Free Radical Research最新文献

{"title":"Comparison of microbubbling and conventional bubbling methods for ozonated saline solution in CKD patients: a pilot study.","authors":"Estoneck Guevara-Aguilar, Diana Moroni-González, José Carlos Jiménez-Ortega, Samuel Treviño, Victor Enrique Sarmiento-Ortega","doi":"10.1080/10715762.2025.2483454","DOIUrl":"10.1080/10715762.2025.2483454","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a progressive condition marked by persistent kidney damage, leading to high mortality rates and economic burden in advanced stages. Ozone therapy has emerged as a complementary alternative capable of mitigating oxidative stress involved in CKD progression. Ozonated saline solution (OSS) prepared <i>via</i> microbubbling offers enhanced efficacy due to greater ozone dissolution, homogeneity, and stability compared to conventional methods. This study compared the biosafety and efficacy of OSS prepared through bubbling and microbubbling methods in advanced CKD patients. <i>In vitro</i>, hydrogen peroxide (H₂O₂) concentrations were measured at various doses and times for both methods. In healthy volunteer, biosafety was assessed using TMRE and Annexin V in leukocytes. In CKD patients, TMRE, Annexin V, redox markers (catalase, superoxide dismutase, glutathione system, H₂O₂, lipoperoxidation), and renal function markers (urea, creatinine, glomerular filtration rate) were evaluated. Microbubbling produced lower H₂O₂ concentrations <i>in vitro</i>, depending on time and ozone dose. <i>In vivo</i>, both methods increased mitochondrial activity and apoptosis in CKD patient leukocytes. However, microbubbling notably enhanced antioxidant capacity, catalase and superoxide dismutase activity, and redox balance (elevated reduced-to-oxidized glutathione ratio) compared to conventional bubbling. It also showed slight improvements in serum clinical parameters. In conclusion, the microbubbling method demonstrated superior biosafety and therapeutic efficacy in advanced CKD patients, highlighting its potential as a preferred approach in ozone therapy.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"297-307"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel tetrahydroxynaphthalene derivative by chemical screening with ferroptosis inhibitory activity and promising therapeutic potential.","authors":"Takujiro Homma, Chihiro Tada, Moeka Yamauchi, Yuto Matsumoto, Shinji Matsunaga, Shuji Akai, Hiroaki Gotoh, Shuhei Tomita","doi":"10.1080/10715762.2025.2497033","DOIUrl":"10.1080/10715762.2025.2497033","url":null,"abstract":"<p><p>Hydroxyl radicals produced by the iron-mediated Fenton reaction are highly reactive, increase lipid peroxide levels, and damage cell membranes, resulting in ferroptosis, an iron-dependent form of cell death. In recent years, the role of ferroptosis in various pathological conditions has garnered interest. Because it is responsible for oxidative stress-induced organ damage, especially cell death associated with ischemia-reperfusion injury and neurological disorders, the inhibition of ferroptosis may ameliorate organ damage. Through a screen of a unique chemical compound library from Osaka University, we identified several structurally distinct compounds that were highly protective against ferroptosis <i>in vitro</i>. Notably, compound #562, which is a tetrahydroxynaphthalene derivative, exhibited a remarkable ability to fully rescue cells from ferroptosis at low concentrations (0.1 µM). A computational analysis revealed its structural uniqueness and high drug-likeness score, indicating its clinical potential. Along with its enhanced efficacy, this suggests that compound #562 may provide alternative modes of action or improved therapeutic potential for ferroptosis-related diseases.