Chemico-Biological Interactions最新文献

{"title":"Identifying KDM5B as the synthetic lethal target of KMT2D-mutated osteosarcoma","authors":"Liyu Yang ,&nbsp;Jing Zhang ,&nbsp;Yiting Jiang ,&nbsp;Jiayu Zhang ,&nbsp;Zhonghua Wang ,&nbsp;Lihui Wang ,&nbsp;Xinyu Fan ,&nbsp;Gen Ba","doi":"10.1016/j.cbi.2025.111451","DOIUrl":"10.1016/j.cbi.2025.111451","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a malignant bone tumor that occurs commonly in adolescents or children, previous studies have shown its complex epigenetic signature. Histone methyltransferases KMT2D loss-of-function mutation is common in various types of human cancer. Here we revealed that KMT2D loss promotes malignant phenotypes in osteosarcoma. Based on the result of epigenetic inhibitor library screening we discovered that KDM5B inhibitors selectively killed KMT2D-deficient cells. Also, the knockdown of KDM5B by shRNA could reduce cell proliferation, migration and induce apoptosis in KMT2D-KO cells, while no similar appearance was observed in wild-type cells. Furthermore, we testified the efficiency and safety of KDM5B inhibition in patient-derived xenografts (PDX) mouse models driven by KMT2D low-expressing patients. These results demonstrated KDM5B as a synthetic lethal factor of KMT2D-loss mutation. Our findings suggest a novel therapeutic strategy for treating KMT2D mutated osteosarcoma by targeting KDM5B.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111451"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The anti-Alzheimer's disease effects of ganoderic acid A by inhibiting ferroptosis-lipid peroxidation via activation of the NRF2/SLC7A11/GPX4 signaling pathway","authors":"Qingyang Lu ,&nbsp;Nan Shao ,&nbsp;Ziyi Fang ,&nbsp;Zhaorong Ouyang ,&nbsp;Yiran Shen ,&nbsp;Ruiling Yang ,&nbsp;Houli Liu ,&nbsp;Biao Cai ,&nbsp;Tao Wei","doi":"10.1016/j.cbi.2025.111459","DOIUrl":"10.1016/j.cbi.2025.111459","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a degenerative disease of the central nervous system, characterized by a gradual decline in cognitive and memory abilities, social disorders, and behavioral abnormalities. Ferroptosis, an iron-dependent type of programmed cell death, is closely associated with the pathogenesis of AD. Ferroptosis is characterized by the accumulation of iron within cells, leading to increased oxidative stress, and ultimately lipid peroxidation and cell death. Ganoderic acid A (GAA), one of the major pharmacologically active components in <em>Ganoderma lucidum</em>, exhibits an excellent neuroprotective effect against AD. However, it is unclear whether GAA improves the symptoms of AD by inhibiting ferroptosis. This study investigated the anti-AD effects of GAA through both <em>in vivo</em> and <em>in vitro</em> experiments, and determined its molecular mechanism from the perspective of ferroptosis modulation. The results showed that GAA administration attenuated hippocampal neuronal loss, improved mitochondrial ultrastructure, and enhanced the memory and learning ability of the AD mice. <em>In vitro</em> assays suggested that GAA effectively protected HT22 AD cells against ferroptosis-related morphological damage, enhanced their antioxidant capacity, maintained their iron metabolism, and reduced mitochondrial dysfunction. Moreover, the immunofluorescence and western blotting results showed that the levels of NFE2 like bZIP transcription factor 2 (NRF2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) both in the hippocampus of APP/PS1 mice and amyloid beta (Aβ)_25-35-induced HT22 AD cells were markedly enhanced after GAA administration. In summary, these results revealed that GAA improves AD by activating on the NRF2/SLC7A11/GPX4 axis to inhibit ferroptosis-lipid peroxidation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111459"},"PeriodicalIF":4.