Chemico-Biological Interactions最新文献

{"title":"Subchronic exposure to CeCl3 promotes macrophage ferroptosis and atherosclerotic plaque formation by inhibiting the Keap1/Nrf2/GPX4 pathway","authors":"Baoping Xie ,&nbsp;Liuyan Xin ,&nbsp;Wen Liu ,&nbsp;An Li ,&nbsp;Qi Jin ,&nbsp;Shuping Xu ,&nbsp;Gonghua Hu","doi":"10.1016/j.cbi.2025.111671","DOIUrl":"10.1016/j.cbi.2025.111671","url":null,"abstract":"<div><div>Cerium chloride (CeCl₃), a prevalent by-product of rare earth mining, accumulates in the biota and environment of mining regions, including plants, animals, water resources, and air, posing potential health risks to local residents. Atherosclerosis (AS) is the pathological basis of cardiovascular disease. However, the relationship between subchronic CeCl₃ exposure and AS progression, along with the underlying regulatory mechanisms by which CeCl₃ modulates AS, remains unclear. In this study, we first demonstrated confirmed that CeCl₃ significantly exacerbated AS plaque formation in ApoE^−/− mice fed with high-fat diet (HFD). Moreover, CeCl₃ elevated serum levels of triglycerides (TG), cholesterol (CHO), and low-density lipoprotein (LDL). Further studies showed that CeCl₃ significantly inhibited the expression of key regulators of ferroptosis, such as GPX4 and FTH1, as well as antioxidant enzyme glutathione peroxidase 4 (GPx4) and superoxide dismutase (SOD), and upregulated the levels of lipid peroxidation markers, including reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous iron (Fe²⁺). Besides, CeCl₃ significantly inhibited the expression of Nrf2, NQO1, and HO-1, and impeded Nrf2 nuclear translocation. Mechanistically, CeCl₃ significantly promoted the formation of the Keap1/Nrf2 complex, leading to ubiquitin-mediated Nrf2 degradation. Pharmacological activation of Nrf2 by NK-252 significantly reduced CeCl₃-induced inhibition of GPX4 and FTH1 expression, and reversed its pro-atherosclerotic effects. Dual-luciferase reporter assays confirmed Nrf2 as a transcriptional regulator of GPX4. Taken together, our study demonstrates that CeCl₃ exacerbates HFD-induced AS plaque formation and promotes ferroptosis in macrophages via the Keap1/Nrf2/GPX4 signaling pathway, providing new insights into strategies for preventing cardiovascular diseases with subchronic exposure to CeCl₃.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111671"},"PeriodicalIF":4.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703695","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":"Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease","authors":"Urban Košak ,&nbsp;Damijan Knez ,&nbsp;Svit Ferjančič Benetik ,&nbsp;Peter Mastnak Sokolov ,&nbsp;Anja Pišlar ,&nbsp;Selena Horvat ,&nbsp;Jure Stojan ,&nbsp;Bingbing Lv ,&nbsp;Weiting Zhang ,&nbsp;Yuanyuan Wang ,&nbsp;Qinjie Wang ,&nbsp;Alexandre Igert ,&nbsp;José Dias ,&nbsp;Florian Nachon ,&nbsp;Xavier Brazzolotto ,&nbsp;Haopeng Sun ,&nbsp;Stanislav Gobec","doi":"10.1016/j.cbi.2025.111670","DOIUrl":"10.1016/j.cbi.2025.111670","url":null,"abstract":"<div><div>Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic <em>N</em>-benzylpiperidine-based naphthalene-2-sulfonamide <strong>2</strong>, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers <strong>(<em>R</em>)-(−)-2</strong> and <strong>(<em>S</em>)-(+)-2</strong> and confirmed that <strong>(<em>R</em>)-(−)-2</strong> is the eutomer and <strong>(<em>S</em>)-(+)-2</strong> is the distomer with respect to human (h)BChE inhibition. Notably, <strong>(<em>R</em>)-(−)-2</strong> is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate <strong>2</strong> and <strong>(<em>S</em>)-(+)-2</strong>, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with <strong>(<em>R</em>)-(−)-2</strong> confirmed our previous hypothesis that only the <strong>(<em>R</em>)-(−)-2</strong> is bound in the active site of hBChE when the racemate is crystallized. The synthesis of <strong>(<em>R</em>)-2 hydrochloride</strong> has a higher overall yield (73 %) than the synthesis of racemate <strong>2 hydrochloride</strong> (64 %) and is safer as it avoids the use of LiAlH₄. <strong>(<em>R</em>)-(−)-2</strong> has <em>in vivo</em> efficacy in mice with scopolamine-induced AD-like symptoms, and <strong>(<em>R</em>)-(−)-2</strong> is less toxic in mice (LD₅₀ = 169 mg/kg) than racemate <strong>2</strong> (LD₅₀ = 112 mg/kg). These results support the chiral switch from racemate <strong>2</strong> to <strong>(<em>R</em>)-(−)-2</strong> as a safer and more selective lead compound in the anti-AD drug development pipeline.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111670"},"PeriodicalIF":4.