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"321-331"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidative activity of a novel antioxidant resorcimoline.","authors":"Osamu Tokumaru, Akihiro Higuchi, Takayuki Kawashima, Kazue Ogata, Kazuhiro Ueno, Takanori Inoue, Shinji Miyamoto","doi":"10.1080/10715762.2025.2497040","DOIUrl":"10.1080/10715762.2025.2497040","url":null,"abstract":"<p><p>During the synthesis of a known drug, we synthesized a novel compound impromptu, which we have named resorcimoline. This compound exhibited significant antioxidative activity. In this report, we present the concentration-dependent free radical scavenging activity of resorcimoline against various free radical species. The scavenging activity of resorcimoline was evaluated against nine free radicals using electron spin resonance spectroscopy with a spin-trapping method. These free radicals were hydroxyl radical, superoxide anion, <i>tert</i>-butyl peroxyl radical, <i>tert</i>-butoxyl radical, ascorbyl free radical, singlet oxygen, nitric oxide, 2,2-diphenyl-1-picrylhydrazyl, and tyrosyl radical. Sigmoid concentration-response curves were fitted to estimate the reaction rate constants of resorcimoline for the free radicals, and these were compared with those of edaravone, the only current clinically approved free radical scavenger. The antioxidative activity of resorcimoline against lipid peroxidation within tissue was assessed using the thiobarbituric acid reactive substance (TBARS) assay. The cytotoxicity and stability of resorcimoline were also evaluated. Resorcimoline demonstrated significant concentration-dependent scavenging activity against all tested free radicals. Notably, the reaction rate constants for superoxide anion and nitric oxide were significantly higher than those of edaravone, while the rate constant for hydroxyl radical was significantly lower. The TBARS assay revealed that resorcimoline inhibited tissue lipid peroxidation in a concentration-dependent manner. Moreover, resorcimoline exhibited no cytotoxicity at concentrations up to 100 μM and remained stable at room temperature under ambient light for 7 d. These findings indicate that resorcimoline's direct free radical scavenging activity could contribute to its potential clinical antioxidative effects.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"332-341"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen alleviates myocardial infarction by impeding apoptosis via ROS-mediated mitochondrial endogenous pathway.","authors":"Shuang Pan, Bin Wang, Mengshu Yu, Jiawen Zhang, Bowei Fan, Chaoqun Nie, Rentong Zou, Xinrui Yang, Zhuoqun Zhang, Xiaojian Hong, Wei Yang","doi":"10.1080/10715762.2025.2474014","DOIUrl":"10.1080/10715762.2025.2474014","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) is a deadly cardiovascular disease with no effective solution except for percutaneous coronary intervention and coronary artery bypass grafting. Inflammation and apoptosis of the injured myocardium after revascularization seriously affect the prognosis. Hydrogen possesses anti-inflammatory, anti-oxidative, and anti-apoptotic effects and may become a new treatment for AMI. This study explored the specific mechanism by which hydrogen operates during AMI treatment.</p><p><strong>Methods: </strong>Thirty Sprague-Dawley rats were randomly divided into three groups: control, myocardial infarction (MI), and myocardial infarction + hydrogen (MI+H₂), each containing 10 rats. The MI rat model was established by ligation of the left anterior descending branch. The MI+H₂ group received 2% hydrogen inhalation treatment for 3 h/Bid.</p><p><strong>Results: </strong>Myocardial infarct size was evaluated using triphenyl tetrazolium chloride staining. Transmission electron microscopy showed reduced mitochondrial damage compared with the MI group. JC-1 staining, which indicates mitochondrial membrane potential, showed a low red/green fluorescence intensity ratio in the MI group compared to that in the control group, indicating mitochondrial membrane potential loss. After hydrogen inhalation, this ratio increased, suggesting partial recovery of membrane potential. In addition, mitochondrial ATP content, mitochondrial complex I, and mitochondrial complex III activity were significantly decreased in the MI group, which was improved after hydrogen administration. Western blotting analysis showed decreased Cyt-c protein levels in the myocardial mitochondria and increased levels in the cytoplasm of MI rats. Following hydrogen inhalation, the levels of ROS, 8-OHdG, and MDA that could represent oxidative stress injury significantly decreased. Besides, the expression of Cyt-C, Bax, cleaved-caspase-9, and cleaved-caspase-3 in MI group significantly increased, while the Bcl-2, TRX2, SOD2 expression decreased. The expression of these proteins in MI+H2 group was improved compared with the MI group.