Chemico-Biological Interactions最新文献

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N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors n -丙基吡咯烷基丁基胆碱酯酶和单胺氧化酶抑制剂
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-30 DOI: 10.1016/j.cbi.2025.111681
Urban Košak , Damijan Knez , Anja Pišlar , Selena Horvat , Simon Žakelj , Alexandre Igert , José Dias , Florian Nachon , Xavier Brazzolotto , Stanislav Gobec
{"title":"N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors","authors":"Urban Košak ,&nbsp;Damijan Knez ,&nbsp;Anja Pišlar ,&nbsp;Selena Horvat ,&nbsp;Simon Žakelj ,&nbsp;Alexandre Igert ,&nbsp;José Dias ,&nbsp;Florian Nachon ,&nbsp;Xavier Brazzolotto ,&nbsp;Stanislav Gobec","doi":"10.1016/j.cbi.2025.111681","DOIUrl":"10.1016/j.cbi.2025.111681","url":null,"abstract":"<div><div>Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors are or could be used for the treatment of depression, anxiety, Alzheimer's disease, Parkinson's disease, cancer, cardiovascular disease and chronic inflammatory diseases. We have designed, synthesized, and evaluated ten new <em>N</em>-propargylpyrrolidine-based inhibitors of these enzymes. Sulfonamide <strong>10</strong> is the most potent human (h)BChE (IC<sub>50</sub> = 0.203 μM) of the series, and secondary carboxamide <strong>1</strong> is a time-dependent and irreversible inhibitor of hMAO-A (IC<sub>50</sub> = 6.42 μM) and hMAO-B (IC<sub>50</sub> = 7.83 μM). The X-ray crystal structures of carboxamide <strong>4</strong> [IC<sub>50</sub>(hBChE) = 3.89 μM] and sulfonamide <strong>10</strong> with hBChE confirmed our previous observation that carboxamides and sulfonamides have distinct binding poses in the active site of hBChE. The X-ray crystal structure of the complex of pyrrolidine <strong>4</strong> with hBChE also revealed a distinct binding pose compared to its direct piperidine analogue (PDB code 5LKR). Furthermore, compounds <strong>1</strong> and <strong>10</strong> should be able to cross the blood-brain barrier, exhibit low cytotoxicity (&gt;50 μM) in two cell lines and protect against amyloid β<sub>1–42</sub>-induced neuronal cell death.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111681"},"PeriodicalIF":5.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749999","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}
引用次数: 0
PXR mediates maternal cholestatic liver injury and associated fetal dysplasia induced by antenatal dexamethasone exposure PXR介导由产前地塞米松暴露引起的母体胆汁淤积性肝损伤和相关的胎儿发育不良
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-30 DOI: 10.1016/j.cbi.2025.111684
Man Fang , Xiaoqian Lu , Meitao Yang , Juanjuan Guo , Yuan Qiao , Dan Xu , Huijun Chen , Yuanzhen Zhang , Hui Wang
{"title":"PXR mediates maternal cholestatic liver injury and associated fetal dysplasia induced by antenatal dexamethasone exposure","authors":"Man Fang ,&nbsp;Xiaoqian Lu ,&nbsp;Meitao Yang ,&nbsp;Juanjuan Guo ,&nbsp;Yuan Qiao ,&nbsp;Dan Xu ,&nbsp;Huijun Chen ,&nbsp;Yuanzhen Zhang ,&nbsp;Hui Wang","doi":"10.1016/j.cbi.2025.111684","DOIUrl":"10.1016/j.cbi.2025.111684","url":null,"abstract":"<div><div>Previous studies have focused on advantages and disadvantages of antenatal dexamethasone therapy (ADT) on offspring development, but the effects on the mother have yet to be reported. In this study, the clinical cohort study found that ADT caused maternal susceptibility to cholestatic liver injury, which was manifested by elevated plasma total bile acid (TBA) levels, altered bile acid metabolic profiles and changed gut microbiota (mainly characterized by increased <em>Bacteroides</em>), accompanied by fetal dysplasia associated with high bile acids. Animal experiments confirmed that prenatal dexamethasone exposure (PDE) caused maternal cholestatic liver injury and associated fetal dysplasia, related to enhanced maternal hepatic bile acid synthesis and intestinal flora transformation. Furthermore, the <em>in vitro</em> experiments demonstrated that dexamethasone increased hepatocyte