in each group was determined and the cell morphology and mitochondrial ultrastructure were observed. Then, the levels of intracellular reactive oxygen species(ROS), ferrous ion(Fe~(2+)), glutathione(GSH), and malondialdehyde(MDA) and the protein levels of Nrf2, HO-1, GPX4, and xCT were measured. The optimal concentration and intervention time of Shenqi Dihuang Decoction-medicated serum were determined to be 10% and 24 h, respectively. Compared with the high glucose group, high-dose Shenqi Dihuang Decoction promoted the proliferation of HK-2. The cells in the low-, medium-, and high-dose Shenqi Dihuang Decoction groups presented tight arrangement, an increased cell count, improved morphology from a spindle-fiber shape to a cobblestone shape, and improved morphology and structure of mitochondrial membrane and cristae, compared with those in the high glucose group. Meanwhile, all the doses of Shenqi Dihuang Decoction inhibited ROS elevation to mitigate the peroxidation damage, lowered the Fe~(2+) and MDA levels and elevated the GSH level to inhibit lipid peroxidation, and activated the antioxidant pathway to upregulate the protein levels of Nrf2, HO-1, xCT, and GPX4. In conclusion, Shenqi Dihuang Decoction-medicated serum can inhibit high-glucose induced ferroptosis of HK-2 in vitro, which involves the antioxidant effect and the activation of the Nrf2/HO-1/GPX4 pathway.


Subject(s)
Humans , Ferroptosis , NF-E2-Related Factor 2/genetics , Reactive Oxygen Species , Epithelial Cells , Antioxidants , Glutathione , Glucose
7.
文章 在 中文 | WPRIM | ID: wpr-1008726

摘要

This study aims to investigate the pathogenesis of chronic heart failure based on ferroptosis-mediated oxidative stress and predict the targets of Shenfu Injection in treating chronic heart failure. A rat model of chronic heart failure was established by the isoproterenol induction method. According to the random number table method, the modeled rats were assigned into three groups: a model group, a Shenfu Injection group, and a ferrostatin-1(ferroptosis inhibitor) group. In addition, a normal group was designed. After 15 days of intervention, the cardiac mass index and left ventricular mass index were determined. Echocardiography was employed to eva-luate the cardiac function. Hematoxylin-eosin staining and Masson staining were employed to reveal the pathological changes and fibrosis of the heart, and Prussian blue staining to detect the aggregation of iron ions in the myocardial tissue. Transmission electron microscopy was employed to observe the mitochondrion ultrastructure in the myocardial tissue. Colorimetry was adopted to measure the levels of iron metabolism, lipid peroxidation, and antioxidant indicators. Flow cytometry was employed to measure the content of lipid-reactive oxygen species(ROS) and the fluorescence intensity of ROS. Western blot and RT-qPCR were employed to determine the protein and mRNA levels, respectively, of ferroptosis-related factors in the myocardial tissue. The results showed that the rats in the model group had reduced cardiac function, elevated levels of total iron and Fe~(2+), lowered level of glutathione(GSH), increased malondialdehyde(MDA), decreased superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px), and rising levels of ROS and lipid-ROS. In addition, the model group showed fibrous tissue hyperplasia with inflammatory cell infiltration and myocardial fibrosis, iron ion aggregation, and characteristic mitochondrial changes specific for iron death. Moreover, the model group showcased upregulated protein and mRNA levels of p53 and COX2 and downregulated protein and mRNA levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. The intervention with Shenfu Injection significantly improved the cardiac function, recovered the iron metabolism, lipid peroxidation, and antioxidant indicators, decreased iron deposition, improved mitochondrial structure and function, and alleviated inflammatory cell infiltration and fibrosis. Furthermore, Shenfu Injection downregulated the mRNA and protein levels of p53 and COX2 and upregulated the mRNA and protein levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. Shenfu Injection can improve the cardiac function by regulating iron metabolism, inhibiting ferroptosis, and reducing oxidative stress injury.


