Chemico-Biological Interactions最新文献

{"title":"Implications of early-life BPS-induced thyroid disruption on adult female reproductive disorders","authors":"Lina Chouchene,&nbsp;Mariem Ben Rhouma,&nbsp;Sana Boughammoura,&nbsp;Imed Messaoudi,&nbsp;Kaouthar Kessabi","doi":"10.1016/j.cbi.2025.111891","DOIUrl":"10.1016/j.cbi.2025.111891","url":null,"abstract":"<div><div>Reproductive disorders have become a growing public health concern, with early-life environmental exposures increasingly recognized as critical determinants of long-term reproductive outcomes. Among emerging endocrine disruptors, bisphenol S (BPS) raises concern due to its potential to interfere with hormone signaling during sensitive developmental windows. This study examined whether prenatal BPS exposure affects reproductive outcomes in adulthood through maternal thyroid disruption. Pregnant rats were exposed to BPS and the thyroid hormone receptor (THR) antagonist (AT 1–850). Key parameters studied included body weight, ovarian function (puberty onset, estrous cyclicity, histology, hormone levels), oxidative status, and oocyte development gene expression. Our findings support a model in which maternal thyroid disruption during critical developmental stages leads to long-term alterations in ovarian function and architecture, significantly impacting female reproductive health. This disruption is further corroborated by the striking similarity between the effects observed with BPS exposure and those induced by the THR antagonist, suggesting a common underlying mechanism. Despite a normal oxidative status, reproductive disturbances emerged as early pubertal onset, with accelerated vaginal opening and earlier first estrous. Irregular estrous cycles were noted, with prolonged estrus and metestrus phases. Folliculogenesis was impaired, marked by the accumulation of primordial, primary, and atretic follicles, and a blockade in progression to the secondary stage. Oocyte development was also altered, evidenced by elevated FIGLα and H1FOO expression. These disruptions were associated with hormonal imbalance, particularly decreased E2 levels. Altogether, these outcomes suggest that early-life BPS exposure compromises female reproductive function and efficiency in adulthood through maternal thyroid disruption.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111891"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879526","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":"Novel MicroRNA biomarkers revealed in the serum and bile of thioacetamide induced cholangiocarcinoma","authors":"Weisheng Chen ,&nbsp;Brendon R. Herring ,&nbsp;Jasmine Watts ,&nbsp;Caroline MacVicar ,&nbsp;David Crossman ,&nbsp;Nilesh Kumar ,&nbsp;M. Shahid Mukhtar ,&nbsp;Flavio Rocha ,&nbsp;Kris V. Kowdley ,&nbsp;J. Bart Rose","doi":"10.1016/j.cbi.2025.111873","DOIUrl":"10.1016/j.cbi.2025.111873","url":null,"abstract":"<div><div>Cholangiocarcinoma is often very challenging to diagnose due to high false negative biopsy rates. There are known precursors to cholangiocarcinoma such as primary sclerosing cholangitis and hepatitis; however, identifying early and sensitive biomarkers for liver injury and tumor progression could enhance cancer diagnosis, prognosis, and management. Recent studies have suggested blood and bile-based microRNA (miRNA) panels performed better than existing tumor markers. To further investigate this, we conducted next-generation sequencing of thioacetamide (TAA) induced cholangiocarcinoma in an established rat model. We identified 2938 unique differentially expressed genes (DEGs) and 27 differentially expressed miRNAs (DEMs) between tumor bearing rats and normal controls. Pathway analyses on the DEGs and DEMs revealed the molecular mechanisms of hepatic hyperplasia and nephritis. To filter for ideal biomarkers, we further performed qPCR on bile and serum. Three miRNAs (miR-146b-5p, miR-223–3p and miR-214–3p) overlapped with the DEMs from solid tumors. Therefore, those miRNAs have the potential to serve as early and sensitive biomarkers for TAA-induced cholangiocarcinoma. Notably, no previous study has demonstrated the role of miR-146–5p on cancer development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111873"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783819","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":"Melatonin suppresses glycolysis and coordinately disrupts DNA repair via targeting the YAP1-NAMPT signaling in breast cancer","authors":"Yi-Wen Lai ,&nbsp;Cheng-Ying Chu ,&nbsp;Zei-Wei Liu ,&nbsp;Hsin-Ying Lu ,&nbsp;Chi-Ching Lee ,&nbsp;Mei-Hsiang Lin ,&nbsp;Cheng-Wei Lin","doi":"10.1016/j.cbi.2026.111900","DOIUrl":"10.1016/j.cbi.2026.111900","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and high recurrence rates, contributing to poor prognoses of TNBC patients. However, the lack of appropriate molecular targets