Free Radical Biology and Medicine最新文献

{"title":"Soybean genistin-driven gut microbiota-derived butyrate synthesis activates the SIRT1 signaling pathway to ameliorate metabolic fatty liver","authors":"Guohui Yi ,&nbsp;Wanying Sun ,&nbsp;Xueer Zhang ,&nbsp;Zhongtao Wang ,&nbsp;Xiaodan Yu ,&nbsp;Canyang Zhu ,&nbsp;Kaiwen Lin","doi":"10.1016/j.freeradbiomed.2025.07.053","DOIUrl":"10.1016/j.freeradbiomed.2025.07.053","url":null,"abstract":"<div><div>Genistin (Gen), an isoflavone derived from soybeans, possesses lipid-lowering and anti-metabolic syndrome properties. Nonetheless, its impact on mitigating metabolic dysfunction-associated fatty liver disease (MAFLD) is insufficiently researched. We assessed the impact of GEN on lipid metabolism using a rat MAFLD model and an <em>in vitro</em> model of cellular lipid accumulation. The results indicated that Gen alleviated liver injury in MAFLD by reducing inflammation, lowering lipid levels, and normalizing liver function indicators. The diversity of harmful gut microbiota was significantly affected by Gen, which also boosted the abundance of beneficial bacteria such as Bacteroidetes and notably promoted the production of short-chain fatty acids (SCFAs). Butyrate, in particular, demonstrated a significant association with MAFLD biomarkers like triglyceride, total cholesterol, LDL-C, and TNF-α. In vitro experiments showed that butyrate counteracted sodium oleate's effects by restoring mitochondrial membrane potential, reducing active ROS levels and cell apoptosis, increasing SIRT1 protein and mRNA expression, and decreasing AKT1, PTGS2, and MAOA protein and mRNA levels. Additionally, sodium butyrate improved the expression of lipid-related genes, reversing changes in PPARα, SREBP1, ACACA, and FASN. Our study suggests that genistein activates the SIRT1 signaling pathway by enhancing gut microbiota-derived butyrate production, thereby improving liver function and lipid metabolism in MAFLD rats. In conclusion, soy-derived Gen shows promise as a supplementary dietary option for enhancing MAFLD management.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 336-351"},"PeriodicalIF":8.2,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of NAD+ metabolism alterations during follicular atresia in porcine ovaries and their regulatory mechanisms in granulosa cell apoptosis","authors":"Zhe Wang,&nbsp;Quanwei Wei,&nbsp;He Geng,&nbsp;Rahmani Mohammad Malyar,&nbsp;Tevanu Berthier,&nbsp;Fangxiong Shi","doi":"10.1016/j.freeradbiomed.2025.07.049","DOIUrl":"10.1016/j.freeradbiomed.2025.07.049","url":null,"abstract":"<div><div>Follicular atresia plays a significant role in the depletion of the ovarian reserve and the decline of overall ovarian function. Understanding its molecular mechanisms is essential to preventing ovarian aging and maintaining female reproductive health. Although NAD + depletion is known to induce apoptosis in various cell types, the dynamic changes in NAD + metabolism during follicular atresia remain unclear. Moreover, its specific impact on granulosa cells has not been fully elucidated.</div><div>In this study, we examined the metabolic alterations of NAD+ during follicular atresia. We also explored the molecular mechanisms underlying granulosa cell apoptosis to provide a theoretical basis for developing novel therapeutic strategies to preserve female fertility. Using a well-established porcine model of follicular atresia, we observed a downregulation of key enzymes involved in NAD + biosynthesis during follicular regression, accompanied by an increased progesterone to estradiol (P4/E2) ratio in the follicular fluid. In granulosa cells, reduced NAD + levels and decreased NAD+/NADH ratios activated caspase-3 thereby triggering apoptosis. In a vitro model of granulosa cell apoptosis, we further demonstrated that NAD + precursors can bypass the rate-limiting enzyme NAMPT but NMNAT1 remaines essential for effective NAD⁺ salvage. Deficiency of NMNAT1 compromised nuclear SIRT1 activity, leading to excessive p53 acetylation and the induction of apoptosis Additionally, pharmacological inhibition of NAMPT impaired mitochondrial SIRT3 activity, which enhanced p53-mediated apoptotic pathways.