Journal of Biochemical and Molecular Toxicology最新文献_第10页

Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells 奥拉帕尼通过CDK5/Drp-1信号通路触发卵巢癌细胞线粒体分裂

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-18 DOI: 10.1002/jbt.70273

Xun Gao, Qinghua Yin, Zhilian Wang

{"title":"Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells","authors":"Xun Gao, Qinghua Yin, Zhilian Wang","doi":"10.1002/jbt.70273","DOIUrl":"https://doi.org/10.1002/jbt.70273","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Alterations in mitochondrial metabolism are considered defining characteristics and therapeutic targets of OC. Olaparib, an oral inhibitor of poly (ADP-ribose) polymerase, has been approved for the treatment of OC. However, the precise mechanisms by which it exerts its effects remain unclear. In this study, we uncover a novel pharmacological function of Olaparib by demonstrating that it induces mitochondrial dysfunction in human SKOV3 ovarian cancer cells. Our findings revealed that Olaparib exposure induced mitochondrial oxidative stress by elevating mitochondrial ROS levels and diminishing GPx activity. Additionally, treatment with Olaparib led to mitochondrial dysfunction, as evidenced by decreased complex I and complex IV activity and reduced ATP production. We observed that Olaparib induced mitochondrial fission by decreasing the average length of mitochondria. Olaparib did not affect the levels of Mfn1, Mfn2, or the total expression of Drp-1. Intriguingly, Olaparib increased the levels of phosphorylated Drp-1 at Ser616. Further investigation revealed that Olaparib facilitated the activation of the CDK5 signaling pathway and induced Caspase 3 activation. Notably, inhibition of CDK5 signaling using roscovitine mitigated the effects of Olaparib on mitochondrial fission and dysfunction, indicating a role for CDK5 in this process. In summary, our research identifies that CDK5/Drp-1-mediated mitochondrial fission may represent a novel mechanism through which Olaparib exerts its anticancer effects in OC.</p>\u0000 </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Evaluation of Novel Quinazolin-4(3H)-One Derivatives: Anti-Leishmanial Activity, Selectivity, and Molecular Docking Insights 新型喹唑啉-4(3H)- 1衍生物的设计、合成和评价：抗利什曼原虫活性、选择性和分子对接见解

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-18 DOI: 10.1002/jbt.70309

Baycan Mor, Feyzi Sinan Tokalı, Barış Yıldız, Halil Şenol, Şeyma Aksu, Neriman Mor

{"title":"Design, Synthesis, and Evaluation of Novel Quinazolin-4(3H)-One Derivatives: Anti-Leishmanial Activity, Selectivity, and Molecular Docking Insights","authors":"Baycan Mor, Feyzi Sinan Tokalı, Barış Yıldız, Halil Şenol, Şeyma Aksu, Neriman Mor","doi":"10.1002/jbt.70309","DOIUrl":"https://doi.org/10.1002/jbt.70309","url":null,"abstract":"<div>\u0000 \u0000 <p>In this study, 16 novel quinazolin-4(3<i>H</i>)-one derivatives were synthesized and evaluated for their antileishmanial activity against <i>Leishmania major</i> and <i>Leishmania donovani</i>. Among them, compounds <b>2</b> (4-hydroxy substituted) and 9 (4-morpholino substituted) exhibited the highest efficacy, with compound <b>2</b> showing IC<sub>50</sub> values of 23.94 μM for <i>L. major</i> and 90.80 μM for <i>L. donovani</i>, while compound <b>9</b> demonstrated IC<sub>50</sub> values of 23.05 μM for <i>L. major</i> and 56.30 μM for <i>L. donovani</i>. Miltefosine, the reference drug, showed IC<sub>50</sub> values of 32.89 μM for <i>L. major</i>, 4.78 μM for <i>L. donovani</i>, and 7.53 μM for HUVEC cells. Compound <b>2</b> showed superior selectivity (SI = 15.2 for <i>L. major</i> and 4.0 for <i>L. donovani</i>) compared to miltefosine (SI = 4.4 for <i>L. major</i> and 0.6 for <i>L. donovani</i>). Molecular docking studies identified phosphodiesterase B1 (PDEB1) as a key target, with compound <b>2</b> showing the strongest binding affinity. The docking score of compound <b>2</b> was calculated as –11.909 kcal/mol for PDEB1. ADME predictions indicated compound <b>2</b>'s favorable pharmacokinetic profile, including good solubility, permeability, and adherence to Lipinski's Rule of Five. Overall, compound <b>2</b> exhibited the most promising therapeutic profile, highlighting its potential as a lead compound for antileishmanial drug development.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation Underlie Silver Nanoparticles-Induced Neurologic Deficits in Adult Mice 内质网应激和NLRP3炎性体激活是银纳米颗粒诱导的成年小鼠神经功能缺陷的基础

