Pub Date : 2025-12-08DOI: 10.1016/j.cbi.2025.111866
Pinya Liu , Lei Zhang , Qing Zhou , Zhushan Fu , Shuhua Xi
Epidemiologic research has demonstrated a clear correlation between prolonged exposure to inorganic arsenic and an elevated risk of bladder cancer, but the specific mechanisms are unknown. Calcium ions (Ca2+), as key second messengers, are crucial in cellular physiological and pathological processes. Loss of Ca2+ homeostasis is thought to be an important driver of malignant disease. In this study, C57BL/6 mice were treated with 0, 8, 20 and 50 mg/L NaAsO2 via drinking water during 20 weeks, and human normal bladder epithelial cells (SV-HUC-1) received continuous exposure to 0.5 μM NaAsO2 over 40 weeks. The results revealed that long-term arsenic treatment led to elevated Ca2+ levels in SV-HUC-1 cells and enhanced cell proliferation, stemness, and epithelial-mesenchymal transition (EMT). Our study revealed that store-operated calcium entry (SOCE) was essential in arsenic-induced elevation of Ca2+ levels. STIM1 serves as a critical mediator of arsenic-triggered malignant transformation in urothelial cells by regulating store-operated calcium channels (SOCC). STIM1 undergoes N-linked glycosylation at its N131 site. This post-translational modification is essential for proper STIM1 localization and binding with ORAI1. The evidence, similar to the cellular experiments in vitro, was also observed in animal experiments in vivo. Our research results provide a new mechanism for the role of calcium homeostasis imbalance in arsenic-induced initiation and progression of bladder cancer.
{"title":"STIM1 N-linked glycosylation promotes arsenic-induced malignant phenotype by activating SOCE in bladder epithelial cells","authors":"Pinya Liu , Lei Zhang , Qing Zhou , Zhushan Fu , Shuhua Xi","doi":"10.1016/j.cbi.2025.111866","DOIUrl":"10.1016/j.cbi.2025.111866","url":null,"abstract":"<div><div>Epidemiologic research has demonstrated a clear correlation between prolonged exposure to inorganic arsenic and an elevated risk of bladder cancer, but the specific mechanisms are unknown. Calcium ions (Ca<sup>2+</sup>), as key second messengers, are crucial in cellular physiological and pathological processes. Loss of Ca<sup>2+</sup> homeostasis is thought to be an important driver of malignant disease. In this study, C57BL/6 mice were treated with 0, 8, 20 and 50 mg/L NaAsO<sub>2</sub> via drinking water during 20 weeks, and human normal bladder epithelial cells (SV-HUC-1) received continuous exposure to 0.5 μM NaAsO<sub>2</sub> over 40 weeks. The results revealed that long-term arsenic treatment led to elevated Ca<sup>2+</sup> levels in SV-HUC-1 cells and enhanced cell proliferation, stemness, and epithelial-mesenchymal transition (EMT). Our study revealed that store-operated calcium entry (SOCE) was essential in arsenic-induced elevation of Ca<sup>2+</sup> levels. STIM1 serves as a critical mediator of arsenic-triggered malignant transformation in urothelial cells by regulating store-operated calcium channels (SOCC). STIM1 undergoes N-linked glycosylation at its N131 site. This post-translational modification is essential for proper STIM1 localization and binding with ORAI1. The evidence, similar to the cellular experiments in vitro, was also observed in animal experiments in vivo. Our research results provide a new mechanism for the role of calcium homeostasis imbalance in arsenic-induced initiation and progression of bladder cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111866"},"PeriodicalIF":5.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145727706","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}
Pub Date : 2025-12-05DOI: 10.1016/j.cbi.2025.111863
Jiyan Su , Kaihong Zhao , Xiaoling Zhou , Ziyu Pan , Chenglai Xia
Background and objectives
Linezolid is a broad-spectrum antibiotic against Gram-positive bacterial infections. Widespread use of linezolid has brought about significant adverse effects and potential reproductive toxicity, but there is not yet any study regarding to the transgenerational impact.
Methods
Gut microbiota and metabolites from the 12-weeks old male mice who were treated with one-week linezolid at 4 weeks of age, as well as those from their offsprings, were analyzed by metagenomics and metabolomics, respectively. Reproductivity of the male parents were monitored, including fertility, litter size, survival and weight gain of offsprings.
Results
Offsprings survival from the linezolid-treated male parents was obviously decreased, although fertilities, litter size, or weight gain was not affected. The linezolid-induced gut microbiota perturbation in male parents was manifested as lower alpha diversity, distinguishing beta diversity, and the dramatically altered profiles of function genes and metabolites. Especially, linezolid exposure reversed the relationship between Dysosmobacter and butyrogenic species, and that between Dysosmobacter and inflammation-associated species. Interestingly, gut microbiota dysbiosis also existed in both female and male offsprings from the treated male parents. Moreover, it was found that the differential metabolites enriched in ABC transporter pathway were found male parents and offsprings, while those enriched in sphingolipid signaling pathway were only found in offsprings of both sexes.