</p><p><strong>Conclusion: </strong>Overall, hydrogen inhalation reduces myocardial infarct size, improves mitochondrial dysfunction, and modulates the levels of apoptosis-related substances. Importantly, Hydrogen reduces acute myocardial infarction damage by downregulating ROS and upregulating antioxidant proteins.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"226-238"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOD mimics delivered to the gut using lactic acid bacteria mitigate the colitis symptoms in a mouse model of inflammatory bowel diseases.","authors":"Gabrielle Schanne, Amandine Vincent, Florian Chain, Pauline Ruffié, Célia Carbonne, Elodie Quévrain, Emilie Mathieu, Alice Balfourier, Luis G Bermúdez-Humarán, Philippe Langella, Sophie Thenet, Véronique Carrière, Nassim Hammoudi, Magali Svrcek, Sylvie Demignot, Philippe Seksik, Clotilde Policar, Nicolas Delsuc","doi":"10.1080/10715762.2025.2478121","DOIUrl":"10.1080/10715762.2025.2478121","url":null,"abstract":"<p><p>Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, represent a global health issue as a prevalence of 1% is expected in the western world by the end of this decade. These diseases are associated with a high oxidative stress that induces inflammatory pathways and severely damages gut tissues. IBD patients suffer from antioxidant defenses weakening, through, for instance, an impaired activity of superoxide dismutases (SOD)-that catalyze the dismutation of superoxide-or other endogenous antioxidant enzymes including catalase and glutathione peroxidase. Manganese complexes mimicking SOD activity have shown beneficial effects on cells and murine models of IBD. However, efficient SOD mimics are often manganese complexes that can suffer from decoordination and thus inactivation in acidic stomachal pH. To improve their delivery in the gut after oral administration, two SOD mimics <b>Mn1</b> and <b>Mn1C</b> were loaded into lactic acid bacteria that serve as delivery vectors. When orally administrated to mice suffering from a colitis, these chemically modified bacteria (CMB) showed protective effects on the global health status of mice. In addition, they have shown beneficial effects on lipocalin-2 content and intestinal permeability. Interestingly, mRNA SOD2 content in colon homogenates was significantly decreased upon mice feeding with CMB loaded with <b>Mn1C</b>, suggesting that the beneficial effects observed may be due to the release of the SOD mimic in the gut that complement for this enzyme. These CMB represent new efficient chemically modified antioxidant probiotics for IBD treatment.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"262-273"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the oxidative mechanism of methotrexate on catalase enzyme: an in vitro study.","authors":"Fatemeh Jamali, Farzaneh Jafary, Mohammad Hossein Aarabi, Farjam Goudarzi, Bahareh Koohshekan, Adel Mohammadalipour","doi":"10.1080/10715762.2025.2481517","DOIUrl":"10.1080/10715762.2025.2481517","url":null,"abstract":"<p><p>Methotrexate (MTX) is a well-known anti-metabolite agent recognized for its oxidative effects, particularly in the liver where the enzyme catalase is abundant. This research aimed to clarify the impact of MTX on the behavior of liver catalase. The cytotoxicity of HepG2 cells was assessed across various concentrations of MTX. Following that, the examination focused on the generation of reactive oxygen species (ROS) and the activity of catalase. Furthermore, the kinetic activity of bovine liver catalase (BLC) was examined in the presence of MTX. Finally, the interaction between MTX and the enzyme's protein structure was investigated using docking and dynamic light scattering (DLS) methods. The results indicated a significant decrease in catalase activity and a significant increase in ROS production in HepG2 cells treated with MTX. Although the activity of BLC remained unaffected by MTX directly, molecular docking and DLS techniques revealed MTX binding to BLC, inhibiting its tetramerization. The oxidative effects of MTX were associated with elevated ROS levels in cellular processes, leading to excessive catalase activity and subsequent suicide inactivation. Furthermore, MTX influenced the protein structure of catalase.