glucocorticoid receptor (GR) and estrogen receptor α (ERα) translocation into the nucleus, and then inhibited pregnane X receptor (PXR) by binding to its promoter region, which in turn increased cytochrome P4507A1 (CYP7A1) expression and TBA levels. Finally, the PXR agonist pregnenolone carbonitrile (PCN) effectively reversed PDE-induced maternal cholestatic liver injury and associated fetal dysplasia. The study systematically elucidated the liver-gut circulation mechanism of maternal cholestatic liver injury induced by ADT and confirmed potential drug intervention target-PXR, essential for guiding rational use of ADT and conducting early prevention and treatment research.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111684"},"PeriodicalIF":5.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756814","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}
引用次数: 0
N-acyl hydrazone derivatives reduce pro-inflammatory cytokines, iNOS and COX-2 in acute lung inflammation model n -酰基腙衍生物在急性肺炎症模型中降低促炎细胞因子、iNOS和COX-2
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-29 DOI: 10.1016/j.cbi.2025.111677
Katharina Rodrigues de Lima Porto Ramos , Jéssica de Andrade Gomes Silva , Rayane Siqueira de Sousa , Elizabeth Fernanda de Oliveira Borba , Marília Grasielly de Farias Silva , Sonaly Lima Albino , Silvana Tavares Paz , Rodrigo Soares da Silva , Christina Alves Peixoto , Vanda Lúcia dos Santos , Ricardo Olímpio Moura , Teresinha Gonçalves da Silva
{"title":"N-acyl hydrazone derivatives reduce pro-inflammatory cytokines, iNOS and COX-2 in acute lung inflammation model","authors":"Katharina Rodrigues de Lima Porto Ramos ,&nbsp;Jéssica de Andrade Gomes Silva ,&nbsp;Rayane Siqueira de Sousa ,&nbsp;Elizabeth Fernanda de Oliveira Borba ,&nbsp;Marília Grasielly de Farias Silva ,&nbsp;Sonaly Lima Albino ,&nbsp;Silvana Tavares Paz ,&nbsp;Rodrigo Soares da Silva ,&nbsp;Christina Alves Peixoto ,&nbsp;Vanda Lúcia dos Santos ,&nbsp;Ricardo Olímpio Moura ,&nbsp;Teresinha Gonçalves da Silva","doi":"10.1016/j.cbi.2025.111677","DOIUrl":"10.1016/j.cbi.2025.111677","url":null,"abstract":"<div><div>N-acyl hydrazone derivatives are widely employed in medicinal chemistry due to the simplicity of their synthesis and wide range of pharmacological activities described in the literature. In this study, the toxicity and anti-inflammatory activity of four N-acyl hydrazone derivatives were evaluated. The N-acyl hydrazone derivatives JR-13, JR-15, JR-17, and JR-18 were subjected to acute toxicity testing in accordance with the OECD 426 method. Cytotoxic activity was assessed in normal cells, whereas anti-inflammatory activity was evaluated in macrophages <em>in vitro</em> and in an animal model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). The derivatives did not show any changes indicative of <em>in vitro</em> or <em>in vivo</em> toxicity. A reduction in the levels of nitric oxide (NO) and the cytokines IL-18 and TNF-α was observed in the <em>in vitro</em> anti-inflammatory activity test. In the ALI model, the derivatives JR-13, JR-15, JR-17, and JR-18 inhibited cell migration, with a percentage of inflammation inhibition of 62.8 %, 40.9 %, 83.2 %, and 86.9 %, respectively, when compared to the control. The derivatives also reduced NO concentration in bronchoalveolar lavage, myeloperoxidase (MPO) and malondialdehyde (MDA) activity in lung tissue. Immunohistochemical analyses of lung tissue showed decreased COX-2 and iNOS levels. The compounds JR-17 and JR-18 decreased the levels of pro-inflammatory cytokines IL-6, IL-18 and TNF-α and increased the levels of anti-inflammatory cytokines IL-4 and IL-10 in the ALI model. In conclusion, the N-acyl hydrazone derivatives demonstrated the capacity to attenuate inflammation <em>in vitro</em> and <em>in vivo</em> assays, involving the reduction of COX-2, iNOS, and pro-inflammatory cytokines.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111677"},"PeriodicalIF":5.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749996","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}