Conclusions
The early-life short-term exposure to linezolid make long-term gut microbiota dysregulation, which was even inherited from parents to offsprings. These findings raised critical concern about the ecological consequences of early-life antibiotic exposure and clinical safety evaluations.
{"title":"Early-life exposure to linezolid caused gut microbiota dysbiosis can be inherited from parents to offspring","authors":"Jiyan Su , Kaihong Zhao , Xiaoling Zhou , Ziyu Pan , Chenglai Xia","doi":"10.1016/j.cbi.2025.111863","DOIUrl":"10.1016/j.cbi.2025.111863","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Linezolid is a broad-spectrum antibiotic against Gram-positive bacterial infections. Widespread use of linezolid has brought about significant adverse effects and potential reproductive toxicity, but there is not yet any study regarding to the transgenerational impact.</div></div><div><h3>Methods</h3><div>Gut microbiota and metabolites from the 12-weeks old male mice who were treated with one-week linezolid at 4 weeks of age, as well as those from their offsprings, were analyzed by metagenomics and metabolomics, respectively. Reproductivity of the male parents were monitored, including fertility, litter size, survival and weight gain of offsprings.</div></div><div><h3>Results</h3><div>Offsprings survival from the linezolid-treated male parents was obviously decreased, although fertilities, litter size, or weight gain was not affected. The linezolid-induced gut microbiota perturbation in male parents was manifested as lower alpha diversity, distinguishing beta diversity, and the dramatically altered profiles of function genes and metabolites. Especially, linezolid exposure reversed the relationship between <em>Dysosmobacter</em> and butyrogenic species, and that between <em>Dysosmobacter</em> and inflammation-associated species. Interestingly, gut microbiota dysbiosis also existed in both female and male offsprings from the treated male parents. Moreover, it was found that the differential metabolites enriched in ABC transporter pathway were found male parents and offsprings, while those enriched in sphingolipid signaling pathway were only found in offsprings of both sexes.</div></div><div><h3>Conclusions</h3><div>The early-life short-term exposure to linezolid make long-term gut microbiota dysregulation, which was even inherited from parents to offsprings. These findings raised critical concern about the ecological consequences of early-life antibiotic exposure and clinical safety evaluations.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111863"},"PeriodicalIF":5.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696427","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}
Growing evidence suggests that trimethylamine N-oxide (TMAO) is closely associated with cognitive impairment. However, the mechanisms by which TMAO causes cognitive impairment remain unclear. TMAO has been reported to regulate blood-brain barrier (BBB) integrity and suppress the expression of tight junction proteins (TJs) in the microvasculature. This study aims to investigate whether disruption of the BBB contributes to TMAO-induced cognitive impairment and to elucidate the underlying molecular mechanisms. Mice recieved an intraperitoneal injection (1.1 mg/kg) of TMAO and underwent the Y-maze test, novel object recognition test, and passive avoidance test 72 h post-treatment. To assess BBB integrity, Evans blue staining, immunofluorescence, western blotting, and qRT-PCR analysis were carried out. Our findings indicated that TMAO treatment induced cognitive impairment and disrupted the BBB integrity in mice. In the hippocampus, TMAO reduced the expression of ZO-1, occludin, claudin1, and CD31 and caused significant ultrastructural changes in the microvasculature. To explore the underlying molecular mechanisms, human cerebral microvascular endothelial cells (hCMEC/D3) were cultured with TMAO. TMAO treatment suppressed TJs and increased monolayer permeability in hCMEC/D3 cells. Transcriptomic analysis revealed that TMAO activated multiple inflammation-related pathways while inhibiting the TGF-β pathway. Moreover, TGF-β1 intervention rescued the down-regulation of TJs and reduced permeability in TMAO-treated hCMEC/D3 cells. Our research demonstrates that TMAO-induced cognitive impairment occurs through the disruption of the BBB by inhibiting the TGF-β pathway in endothelial cells. The current investigation provides new insights into the mechanisms of TMAO neurotoxicity and suggests that increasing TGF-β1 level represents an effective strategy to counteract TMAO-induced cognitive impairment.
