Chemico-Biological Interactions最新文献

{"title":"Naringenin targets and inhibits Monoamine Oxidase A/B to bidirectionally regulate intestinal motility.","authors":"Qi Li ,&nbsp;Yi Chen ,&nbsp;Yige Zhang ,&nbsp;Canwei Xu ,&nbsp;Ting Tang ,&nbsp;Yunzhi Qian ,&nbsp;Ong Shun seng ,&nbsp;Yujuan Wang ,&nbsp;Ling Fang ,&nbsp;Tianshu Xu","doi":"10.1016/j.cbi.2025.111742","DOIUrl":"10.1016/j.cbi.2025.111742","url":null,"abstract":"<div><h3>Background</h3><div>Monoamine oxidase (MAO), the principal enzymatic regulator of monoamine neurotransmitter catabolism, plays a critical role in modulating intestinal motility dynamics. In colonic tissues, MAO-A is predominantly expressed during monoamine degradation, whereas MAO-B exhibits a relatively lower expression level. This differential expression of MAO subtypes endows naringenin (NAR), a flavonoid compound that can competitively bind to the active sites of both MAO-A and MAO-B, with distinct dose-response thresholds for inhibiting these two enzyme isoforms. Consequently, this study aims to systematically elucidate the molecular mechanisms underlying NAR's regulation of intestinal motility through its selective inhibition of the two MAO subtypes, and to comprehensively analyze the associated dose-effect relationships. Ultimately, the research seeks to provide a theoretical basis for its dose optimization and the mitigation of toxicity and side effects.</div></div><div><h3>Methods</h3><div>In this study, we constructed a slow-transmission constipation model in male C57BL/6 mice induced by loperamide (LOP), and systematically investigated the effects of NAR at different concentrations on intestinal motility, MAO activity and neurotransmitter metabolism.</div></div><div><h3>Results</h3><div>This research showed that NAR at a dose of 25–300 mg/kg selectively targeted intestinal MAO-A, suppressing enzymatic activity and reducing 5-hydroxytryptamine (5-HT) catabolism. This accumulation of 5-HT enhanced intestinal motility. However, when the NAR concentration is ≥ 150 mg/kg, it can additionally cause MAO-B inhibition, which resulted in significant blockage of dopamine metabolism and caused an abnormal increase in dopamine content. Ultimately, it inhibited colonic peristalsis through the activation of the dopamine signaling pathway.</div></div><div><h3>Conclusion</h3><div>The results confirmed that NAR can regulate the activities of MAO-A/B in a threshold-dependent manner to achieve bidirectional regulation of intestinal motility.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111742"},"PeriodicalIF":5.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058824","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}

{"title":"Investigating the interaction mechanism of five flavonoids and PD-L1 based on multi-spectroscopy and molecular dynamics","authors":"Yijie Cai ,&nbsp;Yijun Tu ,&nbsp;Hong Cheng ,&nbsp;Jianqing Yu","doi":"10.1016/j.cbi.2025.111741","DOIUrl":"10.1016/j.cbi.2025.111741","url":null,"abstract":"<div><div>PD-L1 is an important protein overexpressed in various types of cancer. Flavonoids as common antioxidants have extensive bioactivities. In this study, the interaction mechanism and the structure-activity relationship between the five flavonoids and extracellular domain of PD-L1 (PD-L1-ECD) were investigated using integrated spectroscopy and computational simulation. Fluorescence spectra showed that the quenching mechanisms of the interaction between the five flavonoids and PD-L1-ECD were static quenching. Circular dichroism (CD) spectra showed that the five flavonoids caused conformational changes of PD-L1-ECD. Computational simulation data showed the different binding patterns between five flavonoids and PD-L1-ECD. The binding affinity of the five flavonoids which affected by hydrogenation of C2=C3 bond and the substitution of C3 decreased in the following order: luteolin &gt; kaempferol &gt; spinacetin &gt; axillarin &gt; hesperetin. This study suggested that five flavonoids could bind to the PD-L1-ECD, thereby establishing a foundation for developing these compounds as small-molecule PD-L1 inhibitors. Subsequent structure-activity relationship was studied based on distinct binding modes and binding affinity, and it will contribute to structural modifications to optimize therapeutic potency.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111741"},"PeriodicalIF":5.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042523","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}