引用次数: 0
Targeted delivery of 2-PAM to the brain using cationic liposomes modified with lipid-like surfactants for the treatment of acute organophosphorus poisoning 用类脂表面活性剂修饰的阳离子脂质体靶向递送2-PAM到脑治疗急性有机磷中毒
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-28 DOI: 10.1016/j.cbi.2025.111678
Darya A. Kuznetsova , Denis M. Kuznetsov , Gulnara A. Gaynanova , Irina V. Zueva , Vasily M. Babaev , Alexandra D. Voloshina , Guzel V. Sibgatullina , Konstantin A. Petrov , Lucia Ya. Zakharova , Oleg G. Sinyashin
{"title":"Targeted delivery of 2-PAM to the brain using cationic liposomes modified with lipid-like surfactants for the treatment of acute organophosphorus poisoning","authors":"Darya A. Kuznetsova ,&nbsp;Denis M. Kuznetsov ,&nbsp;Gulnara A. Gaynanova ,&nbsp;Irina V. Zueva ,&nbsp;Vasily M. Babaev ,&nbsp;Alexandra D. Voloshina ,&nbsp;Guzel V. Sibgatullina ,&nbsp;Konstantin A. Petrov ,&nbsp;Lucia Ya. Zakharova ,&nbsp;Oleg G. Sinyashin","doi":"10.1016/j.cbi.2025.111678","DOIUrl":"10.1016/j.cbi.2025.111678","url":null,"abstract":"<div><div>The search for new systems for drug delivery to the brain is stimulated by the low ability of medicines to overcome the blood-brain barrier (BBB). Liposomes modified with cationic surfactants are promising systems from this point of view. Therefore, new cationic lipid-like surfactants with hexadecyl hydrocarbon tail and different head group structures were synthesized for modification of phosphatidylcholine-based liposomes. To obtain the optimal composition, the surfactant/lipid molar ratio was varied. Modified vesicular nanocontainers were used to load the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM). The physicochemical parameters (hydrodynamic diameter, zeta potential, polydispersity index, aggregate morphology), substrate release profile <em>in vitro</em>, hemolytic activity and hemagglutination ability, as well as 2-PAM pharmacokinetics and AChE reactivation <em>in vivo</em> were examined. The optimized liposomal formulations demonstrated long-term stability. Subsequent evaluation of BBB penetration, 2-PAM pharmacokinetic profile, and <em>in vivo</em> AChE reactivation revealed that the top-performing systems achieved notable brain uptake and reactivated rat brain AChE by 25–38 %.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111678"},"PeriodicalIF":5.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749998","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}
引用次数: 0
Chitosan oligosaccharide improves diabetic nephropathy by attenuating renal fibrogenesis and strengthening intestinal barriers in type 2 diabetic rats 低聚壳聚糖通过减轻2型糖尿病大鼠肾纤维化和增强肠道屏障改善糖尿病肾病
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-28 DOI: 10.1016/j.cbi.2025.111680
Prempree Sutthasupha , Sasivimon Promsan , Nattavadee Pengrattanachot , Nichakorn Phengpol , Chorchat Lalichatsakul , Laongdao Thongnak , Krit Jaikumkao , Rath Pichyangkura , Chatchai Muanprasat , Anusorn Lungkaphin
{"title":"Chitosan oligosaccharide improves diabetic nephropathy by attenuating renal fibrogenesis and strengthening intestinal barriers in type 2 diabetic rats","authors":"Prempree Sutthasupha ,&nbsp;Sasivimon Promsan ,&nbsp;Nattavadee Pengrattanachot ,&nbsp;Nichakorn Phengpol ,&nbsp;Chorchat Lalichatsakul ,&nbsp;Laongdao Thongnak ,&nbsp;Krit Jaikumkao ,&nbsp;Rath Pichyangkura ,&nbsp;Chatchai Muanprasat ,&nbsp;Anusorn Lungkaphin","doi":"10.1016/j.cbi.2025.111680","DOIUrl":"10.1016/j.cbi.2025.111680","url":null,"abstract":"<div><div>It has been demonstrated that systemic low-grade inflammation and renal oxidative stress induce renal complications and diabetic nephropathy (DN) in conditions associated with diabetes. Chitosan oligosaccharide (COS) has been shown to attenuate kidney injury by enhancing renal autophagy in prediabetic rats. This study explored the effects of COS on renal injury and the mechanisms involved in a type 2 diabetes mellitus (T2DM) model. Wistar rats