</div><div>In conclusion, the NAD + salvage pathway is crucial for regulating follicular atresia, NMNAT1 acts as a key regulator in granulosa cells within this pathway. It supports cell survival through SIRT1-mediated deacetylation of p53. These findings identify NMNAT1 as a potential therapeutic target to delay ovarian aging and preserve females fertility.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 257-269"},"PeriodicalIF":8.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscone inhibits ferroptosis for neuroprotection in a Parkinson's disease model","authors":"Miaojing Xu ,&nbsp;Li Zhao ,&nbsp;Fenliang Xiao ,&nbsp;Chang Zhou ,&nbsp;Yi Ouyang ,&nbsp;Shaogang Qu","doi":"10.1016/j.freeradbiomed.2025.07.052","DOIUrl":"10.1016/j.freeradbiomed.2025.07.052","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a common neurodegenerative disorder with no currently available effective treatments. Muscone is a bioactive compound extracted from musk, a widely used traditional Chinese medicine, that has demonstrated notable pharmacological properties and is considered beneficial for various models of neurological disorders. However, no studies have in vestigated the potential link between muscone and PD. This study tested the neuroprotective properties and mechanisms of muscone in a PD model. The behavioral findings revealed that muscone significantly improved motor deficits in PD mice while Cell Counting Kit-8 testing suggested that muscone substantially elevated cell viability in PD <em>cellular models</em>. Immunohistochemistry and Western blot analysis demonstrated that muscone alleviated the degeneration of dopamine neurons in PD model mice. Mechanistic studies revealed that muscone obstructs multiple routes of ferroptosis to alleviate symptoms of PD, indicating its potential to decrease iron accumulation, mitigate reactive oxygen species, inhibit lipid peroxidation, and augment antioxidant capacity. Moreover, bioinformatics study revealed that glycogen synthase kinase 3β (GSK-3β) is a vital target for muscone in the suppression of ferroptosis and is crucial in the treatment of PD. GSK-3β activity was significantly increased in both animal and cellular models of PD, while the expression of its principal downstream component, β-catenin, was diminished. However, muscone ameliorated these changes. Intracellular overexpression of GSK-3β subsequently nullified the protective effects of muscone on PD cell models and promoted ferroptosis in PD models by increasing iron levels, augmenting lipid peroxidation, and reducing antioxidant capacity. In conclusion, muscone can inhibit GSK-3β, alter ferroptosis, and confer protection against PD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 298-316"},"PeriodicalIF":8.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytol enhances catalase-dependent ethanol metabolism in liver independent of PPARα","authors":"Anna Mazur ,&nbsp;Xue Chen ,&nbsp;Krista L. Denning ,&nbsp;Wei Xu ,&nbsp;Logan M. Lawrence ,&nbsp;Yongke Lu","doi":"10.1016/j.freeradbiomed.2025.07.050","DOIUrl":"10.1016/j.freeradbiomed.2025.07.050","url":null,"abstract":"<div><div>There is an interaction between peroxisomal fatty acid β-oxidation and catalase-dependent ethanol metabolism. H₂O₂ is essential for catalase to metabolize ethanol. Peroxisomal fatty acid β-oxidation rate limiting enzyme is acyl-CoA oxidase (ACOX), which generates H₂O₂ for catalase to metabolize ethanol. Usually, ACOX1 oxidizes very long-chain