Chemico-Biological Interactions最新文献

{"title":"Natural lignan justicidin A-induced mitophagy as a targetable niche in bladder cancer","authors":"Kai-Hsun Chang ,&nbsp;Hsin-Chih Chen ,&nbsp;Ching-Ying Chen ,&nbsp;Shu-Ping Tsai ,&nbsp;Man-Yuan Hsu ,&nbsp;Pao-Yuan Wang ,&nbsp;Shan-Ying Wu ,&nbsp;Chun-Li Su","doi":"10.1016/j.cbi.2025.111723","DOIUrl":"10.1016/j.cbi.2025.111723","url":null,"abstract":"<div><div>Accumulated dysfunctional mitochondria are involved in tumorigenesis, and it is conceivable that mitophagy, a selective form of autophagic degradation of mitochondria, plays a tumor-suppressive role. Our bioinformatics analysis identified lignan justicidin A (JA) as a potential mitophagy inducer. In <em>HRAS</em>-mutant human bladder cancer T24 cells, JA reduced population cell growth, changed mitochondrial membrane potential, and induced autophagy. JA-induced mitophagy was demonstrated by a reduction of mitochondrial puncta by confocal microscopy and co-localization of autophagy marker LC3 and mitochondrial matrix protein HSP60 in the autophagic vesicles by electron microscopy. These phenomena were associated with altered mitochondrial dynamics, increased expressions of HIF-1α and its target gene BNIP3, and induced co-immunoprecipitation of LC3 with BNIP3 homo-dimer. Confocal microscopy further observed co-localizations among puncta of LC3, BNIP3, and HSP60. JA raised BNIP3 expression in T24 but not E7 (<em>HRAS</em> wild-type) and induced stronger autophagy in T24 than in E7 cells, indicating JA preferentially caused BNIP3-mediated mitophagy in urinary tract cells with oncogenic HRAS. Furthermore, JA enhanced cytotoxicity of T24 cells to anti-cancer drugs cisplatin combined with gemcitabine. Analyses of patients’ data further showed that, in contrast to other major cancer types, lowered mitophagy in bladder urothelial carcinoma compared with normal tissues and reduced expression of mitochondrial genes in cisplatin-responsive bladder cancer cells compared with non-responsive cells suggest mitophagy acts as a tumor suppressor to avoid cisplatin resistance in bladder cancer. Overall, our data suggest the role of BNIP3 and mitophagy in anti-cancer mechanism of human bladder cancer with <em>HRAS</em> mutation in response to JA.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111723"},"PeriodicalIF":5.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007004","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":"YY1 lactylation promotes fibroblast senescence by targeting the PU.1-BTG2 axis to promote oral submucous fibrosis","authors":"Muhammad Tufail ,&nbsp;Jing Zhang ,&nbsp;Cai-Yun He ,&nbsp;Jia-Ju Hu ,&nbsp;Jie Liang ,&nbsp;Wen-Dong Wan ,&nbsp;Yu-Qi Huang ,&nbsp;Zhen Rao ,&nbsp;Hong Wu ,&nbsp;Can-Hua Jiang ,&nbsp;Ning Li","doi":"10.1016/j.cbi.2025.111716","DOIUrl":"10.1016/j.cbi.2025.111716","url":null,"abstract":"<div><div>Oral submucous fibrosis (OSF) is a chronic fibrotic disease common in Asia-Pacific regions and strongly linked to long-term areca nut chewing. Fibroblast senescence is known to contribute to tissue fibrosis, but the molecular mechanisms behind it remain unclear. In this study, we explored how arecoline, a key component of areca nut, influences fibroblast behavior. Specifically, human oral fibroblasts were treated with 100 μM arecoline, which significantly increased the expression of the transcription factor PU.1(Purine-rich box 1) (∼3.5-fold mRNA, ∼3-fold protein). Notably, overexpression of PU.1 (encoded by SPI1) enhanced collagen production, while its inhibition reduced fibrotic markers. To further investigate, RNA sequencing and bioinformatics analysis identified BTG2 (B-cell Translocation Gene 2) as a downstream target of PU.1. Moreover, ChIP-qPCR confirmed PU.1 binding to the BTG2 promoter. Further assays, including western blotting, immunofluorescence, and SA-β-gal staining, showed that the PU.1-BTG2 axis promoted fibroblast senescence and collagen accumulation. Moreover, further analysis revealed that arecoline-treated