Journal of pharmacological and toxicological methods最新文献

{"title":"Surgical instrumentation of cardiovascular telemetry device has minimal impact on the general toxicology data interpretation in Cynomolgus monkeys","authors":"Xiefan Fang,&nbsp;Jui-Tung (Ray) Liu,&nbsp;Stephen D. Tichenor","doi":"10.1016/j.vascn.2025.107740","DOIUrl":"10.1016/j.vascn.2025.107740","url":null,"abstract":"<div><div>Increasing numbers of general toxicology studies with integrated implanted cardiovascular (CV) telemetry are being conducted due to the constrained supply of nonhuman primates and demands for higher method sensitivities as per ICH S7B Q&amp;A. However, limited information is available for the potential impact of surgical instrumentation on the toxicology data. In this study, we reviewed the reports of implanted CV telemetry studies conducted in cynomolgus monkeys from 2017 to 2022 at our facility. The instrumentation had no impact on food consumption, respiration, pulse oximetry, neurological parameters, ophthalmology, troponin I, urinalysis, immunophenotyping, or organ weights. There was a low probability of needing to exclude animals from studies due to instrumentation-related technical (4.8 %) or health issues (0.8 %). Incidences were low (0.3 % to 2.6 %) to have instrumentation-related in-life or laboratory findings. Pathology findings were regional, rarely associated with clinical pathology changes, non-adverse, and clearly distinguishable from the test article effects in the studies examined. They were limited to localized effects (fibrosis and low-grade inflammation) associated with a foreign body reaction in the area immediately in contact with the device. Also, thrombus formation (0.2 %) was noted when the femoral artery was used for blood pressure catheter placement. Changing from intramuscular to intra-peritoneal placement greatly reduced the incidence of unusable ECG data and abnormal clinical signs. Use of the internal iliac artery for catheter placement also eliminated thrombus formation and the subsequent health impact. In conclusion, implanted telemetry integrated into a nonhuman primate toxicology study does not compromise the study objectives, study execution, or toxicology data interpretation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107740"},"PeriodicalIF":1.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intra-laboratory validation of yeast-based reporter gene assays for human thyroid hormone receptors","authors":"Masahiro Ogawa ,&nbsp;Junya Kitamoto ,&nbsp;Mayuko Nakashima ,&nbsp;Yuto Hanaichi ,&nbsp;Sayoko Ito-Harashima ,&nbsp;Itaru Takeda ,&nbsp;Takashi Yagi ,&nbsp;Masanobu Kawanishi ,&nbsp;Taku Tanaka","doi":"10.1016/j.vascn.2025.107593","DOIUrl":"10.1016/j.vascn.2025.107593","url":null,"abstract":"<div><div>Thyroid hormones (THs) function by activating TH receptors (THRα and THRβ) on the target cells. Several chemicals adversely affect human health and ecosystems by disrupting TH signaling. Multiple assays for thyroid disruption have been reviewed for validation, especially with respect to assay reliability, sensitivity, efficiency, and technical criteria in the OECD Test Guidelines framework. The reporter gene assay is a sensitive method used to observe cellular events associated with signal transduction and gene expression. Some mammalian cell-based THR reporter gene assays have been developed optimized, and verified. In contrast, yeast-based reporter gene assays offer a cost-effective and rapid approach compared to mammalian-based assays and are considered advantageous for detecting direct or indirect interactions between test chemicals and the receptor of interest. In this study, the previously developed yeast-based reporter gene assays for human-derived THRα and THRβ were validated using several test substances, including THs and TH-disrupting chemicals, to establish scientific confidence. Our results showed that the yeast-based THRs reporter gene assays had high repeatability and the use of a fluorescent substrate improved the detection of TH disruption caused by several chemicals. Although inter-laboratory studies are needed to verify the acceptance and data interpretation criteria, our assays can provide information on the potential of chemicals to interfere with THR transactivation as animal-free <em>in vitro</em> assays.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"132 ","pages":"Article 107593"},"PeriodicalIF":1.