Ruiying Zhang , Penghui Nie , Yuankun Zhou , Juanjuan He , Lihong Wang , Hengyi Xu , Fen Fu
{"title":"Maternal co-exposure to Cd and PS-NPLs induces offspring ovarian inflammatory aging via promoting M1 macrophage polarization","authors":"Ruiying Zhang , Penghui Nie , Yuankun Zhou , Juanjuan He , Lihong Wang , Hengyi Xu , Fen Fu","doi":"10.1016/j.cbi.2025.111535","DOIUrl":"10.1016/j.cbi.2025.111535","url":null,"abstract":"<div><div>With the growing crisis of plastic pollution, the severe environmental problem threatens human and ecosystem health. And nanoplastics can carry other environmental contaminants, thereby causing severe toxic effects. Cadmium (Cd), as a metal, has been widely concerned because of its long biological half-life, high toxicity and low excretion rate. Additionally, Cd as an endocrine disrupting chemical also has reproductive toxicity and genotoxicity. Studies have found that co-exposed to Cd and PS-NPLs complexes may lead to more severe adverse effects in aquatic and mammals. And the utilization of other non-essential heavy metals such as cadmium are increased due to iron deficiency anemia in women during pregnancy. Therefore, in our study, 8 week-old female C57BL/6 J mice were co-exposed to Cd and NPLs during pregnancy and lactation, and the offspring are raised to four weeks to explore and predict the potential effect on the development of offspring reproductive system by transcriptomics. The results showed that sex hormone levels were interfered in offspring female mice, and gut microbiota disorder and increased LPS levels originated from the mother, which activating TLR4-related signaling pathways, and promoting ovarian M1 macrophage polarization, thereby increasing the risk of ovarian inflammatory aging in female offspring.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111535"},"PeriodicalIF":4.7,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894594","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}
Wenjing Zhang , Fei Ma , Xuhong Su , Mingxing Zhu , Xiuqing Wang
{"title":"Antimicrobial peptide WK-13-3D promotes apoptosis, autophagy, and ubiquitination in triple-negative breast cancer via binding immunoglobulin protein (BiP)","authors":"Wenjing Zhang , Fei Ma , Xuhong Su , Mingxing Zhu , Xiuqing Wang","doi":"10.1016/j.cbi.2025.111530","DOIUrl":"10.1016/j.cbi.2025.111530","url":null,"abstract":"<div><h3>Purpose</h3><div>To elucidate the inhibitory mechanism of antimicrobial peptide WK-13-3D on triple-negative breast cancer (TNBC) by targeting the binding immunoglobulin protein (BiP), a key endoplasmic reticulum (ER) chaperone regulating unfolded protein response and tumor survival.</div></div><div><h3>Methods</h3><div>TNBC cell lines (MDA-MB-231 and MDA-MB-468) were treated with WK-13-3D to assess proliferation, migration, invasion, and apoptosis. Pull-down assays identified interacting proteins, and Western blotting (WB) analyzed alterations in BiP, PERK, eIF2α, <em>p</em>-eIF2α, Caspase3, Cleaved-Caspase3, Bax, LC3, P62, AKT, <em>p</em>-AKT, mTOR, and <em>p</em>-mTOR. Transmission electron microscopy examined intracellular structures, while qPCR measured BiP mRNA levels. The effects of WK-13-3D on BiP ubiquitination were explored via co-immunoprecipitation (Co-IP). Animal tumor models were used to confirm the inhibitory effects, with BiP and Ki67 (a nuclear proliferation marker indicating actively dividing tumor cells) expression analyzed by immunohistochemistry (IHC).</div></div><div><h3>Results</h3><div>WK-13-3D inhibited TNBC cell proliferation, migration, and invasion, while promoting apoptosis. Pull-down experiments identified 268 interacting proteins, with BiP being the most frequent. Databases (TIMER and TCGA) showed high BiP expression in breast cancer, associated with poor prognosis. WB assays revealed that WK-13-3D activated ER stress-induced apoptosis and autophagy via BiP. Co-IP demonstrated that WK-13-3D mediated BiP ubiquitination at sites 352 and 547 through K6 and K29 chains. IHC analysis further confirmed decreased Ki67 levels in WK-13-3D-treated tumors, reflecting suppressed proliferative activity. Animal experiments confirmed tumor growth inhibition.</div></div><div><h3>Conclusion</h3><div>WK-13-3D promotes apoptosis, autophagy and Ubiquitination in TNBC by modulating BiP.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111530"},"PeriodicalIF":4.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882994","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}
Jiejun Liu , Jing Wang , Qiang Yuan , Zhipeng Wang , Fasheng Liu , Xinjun Liao , Huiming Li , Shouhua Zhang , Juhua Xiao , Zigang Cao