{"title":"Trimethylamine N-oxide induced cognitive impairment through disruption of blood-brain barrier by inhibiting TGF-β pathway","authors":"Yue Liu, Hua-Yue Zhang, Xi-Yan Hong, Yi-Xiao Wu, Ming-Jie Li, Hua-Jun Zheng","doi":"10.1016/j.cbi.2025.111862","DOIUrl":"10.1016/j.cbi.2025.111862","url":null,"abstract":"<div><div>Growing evidence suggests that trimethylamine N-oxide (TMAO) is closely associated with cognitive impairment. However, the mechanisms by which TMAO causes cognitive impairment remain unclear. TMAO has been reported to regulate blood-brain barrier (BBB) integrity and suppress the expression of tight junction proteins (TJs) in the microvasculature. This study aims to investigate whether disruption of the BBB contributes to TMAO-induced cognitive impairment and to elucidate the underlying molecular mechanisms. Mice recieved an intraperitoneal injection (1.1 mg/kg) of TMAO and underwent the Y-maze test, novel object recognition test, and passive avoidance test 72 h post-treatment. To assess BBB integrity, Evans blue staining, immunofluorescence, western blotting, and qRT-PCR analysis were carried out. Our findings indicated that TMAO treatment induced cognitive impairment and disrupted the BBB integrity in mice. In the hippocampus, TMAO reduced the expression of ZO-1, occludin, claudin1, and CD31 and caused significant ultrastructural changes in the microvasculature. To explore the underlying molecular mechanisms, human cerebral microvascular endothelial cells (hCMEC/D3) were cultured with TMAO. TMAO treatment suppressed TJs and increased monolayer permeability in hCMEC/D3 cells. Transcriptomic analysis revealed that TMAO activated multiple inflammation-related pathways while inhibiting the TGF-β pathway. Moreover, TGF-β1 intervention rescued the down-regulation of TJs and reduced permeability in TMAO-treated hCMEC/D3 cells. Our research demonstrates that TMAO-induced cognitive impairment occurs through the disruption of the BBB by inhibiting the TGF-β pathway in endothelial cells. The current investigation provides new insights into the mechanisms of TMAO neurotoxicity and suggests that increasing TGF-β1 level represents an effective strategy to counteract TMAO-induced cognitive impairment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111862"},"PeriodicalIF":5.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703334","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}
Pub Date : 2025-12-03DOI: 10.1016/j.cbi.2025.111832
Edward J. Calabrese, Paul B. Selby
The US NAS BEAR I Genetics Panel in 1956 offered a profoundly influential recommendation to switch from a threshold to a linear dose response model for radiation-induced hereditary changes and key gene-mutation-mediated somatic endpoints. Historical and recent findings indicate that this NAS Report is based on falsified data from panelist William L. Russell that significantly inflated panelist estimates of radiation-induced mutational risks and that panelist James Crow disguised massive panelist uncertainty and variability to promote acceptance of its LNT-risk-based recommendations. This paper extends those challenges to the integrity and credibility of the 1956 NAS report and of decisions by regulatory agencies such as the US EPA to adopt such recommendations by showing that: (1) the “esteemed” NAS panel lacked the necessary expertise to guide the country on radiation-induced genetic risks based on a strikingly anemic research publication record on that topic, (2) selection of the panelists was influenced by commitments toward an evolutionary-based eugenics framework, (3) a key eugenics strategy involved the adoption of an LNT model for risk assessment to reduce population genetic variability, and (4) Muller persuaded the Panel chair to add Crow to blunt an anticipated challenge to Muller's genetic load hypothesis by population geneticists based on enhanced fitness in heterozygotes at optimized radiation exposures, which challenged his eugenics framework. In addition, the selection of a Panel scientifically weak regarding radiation experiments may have been intentional to allow Muller to dominate Panel activities consistent with his eugenics perspectives. It appears likely that Muller and Crow conspired to manipulate Panel activities, leading to the adoption of LNT for radiation risk assessment, as part of the larger RF plan to control the direction of human evolution via eugenics principles and practices.
