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Oxidative imbalance linked to impaired mitochondrial bioenergetics mediates the toxicity of mesoionic compounds MI-D and MI-J in hepatocarcinoma cells (HepG2).
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-04-01 DOI: 10.1080/10715762.2025.2485219
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
{"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":"1-13"},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","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}
引用次数: 0
Comparison of microbubbling and conventional bubbling methods for ozonated saline solution in CKD patients: a pilot study.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-30 DOI: 10.1080/10715762.2025.2483454
Estoneck Guevara-Aguilar, Diana Moroni-González, José Carlos Jiménez-Ortega, Samuel Treviño, Victor Enrique Sarmiento-Ortega
{"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 (H<sub>2</sub>O<sub>2</sub>) 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, H<sub>2</sub>O<sub>2</sub>, lipoperoxidation), and renal function markers (urea, creatinine, glomerular filtration rate) were evaluated. Microbubbling produced lower H<sub>2</sub>O<sub>2</sub> 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":"1-11"},"PeriodicalIF":3.6,"publicationDate":"2025-03-30","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}
引用次数: 0
Edaravone inhibits neuronal ferroptosis and alleviates acute Central nervous system injury induced by diquat via enhancement of METTL14-mediated m6A methylation of Aldh1l1.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-28 DOI: 10.1080/10715762.2025.2482774
Liaozhang Wu, Zunwei Luo, Fuli Luo, Tingting Huang, Yifang Cen, Guosheng Rao, Zhijie Zhao, Renyang Ou, Manhong Zhou
{"title":"Edaravone inhibits neuronal ferroptosis and alleviates acute Central nervous system injury induced by diquat <i>via</i> enhancement of METTL14-mediated m6A methylation of Aldh1l1.","authors":"Liaozhang Wu, Zunwei Luo, Fuli Luo, Tingting Huang, Yifang Cen, Guosheng Rao, Zhijie Zhao, Renyang Ou, Manhong Zhou","doi":"10.1080/10715762.2025.2482774","DOIUrl":"10.1080/10715762.2025.2482774","url":null,"abstract":"<p><p>The biological effects of edaravone (Eda), a free radical scavenger, include anti-inflammatory, antioxidant, and neuroprotective qualities. Nevertheless, the function and potential mechanisms of Eda in central nervous system injury damage are still unknown. A rat model of acute diquat toxicity was constructed to observe the pathological changes in brain tissues after diquat administration. The changes of mitophagy and ferroptosis in PC12 cells were assessed to the protective activity of Eda. To assess the methylation levels of m6A RNA, the EpiQuik m6A RNA Methylation Quantification Kit was utilized. RIP, dual luciferase reporter assay and mRNA stability detection confirm the relationship between METTL14 and Aldh11l1. Knockdown and overexpression experiments were performed to determine the effects of METTL14 and Aldh1l1 on rats and PC12 cells stimulated with diquat under Eda treatment. Eda dramatically ameliorated diquat-induced central nervous system injury. Eda notably attenuated apoptosis, pro-inflammatory cytokines activation, and oxidative stress damage in diquat-induced rats. Eda significantly suppressed apoptosis, mitophagy and ferroptosis after diquat-stimulated PC12 cells. Mitophagy inhibitor Mdivi-1 reversed the induction of ferroptosis effects of diquat via decreased Fe2+ content and increased Ca2+ level. knockdown of METTL14 reversed the therapeutic effect of Eda on diquat-induced injury. Eda promoted METTL14-mediated Aldh1l1 m6A methylation and alleviates acute central nervous system injury induced by diquat in vivo and in vitro. Eda has a protective effect on diquat-induced nervous system injury, and its mechanism may be related to the activation of m6A modification of Aldh11l1 by METTL14 and the inhibition of mitophagy and.</p><p><p>ferroptosis.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-15"},"PeriodicalIF":3.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700054","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}
引用次数: 0
SOD mimics delivered to the gut using lactic acid bacteria mitigate the colitis symptoms in a mouse model of inflammatory bowel diseases.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-21 DOI: 10.1080/10715762.2025.2478121
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