fatty acids and ACOX2 oxidizes branched-chain fatty acids. Previously we reported that PPARα agonist WY-14,643 induced ACOX1 to ameliorate alcoholic steatosis, and the induced ACOX1 coordinated with the induced catalase to enhance ethanol metabolism. In this study, we examined the effects of phytol on alcoholic steatosis and ethanol metabolism. Phytol is a precursor of pristanic acid, a substrate for ACOX2. Phytol can also induce ACOX1 and catalase. Phytol was added in the Lieber-DeCarli liquid diets up to 0.2 %. After 3 weeks of feeding, phytol induced ACOX1 to ameliorate alcoholic steatosis, which was not observed in the <em>Pparα</em>^{<em>−/−</em>} mice, implicating that the induction of ACOX1 is essential for protection against alcoholic steatosis. Phytol also enhanced ethanol metabolism, and among the ethanol metabolizing enzymes, only catalase was induced by phytol, suggesting that phytol enhances catalase-dependent ethanol metabolism. However, unlike WY-14,643, phytol induced catalase to enhance ethanol metabolism in a PPARα-independent manner because phytol but not WY-14,643 still induced catalase to enhance ethanol metabolism in the <em>Pparα</em>^{<em>−/−</em>} mice, suggesting that ACOX1 is dispensable for catalase-dependent ethanol metabolism. It is possible that when phytol cannot induce ACOX1 in the <em>Pparα</em>^{<em>−/−</em>} mice, phytol-derived pristanic acid is still oxidized by ACOX2 to generate H₂O₂ for catalase metabolism of ethanol.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 213-218"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic aldehyde storm induced by allyl alcohol exposure results in extensive hepatic ferroptosis in Aldh2∗2 knock-in mice","authors":"Yuki Takami ,&nbsp;Jun Nakamura ,&nbsp;Jun Katahira ,&nbsp;Yuhei Maeda ,&nbsp;Miyuu Tanaka ,&nbsp;Mitsuru Kuwamura ,&nbsp;Toshiya Okada ,&nbsp;Takeshi Izawa","doi":"10.1016/j.freeradbiomed.2025.07.045","DOIUrl":"10.1016/j.freeradbiomed.2025.07.045","url":null,"abstract":"<div><div>Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies multiple aldehyde species in the body. The <em>ALDH2∗2</em> allele (E487K) is one of the most common gene polymorphisms in humans, resulting in dysfunction of its enzyme activity. This study investigated <em>in vivo</em> mechanism of acute liver injury caused by exposure to allyl alcohol (AA) using <em>Aldh2∗2</em> knock-in (KI) mice with the same amino acid replacement as human <em>ALDH2∗2</em>. A rapid burst of plasma acrolein as an active metabolite of AA, as well as plasma endogenous reactive aldehydes malondialdehyde and formaldehyde, was observed at 10 min after exposure to 75 mg/kg of AA in the <em>Aldh2∗2</em> KI homozygous mice, but not in the wild-type mice. Histopathological examination demonstrated that the systemic storm of reactive aldehydes results in tissue damage across multiple organs in the <em>Aldh2∗2</em> KI homozygous mice, with the liver being most severely affected. Hepatocellular necrosis was more extensive in the <em>Aldh2∗2</em> KI homozygous mice than in the wild-type mice, which was preceded by hepatic glutathione depletion and was coincident with an accumulation of acrolein, malondialdehyde, and 4-hydroxy-2-nonenal adducts and iron deposition, suggesting an involvement of ferroptosis in the exacerbation of hepatic necrosis. Recovery from hepatic glutathione depletion was delayed in the homozygous mice compared with the wild-type mice, with a decreasing tendency of hepatic expression of cystine transporter xCT. These results suggest that increased hepatic glutathione consumption, due to decreased aldehyde detoxification capacity, can sensitize the <em>Aldh2∗2</em> KI homozygous mice to hepatic ferroptosis after the rapid “aldehyde storm”. Our study would re-focus on the crosstalk between aldehyde metabolism and redox homeostasis and potential health impacts of endogenous reactive aldehydes on <em>ALDH2∗2</em> carriers.