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The application of Bayesian forecasting to explore the effects of sex and high-fat diet on the pharmacokinetics of ropivacaine in the rat","authors":"Shamima Parvin,&nbsp;Hamdah M. Al Nebaihi,&nbsp;John R. Ussher,&nbsp;Dion R. Brocks","doi":"10.1016/j.vascn.2025.107592","DOIUrl":"10.1016/j.vascn.2025.107592","url":null,"abstract":"<div><div>Bayesian forecasting is commonly applied as part of therapeutic drug monitoring to obtain individual estimates of pharmacokinetic parameters in patients. Here its utility was explored in a preclinical study involving ropivacaine, in which sparse blood sampling data was available in the rat. Initially sample-population estimates of parameters were obtained by injecting male cannulated male Sprague-Dawley rats subcutaneously with ropivacaine HCl. Blood samples were serially drawn from each rat for 12 h after the dose (rich sampling); the concentrations were used with compartmental analysis to optimize model selection and obtain mean and variances of pharmacokinetic parameters. Two additional single doses, spaced by 5 days, were injected, each followed by 1 to 3 sparse blood draws. Other sparsely sampled age-matched groups of male and female rats given standard diet, and a group of males given high-fat diet, were dosed. Bayesian forecasting was conducted for each of these sparsely sampled rats to estimate pharmacokinetic parameters. Plasma was assayed using liquid-chromatographic method using mass spectrometry. For validation, the Bayesian parameter forecasts were compared to those using nonlinear mixed-effects modelling (NLMEM). Ropivacaine had a high clearance compared to hepatic blood flow, and a large volume of distribution. Excellent correlations were present between observed and estimated plasma concentrations using Bayesian forecasting, as was the relationship between those estimates and those obtained from NLMEM. The male rats given high-fat diet had a significant decrease in the weight-normalized clearance of ropivacaine, and female rats had a slower absorption rate. The effects were also identified using NLMEM. Bayesian forecasting has applicability in estimating pharmacokinetic properties of drugs in preclinical studies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"132 ","pages":"Article 107592"},"PeriodicalIF":1.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug combination assays using Caenorhabditis elegans as a model system","authors":"Guillermina Hernando,&nbsp;Cecilia Bouzat","doi":"10.1016/j.vascn.2025.107583","DOIUrl":"10.1016/j.vascn.2025.107583","url":null,"abstract":"<div><div>The <em>C. elegans</em> drug combination assay evaluates the effects of drug combinations in the nematode <em>Caenorhabditis elegans</em>, serving as a valuable tool to assess the efficacy of pharmaceutical agents and natural compounds. Using <em>C. elegans</em> as a model organism, this method allows for the efficient screening of the combined effects of different drugs and evaluation of synergistic effects in drug combinations, which reduces the risk of developing drug resistance.</div><div>Combination therapy, involving commercial drugs, new agents, or natural products, broadens treatment effectiveness by targeting multiple pathways, effectively managing complex diseases with minimized side effects. The method focuses on discovering effective drug combinations, such as anthelmintic drugs, streamlining early-stage drug discovery to save time and resources. Additionally, its versatility allows for application across most areas of pharmacology and toxicology, extending its usefulness beyond anthelmintic treatments.</div><div>In the experiments, synchronized worms are exposed to different drug concentrations to evaluate behavioral changes, mostly alterations in worm locomotion. Concentration-response curves for changes in behavior are generated and EC₅₀ or IC₅₀ values determined for the individual drugs. To determine whether the effects of a drug combination are synergistic, additive, or antagonistic, at least three different concentration ratios must be tested. These combinations are then analyzed using specialized drug combination analysis software. This methodology ensures consistent and precise outcomes and evaluates drug impacts on worm behavior parameters crucial for effective pharmacological activity.</div><div>In conclusion, the <em>C. elegans</em> drug combination assay provides critical insights for developing successful market formulations applicable across a wide range of pharmacological treatments. Its ability to efficiently screen for synergistic, additive, or antagonistic effects makes it a valuable tool for identifying effective therapeutic strategies, potentially reducing drug resistance and improving treatment outcomes in various medical and toxicological fields.