Subject(s)
Animals , Rats , Antioxidants , Reactive Oxygen Species , Cyclooxygenase 2 , Ferroptosis , NF-E2-Related Factor 2 , Tumor Suppressor Protein p53 , Heart Failure/genetics , Oxidative Stress , Chronic Disease , Glutathione , Fibrosis , Iron , RNA, Messenger , Lipids
8.
文章 在 中文 | WPRIM | ID: wpr-1008648

摘要

Chronic heart failure is the end stage of heart diseases caused by multiple causes. Myocardial cell injury is the key cause of cardiac function deterioration. Ferroptosis, an iron-dependent programmed death mode, is characterized by iron overload and excessive accumulation of lipid peroxides. Studies have demonstrated that inhibiting ferroptosis has a protective effect on myocardial cells. The theory of "harmful hyperactivity and responding inhibition" is an important rule developed by physicians to explain the generation and restriction of the five elements and the pathological imbalance of the human body, and can guide medication. Correlating with the nature, humans need to rely on the law of responding inhibition to maintain the harmony of five Zang-organs and the steady state of Fu-organs. The pathogenesis of ferroptosis in chronic heart failure highly coincides with the process of failing to "inhibition and hyperactivity becoming harmful". The initial factor of ferroptosis is the deficiency of heart Qi, which results in the inability to maintain the balance of cardiomyocyte redox system. The involvement of the five Zang-organs leads to the loss of distribution of body fluid and blood. As a result, the phlegm turbidity, blood stasis, and water retention in the meridians occur, which are manifested as the accumulation of iron and lipid peroxides, which is the aggravating factor of ferroptosis. The two factors interact with each other, leading to the spiral development and thus aggravating heart failure. According to the traditional Chinese medicine(TCM) pathogenesis of ferroptosis, the authors try to treat the chronic heart failure by stages in accordance with the general principle of restraining excess and alleviating hyperactivity. The early-stage treatment should "nourish heart Qi, regulate the five Zang-organs, so as to restrain excess". The middle-stage treatment should "active blood, resolve phlegm, dispel pathogen, and eliminate turbidity", so as to alleviate hyperactivity. The late-stage treatment should "warm Yang, replenish Qi, active blood, and excrete water". Following the characteristics of pathogenesis, the TCM intervention can reduce iron accumulation and promote the clearance of lipid peroxide, thus inhibiting ferroptosis and improving cardiac function.


Subject(s)
Humans , Ferroptosis , Lipid Peroxides , Medicine, Chinese Traditional , Heart Failure/drug therapy , Chronic Disease , Iron , Water
9.
文章 在 中文 | WPRIM | ID: wpr-970632

摘要

The purpose of this study is to investigate whether chrysin reduces cerebral ischemia-reperfusion injury(CIRI) by inhi-biting ferroptosis in rats. Male SD rats were randomly divided into a sham group, a model group, high-, medium-, and low-dose chrysin groups(200, 100, and 50 mg·kg~(-1)), and a positive drug group(Ginaton, 21.6 mg·kg~(-1)). The CIRI model was induced in rats by transient middle cerebral artery occlusion(tMCAO). The indexes were evaluated and the samples were taken 24 h after the operation. The neurological deficit score was used to detect neurological function. The 2,3,5-triphenyl tetrazolium chloride(TTC) staining was used to detect the cerebral infarction area. Hematoxylin-eosin(HE) staining and Nissl staining were used to observe the morphological structure of brain tissues. Prussian blue staining was used to observe the iron accumulation in the brain. Total iron, lipid pero-xide, and malondialdehyde in serum and brain tissues were detected by biochemical reagents. Real-time quantitative polymerase chain reaction(RT-qPCR), immunohistochemistry, and Western blot were used to detect mRNA and protein expression of solute carrier fa-mily 7 member 11(SLC7A11), transferrin receptor 1(TFR1), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long chain family member 4(ACSL4), and prostaglandin-endoperoxide synthase 2(PTGS2) in brain tissues. Compared with the model group, the groups with drug intervention showed restored neurological function, decreased cerebral infarction rate, and alleviated pathological changes. The low-dose chrysin group was selected as the optimal dosing group. Compared with the model group, the chrysin groups showed reduced content of total iron, lipid peroxide, and malondialdehyde in brain tissues and serum, increased mRNA and protein expression levels of SLC7A11 and GPX4, and decreased mRNA and protein expression levels of TFR1, PTGS2, and ACSL4. Chrysin may regulate iron metabolism via regulating the related targets of ferroptosis and inhibit neuronal ferroptosis induced by CIRI.