1956年，美国NAS BEAR I遗传学小组提出了一项影响深远的建议，建议从辐射诱导的遗传变化和关键基因突变介导的体细胞终点的阈值转向线性剂量反应模型。历史和最近的研究结果表明，这份NAS报告是基于小组成员William L. Russell的伪造数据，这些数据大大夸大了小组成员对辐射引起的突变风险的估计，小组成员James Crow掩盖了小组成员的大量不确定性和可变性，以促进对其基于lnt风险的建议的接受。本文将这些挑战扩展到1956年NAS报告的完整性和可信度，以及美国环保局等监管机构采纳这些建议的决定，表明：(1)“受人尊敬的”NAS小组缺乏必要的专业知识来指导国家应对辐射引起的遗传风险，因为该主题的研究出版物记录明显缺乏；(2)小组成员的选择受到对基于进化的优生学框架的承诺的影响；(3)关键的优生学策略涉及采用LNT模型进行风险评估，以减少群体遗传变异；(4) Muller说服小组主席加入Crow，以缓和种群遗传学家对Muller遗传负荷假说的挑战，该假说基于优化辐射暴露下杂合子的适应性增强，这挑战了他的优生学框架。此外，选择一个在辐射实验方面科学薄弱的小组可能是有意的，以便让穆勒根据他的优生学观点主导小组的活动。Muller和Crow似乎合谋操纵专家组的活动，导致采用LNT进行辐射风险评估，作为更大的RF计划的一部分，通过优生学原则和实践来控制人类进化的方向。
{"title":"Embracing dishonesty: How LNT became king","authors":"Edward J. Calabrese, Paul B. Selby","doi":"10.1016/j.cbi.2025.111832","DOIUrl":"10.1016/j.cbi.2025.111832","url":null,"abstract":"<div><div>The US NAS BEAR I Genetics Panel in 1956 offered a profoundly influential recommendation to switch from a threshold to a linear dose response model for radiation-induced hereditary changes and key gene-mutation-mediated somatic endpoints. Historical and recent findings indicate that this NAS Report is based on falsified data from panelist William L. Russell that significantly inflated panelist estimates of radiation-induced mutational risks and that panelist James Crow disguised massive panelist uncertainty and variability to promote acceptance of its LNT-risk-based recommendations. This paper extends those challenges to the integrity and credibility of the 1956 NAS report and of decisions by regulatory agencies such as the US EPA to adopt such recommendations by showing that: (1) the “esteemed” NAS panel lacked the necessary expertise to guide the country on radiation-induced genetic risks based on a strikingly anemic research publication record on that topic, (2) selection of the panelists was influenced by commitments toward an evolutionary-based eugenics framework, (3) a key eugenics strategy involved the adoption of an LNT model for risk assessment to reduce population genetic variability, and (4) Muller persuaded the Panel chair to add Crow to blunt an anticipated challenge to Muller's genetic load hypothesis by population geneticists based on enhanced fitness in heterozygotes at optimized radiation exposures, which challenged his eugenics framework. In addition, the selection of a Panel scientifically weak regarding radiation experiments may have been intentional to allow Muller to dominate Panel activities consistent with his eugenics perspectives. It appears likely that Muller and Crow conspired to manipulate Panel activities, leading to the adoption of LNT for radiation risk assessment, as part of the larger RF plan to control the direction of human evolution via eugenics principles and practices.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111832"},"PeriodicalIF":5.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673060","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}
Pub Date : 2025-12-03DOI: 10.1016/j.cbi.2025.111861
Łukasz Niżnik , Kamil Jurowski
Threo-4-methylmethylphenidate (4-Mmph, 4-MeTMP, CAS: 467468-40-2) is a stimulant that could be recognized as a new psychoactive substance. It is a derivative of methylphenidate, which is a medicament for treating attention deficit hyperactivity disorder. This study aims to use integrated in silico methods to predict the absorption, distribution, metabolism, and excretion (ADME) of 4-Mmph for the first time. The absorption potential of 4-Mmph indicates gastrointestinal absorption and potential brain penetration, however that it is neither a substrate nor an inhibitor of P-glycoprotein. The predictions of water solubility show a range of estimates, all indicating high gastrointestinal absorption. However, the Caco-2 permeability data are inconsistent between the methods, necessitating further experimental validation. Metabolism predictions focus on interactions with CYP450 enzymes, showing varied results across different tools. Consistent predictions are seen for CYP2C19 and CYP2C9, with low substrate and inhibitor activity. The predictions of CYP2D6 and CYP3A4 show discrepancies, highlighting the importance of using multiple tools for a complete metabolic profile. Potential phase I and phase II reactions are also indicated within this study. 4-Mmph is not identified as a substrate for the renal organic cation transporter OCT2, implying alternative renal excretion pathways.
