Chemico-Biological Interactions最新文献_第2页

Pachymic acid suppresses proliferation and invasion in colon cancer by inhibiting glycolysis via PPARγ/ENO1 pathway 厚青酸通过PPARγ/ENO1途径抑制糖酵解抑制结肠癌的增殖和侵袭。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-11 DOI: 10.1016/j.cbi.2025.111881

Zhiwei Wang , Peiyao Wu , Chuanzhuo Zhang , Ting Zhang , Chunlin Gu , Xiaodong Xie , Xiao Feng , Zhiwei Jiang

Aerobic glycolysis constitutes a fundamental aspect of the process of tumor development. Pachymic acid, a major active ingredient in Poria cocos, has been reported to impair glucose metabolism in several cancers. However, whether pachymic acid could inhibit the aerobic glycolysis of colon cancer remains to be elucidated. Our study revealed that the treatment of pachymic acid significantly inhibited the proliferation and invasion of HT-29 and HCT-116 cells. Moreover, it led to a substantial reduction in the expression level of glycolysis-related proteins including phosphoglycerate kinase 1 (PGK1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and α-enolase (ENO1). Potential targets of pachymic acid were screened by network pharmacology analysis and molecular docking, and PPARγ was determined as the primary target of pachymic acid according to Western blot and real-time qPCR. Further experiments indicated that the overexpression of PPARγ reversed the inhibitory effects of pachymic acid on the proliferation, invasion and aerobic glycolysis of HT-29 and HCT-116 cells. The inhibition of PPARγ led to a significant reduction in the expression of PGK1, GLUT1, LDHA and ENO1. Subcutaneous tumor-bearing experiments in nude mice verified the antitumor effect of pachymic acid on colon cancer, which could be reversed by the overexpression of PPARγ. The present study confirmed that pachymic acid played an inhibitory role in the proliferation and invasion of colon cancer by intervening in the process of glycolysis. PPARγ was identified as the primary target of pachymic acid in regulating the glucose metabolism in colon cancer.

有氧糖酵解是肿瘤发展过程的一个基本方面。茯苓中的一种主要活性成分厚皮酸，据报道会损害几种癌症患者的葡萄糖代谢。然而，厚青酸是否能抑制结肠癌的有氧糖酵解还有待进一步研究。我们的研究发现，厚皮酸处理显著抑制HT-29和HCT-116细胞的增殖和侵袭。此外，它还导致糖酵解相关蛋白包括磷酸甘油激酶1 （PGK1）、葡萄糖转运蛋白1 （GLUT1）、乳酸脱氢酶a （LDHA）和α-烯醇化酶（ENO1）的表达水平大幅降低。通过网络药理学分析和分子对接筛选厚皮酸的潜在靶点，通过western blot和real-time qPCR确定PPARγ为厚皮酸的主要靶点。进一步的实验表明，PPARγ的过表达逆转了厚皮酸对HT-29和HCT-116细胞增殖、侵袭和有氧糖酵解的抑制作用。抑制PPARγ导致PGK1、GLUT1、LDHA和ENO1的表达显著降低。裸鼠皮下荷瘤实验证实了厚皮酸对结肠癌的抗肿瘤作用，该作用可通过过表达PPARγ逆转。本研究证实厚皮酸通过干预糖酵解过程，对结肠癌的增殖和侵袭有抑制作用。PPARγ被确定为厚皮酸调节结肠癌糖代谢的主要靶点。

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引用次数: 0

The p -JNKThr183/Tyr185 / p -Keap1Thr43 /Keap1 axis mediates arsenic-induced endothelial dysfunction by coordinating Chaperone-mediated autophagy with macroautophagy p -JNKThr183/Tyr185 / p -Keap1Thr43 /Keap1轴通过协调伴侣介导的自噬和巨噬介导砷诱导的内皮功能障碍。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-11 DOI: 10.1016/j.cbi.2025.111874

Jinyu Li , Jin Cheng , Zhihan Yang , Lin Gao , Qiaoling Liu , Jing He , Yishan Dong , Shuo Wang , Jing Cui , Ziqi Xu , Dianjun Sun , Wei Zhang