Subject(s)
Rats , Male , Animals , Rats, Sprague-Dawley , Ferroptosis , Signal Transduction , Brain Ischemia/metabolism , Cyclooxygenase 2/metabolism , RNA, Messenger , Cerebral Infarction , Reperfusion Injury/metabolism , Malondialdehyde , Infarction, Middle Cerebral Artery
10.
Acta Physiologica Sinica ; (6): 82-90, 2023.
文章 在 中文 | WPRIM | ID: wpr-970108

摘要

Apoptosis and autophagy of follicular granulosa cells play an important regulatory role in the process of ovarian follicular atresia in animals. Recent studies have shown that ferroptosis and pyroptosis are also involved in the process of ovarian follicular atresia. Ferroptosis is a form of cell death caused by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation. Studies have confirmed that autophagy- and apoptosis-mediated follicular atresia also have typical characteristics of ferroptosis. Pyroptosis is a pro-inflammatory cell death dependent on Gasdermin protein, which can regulate ovarian reproductive performance by regulating follicular granulosa cells. This article reviews the roles and mechanisms of several types of programmed cell death independently or interactively regulating follicular atresia, in order to expand the theoretical research on follicular atresia mechanism and provide the theoretical reference for the mechanism of programmed cell death-induced follicular atresia.


Subject(s)
Female , Animals , Follicular Atresia , Apoptosis , Cell Death , Ferroptosis , Pyroptosis
11.
文章 在 中文 | WPRIM | ID: wpr-971532

摘要

OBJECTIVE@#To explore the mechanism that mediates the effect of soybean isoflavones (SI) against cerebral ischemia/reperfusion (I/R) injury in light of the regulation of regional cerebral blood flow (rCBF), ferroptosis, inflammatory response and blood-brain barrier (BBB) permeability.@*METHODS@#A total of 120 male SD rats were equally randomized into sham-operated group (Sham group), cerebral I/R injury group and SI pretreatment group (SI group). Focal cerebral I/R injury was induced in the latter two groups using a modified monofilament occlusion technique, and the intraoperative changes of real-time cerebral cortex blood flow were monitored using a laser Doppler flowmeter (LDF). The postoperative changes of cerebral pathological morphology and the ultrastructure of the neurons and the BBB were observed with optical and transmission electron microscopy. The neurological deficits of the rats was assessed, and the severities of cerebral infarction, brain edema and BBB disruption were quantified. The contents of Fe2+, GSH, MDA and MPO in the ischemic penumbra were determined with spectrophotometric tests. Serum levels of TNF-α and IL-1βwere analyzed using ELISA, and the expressions of GPX4, MMP-9 and occludin around the lesion were detected with Western blotting and immunohistochemistry.@*RESULTS@#The rCBF was sharply reduced in the rats in I/R group and SI group after successful insertion of the monofilament. Compared with those in Sham group, the rats in I/R group showed significantly increased neurological deficit scores, cerebral infarction volume, brain water content and Evans blue permeability (P < 0.01), decreased Fe2+ level, increased MDA level, decreased GSH content and GPX4 expression (P < 0.01), increased MPO content and serum levels of TNF-α and IL-1β (P < 0.01), increased MMP-9 expression and lowered occludin expression (P < 0.01). All these changes were significantly ameliorated in rats pretreated with IS prior to I/R injury (P < 0.05 or 0.01).@*CONCLUSION@#SI preconditioning reduces cerebral I/R injury in rats possibly by improving rCBF, inhibiting ferroptosis and inflammatory response and protecting the BBB.


Subject(s)
Rats , Male , Animals , Rats, Sprague-Dawley , Matrix Metalloproteinase 9/metabolism , Glycine max/metabolism , Occludin/metabolism , Tumor Necrosis Factor-alpha/metabolism , Ferroptosis , Blood-Brain Barrier/ultrastructure , Brain Ischemia/metabolism , Cerebral Infarction , Reperfusion Injury/metabolism , Isoflavones/therapeutic use , Infarction, Middle Cerebral Artery
12.
文章 在 英语 | WPRIM | ID: wpr-971474

摘要

Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. Ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.


