Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Immunopharmacological design of a multi-epitope vaccine targeting hepatitis C virus genotype 3a.","authors":"Aasia Kalsoom, Zahra Aleem, Hafiz Muzzammel Rehman, Muhammad Sajjad, Ghulam Shabbir, Muhammad Shakil Khan, Awais Altaf, Inam Ur Rahman, Metab Alharbi, Abdullah F Alasmari","doi":"10.1007/s00210-026-05944-z","DOIUrl":"https://doi.org/10.1007/s00210-026-05944-z","url":null,"abstract":"<p><p>Hepatitis C is one of the leading causes of acute and chronic hepatitis worldwide. Immunoinformatics has emerged as a reliable and practical approach for identifying immunogenic regions. We analyzed the HCV genotype 3a polyprotein for antigenicity, allergenicity, and physicochemical characteristics. Four vaccine constructs with possible immunogenic qualities were assembled. B-cell epitopes were examined to predict antigenic determinants, and T-cell epitopes were assessed for MHC class I and II binding. All were linked together using linker peptides, a reliable adjuvant, the PADRE sequence, and a His tag. All models were analyzed for structural refinement, population coverage, molecular docking, molecular dynamics, and immune simulation. The vaccine constructs exhibited antigenicity > 0.6 in E. coli, solubility > 0.8, and GRAVY values between - 0.124 and - 0.518, indicating a hydrophilic nature. The Ramachandran plot showed that 90% of residues were within the allowed regions, confirming structural stability. The vaccine constructs showed more than 99% global coverage and 97% coverage for the Pakistani population. Docking analysis showed strong binding of the Vaccine2-TLR8 and Vaccine4-TLR3 complexes, with docking energies of - 1153.5 kcal/mol and - 1015.8 kcal/mol, respectively. Molecular dynamics simulations revealed a stabilized and consistent complex of TLRs. A strong humoral response was predicted by recording IgG and IgM titers within 5 days, which remained for 35 days. In silico cloning showed successful insertion into the pET-29a ( +) vector. These results indicate that multiple-epitope vaccine constructs have strong binding properties and are good candidates for developing a vaccine against HCV3a.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112270","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":"Baicalein-loaded nanocochleates for improving oral bioavailability: design, statistical optimization, and in vivo pharmacokinetic evaluation.","authors":"Avinash S Poojari, Yogesh A Kulkarni, Sarika Wairkar","doi":"10.1007/s00210-026-05959-6","DOIUrl":"https://doi.org/10.1007/s00210-026-05959-6","url":null,"abstract":"<p><p>Baicalein, a naturally occurring flavonoid, exhibits potent lipoxygenase-inhibitory, anti-inflammatory, and immunomodulatory activities that are beneficial for treating osteoporosis. However, its poor aqueous solubility, low oral bioavailability, and extensive presystemic metabolism restrict its clinical applicability. Thus, the present work aimed to develop baicalein-loaded nanocochleates to improve its oral bioavailability. Baicalein-loaded nanocochleates were prepared from preformed liposomes using the trapping method and further statistically optimized using a 3-factor, 3-level Box-Behnken Design (BBD). The optimized batch showed a particle size of 230.53 ± 7.86 nm, a polydispersity index (PDI) of 0.39 ± 0.01, a zeta potential of -19.07 ± 1.21 mV, and an entrapment efficiency of 93.50 ± 1.32%. Further, DSC and ATR-FTIR results confirmed the successful encapsulation of baicalein within the lipid matrix of nanocochleates, while TEM images revealed elongated, rod-like nanocochleate structures. Importantly, the optimized formulation showed 88.59 ± 1.53% drug release over 24 h compared with baicalein-loaded liposomes (96.10 ± 7.03%), indicating sustained drug release. In vivo oral pharmacokinetic studies demonstrated a 1.49-fold and 11.50-fold increase in C_max and a 2.47-fold and 14.71-fold increase in AUC_0-24 h compared with baicalein-loaded liposomes and plain baicalein, respectively. Collectively, the results suggest that nanocochleates represent a promising carrier system to improve the oral bioavailability of baicalein.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112355","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":"Structural and proliferative responses of the prostate to abrupt versus tapered discontinuation of dutasteride in short- and long-term treated rats.","authors":"Ahmed A Morsi, Ezat A Mersal, Nihal Almuraikhi, Ghaiath Hussein, Thamer Almutairi, Heba Almuslet, Hasnaa Almuslet, Ali Almuslet, Nehad Ahmed Sadek","doi":"10.1007/s00210-026-05922-5","DOIUrl":"https://doi.org/10.1007/s00210-026-05922-5","url":null,"abstract":"<p><p>This study aimed to assess the structural response of the normal prostate during its recovery following dutasteride discontinuation, either abruptly or gradually, in short-term or long-term treated rats. Fifty-six adult male Wistar rats were randomly allocated into seven groups: a control group and two dutasteride-treated groups (for 4 or 8 weeks, 0.5 mg/kg/day, orally). Furthermore, each corresponding group of the 4- and 8-week groups was subjected to abrupt or tapered drug discontinuation. At the end, blood samples were withdrawn for testosterone (T) and dihydrotestosterone (DHT) analyses. Ventral prostates (VP) were resected and subjected to hematoxylin and eosin (H&E) and Masson trichrome (MTC) staining. Besides, polymerase chain reaction (PCR) analysis and immunohistochemical identification of proliferating cell nuclear antigen (PCNA), caspase-3, and androgen receptors (AR) were performed. After 4 and 8 weeks of treatment, VP showed acinar trophic changes with reduced epithelial thickness in H&E, increased Masson-stained collagen distribution area, suppression of proliferation marker PCNA, activation of apoptosis, and AR downregulation. Discontinuation of dutasteride, whether abruptly or gradually, after short-term treatment showed prostate re-expansion and proliferation in both designs of withdrawal. However, in long-term dutasteride-treated rats, tapered discontinuation maintained the attained atrophic changes provoked in the prostate versus abrupt discontinuation. Abrupt discontinuation was associated with enhanced AR expression coupled with prostate proliferation and caspase-3 downregulation, leading to marked prostate rebound. As a preclinical study, it was concluded that the duration of exposure and the discontinuation design, whether abrupt or tapered, were found to have an impact on the prostate's recovery following dutasteride cessation. Abrupt discontinuation was linked to structural prostate rebound, which may be explained by AR upregulation.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112265","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":"Vildagliptin attenuates the development of CCl₄-induced liver fibrosis: associations with gut-liver axis modulation and LPS/notch-related signaling.","authors":"Aya M Eid, Ahmed O El-Gendy, Mohamed Gamal El-Din Ewees","doi":"10.1007/s00210-026-05961-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05961-y","url":null,"abstract":"<p><p>Liver fibrosis is a progressive pathological condition closely linked to gut microbiota dysbiosis and impaired intestinal barrier integrity. Vildagliptin, a dipeptidyl peptidase-4 inhibitor used in type 2 diabetes, exhibits pleiotropic anti-inflammatory and antioxidant properties; however, its impact on the gut-liver axis during hepatic fibrogenesis remains insufficiently defined. This experimental study investigated whether concomitant vildagliptin administration attenuates the development of CCl₄-induced liver fibrosis and whether this effect is associated with alteration in gut microbial composition, intestinal barrier-related markers, and circulating lipopolysaccharide (LPS), and hepatic fibrosis-associated molecular changes. Male rats were allocated to five groups: normal control, Vildagliptin alone (20 mg/kg/day), CCl₄-fibrosis, and CCl₄ + Vildagliptin (10 or 20 mg/kg/day). Liver fibrosis was induced by CCl₄ administration for six weeks, with concomitant daily oral Vildagliptin in the treatment groups. Liver function indices, fibrotic markers, oxidative stress parameters, and serum LPS were assessed. Intestinal barrier-related changes were assessed by measuring colonic ZO-1 and occludin levels, while circulating LPS was quantified as a marker of systemic endotoxemia. Hepatic ADAM17, Notch-1, DNMT3A, and Smad7 protein levels and β-Klotho mRNA expression were assessed. Liver and colon histopathology was examined, and gut microbiota composition was profiled using 16S rRNA gene amplicon sequencing. Vildagliptin significantly ameliorated CCl₄-induced liver injury and fibrosis, evidenced by improved biochemical parameters, reduced collagen deposition and hydroxyproline, and attenuation of hepatic stellate cell activation. These effects were accompanied by increased colonic ZO-1 and occludin levels, reduced circulating LPS, decreased hepatic ADAM17, Notch-1, and DNMT3A protein levels, increased β-Klotho mRNA expression and Smad7 protein levels, and alterations in gut microbiota composition. Collectively, concomitant vildagliptin administration attenuated the development of CCl₄-induced liver fibrosis and was associated with modulation of gut-liver axis -related changes and alterations in LPS- and Notch-related molecular markers.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112275","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":"Development of ursolic acid-loaded cubosomal nanocarriers: enhanced dissolution, pharmacokinetics, bioavailability, and anticancer activity.","authors":"Amol Patil, Durgacharan Bhagwat, Harinath More, Vijay Kumbar, Madhu Gupta","doi":"10.1007/s00210-026-05967-6","DOIUrl":"https://doi.org/10.1007/s00210-026-05967-6","url":null,"abstract":"<p><p>Ursolic acid (UA) is a promising anticancer agent whose therapeutic application is hindered by poor aqueous solubility, limited permeability, rapid elimination, and low oral bioavailability. In this study, UA-loaded cubosomal nanoparticles (UA-CN) were developed and optimized using a three-factor, three-level Box-Behnken design. The effects of glyceryl monooleate, Poloxamer 407, and microfluidization cycles on particle size, zeta potential, and entrapment efficiency were systematically evaluated. The optimized UA-CN exhibited a particle size of 131.9 ± 4.12 nm, zeta potential of - 44.2 ± 3.67 mV, and entrapment efficiency of 96.16 ± 1.89%. FTIR, XRD, and DSC analyses supported UA incorporation into the cubosomal matrix and a reduction in its crystalline character. In vitro dissolution studies demonstrated markedly enhanced drug release from UA-CN, with approximately 90% of UA released within 24 h compared with 38% from the pure drug. Pharmacokinetic evaluation in rabbits showed an approximately six-fold increase in oral bioavailability following UA-CN administration. The optimized cubosomal formulation also exhibited enhanced anticancer activity, supporting its potential to improve the biopharmaceutical performance of UA and its utility as a nanocarrier for breast cancer therapy.