fibroblasts produced more lactate, which led to increased lactylation of the transcription factor YY1(Yin Yang 1). Interestingly, YY1 was found to enhance PU.1-BTG2 transcription and drive fibrotic responses. Critically, mutation of YY1 at lysine 183 blocked its lactylation and eliminated its ability to activate PU.1 and BTG2. Finally, an arecoline-exposed OSF mouse model validated key in vivo aspects of this pathway, supporting its physiological relevance. Overall, we demonstrate that lactylated YY1 promotes fibroblast senescence and collagen deposition by activating the PU.1-BTG2 axis. This newly identified mechanism highlights potential therapeutic targets for treating OSF.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111716"},"PeriodicalIF":5.4,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926568","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":"Reprogramming the hepatic immune microenvironment with mirtazapine in early neoplastic transformation: Evidence from a diethylnitrosamine-induced rat model","authors":"Elsayed A. Elmorsy ,&nbsp;Sameh Saber ,&nbsp;Ahmad H. Alhowail ,&nbsp;Abousree T. Ellethy ,&nbsp;Enas A. Mohamed ,&nbsp;Hamad Alsaykhan ,&nbsp;Hatim Y. Alharbi ,&nbsp;Omar Almansour ,&nbsp;Abdelrahman El-Sayed ,&nbsp;Manal Mohamed Hatem ,&nbsp;Ahmed Kaid Alantry ,&nbsp;Walaa A. Allam ,&nbsp;Asmaa Ramadan ,&nbsp;Mohamed A.M. Ali ,&nbsp;Ahmed Gaafar ,&nbsp;Sarah Abu-Sham ,&nbsp;Mostafa M. Khodeir","doi":"10.1016/j.cbi.2025.111720","DOIUrl":"10.1016/j.cbi.2025.111720","url":null,"abstract":"<div><div>Hepatic neoplastic transformation is a multistep process driven by chronic inflammation, oxidative stress, immune evasion, and dysregulated cell proliferation. Intercepting these early events may offer a viable strategy for preventing hepatocellular carcinoma. In this study, we investigated the chemopreventive potential of mirtazapine, an FDA-approved antidepressant with known anti-inflammatory and antioxidant properties, in a diethylnitrosamine-induced rat model of early hepatic neoplasia. Mirtazapine significantly attenuated hepatotoxicity, reducing serum transaminases, oxidative stress markers, and restoring antioxidant defenses. Histopathological evaluation revealed that mirtazapine markedly reduced the incidence of foci of altered hepatocytes (FAH), nuclear atypia, and inflammatory infiltration. Our results showed enhanced infiltration and tissue levels of CD4⁺ and CD8⁺ T cells, along with upregulation of Th1/Th17 cytokines (IFN-γ, IL-2, IL-12, IL-17) and the chemokine CXCL10, alongside suppression of immunosuppressive mediators (IL-10, TGF-β, sCD163). Additionally, mirtazapine downregulated pro-inflammatory cytokines IL-6 and TNF-α, promoted macrophage recruitment (CD68), and shifted polarization toward an M1-like phenotype, as evidenced by increased iNOS expression. Mirtazapine also inhibited pro-proliferative and angiogenic markers (Ki67, Cyclin D1, VEGF, MMP-2), reactivated apoptotic pathways (Bax, caspase-3, p53), and suppressed oncogenic STAT3 and ERK1/2 signaling. Correlation and disease prediction analyses identified immune activation markers as strong negative predictors of FAH burden. Importantly, systems biology and network analysis confirmed these findings by demonstrating that mirtazapine modulates key immune-regulatory networks, particularly those governing T cell responses, cytokine signaling, and macrophage polarization, thus mechanistically validating its immunomodulatory and anti-tumor effects. These results highlight mirtazapine's potential for repurposing as a chemopreventive agent in inflammation-driven hepatic neoplasia.