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Antioxidant flavonoid baicalein as a dual purpose radiomodifier with promising bench to bedside potential. 抗氧化黄酮类黄芩素作为一种双重用途的放射改性剂,具有良好的临床应用潜力。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-10-21 DOI: 10.1080/10715762.2025.2568922
Raghavendra S Patwardhan, Deepak Sharma, Santosh K Sandur
{"title":"Antioxidant flavonoid baicalein as a dual purpose radiomodifier with promising bench to bedside potential.","authors":"Raghavendra S Patwardhan, Deepak Sharma, Santosh K Sandur","doi":"10.1080/10715762.2025.2568922","DOIUrl":"10.1080/10715762.2025.2568922","url":null,"abstract":"<p><p>Despite the potential of drug-radiotherapy combinations, a limited number of oncology drugs are approved by FDA for use along with radiotherapy. Currently, there is no agent available in the clinic that can exhibit dual radiomodifying behavior. Despite availability of sophisticated, high-precision techniques in radiotherapy for accurate targeting of tumors, normal tissue toxicity impedes its use in curative settings. Combining radiotherapy with an agent that can protect normal tissue and augment tumor killing can improve therapy outcomes. Other than combining drugs for therapeutic radiation exposure, there is a pressing need of identifying agents for management of unwanted effects of accidental radiation exposure. There is a serious deficit in the repertoire of currently available safe and effective radiation countermeasures. Baicalein, a bioactive component from the roots of traditional Chinese medicinal herb <i>Scutellaria baicalensis</i> has been shown to protect against acute as well as chronic effects of radiation exposure including normal tissue injury to lungs, gut, hematopoietic system, intestine, endothelial and neuronal cells by us and other labs worldwide. Further, administration of baicalein alone or in combination with other agents prevents radiation-induced mortality in mice. Additionally, numerous studies have reported radiosensitizing potential of baicalein in lung, breast, esophageal, cervical and prostate cancer. Moreover, safety, tolerability, and pharmacokinetics of baicalein is well established in healthy human subjects. Here we provide a succinct overview of the distinctive radiomodifying potential of baicalein, safety, pharmacology underscoring its utility as a prospective radiomodifier in clinical settings.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-24"},"PeriodicalIF":2.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291799","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
Spatiotemporal analysis of ROS in hepatic ischemia-reperfusion and prediction of organ damage using MRI. 肝缺血再灌注中ROS的时空分析及MRI预测器官损伤。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-10-11 DOI: 10.1080/10715762.2025.2573374
Atsushi Yamashita, Hitoshi Togashi, Kazuyuki Haga, Shingo Nakai, Yoshinori Kuroda, Mitsuaki Sadahiro, Tetsuro Uchida
{"title":"Spatiotemporal analysis of ROS in hepatic ischemia-reperfusion and prediction of organ damage using MRI.","authors":"Atsushi Yamashita, Hitoshi Togashi, Kazuyuki Haga, Shingo Nakai, Yoshinori Kuroda, Mitsuaki Sadahiro, Tetsuro Uchida","doi":"10.1080/10715762.2025.2573374","DOIUrl":"10.1080/10715762.2025.2573374","url":null,"abstract":"<p><p>Our study focused on the spatiotemporal analysis of reactive oxygen species (ROS), a key factor in hepatic ischemia-reperfusion injury, using a rat model to evaluate potential clinical applications. By inducing partial hepatic ischemia-reperfusion in rats through ligation of left portal vein and hepatic artery (one hour ischemia followed by reperfusion), we explored ROS generation using an imaging probe, 1-acetoxy-3-carbamoyl-2,2,5,5-tetramethylpyrroline (ACP), which reacts with ROS to produce a detectable T1-enhanced magnet resonance imaging (MRI) signal. In the rat model, the region of the left liver ischemia-reperfusion showed extremely mild liver injury one hour after reperfusion. After 12 h of reperfusion, extensive hepatocellular necrosis was observed, mainly in the hepatic interlobular region. One hour after reperfusion, the ACP-derived MRI signal increased in the region of left lobe ischemia-reperfusion was significantly higher than that in the non-ischemia-reperfusion region of the same rat right lobe. Administration of edaravone targeting the period of excessive ROS production at 1 h after reperfusion significantly suppressed hepatic injury 12 h after ischemia-reperfusion. Given MRI's crucial role in clinical diagnostics and its adaptability, our research suggests a promising strategy for early intervention in organ damage by monitoring and modulating ROS levels, potentially revolutionizing patient care.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-11"},"PeriodicalIF":2.9,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250632","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