{"title":"Dimethyl sulfate induces zebrafish embryo cardiotoxicity and behavioral disturbances by upregulating oxidative stress levels","authors":"Jiejun Liu , Jing Wang , Qiang Yuan , Zhipeng Wang , Fasheng Liu , Xinjun Liao , Huiming Li , Shouhua Zhang , Juhua Xiao , Zigang Cao","doi":"10.1016/j.cbi.2025.111532","DOIUrl":"10.1016/j.cbi.2025.111532","url":null,"abstract":"<div><div>Dimethyl sulfate (DMS) is a versatile chemical compound used in various industries, including pharmaceuticals, pesticides, dyes, and fragrances. Due to the widely application of Dimethyl sulfate (DMS), it is necessary to study its potential toxicity. According to ecological data analysis, DMS has been identified as a potential environmental hazard, particularly in water bodies. However, its toxicity to aquatic organisms remains largely unexplored. In this study, using zebrafish embryos as a model system, we evaluated the toxicity of DMS for the first time and uncovered significant adverse effects on early embryonic development, characterized by extensive cardiac damage and neurotoxicity. DMS inhibited the activity of antioxidant enzymes, resulting in excessive production of reactive oxygen species (ROS) and subsequent apoptosis of myocardial cells, along with pericardial edema, bradycardia, and elongated SV-BA distance. Additionally, DMS directly induced oxidative stress and altered the activity of acetylcholinesterase (ACHE) and adenosine triphosphatase (ATPase), thereby disrupting the expression of genes involved in neural development and neurotransmission. These findings may contribute to the DMS-induced behavioral abnormalities, such as reduced and unbalanced locomotion in larvae and altered swimming behavior. Importantly, astaxanthin, an antioxidant carotenoid, was able to rescue the embryonic cardiac and neurotoxic effects triggered by DMS exposure, suggesting that DMS primarily induces zebrafish cardiac and neural developmental toxicity through upregulation of oxidative stress. Overall, our study demonstrates the potential of DMS to induce cardiac and neurotoxicity in zebrafish embryos, suggesting toxicity risks to other aquatic organisms and even humans. These findings provide a basis for a comprehensive assessment of DMS toxicity and serve as an early warning for its environmental presence and product residues.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111532"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941210","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}
Lingyu Li , Qingying Liu , Yuyu Shao , Shuo Wang , Shuangyu Liu , Xiaoning Wang , Shuqi Wang , Dongmei Ren
{"title":"Gaudichaudion H inhibits KRAS-mutant pancreatic cancer cell growth through interfering PDEδ-KRAS interaction","authors":"Lingyu Li , Qingying Liu , Yuyu Shao , Shuo Wang , Shuangyu Liu , Xiaoning Wang , Shuqi Wang , Dongmei Ren","doi":"10.1016/j.cbi.2025.111529","DOIUrl":"10.1016/j.cbi.2025.111529","url":null,"abstract":"<div><div><em>KRAS</em> mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome <em>KRAS</em>-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from <em>Garcinia oligantha.</em> In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from <em>G. oligantha.</em> Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with <em>KRAS</em> mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111529"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882993","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}
Pradeep M. Uppar , Na Young Kim , Keshav Kumar Harish , Narasimha M. Beeraka , Santhosh L. Gaonkar , Mahendra Madegowda , Gautam Sethi , Kanchugarakoppal S. Rangappa , Vladimir N. Nikolenko , Arunachalam Chinnathambi , Sulaiman Ali Alharbi , Kwang Seok Ahn , Basappa Basappa
{"title":"Targeting breast cancer cells with 2-indolyl-1,3,4-oxadiazole compounds by inducing apoptosis, paraptosis and autophagy","authors":"Pradeep M. Uppar , Na Young Kim , Keshav Kumar Harish , Narasimha M. Beeraka , Santhosh L. Gaonkar , Mahendra Madegowda , Gautam Sethi , Kanchugarakoppal S. Rangappa , Vladimir N. Nikolenko , Arunachalam Chinnathambi , Sulaiman Ali Alharbi , Kwang Seok Ahn , Basappa Basappa","doi":"10.1016/j.cbi.2025.111528","DOIUrl":"10.1016/j.cbi.2025.111528","url":null,"abstract":"<div><div>While 2-Indolyl-1,3,4-oxadiazole derivatives are recognized for their antibacterial properties, their potential as anticancer agents remains underexplored. This study investigates the anti-breast cancer properties of a novel 2-Indolyl-1,3,4-oxadiazole compound, 5l, focusing on its ability to induce