Chemico-Biological Interactions最新文献_第7页

Early-life exposure to linezolid caused gut microbiota dysbiosis can be inherited from parents to offspring 早年接触利奈唑胺引起的肠道菌群失调可以从父母遗传给后代。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-05 DOI: 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.

背景和目的：利奈唑胺是一种抗革兰氏阳性细菌感染的广谱抗生素。利奈唑胺的广泛使用带来了显著的不良影响和潜在的生殖毒性，但尚未有任何关于跨代影响的研究。方法：采用宏基因组学和代谢组学方法，对4周龄给予1周利奈唑胺治疗的12周龄雄性小鼠及其后代的肠道微生物群和代谢物进行分析。监测雄性父母的繁殖能力，包括生育力、产仔数、存活率和后代的体重增加。结果：利奈唑胺处理的雄性亲本的后代存活率明显下降，但生育能力、产仔数或体重增加没有受到影响。利奈唑胺诱导的雄性亲本肠道菌群扰动表现为α多样性降低，β多样性显著降低，功能基因和代谢物谱显著改变。特别是，利奈唑胺暴露逆转了厌氧菌和产丁酸菌之间的关系，以及厌氧菌和炎症相关菌之间的关系。有趣的是，在接受治疗的雄性父母的雌性和雄性后代中，肠道微生物群失调也存在。此外，我们还发现，在雄性亲代和后代中均存在富集ABC转运蛋白通路的差异代谢物，而在雌雄后代中均存在富集鞘脂信号通路的差异代谢物。结论：幼年期短期接触利奈唑胺会导致肠道菌群长期失调，甚至会遗传给后代。这些发现引起了对生命早期抗生素暴露和临床安全性评估的生态后果的严重关注。

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引用次数: 0

Trimethylamine N-oxide induced cognitive impairment through disruption of blood-brain barrier by inhibiting TGF-β pathway 三甲胺n -氧化物通过抑制TGF-β通路破坏血脑屏障诱导认知障碍。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-05 DOI: 10.1016/j.cbi.2025.111862

Yue Liu, Hua-Yue Zhang, Xi-Yan Hong, Yi-Xiao Wu, Ming-Jie Li, Hua-Jun Zheng

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.

越来越多的证据表明，三甲胺n -氧化物（TMAO）与认知障碍密切相关。然而，氧化三甲胺引起认知障碍的机制尚不清楚。据报道，TMAO可以调节血脑屏障（BBB）的完整性，抑制微血管中紧密连接蛋白（TJs）的表达。本研究旨在探讨血脑屏障的破坏是否有助于tmao诱导的认知障碍，并阐明潜在的分子机制。小鼠腹腔注射TMAO (1.1mg/kg)， 72h后进行y迷宫实验、新物体识别实验和被动回避实验。为了评估血脑屏障的完整性，进行了Evans蓝染色、免疫荧光、western blotting和qRT-PCR分析。我们的研究结果表明，氧化三甲胺治疗可引起小鼠认知障碍并破坏血脑屏障完整性。在海马中，TMAO降低了ZO-1、occludin、claudin1和CD31的表达，并引起微血管超微结构的明显改变。为了探究其潜在的分子机制，我们用氧化三甲胺培养人大脑微血管内皮细胞（hCMEC/D3）。TMAO处理抑制TJs并增加hCMEC/D3细胞的单层通透性。转录组学分析显示，TMAO激活了多种炎症相关通路，同时抑制了TGF-β通路。此外，TGF-β1干预挽救了tmao处理的hCMEC/D3细胞中TJs的下调和通透性的降低。我们的研究表明，tmao诱导的认知障碍是通过抑制内皮细胞中TGF-β通路破坏血脑屏障而发生的。目前的研究为TMAO神经毒性机制提供了新的见解，并表明增加TGF-β1水平是对抗TMAO诱导的认知障碍的有效策略。

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引用次数: 0

Embracing dishonesty: How LNT became king 拥抱不诚实：LNT如何成为王者。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-03 DOI: 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。

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引用次数: 0

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 新型精神活性物质（NPS）的ADME谱（4-Mmph, 4-MeTMP, CAS: 467468-40-2）：用于临床和法医目的的集成计算机方法的吸收、分布、代谢和排泄参数预测

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-03 DOI: 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.

