Free Radical Research最新文献

{"title":"Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion <i>via</i> orosomucoid 1-like protein 3 in airway epithelia.","authors":"Rui Chen, Yuting Cui, Mary Sau-Man Ip, Judith Choi-Wo Mak","doi":"10.1080/10715762.2025.2501019","DOIUrl":"10.1080/10715762.2025.2501019","url":null,"abstract":"<p><p>Apart from a strong association with childhood-onset asthma, orosomucoid 1-like protein 3 (ORMDL3), an endoplasmic reticulum (ER)-localized transmembrane protein, is also linked with chronic obstructive pulmonary disease (COPD), in which cigarette smoke (CS) is the crucial risk factor. Compared to healthy subjects, COPD patients had elevated ORMDL3 mRNA in well-differentiated primary human bronchial epithelial cells (HBECs). However, its role in COPD remains understudied. We, therefore, hypothesize that ORMDL3 may play an essential role in CS-induced chronic mucus hypersecretion and inflammation <i>via</i> activation of specific unfolded protein response (UPR) pathways under ER stress in primary HBECs. Gene silencing using siRNA for ORMDL3 was performed in submerged culture of primary HBECs before 24-h cigarette smoke medium (CSM) exposure. The mucin, inflammatory and mitochondrial markers, and the activation of the UPR pathways were evaluated. CSM triggered significant induction of ORMDL3 expression at both mRNA and protein level, which was significantly inhibited by silencing ORMDL3. In addition, ORMDL3 knockdown inhibited CSM-induced mucin MUC5AC mRNA and release of inflammatory marker interleukin (IL)-8. Silencing ORMDL3 reduced CSM-induced ER stress <i>via</i> inhibiting the activating transcription factor (ATF)6 and the inositol-requiring enzyme (IRE)1 of the UPR pathways. The involvement of ORMDL3 was demonstrated in mitochondrial dynamics <i>via</i> fusion protein Mfn2 and mitochondrial respiration after CSM stimulation. In conclusion, ORMDL3 is an inducible gene in mediating CS-induced activation of specific ATF6 and IRE1 pathways to regulate mucus hypersecretion and inflammation. Therefore, ORMDL3 may be a promising therapeutic target to treat smoking-associated mucus hypersecretion and inflammation in COPD.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"342-355"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993850","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":"Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of <i>N</i>⁴-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>⁴-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 H₂O₂-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 H₂O₂ 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 H₂O₂ 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":"205-214"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","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}

{"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":"239-249"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","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}

{"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}