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"289-296"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative imbalance linked to impaired mitochondrial bioenergetics mediates the toxicity of mesoionic compounds MI-D and MI-J in hepatocarcinoma cells (HepG2).","authors":"Ana Paula Perbiche Neves, Fernando Diego Kaziuk, Marília Locatelli Corrêa-Ferreira, Glaucia Regina Martinez, Ester Mazepa, Danilo Sousa-Pereira, Aurea Echevarria, Sheila Maria Brochado Winnischofer, Amanda do Rocio Andrade Pires, Silvia Maria Suter Correia Cadena","doi":"10.1080/10715762.2025.2485219","DOIUrl":"10.1080/10715762.2025.2485219","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a common and deadly form of liver cancer with limited treatment options for advanced stages. Mesoionic compounds MI-D and MI-J have shown potential for treating HCC due to their significant toxicity to these cells. This study investigated whether this toxicity is linked to their effects on oxidative balance in HepG2 cells cultured in high glucose (HG-glycolysis-dependent) and galactose plus glutamine supplemented (GAL-oxidative phosphorylation-dependent) DMEM medium. ROS levels were increased in cells cultured in both media when exposed to MI-D and MI-J (50 μM). However, MI-D at an intermediate concentration (25 μM) decreased ROS levels in the GAL medium. Superoxide dismutase (SOD) activity increased under all tested conditions by compounds (25 μM). Conversely, MI-D and MI-J decreased total peroxidase activity in both media at 25 and 50 μM, respectively. MI-D in the HG medium decreased glutathione peroxidase (GPX) activity, whereas MI-J reduced the enzyme activity at a concentration of 25 μM and increased it at 50 μM. In the GAL medium, MI-J (50 μM) increased GPx activity, while glutathione reductase (GR) activity was decreased by the compounds (50 μM) in both media. Furthermore, the P-AMPK/tAMPk ratio was increased by MI-J at 25 μM in the GAL medium. Our results show that MI-D and MI-J caused oxidative imbalance, particularly affecting cells cultured in the GAL medium. The data also support that the mesoionic effects depended on their concentration and substituent in the mesoionic ring.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"308-320"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Down-regulation of Selenoprotein K impairs the proliferation and differentiation of chicken skeletal muscle satellite cells by inhibiting the Nrf2 antioxidant signaling pathway.","authors":"Xue-Wei Chen, Yue Li, Yi-Tong Fu, Wan-Xue Xu, Jie Yang, Xue Wen, Rui-Feng Fan","doi":"10.1080/10715762.2025.2470900","DOIUrl":"10.1080/10715762.2025.2470900","url":null,"abstract":"<p><p>Skeletal muscle satellite cells (SMSCs) are pivotal for skeletal muscle regeneration post-injury, and their development is intricately influenced by regulatory factors. Selenoprotein K (SELENOK), an endoplasmic reticulum resident selenoprotein, is known for its crucial role in maintaining skeletal muscle redox sensing. However, the specific molecular mechanism of SELENOK in SMSCs remains unclear. In this study, a SELENOK knockdown model was established to delve into its role in SMSCs. The results revealed that SELENOK knockdown hindered SMSCs proliferation and differentiation, as evidenced by the regulation of key proteins such as Pax7, Myf5, CyclinD1, MyoD, and Myf6, and the inhibitory effects were mitigated by N-Acetyl-l-cysteine (NAC). SELENOK knockdown induced oxidative stress, further analyses uncovered that SELENOK knockdown downregulated nuclear transcription factor nuclear erythroid factor 2-like 2 (Nrf2) protein expression while upregulating cytoplasmic kelch-like ECH-associated protein 1 (Keap1) protein expression. SELENOK knockdown impeded Nestin and sequestosome 1/p62 (p62) interaction with Keap1, leading to increased Nrf2 ubiquitination. This prevented Nrf2 transportation from cytoplasm to nucleus mediated by Keap1, ultimately resulting in the downregulation of catalase (CAT), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) protein expression. Notably, SELENOK knockdown-induced inhibition of SMSCs proliferation and differentiation was alleviated by Oltipraz, an activator of the Nrf2 pathway. This study provided novel insights, demonstrating that SELENOK is a key player in SMSCs proliferation and differentiation by influencing the Nrf2 antioxidant signaling pathway.