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111720"},"PeriodicalIF":5.4,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912617","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":"Larvicidal mechanism of the rare sesquiterpene ishwarol B from Piper alatipetiolatum (Piperaceae) against Aedes aegypti, Anopheles darlingi, and Culex quinquefasciatus (Culicidae): oxidative damage, defense enzyme modulation, and acetylcholinesterase inhibition","authors":"André Correa de Oliveira ,&nbsp;Felipe Moura Araujo da Silva ,&nbsp;Ingrity Suelen Sá ,&nbsp;Maria Luiza Lima da Costa ,&nbsp;Sergio Massayoshi Nunomura ,&nbsp;Rosemary Aparecida Roque ,&nbsp;Rita de Cássia Saraiva Nunomura","doi":"10.1016/j.cbi.2025.111719","DOIUrl":"10.1016/j.cbi.2025.111719","url":null,"abstract":"<div><div>Dengue, Oropouche, lymphatic filariasis, and malaria remain serious public health problems in Brazil, transmitted by <em>Aedes aegypti</em>, <em>Culex quinquefasciatus</em>, and <em>Anopheles darlingi</em> resistant to pyrethroid insecticides. As alternatives, plant-derived natural insecticides have gained attention for their potential. In this study, we evaluated ishwarol B for its larvicidal activity and explored its mechanism of action against these mosquitoes. Ishwarol B exhibited larvicidal activity against all larvae (LC₅₀ from 19.57 to 26.23 μg/mL) and a residual effect of approximately 50 % observed, accompanied by increased production of H₂O₂ (24.3 ± 5 to 41.0 ± 5 μmol of H₂O₂ per gram⁻¹), lipid peroxidation (11.00 ± 2 to 22.67 ± 2 ηmol of MDA per gram⁻¹), and protein oxidation (10.00 ± 1 to 17.00 ± nM of reactive carbonyls/mg protein). Additionally, there was an increase in the activity of SOD (14.33 ± 2 to 14.67 ± 8 mU/mg protein), CAT (10.47 ± 9 to 11.23 ± 1 mmol of H₂O₂ consumed/min/mg of protein), and GPx (11.91 ± 1 to 16.46 ± 2 mmol NADPH/min/mL). In contrast, AChE activity decreased (8.33 ± 1 to 6.67 ± 2 μmol/min/mg of protein), compared to negative control DMSO (105.30 ± 2 to 111.30 ± 3 μmol μmol/min/mg of protein), indicating enzymatic inhibition, further confirmed by an inhibition from 100 ± 0 to 4.41 ± 2 % (IC₅₀ of 3.46 μg/mL). Molecular docking revealed a binding energy of −8.4 kcal/mol and Ki = 0.695 μM, indicating a favorable interaction between ishwarol B and the AChE active site including Trp441, Tyr493, Tyr494, Ser280, Phe449, Ile446, Leu444, Gly445, Pro450, and Cys447. These findings confirm the broad mechanism of action of ishwarol B, highlighting its potential as a natural larvicide against the mosquito vectors investigated.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111719"},"PeriodicalIF":5.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896684","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 aryloxy-hydrazone-thiazoles: Design, synthesis, ADMET prediction and antifungal activity against Sporothrix spp.","authors":"Vanessa Gouveia de Melo Silva ,&nbsp;Bruna Rodrigues de Sousa ,&nbsp;Débora Lopes de Santana ,&nbsp;Robert da Silva Tibúrcio ,&nbsp;Lucas Manoel da Silva Sousa ,&nbsp;Graziella Leite Brondani ,&nbsp;Vanessa Soares Sales ,&nbsp;Policarpo Ademar Sales Junior ,&nbsp;Valéria Rêgo Alves Pereira ,&nbsp;Danielle Patrícia Cerqueira Macêdo ,&nbsp;Reginaldo Gonçalves de Lima-Neto ,&nbsp;Ana Cristina Lima Leite","doi":"10.1016/j.cbi.2025.111715","DOIUrl":"10.1016/j.cbi.2025.111715","url":null,"abstract":"<div><div>Sporotrichosis is an emerging fungal infection caused by species of the genus <em>Sporothrix</em>. Itraconazole is the first-line treatment for cutaneous sporotrichosis; however, there is a growing number of strains resistant to this drug. Recently, acylhydrazone derivatives have demonstrated activity against itraconazole-resistant sporotrichosis cases, and thiazole derivatives have emerged as promising antifungal agents. These findings led us to investigate twenty aryloxy-hydrazone-thiazoles against <em>Sporothrix</em> spp. <em>In vitro</em> antifungal testing showed that among the aryloxy-hydrazone-thiazoles (<strong>1–20</strong>), compounds <strong>1</strong>, <strong>2</strong>, <strong>5</strong>, <strong>6</strong>, and <strong>8</strong> exhibited significant activity, with minimum inhibitory concentration values below 2 μg/mL against strains <em>S. brasiliensis, S. mexicana</em> and <em>S. chilensis</em>. Compounds <strong>1</strong>, <strong>2</strong>, and <strong>5</strong>, in