{"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":"1-12"},"PeriodicalIF":3.6,"publicationDate":"2025-03-21","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}
引用次数: 0
Exploring the Oxidative Mechanism of Methotrexate on Catalase Enzyme: An In Vitro Study.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-17 DOI: 10.1080/10715762.2025.2481517
Fatemeh Jamali, Farzaneh Jafary, Mohammad Hossein Aarabi, Farjam Goudarzi, Bahareh Koohshekan, Adel Mohammadalipour
{"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":"https://doi.org/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":"1-9"},"PeriodicalIF":3.6,"publicationDate":"2025-03-17","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}
引用次数: 0
FABP3 promotes cell apoptosis and oxidative stress by regulating ferroptosis in lens epithelial cells.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-13 DOI: 10.1080/10715762.2025.2475390
Qi Wang, Chunxiao Zhang, Bin Yu, Yanyan Zhang, Yuanyuan Guo
{"title":"FABP3 promotes cell apoptosis and oxidative stress by regulating ferroptosis in lens epithelial cells.","authors":"Qi Wang, Chunxiao Zhang, Bin Yu, Yanyan Zhang, Yuanyuan Guo","doi":"10.1080/10715762.2025.2475390","DOIUrl":"10.1080/10715762.2025.2475390","url":null,"abstract":"<p><p>The purpose of this study is to investigate FABP3's biological function and potential mechanism in cataract. Treatment of H<sub>2</sub>O<sub>2</sub> raised FABP3 expression. H<sub>2</sub>O<sub>2</sub> decreased cell viability, enhanced apoptosis, promoted Bax and cleaved caspase-3 expression, inhibited Bcl-2 expression, enhanced the levels of IL-6, IL-1β, and TNF-α, raised MDA level, and decreased SOD and GSH levels in HLE-B3 cells. However, the effects of H<sub>2</sub>O<sub>2</sub> on cell viability, apoptosis, inflammatory cytokines, and oxidative stress were reversed by FABP3 knockdown and aggravated by FABP3 overexpression. H<sub>2</sub>O<sub>2</sub> increased the levels of lipid hydroperoxides and Fe<sup>2+</sup>, but reduced the expression of GPX4, SLC7A11, and Ferritin protein. Nevertheless, knockdown of FABP3 reversed the changes of lipid hydroperoxides, Fe<sup>2+</sup>, GPX4, SLC7A11, and Ferritin protein, and FABP3 overexpression caused the opposite results. In addition, the inhibition of FABP3 knockdown on cell apoptosis, inflammation, and oxidative stress was reversed by ferroptosis inducer (erastin), and the promotion of FABP3 overexpression on cell apoptosis, inflammation, and oxidative stress was reversed by ferroptosis inhibitor (Fer-1). Taken together, knockdown of FABP3 in lens epithelial cells treated with H<sub>2</sub>O<sub>2</sub> restrained apoptosis, inflammation, and oxidative stress through regulating ferroptosis, suggesting that FABP3 might be a potential target for cataract treatment.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-12"},"PeriodicalIF":3.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566561","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}
引用次数: 0
Hydrogen alleviates myocardial infarction by impeding apoptosis via ROS-mediated mitochondrial endogenous pathway.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-07 DOI: 10.1080/10715762.2025.2474014
Shuang Pan, Bin Wang, Mengshu Yu, Jiawen Zhang, Bowei Fan, Chaoqun Nie, Rentong Zou, Xinrui Yang, Zhuoqun Zhang, Xiaojian Hong, Wei Yang
{"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+H<sub>2</sub>), each containing 10 rats. The MI rat model was established by ligation of the left anterior descending branch. The MI+H<sub>2</sub> 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":"1-13"},"PeriodicalIF":3.6,"publicationDate":"2025-03-07","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}
引用次数: 0
Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-06 DOI: 10.1080/10715762.2025.2469738
Yurie Mori, Rinya Yogo, Hatasu Kobayashi, Hirotaka Katsuzaki, Yuichiro Hirao, Shinya Kato, Hirokazu Kotani, Shosuke Kawanishi, Mariko Murata, Shinji Oikawa
