Chemico-Biological Interactions最新文献

{"title":"Genotoxicity and fibrosis in human hepatocytes in vitro from exposure to low doses of PBDE-47, arsenic, or both chemicals","authors":"Chonnikarn Jirasit ,&nbsp;Panida Navasumrit ,&nbsp;Krittinee Chaisatra ,&nbsp;Chalida Chompoobut ,&nbsp;Somchamai Waraprasit ,&nbsp;Varabhorn Parnlob ,&nbsp;Mathuros Ruchirawat","doi":"10.1016/j.cbi.2025.111410","DOIUrl":"10.1016/j.cbi.2025.111410","url":null,"abstract":"<div><div>Improper disposal and recycling of electronic waste (e-waste) has been shown to cause extensive environmental pollution and human health effects. Among the pollutants, 2,2′,4,4’ Tetrabromodiphenyl Ether (PBDE-47) and arsenic are highly prevalent. This study aimed to investigate genotoxic and fibrosis effects, and their mechanistic relationships from exposure to PBDE-47, arsenic, or both chemicals in a human hepatocyte epithelial cell line (THLE-2). Non-cytotoxic concentrations of 5 μM PBDE-47 (2848 ppb), 0.5 μM arsenite (37.46 ppb), or co-exposure to both were selected and cells were exposed for 7 days. The co-exposure increased the effect of lipid peroxidation (MDA and 4-HNE) and the expression of inflammatory genes (<em>CXCL6</em>, <em>CXCL8</em>, and <em>TGF-β1</em>) over that of PBDE-47 or arsenite alone. Furthermore, the co-exposure significantly increased the level of mutagenic DNA adducts including MDA-derived DNA adducts (Pyrimido[1,2-<em>a</em>]purin-10(3H)-one, M1dG), 8-hydroxydeoxyguanosine (8-OHdG) and 8-nitroguanine; but decreased mRNA expression of an antioxidant defense regulator (<em>NFE2L2</em>) and DNA repair genes (<em>hOGG1</em> and <em>XRCC1</em>). Regarding biological effects, the co-exposure increased cell migration, a hallmark of epithelial-mesenchymal transition (EMT); down-regulated the epithelial expression (<em>E-cadherin</em>); up-regulated mesenchymal expression (<em>Vimentin</em>); and promoted fibrosis expression (up-regulated <em>ACTA2, FSP-1,</em> and <em>COL1A1</em>). Collectively, these findings indicate that the co-exposure significantly induced a cascade of toxicological effects of overexposure to individual chemicals. The observed genotoxicity, abnormal gene expression, and fibrosis in hepatocytes indicate mechanisms and potentially further increase of health hazards than currently recognized in populations exposed to e-waste chemicals.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"410 ","pages":"Article 111410"},"PeriodicalIF":4.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374992","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":"Fraxetin inhibits IKKβ, blocks NF-κB pathway and NLRP3 inflammasome activation, and alleviates spleen injury in sepsis","authors":"Liwei Huangfu ,&nbsp;Jing Wang ,&nbsp;Da Li ,&nbsp;Haiyang Fei ,&nbsp;Xuan Chen ,&nbsp;Jingquan Dong ,&nbsp;Lan Sun","doi":"10.1016/j.cbi.2025.111406","DOIUrl":"10.1016/j.cbi.2025.111406","url":null,"abstract":"<div><div>Sepsis is a systemic inflammatory condition associated with severe organ failure, particularly splenic injury. Fraxetin (Fra), a natural product isolated from ash bark, exhibits anti-inflammatory and antioxidant properties. This study explores the function and mechanism of Fra in sepsis-induced splenic injury using an <em>in vivo</em> mouse model induced by Cecal Ligation and Puncture and an <em>in vitro</em> sepsis model based on LPS/ATP co-stimulated J774A.1 cells. The experimental groups are as follows: Sham operation or control group, Fra control group, CLP or LPS/ATP group, CLP + Fra group or LPS/ATP + Fra group, with Dexamethasone as a positive control. The results indicated that Fra improved the survival rate, inhibited bacteria burden, and reduced spleen edema. Fra also alleviated spleen necrosis, and restored the structural integrity. Blood results showed that Fra restored platelet count and lymphocyte percentage, reduced neutrophil ratio and C-reactive protein increase, and prevented lymphocyte depletion. Immunohistochemistry demonstrated that Fra inhibited MPO levels. Additionally, Fra downregulated Procalcitonin, inhibited pro-inflammatory cytokines, NO release and Arg-1 expression, illustrating its anti-inflammatory effects. DHE staining revealed that Fra inhibited ROS and MDA, enhanced CAT, GSH-PX, and SOD activities. Furthermore, Fra inhibited NLRP3 inflammasome activation, <em>p</em>-IKKβ expression and NF-κB pathway. Mechanistically, molecular docking studies revealed that Fra could bind to IKKβ, thereby blocking the NF-κB pathway and NLRP3 inflammasome, functioning anti-inflammatory effects. In summary, Fra targets IKKβ to block the NF-κB pathway and NLRP3 inflammasome activation, alleviating sepsis-induced splenic injury, making it a promising therapeutic strategy for treating sepsis-induced splenic injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111406"},"PeriodicalIF":4.