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-18 DOI: 10.1002/jbt.70289

Wenhui Zhang, Mengdi Zhai, Meijia Wu, Yongke Yuan, Xiao Su, Mingzhi Yang, Yue Ba, Qihong Deng, Yu Zhang, Lin Han, Lihua Gao, Hui Huang

{"title":"Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation Underlie Silver Nanoparticles-Induced Neurologic Deficits in Adult Mice","authors":"Wenhui Zhang, Mengdi Zhai, Meijia Wu, Yongke Yuan, Xiao Su, Mingzhi Yang, Yue Ba, Qihong Deng, Yu Zhang, Lin Han, Lihua Gao, Hui Huang","doi":"10.1002/jbt.70289","DOIUrl":"https://doi.org/10.1002/jbt.70289","url":null,"abstract":"<div>\u0000 \u0000 <p>Silver nanoparticles (AgNPs) are extensively mass-produced and widely utilized across diverse fields owing to their potent bactericidal properties. Nevertheless, prior research regarding the distribution of AgNPs In Vivo has revealed that they can penetrate into and accumulate in brain tissue, potentially leading to neurotoxicity. In the current study, we initially delved into the impacts of different dosages of AgNPs (10−250 mg/kg body weight) on behavioral cognitive function. After 28 days of oral ingestion of AgNPs, we observed impaired learning and memory performance in the high-dose-treated group of mice. Moreover, we evaluated the alterations in molecules associated with endoplasmic reticulum (ER) stress and the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, conducting a preliminary exploration of the neurotoxic mechanisms of AgNPs. The results demonstrated that subacute oral exposure to AgNPs might disrupt cognitive function via the ER stress and NLRP3 inflammasome activation pathways. Our data highlight the neurotoxic effects of AgNPs and the significant role played by NLRP3 inflammasome activation in neurological deficits.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Model Systems of Chronic Kidney Disease: A Detailed Overview and Recent Advances 慢性肾脏疾病模型系统：详细概述和最新进展

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-18 DOI: 10.1002/jbt.70302

Ganesh Panditrao Lahane, Arti Dhar, Audesh Bhat

{"title":"Model Systems of Chronic Kidney Disease: A Detailed Overview and Recent Advances","authors":"Ganesh Panditrao Lahane, Arti Dhar, Audesh Bhat","doi":"10.1002/jbt.70302","DOIUrl":"https://doi.org/10.1002/jbt.70302","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Experimental model systems, especially animal models, are indispensable tools to study human diseases and to develop new therapeutics. Chronic kidney disease (CKD) is a major global health problem having significantly higher rate of morbidity and mortality. In a pursuit to enhance our understanding of the pathophysiology of CKD and to develop effective treatments, three main model systems, namely In Vivo, In Vitro, and computational, are commonly employed. Each of these models has its own advantages and disadvantages, and despite some limitations, each model has provided valuable insights into CKD progression and the effect of therapeutic interventions. The emergence of organotypic models, such as iPSC-derived kidney organoids and tubuloids, offers physiologically relevant In Vitro systems that more accurately mimic the human kidney development and disease. With the advent of artificial intelligence (AI), a new and potent fourth model is in the making that is expected to revolutionize the management of complex human diseases. Our discussion in this review will mainly revolve around the three major model systems of CKD; In Vivo, In Vitro organotypic, and the computational model with a brief discussion on the AI model. By comprehensively evaluating these model systems, this review aims to provide a foundation for future CKD research and clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FOXC1 Aggravates the Ischemia-Reperfusion Induced Injury in Renal Tubular Epithelial Cells by Activating NF-κB/NLRP3 Signaling FOXC1通过激活NF-κB/NLRP3信号通路加重肾小管上皮细胞缺血再灌注损伤