{"title":"Mitochondrial physiology and beyond: Mechanistic insights into kaempferol actions","authors":"Marcos Roberto de Oliveira","doi":"10.1016/j.cbi.2025.111743","DOIUrl":"10.1016/j.cbi.2025.111743","url":null,"abstract":"<div><div>Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse <em>in vitro</em> and <em>in vivo</em> models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111743"},"PeriodicalIF":5.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045784","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}

{"title":"CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling","authors":"Yuan Liu ,&nbsp;Xiao Qi ,&nbsp;Xin-peng Luo ,&nbsp;Yi-fei Wang ,&nbsp;Jia-jun Wan ,&nbsp;Feng-ze Wang ,&nbsp;Wei-ying Zhang","doi":"10.1016/j.cbi.2025.111735","DOIUrl":"10.1016/j.cbi.2025.111735","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the most common histologic subtype of lung cancer associated with a relatively high mortality rate. CUDC-907, a dual-target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K), has the potential to suppress the progression of various malignancies. However, the anti-cancer effect of CUDC-907 on NSCLC remains to be fully elucidated. In this study, we explored the anti-NSCLC effects of CUDC-907 and the possible underlying mechanisms. NSCLC cells were treated with different concentrations of CUDC-907, and cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated using colony formation and 5-ethynyl-2′-deoxyuridine (EdU) assays, while γ- H2A.X histone variant (H2AX) immunofluorescence was used to monitor DNA damage. The <em>in vivo</em> anti-tumor efficacy of CUDC-907 against NSCLC was evaluated using a xenograft mouse model, and protein expression levels were examined via Western blot analysis. The results revealed that CUDC-907 reduced the viability of A549 and H1299 cells in a concentration-dependent manner. Colony formation and EdU assays showed that CUDC-907 suppressed the proliferation of NSCLC cells. Exposure to CUDC-907 caused G2/M phase arrest in both A549 and H1299 cells by decreasing the expression of cyclin A, cell division cycle 25C (Cdc25C), p-Cdc25C, Cdc2, and cyclin B1, and increasing the protein levels of p21. Treatment with CUDC-907 induced γ-H2AX foci formation and abnormal mitosis in NSCLC cells by downregulating the expression of Aurora A, Aurora B, and polo-like kinase 1 (PLK1). In addition, CUDC-907 triggered A549 and H1299 cell apoptosis by increasing the cleavage of caspase-3, caspase-8, caspase-9, and poly (ADP-ribose) polymerase (PARP). Mechanistic studies revealed that CUDC-907 activated inositol-requiring enzyme 1 α (IRE1α)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and blocked -Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in A549 and H1299 cells. Additionally, CUDC-907 treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model. Taken together, this study revealed the cytotoxic effects of CUDC-907 and its underlying mechanism, which suggests that CUDC-907 may be an effective therapeutic approach for treating NSCLC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111735"},"PeriodicalIF":5.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042570","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}