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 177-188"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malic enzyme 1 reverses cardiomyocyte senescence in a nitric oxide-dependent manner","authors":"Wei Wu ,&nbsp;Ruoxuan Lei ,&nbsp;Huanhuan Xu ,&nbsp;Lulu Lu ,&nbsp;Chuhui Song ,&nbsp;Danyi Wu ,&nbsp;Min Li ,&nbsp;Luyi Chen ,&nbsp;Yingying Yu ,&nbsp;Xuexian Fang","doi":"10.1016/j.freeradbiomed.2025.07.048","DOIUrl":"10.1016/j.freeradbiomed.2025.07.048","url":null,"abstract":"<div><div>Progressive cardiac aging represents a major risk factor for heart diseases in the elderly population. Malic enzyme 1 (ME1) is an important regulator of redox homeostasis in multiple organs. However, the relationship and underlying mechanism between ME1 and cardiomyocyte senescence in aged heart have not yet been described. Here, we reveal that murine hearts and cardiomyocytes demonstrate age-dependent up-regulation of Me1 gene and protein. Mice with cardiomyocyte-specific <em>Me1</em> ablation exhibit increased oxidative stress and aggravated heart aging under D-galactose (D-gal) treatment. Moreover, loss of cardiac <em>Me1</em> also damages heart structure and function during natural aging processes. Supplementation with L-malate (LM), the substrate of ME1, significantly prevents cardiomyocyte senescence both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, the anti-aging effect of cardiac ME1 is dependent on its product nicotinamide adenine dinucleotide phosphate (NADPH), which promotes the enzymatic formation of nitric oxide (NO). Sufficient NO is essential for longevity, and the inhibition of NO synthase (NOS) abrogates LM-provided cardioprotection. These findings collectively demonstrate that targeting ME1 may offer new preventive or therapeutic insights into the treatment of age-associated cardiovascular diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 202-212"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Valvular oxidized phospholipids correlate with severity of human aortic valvular stenosis","authors":"Craig Resch ,&nbsp;Aleksandra Stamenkovic ,&nbsp;Arun Surendran ,&nbsp;Anran Zhang ,&nbsp;Gavin Y. Oudit ,&nbsp;Ashish Shah ,&nbsp;Amir Ravandi","doi":"10.1016/j.freeradbiomed.2025.07.042","DOIUrl":"10.1016/j.freeradbiomed.2025.07.042","url":null,"abstract":"<div><div>Calcific aortic valve stenosis (CAVS) is a degenerative disease characterized by progressive calcification and narrowing of the aortic valve, driven by a multifactorial inflammatory process. Oxidized phospholipids (OxPL) have been implicated in CAVS pathogenesis, but their presence within aortic valve tissue remains poorly defined. In this study, we developed a sensitive 2,4-dinitrophenylhydrazine (DNPH)-based LC/MS/MS method to identify and quantify 60 individual OxPL species across five phospholipid classes in plasma and tissue samples from patients with severe CAVS. Aortic valve tissue was collected from 70 patients undergoing valve replacement surgery and compared with tissue from 20 healthy donors. We identified 32 distinct OxPL species, including oxidized phosphatidylcholine (OxPC), phosphatidylethanolamine (OxPE), phosphatidylinositol (OxPI), and phosphatidylserine (OxPS). OxPC was the most abundant class, with 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC) being the predominant species, accounting for 35 % of total OxPL. We observed a significant increase in 30 OxPL species with advancing disease severity, with the most pronounced changes occurring between early (healthy and mild) and advanced (moderate and severe) stages of CAVS. Specifically, PONPC levels increased by 90 % (p = 0.012), and total OxPC levels rose by 83 % (p = 0.004) from mild to moderate disease. Compared to healthy valves, OxPC levels increased by 123 % (p &lt; 0.0001) in moderate CAVS and by 239 % (p = 0.02) in severe CAVS. However, OxPL levels did not significantly increase between moderate and severe stages. These findings suggest that OxPL accumulation in valve tissue is an early event in CAVS progression, supporting the rationale for early intervention with OxPL-lowering therapies as a potential strategy to mitigate disease advancement.