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711147","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":"From inert to bioactive: Titanium surfaces engineered to suppress oral cancer cell proliferation and migration","authors":"Evelina Herendija ,&nbsp;Milica Jakšić Karišik ,&nbsp;Marijana R. Pantović Pavlović ,&nbsp;Miroslav M. Pavlović ,&nbsp;Olivera Mitrović-Ajtić ,&nbsp;Nenad L. Ignjatović ,&nbsp;Miloš Lazarević","doi":"10.1016/j.cbi.2025.111667","DOIUrl":"10.1016/j.cbi.2025.111667","url":null,"abstract":"<div><div>The chemical modification of the titanium implant surface altered the nature of its interactions with the biological environment. A surface was designed that transformed from anticancer-inert to highly anticancer-active against oral squamous cell carcinoma (OSCC) cells. Titanium implants were coated using a combined anodizing/anaphoretic electrodeposition process. The biological effects of coated (Ti/Coating) versus uncoated (Ti) titanium were tested on the SCC-25 cells. Apoptosis, cellular uptake, cell cycle, and intracellular ROS generation were evaluated by flow cytometry. Gene and protein expression levels related to apoptosis (<em>BAX</em>, <em>BCL2, CASP3, CASP8, CASP9</em>), proliferation (<em>Cyclin D1</em>), EMT (<em>VIM, SNAIL, SLUG, CDH1,</em> HDAC 2), and signaling pathways (AKT/mTOR, Wnt/β-catenin) were assessed via qPCR and Western blot. Migration was analyzed through a wound healing assay. The Ti/Coating system significantly reduced cell viability and induced early apoptosis without increasing necrosis. Apoptosis was associated with <em>BAX</em> upregulation and <em>BCL2</em> downregulation. Cell cycle arrest in G2/M phase was noted. ROS generation was markedly elevated, contributing to cytotoxic effects. Ti/Coating inhibited the expression of EMT-related markers (<em>VIM, SLUG, SNAIL</em>) and upregulated <em>CDH1</em>, correlating with reduced cell migration. Additionally, Ti/Coating downregulated <em>AKT</em>, <em>mTOR</em>, and <em>β-catenin</em> expression, indicating suppression of key oncogenic signaling pathways. The uncoated titanium surface showed no significant effects. The Ti/Coating system had a substantial anticancer effect on oral cancer cells by inducing apoptosis, elevating oxidative stress, and modulating EMT, cell cycle, and oncogenic signaling. These findings highlight its potential as a biologically active implant material for localized postoperative therapy in OSCC, combining structural support with preventive anticancer activity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111667"},"PeriodicalIF":4.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676850","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":"Triazolyl-indolo-quinoxaline triggers differential cell death pathways in pancreatic cancer via ROS/p38 axis","authors":"Bada Yoon ,&nbsp;Rajaghatta N. Suresh ,&nbsp;C.S. Shivakumara ,&nbsp;Kachigere B. Harsha ,&nbsp;Chakrabhavi Dhananjaya Mohan ,&nbsp;Gautam Sethi ,&nbsp;Kanchugarakoppal S. Rangappa ,&nbsp;Kwang Seok Ahn","doi":"10.1016/j.cbi.2025.111668","DOIUrl":"10.1016/j.cbi.2025.111668","url":null,"abstract":"<div><div>Pancreatic cancer is characterized by aggressive progression, rapid metastasis, and resistance to conventional therapies, resulting in poor survival outcomes. Despite significant advances in research, effective treatment options for pancreatic cancer remain limited. In this study, we investigated the mechanisms of SRN-19-induced cell death in pancreatic cancer cells. Our findings demonstrated that SRN-19 promotes both apoptosis and paraptosis. Molecular analyses confirmed the upregulation of apoptotic markers, including cleaved PARP, Bax, and caspase-9/3, along with the downregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL in both MIA PaCa-2 and AsPC-1 cells. Additionally, SRN-19 treatment led to reduced Alix expression and elevated levels of ATF4 and CHOP, markers associated with paraptosis, accompanied by alterations in mitochondrial membrane potential (MMP) in BxPC-3 cells. SRN-19 also induced a dose-dependent increase in reactive oxygen species (ROS) production and a corresponding decrease in the GSH/GSSG ratio. Pretreatment with N-acetylcysteine (NAC) attenuated ROS accumulation, restored Alix expression, and reduced cleaved PARP levels, confirming the involvement of ROS in apoptosis induction. Furthermore, SRN-19 activated the p38 MAPK pathway, and inhibition of p38 by SB203580 diminished ROS levels, reduced cleaved PARP expression, and restored MMP. Collectively, these results suggest that SRN-19 promotes ROS generation, activates the p38 MAPK pathway, and induces cell death in pancreatic cancer cells through both apoptotic and paraptotic mechanisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111668"},"PeriodicalIF":4.