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-15 DOI: 10.1002/jbt.70301

Donghao Qiu, Ning Zhao, Qi Chen, Ming Wang

{"title":"FOXC1 Aggravates the Ischemia-Reperfusion Induced Injury in Renal Tubular Epithelial Cells by Activating NF-κB/NLRP3 Signaling","authors":"Donghao Qiu, Ning Zhao, Qi Chen, Ming Wang","doi":"10.1002/jbt.70301","DOIUrl":"https://doi.org/10.1002/jbt.70301","url":null,"abstract":"<div>\u0000 \u0000 <p>Renal ischemia-reperfusion injury (RIRI) is a condition characterized by inflammation and cell damage in the kidneys following a period of ischemia and subsequent reperfusion, which lacks effective treating method in the clinic. Exploring molecular mechanisms holds profound significance in guiding the clinical prevention and treatment of RIRI. Herein, the potential function of Forkhead box C1 (FOXC1), a protein belongs to FOX family, in I/R-induced injury in renal tubular epithelial cells (RTECs) was studied to explore potential targets for RIRI. FOXC1 was upregulated in RIRI rats, expressions of which were elevated as time prolonged. FOXC1-overexpressed or knockdown HK-2 cells were constructed, followed by I/R stimulation. FOXC1 was found markedly upregulated in I/R-stimulated HK-2 cells. Notably repressed cell viability, enhanced apoptosis, increased release of inflammatory cytokines, boosted reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inactivated superoxide dismutase (SOD) enzyme were observed in I/R-stimulated HK-2 cells, which were sharply reversed by silencing FOXC1 and aggravated by overexpression FOXC1. Furthermore, largely increased levels of NLRP3, caspase-1, GSDMD-N, IL-18, IL-1β, and p-p65/p65 were observed in I/R-stimulated HK-2 cells, which were notably suppressed by silencing FOXC1 and further elevated by overexpression FOXC1. Additionally, FOXC1-overexpressed HK-2 cells were stimulated by I/R with or without 10 μM MCC950, an inhibitor of NLRP3. The enhanced apoptosis, triggered inflammation, and facilitated ROS by FOXC1 overexpression in I/R-stimulated HK-2 cells were remarkably abolished by the coculture of MCC950, accompanied by an inhibition on the NF-κB/NLRP3 signaling. Collectively, FOXC1 aggravated the I/R induced injury in RTECs by activating NF-κB/NLRP3 signaling.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LncRNA OIP5-AS1/miR-186-5p/NLRP3 Axis Contributes to Sepsis-Induced Kidney Injury Through Enhancing NLRP3 Inflammasome Activation LncRNA OIP5-AS1/miR-186-5p/NLRP3轴通过增强NLRP3炎性体激活参与脓毒症诱导的肾损伤

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-15 DOI: 10.1002/jbt.70305

Jingdong Li, Zhe Dong, Liting Tang, Lu Liu, Cuijing Su, Shan Yu

{"title":"LncRNA OIP5-AS1/miR-186-5p/NLRP3 Axis Contributes to Sepsis-Induced Kidney Injury Through Enhancing NLRP3 Inflammasome Activation","authors":"Jingdong Li, Zhe Dong, Liting Tang, Lu Liu, Cuijing Su, Shan Yu","doi":"10.1002/jbt.70305","DOIUrl":"https://doi.org/10.1002/jbt.70305","url":null,"abstract":"<div>\u0000 \u0000 <p>Today, acute kidney injury (AKI) caused by sepsis, with its high incidence and rising mortality, is becoming a global problem. Many previous studies have proved that NLRP3 is a critical role in NLRP3 inflammasome activation to regulate inflammatory responses in a variety of diseases including AKI. Our study is aimed to explore the role and upstream regulatory mechanism of NLRP3 in AKI. In this study, we demonstrated that LPS treatment induced the upregulation of NLRP3 in HK-2 cells. Functionally, NLRP3 knockdown inhibited cell apoptosis, inflammatory response and NLRP3 inflammasome activation. Mechanistically, OIP5-AS1 competitively bound with miR-186-5p to promote NLRP3 level, and further activate TLR4/NF-κB signaling. Additionally, OIP5-AS1 was negatively associated with miR-186-5p but positively correlated with NLRP3 in rat renal tissues. The rescue assays suggested that NLRP3 reversed the effects of silencing OIP5-AS1 on cell apoptosis and inflammatory response. At last, OIP5-AS1 aggravated renal injury and inflammation in vivo. All findings indicated that the OIP5-AS1 contributed to sepsis-induced AKI by promoting NLRP3 inflammasome activation via miR-186-5p/NLRP3 axis. OIP5-AS1 could serve as a potential diagnostic and therapeutic marker in sepsis-induced AKI.</p>\u0000 </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Indomethacin Partially Alleviates Depressive-Like Behaviors in Maternally Separated Mice: Targeting Neuroinflammatory Response in the Hippocampus 吲哚美辛部分缓解母分离小鼠的抑郁样行为：针对海马的神经炎症反应