Arsenic exposure leads to vascular endothelial dysfunction (VED), which plays a driving role in the development of cardiovascular disease. Macroautophagy and chaperone-mediated autophagy (CMA), two major forms of autophagy in mammals, jointly maintain intracellular homeostasis. Our group has revealed that excessive macroautophagy induces VED. However, the function of CMA in arsenic-induced endothelial dysfunction as well as the regulatory relationship between macroautophagy and CMA have not been unveiled. Here, we demonstrate that the co-activation of macroautophagy and CMA promotes VED in vivo and in vitro. We also identify a damaging role of CMA in arsenic-induced vascular endothelial dysfunction, which contrasts with its previously reported protective effects. In addition, our results showed that macroautophagy and CMA were activated successively, and macroautophagy played a dominant regulatory role in VED induced by arsenic. Mechanistically, phosphorylation proteomics suggested that KEAP1 may play a pivotal role in arsenic-induced macroautophagy and CMA in mouse aortic endothelial cells. Moreover, a novel Keap1 phosphorylation site, Thr43, was significantly activated by the JNK pathway. Furthermore, when Keap1 levels decrease to a considerable lower level, macroautophagy and CMA decrease remarkably, endothelial dysfunction was accordingly alleviated. Collectively, our study demonstrates that the p-JNK^{Thr183/Tyr185}/p-Keap1^Thr43/Keap1 axis mediates arsenic-induced VED by coordinately activating both CMA and macroautophagy, which revealing a new regulation mechanism of Keap1 in autophagy. Additionally, the genetic polymorphism of Keap1 was found have a significant correlation with the susceptibility to hypertension in arsenicosis areas. Collectively, these findings provide promising new ideas for the prevention and treatment of arsenic-induced CVD through regulating autophagy.

砷暴露导致血管内皮功能障碍（VED），这在心血管疾病的发展中起驱动作用。巨噬（Macroautophagy）和伴侣介导的自噬（chaperone-mediated autophagy， CMA）是哺乳动物自噬的两种主要形式，它们共同维持细胞内的稳态。我们的研究小组发现，过度的巨噬可诱导VED。然而，CMA在砷诱导的内皮功能障碍中的作用以及巨噬与CMA之间的调节关系尚不清楚。在这里，我们证明了巨噬和CMA的共同激活在体内和体外促进了VED。我们还确定了CMA在砷诱导的血管内皮功能障碍中的破坏作用，这与之前报道的保护作用形成对比。此外，我们的研究结果表明，大自噬和CMA先后被激活，大自噬在砷诱导的VED中起主导调节作用。在机制上，磷酸化蛋白质组学表明KEAP1可能在砷诱导的小鼠主动脉内皮细胞巨噬和CMA中起关键作用。此外，一个新的Keap1磷酸化位点Thr43被JNK途径显著激活。此外，当Keap1水平降低到较低水平时，巨噬和CMA显著减少，内皮功能障碍相应减轻。综上所述，我们的研究表明，p-JNKThr183/Tyr185/p-Keap1Thr43/Keap1轴通过协调激活CMA和巨噬来介导砷诱导的VED，揭示了Keap1在自噬中的新的调控机制。此外，发现Keap1基因多态性与砷中毒地区高血压易感性有显著相关性。总的来说，这些发现为通过调节自噬来预防和治疗砷诱导的心血管疾病提供了有希望的新思路。

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引用次数: 0

New insights into Lambda-cyhalothrin-induced lipid metabolism disorder in liver: Crosstalk between oxidative stress and PPARα signaling pathway 高效氯氰菊酯诱导肝脏脂质代谢紊乱的新认识：氧化应激与PPARα信号通路的串扰

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-10 DOI: 10.1016/j.cbi.2025.111872

Haoran Zhang , Chunye He , Zhaohong Pu , Lu Guo , Liying Pan , Haiyue Gong , Jingyi Zhang , Farooque Laghari , Shengzi Jin , Runxiang Zhang