were given a high‐fat diet (HFD) and streptozotocin injection to induce T2DM. COS 5 or 10 or metformin 30 mg/kg/day were given orally to T2DM rats for 8 weeks. COS exerted nephroprotection through activation of renal AMP-activated protein kinase (AMPK), alleviation of the renal oxidative stress-fibrosis axis and impaired organic anion transporter (Oat3) function. COS also strengthened intestinal barriers via suppression of myosin light chain kinase (MLCK) and stimulation of calcium-sensing receptor (CaSR), limiting leaky gut and providing anti-inflammatory effects. Metformin had no effect on CaSR. COS10 and metformin had comparable effects regarding the reduction of renal oxidative stress. Metformin showed a greater efficacy in attenuating oxidative stress than COS5. However, the anti-fibrotic efficacy of COS10 was greater than metformin partly through the inhibition of the transforming growth factor beta (TGF-β)/epithelial-mesenchymal transition (EMT) process. A clinical therapeutic approach using COS supplementation could potentially increase the efficacy regarding the attenuation of hyperlipidemia, leaky gut, and protection against kidney injury in diabetic conditions.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111680"},"PeriodicalIF":5.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749997","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}
引用次数: 0
Dimethoate-induced inflammation results in neurodevelopmental toxicity in zebrafish larvae 乐果诱导的炎症导致斑马鱼幼体的神经发育毒性
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-28 DOI: 10.1016/j.cbi.2025.111679
Xin Geng , Xiang Ji , Buwen Pang , Lei Ai , Guanghua Mao , Yao Chen , Yangyang Ding , Emmanuel Sunday Okeke , Weiwei Feng , Xiangyang Wu
{"title":"Dimethoate-induced inflammation results in neurodevelopmental toxicity in zebrafish larvae","authors":"Xin Geng ,&nbsp;Xiang Ji ,&nbsp;Buwen Pang ,&nbsp;Lei Ai ,&nbsp;Guanghua Mao ,&nbsp;Yao Chen ,&nbsp;Yangyang Ding ,&nbsp;Emmanuel Sunday Okeke ,&nbsp;Weiwei Feng ,&nbsp;Xiangyang Wu","doi":"10.1016/j.cbi.2025.111679","DOIUrl":"10.1016/j.cbi.2025.111679","url":null,"abstract":"<div><div>Dimethoate (DMT), a widely used organophosphorus insecticide and recognized endocrine disruptor, has emerged as a significant contaminant in aquatic ecosystems. While its environmental prevalence is well-documented, limited research exists on its neurodevelopmental toxicity in aquatic organisms. This study investigated the adverse effects of DMT exposure on zebrafish larvae, focusing on neurobehavioral impairments and underlying molecular mechanisms. Following 96-h exposure to 20 μg/L DMT, larvae exhibited marked neurodevelopmental disruptions, including reduced heart rate and diminished tail motility. Concurrently, pro-inflammatory cytokine levels (IL-8, IL-1β) were significantly elevated, suggesting systemic inflammation. Mechanistic analysis revealed dysregulation of inflammatory mediators within the TRP pathway and aberrant activation of the JAK-STAT signaling cascade. Central to these effects was the overexpression of IL-1β, which potentially drives neurotoxicity through multiple pathways: induction of apoptosis, dysregulation of neurotransmitter-associated signaling, and altered expression of genes linked to neurodegenerative disorders. These findings demonstrate that DMT compromises neurodevelopment in zebrafish larvae via IL-1β-mediated inflammatory imbalance and subsequent pathway dysregulation. This study provides critical insights into the ecotoxicological risks of DMT in aquatic environments and establishes a mechanistic framework for understanding organophosphorus-induced neurotoxicity in fish models.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111679"},"PeriodicalIF":5.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738101","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}
引用次数: 0
Evidence of biological aging through mitochondrial DNA damage and dysregulation of mitophagy-related genes in veterans with delayed sulfur mustard toxicity 迟发性芥子气中毒退伍军人线粒体DNA损伤和线粒体自噬相关基因失调的生物学老化证据