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107583"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting clinical outcomes from off-target receptor interactions using Secondary Intelligence™","authors":"Will S. Redfern ,&nbsp;Chris E. Pollard ,&nbsp;Mark Holbrook ,&nbsp;Barira Islam ,&nbsp;Mitra Abbasi ,&nbsp;Joanne Mahmud ,&nbsp;Katie Lambert ,&nbsp;Augustus Haslam ,&nbsp;Heeseung Jo ,&nbsp;Hiba Khalidi ,&nbsp;Zofia Bielecka ,&nbsp;Josh Starkey ,&nbsp;Thomas Ellinger ,&nbsp;Simon Bryan ,&nbsp;Angeli Savas ,&nbsp;Steve Andrews ,&nbsp;Rob Aspbury ,&nbsp;Lyn Rosenbrier Ribeiro ,&nbsp;Kim A. Henderson Park ,&nbsp;Hugo M. Vargas ,&nbsp;Clare R. Gilmer","doi":"10.1016/j.vascn.2024.107570","DOIUrl":"10.1016/j.vascn.2024.107570","url":null,"abstract":"<div><div>Adverse effects due to off-target activity can be predicted by careful comparison of the relationship between expected plasma concentration and off-target activity of the test compound with that of reference drugs targeting that receptor for their therapeutic efficacy. The ratio between plasma concentration (unbound) and the K_i at the receptor is a surrogate measure reflecting receptor occupancy. Where data are available for reference drugs, we have curated and evaluated this at 100 receptors, 72 of which can involve both negative and positive modulations by drugs: a total of 172 ‘receptor modulations’. This provides a quantitative framework upon which to achieve consistent risk assessment of off-target interactions across receptors, across compounds and between assessors. It therefore represents a significant departure from an opinion-based to an evidence-based approach to secondary pharmacology. Demonstration of proof-of-principle was achieved for one of the receptor interactions (α_1A-adrenoceptor antagonism leading to postural hypotension in clinical use) due to the availability of high-quality off-target K_i data for &gt;30 drugs at this receptor.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107570"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a sensitive LC-MS/MS assay for determination of upadacitinib in human plasma and its application in patients with inflammatory bowel disease","authors":"Jing-jing Wu ,&nbsp;Lang Lin ,&nbsp;Jia-jia Yan ,&nbsp;Jia-he Kong ,&nbsp;Qiao-lan Xuan ,&nbsp;Xiang Gao ,&nbsp;Kang Chao ,&nbsp;Xia Zhu","doi":"10.1016/j.vascn.2025.107581","DOIUrl":"10.1016/j.vascn.2025.107581","url":null,"abstract":"<div><h3>Background</h3><div>Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor approved by the Food and Drug Administration for the treatment of moderate-to-severe inflammatory bowel disease (IBD). We aimed to establish and validate a method for determining Upadacitinib in patients with IBD by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.</div></div><div><h3>Methods</h3><div>The mobile phase was 0.1 % formic acid: acetonitrile (35:65, <em>v</em>/v) at a flow rate of 0.40 mL/min. Upadacitinib and its internal standard Upadacitinib <img>¹⁵N, d₂ were separated by a Waters Xbridge BEH C18 column (4.6 × 100 mm, 2.5 μm) and subjected to mass analysis using positive electrospray ionization (ESI).</div></div><div><h3>Results</h3><div>The calibration range of Upadacitinib was 0.5–200 ng/mL with the correlation coefficient r² ≥ 0.99. Accuracies ranged from −9.48 % ∼ 8.27 % and the inter- and intra-day precisions were less than 15 % for all analytes in quality control samples. There was no significant matrix effect. The range of extraction recoveries was 87.53–93.47 % for all analytes. Twenty-one plasma samples were obtained from the sixth affiliated hospital of Sun Yat-sen University. The median plasma concentration of Upadacitinib was 7.32 (0.56–26.78) ng/mL.</div></div><div><h3>Conclusion</h3><div>This newly developed method is sensitive, simple, and successfully applied in determining Upadacitinib in IBD patients to provide reference for safe and effective drug administration in clinical practice.