{"title":"Celecoxib blocks AKT/mTOR in AKT/YapS127A-driven intrahepatic cholangiocarcinoma, activating p21/p27 for cycle arrest and suppressing Mcl-1 for apoptosis","authors":"Xiangyun Tan ,&nbsp;Yuan Yang ,&nbsp;Junjie Hu ,&nbsp;Yan Meng ,&nbsp;Liang Chen ,&nbsp;Guohua Zheng ,&nbsp;Han Xiao ,&nbsp;Zhenpeng Qiu","doi":"10.1016/j.cbi.2025.111737","DOIUrl":"10.1016/j.cbi.2025.111737","url":null,"abstract":"<div><div>Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with insidious onset, limited treatments, and poor prognosis. Recent studies have shown that celecoxib exerts marked cytotoxic effects on cholangiocarcinoma cell lines, suggesting its potential as an iCCA therapy. However, the potential molecular and cellular mechanisms that link celecoxib treatment to its toxicological outcomes remain unclear. In this study, we induced iCCA in mice by overexpressing AKT and YapS127A (hereafter referred to as AKT/YapS127A) and administered celecoxib continuously to evaluate its antitumor effects <em>in vivo</em>. The results demonstrated that celecoxib effectively inhibited tumor growth in AKT/YapS127A-driven iCCA mice. Mechanistically, celecoxib boosted levels of cell cycle inhibitors p21^Waf1/Cip1 and p27^Kip1, leading to cell cycle arrest. It also promoted apoptosis by downregulating the expression of anti-apoptotic proteins Mcl-1 and Bcl-2. These effects were associated with the modulation of the AKT/mTORC1 signaling pathway. Consistently, celecoxib recapitulated AKT/mTORC1 inhibition and subsequent cell cycle/apoptotic regulator alterations in iCCA cell lines. Collectively, our study elucidated the molecular mechanisms through which celecoxib exerted its anti-tumor effects in iCCA, demonstrating its capacity to induce cytotoxic outcomes <em>via</em> the precise regulation of the AKT/mTORC1 pathway. These findings deepen understanding of the toxicological actions of celecoxib and provide critical insights for developing targeted iCCA therapies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111737"},"PeriodicalIF":5.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034767","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}

{"title":"Integration of in vivo stress reporters with transcription profiling to define chemical mixtures mechanisms of toxicity, including trans-generational effects","authors":"Francisco Inesta-Vaquera ,&nbsp;Wenduo Qi ,&nbsp;Silviya Dimova-Vasileva ,&nbsp;G. Jean Campbell ,&nbsp;Febe Ferro ,&nbsp;Richard Meehan ,&nbsp;Sari Pennings ,&nbsp;C. Roland Wolf","doi":"10.1016/j.cbi.2025.111699","DOIUrl":"10.1016/j.cbi.2025.111699","url":null,"abstract":"<div><div>Humans are exposed to mixtures of chemical pollutants from various environmental sources at all stages of life. Understanding how these compounds are causally linked to population health effects is challenging because of the ethical limitations on studying controlled human exposures and the complexity of the many potential molecular mechanisms involved. We hypothesized that studies using a combination of <em>in vivo</em> murine stress reporter models together with non-targeted global transcriptome analysis will define the toxic mechanisms of complex chemical mixtures in a physiological context. To test this hypothesis, a panel of stress reporter mice were subjected to a mixture of polychlorinated biphenyls (PCBs), persistent environmental pollutants typified by Aroclor 1254 (A1254). In time-dependent and <em>trans</em>-lactational exposure studies we observed activation of stress responses in liver using reporters for <em>Cyp1a1</em> (aryl hydrocarbons receptor, AHR pathway) and <em>Hmox1</em> (oxidative stress and inflammation). Whole liver transcriptional analysis revealed distinct Aroclor 1254-linked signatures including xenobiotic metabolism (AHR, CAR/PXR), oxidative stress (Nrf2), cell proliferation, and carcinogenesis. A combination of genetic and biochemical approaches revealed that NRF2 does not mediate <em>Hmox1</em> activation following A1254 exposure but plays a major role in regulating the expression of genes involved in mitosis. We further demonstrate the utility of our reporter approach to detect the activation of stress responses in mouse neonates exposed to A1254 by lactational transfer. Intriguingly, we observed robust <em>Hmox1</em> reporter activation in neonate livers for up to two generations following initial maternal exposure. Thus, we exemplify how a combination of <em>in vivo</em> reporter and transcriptional analysis captures novel mechanistic insights into the effects of chemical mixtures of persistent organic pollutants in a relevant physiological context and with cellular resolution, after both primary exposure and in a transgenerational manner. This approach may be applied to understand the full spectrum of mechanisms of toxicity of other chemical mixtures of concern in the physiological context.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111699"},"PeriodicalIF":5.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034784","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}