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-26 DOI: 10.1016/j.cbi.2025.111666
Maryam-Sadat Kalantar , Mohammad-Reza Vaez-Mahdavi , Leila Nasiri , Hossein Hassanpour , Sussan Kaboudanian-Ardestani
{"title":"Evidence of biological aging through mitochondrial DNA damage and dysregulation of mitophagy-related genes in veterans with delayed sulfur mustard toxicity","authors":"Maryam-Sadat Kalantar ,&nbsp;Mohammad-Reza Vaez-Mahdavi ,&nbsp;Leila Nasiri ,&nbsp;Hossein Hassanpour ,&nbsp;Sussan Kaboudanian-Ardestani","doi":"10.1016/j.cbi.2025.111666","DOIUrl":"10.1016/j.cbi.2025.111666","url":null,"abstract":"<div><div>Sulfur mustard (SM) is a potent alkylating agent known to cause long-term health effects, including accelerated aging. This study investigated mitochondrial dysfunction as a key mechanism underlying biological aging in 142 SM-exposed veterans (25 years post-exposure) and 54 matched controls. The SM-exposed veterans <em>were stratified into subgroups (asymptom, mild, and severe) based on clinical criteria and lung function tests.</em> Using buffy coat-derived leukocytes, we assessed mitochondrial DNA (mtDNA) copy number and damage frequency of long/short mtDNA fragments, and mitophagy-related gene expression (<em>PINK1, PRKN, DRP1, FIS1</em>). Demographic variables (age, marital status, income, smoking status, education) did not differ significantly between SM-exposed and control groups, ensuring comparability. Results showed no significant differences in mtDNA copy number between groups; however, mtDNA damage frequency was significantly elevated in the severe exposure subgroup. Gene expression analysis revealed significantly increased mRNA levels of <em>PINK1, PRKN, DRP1,</em> and <em>FIS1</em> in SM-exposed veterans compared to controls, with the highest expression observed in the severe and mild subgroups, while <em>PINK1</em> expression showed no significant subgroup differences. These findings demonstrate that SM exposure induces persistent mitochondrial dysfunction through cumulative mtDNA damage, dysregulated mitophagy signaling, and aberrant fission activation. While preserved mtDNA copy numbers suggest adaptive biogenesis, the severity-dependent patterns in fission genes and mtDNA lesions establish mitochondrial impairment as a central pathway in SM-related aging.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111666"},"PeriodicalIF":5.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723894","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}
引用次数: 0
Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission 阿特拉津诱导的海马神经毒性:drp1介导的线粒体裂变的参与
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-26 DOI: 10.1016/j.cbi.2025.111676
Jingran Yang , Ling Qi , Cheng Zhang , Ruirui Ding , Haoran Bi , Peng Li , Zhipeng Qi , Qiao Niu , Weiyi Song , Jianan Li
{"title":"Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission","authors":"Jingran Yang ,&nbsp;Ling Qi ,&nbsp;Cheng Zhang ,&nbsp;Ruirui Ding ,&nbsp;Haoran Bi ,&nbsp;Peng Li ,&nbsp;Zhipeng Qi ,&nbsp;Qiao Niu ,&nbsp;Weiyi Song ,&nbsp;Jianan Li","doi":"10.1016/j.cbi.2025.111676","DOIUrl":"10.1016/j.cbi.2025.111676","url":null,"abstract":"<div><div>The widespread use of atrazine (ATR), a commonly applied herbicide, has raised growing concerns about its neurotoxic effects. However, the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that ATR disrupts hippocampal function by inducing Drp1-mediated mitochondrial fission. Using both <em>in vivo</em> and <em>in vitro</em> tests, we show that ATR exposure leads to mitochondrial swelling, cristae loss, and fragmentation in hippocampal neurons, correlating with impaired spatial learning and memory. ATR significantly increases Ser616-Drp1 phosphorylation, promoting excessive mitochondrial fission and exacerbating neuronal damage. In contrast, the Drp1 inhibitor Mdivi-1 effectively restores mitochondrial integrity, mitigates mitochondrial membrane