Subject(s)
Humans , Antioxidants/metabolism , Ferroptosis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Iron Overload/metabolism
13.
Chinese Critical Care Medicine ; (12): 684-689, 2023.
文章 在 中文 | WPRIM | ID: wpr-982655

摘要

OBJECTIVE@#To observe the ferroptosis triggered by in different pathways during cecal ligation and puncture (CLP)-induced liver injury in septic mice, and to investigate whether mitochondrial aldehyde dehydrogenase 2 (ALDH2) can alleviate sepsis-induced liver injury by inhibiting ferroptosis.@*METHODS@#Sixty 8-week-old male C57BL/6J mice were randomly divided into sham operation group (Sham group), CLP group, ferroptosis inhibitor ferrostain-1 (Fer-1) group, ALDH2-specific agonist Alda-1 group, iron chelator deferasirox Fe3+ chelate (DXZ) group and dimethyl sulfoxide (DMSO) group, with 10 mice in each group. The septic liver injury was induced by CLP in mice model. In the Sham group, only laparotomy was performed without ligation and puncture of the cecum. 10 mL/kg 5% DMSO, 5 mg/kg Fer-1, 50 mg/kg DXZ and 10 mg/kg Alda-1 were injected intraperitoneally 1 hour before CLP in the DMSO, Fer-1, DXZ and Alda-1 groups respectively. At 24 hours after operation, eyeball blood and liver tissue were collected from anesthetized mice. The hepatic structure and inflammatory infiltration were observed by hematoxylin-eosin (HE) staining. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum, the levels of hepatic malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) were detected. Western blotting was used to detect the protein expressions of ALDH2, ferroptosis-related proteins glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1) and transferrin receptor 1 (TFR1) in liver tissue.@*RESULTS@#Compared with Sham group, the mice in CLP group showed varying degrees of congestion, disorganized hepatocyte arrangement, inflammatory cell infiltration at 24 hours after operation. Compared with the CLP group, the mice in the Fer-1 group, DXZ group and Alda-1 group liver morphology, liver injury and inflammatory cell infiltration was improved. Compared with Sham group, the serum levels of ALT and AST, the contents of MDA and ROS, and the expression of TFR1 protein in CLP group were significantly increased, while the activity of SOD and the expressions of ALDH2, GPX4 and FSP1 protein in CLP group were significantly decreased. Compared with CLP group, serum ALT and AST levels in Fer-1, DXZ and Alda-1 groups were significantly decreased [ALT (U/L): 45.76±10.81, 37.30±2.98, 36.40±12.75 vs. 73.06±12.20, AST (U/L): 61.57±2.69, 52.41±6.92, 56.05±8.29 vs. 81.59±5.46, all P < 0.05], and the contents of MDA, ROS and TFR1 protein expression in liver tissue were significantly decreased [MDA (μmol/L): 0.60±0.10, 0.57±0.18, 0.83±0.39 vs. 1.61±0.30, ROS (fluorescence intensity): 270.34±9.64, 276.02±62.33, 262.05±18.55 vs. 455.38±36.07, TFR1/GAPDH: 0.90±0.04, 1.01±0.09, 0.55±0.08 vs. 1.18±0.06, all P < 0.05], and the SOD activity and ALDH2, GPX4 and FSP1 protein expressions in liver tissue were significantly increased [SOD (kU/g): 88.77±8.20, 88.37±4.47, 93.43±7.24 vs. 50.27±3.57, ALDH2/GAPDH: 1.10±0.15, 1.02±0.07, 1.14±0.07 vs. 0.70±0.04, GPX4/GAPDH: 1.02±0.12, 0.99±0.08, 1.05±0.19 vs. 0.71±0.10, FSP1/GAPDH: 1.06±0.24, 1.02±0.08, 0.93±0.09 vs. 0.66±0.03, all P < 0.05]. There was no significant difference in the parameters between DMSO group and CLP group.@*CONCLUSIONS@#Both GPX4 and FSP1 mediated ferroptosis are involved in liver injury in septic mice. Activation of ALDH2 and inhibition of ferroptosis can alleviatehepatic injury. ALDH2 may play a protective role by regulating FSP1 and GPX4 mediated ferroptosis.