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107581"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compromising the immunogenicity of diphtheria toxin-based immunotoxins through epitope engineering: An in silico approach","authors":"Behrouz Golichenari ,&nbsp;Mohammad Heiat ,&nbsp;Ehsan Rezaei ,&nbsp;Amirreza Ramshini ,&nbsp;Amirhossein Sahebkar ,&nbsp;Nazila Gholipour","doi":"10.1016/j.vascn.2024.107571","DOIUrl":"10.1016/j.vascn.2024.107571","url":null,"abstract":"<div><div>Immunotoxins are genetically engineered recombinant proteins consisting of a targeting moiety, such as an antibody, and a cytotoxic toxin moiety of microbial origin. <em>Pseudomonas</em> exotoxin A and diphtheria toxin (DT) have been abundantly used in immunotoxins, with the latter applied as the toxin moiety of the FDA-approved drug Denileukin diftitox (ONTAK®). However, the use of immunotoxins provokes an adverse immune response in the host body against the toxin moiety, limiting their efficacy. <em>In silico</em> approaches have received increasing attention in protein engineering. In this study, the epitopes responsible for immunogenicity were identified through multiple platforms. By subtracting conserved and ligand-binding residues, K33, T111, and E112 were identified as common epitopes across all platforms. Substitution analysis evaluated alternative residues regarding their impact on protein stability, considering 19 different amino acid substitutions. Among the mutants explored, the T111A-E112G mutant exhibited the most destabilizing substitution for DT, thereby reducing immunogenicity. Finally, a 3D model of the mutant was generated and verified. The model was then docked with its native ligand NADH, and the complex's molecular behavior was simulated using molecular dynamics.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107571"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demonstrating the statistical and pharmacological sensitivity of nonclinical QTc analysis using a dofetilide dose–response in nonhuman primates","authors":"Derek J. Leishman ,&nbsp;David L. Holdsworth ,&nbsp;Derek D. Best ,&nbsp;Matthew M. Abernathy ,&nbsp;Brian M. Roche","doi":"10.1016/j.vascn.2024.107572","DOIUrl":"10.1016/j.vascn.2024.107572","url":null,"abstract":"<div><div>Nonclinical QTc studies can augment clinical QTc assessments in regulatory submissions provided they are of sufficient quality and sensitivity. Both the statistical performance and species translation play a role in determining the sensitivity of the model.</div><div>The current analyses examine the effects of dofetilide or vehicle on the QT interval in nonhuman primate (NHP; n = 16) using a one-step estimated marginal means method where both treatment and animal ID are used in regression models to avoid a separate rate correction step, in comparison to other commonly utilized methods. The doses of dofetilide were chosen to span a threshold dose with exposure only just exceeding the concentration associated with 10 ms QTc prolongation in man, to a dose where exposures exceed the Emax for QTc prolongation. The primary objective was an evaluation of which doses and exposures can be detected as eliciting a statistically significant change in QTc.</div><div>A group size of 8 for cross-over analysis was insufficient to detect, as statistically significant, the effects of the threshold dose of 0.01 mg/kg dofetilide using common correction and statistical analysis methods and hourly time intervals. Higher doses were all detected as causing a statistically significant effect using the same techniques. The ‘One-Step’ method was able to detect as statistically significant effects at all doses of dofetilide across a wide range of time and exposure. There were also temporal differences between the mean effects observed using the common and ‘One-Step’ methods. Preliminary concentration-QTc assessment suggests a higher maximum prolongation in concentration QTc with the ‘One-Step’ method. Furthermore, this analysis suggests that at exposures associated with a 10 ms QTc prolongation in man a 10 ms prolongation is also observed in NHP. The observed ED₅₀ concentration (0.85 ng/ml unbound) is close to that described in man (0.98 ng/ml).</div><div>These analyses demonstrate the statistical sensitivity of the ‘One-Step’ method of QTc assessment in NHP. The pharmacological sensitivity was also demonstrated and a detection threshold of 10 ms was consistent in terms of exposure between NHP and man. Overall, QTc assessment using the ‘One-Step’ method in NHP is a robust and sensitive model to supplement clinical QTc assessment.