potential loss, and alleviates neurotoxicity. Interestingly, ATR exposure results in a non-linear response in the expression of mitochondrial regulatory genes, suggesting complex dose-dependent effects. These findings provide novel insights into the role of mitochondrial dysfunction in ATR-induced cognitive impairment and underscore the importance of Drp1-mediated fission in herbicide neurotoxicity. Our study highlights the need for further investigation into the long-term effects of ATR exposure and suggests that targeting mitochondrial dynamics may offer a promising therapeutic strategy for ATR-induced neuronal dysfunction.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111676"},"PeriodicalIF":5.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720745","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}
引用次数: 0
Imidazopyrimidine-based pyruvate kinase M2 activator halts diabetic nephropathy progression via modulating epithelial-to-mesenchymal transition and fibrosis 咪唑嘧啶型丙酮酸激酶M2激活剂通过调节上皮-间质转化和纤维化阻止糖尿病肾病进展。
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-25 DOI: 10.1016/j.cbi.2025.111673
Meenakshi Jain , Adil Ali Sayyed , Piyush Gondaliya , Saumya Kapoor , Deep Rohan Chatterjee , Rudradip Das , Kiran Kalia , Amit Khairnar , Amit Shard
{"title":"Imidazopyrimidine-based pyruvate kinase M2 activator halts diabetic nephropathy progression via modulating epithelial-to-mesenchymal transition and fibrosis","authors":"Meenakshi Jain ,&nbsp;Adil Ali Sayyed ,&nbsp;Piyush Gondaliya ,&nbsp;Saumya Kapoor ,&nbsp;Deep Rohan Chatterjee ,&nbsp;Rudradip Das ,&nbsp;Kiran Kalia ,&nbsp;Amit Khairnar ,&nbsp;Amit Shard","doi":"10.1016/j.cbi.2025.111673","DOIUrl":"10.1016/j.cbi.2025.111673","url":null,"abstract":"<div><div>Diabetic nephropathy affects nearly 40 % of diabetic patients, causing kidney damage through metabolic dysregulation and the build-up of toxic glucose metabolites. Upregulated pyruvate kinase M2 (PKM2) promotes glycolysis, activates hypoxia-inducible factor-1 (HIF-1), and induces epithelial-to-mesenchymal transition (EMT), collectively driving renal fibrosis and dysfunction. The dimeric form of PKM2 amplifies inflammation, while its tetrameric form protects against DN. Pharmacological activation of PKM2 tetramers, using agents like TEPP-46, restores metabolic balance and protects kidney function in animal models, suggesting that PKM2 activation may offer a promising strategy for preventing fibrotic kidney disease in DN. Our group recently developed a novel imidazopyrimidine-based derivative, <strong>15n</strong>, as a PKM2 activator with an AC<sub>50</sub> of 90 nM. This study evaluated the efficacy of <strong>15n</strong> as a PKM2 activator in an <em>in vitro</em> DN-induced human renal proximal tubular epithelial cell line and in a Streptozotocin-induced DN mouse model. Treatment with <strong>15n</strong> (10 μM) increased PKM2 tetramer expression in DN-induced hRPTEC cells, reducing EMT and fibrosis progression. Histological analysis revealed that the <strong>15n</strong>-treated group showed attenuated progression of DN, accompanied by decreased serum levels of urea and creatinine compared to the disease group. These findings indicate that <strong>15n</strong> confers renal protection, likely through modulation of the EMT pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111673"},"PeriodicalIF":5.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736069","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}
引用次数: 0
METTL3-mediated modification of SIRT1 m6A methylation protects osteoblasts from TBHP-induced senescence and promotes osteoblast proliferation mettl3介导的SIRT1 m6A甲基化修饰可保护成骨细胞免受thbp诱导的衰老,并促进成骨细胞增殖
IF 5.4 2区 医学
Chemico-Biological Interactions Pub Date : 2025-07-25 DOI: 10.1016/j.cbi.2025.111672
Yi Chen , Yaobin Wang , Hefang Xiao , Fei Teng , Ao Yang , Jinmin Liu , Zirui Liu , Xiaoyun Sheng , Chengjun Zhang , Shifeng Zhang , Bin Geng , Yayi Xia
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