{"title":"NR1I3 inhibits colorectal cancer growth by enhancing PCK1-mediated gluconeogenesis","authors":"Huanying Shi ,&nbsp;Zimei Wu ,&nbsp;Jiafeng Liu ,&nbsp;Tianxiao Wang ,&nbsp;Zhengchuan Niu ,&nbsp;Wenxin Zhang ,&nbsp;Bicui Chen ,&nbsp;Xiang Mao ,&nbsp;Yuxin Huang ,&nbsp;Jiyifan Li ,&nbsp;Huijie Qi ,&nbsp;Xinhai Wang ,&nbsp;Lu Chen ,&nbsp;Qunyi Li","doi":"10.1016/j.cbi.2025.111734","DOIUrl":"10.1016/j.cbi.2025.111734","url":null,"abstract":"<div><div>There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT‒PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111734"},"PeriodicalIF":5.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027548","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}

{"title":"NIR fluorescent substrate-driven discovery of prolyl endopeptidase natural inhibitors and its inhibition of alpha-synuclein aggregation and promotion of autophagy","authors":"Jing Zhang ,&nbsp;Kun-Jie Bian ,&nbsp;Yi-Jing Wang ,&nbsp;Xing-Kai Qian ,&nbsp;Jin Geng ,&nbsp;Hai-Dong Guo ,&nbsp;Li-Wei Zou","doi":"10.1016/j.cbi.2025.111733","DOIUrl":"10.1016/j.cbi.2025.111733","url":null,"abstract":"<div><div>Prolyl endopeptidase (PREP) drives neurodegenerative diseases through dual mechanisms involving enzymatic activity and protein-protein interactions (PPIs), yet current inhibitors predominantly target single pathways.</div><div>Prolyl endopeptidase (PREP) fuels neurodegeneration via enzymatic cleavage and pathological PPIs, yet current inhibitors usually target only one facet. In this study, leveraging our developed high-sensitivity and high-specificity near-infrared fluorescent probe Z-GP-ACM, we established and validated a screening platform for PREP inhibitors with mouse brain S9 instead of the human recombinant PREP.</div><div>Screening a library of 110 natural compounds identified a series of flavonoid derivatives (FV64-FV68) as potent PREP inhibitors, with FV67 and FV68 exhibiting particularly strong inhibition (IC₅₀ values of 0.65 μM and 0.31 μM, respectively). Reversibility assays revealed that all new inhibitors display time-independent potency (IC₅₀ unchanged after 5 vs 35 min pre-incubation), confirming reversible inhibition.</div><div>Furthermore. Kinetic analyses classified FV66/FV67 as mixed-type and FV64/FV65/FV68 as non-competitive inhibitors. Molecular docking simulations further revealed that FV68 binds the S1 and S2 sub-sites of PREP through hydrogen bonding and π-π stacking, which is the structural basis for its high activity. Further studies showed that both FV67 and FV68 inhibited PREP activity in HT22 and SH-SY5Y cells with a dose-dependent manner. Notably, FV68 enhanced autophagy, reduced α-synuclein aggregation, and mitigated H₂O₂-induced oxidative stress. These studies not only provide directions for the development of novel PREP inhibitors derived from natural products, also reveal new mechanisms by which natural compounds may intervene in neurodegenerative diseases by PREP-inhibited modulating PPIs.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111733"},"PeriodicalIF":5.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010582","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}

