Chemico-Biological Interactions最新文献

{"title":"Simplified assessment of acetylcholinesterase inhibition by environmental organophosphorus pesticides","authors":"Ruihong Zhu ,&nbsp;Yiyun Liu ,&nbsp;Yongchao Ma ,&nbsp;Tong Xu ,&nbsp;Guanglei Yang ,&nbsp;Antonio Zandona ,&nbsp;Tena Čadež ,&nbsp;Zrinka Kovarik ,&nbsp;Heidi Qunhui Xie ,&nbsp;Li Xu ,&nbsp;Bin Zhao","doi":"10.1016/j.cbi.2025.111722","DOIUrl":"10.1016/j.cbi.2025.111722","url":null,"abstract":"<div><div>Environmental contaminants, such as pesticides, can inhibit the enzymatic activity of acetylcholinesterase (AChE), an enzyme necessary for neurotransmission. The inhibitory effects of structurally diverse pesticides on AChE may result from either reversible or covalent interactions. Therefore, assessing their potency typically requires different assay design to determine either dissociation constants or rate constants, respectively. To avoid complex kinetic experiments and enable comparison of potencies across structurally diverse pesticides, we optimized an AChE inhibitor detection system using an endpoint Ellman assay in 96-well plates. Given the significant interspecies variability in sensitivity to inhibitors, we investigated AChE inhibition using both electric eel AChE (eeAChE) and human AChE (hAChE). After confirming the repeatability, reproducibility, and solvent compatibility of the detection system using the reversible inhibitor BW284c51, we determined the inhibition potency of selected organophosphorus (OP) pesticides based on IC₅₀ values. We found that chlorpyrifos, fenamiphos and ethoprophos were more potent inhibitors of hAChE than eeAChE. In contrast, phosalone and methamidophos showed similar inhibitory effects on both enzymes. The potencies aligned well with previously reported inhibitory rate constants. In conclusion, since OPs acts as progressive inhibitors of AChE, our optimized assay offers a simplified yet effective method for assessing their inhibitory potency. It also allows for comparative evaluation of various environmental pollutants based solely on IC₅₀ values, eliminating the need for complex kinetic studies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111722"},"PeriodicalIF":5.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006923","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":"Formoterol, a clinically approved drug, inhibits ferroptosis by suppressing lipid peroxidation and attenuates APAP-induced acute liver injury","authors":"Lin-Song Teng ,&nbsp;Zhen-Dong Ying ,&nbsp;Xiao-Han Sun ,&nbsp;Hao-Cheng Hou ,&nbsp;Shi-Dong Qiu ,&nbsp;Peng Liu ,&nbsp;Ke-Jing Li ,&nbsp;Lei Zhang ,&nbsp;Xie-Huang Sheng","doi":"10.1016/j.cbi.2025.111724","DOIUrl":"10.1016/j.cbi.2025.111724","url":null,"abstract":"<div><div>Ferroptosis is an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation and implicated in various human diseases. Despite intensive research, clinically applicable ferroptosis inhibitors remain unavailable. In this study, we identify formoterol, a β₂-adrenergic agonist widely used to treat asthma and COPD, as a potent and selective ferroptosis inhibitor through scaffold-based screening of FDA-approved drugs. Formoterol confers robust protection against ferroptotic cell death induced by diverse triggers across multiple human and rodent cell lines, functioning independently of classical pathways such as GPX4, FSP1, or iron chelation. Mechanistic studies reveal that formoterol suppresses ferroptosis by directly scavenging lipid peroxyl radicals, mediated by its unique <em>ortho</em>-amino phenol moiety. <em>In vivo,</em> formoterol significantly alleviates acetaminophen-induced acute liver injury, reducing hepatic lipid peroxidation and preserving tissue integrity. These findings establish formoterol as a clinically approved agent with previously unrecognized anti-ferroptotic activity, offering a compelling example of drug repurposing to accelerate the development of ferroptosis-targeted therapies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111724"},"PeriodicalIF":5.