{"title":"The ADME profile of threo-4-methylmethylphenidate (4-Mmph, 4-MeTMP, CAS: 467468-40-2) as new psychoactive substance (NPS): Prediction of absorption, distribution, metabolism and excretion parameters using integrated in silico approach for clinical and forensic purposes","authors":"Łukasz Niżnik , Kamil Jurowski","doi":"10.1016/j.cbi.2025.111861","DOIUrl":"10.1016/j.cbi.2025.111861","url":null,"abstract":"<div><div>Threo-4-methylmethylphenidate (4-Mmph, 4-MeTMP, CAS: 467468-40-2) is a stimulant that could be recognized as a new psychoactive substance. It is a derivative of methylphenidate, which is a medicament for treating attention deficit hyperactivity disorder. This study aims to use integrated <em>in silico</em> methods to predict the absorption, distribution, metabolism, and excretion (ADME) of 4-Mmph for the first time. The absorption potential of 4-Mmph indicates gastrointestinal absorption and potential brain penetration, however that it is neither a substrate nor an inhibitor of P-glycoprotein. The predictions of water solubility show a range of estimates, all indicating high gastrointestinal absorption. However, the Caco-2 permeability data are inconsistent between the methods, necessitating further experimental validation. Metabolism predictions focus on interactions with CYP450 enzymes, showing varied results across different tools. Consistent predictions are seen for CYP2C19 and CYP2C9, with low substrate and inhibitor activity. The predictions of CYP2D6 and CYP3A4 show discrepancies, highlighting the importance of using multiple tools for a complete metabolic profile. Potential phase I and phase II reactions are also indicated within this study. 4-Mmph is not identified as a substrate for the renal organic cation transporter OCT2, implying alternative renal excretion pathways.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111861"},"PeriodicalIF":5.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682633","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}
Pseudomonas aeruginosa is a Gram-negative pathogen responsible for severe infections, particularly in immunocompromised patients. Its widespread antibiotic resistance is a growing concern, primarily due to the overexpression of efflux pumps (EPs) such as the MexXY-OprM system, which plays a major role in aminoglycoside resistance. Targeting EPs with specific inhibitors (EPIs) represents a promising strategy to restore antibiotic efficacy. In this study, we performed High-Throughput Virtual Screening (HTVS) of a library of synthetic berberine derivatives (tetrahydro and dihydro) targeting MexY, the inner membrane protein of the MexXY-OprM system. Based on affinity data, four racemic compounds were selected for further investigation, but only two exhibited in vitro activity against P. aeruginosa laboratory and clinical strains. Subsequent experimental and computational analyses identified compound 2f as the most effective inhibitor, selectively binding to the allosteric pocket ALP. Notably, the differences in activity between its enantiomers highlighted the importance of the chiral environment at the binding cleft, with the (S)-enantiomer showing significantly higher efficacy than the (R)-enantiomer, particularly against PA7 and CF48 clinical strain. Structural investigations comparing all previously identified berberine derivatives revealed key interactions at the ALP site, mainly involving apolar and aromatic residues, providing a valuable framework for rational drug design. These findings led to the rationalization of a 3D-pharmacophoric model for berberine-derived EPIs, offering a foundation for further optimization.
{"title":"Stereochemical insight for MexXY-OprM efflux system inhibition in Pseudomonas aeruginosa from a pool of dihydro and tetrahydro berberine derivatives","authors":"Venanzio Daniele Tosiani , Alessandra Di Gregorio , Giorgia Giorgini , Carla Vignaroli , Giacomo Mari , Fabio Mantellini , Gianfranco Favi , Cristina Minnelli , Giovanna Mobbili , Serena Simoni , Roberta Galeazzi","doi":"10.1016/j.cbi.2025.111850","DOIUrl":"10.1016/j.cbi.2025.111850","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> is a Gram-negative pathogen responsible for severe infections, particularly in immunocompromised patients. Its widespread antibiotic resistance is a growing concern, primarily due to the overexpression of efflux pumps (EPs) such as the MexXY-OprM system, which plays a major role in aminoglycoside resistance. Targeting EPs with specific inhibitors (EPIs) represents a promising strategy to restore antibiotic efficacy. In this study, we performed High-Throughput Virtual Screening (HTVS) of a library of synthetic berberine derivatives (tetrahydro and dihydro) targeting MexY, the inner membrane protein of the MexXY-OprM system. Based on affinity data, four racemic compounds were selected for further investigation, but only two exhibited <em>in vitro</em> activity against <em>P. aeruginosa</em> laboratory and clinical strains. Subsequent experimental and computational analyses identified compound <strong>2f</strong> as the most effective inhibitor, selectively binding to the allosteric pocket ALP. Notably, the differences in activity between its enantiomers highlighted the importance of the chiral environment at the binding cleft, with the (S)-enantiomer showing significantly higher efficacy than the (R)-enantiomer, particularly against PA7 and CF48 clinical strain. Structural investigations comparing all previously identified berberine derivatives revealed key interactions at the ALP site, mainly involving apolar and aromatic residues, providing a valuable framework for rational drug design. These findings led to the rationalization of a 3D-pharmacophoric model for berberine-derived EPIs, offering a foundation for further optimization.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111850"},"PeriodicalIF":5.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617269","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}
Pub Date : 2025-11-28DOI: 10.1016/j.cbi.2025.111847
Quynh Dieu Trinh , Ji Hoon Jeong , Naveen Sharma , Yen Nhi Doan Nguyen , Jung Hoon Park , Duc Toan Pham , Hoang-Yen Phi Tran , Duy-Khanh Dang , Dae-Joong Kim , Dae-Hun Park , Toshitaka Nabeshima , Hyoung-Chun Kim , Eun-Joo Shin
Methamphetamine (MA)-induced neurodegeneration has been reported to resemble behavioral and neurochemical changes in patients with Parkinson's disease. Although it is recognized that platelet-activating factor receptor (PAFR) is involved in the neurodegenerative change, little is known about the role of PAFR in the MA-induced neurodegeneration. Thus, we investigated the mechanistic role of PAFR in MA-induced neurodegeneration. Simultaneously, we asked whether PAFR can interplay with another inflammatory/proapoptotic factor protein kinase Cδ (PKCδ). A single dose of MA (35 mg/kg, i.p.) caused significant increases in PAFR and phospho-protein kinase Cδ (p-PKCδ) expression in the striatum of wild-type mice. MA also increased the interaction between PAFR and p-PKCδ, as assessed by co-immunoprecipitation. Furthermore, triple labelling immunocytochemical analysis showed that PAFR-immunoreactivity (IR) and p-PKCδ-IR were localized in the same Iba-1-labeled microglial cells, suggesting that they express PAFR and PKCδ. Consistently, rottlerin, a PKCδ inhibitor or ginkgolide B, a PAFR inhibitor significantly attenuated MA-induced pro-apoptotic changes (i.e., TUNEL-positive cells and cleaved caspase-3/Bax expression) in Taconic ICR mice. Genetic and pharmacological inhibition of PAFR or PKCδ reduced the MA-caused dopaminergic degenerative effects (i.e., a decrease in tyrosine hydroxylase expression, an increase in dopamine turnover rate, microgliosis, and behavioral impairments), suggesting that PAFR and PKCδ mediate dopaminergic neurodegeneration. MA-induced increases in PAFR and p-PKCδ were attenuated by rottlerin or PKCδ gene knockout. However, ginkgolide B or PAFR gene knockout failed to affect the increase in p-PKCδ expression after MA treatment. Therefore, we suggest that PKCδ is an upstream molecule that increases PAFR for activating the morbid signaling cascade induced by MA.