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676851","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":"Safety pharmacology of sibutramine analogues evaluated by in silico and in vitro biological target screening","authors":"Michael F. Santillo,&nbsp;Robert L. Sprando","doi":"10.1016/j.cbi.2025.111669","DOIUrl":"10.1016/j.cbi.2025.111669","url":null,"abstract":"<div><div>Many weight loss products marketed as foods and dietary supplements are adulterated with structurally modified versions (analogues) of sibutramine, a weight loss drug withdrawn from the market due to adverse effects in the heart and nervous system. Unlike sibutramine, its analogues lack <em>in vitro</em> and <em>in vivo</em> safety data. Therefore, to identify potential health effects of sibutramine analogues, binding was predicted and measured between sibutramine analogues and a panel of 45 safety-related biological targets (e.g., receptors, ion channels, transporters, and enzymes) related to the heart, nervous system, and other organs. Target binding concentrations (K_i) were predicted <em>in silico</em> based upon quantitative structure-activity relationship (QSAR) models and measured <em>in vitro</em> by competitive ligand binding assays. The <em>in vitro</em> and <em>in silico</em> K_i values closely agreed for transporters of serotonin (SERT), norepinephrine (NET), and dopamine (DAT), which are linked to adverse health effects in the heart and nervous system. The chloro, homo, and desmethylsibutramine analogues exhibited similar binding profiles and particularly potent binding to SERT, NET and DAT (K_i, 9–403 nM). However, despite structural similarity among the compounds, benzyl and formyl analogues exhibited weaker binding to nearly all targets evaluated (K_i, 0.447 to &gt;10 μM). Additionally, for selected analogues, target binding was predicted for metabolites; a majority of metabolites (70 %) exhibited similar binding potency (K_i within 10-fold) to their respective parent chemicals, suggesting they may also contribute to potential health effects. Overall, biological target binding profiles illustrate important structure-activity relationships among sibutramine analogues that can help identify potential adverse health effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111669"},"PeriodicalIF":4.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669111","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":"Preconception paternal exposure to zearalenone impairs male fertility and IVF embryo survival in mice","authors":"Peiwen Wang ,&nbsp;Yaxin Chen ,&nbsp;Yuan Jiao ,&nbsp;Yating Zhu ,&nbsp;Mengyao Wang ,&nbsp;Dongmei Ji ,&nbsp;Weiwei Zou ,&nbsp;Yunxia Cao ,&nbsp;Yajing Liu ,&nbsp;Dan Liang","doi":"10.1016/j.cbi.2025.111646","DOIUrl":"10.1016/j.cbi.2025.111646","url":null,"abstract":"<div><div>Zearalenone (ZEA), a fungal mycotoxin commonly found in various human foods, exhibits a structural similarity to naturally occurring estrogen, raising significant concerns regarding its reproductive toxicity. This study aimed to assess the impact of preconceptional ZEA exposure on male reproductive health and early embryonic development. Healthy B6D2F1 male mice were exposed to corn oil or varying doses of ZEA for two weeks. Our findings revealed that ZEA exposure caused a notable reduction in sperm count and motility, accompanied by significant weight loss in the high-dose group. Additionally, high-dose ZEA exposure induced oxidative stress, mitochondrial dysfunction, and activation of the ERK and p38 MAPK signaling pathways. Furthermore, preconception paternal exposure to ZEA adversely affected <em>in vitro</em> fertilization (IVF) outcomes. Specifically, male mice exposed to high-dose ZEA exhibited significantly reduced fertilization rates and impaired embryonic development, resulting in embryonic arrest. Metabolic assessment of blastocysts demonstrated elevated levels of reactive oxygen species (ROS) and a pronounced decrease in mitochondrial membrane potential (MMP), indicating compromised developmental potential in blastocysts derived from sperm of ZEA-exposed males. In conclusion, this study highlights that high-dose ZEA exposure induces testicular damage, disrupts mitochondrial function, impairs early embryo quality post-IVF, and activates the p38/ERK MAPK signaling pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111646"},"PeriodicalIF":4.