particular, demonstrated MICs ≤2 μg/mL across all tested species and inhibited biofilm formation in both yeast-like and filamentous forms of <em>S. brasiliensis</em> more effectively than itraconazole and amphotericin B. These compounds were also capable of eradicating mature biofilms, especially in the filamentous phase. Itraconazole could not achieve. Molecular docking studies were performed to analyze intermolecular interactions and evaluate the phenoxy-1,3-thiazole derivatives as potential inhibitors of CYP51. It was observed that compounds <strong>1</strong>, <strong>2</strong> and <strong>5</strong> which exhibited MICs ≤2 μg/mL for all tested <em>Sporothrix</em> species, shared common intermolecular interactions with itraconazole, the co-crystallized ligand. In silico ADME analysis showed that compounds <strong>1</strong>–<strong>20</strong> meet at least two of Lipinski's and Veber's criteria for drug-likeness, and cytotoxicity tests indicated low toxicity to L929 cells. These data suggest that aryloxy-hydrazone-thiazoles possess promising properties that position them as candidates for new antifungal agents.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111715"},"PeriodicalIF":5.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917350","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":"Modeling skin sensitization: hierarchical support vector regression−based prediction of lysine depletion in DPRA","authors":"Giang H. Ta ,&nbsp;Max K. Leong","doi":"10.1016/j.cbi.2025.111714","DOIUrl":"10.1016/j.cbi.2025.111714","url":null,"abstract":"<div><div>Skin sensitization is a critical endpoint in toxicology, especially in the context of drug discovery and development process for topical and transdermal treatments. Accurate evaluation of skin sensitization potential is essential to ensure the safety and efficacy of new compounds before their incorporation into commercial products. In this study, a quantitative structure−activity relationship (QSAR) model employing a hierarchical support vector regression (HSVR) scheme was developed to quantitatively predict the percentage of lysine depletion measured by the Direct Peptide Reactivity Assay (DPRA) that is one of the keys factors used to identify the skin sensitization potential of chemical compounds. The results demonstrated that the HSVR model produced accurate and consistent predictions across the training, test, and outlier sets, underscoring its robustness and reliability across various datasets. Moreover, the HSVR model showed outperformed other available models in terms of predictive accuracy. These findings highlight the potential of computational modeling as a rapid, cost−effective, and ethically sound alternative to traditional methods. This advancement represents a significant contribution to safer product development in the cosmetic and pharmaceutical industries.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111714"},"PeriodicalIF":5.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903957","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":"Identification of mechanisms underlying ventilatory dysfunction in organophosphorus chemical warfare agent-exposed mice","authors":"Marilène Trancart ,&nbsp;Nicolas Taudon ,&nbsp;Mylène Penot ,&nbsp;Gwladys Meesemaecker ,&nbsp;Anne-Sophie Hanak ,&nbsp;André-Guilhem Calas","doi":"10.1016/j.cbi.2025.111713","DOIUrl":"10.1016/j.cbi.2025.111713","url":null,"abstract":"<div><div>Chemical warfare nerve agents (CWNA), such as VX, pose significant threats due to their profound impact on vital physiological systems. The primary concern is the risk of respiratory failure resulting from cholinergic dysregulation, a signaling pathway crucial for ventilatory function regulation. This study aims to elucidate the key mechanisms underlying the induction of respiratory failure in mice following sub-lethal VX exposure in order to optimize therapeutic management. We evaluated candidate compounds targeting cholinergic signaling pathways associated with the CWNA