Impact of genetic variability on NADPH oxidase activity: an extensive genotype-phenotype assessment. 遗传变异对NADPH氧化酶活性的影响:一项广泛的基因型-表型评估。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-10-07 DOI: 10.1080/10715762.2025.2526057
Tana Takacova, Markus Anton Schirmer
{"title":"Impact of genetic variability on NADPH oxidase activity: an extensive genotype-phenotype assessment.","authors":"Tana Takacova, Markus Anton Schirmer","doi":"10.1080/10715762.2025.2526057","DOIUrl":"10.1080/10715762.2025.2526057","url":null,"abstract":"<p><p><b>Introduction:</b> Oxidative stress is implicated in various diseases, and the NADPH oxidase enzyme complex (NOX) is a significant source of reactive oxygen species (ROS). Research linking genetic polymorphisms to enzyme activity has produced conflicting results. <b>Methods:</b> We aimed to establish a robust protocol to assess NOX activity <i>in vitro</i> under highly standardized conditions and correlate these measurements with genetic polymorphisms catalogued by the 1000 Human Genome Project and the HapMap Project. Lymphoblastoid cell lines (LCLs) served as a model system with samples from healthy participants from three Caucasian populations. NOX activity stimulated by phorbol 12-myristate 13-acetate was measured using chemiluminescence in 290 LCLs (198 in a training and 92 in a test set) through a series of multiply repeated measurements per LCL comprising in total over 1,500 NOX activity assessments. The association between NOX activity and single nucleotide polymorphisms (SNPs) in the NOX subunit genes <i>CYBA</i>, <i>CYBB</i>, <i>NCF1</i>, <i>NCF2</i>, and <i>NCF4</i> was subsequently examined. <b>Results:</b> Out of 651 valid polymorphic markers, 308 had a minor allele frequency of ≥ 5%, and 15 SNPs showed a statistically significant correlation with NOX activity in the training set. However, these 15 associations were not confirmed in the test set (all <i>p</i> ≥ 0.1). Additional analyses treating all 290 LCLs as a single cohort yielded three associations at <i>p</i> < 0.01, i.e. <i>CYBA</i> rs1017828, <i>NCF1</i> rs191081238, and <i>NCF4</i> rs4821544. However, statistical significance could not be called for any of these genetic markers upon adjustment for multiple testing, regardless whether a co-dominant, dominant or recessive allelic effect was assumed. <b>Conclusion:</b> Our results do not support a reproducible impact of common genetic diversity in NOX subunits on the enzyme activity in LCLs of subjects of Caucasian origin. This study represents the largest evaluation concerning relationships between NOX genetic variants and enzyme activity to date.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-9"},"PeriodicalIF":2.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527088","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
Therapeutic potential of nicotine in modulating oxidative and mitochondrial pathways in a C. elegans Parkinson's disease model. 尼古丁在秀丽隐杆线虫帕金森病模型中调节氧化和线粒体通路的治疗潜力
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-10-06 DOI: 10.1080/10715762.2025.2567430
Inam Ullah, Shahab Uddin, Wang Xin, Hongyu Li
{"title":"Therapeutic potential of nicotine in modulating oxidative and mitochondrial pathways in a <i>C. elegans</i> Parkinson's disease model.","authors":"Inam Ullah, Shahab Uddin, Wang Xin, Hongyu Li","doi":"10.1080/10715762.2025.2567430","DOIUrl":"10.1080/10715762.2025.2567430","url":null,"abstract":"<p><p>Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases that affect the central nervous system (CNS) in elderly individuals. As of right now, there is no recognized cure for this illness. Bioactive phytochemicals are a natural alternative that can help older persons postpone age-related cognitive diseases. This study attempts to establish whether nicotine, may diminish Parkinsonism in a model of <i>Caenorhabditis elegans</i> disease. This study analyzes the antioxidant and restorative mitochondrial dysfunction potential of nicotine and its related neuroprotective benefits by utilizing models of Caenorhabditis worm strains that are different from the wild type. We examined the effects of nicotine on oxidative stress tolerance and associated regulatory pathways using a model of Caenorhabditis