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 219-229"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astragalin induces immunogenic cell death in liver cancer by targeting NQO2 to promote ROS-mediated endoplasmic reticulum stress pathway","authors":"Liyun Zheng ,&nbsp;Zhongwei Zhao ,&nbsp;Li Chen ,&nbsp;Wenjing Yang ,&nbsp;Giorgio Ercolani ,&nbsp;Pan Qin ,&nbsp;Bin Lin ,&nbsp;Mengzhu Han ,&nbsp;Qiaoyou Weng ,&nbsp;Yeyu Zhang ,&nbsp;Bin Wu ,&nbsp;Minjiang Chen ,&nbsp;Zouying Yao ,&nbsp;Shiji Fang ,&nbsp;Jiansong Ji","doi":"10.1016/j.freeradbiomed.2025.07.047","DOIUrl":"10.1016/j.freeradbiomed.2025.07.047","url":null,"abstract":"<div><div>Astragalin (ASG), a natural flavonoid glycoside, is known for its multiple pharmacological effects. In this study, we explored the antitumor effects of ASG and its underlying mechanism. Specifically, the growth inhibitory effects of ASG were assessed. Apoptosis rate, reactive oxygen species (ROS) accumulation, mitochondrial damage, and the activation of the endoplasmic reticulum stress induced by ASG were assessed. The potential target of ASG was identified and validated. The effects of ASG on immunogenic cell death (ICD) were determined. Furthermore, ASG's growth inhibition was validated <em>in vivo</em>, and its potential synergistic effects with <em>anti</em>-PD-L1 antibody were examined. Our findings demonstrate that ASG effectively inhibits growth in liver cancer cell lines. ASG treatment induces apoptosis by promoting mitochondrial membrane potential disruption and ROS accumulation. Additionally, ASG directly bounds to quinone oxidoreductase 2 (NQO2), leading to a reduction in NQO2 protein levels and subsequent upregulation of key ER stress markers, including p-PERK, p-eIF2α, GRP78, and CHOP. Moreover, ASG induces hallmark features of ICD, including calreticulin exposure, nuclear high mobility group box 1 reduction, and adenosine triphosphate release. ASG-treated liver cancer cells effectively enhance dendritic cell maturation in a coculture system. <em>In vivo</em>, the tumor growth is synergistically inhibited by ASG combined with <em>anti</em>-PD-L1 antibody in Hepa1-6 tumor-bearing mice. This synergy is associated with increased dendritic cell maturation, enhanced CD8⁺ T cell infiltration, and a reduction in regulatory T cells. In conclusion, ASG can be served as a potential anticancer agent for liver cancer and enhance the antitumor efficacy of immunotherapy by activating the ROS-mediated endoplasmic reticulum stress and ICD pathways.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 317-335"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage NADPH oxidase inhibition by ultralow-dose dextromethorphan alleviates DSS-induced inflammation and colitis","authors":"Yuqian Li ,&nbsp;Lijingzhe Hou ,&nbsp;Kang Cheng ,&nbsp;Guangbo He ,&nbsp;Jau-Shyong Hong ,&nbsp;Sheng Li ,&nbsp;Jie Zhao ,&nbsp;Yanjie Guo","doi":"10.1016/j.freeradbiomed.2025.07.044","DOIUrl":"10.1016/j.freeradbiomed.2025.07.044","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract with limited treatment options and no definitive cure. Emerging evidence implicates NADPH oxidase (Nox) in IBD pathogenesis, but the specific subtype involved and its therapeutic potential remain unclear. To assess the efficacy of dextromethorphan (DM), a potent Nox2 inhibitor, we employed a dextran sulfate sodium (DSS)-induced chronic colitis model in