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107572"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-binding assays validated for quantitative bioanalysis of a novel antibody-drug conjugate in monkey serum and related application in a nonclinical study","authors":"Yingying Hou ,&nbsp;Jie Miao ,&nbsp;Yajun Sun ,&nbsp;Lili Shi ,&nbsp;Lu Ouyang ,&nbsp;Xiaoqiang Chen ,&nbsp;Ziyi Li ,&nbsp;Tingting Liu ,&nbsp;Gang Qin ,&nbsp;Qiuping Qin ,&nbsp;Likun Gong","doi":"10.1016/j.vascn.2024.107580","DOIUrl":"10.1016/j.vascn.2024.107580","url":null,"abstract":"<div><div>Background: Antibody-drug conjugates (ADCs) are an emerging class of targeted therapeutics and are receiving growing attention in the pharmaceutical field. Here we aimed to validate two ligand binding assays for the quantitation of GQ1001, an ADC made of Trastuzumab site-specifically conjugated with DM1, in cynomolgus monkey serum, and then apply the validated assays to a nonclinical study. Methods: The quantitative methods for conjugated GQ1001 and total GQ1001 were validated against regulatory guidance documents on bioanalytical method validation under a Good Laboratory Practice (GLP)-compliant environment. The validated assays were applied to a single-dose pharmacokinetic (PK) study of GQ1001 conducted in cynomolgus monkeys. Results: Both intra- and inter-assay precision and accuracy met the priori-defined acceptance criteria. Neither matrix effect nor hemolysis effect were observed, and the impact of specific interferents on the assays was evaluated. Dilution linearity was good with the expected dilution factors and no hook effect till up to 20.2 mg/mL of GQ1001 was noted. Besides, the stability of the ADC in monkey serum was found to be sufficient to cover the time required for sample storage and analysis. Furthermore, the assays demonstrated good parallelism determined with a study sample and good reproducibility acquired by incurred sample reanalysis (ISR). Using the validated assays, we obtained serum concentrations for the conjugated GQ1001 and the total GQ1001 in the single-dose PK study, and thereafter, evaluated their exposures over the dosing period. Conclusions: All tested performance parameters of the assays met the validation acceptance criteria, which supported the application of the two assays in the nonclinical PK study and allowed the evaluation of the related PK parameters for GQ1001.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"131 ","pages":"Article 107580"},"PeriodicalIF":1.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of gene expression change associated with isoflurane anesthesia and neurocognitive disorders using bioinformatics methods","authors":"Yang Liu ,&nbsp;Ying Zhang ,&nbsp;Jialu Yu ,&nbsp;Hua Fu","doi":"10.1016/j.vascn.2025.107582","DOIUrl":"10.1016/j.vascn.2025.107582","url":null,"abstract":"<div><h3>Background</h3><div>Isoflurane, a commonly used anesthetic, has been linked to neurocognitive dysfunction (NCD). However, the precise relationship between isoflurane anesthesia and NCD remains unclear.</div></div><div><h3>Methods</h3><div>Datasets related to isoflurane anesthesia were obtained from a public database. The hub genes of isoflurane anesthesia were selected using logistic regression with the least absolute shrinkage and selection operator (LASSO). Human neuroblastoma cell line SH-SY5Y was induced to differentiate into terminal neuron-like cells.</div></div><div><h3>Results</h3><div>The signaling pathways involved in isoflurane anesthesia and NCD were subjected to analysis, resulting in the identification of 35 signaling pathways, including the PI3K/AKT pathway, the AGE-RAGE signaling pathway and the apelin signaling pathway, which were found to be associated with both NCD and isoflurane anesthesia. A total of nine cross-expressed genes (Nfe2l2, Fgf2, Edn1, Spp1, Hmox1, Picalm, Gnb5, Eif2s1 and Gls) were identified between isoflurane anesthesia and NCD. The LASSO logistic regression model was employed to identify three hub genes (Fgf2, Gnb5, Spp1). The expression of these three hub genes was validated using other expression datasets. In human neuron-like cells, isoflurane also significantly affected the expression of three corresponding human homologous genes. The expression trends of these three genes in human cells were consistent with the expression in rat brains after isoflurane treatment, providing further evidence for the rationality of the three hub genes.</div></div><div><h3>Conclusions</h3><div>The present study revealed key candidate genes and related functional signaling pathways through bioinformatics analysis and cell experiments, which may serve as the basis for isoflurane-related NCD.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"132 ","pages":"Article 107582"},"PeriodicalIF":1.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}