worms. Our results showed that wild-type <i>C. elegans</i> treated with nicotine had higher survival rates during oxidative stress caused by Juglone than those treated with the control. Nicotine decreased intracellular reactive oxygen species levels in <i>C. elegans</i>. In addition, nicotine increased levels of SOD, CAT, and MDA as well as the expression of genes related to stress response, including gst-4, hsf-6, and hsf-1, and mitochondrial function genes, including mev-1, isp-1, and cox-4. Finally, our molecular analysis indicates that the anti-oxidative effects of nicotine are mediated <i>via</i> skin-1 modulation. After Paraquat was administered, nicotine therapy also resulted in higher levels of ATP and MMP. Our research clarifies the various mechanisms of action and communication pathways that underlie nicotine's antioxidant activity <i>in vivo</i>, offering a solid pharmacological foundation for its potential therapeutic use in neurodegeneration.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-18"},"PeriodicalIF":2.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191506","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
Mitochondria and redox homeostasis - the backseat drivers in glioma. 线粒体和氧化还原稳态-神经胶质瘤的后座驾驶员。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-08-23 DOI: 10.1080/10715762.2025.2548479
Shruti Patrick, Ellora Sen
{"title":"Mitochondria and redox homeostasis - the backseat drivers in glioma.","authors":"Shruti Patrick, Ellora Sen","doi":"10.1080/10715762.2025.2548479","DOIUrl":"10.1080/10715762.2025.2548479","url":null,"abstract":"<p><p>Mitochondrial function and redox regulatory processes are crucial aspects of cellular metabolism and energy production. Cancers, including gliomas, largely exhibit altered mitochondrial function, which can lead to changes in cellular signaling pathways and redox homeostasis. Aberrant redox signaling can promote glioma progression by influencing cell proliferation, metastasis, and therapeutic response. Several cancer-associated driver mutations - genetic alterations that confer survival and growth advantage to cancer cells, are associated with gliomas and affect mitochondrial function and redox states. Here is an overview of the crucial intersection between mitochondrial function and driver genes in glioma, highlighting some of the recent advances that augment our understanding of this intersection.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"557-569"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144845317","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
Selenoprotein GPX3 suppresses gastric adenocarcinoma proliferation and improves patient survival. 硒蛋白GPX3抑制胃腺癌增殖,提高患者生存率。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-09-03 DOI: 10.1080/10715762.2025.2551031
Chunfeng Zhang, Lijuan Ma, Ying Shao, Shanpeng Cui, Li Li
{"title":"Selenoprotein GPX3 suppresses gastric adenocarcinoma proliferation and improves patient survival.","authors":"Chunfeng Zhang, Lijuan Ma, Ying Shao, Shanpeng Cui, Li Li","doi":"10.1080/10715762.2025.2551031","DOIUrl":"10.1080/10715762.2025.2551031","url":null,"abstract":"<p><p>Stomach adenocarcinoma (STAD) is a highly prevalent and lethal malignancy worldwide, with its occurrence and progression regulated by multiple factors. In recent years, selenoprotein glutathione peroxidase 3 (GPX3) has gained significant attention due to its antioxidant properties and role in cellular oxidative stress regulation across various cancers. Our study delved into the expression of GPX3 in STAD and investigated its impact on tumor cell growth, providing insights into its potential anti-tumor mechanisms. The expression levels of GPX3 were analyzed in STAD tissues sourced from the TCGA database and contrasted with the levels found in normal gastric tissues. The expression levels of GPX3 were contrasted between STAD tissues and normal gastric tissues, and their correlation with patient prognosis was assessed by survival analysis. Additionally, we validated GPX3 expression changes and its effects on tumor cell growth using quantitative PCR (qPCR) and CCK-8 proliferation assays in STAD cell lines (MNK-45, MGC-803, N87, and HGC-27). Our findings suggest that GPX3 expression is significantly downregulated in STAD tissues compared to normal gastric tissues. Survival analysis further reveals that patients with high GPX3 expression exhibit better long-term survival rates, suggesting a potential tumor-suppressive function. <i>In vitro</i> experiments confirmed effective knockdown or overexpression of GPX3 in STAD cell lines. CCK-8 proliferation assays demonstrated that GPX3 overexpression significantly inhibited tumor cell proliferation, whereas GPX3 knockdown promoted cell growth. This study provides new experimental evidence supporting GPX3 as a potential therapeutic target for STAD and offers a theoretical foundation for future molecular-targeted therapies for STAD.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"583-591"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948652","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