盐酸哌甲酯（tho -4- methylphenidate, 4-Mmph, 4-MeTMP, CAS: 467468-40-2）是一种新的精神活性物质。它是哌醋甲酯的衍生物，哌醋甲酯是一种治疗注意力缺陷多动障碍的药物。本研究旨在首次利用集成的计算机方法预测4-Mmph的吸收、分布、代谢和排泄（ADME）。4-Mmph的吸收电位表明胃肠道吸收和潜在的脑渗透，但它既不是p -糖蛋白的底物也不是抑制剂。对水溶性的预测显示了一系列的估计，都表明高胃肠道吸收。但两种方法的Caco-2渗透率数据不一致，需要进一步的实验验证。代谢预测的重点是与CYP450酶的相互作用，在不同的工具中显示出不同的结果。CYP2C19和CYP2C9的预测一致，底物和抑制剂活性较低。CYP2D6和CYP3A4的预测显示出差异，强调了使用多种工具来获得完整代谢谱的重要性。本研究还指出了潜在的I期和II期反应。4-Mmph未被确定为肾脏有机阳离子转运体OCT2的底物，这意味着肾脏有其他排泄途径。

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引用次数: 0

Stereochemical insight for MexXY-OprM efflux system inhibition in Pseudomonas aeruginosa from a pool of dihydro and tetrahydro berberine derivatives 二氢和四氢小檗碱衍生物对铜绿假单胞菌MexXY-OprM外排系统抑制的立体化学观察

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-28 DOI: 10.1016/j.cbi.2025.111850

Venanzio Daniele Tosiani , Alessandra Di Gregorio , Giorgia Giorgini , Carla Vignaroli , Giacomo Mari , Fabio Mantellini , Gianfranco Favi , Cristina Minnelli , Giovanna Mobbili , Serena Simoni , Roberta Galeazzi

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.

铜绿假单胞菌是一种革兰氏阴性病原体，可导致严重感染，特别是在免疫功能低下的患者中。其广泛的抗生素耐药性日益受到关注，主要是由于外排泵（EPs）的过度表达，如MexXY-OprM系统，它在氨基糖苷耐药中起主要作用。用特异性抑制剂（EPIs）靶向EPs是一种恢复抗生素疗效的有希望的策略。在这项研究中，我们对合成的小檗碱衍生物（四氢和二氢）库进行了高通量虚拟筛选（HTVS），目标是MexY - oprm系统的内膜蛋白MexY。根据亲和力数据，选择了4个外消旋化合物进行进一步研究，但只有2个化合物对铜绿假单胞菌实验室和临床菌株具有体外活性。随后的实验和计算分析发现，化合物2f是最有效的抑制剂，可以选择性地与变弹性口袋ALP结合。值得注意的是，其对映体之间的活性差异突出了结合间隙处手性环境的重要性，(S)-对映体表现出明显高于(R)-对映体的功效，特别是对PA7和CF48临床菌株。结构研究比较了所有先前鉴定的小檗碱衍生物，揭示了ALP位点的关键相互作用，主要涉及极性和芳香残基，为合理的药物设计提供了有价值的框架。这些发现使小檗碱衍生EPIs的3d药效模型合理化，为进一步优化提供了基础。

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引用次数: 0

Critical interplay between PAF receptor and PKCδ is involved in dopaminergic insult evoked by methamphetamine in mice PAF受体和PKCδ之间的关键相互作用参与了小鼠甲基苯丙胺引起的多巴胺能损伤

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-28 DOI: 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.

据报道，甲基苯丙胺（MA）诱导的神经变性与帕金森病患者的行为和神经化学变化相似。虽然人们认识到血小板活化因子受体（PAFR）参与神经退行性改变，但对PAFR在ma诱导的神经退行性改变中的作用知之甚少。因此，我们研究了PAFR在ma诱导的神经变性中的机制作用。同时，我们询问PAFR是否可以与另一种炎症/促凋亡因子蛋白激酶Cδ (PKCδ)相互作用。单剂量MA （35 mg/kg, i.p）可显著增加野生型小鼠纹状体中PAFR和磷酸蛋白激酶Cδ (p-PKCδ)的表达。MA还增加了PAFR和p-PKCδ之间的相互作用，通过共免疫沉淀来评估。此外，三重标记免疫细胞化学分析显示，PAFR免疫反应性（IR）和p-PKCδ-IR定位于相同的iba -1标记的小胶质细胞中，表明它们表达PAFR和PKCδ。一致地，PKCδ抑制剂rottlerin或PAFR抑制剂银杏内酯B在Taconic ICR小鼠中显著减弱ma诱导的促凋亡变化（即tunel阳性细胞和裂解的caspase-3/Bax表达）。遗传和药理抑制PAFR或PKCδ降低了ma引起的多巴胺能退行性作用（即酪氨酸羟化酶表达降低，多巴胺周转率增加，小胶质细胞增生和行为障碍），表明PAFR和PKCδ介导多巴胺能神经退行性变。ma诱导的PAFR和p-PKCδ的升高通过敲除PKCδ或rottlerin基因减弱。然而，银杏内酯B或PAFR基因敲除未能影响MA处理后p-PKCδ表达的增加。因此，我们认为PKCδ是一个上游分子，可以增加PAFR，激活MA诱导的病态信号级联。