apoptosis, paraptosis, and autophagy, and targeting poly (ADP-ribose) polymerase (PARP1), a critical enzyme in DNA repair. A series of 1,3,4-oxadiazole derivatives (compounds 5a-5m) were synthesized using an optimized multi-step process, enhancing reaction efficiency and yield. In silico molecular docking was used to determine binding efficacy of these derivatives. Lead compound, 5l, underwent cytotoxicity assays against MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as the non-cancerous MCF-10A cell line. Molecular docking assessed the interaction of 5l with the PARP1 active site. Frontier molecular orbital (FMO) and molecular electrostatic potential (MESP) analyses were conducted to map electron distribution and identify reactive regions within compound 5l. The effects of 5l on cellular processes such as apoptosis, autophagy, and endoplasmic reticulum (ER) integrity were evaluated using live and dead assays, Annexin V staining, ER-tracker dye staining, and acridine orange assays. Western blotting analyzed apoptosis, paraptosis, and autophagy-related genomic instability. The optimized synthesis yielded high-purity 1,3,4-oxadiazole derivatives. Compound 5l displayed significant anticancer activity, with IC50 values of 63.7 μM, 29.1 μM, 50.3 μM, and 39.8 μM for MDA-MB-231, MCF-7, BT-474, and SK-BR-3 cell lines respectively, demonstrating its cytotoxic efficacy. Molecular docking revealed that 5l binds to PARP1 active site with a binding energy of −11.7 kcal/mol, indicating a strong interaction supporting its role as a PARP1 inhibitor. Annexin V assays, ER-tracker dye staining, and Acridine orange assays were used to assess apoptosis, ER integrity, and autophagy. 5l induced upregulation of cleaved PARP and downregulation of Alix-loaded proteins, alongside increased LC3-II expression, indicating autophagy-mediated genomic instability. Compound 5l exhibits potent anti-breast cancer activity through paraptosis, apoptosis, and autophagy-mediated genomic instability and by PARP1 inhibition with typically a low IC50 values, highlighting its potential as a therapeutic agent.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111528"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895961","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}
Hang Wu , Yun Yun Gong , John Huntriss , Michael N. Routledge
{"title":"Transcriptome profiling and DNA methylation analysis of human hepatocyte cell line HHL-16 in response to aflatoxin B1","authors":"Hang Wu , Yun Yun Gong , John Huntriss , Michael N. Routledge","doi":"10.1016/j.cbi.2025.111531","DOIUrl":"10.1016/j.cbi.2025.111531","url":null,"abstract":"<div><div>Dietary exposure to aflatoxin B1 (AFB1) can cause acute aflatoxicosis and liver cancer, and is associated with immune suppression and growth impairment, but the molecular mechanisms of the health effects are not fully understood. A non-neoplastic human hepatocyte cell line 16 (HHL-16) was utilized to understand the effects of AFB1 on transcriptome and DNA methylation changes, identifying molecular pathways underlying toxicity and health effects. RNA sequencing and bioinformatic analysis (RNA-Seq) was applied to find the genes and pathways affected by AFB1. Bisulfite pyrosequencing was used to assess DNA methylation levels of CpG sites around promoter regions of gene of interest. RNA-sequencing revealed 280 significantly up-regulated and 296 significantly down-regulated genes in HHL-16 cells after 20 μg/ml AFB1 treatment for 24 h. KEGG pathway enrichment analysis indicated that differentially expressed genes (DEGs) were significantly enriched in the following pathways: cytokine-cytokine receptor interaction, NF-kappa B signalling pathway, TNF signalling pathway, IL-17 signalling pathway, amoebiasis, MAPK signalling pathway, and lipid and atherosclerosis. Further DNA methylation analysis found that there was significant hypomethylation at one CpG site of <em>CCL20</em> after 20 μg/ml AFB1 treatment on HHL-16 cells for 24 h. In conclusion, AFB1 modulates the expression of genes related to the pathways that play important roles in inflammatory response, growth, and cancers, and demonstrates the effects of AFB1 on DNA methylation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111531"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894593","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}
Jaroslav Malina , Hana Kostrhunova , Janice R. Aldrich-Wright , Viktor Brabec