Pesticide pollution has become a pressing global environmental concern, primarily driven by the excessive use of pesticides in agricultural practices, resulting in ecosystem degradation and significant risks to human and animal health. Lambda-cyhalothrin (LCT), a widely utilized pyrethroid pesticide, is known to induce multi-organ toxicity, with pronounced effects on the liver. However, the molecular mechanisms underlying LCT-induced hepatotoxicity and effective mitigation strategies remain poorly understood. In this study, we developed in vivo and in vitro LCT exposure models and employed transcriptomics, histopathology, and molecular biology techniques to investigate alterations in hepatic lipid metabolism, oxidative stress, Peroxisome proliferator-activated receptor alpha (PPARα) signaling, the Cytochrome P450 (CYP450) enzyme system, and the Phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt) signaling pathway. Furthermore, experiments using oxidative stress inhibitors and PPARα agonists in a hepatocyte cell line (LMH) model demonstrated that LCT modulates CYP450 enzyme system gene expression and suppresses PI3K/Akt pathway activity. Through crosstalk between oxidative stress and PPARα signaling, LCT ultimately disrupts lipid metabolism and induces liver injury. This study provides the first evidence that LCT triggers hepatotoxicity via crosstalk between oxidative stress and PPARα pathways, offering novel insights into optimizing LCT safety guidelines and developing targeted interventions for managing the toxicity of environmental pollutants.

农药污染已成为一个紧迫的全球环境问题，其主要原因是在农业实践中过度使用农药，导致生态系统退化，并对人类和动物健康构成重大风险。高效氯氟氰菊酯（LCT）是一种广泛使用的拟除虫菊酯农药，已知可引起多器官毒性，对肝脏有明显影响。然而，lct诱导肝毒性的分子机制和有效的缓解策略仍然知之甚少。在这项研究中，我们建立了体内和体外LCT暴露模型，并采用转录组学、组织病理学和分子生物学技术来研究肝脏脂质代谢、氧化应激、过氧化物酶体增殖物激活受体α (PPARα)信号传导、细胞色素P450 （CYP450）酶系统和磷酸肌肽3激酶(PI3K)/蛋白激酶B （Akt）信号通路的变化。此外，在肝细胞细胞系（LMH）模型中使用氧化应激抑制剂和PPARα激动剂进行的实验表明，LCT调节CYP450酶系统基因表达并抑制PI3K/Akt通路活性。LCT通过氧化应激与PPARα信号之间的串扰，最终破坏脂质代谢，诱导肝损伤。本研究首次证明LCT通过氧化应激和PPARα通路之间的串扰触发肝毒性，为优化LCT安全指南和开发有针对性的干预措施来管理环境污染物的毒性提供了新的见解。

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引用次数: 0

Mechanistic insights into antibody recognition of tetrodotoxin analogues: Implications for neurotoxicological assessment 河豚毒素类似物抗体识别的机制见解：对神经毒理学评估的影响

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-10 DOI: 10.1016/j.cbi.2025.111871

Jaume Reverté , Mounira Alkassar , Maria Rambla-Alegre , Andres Sanchez-Henao , Manolis Mandalakis , Panagiota Peristeraki , Francesc X. Sureda , Jorge Diogène , Mònica Campàs

Tetrodotoxins (TTXs) pose significant food safety risks due to their potent neurotoxicity. Growing concerns about the impact of these toxins on public health have driven the development of new detection methods, with immunoassays showing strong potential. However, limited knowledge of the cross-reactivity of anti-TTX antibodies with analogues may compromise the reliability of these assays in food safety applications. To address this, cross-reactivity factors (CRFs) for five TTX analogues (i.e., 11-norTTX-6(S)-ol, 11-deoxyTTX, 6,11-dideoxyTTX, 5,11-dideoxyTTX, and 5,6,11-trideoxyTTX) were assessed using a magnetic bead-based immunoassay. In parallel, the antibody's ability to neutralise the toxicity of TTX analogues was evaluated in Neuro-2a cells using automated patch clamp, a single-cell biosensing platform specifically designed for in vitro toxicity assessment and characterisation. Antibody cross-reactivity towards the tested analogues correlated with their relative toxicity, enabling a selective detection of the most hazardous compounds. These findings highlight the dual role of molecular structure in dictating both toxicological potency and immunological recognition, and support the use of immunoassays as effective tools for TTX monitoring in food safety applications.