{"title":"Critical interplay between PAF receptor and PKCδ is involved in dopaminergic insult evoked by methamphetamine in mice","authors":"Quynh Dieu Trinh , Ji Hoon Jeong , Naveen Sharma , Yen Nhi Doan Nguyen , Jung Hoon Park , Duc Toan Pham , Hoang-Yen Phi Tran , Duy-Khanh Dang , Dae-Joong Kim , Dae-Hun Park , Toshitaka Nabeshima , Hyoung-Chun Kim , Eun-Joo Shin","doi":"10.1016/j.cbi.2025.111847","DOIUrl":"10.1016/j.cbi.2025.111847","url":null,"abstract":"<div><div>Methamphetamine (MA)-induced neurodegeneration has been reported to resemble behavioral and neurochemical changes in patients with Parkinson's disease. Although it is recognized that platelet-activating factor receptor (PAFR) is involved in the neurodegenerative change, little is known about the role of PAFR in the MA-induced neurodegeneration. Thus, we investigated the mechanistic role of PAFR in MA-induced neurodegeneration. Simultaneously, we asked whether PAFR can interplay with another inflammatory/proapoptotic factor protein kinase Cδ (PKCδ). A single dose of MA (35 mg/kg, i.p.) caused significant increases in PAFR and phospho-protein kinase Cδ (p-PKCδ) expression in the striatum of wild-type mice. MA also increased the interaction between PAFR and p-PKCδ, as assessed by co-immunoprecipitation. Furthermore, triple labelling immunocytochemical analysis showed that PAFR-immunoreactivity (IR) and p-PKCδ-IR were localized in the same Iba-1-labeled microglial cells, suggesting that they express PAFR and PKCδ. Consistently, rottlerin, a PKCδ inhibitor or ginkgolide B, a PAFR inhibitor significantly attenuated MA-induced pro-apoptotic changes (i.e., TUNEL-positive cells and cleaved caspase-3/Bax expression) in Taconic ICR mice. Genetic and pharmacological inhibition of PAFR or PKCδ reduced the MA-caused dopaminergic degenerative effects (i.e., a decrease in tyrosine hydroxylase expression, an increase in dopamine turnover rate, microgliosis, and behavioral impairments), suggesting that PAFR and PKCδ mediate dopaminergic neurodegeneration. MA-induced increases in PAFR and p-PKCδ were attenuated by rottlerin or PKCδ gene knockout. However, ginkgolide B or PAFR gene knockout failed to affect the increase in p-PKCδ expression after MA treatment. Therefore, we suggest that PKCδ is an upstream molecule that increases PAFR for activating the morbid signaling cascade induced by MA.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111847"},"PeriodicalIF":5.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617331","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}
Unsymmetrical dimethylhydrazine (UDMH), a hypergolic propellant widely used in aerospace, is classified as a Group 2B carcinogen. Although UDMH induces dose-dependent hepatotoxicity, the underlying mechanisms remain unclear. This study tested the hypothesis that PI3K/Akt-mediated apoptosis drives UDMH-induced subacute liver injury. Male Sprague–Dawley rats were exposed to filtered air (control), 141 ± 10 ppm (low-dose), or 282 ± 10 ppm (high-dose) UDMH via inhalation (1 h/d, 5 d/wk) for 4 weeks. UDMH exposure caused mild weight loss and elevated serum ALT, ALP, and TBA while reducing ALB, indicating hepatic dysfunction. It also induced oxidative stress, evidenced by decreased T-SOD, GSH, and CAT activities, increased MDA levels, and upregulated proinflammatory cytokines (IL-1β, IL-6, TNF-α). Histology revealed dose-dependent inflammatory cell infiltration and hepatic sinusoidal hemorrhage with severe cytoplasmic disruption; TUNEL staining confirmed increased hepatocyte apoptosis. RNA-seq identified 1700 DEGs enriched in PI3K-Akt and apoptosis pathways. Western blotting confirmed dose-dependent inhibition of PI3K/Akt signaling (reduced p-PI3K/PI3K and p-Akt/Akt ratios) and apoptosis activation (elevated Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratios). Notably, oxidative stress preceded PI3K/Akt suppression, suggesting redox imbalance triggers PI3K/Akt-dependent hepatocyte death. These findings establish PI3K/Akt-mediated apoptosis as a core mechanism of UDMH hepatotoxicity, providing a rationale for targeting this pathway to protect aerospace workers.