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-15 DOI: 10.1002/jbt.70311

Milad Nemati Khoei, Narges Alinaghipour, Elham Saghaei, Ebrahim Saedi-Dezaki, Hossein Amini-Khoei

{"title":"Indomethacin Partially Alleviates Depressive-Like Behaviors in Maternally Separated Mice: Targeting Neuroinflammatory Response in the Hippocampus","authors":"Milad Nemati Khoei, Narges Alinaghipour, Elham Saghaei, Ebrahim Saedi-Dezaki, Hossein Amini-Khoei","doi":"10.1002/jbt.70311","DOIUrl":"https://doi.org/10.1002/jbt.70311","url":null,"abstract":"<div>\u0000 \u0000 <p>Experiencing early-life stress (ELS) plays a fundamental role in the development of mood disorders like depression in adulthood. Neuro-immune response in the brain is coupled with depressive-like behaviors following maternal separation (MS) stress. Indomethacin (IND) is a nonsteroidal anti-inflammatory drug. This study aimed to assess the antidepressant-like effect of IND in a mouse model of MS stress, focusing on its potential effect on neuro-inflammatory response in the hippocampus. To do this, male NMRI mice were treated with IND at doses of 5, 10, and 20 mg/kg, saline (10 mL/kg) or fluoxetine (30 mg/kg). Drugs were injected intraperitoneally for 7 days. Behavioral tests including forced swimming test, splash test, and open field test were performed. Quantitative reverse transcription-PCR was used for evaluation of gene expression of inflammatory mediators including of <i>iNOS</i>, <i>TLR4</i>, <i>NLRP3</i>, <i>TNF-α</i>, and <i>IL-1β</i> in the hippocampus. Results showed that MS provoked depressive-like behavior in mice as observed by a decrease in the grooming activity time in the splash test and an increase in the immobility time in the forced swimming test. Depressive-like behaviors were coupled with neuroinflammation in the hippocampus. IND attenuated depressive-like behaviors as well as decreased the gene expression of neuroinflammation-related mediators in the hippocampus of MS mice. In conclusion, results showed that IND, at least in part, via alleviation of neuro-inflammatory response in the hippocampus, exerted antidepressant-like effects in a mouse model of MS stress.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reprogramming of Hypoxia-Induced Metabolic Disorder in Mouse Kidneys by Mesenchymal Stem Cells Through Improving Mitochondrial Dynamics and Function

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-13 DOI: 10.1002/jbt.70291

Yanjun Wang, Yanling Ding, Tana Wuren, Pengli Luo

{"title":"Reprogramming of Hypoxia-Induced Metabolic Disorder in Mouse Kidneys by Mesenchymal Stem Cells Through Improving Mitochondrial Dynamics and Function","authors":"Yanjun Wang, Yanling Ding, Tana Wuren, Pengli Luo","doi":"10.1002/jbt.70291","DOIUrl":"https://doi.org/10.1002/jbt.70291","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To assess the effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on mitochondrial damage and metabolic disorders induced by acute and chronic hypoxia in mouse kidneys.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Comprehensive analyses were conducted, including histopathology, mitochondrial morphology analysis, biochemical assessments, transcriptomics and metabolomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results revealed that hUC-MSCs significantly improved renal mitochondrial integrity and maintained mitochondrial dynamic balance under both acute and chronic hypoxia. This improvement was achieved by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, which ultimately enhanced mitochondrial function. Furthermore, hUC-MSCs reprogrammed renal metabolic disorders, particularly improvements in urea and purine metabolic dysfunction, increased fatty acid oxidation and amelioration of lipid metabolic disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that hUC-MSCs could be part of a promising strategy for enhancing renal health and metabolic stability in individuals exposed to high altitudes or other hypoxic environments, highlighting their potential therapeutic value in addressing hypoxia-induced mitochondrial damage and renal metabolic disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Daidzein Attenuates Cadmium-Induced Neurotoxicity via Inhibiting Apoptosis and Mitophagy in the Cerebral Cortex of Sprague–Dawley Rats