Subject(s)
Mice , Male , Animals , Aldehyde Dehydrogenase, Mitochondrial , Ferroptosis , Reactive Oxygen Species , Chemical and Drug Induced Liver Injury, Chronic , Dimethyl Sulfoxide , Mice, Inbred C57BL , Sepsis , Disease Models, Animal
14.
Chinese Critical Care Medicine ; (12): 376-380, 2023.
文章 在 中文 | WPRIM | ID: wpr-982597

摘要

OBJECTIVE@#To investigate whether the acetaldehyde dehydrogenase 2 specific activator, Alda-1, can alleviate brain injury after cardiopulmonary resuscitation (CPR) by inhibiting cell ferroptosis mediated by acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 (ACSL4/GPx4) pathway in swine.@*METHODS@#Twenty-two conventional healthy male white swine were divided into Sham group (n = 6), CPR model group (n = 8), and Alda-1 intervention group (CPR+Alda-1 group, n = 8) using a random number table. The swine model of CPR was reproduced by 8 minutes of cardiac arrest induced by ventricular fibrillation through electrical stimulation in the right ventricle followed by 8 minutes of CPR. The Sham group only experienced general preparation. A dose of 0.88 mg/kg of Alda-1 was intravenously injected at 5 minutes after resuscitation in the CPR+Alda-1 group. The same volume of saline was infused in the Sham and CPR model groups. Blood samples were collected from the femoral vein before modeling and 1, 2, 4, 24 hours after resuscitation, and the serum levels of neuron specific enolase (NSE) and S100 β protein were determined by enzyme-linked immunosorbent assay (ELISA). At 24 hours after resuscitation, the status of neurologic function was evaluated by neurological deficit score (NDS). Thereafter, the animals were sacrificed, and brain cortex was harvested to measure iron deposition by Prussian blue staining, malondialdehyde (MDA) and glutathione (GSH) contents by colorimetry, and ACSL4 and GPx4 protein expressions by Western blotting.@*RESULTS@#Compared with the Sham group, the serum levels of NSE and S100β after resuscitation were gradually increased over time, and the NDS score was significantly increased, brain cortical iron deposition and MDA content were significantly increased, GSH content and GPx4 protein expression in brain cortical were significantly decreased, and ACSL4 protein expression was significantly increased at 24 hours after resuscitation in the CPR model and CPR+Alda-1 groups, which indicated that cell ferroptosis occurred in the brain cortex, and the ACSL4/GPx4 pathway participated in this process of cell ferroptosis. Compared with the CPR model group, the serum levels of NSE and S100 β starting 2 hours after resuscitation were significantly decreased in the CPR+Alda-1 group [NSE (μg/L): 24.1±2.4 vs. 28.2±2.1, S100 β (ng/L): 2 279±169 vs. 2 620±241, both P < 0.05]; at 24 hours after resuscitation, the NDS score and brain cortical iron deposition and MDA content were significantly decreased [NDS score: 120±44 vs. 207±68, iron deposition: (2.61±0.36)% vs. (6.31±1.66)%, MDA (μmol/g): 2.93±0.30 vs. 3.68±0.29, all P < 0.05], brain cortical GSH content and GPx4 expression in brain cortical was significantly increased [GSH (mg/g): 4.59±0.63 vs. 3.51±0.56, GPx4 protein (GPx4/GAPDH): 0.54±0.14 vs. 0.21±0.08, both P < 0.05], and ACSL4 protein expression was significantly decreased (ACSL4/GAPDH: 0.46±0.08 vs. 0.85±0.13, P < 0.05), which indicated that Alda-1 might alleviate brain cortical cell ferroptosis through regulating ACSL4/GPx4 pathway.@*CONCLUSIONS@#Alda-1 can reduce brain injury after CPR in swine, which may be related to the inhibition of ACSL4/GPx4 pathway mediated ferroptosis.


Subject(s)
Male , Animals , Swine , Phospholipid Hydroperoxide Glutathione Peroxidase , Ferroptosis , Brain Injuries , Glutathione , Cardiopulmonary Resuscitation , Ligases , Iron
15.
Frontiers of Medicine ; (4): 173-206, 2023.
文章 在 英语 | WPRIM | ID: wpr-982584

摘要

Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.