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003523","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":"Paraquat induced neuro-immunotoxicity: Dysregulated microglial antigen processing and mitochondrial activated mechanisms","authors":"Ge Shi ,&nbsp;Kaidong Wang ,&nbsp;Qi Liu ,&nbsp;Chenyang Wu ,&nbsp;Qianrong Zhang ,&nbsp;Yuan Ma ,&nbsp;Ai Qi ,&nbsp;Min Huang","doi":"10.1016/j.cbi.2025.111721","DOIUrl":"10.1016/j.cbi.2025.111721","url":null,"abstract":"<div><div>Paraquat (PQ) is characterized by neurotoxicity. In daily life, PQ exposure mainly occurs through chronic and trace pathways, which induce progressive neuronal damage or neuronal synaptic loss. Previously, mitochondrial dysfunction was a critical underlying mechanism. Emerging evidence suggests that neuroinflammation mediated by microglial activation and T-cell infiltration may trigger accelerated neuronal degeneration. While antigen presentation constitutes an essential prerequisite for T-cell infiltration and functional activation, the potential association between mitochondrial impairment and microglial antigen presentation dysregulation remains unexplored. In this study, we initially identified paraquat-associated target gene clusters from the CTD database. Following the enrichment analyses of GO and KEGG revealed Parkinson's disease pathways and mitochondrial processes. Further, we constructed a time-dependent model for C57BL/6J (♂) mice continuously treated with PQ (1.25 mg/kg) once/day to imitate early-stage neurotoxicity. For mice, neurobehavioral symptoms showed a decrease in learning and memory abilities. Pathologically, the neuroinflammatory response dominated by microglial activation and T-cell infiltration preceded observable synaptic loss. This correlated with microglial two distinct processes: 1) upregulated surface chemokine expression (CCL2, CCL3, CCL4, CCL5), and 2) enhanced antigen recognition, phagocytosis, and presentation machinery (TLR4, LAMP2, MHC II), facilitating CD4⁺/CD8⁺ T-cell recruitment. Notably, α-synuclein aggregates may act as antigens triggering microglial mitochondrial stress responses, as evidenced by altered expression of mitochondrial proteases (LONP1, CLPP, HTRA2). Remarkably, resveratrol effectively restored BV-2 microglial mitochondrial homeostasis and normalized antigen presentation. This study demonstrated that microglial mitochondrial dysregulation mediates aberrant antigen presentation, thereby driving neuroinflammatory cascades. And provides novel and potential mechanistic insights into chemical neurotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111721"},"PeriodicalIF":5.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006986","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":"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":"Impact of mycotoxins on placental function: Focus on cyclopiazonic acid, deoxynivalenol, patulin, and zearalenone's metabolites","authors":"Huiqian Zhang ,&nbsp;Xiuwei Shen ,&nbsp;Jiayi He ,&nbsp;Qingyuan Wang ,&nbsp;Yunbing Tang ,&nbsp;Peipei Pan ,&nbsp;Ren-Shan Ge ,&nbsp;Xiaoheng Li","doi":"10.1016/j.cbi.2025.111718","DOIUrl":"10.1016/j.cbi.2025.111718","url":null,"abstract":"<div><div>Mycotoxins are secondary metabolites produced by fungi and pose significant risks to human and animal health. This study aimed to determine inhibitory potency of 7 mycotoxins and metabolites (cyclopiazonic acid, deoxynivalenol, patulin, zearalenone, α-zearalenol, β-zearalenol, and β-zearalanol) against human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) and rat homolog r3β-HSD4, as well as their effects on progesterone output in human JAr cells and perform mechanism and structure-activity relationship analysis. In placentas, h3β-HSD1 is responsible for pregnenolone-to-progesterone conversion. Cyclopiazonic acid, deoxynivalenol, patulin, α-zearalenol, β-zearalenol, and β-zearalanol significantly inhibited h3β-HSD1 activity at 100 μM, while zearalenone did not. Their IC₅₀ values ranged from 8.25 μM to 30.50 μM (patulin), and Ki values from 9.04 μM to 31.18 μM, acting as mixed inhibitors. These mycotoxins also inhibited progesterone output by JAr cells at ≥10 μM. For r3β-HSD4, similar inhibitions were observed. IC₅₀ values ranged from 10.55 μM to 42.83 μM. Docking analysis of mycotoxins with h3β-HSD1 and r3β-HSD4 showed interactions like cyclopiazonic acid binding to NAD⁺-binding site. Structure-activity relation analysis revealed correlations between molecular characteristics (hydrophilicity, density) and IC₅₀ values. 3D-QSAR analysis developed ten pharmacophore models, and Hypo1 was selected as the best model, which was validated by testing compounds like cyclopiazonic and patulin.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111718"},"PeriodicalIF":5.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144933263","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}