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-13 DOI: 10.1002/jbt.70299

Shuangquan Wen, Yu Zhao, Liang Wang, Yan Yuan

{"title":"Daidzein Attenuates Cadmium-Induced Neurotoxicity via Inhibiting Apoptosis and Mitophagy in the Cerebral Cortex of Sprague–Dawley Rats","authors":"Shuangquan Wen, Yu Zhao, Liang Wang, Yan Yuan","doi":"10.1002/jbt.70299","DOIUrl":"https://doi.org/10.1002/jbt.70299","url":null,"abstract":"<div>\u0000 \u0000 <p>Cadmium (Cd), a prevalent environmental pollutant, is of significant concern owing to its neurotoxicity; thus, the identification of effective interventions for nerve injury caused by Cd is crucial. Mitochondrial signaling pathway-mediated apoptosis and PTEN-induced putative kinase protein 1 (PINK1)/E3 ubiquitin ligase (Parkin)-mediated mitophagy are the primary mechanisms responsible for the neurotoxic effects of Cd. Daidzein (Dz), a naturally occurring isoflavone found in leguminous plants, exhibits a wide range of pharmacological effects in the brain. To investigate the short-term protective effects of Dz against Cd-induced neurotoxicity in the rat cerebral cortex, 24 male Sprague–Dawley rats were treated with Dz (100 mg/kg) and/or CdCl<sub>2</sub> (2 mg/kg) for 12 days. Histological changes in the cerebral cortex were assessed by Nissl staining. Apoptosis- and mitophagy-related indices were detected using TUNEL staining, western blotting, and immunofluorescence assays. The administration of Dz attenuated Cd-induced nerve injury. Additionally, Dz reduced cell apoptosis by 66%, and the expression of apoptosis-related proteins Bax/Bcl-2 ratio by 27%, cleaved caspase-9 by 42%, and cleaved caspase-3 by 42%. Dz also decreased the expression of the mitophagy-related proteins LC3 by 35%, PINK1 by 37%, and Parkin by 29%, and increased that of COX IV by 36%. Furthermore, Dz abolished the Cd-induced colocalization of PINK1 and Parkin in the cerebral cortex of rats. In summary, our results indicate that Dz exerts neuroprotective effects in the cerebral cortex of rats by inhibiting mitochondrial signaling pathway-mediated apoptosis and PINK1/Parkin-mediated mitophagy. Therefore, Dz is a promising novel neuroprotective agent. However, some challenges remain, such as efficacy, bioavailability, and potential side effects. Further studies are needed to assess its potential as a therapeutic agent for Cd-induced neurotoxicity in humans.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

METTL14 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation via m6A Methylation TEAD1 mRNA

IF 3.2 3区医学

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-05-13 DOI: 10.1002/jbt.70284

Liang Wang, Guojin Xia, Yan Tang, Yuemei Xu, Qing Li, Zhixing Chen, Tong Wen, Yunfeng Wei, Chunying Wei, Jiamin Zhou

{"title":"METTL14 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation via m6A Methylation TEAD1 mRNA","authors":"Liang Wang, Guojin Xia, Yan Tang, Yuemei Xu, Qing Li, Zhixing Chen, Tong Wen, Yunfeng Wei, Chunying Wei, Jiamin Zhou","doi":"10.1002/jbt.70284","DOIUrl":"https://doi.org/10.1002/jbt.70284","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia critically contribute to atherosclerosis and post-angioplasty restenosis. Building on our prior discovery that TEA domain transcription factor 1 (TEAD1) regulates VSMCs differentiation, we now investigate methyltransferase-like 14 (METTL14) in vascular remodeling. METTL14 expression was significantly upregulated in human carotid atherosclerotic plaques versus control arteries, correlating with VSMCs dedifferentiation. This pattern was recapitulated in murine wire-induced carotid injury models during neointima formation. Functionally, METTL14 overexpression suppressed contractile markers while accelerating proliferation and migration in human coronary artery smooth muscle cells (HCASMCs). Conversely, METTL14 knockdown attenuated injury-induced neointimal hyperplasia In Vivo. Mechanistically, METTL14 stabilizes TEAD1 mRNA through m6A modification at nucleotide 513, enhancing YAP1/TEAD1 signaling. Both 513nt mutation and TEAD1 inhibitor VT103 abolished METTL14-driven phenotypic changes, restoring VSMCs differentiation and suppressing proliferation. Collectively, our findings establish METTL14-mediated m6A modification of TEAD1 mRNA as a novel mechanism promoting vascular pathology, highlighting its therapeutic potential for cardiovascular diseases.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0