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669110","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":"Decabromodiphenyl ether (BDE-209) induces learning and memory impairment via JAK2/STAT3/NLRP3 axis-mediated pyroptosis and neuroinflammation","authors":"Liujiangshan Jiang ,&nbsp;Jing Yang ,&nbsp;Haonan Ma ,&nbsp;Yapei Zhu ,&nbsp;Xuan Zhao ,&nbsp;Bin Xu ,&nbsp;Tianyao Yang ,&nbsp;Wei Liu","doi":"10.1016/j.cbi.2025.111665","DOIUrl":"10.1016/j.cbi.2025.111665","url":null,"abstract":"<div><div>Decabromodiphenyl ether (BDE-209), a brominated flame retardant widely used in electronics and construction materials, has garnered significant attention due to its environmental persistence and potential health hazards. However, research on the neurotoxic effects of flame retardants is limited, and the molecular mechanisms underlying BDE-209 neurotoxicity are not fully understood. Neuroinflammation, as a key pathway in the pathological progression of neurological disorders, has received extensive attention. This study aimed to elucidate the molecular mechanisms underlying BDE-209-induced neurotoxicity, with a specific focus on pyroptosis, a form of programmed cell death closely linked to neuroinflammation. Using both in vivo mouse models and in vitro HT22 hippocampal neuron cultures, we found that BDE-209 exposure caused significant cognitive deficits in mice and activated the classical pyroptosis pathway in the hippocampus. Further analysis revealed that BDE-209 activated the JAK2/STAT3 pathway and the NLRP3 inflammasome, triggering pyroptotic cell death in HT22 neurons. Remarkably, pharmacological inhibition of NLRP3 with MCC950 and blockade of JAK2/STAT3 signaling with AG490 significantly attenuated pyroptosis, highlighting the therapeutic potential of targeting these pathways. Collectively, our findings provide new insights into the neurotoxic effects of BDE-209, demonstrating that it induces NLRP3-mediated pyroptosis through the JAK2/STAT3 axis. This study enhances our understanding of BDE-209 neurotoxicity and highlights possible intervention strategies to mitigate its harmful effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111665"},"PeriodicalIF":4.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661263","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":"Ubiquitination: A non-negligible modulator in doxorubicin-induced cardiotoxicity","authors":"Can Gao ,&nbsp;Changxu Lu ,&nbsp;Jinwen Wei ,&nbsp;Zhongyi Mu ,&nbsp;Mingli Sun ,&nbsp;Dan Dong ,&nbsp;Zhenning Liu","doi":"10.1016/j.cbi.2025.111664","DOIUrl":"10.1016/j.cbi.2025.111664","url":null,"abstract":"<div><div>Doxorubicin (DOX), an effective chemotherapeutic drug, is used to alleviate the progression of cancers. However, the cardiotoxic side effects of DOX significantly limit its broader clinical application. Therefore, it is extremely urgent to find effective therapeutic strategies to mitigate doxorubicin-induced cardiotoxicity (DIC). Ubiquitination, a crucial post-translational modification (PTM), is regulated by various ubiquitinases and subsequently marks and modulates the function of proteins. Notably, Numerous studies have found that ubiquitination is closely related to the progression of DIC. However, a comprehensive review of this field remains unreported. Therefore, this review will mainly summarize the critical role of ubiquitination in DIC-associated pathological mechanisms and various potential interventions. Collectively, a comprehensive understanding of ubiquitination in the progression of DIC contributes to providing a crucial theoretical basis and exploring new avenues for the management of DIC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111664"},"PeriodicalIF":4.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661264","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":"The association between exposure to phthalates and cardiovascular disease: A comprehensive study utilizing NHANES data from 2005 to 2018 and network toxicology","authors":"Wei Gong ,&nbsp;Hongyan Zhu ,&nbsp;Xinran Sun ,&nbsp;Jinxiu Zhang ,&nbsp;Meiyun Lin ,&nbsp;Peng Sun","doi":"10.1016/j.cbi.2025.111651","DOIUrl":"10.1016/j.cbi.2025.111651","url":null,"abstract":"<div><div>Phthalates are widely recognized endocrine-disrupting chemicals. This study investigates the association between phthalate exposure and cardiovascular disease (CVD), with a particular focus on elucidating the underlying molecular mechanisms. First, an epidemiological analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005–2018 to assess the relationship between phthalate metabolites and CVD. Generalized linear