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway","authors":"Jui-Ming Liu ,&nbsp;Kuan-I Lee ,&nbsp;Chin-Chuan Su ,&nbsp;Kai-Min Fang ,&nbsp;Shing-Hwa Liu ,&nbsp;Shih-Chang Fu ,&nbsp;Chun-Ying Kuo ,&nbsp;Kai-Chih Chang ,&nbsp;Jun-An Ke ,&nbsp;Ya-Wen Chen ,&nbsp;Ching-Yao Yang ,&nbsp;Chun-Fa Huang","doi":"10.1016/j.cbi.2025.111452","DOIUrl":"10.1016/j.cbi.2025.111452","url":null,"abstract":"<div><div>Chlorpyrifos (CPF) is a widely used organophosphate (OP) pesticide in agriculture and sanitation, known to elicit neurotoxic effects. Chlorpyrifos-oxon (CPO), a metabolite of CPF, is the primary neurotoxic agent, yet its mechanisms are less understood. In this study, we investigated the effects and underlying mechanisms of CPO-induced neurotoxicity. CPO exposure significantly induced cytotoxicity in Neuro-2a cells, alongside the activation of apoptosis, as evidenced by an increase in the apoptotic cell population, caspase-3 activity, and cleavage of caspaspe-3, -7, and PARP proteins. Furthermore, defective autophagy was observed in CPO-treated Neuro-2a cells, indicated by increased expression of Beclin-1, Atg5, LC3-II, and p62 proteins. 3-MA, an autophagy inhibitor, suppressed CPO-activated LC3-II and apoptotic marker proteins expression, but not p62. In contrast, chloroquine and bafilomycin A1, autophagic flux inhibitors, potentiated the CPO-induced elevation of LC3-II, p62, and cleaved caspase-3 and -7 protein levels. CPO exposure also upregulated CHOP protein expression. Transfection with CHOP-specific siRNA markedly reduced CHOP protein expression, autophagic flux dysfunction, and apoptosis. Additionally, CPO exposure significantly increased AMPKα phosphorylation and reactive oxygen species (ROS) generation. Antioxidant <em>N</em>-acetylcysteine (NAC), but not the AMPK inhibitor Compound C, effectively attenuated the CPO-induced ROS generation in neuronal cells, which was accompanied by the prevention of AMPKα activation, downstream CHOP expression, autophagic flux dysfunction, and apoptosis. Collectively, these findings suggest that CPO-induced neurotoxicity arises from autophagic flux dysfunction, contributing to apoptosis via the ROS-activated AMPK pathway, which regulates CHOP expression, ultimately leading to neuronal cell death. Targeting the ROS/AMPK/CHOP axis may offer a promising intervention to against CPO-induced neurotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111452"},"PeriodicalIF":4.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic insights into methamphetamine exposure: 1H-NMR-based urinary biomarker identification and pathway disruption","authors":"Varat Budsayapanpong ,&nbsp;Yutti Amornlertwatana ,&nbsp;Giatgong Konguthaithip ,&nbsp;Somlada Watcharakhom ,&nbsp;Kanicnan Intui ,&nbsp;Jatuporn Chaichana ,&nbsp;Manee Khamenkhetkarn ,&nbsp;Churdsak Jaikang","doi":"10.1016/j.cbi.2025.111449","DOIUrl":"10.1016/j.cbi.2025.111449","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111449"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitic acid-induced insulin resistance triggers granulosa cell senescence by disruption of the UPRmt/mitophagy/lysosome axis","authors":"Yuan Tian ,&nbsp;Pengge Pan ,&nbsp;Xiaoqiang Luo ,&nbsp;Yaqi Sun ,&nbsp;Xintong Yang ,&nbsp;Hui Gao ,&nbsp;Yanzhou Yang","doi":"10.1016/j.cbi.2025.111450","DOIUrl":"10.1016/j.cbi.2025.111450","url":null,"abstract":"<div><div>Insulin resistance (IR) is the main pathological feature of polycystic ovary syndrome (PCOS), but the adverse impacts of IR on ovary and granulosa cells (GCs) are unknown. Therefore, the role of palmitic acid (PA) induced IR in GCs, and a mitochondrial proteostasis and mitochondrial homeostasis control system, the mitochondrial unfolded protein response (UPR^mt)/mitophagy/lysosome axis were investigated to uncover the side effect and the mechanism of IR on GCs. Our results revealed that IR in GC was successfully constructed by 100 μM PA treatment accompanied with cell senescence. In addition, mitochondrial function was impaired by IR-induced GC senescence accompanied by significantly increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential, and mitochondrial proteostasis was impaired by a dysfunctional UPR^mt and increased protein aggregation, leading to more unfolded and misfolded proteins accumulating in mitochondria. Mitochondrial homeostasis was maintained by the mitophagy/lysosome degradation system, although mitophagy was significantly increased, lysosomes were damaged; hence, malfunctional mitochondria were not cleared by the mitophagy/lysosome degradation system, more ROS were produced by malfunctional mitochondria. Therefore, accelerated GC senescence was triggered by excessive ROS, and reversed by the mitophagy inhibitor cyclosporin A (CsA) accompanied with reduced IR. Additionally, the mice were administered with PA, and results revealed that the accelerated ovarian aging was caused by PA, which might be attributed to GC senescence. In conclusion, GC senescence was triggered in PA-induced IR by disruption of the UPR^mt/mitophagy/lysosome axis, and IR induced GC senescence was reversed by the CsA.