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375053","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":"Aristolochic acid I abnormally activates the wnt7b/β-catenin signaling pathway and affects the repair of renal tubules","authors":"Xiaofen Li ,&nbsp;Ying Zhang ,&nbsp;Ailin Lan ,&nbsp;Maojuan Li ,&nbsp;Ming Xia ,&nbsp;Chuanhua Huang ,&nbsp;Didong Lou","doi":"10.1016/j.cbi.2025.111413","DOIUrl":"10.1016/j.cbi.2025.111413","url":null,"abstract":"<div><div>Aristolochic acid I (AAI), which is one of the main forms of aristolochic acid, can cause aristolochic acid nephropathy. Abnormal activation or inhibition of the Wnt7b/β-catenin signaling pathway may lead to the occurrence and development of kidney disease. This study aimed to investigate the effect of the Wnt7b/β-catenin signaling pathway on the damage and repair processes of renal tubular epithelial cells (RTECs) using mouse and zebrafish models of acute aristolochic acid intoxication. Our data revealed that after mice were exposed to 5 mg/kg/day AAI for 4 days and 6 days the expression of Wnt7b on the villi of RTECs increased, the expression of β-catenin on the cytoplasm decreased, and the expression of β-catenin in the nucleus increased. The protein expression levels of PCNA and Kim-1 increased. After zebrafish at 3 days post fertilization were exposed to 2, 4, and 8 μg/mL AAI for 24 h, the results indicated that treatment with AAI resulted in a decrease in the number of RTECs and the occurrence of apoptosis. Importantly, after knockout of the <em>Wnt7ba</em> gene, damage to RTECs in zebrafish larvae was aggravated, the mRNA expression level of PCNA decreased, and that of Kim-1 increased. In addition, we found that AAI exhibits developmental toxicity in fertilized zebrafish eggs. As a result, AAI leads to abnormal activation of the Wnt7b/β-catenin signaling pathway, which affects the repair of renal tubular injury by activating the downstream protein PCNA. The Wnt7ba gene may serve as a potential therapeutic target to promote repair after renal tubular injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111413"},"PeriodicalIF":4.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375052","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":"Covalent binding of Geniposide metabolites to hepatic proteins: A potential mechanism for its hepatotoxicity","authors":"Ai Gao ,&nbsp;Ying Ni ,&nbsp;Chao Chen ,&nbsp;Wenfeng Xin ,&nbsp;Yu Wang ,&nbsp;Wensheng Zhang","doi":"10.1016/j.cbi.2025.111411","DOIUrl":"10.1016/j.cbi.2025.111411","url":null,"abstract":"<div><div>Gardeniae fructus (GF) is a widely used traditional Chinese medicine; however, its application is limited due to the hepatotoxicity of its main active component, Geniposide (GE). To investigate the material basis and mechanisms of GE-induced hepatotoxicity. We utilized an <em>in vitro</em> gastrointestinal model to examine metabolic processes, conducted <em>in vivo</em> experiments to study GE's hepatotoxic effects and performed cellular experiments to verify toxic effects. Results indicated that GE-induced hepatotoxicity is associated with its metabolite Genipin (GP), with GP's hemiacetal structure being a key factor. Upon exposure of the C-1 hydroxyl group of GP, a covalent binding reaction occurs with amino acids. This reaction readily proceeds as a phase II conjugation with the amino group of lysine (LYS), resulting in the formation of genipin-lysine (GP-LYS) adducts. These adducts affect cellular oxidative stress and trigger cascading reactions leading to hepatotoxicity. Our findings not only highlight chemical structure as a crucial factor influencing toxicity but also advance the understanding of GE's toxic action mechanism. This study provides a foundation for guiding rational clinical use of GE and offers valuable insights for the development of novel GE-based pharmaceuticals.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111411"},"PeriodicalIF":4.