河豚毒素由于其强大的神经毒性而构成重大的食品安全风险。对这些毒素对公共卫生影响的日益关注推动了新的检测方法的发展，免疫分析显示出强大的潜力。然而，对抗ttx抗体与类似物的交叉反应性的有限了解可能会损害这些检测在食品安全应用中的可靠性。为了解决这个问题，使用基于磁珠的免疫分析法评估了五种TTX类似物（即11-norTTX-6(S)-ol, 11-deoxyTTX, 6,11- dideoxyttx, 5,11- dideoxyttx和5,6,11- trideoxyttx）的交叉反应性因子（CRFs）。同时，使用自动膜片钳（一种专门用于体外毒性评估和表征的单细胞生物传感平台）在神经-2a细胞中评估了该抗体中和TTX类似物毒性的能力。抗体对被测类似物的交叉反应性与其相对毒性相关，从而能够选择性地检测最危险的化合物。这些发现强调了分子结构在决定毒理学效力和免疫识别方面的双重作用，并支持将免疫测定作为食品安全应用中TTX监测的有效工具。

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引用次数: 0

In vitro methods for evaluation of sulfur mustard on cell senescence 硫芥对细胞衰老作用的体外评价方法。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-10 DOI: 10.1016/j.cbi.2025.111875

S. Emma Sarles , Adrian Neu , Linda N. Pettersson , Tobias Demel , Priscilla Lee , Daniel Angelini , Simone Rothmiller , Dirk Steinritz

Even though the Chemical Weapons Convention forbids the use of chemical weapons, there have been cases of chemical warfare agents used in prior conflicts and terror attacks. Sulfur Mustard (SM), an alkylating and blistering agent, has been reported to seriously harm the skin, mucous membranes, eyes, and lungs. Prolonged wound healing issues or pulmonary oedema may arise. The exact process by which SM results in long-term injury is yet unclear. Senescent cells in wounds, which have been shown to impede the healing process, may be one possible contributing reason. This review summarizes the current state of knowledge in the field of in vitro methods for studying cell senescence after SM exposure. A multitude of studies have demonstrated that several cell types show a higher tendency for senescence induction following SM. This review of the literature not only comprises these cell types and different model types, but also various in vitro methods for SM exposure. In addition, we review the most common endpoints associated with senescence. This overview aims to give scientists a complete summary of the present status of in vitro research on SM and senescence as well as recommendations for new experimental setups and future studies. These recommendations aim to close research gaps and may facilitate the identification of additional druggable targets and the development of novel drug candidates for innovative therapeutic options.

尽管《禁止化学武器公约》禁止使用化学武器，但在以前的冲突和恐怖袭击中使用化学战剂的情况也时有发生。硫芥（SM）是一种烷基化和起泡剂，据报道对皮肤、粘膜、眼睛和肺部造成严重伤害。延长伤口愈合问题或肺水肿可能出现。SM导致长期损伤的确切过程尚不清楚。伤口中的衰老细胞已被证明会阻碍愈合过程，这可能是一个原因。本文综述了SM暴露后细胞衰老的体外研究方法的研究现状。大量的研究表明，几种细胞类型在SM后表现出更高的衰老诱导倾向。本文综述的文献不仅包括这些细胞类型和不同的模型类型，而且还包括各种体外SM暴露方法。此外，我们回顾了与衰老相关的最常见的终点。本综述旨在为科学家提供SM和衰老体外研究现状的完整总结，以及对新的实验设置和未来研究的建议。这些建议旨在缩小研究差距，并可能促进确定额外的可药物靶点和开发用于创新治疗方案的新型候选药物。

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引用次数: 0

Inhibition of NOD-like receptor pyrin domain-containing protein 3 inflammasome activation by MK-571, a multidrug resistance protein inhibitor 多药耐药蛋白抑制剂MK-571对nod样受体pyrin结构域蛋白3炎性小体激活的抑制作用