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111450"},"PeriodicalIF":4.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during the early onset of isoniazid-induced oxidative stress","authors":"Truong Thi My Nhung ,&nbsp;Nguyen Ky Phat ,&nbsp;Trinh Tam Anh ,&nbsp;Tran Diem Nghi ,&nbsp;Nguyen Quang Thu ,&nbsp;Ara Lee ,&nbsp;Nguyen Tran Nam Tien ,&nbsp;Nguyen Ky Anh ,&nbsp;Huy Truong Nguyen ,&nbsp;Kimoon Kim ,&nbsp;Duc Ninh Nguyen ,&nbsp;Dong Hyun Kim ,&nbsp;Sang Ki Park ,&nbsp;Nguyen Phuoc Long","doi":"10.1016/j.cbi.2025.111448","DOIUrl":"10.1016/j.cbi.2025.111448","url":null,"abstract":"<div><div>A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. In this study, we used multi-omics profiling <em>in vitro</em> to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Additional analysis using transcriptomics data from repeated time-course INH treatments on human hepatic microtissues revealed that cellular responses to ER stress and oxidative stress happened prior to disturbances in mitochondrial complexes. Mechanistic validation studies using time-lapse measurements of cytosolic and mitochondrial reactive oxygen species (ROS) revealed that INH initially triggered cytosolic ROS increasement and Nrf2 signaling pathway activation before mitochondrial ROS accumulation. Molecular imaging showed that INH subsequently disrupted mitochondrial function by impairing respiratory complexes I–IV and caused mitochondrial membrane proton leakage without affecting mitochondrial complex V, leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. Our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We also revealed the critical role of Nrf2 signaling in protecting hepatocytes under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming through regulating antioxidant gene expression and cellular lipid abundance. Alternative antioxidant pathways, including selenocompound metabolism, HIF-1 signaling, and the pentose phosphate pathway, also responded to INH-induced oxidative stress. Collectively, our study emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction that underlie INH-induced hepatotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111448"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms underlying the effects of beta-sitosterol on TGF-β1/Nrf2/SIRT1/p53-mediated signaling in the kidney of a high-fat diet and sucrose-induced type-2 diabetic rat","authors":"Selvaraj Jayaraman ,&nbsp;Monisha Prasad ,&nbsp;Sathan Raj Natarajan ,&nbsp;Rajapandiyan Krishnamoorthy ,&nbsp;Mohammad A. Alshuniaber ,&nbsp;Mansour K. Gatasheh ,&nbsp;Vishnu Priya Veeraraghavan ,&nbsp;Ponnulakshmi Rajagopal ,&nbsp;Chella Perumal Palanisamy","doi":"10.1016/j.cbi.2025.111443","DOIUrl":"10.1016/j.cbi.2025.111443","url":null,"abstract":"<div><div>Diabetic nephropathy, a severe problem of diabetes mellitus, is exacerbated by high-fat diets, prompting a need for interventions. Previous study from our laboratory has shown that β-sitosterol, a potent plant sterol has anti-inflammatory and glucose-lowering efficacy by involving insulin metabolic signalling pathway but its role on anti-oxidant signaling pathways, play a crucial role in mitigating oxidative stress and inflammation associated diabetic nephropathy, highlighting its importance as a potential therapeutic target for managing this debilitating complication of diabetes is unknown. This study was aimed to intricate the molecular mechanisms involved in the potential of β-sitosterol (BSIT) on TGF-β1/Nrf2/SIRT1/p53 signaling in high fat diet (HFD) and sucrose induced diabetic nephropathy (DN) in the rat kidney by employing various comprehensive bioinformatic analysis. We have used various comprehensive methods such as pathway predictions, Drug-Protein Interaction, Functional annotation analysis, and molecular docking techniques. Further, <em>in vivo</em> analysis of BSIT on biochemical profiles, gene and protein expression analysis of anti-oxidant and inflammatory signaling molecules was performed in the kidney of high fat