{"title":"Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of <i>N</i><sup>4</sup>-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir.","authors":"Yurie Mori, Rinya Yogo, Hatasu Kobayashi, Hirotaka Katsuzaki, Yuichiro Hirao, Shinya Kato, Hirokazu Kotani, Shosuke Kawanishi, Mariko Murata, Shinji Oikawa","doi":"10.1080/10715762.2025.2469738","DOIUrl":"10.1080/10715762.2025.2469738","url":null,"abstract":"<p><p>Molnupiravir is a prodrug of the antiviral ribonucleoside analogue <i>N</i><sup>4</sup>-hydroxycytidine (NHC), for use in the treatment of coronavirus disease 2019 (COVID-19). However, it is generally considered that NHC-triphosphate is incorporated into the host genome to induce mutations. In our previous preliminary report, we proposed oxidative DNA damage by NHC <i>via</i> cytidine deaminase (CDA)-mediated ROS formation. In the present study, we investigated cell viability using the HL-60 human leukemia cell line and its H<sub>2</sub>O<sub>2</sub>-resistant clone, HP100 cells. The survival rate was significantly reduced in HL-60 cells treated with NHC, but not in HP100 cells. LC-MS analysis revealed that uridine formation occurred from CDA-treated NHC, suggesting that CDA metabolizes NHC to uridine and hydroxylamine. We clarified mechanisms of CDA-mediated reactive oxygen species (ROS) generation and DNA damage by NHC using isolated DNA. CDA-treated NHC induced DNA damage in the presence of Cu(II). The DNA damage was enhanced by NADH addition and piperidine treatment. CDA-treated NHC and Cu(II) caused piperidine-labile sites at thymine, cytosine, and guanine, and the DNA cleavage pattern was similar to that of hydroxylamine. Catalase and bathocuproine inhibited the DNA damage, indicating the involvement of H<sub>2</sub>O<sub>2</sub> and Cu(I). An indicator of oxidative DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanosine formation by CDA-treated NHC, was lower under hypoxic conditions than under normal conditions. Therefore, hydroxylamine, possibly produced from NHC treated with CDA, could induce metal-dependent H<sub>2</sub>O<sub>2</sub> generation during the redox reactions, suggesting that oxidative DNA damage induced by ROS plays an important role in molnupiravir-related cytotoxicity and mutagenicity.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-10"},"PeriodicalIF":3.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457308","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}
引用次数: 0
Examining the prognostic and clinicopathological significance of GPX4 in human cancers: a meta-analysis.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-03-06 DOI: 10.1080/10715762.2025.2475153
Hao Wu, Xiting Liao, Wusixian Huang, Huai Hu, Lan Lan, Qianlei Yang, Yan An
{"title":"Examining the prognostic and clinicopathological significance of GPX4 in human cancers: a meta-analysis.","authors":"Hao Wu, Xiting Liao, Wusixian Huang, Huai Hu, Lan Lan, Qianlei Yang, Yan An","doi":"10.1080/10715762.2025.2475153","DOIUrl":"10.1080/10715762.2025.2475153","url":null,"abstract":"<p><p>Elevated levels of the enzyme GPX4 have been detected in tumor tissues, which may play a role in cancer progression. We did a meta-analysis of eight studies encompassing 1180 individuals to evaluate the importance of GPX4 in cancer, particularly in terms of prognosis and clinicopathological characteristics. Research results indicate that higher levels of GPX4 were linked to worse overall survival (OS) (HR = 1.47 [95%CI = 1.18-1.76], <i>p</i> < .001). Elevated levels of GPX4 were linked to lymph node invasion (OR.69 [95% CI.44-1.10], <i>p</i> =.12), metastasis (OR 1.58 [95% CI.97-2.55], <i>p</i> =.06, p <.0001), and advanced clinical stage III-IV (OR.82 [95% CI.70-.96], <i>p</i> =.001). A sensitivity study revealed that the general findings were constant across all levels of impact intensity. The findings of this meta-analysis suggest that increased GPX4 levels are not only correlated with reduced overall survival rates for patients with tumors but it also offers valuable insights regarding the clinical traits of tumor malignancy and metastasis. Based on these connections, GPX4 has the potential to serve as a biomarker for tumor detection, prognosis, and targeted therapy.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-11"},"PeriodicalIF":3.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540730","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}
引用次数: 0
Down-regulation of Selenoprotein K impairs the proliferation and differentiation of chicken skeletal muscle satellite cells by inhibiting the Nrf2 antioxidant signaling pathway.
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2025-02-26 DOI: 10.1080/10715762.2025.2470900
Xue-Wei Chen, Yue Li, Yi-Tong Fu, Wan-Xue Xu, Jie Yang, Xue Wen, Rui-Feng Fan
{"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":"1-11"},"PeriodicalIF":3.6,"publicationDate":"2025-02-26","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}
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