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-09 DOI: 10.1016/j.cbi.2025.111867

Seungseok Oh , Jeongwoo Park , Won Kim , Keon Wook Kang

Proinflammatory cytokines such as interleukin (IL)-1β and IL-18 are known to be activated through the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, a multi-protein intracellular complex. MK-571 has been identified as an efflux inhibitor of multidrug resistance protein (MRP) transporters. In this study, we have revealed that MK-571 effectively suppresses the activation of the NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) by elevating intracellular cAMP levels. The accumulation of cAMP mediated by MK-571 inhibited the ATP-driven secretion of IL-1β through the ubiquitination of the NLRP3 protein. Additionally, MK-571 suppressed the nuclear factor-κB (NF-κB)-dependent priming signaling of the NLRP3 inflammasome, as evidenced by the reduction in proinflammatory cytokines and proteins as well as NF-κB-driven transcriptional activity. When administered orally, MK-571 significantly lowered mRNA levels of IL-6 and IL-1β, along with serum levels of IL-1β, in mice subjected to lipopolysaccharide/d-galactosamine treatment. These findings underline the crucial role of energy-dependent transporters MRP4 and 5 in regulating the priming and activation signals of the NLRP3 inflammasome in macrophages. Furthermore, MK-571 emerges as a promising therapeutic candidate for managing NLRP3 inflammasome-related diseases.

已知促炎细胞因子如白细胞介素(IL)-1β和IL-18可通过nod样受体pyrin结构域蛋白3 （NLRP3）炎性小体（一种多蛋白胞内复合物）激活。MK-571已被鉴定为多药耐药蛋白（MRP）转运体的外排抑制剂。在这项研究中，我们发现MK-571通过提高细胞内cAMP水平有效抑制骨髓源性巨噬细胞（bmdm）中NLRP3炎性体的激活。MK-571介导的cAMP积累通过NLRP3蛋白的泛素化抑制了atp驱动的IL-1β分泌。此外，MK-571抑制NLRP3炎性小体的核因子-κB （NF-κB）依赖的启动信号，这可以通过降低促炎细胞因子和蛋白以及NF-κB驱动的转录活性来证明。口服MK-571可显著降低脂多糖/ d -半乳糖胺处理小鼠的IL-6和IL-1β mRNA水平以及血清IL-1β水平。这些发现强调了能量依赖性转运体MRP4和mrp5在调节巨噬细胞NLRP3炎性体的启动和激活信号中的关键作用。此外，MK-571成为治疗NLRP3炎性小体相关疾病的有希望的治疗候选药物。

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引用次数: 0

Tracing the cellular consequences of polyethylene microplastics: senescence and apoptosis in A549 and Raw 264.7 macrophage cells 追踪聚乙烯微塑料的细胞后果：A549和Raw 264.7巨噬细胞的衰老和凋亡。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-09 DOI: 10.1016/j.cbi.2025.111868

Shramana Koner, Seenivasan Ramasubbu

The pervasive accumulation of plastic waste has led to widespread microplastics (MPs) pollution, raising concerns about potential human health impacts. Among these, polyethylene microplastics (PEMPs) are one of the most commonly encountered due to their prevalence in consumer products and the environment. This study investigates the cytotoxic and senescence-inducing effects of PEMPs (≤500 nm) on two cell models, A549 lung epithelial cells and Raw 264.7 macrophages. This study specifically examines cells exposed to varying concentrations of PEMPs (50–500 μg/mL), and key indicators of cellular stress were assessed, including viability, reactive oxygen species (ROS) generation, mitochondrial dysfunction, LDH release, apoptosis, and senescence. Our findings indicate that exposure to PEMPs significantly reduced cell viability and increased ROS production and mitochondrial damage in a dose- and time-dependent manner. At higher concentrations (500 μg/mL), both cell lines demonstrated that PEMPs induce apoptosis and senescence, with A549 cells showing early senescence morphology as early as 24 h post-exposure. These findings confirm the potential of PEMPs to disrupt cellular homeostasis and accelerate aging-related processes. Overall, the study reinforces the urgency of curbing plastic pollution and exploring its association with age-related pathologies and chronic health conditions.