Copper induces cystine/glutamate antiporter SLC7A11 through the activation of Nrf2 and Atox1 pathways. 铜通过激活Nrf2和Atox1通路诱导胱氨酸/谷氨酸反转运蛋白SLC7A11。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-09-19 DOI: 10.1080/10715762.2025.2560847
Tetsuro Kamiya, Ryoka Teruya, Haruka Tahara, Yuki Inoue, Aoi Ikeda, Sayaka Hosowari, Tomo Arioka, Tomohiro Otsuka, Hirokazu Hara
{"title":"Copper induces cystine/glutamate antiporter SLC7A11 through the activation of Nrf2 and Atox1 pathways.","authors":"Tetsuro Kamiya, Ryoka Teruya, Haruka Tahara, Yuki Inoue, Aoi Ikeda, Sayaka Hosowari, Tomo Arioka, Tomohiro Otsuka, Hirokazu Hara","doi":"10.1080/10715762.2025.2560847","DOIUrl":"10.1080/10715762.2025.2560847","url":null,"abstract":"<p><p>Amino acid metabolism plays a crucial role in tumor biology. The sodium-independent cystine/glutamate exchange system, known as system X<sub>c</sub><sup>-</sup>, is significantly activated in cancer cells and plays a role in tumor progression. Copper (Cu), an essential micronutrient, plays a crucial role in physiological processes; however, its accumulation in tumors has been associated with tumor progression. Nonetheless, the relationship between system X<sub>c</sub><sup>-</sup>-mediated amino acid metabolism and Cu remains inadequately understood. In this study, CuCl<sub>2</sub> treatment resulted in the significant induction of SLC7A11, a light chain subunit of system X<sub>c</sub><sup>-</sup>, and glutamate receptor mGluR1 expression in human triple-negative MDA-MB-231 cells. Conversely, FeCl<sub>2</sub> treatment induced the expression of SLC7A11 but not mGluR1, indicating that Cu specifically activated SLC7A11-mediated amino acid metabolism. The investigation focused on the role of Nrf2, a redox-sensitive transcription factor, in the induction of SLC7A11 under conditions of oxidative stress induced by CuCl<sub>2</sub> treatment. Upon treatment with CuCl<sub>2</sub>, the nuclear translocation of Nrf2 was observed, and knockdown of Nrf2 significantly suppressed the induction of SLC7A11. Given that the Cu chaperone, antioxidant-1 (Atox1), functions as a Cu-dependent transcription factor, the role of Atox1 in the expression of SLC7A11 was further investigated. Like the effects of Nrf2 knockdown, Atox1 was found to play a pivotal role in the Cu-mediated induction of SLC7A11. Our findings indicate that intratumoral Cu influences the expression of SLC7A11 and may play a role in tumor progression.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"634-645"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052751","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
Differential dihydroethidium fluorescence spectra in cell-free and cellular superoxide models: roles of riboflavin, FMN, FAD, and ions. 在无细胞和细胞超氧化物模型中的差异二氢乙啶荧光光谱:核黄素,FMN, FAD和离子的作用。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-09-24 DOI: 10.1080/10715762.2025.2564671
Bong-Geum Jang, Boyoung Choi, Ji-Eun Kim, Min-Ju Kim
{"title":"Differential dihydroethidium fluorescence spectra in cell-free and cellular superoxide models: roles of riboflavin, FMN, FAD, and ions.","authors":"Bong-Geum Jang, Boyoung Choi, Ji-Eun Kim, Min-Ju Kim","doi":"10.1080/10715762.2025.2564671","DOIUrl":"10.1080/10715762.2025.2564671","url":null,"abstract":"<p><p>Dihydroethidium (DHE) is widely used for superoxide detection, yet reported excitation and emission values vary across studies. To address this, we employed full-spectrum scanning to compare DHE fluorescence between a xanthine oxidase (XO)-based cell-free system and a rotenone-treated cellular model, and to assess factors contributing to spectral shifts. In the XO system, the excitation peak was ∼480 nm, whereas in cells it shifted to ∼520 nm. Riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) accounted for this shift, while calcium and bicarbonate ions modulated both peak position and fluorescence intensity. Riboflavin depletion reduced intracellular flavin levels but did not restore the peak to 480 nm, indicating additional roles for FMN and FAD. Among