mice. Mice exposed to intermittent DSS for 34 days developed IBD-like symptoms, including weight loss, elevated disease activity index (DAI), colon shortening, and epithelial barrier disruption. DM exhibited a bimodal protective effect: both standard-dose DM (10 mg/kg/day) and ultralow-dose DM (ULDM, 10 ng/kg/day) significantly reduced colitis severity, with ULDM proving more effective and selected for further studies. Notably, ULDM remained effective when post-administered after DSS exposure. Histological analyses revealed that ULDM reduced immune cell infiltration, crypt damage, and tissue disruption. It also suppressed pro-inflammatory cytokine expression (MCP-1, IL-6, IL-1β, TNF-α) and oxidative stress markers (myeloperoxidase, malondialdehyde, 8-hydroxydeoxyguanosine), while enhancing anti-inflammatory cytokines (IL-4, IL-10) and antioxidant enzymes (catalase, superoxide dismutase). Importantly, ULDM protected Nox1 KO but not Nox2 KO mice, indicating a Nox2-dependent mechanism. <em>In vitro,</em> ULDM inhibited Nox2 activation in primary macrophages and RAW 264.7 cells by blocking the membrane translocation of p47^phox. Furthermore, our study suggested a feed-forward inflammatory cycle between epithelial cell death and macrophage overactivation that exacerbated colitis. Together, these findings demonstrated that Nox2 played a central role in DSS-induced chronic colitis and identified ultralow-dose dextromethorphan as a promising, mechanism-based therapeutic candidate for IBD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 189-201"},"PeriodicalIF":8.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blue honeysuckle (Lonicera caerulea L.)-anthocyanins and cyanidin-3-O-glucoside protect dopaminergic neurons against ferroptosis by activating the Nrf2-GPX7 axis","authors":"Xiao-Na Li ,&nbsp;Li-Li Fan ,&nbsp;Qian Zhu ,&nbsp;Jia-Hui Liu ,&nbsp;Zhen-Yan Xie ,&nbsp;Jia-Lin Cao ,&nbsp;Jun-Yu Tan ,&nbsp;Li Lin ,&nbsp;Xue-Song Li ,&nbsp;Xin-Hua Wei","doi":"10.1016/j.freeradbiomed.2025.07.038","DOIUrl":"10.1016/j.freeradbiomed.2025.07.038","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a common neurological disease currently with no effective therapy. Blue honeysuckle (<em>Lonicera caerulea</em> L.) berries are rich in anthocyanins, primarily cyanidin-3-O-glucoside (C3G), known for their potent antioxidant properties. However, the therapeutic potential and neuroprotective mechanisms of blue honeysuckle-anthocyanins (BH-an), especially C3G, in mitigating PD are yet to be fully elucidated. BH-an and C3G not only reduced 1-methyl-4-phenylpyridinium (MPP<strong>⁺</strong>)-induced neurotoxicity in SH-SY5Y cells, but also prevented the ferroptotic stimuli erastin-induced cytoxicity and ferroptosis. Importantly, C3G, the predominant component of BH-an (80.1 %–91.3 % of total anthocyanins), significantly ameliorated MPP⁺-induced mitochondrial dysfunction and exhibited comparable effects to the ferroptosis inhibitor Fer-1 against erastin-induced oxidative stress. In addition, C3G mitigated the loss of dopaminergic cells and motor dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of PD. This neuroprotective effect was mediated through the restoration of the MPTP/erastin-induced downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 7 (GPX7), and inhibition of Nrf2 and GPX7 abolished the protective effect of C3G against erastin-induced ferroptosis. In conclusion, we demonstrate that BH-an, especially C3G, exerted significant neuroprotection against dopaminergic neuron ferroptosis through stimulating Nrf2-GPX7 axis. This study highlights the potential of blue honeysuckle anthocyanins, especially C3G, as preventive agents for PD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"239 ","pages":"Pages 242-256"},"PeriodicalIF":8.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}