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引用次数: 0

Unsymmetrical dimethylhydrazine induces dose-dependent liver toxicity in rats via oxidative stress and PI3K/Akt pathway-mediated apoptosis 不对称二甲肼通过氧化应激和PI3K/Akt通路介导的细胞凋亡诱导大鼠剂量依赖性肝毒性

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-28 DOI: 10.1016/j.cbi.2025.111852

Jiawei Zheng , Luting Wu , Xueming Duan , Wei Ding , Jiayou Zhou , Shuai Zhou , Donghui Wu , Hongguo Li

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.

不对称二甲肼（UDMH）是一种广泛用于航空航天的自燃推进剂，被列为2B类致癌物。虽然UDMH诱导剂量依赖性肝毒性，但其潜在机制尚不清楚。本研究验证了PI3K/ akt介导的细胞凋亡驱动udmh诱导的亚急性肝损伤的假设。雄性Sprague-Dawley大鼠分别吸入过滤空气（对照组）141±10 ppm（低剂量）或282±10 ppm（高剂量）UDMH （1 h/d， 5 d/周）4周。UDMH暴露引起轻度体重减轻，血清ALT、ALP和TBA升高，ALB降低，提示肝功能障碍。它还诱导氧化应激，表现为T-SOD、GSH和CAT活性降低，MDA水平升高，促炎细胞因子（IL-1β、IL-6、TNF-α）上调。组织学显示剂量依赖性炎症细胞浸润和肝窦出血伴严重细胞质破坏；TUNEL染色证实肝细胞凋亡增加。RNA-seq鉴定了1700个富集PI3K-Akt和凋亡通路的基因。Western blotting证实了PI3K/Akt信号通路的剂量依赖性抑制（p-PI3K/PI3K和p-Akt/Akt比值降低）和细胞凋亡激活（Bax/Bcl-2和裂解caspase-3/caspase-3比值升高）。值得注意的是，氧化应激先于PI3K/Akt抑制，提示氧化还原失衡触发PI3K/Akt依赖性肝细胞死亡。这些发现证实了PI3K/ akt介导的细胞凋亡是UDMH肝毒性的核心机制，为靶向这一途径保护航空航天工作人员提供了理论依据。

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引用次数: 0

Alkyne modification of DNA cross-linking antitumor agent SJG-136 to monitor induced lesions in cells by click chemistry 烷基修饰DNA交联抗肿瘤剂SJG-136对细胞诱导病变的监测。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-27 DOI: 10.1016/j.cbi.2025.111846

Sara Berrada, Violette Azzoni, Gilles Audoly, Lara Lee, Jean-Hugues Guervilly, Sébastien Abel, Sébastien Combes, Christophe Lachaud

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.

Pyrrolo[2,1-c][1,4]苯二氮卓二聚体SJG-136选择性诱导鸟嘌呤残基之间的DNA链间交联（ICL），并表现出强大的体外细胞毒性。SJG-136在啮齿类动物体内表现出显著的抗肿瘤活性。临床试验显示出有趣但不完全的反应。该分子的药代动力学和药效学特征显示出患者间的高度可变性，强调了生物标志物驱动的患者选择的必要性。准确检测和评估患者样本中的ICL就是这样一种方法。在这里，我们报告了一种改进的SJG-136，它包含一个适合点击化学的炔手柄，命名为click -SJG-136。我们在体外和体内比较了可点击版本与天然分子的细胞毒性和icl生成活性。点击- sjg -136诱导的DNA损伤通过连接到荧光报告细胞和小鼠骨髓中使用原位点击化学显示，允许荧光显微镜和流式细胞术检测和定量。本研究采用的策略快速，可用于SJG-136的直接药效学研究。

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引用次数: 0

Kalirin as a key mediator of aluminum-induced cognitive dysfunction and neurotoxicity: Integrated evidence from occupational and cellular studies 加里林是铝诱导的认知功能障碍和神经毒性的关键介质：来自职业和细胞研究的综合证据。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-27 DOI: 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.