{"title":"Unsymmetrical dimethylhydrazine induces dose-dependent liver toxicity in rats via oxidative stress and PI3K/Akt pathway-mediated apoptosis","authors":"Jiawei Zheng , Luting Wu , Xueming Duan , Wei Ding , Jiayou Zhou , Shuai Zhou , Donghui Wu , Hongguo Li","doi":"10.1016/j.cbi.2025.111852","DOIUrl":"10.1016/j.cbi.2025.111852","url":null,"abstract":"<div><div>Unsymmetrical dimethylhydrazine (UDMH), a hypergolic propellant widely used in aerospace, is classified as a Group 2B carcinogen. Although UDMH induces dose-dependent hepatotoxicity, the underlying mechanisms remain unclear. This study tested the hypothesis that PI3K/Akt-mediated apoptosis drives UDMH-induced subacute liver injury. Male Sprague–Dawley rats were exposed to filtered air (control), 141 ± 10 ppm (low-dose), or 282 ± 10 ppm (high-dose) UDMH via inhalation (1 h/d, 5 d/wk) for 4 weeks. UDMH exposure caused mild weight loss and elevated serum ALT, ALP, and TBA while reducing ALB, indicating hepatic dysfunction. It also induced oxidative stress, evidenced by decreased T-SOD, GSH, and CAT activities, increased MDA levels, and upregulated proinflammatory cytokines (IL-1β, IL-6, TNF-α). Histology revealed dose-dependent inflammatory cell infiltration and hepatic sinusoidal hemorrhage with severe cytoplasmic disruption; TUNEL staining confirmed increased hepatocyte apoptosis. RNA-seq identified 1700 DEGs enriched in PI3K-Akt and apoptosis pathways. Western blotting confirmed dose-dependent inhibition of PI3K/Akt signaling (reduced p-PI3K/PI3K and <em>p</em>-Akt/Akt ratios) and apoptosis activation (elevated Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratios). Notably, oxidative stress preceded PI3K/Akt suppression, suggesting redox imbalance triggers PI3K/Akt-dependent hepatocyte death. These findings establish PI3K/Akt-mediated apoptosis as a core mechanism of UDMH hepatotoxicity, providing a rationale for targeting this pathway to protect aerospace workers.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111852"},"PeriodicalIF":5.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650464","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}
The Pyrrolo[2,1-c][1,4]benzodiazepine dimer, SJG-136, selectively induces DNA interstrand crosslinks (ICL) between guanine residues and exhibits potent in vitro cytotoxicity. SJG-136 demonstrated significant in vivo anti-tumor activity in rodents. Clinical trials showed interesting but incomplete responses. Pharmacokinetic and pharmacodynamic profiles of the molecule displayed high interpatient variability highlighting the need for biomarker-driven patient selection. Accurate detection and assessment of ICL in patients’ samples is one such approach.
Here we report a modified SJG-136 harboring an alkyne handle suitable for click chemistry, designated as Click-SJG-136. We compared cellular toxicity of the clickable version to the native molecule and ICL-generating activity in vitro and in vivo. Click-SJG-136-induced DNA lesions were revealed via ligation to fluorescent reporters using in situ click chemistry in cells and mouse bone marrow, permitting their detection and quantitation by fluorescence microscopy and flow cytometry. The strategy applied in this study is rapid and could be used for direct pharmacodynamic studies of SJG-136.