Subject(s)
Humans , Ferroptosis , Autoimmune Diseases , Cardiovascular Diseases , Iron , Musculoskeletal Diseases
16.
文章 在 中文 | WPRIM | ID: wpr-982074

摘要

OBJECTIVE@#To explore the role of ferroptosis-related genes in multiple myeloma(MM) through TCGA database and FerrDb, and build a prognostic model of ferroptosis-related genes for MM patients.@*METHODS@#Using the TCGA database containing clinical information and gene expression profile data of 764 patients with MM and the FerrDb database including ferroptosis-related genes, the differentially expressed ferroptosis-related genes were screened by wilcox.test function. The prognostic model of ferroptosis-related genes was established by Lasso regression, and the Kaplan-Meier survival curve was drawn. Then COX regression analysis was used to screen independent prognostic factors. Finally, the differential genes between high-risk and low-risk patients were screened, and enrichment analysis was used to explore the mechanism of the relationship between ferroptosis and prognosis in MM.@*RESULTS@#36 differential genes related to ferroptosis were screened out from bone marrow samples of 764 MM patients and 4 normal people, including 12 up-regulated genes and 24 down-regulated genes. Six prognosis-related genes (GCLM, GLS2, SLC7A11, AIFM2, ACO1, G6PD) were screened out by Lasso regression and the prognostic model with ferroptosis-related genes of MM was established. Kaplan-Meier survival curve analysis showed that the survival rate between high risk group and low risk group was significantly different(P<0.01). Univariate COX regression analysis showed that age, sex, ISS stage and risk score were significantly correlated with overall survival of MM patients(P<0.05), while multivariate COX regression analysis showed that age, ISS stage and risk score were independent prognostic indicators for MM patients (P<0.05). GO and KEGG enrichment analysis showed that the ferroptosis-related genes was mainly related to neutrophil degranulation and migration, cytokine activity and regulation, cell component, antigen processing and presentation, complement and coagulation cascades, haematopoietic cell lineage and so on, which may affect the prognosis of patients.@*CONCLUSION@#Ferroptosis-related genes change significantly during the pathogenesis of MM. The prognostic model of ferroptosis-related genes can be used to predict the survival of MM patients, but the mechanism of the potential function of ferroptosis-related genes needs to be confirmed by further clinical studies.


Subject(s)
Humans , Multiple Myeloma , Ferroptosis , Prognosis , Hematopoietic System , Blood Coagulation
17.
Asian Journal of Andrology ; (6): 375-381, 2023.
文章 在 英语 | WPRIM | ID: wpr-981946

摘要

Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability. By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research (ICR) mouse model, we found that a ferroptosis phenomenon may exist. Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days. Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde. Epididymal sperm was also collected for semen analysis, and testicular tissue was collected for ferritin content determination, electron microscope observation of mitochondrial morphology, immunohistochemistry, real-time quantitative polymerase chain reaction, and western blot analysis. Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage, iron accumulation, and mitochondrial damage in the testes of mice. In addition, bisphenol A was confirmed to affect the expression of the ferroptosis-related genes, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), cyclooxygenase 2 (COX2), and acyl-CoA synthetase 4 (ACSL4) in mouse testicular tissues. Accordingly, we speculate that bisphenol A induces oxidative stress, which leads to the ferroptosis of testicular cells. Overall, the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.


Subject(s)
Male , Mice , Animals , Testis/metabolism , Ferroptosis , Semen , Oxidative Stress
18.
文章 在 中文 | WPRIM | ID: wpr-981435