models (GLM) and weighted quantile sum (WQS) regression were employed to evaluate the impact of phthalate exposure. Among 12,127 participants, 1301 were diagnosed with CVD. The results showed a significant positive association between phthalate mixtures and CVD prevalence. GLM analysis identified MECPP, MEHHP, MEOHP, and MBzP as independent predictors of CVD (<em>P</em> &lt; 0.05). WQS regression further demonstrated that the phthalate metabolite mixture exposure index was associated with CVD (OR = 1.21, 95 % CI: 1.07–1.37, <em>P</em> = 0.002), highlighting MEOHP, MECPP, MBzP, and MnBP as key contributors. Subgroup analysis revealed that these associations were strongest among individuals aged ≥60 years, females, and during the 2013–2014 NHANES cycle. To further explore the potential molecular mechanisms, we conducted a network toxicology analysis. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape 3.9.1 to identify key molecular targets associated with phthalate-induced CVD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that phthalate-induced CVD is linked to neuroactive ligand-receptor interactions, GABAergic synapses, the PI3K-Akt and JAK-STAT signaling pathways, and calcium signaling. Among 29 identified CVD-related targets, seven core targets (GABRA3, GABRG2, GABRA5, GABRA2, BCL2, CCND2, and PIK3CA) were strongly implicated in phthalate-induced cardiovascular toxicity. Molecular docking analysis further confirmed strong binding affinities between phthalate metabolites and key targets, particularly GABRA5, PIK3CA, and BCL2. This study provided robust evidence linking phthalate exposure to CVD and suggests that phthalate-induced cardiovascular toxicity may involve neuroactive signaling, apoptosis, and inflammation-related mechanisms. These findings offered valuable insights for future research and potential therapeutic strategies in environmental health and CVD prevention.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111651"},"PeriodicalIF":4.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144628101","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 anticancer inhibitors targeting the PI3K/Akt/mTOR signaling route and apoptosis inducers: A study on the apoptosis mechanism via the intrinsic mitochondrial-mediated pathway","authors":"Digambar Yevale ,&nbsp;Viralkumar Buha ,&nbsp;Deepkumar U. Sangani ,&nbsp;Nishith Teraiya ,&nbsp;Chetan B. Sangani ,&nbsp;Nishant Patel","doi":"10.1016/j.cbi.2025.111635","DOIUrl":"10.1016/j.cbi.2025.111635","url":null,"abstract":"<div><div>The PI3K/Akt/mTOR pathway is a key target for cancer due to its essential role in cell proliferation. This study developed quinoline compounds as a potent PI3Kδ/mTOR inhibitor and apoptosis inducer. The investigation found that <strong>6i</strong> had the highest cytotoxicity against Raji and HeLa cells, with IC_50s values of 0.18μM and 0.39μM, respectively. Further, <strong>6i</strong> demonstrated substantial selectivity against dual targets PI3Kδ (IC₅₀ = 0.034μM) and mTOR (IC₅₀ = 0.047 μM). The kinase assay discovered that <strong>6i</strong> had a greater selectivity for PI3Kδ/mTOR compared to PI3Ks (α, β, and γ). Molecular investigation revealed that <strong>6i</strong> significantly reduced phosphorylated p-PI3K, p-Akt and p-RPS6 levels in Western blot, confirming PI3K/Akt/mTOR as the pathway of action. In addition, compound <strong>6i</strong> stopped the cell cycle at the G0/G1 phase and raised total apoptosis by 16.26%. These findings were substantiated by morphological alterations in the AO/EB staining. Furthermore, <strong>6i</strong>-treated cells increased intracellular ROS levels and reduced mitochondrial membrane polarization in a dose-dependent manner, indicating that apoptosis was mediated by a mitochondrial route. In addition, higher levels of Bax, Bax/Bcl-2 ratio, and cytochrome c also corroborated the fact that apoptosis was mediated <em>via</em> mitochondrial pathway. Also, treatment of compound increased fraction of caspase-3, caspase-9, and PARP-1 (excluding caspase-8), indicating that apoptosis was mediated <em>via</em> the intrinsic route. Besides, <em>in silico</em> studies had validated the anticancer effects of inhibiting PI3Kδ/mTOR. Moreover, <strong>6i</strong> demonstrated a promising safety profile in hERG assay. Taken together, our finding suggest that <strong>6i</strong> may be a potential candidate for further in vivo investigation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111635"},"PeriodicalIF":4.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144628100","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}