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366226","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":"Subtype-selective effect and molecular regulation of celastrol and triptolide at human nicotinic acetylcholine receptors","authors":"Myungmi Moon ,&nbsp;Minsu Pyeon ,&nbsp;Jaehui Yang ,&nbsp;Jeongyeon Yun ,&nbsp;Hye Duck Yeom ,&nbsp;Mee-Hyun Lee ,&nbsp;Gihyun Lee ,&nbsp;Junho H. Lee","doi":"10.1016/j.cbi.2025.111412","DOIUrl":"10.1016/j.cbi.2025.111412","url":null,"abstract":"<div><div>Celastrol and triptolide, bioactive compounds isolated from <em>Tripterygium wilfordii</em> Hook F, have demonstrated significant pharmacological effects across various biological pathways, making them subjects of extensive research for potential therapeutic applications. Celastrol and triptolide are known to have therapeutic use in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease through neuroprotective action. Nicotinic acetylcholine receptors (nAChRs) are a subtype of cholinergic receptors and are ligand-gated ion channels that play an essential role in regulating synaptic transmission in the central nervous system. The results of this study indicate that celastrol and triptolide inhibit nAChR subtypes in a subtype-specific manner. This inhibitory effect was shown to be reversible, concentration-dependent, and noncompetitive. Mutation experiments were then performed to identify mutations in the binding site of nAChR determined by molecular docking studies and prioritize them based on binding energy, and it was found that triptolide had no inhibitory effect in double mutants of nAChR. These findings confirm that celastrol and triptolide selectively and effectively inhibit α3β2 and α3β4 nAChRs among various nAChR subtypes, and that celastrol and triptolide interact with a specific region of α3β4 nAChRs, which play a key role in the autonomic nervous system, without inhibiting the activity of α7 and α4β2, which act in neurodegenerative diseases.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111412"},"PeriodicalIF":4.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366428","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":"Antifibrotic potential of reserpine (alkaloid) targeting Keap1/Nrf2; oxidative stress pathway in CCl4-induced liver fibrosis","authors":"Aamir Sohail ,&nbsp;Faiza Shams ,&nbsp;Aleeza Nawaz ,&nbsp;Qurrat ul Ain ,&nbsp;Bushra Ijaz","doi":"10.1016/j.cbi.2025.111384","DOIUrl":"10.1016/j.cbi.2025.111384","url":null,"abstract":"<div><div>The death rate due to liver cancer approaches 2 million annually, the majority is attributed to fibrosis. Currently, there is no efficient, safe, non-toxic, and anti-fibrotic drug available, suggesting room for better drug discovery. The current study aims to evaluate the anti-fibrotic role of reserpine, an alkaloid plant compound against CCl₄-induced liver fibrosis. <em>In-silico</em> docking analysis showed the interaction of reserpine with keap1 protein with the binding energy −9.0 kcal/mol. In-vitro, biochemical analysis, anti-oxidative indexes, and inflammatory cytokines analysis were performed in HepG2 cells. The non-toxic nature of the compound (&lt;100 μg/ml) was evaluated through MTT assay in HepG2 and Vero cell lines. The antifibrotic potential of the reserpine compound (dose of 0.5 mg/kg) was assessed in CCl₄-administered <em>C5</em>7BL<em>/6J</em> mice models. Hematoxylin &amp; Eosin and Masson staining were performed to study the morphological changes of liver tissues. Immune histochemistry (IHC) analysis was performed to evaluate the effect of reserpine on the liver fibrosis marker. The biochemical assay indicated a significant decrease in ALT, AST, and MDA levels and increased catalase enzyme post-6-week reserpine treatment in mice models. Gene expression analysis revealed that the reserpine targets oxidative stress Keap1/Nrf2 pathway and down-regulated Keap1 expression by 5-fold and up-regulated Nrf2 and Nqo1 expression by 6 and 4.5-fold respectively showing its antioxidant response. It suppressed the expression of Cyp2e1 by 2.2-fold, illustrating the compound's ability to block lipid peroxidation. Histological and immunostaining exhibited improved hepatocyte morphology and reduced collagen deposition in liver tissues due to reserpine. Reserpine treatment lowered the fibrotic markers α-SMA and Col-1 by 1.3 and 1.5 folds respectively as compared to the control group and increased the expression of miR-200a and miR-29b by 15.5 and 8.2 folds (p &lt; 0.05) while decreased miR-128-1-5p expression by 5-fold. A comprehensive In-silico, In-vitro, and In-vivo analysis revealed that reserpine has a strong anti-fibrotic effect against the CCl₄-induced liver fibrosis in <em>C5</em>7BL<em>/6J</em> mice model by targeting the Keap1/Nrf2 pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"407 ","pages":"Article 