摘要

The aim of this study is to explore the mechanism of ligustilide, the main active constituent of essential oils of traditional Chinese medicine Angelicae Sinensis Radix, on alleviating oxygen-glucose deprivation/reperfusion(OGD/R) injury in PC12 cells from the perspective of ferroptosis. OGD/R was induced in vitro, and 12 h after ligustilide addition during reperfusion, cell viability was detected by cell counting kit-8(CCK-8) assay. DCFH-DA staining was used to detect the level of intracellular reactive oxygen species(ROS). Western blot was employed to detect the expression of ferroptosis-related proteins, glutathione peroxidase 4(GPX4), transferrin receptor 1(TFR1), and solute carrier family 7 member 11(SLC7A11), and ferritinophagy-related proteins, nuclear receptor coactivator 4(NCOA4), ferritin heavy chain 1(FTH1), and microtubule-associated protein 1 light chain 3(LC3). The fluorescence intensity of LC3 protein was analyzed by immunofluorescence staining. The content of glutathione(GSH), malondialdehyde(MDA), and Fe was detected by chemiluminescent immunoassay. The effect of ligustilide on ferroptosis was observed by overexpression of NCOA4 gene. The results showed that ligustilide increased the viability of PC12 cells damaged by OGD/R, inhibited the release of ROS, reduced the content of Fe and MDA and the expression of TFR1, NCOA4, and LC3, and improved the content of GSH and the expression of GPX4, SLC7A11, and FTH1 compared with OGD/R group. After overexpression of the key protein NCOA4 in ferritinophagy, the inhibitory effect of ligustilide on ferroptosis was partially reversed, indicating that ligustilide may alleviate OGD/R injury of PC12 cells by blocking ferritinophagy and then inhibiting ferroptosis. The mechanism by which ligustilide reduced OGD/R injury in PC12 cells is that it suppressed the ferroptosis involved in ferritinophagy.


Subject(s)
Animals , Rats , PC12 Cells , Ferroptosis/genetics , Reactive Oxygen Species , Transcription Factors , Glutathione
19.
文章 在 中文 | WPRIM | ID: wpr-981348

摘要

To investigate the protective effect and the potential mechanism of leonurine(Leo) against erastin-induced ferroptosis in human renal tubular epithelial cells(HK-2 cells), an in vitro erastin-induced ferroptosis model was constructed to detect the cell viability as well as the expressions of ferroptosis-related indexes and signaling pathway-related proteins. HK-2 cells were cultured in vitro, and the effects of Leo on the viability of HK-2 cells at 10, 20, 40, 60, 80 and 100 μmol·L~(-1) were examined by CCK-8 assay to determine the safe dose range of Leo administration. A ferroptosis cell model was induced by erastin, a common ferroptosis inducer, and the appropriate concentrations were screened. CCK-8 assay was used to detect the effects of Leo(20, 40, 80 μmol·L~(-1)) and positive drug ferrostatin-1(Fer-1, 1, 2 μmol·L~(-1)) on the viability of ferroptosis model cells, and the changes of cell morphology were observed by phase contrast microscopy. Then, the optimal concentration of Leo was obtained by Western blot for nuclear factor erythroid 2-related factor 2(Nrf2) activation, and transmission electron microscope was further used to detect the characteristic microscopic morphological changes during ferroptosis. Flow cytometry was performed to detect reactive oxygen species(ROS), and the level of glutathione(GSH) was measured using a GSH assay kit. The expressions of glutathione peroxidase 4(GPX4), p62, and heme oxygenase 1(HO-1) in each group were quantified by Western blot. RESULTS:: showed that Leo had no side effects on the viability of normal HK-2 cells in the concentration range of 10-100 μmol·L~(-1). The viability of HK-2 cells decreased as the concentration of erastin increased, and 5 μmol·L~(-1) erastin significantly induced ferroptosis in the cells. Compared with the model group, Leo dose-dependently increased cell via-bility and improved cell morphology, and 80 μmol·L~(-1) Leo promoted the translocation of Nrf2 from the cytoplasm to the nucleus. Further studies revealed that Leo remarkably alleviated the characteristic microstructural damage of ferroptosis cells caused by erastin, inhibited the release of intracellular ROS, elevated GSH and GPX4, promoted the nuclear translocation of Nrf2, and significantly upregulated the expression of p62 and HO-1 proteins. In conclusion, Leo exerted a protective effect on erastin-induced ferroptosis in HK-2 cells, which might be associated with its anti-oxidative stress by activating p62/Nrf2/HO-1 signaling pathway.


Subject(s)
Humans , Ferroptosis , Reactive Oxygen Species/metabolism , NF-E2-Related Factor 2/metabolism , Sincalide/pharmacology , Signal Transduction , Epithelial Cells/metabolism , Glutathione
20.
Acta Physiologica Sinica ; (6): 255-268, 2023.
文章 在 中文 | WPRIM | ID: wpr-981003

摘要

Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.


Subject(s)
Humans , Infant, Newborn , Ferroptosis , Apoptosis , Hypoxia-Ischemia, Brain , Brain Injuries , Iron , Reperfusion Injury
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