diet (HFD) and sucrose-induced diabetic nephropathy. Computational studies provided insights into β-sitosterol's binding affinities and interaction modes with key proteins, suggesting its potential to regulate TGF-β1/Nrf2/SIRT1/p53 signaling pathways. Results of <em>in vivo</em> findings validated computational predictions, showcasing BSIT's multifaceted effects in mitigating diabetic nephropathy and associated complications including regulation of lipid metabolism, combating oxidative stress, and inflammation. The findings underscore BSIT's therapeutic potential by preserving cellular viability, regulating cell death, enhancing antioxidant defence, and stabilizing metabolic processes. Our study concludes that BSIT's ability to potentially regulate TGF-β1/Nrf2/SIRT1/p53 pathways, emphasizing its promising role in managing diabetic nephropathy and associated complications.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111443"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hesperidin alleviates endothelial cell inflammation and apoptosis of Kawasaki disease through inhibiting the TLR4/IĸBα/NF-ĸB pathway","authors":"Yuting Guan ,&nbsp;Jinghua Ruan ,&nbsp;Pingping Tan ,&nbsp;Songwei Qian ,&nbsp;Size Zhou ,&nbsp;Ao Zhang ,&nbsp;Yuchong Fu ,&nbsp;Shuhui Zhao ,&nbsp;Yuqing Ran ,&nbsp;Xing Feng ,&nbsp;Yijia Wang ,&nbsp;Xinlei Wu ,&nbsp;Bing Zhang ,&nbsp;Weiping Ji ,&nbsp;Lianpin Wu ,&nbsp;Xiaoling Guo","doi":"10.1016/j.cbi.2025.111445","DOIUrl":"10.1016/j.cbi.2025.111445","url":null,"abstract":"<div><div>Kawasaki Disease (KD) is an acute and self-limiting vasculitis of unknown etiology that mainly occurs in infancy and can lead to vascular endothelial injury. Hesperidin (HES) is an economical dietary biological flavonoid with anti-oxidant, anti-inflammatory, and anti-apoptotic pharmacological effects. The main objective of this study was to investigate the protective effects of HES on KD, and try to elucidate the underlying mechanism. The Candida albicans water-soluble fraction (CAWS) was used to induce coronary arteritis of KD mouse model <em>in vivo</em>, and tumor necrosis factor α (TNF-α) was employed to induce human umbilical vein endothelial cell (HUVEC) injury of KD cell model <em>in vitro</em> to investigate the anti-inflammatory and anti-apoptotic effects of HES on KD. Our <em>in vivo</em> results showed that HES significantly reduced coronary artery injury in KD mice by alleviating pericoronary inflammatory infiltration and tissue fibrosis, inhibiting inflammatory cytokines and chemokine expressions, and decreasing vascular endothelial cell apoptosis. Our <em>in vitro</em> study confirmed that HES had the opposite ability of the NF-κB agonist NF-ĸB activator 1 (ACT1) to significantly alleviate the inflammatory response, CellROX level, and apoptosis by decreasing BAX/BCL-2 and Cleaved Caspase-3 levels as well as reducing TUNEL positive cells and the ratio of flow cytometric apoptotic cells in TNF-α induced HUVECs. The further mechanism study based on bioinformatics analysis and western blotting demonstrated that HES could protect against vascular inflammation and cell apoptosis of KD through inhibiting the TLR4/IĸBα/NF-ĸB pathway, suggesting that HES may be a promising therapeutic candidate for KD.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111445"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urolithin D: A promising metabolite of ellagitannin in combatting oxidative stress","authors":"Žiko Milanović","doi":"10.1016/j.cbi.2025.111444","DOIUrl":"10.1016/j.cbi.2025.111444","url":null,"abstract":"<div><div>The objective of this research is to examine the function of urolithin D (<strong>UroD,</strong> 3,4,8,9-tetrahydroxy-6H-benzo[<em>c</em>]chromen-6-one), a metabolite obtained from ellagitannins, in the mitigation of oxidative stress. The research is based on estimating the mechanisms through which <strong>UroD</strong> acts as an antioxidant under physiological conditions, emphasizing standard antioxidant mechanisms such as formal Hydrogen Aatom Transfer (<em>f</em>-HAT), Radical Adduct Formation (RAF)/Radical Coupling Formation (RCF), and Single Electron Transfer followed by Proton Transfer (SET-PT). This study utilised advanced quantum mechanical techniques, specifically density functional theory (DFT) and the Quantum