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"215-225"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of iron ions in 6-hydroxydopamine-induced disruption of intracellular copper metabolism.","authors":"Ami Kato, Ayano Tani, Fuka Kamijo, Tomohiro Otsuka, Tetsuro Kamiya, Hirokazu Hara","doi":"10.1080/10715762.2025.2465276","DOIUrl":"10.1080/10715762.2025.2465276","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Recently, disorders in metabolism of metals, including copper (Cu) and iron (Fe), have been reported to be linked to the pathogenesis of PD. We previously demonstrated that 6-hydoroxydopamine (6-OHDA), a neurotoxin used for the production of PD model animals, decreases Atox1, a Cu chaperone, and ATP7A, a Cu transporter, and disrupts intracellular Cu metabolism in human neuroblastoma SH-SY5Y cells. However, the exact mechanisms remain unclear. Meanwhile, intracellular Fe modulates 6-OHDA-induced cellular responses. In this study, we investigated whether Fe participates in 6-OHDA-induced abnormality in Cu metabolism. 6-OHDA-induced reactive oxygen species (ROS) production and cellular injury were suppressed by Fe chelators, deferoxamine and 2,2'-bipyridyl (BIP). These chelators also restored 6-OHDA-induced degradation of Atox1 and ATP7A proteins and subsequent Cu accumulation, indicating that intracellular Fe is involved in the disruption of Cu homeostasis associated with 6-OHDA. Atox1 has redox-sensitive cysteine (Cys) residues in its Cu-binding site. The Cys residues of Atox1 were oxidized by 6-OHDA, and BIP suppressed their oxidation. Moreover, the replacement of Cys with histidine in the Cu-binding site conferred resistance to 6-OHDA-induced Atox1 degradation. These results suggest that oxidized modification of Atox1 by 6-OHDA is likely to accelerate its degradation. Thus, we conclude that Fe and Cu metabolisms are closely related to each other in the pathogenesis of PD.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"129-137"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin ameliorates gestational diabetes mellitus via inhibiting ferroptosis of trophoblasts through the Nrf2/HO-1 signaling pathway.","authors":"Lingya Fang, Sha Lu, Liuyuan Fang, Junxin Yu, Nisile Kakongma, Wensheng Hu","doi":"10.1080/10715762.2025.2468737","DOIUrl":"10.1080/10715762.2025.2468737","url":null,"abstract":"<p><p>Both mothers and infants experience oxidative stress due to gestational diabetes mellitus (GDM), which is strongly associated with adverse pregnancy outcomes. Ferroptosis, a novel form of programmed cell death characterized by iron-dependent lipid peroxidation, is believed to play a critical role in the pathogenesis and progression of GDM. Metformin (MET) has shown potential in alleviating oxidative stress; however, research on its specific mechanisms of action in GDM remains limited. We collected placental tissues from GDM patients and healthy controls and established an <i>in vitro</i> GDM cell model. We measured markers of ferroptosis including malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase 4 (GPX4) activity. Additionally, we evaluated reactive oxygen species (ROS) levels, apoptosis, cell viability, and migration in the cell model. Our findings revealed significant changes in the GDM group compared to controls, including increased MDA and GSSG levels, decreased GSH levels, and reduced expression of GPX4 protein in the GDM placenta. High-glucose (HG) conditions were shown to reduce trophoblast cell viability and migration, accompanied by elevated ROS and MDA levels, as well as reduced expression of GSH, GPX4, Nrf2, and HO-1 proteins. Importantly, treatment with MET reversed these effects, similar to the action of deferoxamine mesylate (DFOM), a known ferroptosis inhibitor. These results confirm the occurrence of ferroptosis in the placentas of GDM patients and demonstrate that MET mitigates high-glucose-induced ferroptosis in trophoblasts through the Nrf2/HO-1 signaling pathway. This study provides novel insights into the protective mechanisms of MET, offering potential therapeutic strategies for GDM. management.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"190-203"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}