111384"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973701","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":"Prophylaxis by a reversible cholinesterase inhibitor and the NMDA receptor antagonist treatment as combinatorial countermeasure against nerve agent poisoning in mice model","authors":"Jiri Kassa ,&nbsp;Jan Konecny ,&nbsp;Barbora Svobodova ,&nbsp;Martin Horak ,&nbsp;Jan Korabecny ,&nbsp;Ondrej Soukup","doi":"10.1016/j.cbi.2025.111386","DOIUrl":"10.1016/j.cbi.2025.111386","url":null,"abstract":"<div><div>The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (<strong>K1959</strong>) and the therapeutic efficacy of a novel NMDA receptor antagonist (<strong>K2060</strong>) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (<strong>K1959</strong>) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (<strong>K2060</strong>) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as <strong>K2060</strong> as a supportive drug for the classic therapy of organophosphorus poisoning.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"407 ","pages":"Article 111386"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981004","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":"Integrated network pharmacology, bioinformatics, and experiment analysis to decipher the molecular mechanism of Salidroside on Gastric cancer via targeting NCOA4-mediated ferritinophagy","authors":"Yu Fu ,&nbsp;Guiqin Huang ,&nbsp;Yawen Cai ,&nbsp;Menghui Ren ,&nbsp;Run Cheng ,&nbsp;Yuhui Chai ,&nbsp;Yingdi Wang ,&nbsp;Yunqi An ,&nbsp;Tianhua Yan ,&nbsp;Lingpeng Zhu ,&nbsp;Xinxin Liu","doi":"10.1016/j.cbi.2024.111368","DOIUrl":"10.1016/j.cbi.2024.111368","url":null,"abstract":"<div><div>Gastric cancer (GC) is a highly aggressive and heterogeneous malignancy. The process of ferroptosis regulates tumor growth and represents a promising therapeutic target for GCs. Despite Salidroside (Sal) being able to regulate ferroptosis in a variety of diseases, there are still limited reports on its therapeutic effects and potential targets in treating GC. This study aimed to investigate the potential mechanism of Sal-induced ferroptosis in GC. Our analysis, integrating databases like PharmMapper, Swiss Target Prediction, TargetNet, GeneCards, TTD, OMIM, STRING, and DAVID. Human gastric cancer MGC803 cells and tumor-bearing mice were used to evaluate the anti-tumor effect of Sal on GC <em>in vitro</em> and <em>in vivo</em>. CCK-8, LDH, and Calcein-AM/PI were used to assess cell viability and damage. FerroOrange, Lillie's Ferrous Iron Stain, MDA, ROS, BODIPY™ 581/591C11, GSH, and GPxs were used to detect intracellular Fe²⁺ concentration, lipid peroxidation level, and antioxidant defense system. qRT-PCR and Western blot were performed to explore relevant mechanism studies. Network pharmacology results showed that Sal shares 322 targets with GC, which have biological functions related to lipid metabolism, cell death, and lipid peroxidation. Experiments further confirmed that Sal inhibits MGC803 cells by inducing ferroptosis, as evidenced by the induction of elevated Fe²⁺ and increased lipid peroxidation. Fer-1, an inhibitor of ferroptosis, reversed the anti-GC effect of Sal in MGC803 cells and GC tumor-bearing mice. Further confirmation of the association between Sal and ferroptosis in GC. Subsequently, bioinformatics and machine learning algorithms identified nuclear receptor coactivator 4 (NCOA4) as a candidate signature gene associated with ferroptosis in GC, and molecular docking shows that NCOA4 binds Sal. We then performed <em>in vivo</em> and <em>in vitro</em> experiments to elucidate that Sal targeting NCOA4, a cargo receptor mediating ferritinophagy, mediates autophagic degradation of ferritin heavy chain 1 (FTH1, Fe²⁺ storage protein), which further increases Fe²⁺ and lipid peroxidation. In addition, Sal induces mitochondrial dysfunction and increases mitochondrial ROS levels, which activates autophagy and triggers autophagic degradation of FTH1. Taken together, we revealed that NCOA4 is a new target for Sal-anchored GC and that Sal may be a potential therapeutic drug for the treatment of GC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"407 ","pages":"Article 111368"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924206","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 nano-sized N-Thiazolylpyridylamines targeting CDK2: Design, divergent synthesis, conformational studies, and multifaceted In silico analysis","authors":"Samir Bondock ,&nbsp;Nada Alabbad ,&nbsp;Aisha Hossan ,&nbsp;Ibrahim A. Shaaban ,&nbsp;Ali A. Shati ,&nbsp;Mohammad Y. Alfaifi ,&nbsp;SeragE.I. Elbehairi ,&nbsp;Rehab H. Abd El-Aleam ,&nbsp;Moaz M. Abdou","doi":"10.1016/j.cbi.2024.111366","DOIUrl":"10.1016/j.cbi.2024.111366","url":null,"abstract":"<div><div>This study involves the design, divergent synthesis, conformational and structural analysis, target prediction, and molecular docking simulations of novel nano <em>N</em>-thiazolylpyridylamines <strong>2–7</strong> and <strong>10</strong> as potential cyclin-dependent kinase 2 (CDK2) inhibitors. Using a divergent synthesis approach, the compounds were designed with structural variation and optimization in mind. The conformational and structural properties were explored through various spectroscopic techniques, confirming the structure, stability, and preferred conformations. Additionally, nanocrystalline characterization, including X-ray diffraction analysis, revealed the nanoscale structural features of the synthesized molecules. Most compounds exhibited a crystalline nature with crystallite sizes ranging from 10.75 to 57.77 nm, which is crucial for improving cellular uptake and anticancer efficacy. Biological testing was performed to evaluate the cytotoxicity of compounds <strong>2–7</strong> and <strong>10</strong> against cancer cell lines, including HepG2, MCF-7, and HCT-116. Compound <strong>5</strong> exhibited significant cytotoxicity with IC₅₀ values of 10.9 ± 0.5 μM, 6.98 ± 0.3 μM, and 6.3 ± 0.2 μM against MCF-7, HePG2, and HCT116, respectively. Other compounds demonstrated varied activities, with compounds <strong>4</strong>, <strong>6</strong>, and <strong>10</strong> showing moderate activity against the MCF-7 cell line. Computational techniques suggested a strong probability of these compounds targeting CDK2, with molecular docking and dynamics used to predict their binding mechanisms. These findings suggest that <em>N</em>-thiazolylpyridylamines may serve as new anticancer agents for further lead optimization.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"407 ","pages":"Article 111366"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928877","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":"Conformation and binding of 12 Microcystin (MC) congeners to PPP1 using molecular dynamics simulations: A potential approach in support of an improved MC risk assessment","authors":"Sabrina Jaeger-Honz ,&nbsp;Raymund Hackett ,&nbsp;Regina Fotler ,&nbsp;Daniel R. Dietrich ,&nbsp;Falk Schreiber","doi":"10.1016/j.cbi.2025.111372","DOIUrl":"10.1016/j.cbi.2025.111372","url":null,"abstract":"<div><div>Microcystins (MCs) occur frequently during cyanobacterial blooms worldwide, representing a group of currently about 300 known MC congeners, which are structurally highly similar. Human exposure to MCs via contaminated water, food or dietary supplements can lead to severe intoxications with ensuing high morbidity and in some cases mortality. Currently, one MC congener (MC-LR) is almost exclusively considered for risk assessment (RA) by the WHO. Many MC congeners co-occur during bloom events, of which MC-LR is not the most toxic. Indeed, MC congeners differ dramatically in their inherent toxicity, consequently raising question about the reliability of the WHO RA and the derived guidance values. Molecular dynamics (MD) simulation can aid in understanding differences in toxicity, as experimental validation for all known MC congeners is not feasible. Therefore, we present MD simulations of a total of twelve MC congeners, of which eight MC congeners were simulated for the first time. We show that depending on their structure and toxicity class, MCs adapt to different backbone conformations. These backbone conformations are specific to certain MC congeners and can change or shift to other conformations upon binding to PPP1, affecting the stability of the binding. Analysis of the interactions with PPP1 demonstrated that there are frequently occurring patterns for individual MC congeners, and that published PPP interactions could be reproduced. In addition, common but also unique patterns were found for individual MC congeners, suggesting differences in binding behaviour. The MD simulations presented here therefore enhance our understanding of MC congener-specific differences and demonstrated that congener-specific investigations are prerequisite for allowing characterisation of yet untested or even unknown MC congeners, thereby allowing for a novel potential approach in support of an improved RA of microcystins in humans.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"407 ","pages":"Article 111372"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}