塑料垃圾的普遍堆积导致了广泛的微塑料污染，引发了人们对潜在的人类健康影响的担忧。其中，聚乙烯微塑料（PEMPs）是最常见的一种，因为它们普遍存在于消费品和环境中。本研究考察了PEMPs（≤500 nm）对A549肺上皮细胞和Raw 264.7巨噬细胞两种细胞模型的细胞毒性和衰老诱导作用。本研究专门检测了暴露于不同浓度PEMPs（50至500 μg/mL）的细胞，并评估了细胞应激的关键指标，包括活力、活性氧（ROS）生成、线粒体功能障碍、LDH释放、凋亡和衰老。我们的研究结果表明，暴露于PEMPs显著降低细胞活力，增加ROS产生和线粒体损伤，并以剂量和时间依赖的方式存在。在较高浓度（500 μg/mL）下，两种细胞系均表现出PEMPs诱导细胞凋亡和衰老，A549细胞早在暴露后24 h就表现出早期衰老形态。这些发现证实了PEMPs破坏细胞稳态和加速衰老相关过程的潜力。总的来说，这项研究强调了遏制塑料污染的紧迫性，并探讨了塑料污染与年龄相关疾病和慢性健康状况的关系。

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引用次数: 0

Immunomodulatory evaluation of caffeic acid and its quinic acid derivatives using Th1/Th2 cytokine secretion profiles and principal component analysis 利用Th1/Th2细胞因子分泌谱和主成分分析评价咖啡酸及其奎宁酸衍生物的免疫调节作用

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-09 DOI: 10.1016/j.cbi.2025.111865

Kai-Chi Chang, Jin-Yuarn Lin

Eleven Caffeic acid and its Quinic acid derivatives, including Caffeic acid, 1-O-Caffeoylquinic acid, 3-O-Caffeoylquinic acid, 4-O-Caffeoylquinic acid, 5-O-Caffeoylquinic acid, 1,3-Dicaffeoylquinic acid, 1,4-Dicaffeoylquinic acid, 1,5-Dicaffeoylquinic acid, 3,4-Dicaffeoylquinic acid, 3,5-Dicaffeoylquinic acid, and 4,5-Dicaffeoylquinic acid, were selected to evaluate their Th1/Th2 immune balance using mouse primary splenocytes. The optimal non-cytotoxic concentrations of each test compound were determined using the 3-(4,5-dimethylthiazol-2-diphenyl)-2,5-tetrazolium bromide assay. Th1 (IL-2, TNF-α) and Th2 (IL-4, IL-10) cytokine secretion levels by treated splenocytes were measured using an enzyme-linked immunosorbent assay. The tendency of each test sample towards the Th1/Th2 immune balance was further analyzed by Principal Component Analysis. The results showed that the half-maximal inhibitory concentration of Dicaffeoylquinic acids (18.0–37.8 μM) had higher cytotoxicity to splenocytes than that of Caffeic acid (49.4 μM) and Caffeoylquinic acids (45.6–52.3 μM). Caffeic acid, 3-O-Caffeoylquinic acid, and 5-O-Caffeoylquinic acid among eleven selected compounds exhibited a much higher Th1-inclined immune response, suggesting their potent Th1-inclined immunomodulatory and anti-allergic potential, but they might slightly enhance inflammation. In contrast, 1,4-Dicaffeoylquinic acid, 1,5-Dicaffeoylquinic acid, and 3,4-Dicaffeoylquinic acid tended to have a relative Th2-inclined immunomodulatory property but were speculated to have anti-inflammatory potential.