{"title":"Antitumor platinum(II) complex 56MESS binds to DNA G-quadruplexes, downregulates expression of c-MYC and k-RAS oncogenes, and triggers DNA damage in cancer cells","authors":"Jaroslav Malina , Hana Kostrhunova , Janice R. Aldrich-Wright , Viktor Brabec","doi":"10.1016/j.cbi.2025.111534","DOIUrl":"10.1016/j.cbi.2025.111534","url":null,"abstract":"<div><div>Previous research indicated that the cytotoxic activity of the antitumor platinum(II) complex [Pt(1<em>S</em>,2<em>S</em>-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]<sup>2+</sup> (56ME<em>SS</em>) was not primarily attributed to DNA binding, despite the complex being confirmed to localize also in the nucleus. In this study, we have demonstrated that the antiproliferative activity of 56ME<em>SS</em> indeed involves DNA binding. Furthermore, in addition to binding duplex DNA, the complex also interacts with non-canonical secondary DNA structures, such as G-quadruplexes (G4s) and i-Motifs (iMs). This interaction leads to the suppression of G-regulated oncogene expression and disrupts key enzymatic processes associated with DNA, potentially contributing to DNA damage and the biological activity of 56ME<em>SS</em>. These findings build upon previously published results, revealing that the anticancer activity of 56ME<em>SS</em> is significantly more multifaceted than previously understood, involving multiple distinct mechanisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111534"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899502","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}
Erika L. Meaddough , Sara M. Sarasua , Deborah Kunkel , Luigi Boccuto , Satishkumar R. Ganakammal , Matt Moersen , Christopher L. Farrell
{"title":"Assessment of CYP2D6 gene expression in liver tissue: Variability in CYP2D6 mRNA levels within genotype-predicted metabolizer phenotype groups","authors":"Erika L. Meaddough , Sara M. Sarasua , Deborah Kunkel , Luigi Boccuto , Satishkumar R. Ganakammal , Matt Moersen , Christopher L. Farrell","doi":"10.1016/j.cbi.2025.111526","DOIUrl":"10.1016/j.cbi.2025.111526","url":null,"abstract":"<div><div>Pharmacogenetic (PGx) testing can be used to help guide drug therapy and decrease or avoid the risk of adverse drug reactions. <em>CYP2D6</em> is an important pharmacogene in pharmacogenomics testing panels. However, phenoconversion, whereby an individual's ability to metabolize a drug does not match the genotype-predicted metabolizer status, is a confounding factor to the accurate application of PGx testing results to patient care. To address this issue, <em>CYP2D6</em> expression between and within genotype-predicted CYP2D6 metabolizer phenotype groups was compared using WGS and RNA-Seq data from 134 normal liver tissue donors obtained from the GTEx program. Wide variability in <em>CYP2D6</em> mRNA levels was observed within metabolizer phenotype groups. The median expression level for ultrarapid metabolizers (UMs) was 738.9 TPM (transcripts per million; 196.8–778.9 TPM), 212.5 TPM (32.1–666.5 TPM) for normal metabolizers (NMs), 219.6 TPM for intermediate metabolizers (IMs) (22–389.8 TPM), and 121.2 TPM for poor metabolizers (PMs) (9.3–298.2 TPM). The PM and UM phenotypes were significant predictors of <em>CYP2D6</em> expression (<em>p</em> = 0.0004 and <em>p</em> = 0.019, respectively). Interestingly, expression of the gene encoding human serum albumin (<em>ALB</em>) was also a significant predictor of <em>CYP2D6</em> expression (<em>p</em> = 0.0003). Data from 50 patients with hepatocellular carcinoma obtained from the TCGA program showed no significant difference in expression between tumor tissue (median = 119.7 TPM, range 0.16–817.7 TPM) and normal matched tissue (median = 143.3 TPM, range 26.2–810.7 TPM). Transcriptional regulation of <em>CYP2D6</em> expression may contribute to differences in drug response and risk for CYP2D6 phenoconversion. Efforts to understand the role of gene expression to predict CYP2D6 phenoconversion may inform the use of PGx testing in the clinical setting.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111526"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941212","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}
Brenda Rosales-Castro , Isabel Bravo-Ontiveros , Keyla Betanzos-Rau , Kenia Nava-Aparicio , Laura Ramírez-González , Elizabeth Undiano , Iván Flores-Pérez , Eugenio Vilanova , Antonio Monroy-Noyola