{"title":"Alkyne modification of DNA cross-linking antitumor agent SJG-136 to monitor induced lesions in cells by click chemistry","authors":"Sara Berrada, Violette Azzoni, Gilles Audoly, Lara Lee, Jean-Hugues Guervilly, Sébastien Abel, Sébastien Combes, Christophe Lachaud","doi":"10.1016/j.cbi.2025.111846","DOIUrl":"10.1016/j.cbi.2025.111846","url":null,"abstract":"<div><div>The Pyrrolo[2,1-c][1,4]benzodiazepine dimer, SJG-136, selectively induces DNA interstrand crosslinks (ICL) between guanine residues and exhibits potent <em>in vitro</em> cytotoxicity. SJG-136 demonstrated significant <em>in vivo</em> anti-tumor activity in rodents. Clinical trials showed interesting but incomplete responses. Pharmacokinetic and pharmacodynamic profiles of the molecule displayed high interpatient variability highlighting the need for biomarker-driven patient selection. Accurate detection and assessment of ICL in patients’ samples is one such approach.</div><div>Here we report a modified SJG-136 harboring an alkyne handle suitable for click chemistry, designated as Click-SJG-136. We compared cellular toxicity of the clickable version to the native molecule and ICL-generating activity <em>in vitro</em> and <em>in vivo</em>. Click-SJG-136-induced DNA lesions were revealed via ligation to fluorescent reporters using <em>in situ</em> click chemistry in cells and mouse bone marrow, permitting their detection and quantitation by fluorescence microscopy and flow cytometry. The strategy applied in this study is rapid and could be used for direct pharmacodynamic studies of SJG-136.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111846"},"PeriodicalIF":5.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145643936","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}
Pub Date : 2025-11-27DOI: 10.1016/j.cbi.2025.111853
Le Zhao , Jinzhu Yin , Mingxing Li , Yujun Ma , Shihui Guo , Guangsen Feng , Jing Song , Linping Wang , Huifang Zhang , Baolong Pan , Xiaoting Lu
Occupational aluminum (Al) exposure is associated with cognitive decline, but the underlying molecular mechanisms remain unclear. This study investigates the role of Kalirin in Al-induced neurotoxicity. A cross-sectional study was conducted in 2019 with 172 workers from a Shanxi aluminum plant. Participants were categorized into high and low Al exposure groups based on plasma aluminum levels, and cognitive function was assessed using the MoCA test. Phosphoproteomic analysis revealed a significant 90 % reduction in Kalirin expression in the high-exposure group compared to the low-exposure group (P < 0.05). Multiple regression analysis demonstrated that Al exposure negatively correlated with Kalirin, GAP43, MAP2 expression, and cognitive function, while Kalirin was positively correlated with these factors (q < 0.05). Bayesian network modeling indicated that decreased Kalirin expression, along with reduced GAP43 and MAP2 levels, increased the risk of cognitive impairment. In vitro, HT22 neurons exposed to aluminum maltolate showed reduced neuronal activity, impaired dendritic development, and disruption of the Kalirin-Rac1 pathway. Overexpression of Kalirin via lentiviral transfection reversed these effects, restoring neuronal integrity (P < 0.05). These findings suggest that Al-induced neurotoxicity involves disruption of the Kalirin pathway, highlighting Kalirin as a potential therapeutic target for mitigating Al-related cognitive dysfunction.
{"title":"Kalirin as a key mediator of aluminum-induced cognitive dysfunction and neurotoxicity: Integrated evidence from occupational and cellular studies","authors":"Le Zhao , Jinzhu Yin , Mingxing Li , Yujun Ma , Shihui Guo , Guangsen Feng , Jing Song , Linping Wang , Huifang Zhang , Baolong Pan , Xiaoting Lu","doi":"10.1016/j.cbi.2025.111853","DOIUrl":"10.1016/j.cbi.2025.111853","url":null,"abstract":"<div><div>Occupational aluminum (Al) exposure is associated with cognitive decline, but the underlying molecular mechanisms remain unclear. This study investigates the role of Kalirin in Al-induced neurotoxicity. A cross-sectional study was conducted in 2019 with 172 workers from a Shanxi aluminum plant. Participants were categorized into high and low Al exposure groups based on plasma aluminum levels, and cognitive function was assessed using the MoCA test. Phosphoproteomic analysis revealed a significant 90 % reduction in Kalirin expression in the high-exposure group compared to the low-exposure group (<em>P</em> < 0.05). Multiple regression analysis demonstrated that Al exposure negatively correlated with Kalirin, GAP43, MAP2 expression, and cognitive function, while Kalirin was positively correlated with these factors (<em>q</em> < 0.05). Bayesian network modeling indicated that decreased Kalirin expression, along with reduced GAP43 and MAP2 levels, increased the risk of cognitive impairment. In vitro, HT22 neurons exposed to aluminum maltolate showed reduced neuronal activity, impaired dendritic development, and disruption of the Kalirin-Rac1 pathway. Overexpression of Kalirin via lentiviral transfection reversed these effects, restoring neuronal integrity (<em>P</em> < 0.05). These findings suggest that Al-induced neurotoxicity involves disruption of the Kalirin pathway, highlighting Kalirin as a potential therapeutic target for mitigating Al-related cognitive dysfunction.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111853"},"PeriodicalIF":5.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145643931","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号