选择11种咖啡酸及其奎宁酸衍生物，包括咖啡酸、1- o -咖啡酰奎宁酸、3- o -咖啡酰奎宁酸、4- o -咖啡酰奎宁酸、5- o -咖啡酰奎宁酸、1,3-二咖啡酰奎宁酸、1,4-二咖啡酰奎宁酸、1,5-二咖啡酰奎宁酸、3,4-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸和4,5-二咖啡酰奎宁酸，利用小鼠原代脾细胞评价其Th1/Th2免疫平衡。采用3-（4,5-二甲基噻唑-2-二苯基）-2,5-溴化四唑测定法确定各试验化合物的最佳非细胞毒浓度。采用酶联免疫吸附法测定处理后脾细胞的Th1 （IL-2、TNF-α）和Th2 （IL-4、IL-10）细胞因子分泌水平。通过主成分分析进一步分析各检测样品趋向于Th1/Th2免疫平衡的趋势。结果表明，双咖啡酰奎宁酸半最大抑制浓度（18.0 ~ 37.8 μM）比咖啡酸（49.4 μM）和咖啡酰奎宁酸（45.6 ~ 52.3 μM）对脾细胞具有更高的细胞毒性。咖啡酸、3- o -咖啡酰奎宁酸和5- o -咖啡酰奎宁酸在11种化合物中表现出更高的th1倾斜免疫反应，表明它们具有有效的th1倾斜免疫调节和抗过敏潜力，但可能轻微增强炎症反应。相比之下，1,4-二咖啡酰基奎宁酸、1,5-二咖啡酰基奎宁酸和3,4-二咖啡酰基奎宁酸倾向于具有相对的th2倾向免疫调节特性，但推测其具有抗炎潜能。

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引用次数: 0

Casticin in cancer research: in vitro evidence and mechanistic insights into its antitumor potential 蓖麻素在癌症研究中的应用：体外证据及其抗肿瘤潜能的机制研究。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-09 DOI: 10.1016/j.cbi.2025.111870

Aleksandra Łapa , Natalia Kocot , Kamil Piska , Katarzyna Wójcik-Pszczoła , Elżbieta Pękala , Paulina Koczurkiewicz-Adamczyk

Casticin (CAS), a natural flavonoid compound, has garnered increasing scientific interest due to its broad-spectrum anticancer properties. Originally recognized for its anti-inflammatory potential, CAS is now being extensively investigated for its ability to modulate key cellular processes involved in tumorigenesis. In vitro studies across a wide range of human cancer cell lines have consistently demonstrated that CAS inhibits cell viability, proliferation, and migration.

Mechanistically, CAS exerts its antitumor effects through the modulation of multiple intracellular signaling pathways. Notably, CAS downregulates the PI3K/Akt/mTOR and MAPK/ERK pathways, both of which are critical regulators of cell growth and survival. It also activates the p53 tumor suppressor pathway and promotes mitochondrial apoptosis via the Bax/Bcl-2/caspase cascade. Furthermore, CAS has been shown to suppress the NF-κB signaling pathway, leading to reduced expression of pro-inflammatory and pro-survival genes, and to modulate the STAT3 signaling axis, contributing to the inhibition of tumor-promoting inflammation and metastasis. Through these pathways, CAS induces multiple forms of programmed cell death, including apoptosis, autophagy, ferroptosis, and pyroptosis. Additionally, CAS arrests the cell cycle at critical checkpoints—particularly at the G2/M phase—thereby disrupting uncontrolled cell division and enhancing cellular susceptibility to chemotherapeutic agents.

This review provides a comprehensive overview of the current in vitro evidence supporting the anticancer potential of CAS, with a particular focus on its molecular mechanisms of action. The multifaceted nature of CAS activity highlights its promise as a potential adjunct or alternative in future cancer therapies.