poisoning toxidrome or implicated in respiratory disorders with similar symptoms (e.g., asthma or opioid overdose). The efficacy of these compounds in preventing ventilatory abnormalities induced by subcutaneous exposure to 0.9 LD₅₀ of VX was assessed using dual-chamber plethysmography, and survival tests were conducted to confirm their therapeutic effectiveness. Among all the pathways evaluated, only the muscarinic pathway appeared to be involved, with atropine, a standard muscarinic receptor (mAChR) antagonist, which effectively preserved respiratory function by reducing VX-induced bronchoconstriction and preventing respiratory depression. Methylatropine, a peripheral mAChR antagonist that does not cross the blood-brain barrier (BBB), also limited bronchoconstriction but failed to prevent respiratory depression, suggesting that bronchoconstriction is not the primary determinant of this respiratory toxidrome. Surprisingly, tiotropium, a selective M3 mAChR antagonist that also does not cross the BBB, exhibited similar effects to those of atropine. Antagonizing muscarinic pathway overstimulation thus emerges as a key strategy for managing respiratory depression and improving survival outcomes in CWNA-poisoned individuals.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111713"},"PeriodicalIF":5.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920236","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":"Palmitate-induced hepatic insulin resistance as an in vitro model for natural and synthetic drug screening: A scoping review of therapeutic candidates and mechanisms","authors":"Bruno Quintanilha Faria ,&nbsp;Patricia Sthefani Calixto ,&nbsp;Geraldo Picheth ,&nbsp;Luana Mota Ferreira ,&nbsp;F.G.M. Rego ,&nbsp;J.F.C. Guerra ,&nbsp;Marcel Henrique Marcondes Sari","doi":"10.1016/j.cbi.2025.111717","DOIUrl":"10.1016/j.cbi.2025.111717","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance (IR) and β-cell dysfunction, often exacerbated by excessive intake of saturated fatty acids, particularly palmitic acid (PA). As the most abundant saturated fatty acid in Western diets, PA contributes to metabolic dysregulation by inducing mitochondrial dysfunction, enhancing reactive oxygen species (ROS) generation, activating inflammatory pathways, and impairing insulin signaling in hepatocytes. Consequently, PA-induced hepatic IR has become a widely accepted <em>in vitro</em> model for investigating therapeutic strategies to restore insulin sensitivity. This scoping review aims to identify and summarize natural and synthetic compounds evaluated in this model, emphasizing mechanisms of action and highlighting research gaps. A total of 78 eligible studies were selected through a systematic search of PubMed, Scopus, and Web of Science. Most studies employed HepG2 cells and adopted co-incubation or post-treatment protocols to simulate preventive or therapeutic contexts. Natural compounds predominate, particularly polyphenols, flavonoids, alkaloids, and plant extracts. Reported mechanisms involved activation of insulin signaling pathways (phosphoinositide 3-kinase/protein kinase B [PI3K/Akt], adenosine monophosphate-activated protein kinase [AMPK]), attenuation of oxidative stress (reduced ROS and malondialdehyde [MDA], increased superoxide dismutase [SOD] and catalase [CAT]), inhibition of inflammatory mediators (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], nuclear factor kappa B [NF-κB]), and regulation of apoptosis (caspase-3, Bcl-2-associated X protein/B-cell lymphoma 2 [BAX/Bcl-2]). Overall, this model provides a robust and translationally relevant platform for screening bioactive compounds targeting multiple pathological features of T2DM.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111717"},"PeriodicalIF":5.