职业性铝（Al）暴露与认知能力下降有关，但潜在的分子机制尚不清楚。本研究探讨了加里林在铝致神经毒性中的作用。2019年，对山西一家铝厂的172名工人进行了一项横断面研究。参与者根据血浆铝水平分为高铝暴露组和低铝暴露组，并使用MoCA测试评估认知功能。磷蛋白组学分析显示，与低暴露组相比，高暴露组的Kalirin表达显著降低90% （P < 0.05）。多元回归分析显示，Al暴露与Kalirin、GAP43、MAP2表达和认知功能呈负相关，而Kalirin与这些因素呈正相关（q < 0.05）。贝叶斯网络模型显示，Kalirin表达的降低以及GAP43和MAP2水平的降低增加了认知功能障碍的风险。在体外，暴露于麦芽糖酸铝的HT22神经元表现出神经元活性降低，树突发育受损，Kalirin-Rac1通路中断。通过慢病毒转染过表达Kalirin逆转了这些作用，恢复了神经元的完整性（P < 0.05）。这些发现表明，铝诱导的神经毒性涉及到Kalirin通路的破坏，强调Kalirin作为减轻铝相关认知功能障碍的潜在治疗靶点。

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引用次数: 0

Multimodal cell death induced by indirubin-3′-oxime through inhibition of Akt/mTOR axis in lung cancer cells 靛红素-3′-肟通过抑制Akt/mTOR轴诱导肺癌细胞多模式死亡

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-26 DOI: 10.1016/j.cbi.2025.111851

Na Young Kim , Shalini V. Gowda , Kachigere B. Harsha , D.C. Vinay Kumar , Chakrabhavi Dhananjaya Mohan , C.S. Shivakumara , Kanchugarakoppal S. Rangappa , Kwang Seok Ahn

Lung cancer is a major type of malignancy that has contributed to a high mortality rate for many years. Discovering new small molecules with strong cytotoxic effects on lung cancer is crucial for developing new therapies. In this study, we describe the synthesis of a novel triazole-indirubin-3′-oxime derivative (designated as CRM1) and examine its ability to induce distinct forms of cell death, as well as elucidate the cytotoxicity-associated molecular mechanisms in lung cancer cells. CRM1 selectively reduced cell viability in lung cancer cell lines (A549, PC9, and H1299) without significantly affecting the viability of normal lung cells (HEL299). Mechanistic investigations have demonstrated that CRM1 induces paraptosis through the downregulation of Alix and the upregulation of ATF4 and CHOP. This process is associated with disruption of mitochondrial membrane potential, induction of endoplasmic reticulum stress, and accumulation of reactive oxygen species (ROS). CRM1 was observed to induce apoptosis, as indicated by DNA fragmentation, an increase in Sub-G1 cell population, as well as elevated caspase-3 cleavage and Bax expression. CRM1 also promoted autophagy, as evidenced by increased expression of Atg7, phosphorylated Beclin-1, and LC3-II, as well as enhanced autophagosome formation. Pharmacological inhibition studies confirmed the independent induction of apoptosis, paraptosis, and autophagy. Pre-exposure of cancer cells to N-acetyl cysteine abrogated CRM1-induced cytotoxicity. Mechanistic studies demonstrated that CRM1 suppresses the activation of Akt, mTOR, and p70S6K, while the overexpression of Akt counteracts the CRM1-driven cytotoxic effects. CRM1 also synergistically potentiated the cytotoxic efficacy of paclitaxel by co-targeting multiple cell death processes. Collectively, these results suggest CRM1 as a promising cytotoxic candidate with a multimodal mechanism of action in lung cancer cells.

肺癌是一种主要的恶性肿瘤，多年来造成了很高的死亡率。发现对肺癌具有强细胞毒性作用的新小分子对于开发新疗法至关重要。在这项研究中，我们描述了一种新的三唑-靛红素-3 ' -肟衍生物（称为CRM1）的合成，并研究了其诱导不同形式细胞死亡的能力，以及阐明肺癌细胞毒性相关的分子机制。CRM1选择性地降低肺癌细胞系（A549、PC9和H1299）的细胞活力，而不显著影响正常肺细胞（HEL299）的活力。机制研究表明，CRM1通过下调Alix和上调ATF4和CHOP诱导细胞凋亡。这一过程与线粒体膜电位的破坏、内质网应激的诱导和活性氧（ROS）的积累有关。观察到CRM1诱导细胞凋亡，如DNA断裂，亚g1细胞群增加，以及caspase-3切割和Bax表达升高。CRM1也促进自噬，Atg7、磷酸化Beclin-1和LC3-II的表达增加，自噬体形成增强。药理抑制研究证实了细胞凋亡、细胞凋亡和自噬的独立诱导。将癌细胞预先暴露于n -乙酰半胱氨酸可消除crm1诱导的细胞毒性。机制研究表明，CRM1抑制Akt、mTOR和p70S6K的激活，而Akt的过表达抵消了CRM1驱动的细胞毒性作用。CRM1还通过共同靶向多个细胞死亡过程协同增强紫杉醇的细胞毒性作用。总的来说，这些结果表明，CRM1在肺癌细胞中具有多模态作用机制，是一种有希望的细胞毒性候选者。

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引用次数: 0