{"title":"Involvement of ductal reaction in Di-(2-ethylhexyl)-phthalate-caused hepatic fibrosis: Molecular mechanisms and potential intervention strategies","authors":"Xinru Du ,&nbsp;Shu Zhang ,&nbsp;Sha Liu ,&nbsp;Yancheng Gao ,&nbsp;Zhendong Wang ,&nbsp;Na Dong ,&nbsp;Sisi Song ,&nbsp;Qinming Hui ,&nbsp;Ziyi Wang ,&nbsp;Yue Ma ,&nbsp;Chunxiao Zhou ,&nbsp;Ye Yang ,&nbsp;Mengyue Ji ,&nbsp;Yuan Li","doi":"10.1016/j.cbi.2025.111738","DOIUrl":"10.1016/j.cbi.2025.111738","url":null,"abstract":"<div><div>Di-(2-ethylhexyl)-phthalate (DEHP) is a persistent environmental endocrine toxicant present in many products, and liver is the main target organ for DEHP metabolism. Long-term exposure to DEHP induces hepatic fibrosis, which is reversible in the early stages, while progresses to cirrhosis without timely intervention. Ductular reaction (DR) is a characteristic pathological change in hepatobiliary diseases, however, the involvement of DR in DEHP-caused hepatic fibrosis, the underlying molecular mechanisms, remail largely uninvestigated. Here, we found that the DEHP exposure is positively correlated with hepatic fibrosis index in male population, revealing a sex-specific disparity. A low dose of DEHP chronic exposure induced the development of DR in male C57BL/6J mice and in cholangiocytes. Through high-throughput screening and bioinformatics analysis, we identified a potential key molecule, squalene epoxidase (SQLE). For the molecular mechanisms, DEHP elevated the expression of SQLE, which in-turn induced the epithelial to mesenchymal transition (EMT) process in reactive-appearing duct-like cells (RDCs), leading to acquire the functional properties of mesenchymal cells, and promote DR amplification. These processes promoted the DEHP-caused hepatic fibrosis. Furthermore, via drug screening and functional analysis, we identified a traditional Chinese medicine monomer, luteolin, targeting inhibited the SQLE protein. Finally, we found that, targeted intervention of SQLE by luteolin prevented the DEHP induced EMT, DR, and hepatic fibrosis. Our present study offered new insights into environmental toxin-induced hepatobiliary diseases and suggested a potential key intervention target/approach for the prevention of hepatic fibrosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111738"},"PeriodicalIF":5.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016951","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}

{"title":"Aluminum exposure disturbs epigenetic modification and organelle function during early embryo development","authors":"Xiao-Ting Yu ,&nbsp;Zhen-Hui Fu ,&nbsp;Wen-Lin Pan ,&nbsp;Yan-Lun Song ,&nbsp;Rui-Jie Ma ,&nbsp;Hao-Lin Zhang ,&nbsp;Xing-He Ke ,&nbsp;Shao-Chen Sun ,&nbsp;Jun-Li Wang ,&nbsp;Lin-Lin Hu","doi":"10.1016/j.cbi.2025.111736","DOIUrl":"10.1016/j.cbi.2025.111736","url":null,"abstract":"<div><div>Aluminum is a lightweight and corrosion-resistant metal element that is widely used in industries, construction, food, and pharmaceuticals, and it can adversely affect multiple organ systems including the nervous system, skeletal system, reproductive system, blood system, and immune system. In present study, we investigated the effects of aluminum exposure on mammalian embryo development. Our data demonstrate that aluminum exposure induces mouse early embryo development defects, including those at the zygotes and 2-cell stages, causing a decrease in general transcription activity. We found mitochondrial dysfunction and a significant increase in reactive oxygen species (ROS) levels, thereby triggering oxidative stress, and this oxidative stress subsequently results in DNA damage. Additionally, we observed substantial alterations in histone modification levels, specifically H3K4me2, H3K4me3, H3K27me3, and H4K12ac. These changes in histone modifications were found to be closely associated with the observed DNA damage and mitochondrial dysfunction. We also observed aberrant distribution of lysosomes, endoplasmic reticulum, and Golgi apparatus, indicating that aluminum could disturb protein modification and transport in embryos. In conclusion, our results indicated that aluminum exposure disrupted early embryo development by inducing mitochondria-based oxidative stress, which further caused DNA damage, aberrant histone modifications and organelle functions in mouse embryos.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111736"},"PeriodicalIF":5.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016960","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}