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903873","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 underexplored pulmonary toxicity of pyrrolizidine alkaloids: Emerging hazard from food contamination","authors":"Caibin Zhang ,&nbsp;Zijing Song ,&nbsp;Yuxuan Zhao ,&nbsp;Xiaokai Guo ,&nbsp;Tianyang Huang ,&nbsp;Yihang Guo ,&nbsp;Jiang Ma ,&nbsp;Chengliang Zhang ,&nbsp;Jihang Chen ,&nbsp;Yisheng He","doi":"10.1016/j.cbi.2025.111709","DOIUrl":"10.1016/j.cbi.2025.111709","url":null,"abstract":"<div><div>Pyrrolizidine alkaloids (PAs) are the most widespread plant-derived toxins globally. Humans are frequently exposed to PAs through ingestion of PA-contaminated food products, with chronic dietary exposure estimated at up to 48.4 ng/kg body weight/day, posing a significant global health threat. Aside from the well-documented hepatotoxicity, dietary exposure to PAs is strongly implicated in the development of pulmonary arterial hypertension (PAH), a serious and often fatal disease with limited treatment options. However, the underlying molecular mechanisms remain poorly defined. This review provided updated information of PA contamination in representative food and herbal products. For PAs’ characterized toxic effects on pulmonary vasculature, our review shifts previous focus from downstream pathological processes to the etiological role of dietary PA exposure in PAH development. The activation of pulmonary arterial endothelial cells (PAECs), together with vasoconstriction, inflammation, and vascular remodeling, is recognized as an early event in PAH pathogenesis. Subsequently, activated immune cells, platelets, and dysfunctional PAECs release a complex array of growth factors, inducing pulmonary vascular remodeling and PAH progression. By reviewing intoxication targets and molecular pathways, we propose potentially novel therapeutic targets for dietary PA-related PAH. Given the ubiquitous distribution in the global food chain and their underexplored link to cardiopulmonary disease, we also provide perspectives and outlooks of preventive strategies and targeted interventions.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111709"},"PeriodicalIF":5.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896685","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":"Artemisinin toxicity in HepG2 liver carcinoma cells is linked to protein network in host and molecular interactions with cellular drug targets","authors":"Eena Dodwani,&nbsp;Vishal Trivedi","doi":"10.1016/j.cbi.2025.111707","DOIUrl":"10.1016/j.cbi.2025.111707","url":null,"abstract":"<div><div>Artemisinin treatment at high concentration or prolonged period is exhibiting severe toxicity in liver, kidney and cardio toxicity. Artemisinin is killing HepG2 liver carcinoma cells with an IC₅₀ of 17.33 ± 2.64 μM and cells are showing distorted morphology with appearance of holes on the cell surface. The cells are leaky and releasing the marker enzymes into the culture supernatant. Surprisingly, Artemisinin is inhibiting cell migration potentials in a dose-dependent manner. Drug Bank and Swiss target prediction indicate that the drug molecule is interacting with 118 protein nodes recognizing different pharmacological sites on the molecule. Gene ontology enrichment analysis indicate presence of protein belonging to 266 biological processes, 68 cellular components and 90 molecular functions. KEGG analysis predicts off-target proteins to disrupt cell-cycle, apoptosis, autophagy and other biological pathways. The protein-protein interaction network comprises 104 nodes and 30 edges. Artemisinin is fitting into these proteins and Artermisnin-protein complex is stable under the molecular dynamic simulation. Cells treated with Artemisinin is exhibiting disturbance of cell-cycle, apoptosis following intrinsic pathway and modulation of cyclin D1, activation of MLKL, caspase-8, caspase-3 and degradation of PARP. Artemisinin is curing malaria but current study highlight the importance of off-target effects to understand the liver toxicity in patients.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111707"},"PeriodicalIF":5.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903874","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}