Mechanics-based test for Overall free Radical Scavenging activity (QM-ORSA) methodology, to assess the thermodynamic and kinetic parameters of <strong>UroD</strong> in the presence of reactive radical species HOO^•, CH₃OO^• and CCl₃OO^•. The estimated overall rate constants (<em>k</em>_overall) indicate a reactivity order of CCl₃OO^• (<em>k</em>_overall = 2.06 × 10¹⁰ M⁻¹s⁻¹) &gt; HOO^• (<em>k</em>_overall = 2.59 × 10⁹ M⁻¹s⁻¹) &gt; CH₃OO^• (<em>k</em>_overall = 1.89 × 10⁹ M⁻¹s⁻¹). The examination of the relative proportions of products (%) indicates that <strong>UroD</strong> exhibits antiradical action primarily through all examined mechanisms, with the predominant involvement of mononion and dianion acid-base species. In addition to its capacity to directly counteract ROS, <strong>UroD</strong> can restore oxidative DNA damage, specifically targeting oxidative byproducts commonly associated with 2-deoxyguanosine (<strong>2 dG</strong>), which are susceptible to oxidative stress. The <strong>UroD</strong> regenerates G-centered radical cations (<strong>2 dG</strong>^•+) through the SET mechanism, C-centered radicals (<strong>2 dG</strong>^•) in the sugar moiety through <em>f</em>-HAT, and repairs <em>i</em>-OH-2dG lesions through sequential hydrogen atom transfer dehydration (SHATD). Additionally, the radical products formed during antioxidant action can be regenerated in the presence of O₂^•− into anionic species, which are subsequently protonated into neutral species that can re-engage in antioxidant activity. These findings underscore the efficiency of <strong>UroD</strong> in scavenging free radicals and suggest its potential role in preserving cellular integrity and protecting against oxidative stress-related diseases.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111444"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protosappanin B activates the Wnt pathway to protect against glucocorticoid-induced osteoblast inhibition and enhance bone formation","authors":"Jigeng Fan ,&nbsp;Yahui Wang ,&nbsp;Houzhi Yang ,&nbsp;Shaoyuan Huang ,&nbsp;Yuan Ma ,&nbsp;Jie Guo ,&nbsp;YuTao Jia ,&nbsp;Ying Zhang ,&nbsp;Yonggang Fan ,&nbsp;Donglun Xiao ,&nbsp;Jiawei Zhang ,&nbsp;Jianwei Li ,&nbsp;Yu Dong ,&nbsp;Ying Zhao ,&nbsp;Miao Guo ,&nbsp;Qiong Tang ,&nbsp;Shan-shan Li ,&nbsp;Tianwei Sun ,&nbsp;Xin Jin","doi":"10.1016/j.cbi.2025.111436","DOIUrl":"10.1016/j.cbi.2025.111436","url":null,"abstract":"<div><div>Osteoporosis remains a major health challenge due to impaired osteoblast function and reduced bone formation, particularly in glucocorticoid-induced osteoporosis (GIOP). The Wnt/β-catenin signaling pathway plays a critical role in osteogenesis, making it a promising target for protective interventions against osteoporosis-related bone loss. In this study, virtual screening of a natural product library identified Protosappanin B (PB) as a potential Wnt pathway activator with high binding affinity for Wnt receptors. We investigated PB's protective effects on osteoblast function under glucocorticoid exposure using MC3T3-E1 cells treated with dexamethasone (DEX) and an in vivo zebrafish model of GIOP. PB significantly promoted osteoblast proliferation, facilitated cell cycle progression, and attenuated DEX-induced apoptosis in a dose-dependent manner. Additionally, PB enhanced osteoblast differentiation and mineralization, counteracting DEX's inhibitory effects on alkaline phosphatase (ALP) activity and calcium deposition. In zebrafish, PB mitigated DEX-induced skeletal defects, improving bone and craniofacial cartilage formation. Western blot analysis confirmed that PB restored β-catenin levels, activating the Wnt/β-catenin pathway. Notably, the osteogenic effects of PB were abolished by XAV939, a Wnt signaling inhibitor, further supporting its Wnt-dependent mechanism of action. These findings indicate that PB provides protective effects against glucocorticoid-induced osteoblast dysfunction and bone loss by modulating Wnt signaling. This study highlight the potential of PB as a natural agent for preventing GIOP-related bone deterioration and warrants further investigation into its clinical applicability.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"410 ","pages":"Article 111436"},"PeriodicalIF":4.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}