limits the effectiveness of current antineoplastic therapies. Therefore, effective therapeutic strategies are urgently needed. Melatonin (<em>N</em>-acetyl-5-methoxytryptamine) has shown a broad spectrum of anticancer activities, but its potential for treating TNBC remains elusive. In this study, we discovered that melatonin suppressed the growth and invasiveness of TNBC cells through downregulating glycolytic capacity in association with inhibition of Yes-associated protein 1 (YAP1) signaling. Notably, melatonin suppressed expression of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme participated in nicotinamide adenine dinucleotide (NAD) turnover and contributes to protein poly(ADP)-ribosylation (PARylation). As a result, melatonin potentiated DNA damage and elevated apoptosis. Furthermore, it is found that melatonin suppressed NAMPT expression via inhibition of YAP1. Moreover, downregulation of glycolysis decreased protein PARylation levels and increased DNA damage accumulation, suggesting that melatonin suppresses the crosstalk between glycolysis and DNA repair signaling. Combined treatment with melatonin and Olaparib, an inhibitor of the major conductor of protein PARylation, poly(ADP-ribose) polymerase (PARP), showed additive inhibitory effects on breast cancer proliferation compared to their single treatment. These findings demonstrated that melatonin may be a promising agent for targeting YAP1-mediated glycolysis and DNA repair in breast cancer for enhancing the therapeutic efficacy of Olaparib in TNBC patients.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111900"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145901905","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":"New insights into Lambda-cyhalothrin-induced lipid metabolism disorder in liver: Crosstalk between oxidative stress and PPARα signaling pathway","authors":"Haoran Zhang ,&nbsp;Chunye He ,&nbsp;Zhaohong Pu ,&nbsp;Lu Guo ,&nbsp;Liying Pan ,&nbsp;Haiyue Gong ,&nbsp;Jingyi Zhang ,&nbsp;Farooque Laghari ,&nbsp;Shengzi Jin ,&nbsp;Runxiang Zhang","doi":"10.1016/j.cbi.2025.111872","DOIUrl":"10.1016/j.cbi.2025.111872","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111872"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733773","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":"Inhibition of NOD-like receptor pyrin domain-containing protein 3 inflammasome activation by MK-571, a multidrug resistance protein inhibitor","authors":"Seungseok Oh ,&nbsp;Jeongwoo Park ,&nbsp;Won Kim ,&nbsp;Keon Wook Kang","doi":"10.1016/j.cbi.2025.111867","DOIUrl":"10.1016/j.cbi.2025.111867","url":null,"abstract":"<div><div>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/<span>d</span>-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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111867"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145727655","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":"Hexavalent chromium promotes malignant transformation via enhanced translation of SUV39H1","authors":"Yiwei Gu ,&nbsp;Yanan Cao ,&nbsp;Qing Ye ,&nbsp;Yujing Zhang ,&nbsp;Zhishan Wang ,&nbsp;Chengfeng Yang ,&nbsp;Side Liu ,&nbsp;Qing-Bai She","doi":"10.1016/j.cbi.2025.111869","DOIUrl":"10.1016/j.cbi.2025.111869","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111869"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145727619","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":"Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing","authors":"Dinara Afrose ,&nbsp;Sofía Alfonso-Sánchez ,&nbsp;Ashleigh Philp ,&nbsp;Philip M. Hansbro ,&nbsp;Qian Peter Su ,&nbsp;Lana McClements","doi":"10.1016/j.cbi.2025.111883","DOIUrl":"10.1016/j.cbi.2025.111883","url":null,"abstract":"<div><div>Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D <em>in vitro</em> model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclampsia-like conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), or inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 h with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM), in the presence of DMOG, Rho-6G or TNF--α. Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (<em>mfn1</em>), fission (<em>dnm1l</em>), and autophagy (<em>atg5, map1lc3b</em>). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p &lt;0.05-0.0001), increasing circularity (p &lt; 0.05-0.0001), and decreasing mitochondrial number per cell (p &lt; 0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized <em>mfn1</em> (p &lt; 0.05) and <em>atg5</em> expression (p &lt; 0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p &lt; 0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration under inflammatory stress (p &lt; 0.0001). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111883"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776494","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":"Celastrol induces cardiotoxicity by directly targeting AMOTL2 and inhibiting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis","authors":"Huiying Shang ,&nbsp;Hongbo Cheng ,&nbsp;Wei Zhou ,&nbsp;Xianglin Tang ,&nbsp;Weiye Han ,&nbsp;Xiaotong Zhang ,&nbsp;Chengrong Xiao ,&nbsp;Yehui Gao ,&nbsp;Xian Liu ,&nbsp;Yue Gao","doi":"10.1016/j.cbi.2025.111885","DOIUrl":"10.1016/j.cbi.2025.111885","url":null,"abstract":"<div><div>Celastrol is a promising therapeutic candidate for cancers, metabolic diseases, and autoimmune disorders. However, recent studies demonstrated consecutive administration of celastrol at anticancer doses may induce severe heart injuries, which significantly limited its clinical translation. This study aimed to investigate the cellular target and potential mechanism underlying celastrol-induced cardiotoxicity. Consecutive <em>i.p.</em> injection of celastrol for 14 days induces cardiotoxicity in mice, as evidenced by reduced heart-to-body weight ratio, decreased cardiac output and stroke volume, and increased serum cardiac enzymes and proinflammatory cytokine levels in heart tissues. At the cellular level, celastrol triggered mitochondrial dysfunction and promoted cardiomyocyte apoptosis through activation of the mitochondrial pathway, as evidenced by altered B-Cell Lymphoma 2/Bcl-2-Associated X Protein (Bax/Bcl-2) ratio and expression of Cysteinyl aspartate specific proteinase 3 (caspase-3). Mechanistically, we identified Angiomotin-Like Protein 2 (AMOTL2) as a direct cellular target of celastrol using activity-based protein profiling (ABPP). Celastrol-AMOTL2 binding initiated a signaling cascade through Hippo pathway activation, promoting Yes-Associated Protein 1 (YAP1) phosphorylation and subsequent degradation. Knockdown of AMOTL2 by short hairpin RNA attenuated celastrol-induced cardiomyocyte apoptosis by enhancing YAP1 expression and mitochondrial biogenesis. These findings demonstrate that celastrol induces cardiotoxicity by directly targeting AMOTL2 and disrupting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111885"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783735","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":"Alkyne modification of DNA cross-linking antitumor agent SJG-136 to monitor induced lesions in cells by click chemistry","authors":"Sara Berrada,&nbsp;Violette Azzoni,&nbsp;Gilles Audoly,&nbsp;Lara Lee,&nbsp;Jean-Hugues Guervilly,&nbsp;Sébastien Abel,&nbsp;Sébastien Combes,&nbsp;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":"2026-01-25","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}

{"title":"5-Hydroxymethylfurfural triggers autophagy and apoptosis in sertoli and spermatogonial cells via suppression of the PI3K/AKT/mTOR pathway","authors":"Yasemin Aydin,&nbsp;Banu Orta Yilmaz","doi":"10.1016/j.cbi.2025.111886","DOIUrl":"10.1016/j.cbi.2025.111886","url":null,"abstract":"<div><div>5-Hydroxymethylfurfural (HMF) is a heat-induced food contaminant commonly present in processed products and regularly ingested through the diet. Although its genotoxic, neurotoxic, and carcinogenic effects have been demonstrated in various tissues, the cellular effects of HMF on the male reproductive system are still not sufficiently elucidated. For the first time, this study comprehensively evaluated the toxic effects of HMF on Sertoli (TM4) and type B spermatogonium (GC-1) cell lines. HMF was administered to TM4 and GC-1 cells at concentrations of 0.1, 1, and 10 mM for 24 h. The findings revealed that HMF caused concentration-dependent cytotoxicity in both cell types. HMF was found to cause significant increases in total reactive oxygen species and lipid peroxidation levels in germ cells. Gene expression analyses indicated disruptions in the <em>Nrf2</em>, <em>Keap1</em>, and <em>Parp1</em> genes that affect cell defense mechanisms. HMF exposure led to significant increases in <em>Trp53</em>, <em>Bax</em>, and <em>Casp3</em> gene expression, a decrease in the anti-apoptotic <em>Bcl2</em> gene, and elevated CASP3 protein levels in both cell lines. Furthermore, significant increases in autophagy-related Atg5, Lc3a/b, and Beclin-1 genes and proteins were observed following HMF administration. Also, our study demonstrated that the PI3K/AKT/mTOR signaling pathway was suppressed, and cellular death mechanisms were modulated through this pathway. Our results suggest that the toxic effects of HMF vary depending on the cell type and elicit a more pronounced response, particularly in GC-1 cells. In conclusion, HMF can cause cytotoxic effects in male germ cells by activating oxidative stress, apoptosis, and autophagy pathways.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"424 ","pages":"Article 111886"},"PeriodicalIF":5.4,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775520","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}