scavengers, only tiron directly inhibited DHE fluorescence in the cell-free system, with enhanced activity in the presence of Ca<sup>2+</sup> and Mg<sup>2+</sup>. In contrast, responses in cells varied by type and rotenone concentration, suggesting indirect modulation through endogenous antioxidant defenses. Addition of FMN, FAD, or cell lysates to the cell-free system attenuated scavenger efficacy, supporting intracellular interference. These findings demonstrate that riboflavin metabolism and ionic microenvironments critically shape DHE spectral behavior. Accurate interpretation of DHE-based superoxide detection therefore requires prior spectral evaluation to distinguish genuine superoxide signals from cofactor- or ion-dependent effects.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"646-666"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112113","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
Betulinic acid protects SH-SY5Y cells exposed to lipopolysaccharide and ferrous sulfate through p38MAPK/NF-κB/GPX4/Nrf2/keap-1/HO-1 signaling axis. 白桦酸通过p38MAPK/NF-κB/GPX4/Nrf2/Keap-1/HO-1信号轴保护暴露于脂多糖和硫酸亚铁的SH-SY5Y细胞。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-09-27 DOI: 10.1080/10715762.2025.2565686
Shivam Kumar Pandey, Hardev Singh, Shad Ahmad, Rakesh Kumar Singh
{"title":"Betulinic acid protects SH-SY5Y cells exposed to lipopolysaccharide and ferrous sulfate through p38MAPK/NF-κB/GPX4/Nrf2/keap-1/HO-1 signaling axis.","authors":"Shivam Kumar Pandey, Hardev Singh, Shad Ahmad, Rakesh Kumar Singh","doi":"10.1080/10715762.2025.2565686","DOIUrl":"10.1080/10715762.2025.2565686","url":null,"abstract":"<p><p>Betulinic acid (BA) is a pentacyclic triterpenoid with broad pharmacological potential and widely recognized for its neuroprotective effects. This study investigated the potential protective effects of this compound on <i>in vitro</i> differentiated human neuroblastoma SH-SY5Y cells against LPS and FeSO<sub>4</sub>-induced ferroptosis, apoptosis, neuroinflammation, and dopaminergic cell death, and explored the underlying mechanisms. Differentiated human neuroblastoma SH-SY5Y cells were exposed to LPS and FeSO<sub>4</sub>, and the cellular viability was evaluated using the MTT assay. Flow cytometry was performed to assess apoptotic cell death. Additionally, the expression levels of key markers associated with ferroptosis, apoptosis, and other relevant signaling proteins were analyzed through western blotting and Immunocytochemical staining techniques. However, co<b>-</b>exposure with LPS and FeSO<sub>4</sub> resulted in a dose-dependent reduction in cell viability, which was significantly reversed by pretreatment with BA (0.3-30μM). Exposure to LPS and FeSO<sub>4</sub> increased the DMT1, Bax, caspase-3, and alpha-synuclein, and decreased the GPX4, FTH1, SLC7A11, Nrf2, Keap1, HO-1, PARK7, Bcl-2, NeuN, and TH levels, resulting in cell ferroptosis, apoptosis, and dopaminergic cell death. Furthermore, LPS and FeSO<sub>4</sub> significantly increased the expression of IL-6, TNF-α, and phosphorylation of p38, pMAPK, and pNFkB in the cells. Pretreatment with BA markedly suppressed LPS and FeSO<sub>4</sub>-induced upregulation of pro-inflammatory cytokines, ferroptosis, apoptosis, and dopaminergic cell death markers. These findings suggest that BA exerts neuroprotection by modulating the GPX4/Nrf2/Keap-1/HO-1 antioxidant defense and p38MAPK/NF-κB inflammatory signaling pathways, highlighting its potential as a therapeutic agent for oxidative stress-related neurodegenerative conditions, such as Parkinson's disease (PD).</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"688-706"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124248","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
Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer. 铁螯合剂诱导的假性缺氧激活肺癌肿瘤免疫反应。
IF 2.9 3区 生物学
Free Radical Research Pub Date : 2025-08-01 Epub Date: 2025-08-30 DOI: 10.1080/10715762.2025.2551030
Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa
{"title":"Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.","authors":"Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa","doi":"10.1080/10715762.2025.2551030","DOIUrl":"10.1080/10715762.2025.2551030","url":null,"abstract":"<p><p>Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation <i>in vitro</i>, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"570-582"},"PeriodicalIF":2.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948637","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
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