{"title":"Neuroprotective effect of copper on neurotoxicity of TOCP in vivo","authors":"Brenda Rosales-Castro , Isabel Bravo-Ontiveros , Keyla Betanzos-Rau , Kenia Nava-Aparicio , Laura Ramírez-González , Elizabeth Undiano , Iván Flores-Pérez , Eugenio Vilanova , Antonio Monroy-Noyola","doi":"10.1016/j.cbi.2025.111527","DOIUrl":"10.1016/j.cbi.2025.111527","url":null,"abstract":"<div><div>A single or repeated dose of tri-ortho-cresyl phosphate (TOCP) induces in humans and animals a known neuropathy as organophosphorus-induced delayed polyneuropathy (OPIDP). This syndrome is related to the inhibition of neuropathy target esterase (NTE), causing signs and symptoms in the nervous system, such as ataxia and paralysis. Currently, there is no antidotal treatment for OPIDP. In the present study, the neuroprotective effect of Cu(II) on the acute <em>in vivo</em> neurotoxicity of TOCP is characterized. Adult hens (27 and 65 weeks old) were administered a single dose of 380, 500, 750, or 1000 mg/kg of TOCP dissolved in vegetable oil. One hour before, the animals were administered a single dose of 160 mg/kg of Cu(II) or vehicle by the same route. Twenty-four hours later, half of the animals (n = 5) in each group were decapitated to obtain the brain and blood (serum) for measuring NTE, acetylcholinesterase (AChE), cholinesterases (ChEs), and kidney and hepatic biochemical parameters (ALT, AST, creatinine, urea). The other half of the animals in each group were kept under observation for 21 days for clinical evaluation of OPIDP using a scale from 1 to 4. The 24-h brain NTE residual activity of all TOCP-treated groups was around 5 % (∼95 % inhibition) compared to the control group (vehicles). However, the group of hens treated with 380 mg/kg TOCP (27 weeks old) pre-treated with Cu(II) presented significantly higher brain NTE activity (p < 0.05), which was around 55 %. This activity value correlated with the OPIDP clinical score over 21 days. Hens treated with TOCP showed an OPIDP score of 3, whereas those pre-treated with Cu(II) showed no signs of OPIDP. The protective effect of Cu(II) on brain NTE and serum ChEs inhibition levels was associated with the degree of OPIDP. The levels of both activities decreased with the increase in OPIDP score (1–4) due to higher TOCP doses and the age of the hens. Brain AChE inhibition ranged from 16 % to 43 %, and hens showed no cholinergic signs in any group. The dose of Cu(II) used in this <em>in vivo</em> study demonstrated a neuroprotective effect and did not induce adverse effects in the liver and kidneys. However, it will be necessary to carry out specific experimental studies to investigate the neuroprotective mechanism of Cu(II).</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111527"},"PeriodicalIF":4.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890912","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}
Denise Cristian Ferreira Neto , Joyce Sobreiro Francisco Diz , Sulayne Janayna Araújo Guimarães , Eduardo Mendes dos Santos , Maria do Desterro Soares Brandão Nascimento , Ana Paula Silva de Azevedo-Santos , Tanos Celmar Costa França , Steven R. LaPlante , Claudia Jorge do Nascimento , Josélia Alencar Lima
{"title":"Guanylhydrazone and semicarbazone derivatives as potential prototypes for the design of cholinesterase inhibitors against Alzheimer's disease: biological evaluation and molecular modeling studies","authors":"Denise Cristian Ferreira Neto , Joyce Sobreiro Francisco Diz , Sulayne Janayna Araújo Guimarães , Eduardo Mendes dos Santos , Maria do Desterro Soares Brandão Nascimento , Ana Paula Silva de Azevedo-Santos , Tanos Celmar Costa França , Steven R. LaPlante , Claudia Jorge do Nascimento , Josélia Alencar Lima","doi":"10.1016/j.cbi.2025.111515","DOIUrl":"10.1016/j.cbi.2025.111515","url":null,"abstract":"<div><div>Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (<strong>1</strong>, <strong>2</strong>, and <strong>3</strong>) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound <strong>2</strong> (phenanthrenequinone) demonstrated superior inhibitory potency with an IC<sub>50</sub> of 0.68 μM, compared to compound <strong>1</strong> (acridinone) with an IC<sub>50</sub> of 3.87 μM, and compound <strong>3</strong> (benzodioxole) with an IC<sub>50</sub> of 101.7 μM. In contrast, semicarbazones (<strong>4</strong> and <strong>5</strong>) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds <strong>3</strong>, <strong>4</strong>, and <strong>5</strong> may be more effective in the early phase, when AChE activity remains high; compound <strong>1</strong> could be useful in the intermediate phase; and compound <strong>2</strong> appears particularly promising for the severe phase, when BChE plays a more dominant role.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111515"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848411","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}