Casticin （CAS）是一种天然的类黄酮化合物，由于其广谱抗癌特性而引起了越来越多的科学兴趣。CAS最初因其抗炎潜力而被认可，现在正因其调节肿瘤发生过程的关键细胞过程的能力而被广泛研究。广泛的人类癌细胞系的体外研究一致表明，CAS抑制细胞活力、增殖和迁移。在机制上，CAS通过调节多种细胞内信号通路发挥其抗肿瘤作用。值得注意的是，CAS下调了PI3K/Akt/mTOR和MAPK/ERK通路，这两个通路都是细胞生长和存活的关键调节因子。它还激活p53肿瘤抑制通路，并通过Bax/Bcl-2/caspase级联促进线粒体凋亡。此外，CAS已被证明可抑制NF-κB信号通路，导致促炎和促生存基因的表达减少，并调节STAT3信号轴，从而抑制促肿瘤的炎症和转移。通过这些途径，CAS诱导多种形式的程序性细胞死亡，包括凋亡、自噬、铁凋亡和焦亡。此外，CAS在关键检查点（特别是G2/M期）阻止细胞周期，从而破坏不受控制的细胞分裂并增强细胞对化疗药物的易感性。本文综述了目前体外证据支持CAS抗癌潜力的全面概述，特别关注其作用的分子机制。CAS活性的多面性突出了其作为未来癌症治疗的潜在辅助或替代方案的前景。

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引用次数: 0

Hexavalent chromium promotes malignant transformation via enhanced translation of SUV39H1 六价铬通过增强SUV39H1的翻译促进恶性转化。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-08 DOI: 10.1016/j.cbi.2025.111869

Yiwei Gu , Yanan Cao , Qing Ye , Yujing Zhang , Zhishan Wang , Chengfeng Yang , Side Liu , Qing-Bai She

Hexavalent chromium [Cr(VI)] is a widespread environmental carcinogen linked to lung cancer and other malignancies. Although genetic and epigenetic mechanisms of Cr(VI)-induced carcinogenesis have been extensively investigated, the role of translational control has remained largely unexplored. Here, we show that chronic low-dose Cr(VI) exposure in BEAS-2BR human bronchial epithelial cells activates eIF4E-driven cap-dependent translation through mTORC1-mediated phosphorylation and inactivation of the translational repressor 4E-BP1. Pharmacological inhibition of this pathway markedly suppresses Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like properties, and DNA damage. Comparable inhibitory effects are observed following raptor knockdown, which disrupts mTORC1, or expression of a constitutively active non-phosphorylatable 4E-BP1 mutant. Notably, the histone methyltransferase SUV39H1 is selectively upregulated at the translational level and contributes to Cr(VI)-induced malignant phenotypes. Inhibition of the mTORC1/4E-BP1 signaling pathway, either pharmacologically or genetically, reduces SUV39H1 translation, whereas ectopic SUV39H1 expression restores CSC-like properties and DNA damage even in the presence of pathway inhibition. Together, these findings identify mTORC1/4E-BP1-mediated translational upregulation of SUV39H1 as an important mechanistic link in Cr(VI)-induced carcinogenesis, revealing a novel layer of regulation that integrates translational control with environmental carcinogen-induced epigenetic reprogramming.

六价铬[Cr(VI)]是一种广泛存在的环境致癌物，与肺癌和其他恶性肿瘤有关。虽然Cr（VI）诱导的癌变的遗传和表观遗传机制已被广泛研究，但翻译控制的作用仍未被广泛探索。在这里，我们发现慢性低剂量Cr（VI）暴露在BEAS-2BR人支气管上皮细胞中，通过mtorc1介导的翻译抑制因子4E-BP1的磷酸化和失活，激活了eif4e驱动的帽依赖翻译。药物抑制该途径可显著抑制Cr（VI）诱导的细胞转化、癌症干细胞（CSC）样特性和DNA损伤。在raptor敲除mTORC1或组成活性的非磷酸化4E-BP1突变体的表达后，观察到类似的抑制作用。值得注意的是，组蛋白甲基转移酶SUV39H1在翻译水平上选择性上调，并有助于Cr（VI）诱导的恶性表型。抑制mTORC1/4E-BP1信号通路，无论是药理学上还是遗传学上，都可以减少SUV39H1的翻译，而异位SUV39H1表达即使在存在通路抑制的情况下，也可以恢复csc样特性和DNA损伤。总之，这些发现确定了mtorc1 / 4e - bp1介导的SUV39H1的翻译上调是Cr（VI）诱导的癌变的重要机制链接，揭示了将翻译控制与环境致癌物质诱导的表观遗传重编程相结合的新调控层。

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引用次数: 0