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112412","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":"Repurposing FDA approved drugs targeting IL-6 associated signalling for the management of rheumatoid arthritis: an in silico and experimental approach.","authors":"Dhawal Jain, Anugya Gupta, Vipul Agarwal, Bhuvnesh Kumar Singh, Amit Chaudhary, Pranesh Kumar","doi":"10.1007/s00210-026-05964-9","DOIUrl":"https://doi.org/10.1007/s00210-026-05964-9","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that is mediated by pro-inflammatory cytokines, like interleukin-6 (IL-6). IL-6 plays an important role in synovial inflammation and joint degradation. In this study, a combined in silico, in vitro and in vivo approach was used to identify and preliminarily evaluate valganciclovir hydrochloride as potential modulator of IL-6 receptor mediated inflammatory signalling. Docking studies showed that valganciclovir hydrochloride had favourable binding affinity with IL-6 receptor, and interacted stably with active site. ADMET analysis showed that compound possessed desirable ADMET properties, with good absorption and distribution, and low toxicity. Molecular binding free energy indicated stability of the protein-ligand complex. Moreover, 100 ns molecular dynamics simulation showed stable RMSD, with consistent key interactions, suggesting a dynamically stable protein-ligand complex in the physiological environment. Binding assay further demonstrated concentration dependent inhibition of IL-6:IL-6R interaction. Furthermore, in vivo assessment in collagen induced arthritis rats showed that treatment with valganciclovir hydrochloride resulted in marked reduction in disease severity. The treatment groups demonstrated a decrease in paw swelling, ESR, CRP, RF and IL-6 expression. Treatment also reduced downstream inflammatory mediators such as IL-17, MMP-9, p-STAT3, STAT3 and JAK2, suggesting attenuation of IL-6 associated inflammatory signalling In addition, antioxidant enzyme levels were restored with reduction in lipid peroxidation. The results indicate that valganciclovir hydrochloride has favourable binding interactions, and pharmacokinetics, as well as strong anti-inflammatory and anti-arthritic potential. The combined computational and experimental results support the possible involvement of IL-6/JAK2/STAT3 associated signalling pathways in observed anti-arthritic effects of valganciclovir hydrochloride.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112310","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":"Institute-created electronic flashcards, associated development effort, and exam performance in pharmacology education in human medicine.","authors":"Fridtjof Harder, Holger Barth, Susanne Hafner","doi":"10.1007/s00210-026-05954-x","DOIUrl":"https://doi.org/10.1007/s00210-026-05954-x","url":null,"abstract":"<p><p>Electronic flashcards are popular among medical students, although their real-world effectiveness, and staff resources required to develop tailored decks, is not well understood. The Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products at the Ulm University Medical Center, Germany, created 1007 flashcards on 228 drugs aligned to the local and national curriculum using the Anki flashcard software. The time needed for card development was documented. Medical students participated in an observational study over four semesters and were encouraged to use the cards alongside established study materials for exam preparation in clinical pharmacology. Exams concluded either a lecture-based course focusing on declarative knowledge, or concluded a seminar-based course focusing on case-based application. A survey assessed usage patterns and helpfulness of flashcards and other study materials, demographics, and self-rated general academic performance. Pseudonymous codes linked survey responses to individual exam scores. Flashcard use was reported by 38.4% of participants overall, with higher use when preparing for lecture-based exams than for seminar-based exams. In total, 83.3% of users considered the cards helpful. Participants with lower self-rated general academic performance were more likely to use flashcards. Flashcard users scored lower in the exam than non-users, but this association was no longer significant after adjusting for self-rated general academic performance. Flashcard development took on average 7 min per card. These findings suggest that academically weaker students, and students preparing for exams testing declarative knowledge, may prefer flashcards. Given the substantial staff time required, and the lacking benefit of our flashcard-decks, the decision to tailor curriculum-aligned flashcards should be made cautiously.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112283","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":"Hypersensitivity reactions to pertuzumab/trastuzumab fixed-dose combination (PHESGO®): successful management with a simplified 9-step subcutaneous desensitization protocol.","authors":"Mattia Cristallo, Mirco Filieri, Luigia Stefania Stucci, Nada Chaoul, Marcello Albanesi, Cataldo Piarulli, Attilio Di Girolamo","doi":"10.1007/s00210-026-05957-8","DOIUrl":"https://doi.org/10.1007/s00210-026-05957-8","url":null,"abstract":"<p><p>Hypersensitivity reactions (HSRs) to anti-HER2 monoclonal antibodies may limit access to optimal therapy in HER2-positive breast cancer. HSRs have been reported with both intravenous pertuzumab/trastuzumab and the fixed-dose subcutaneous pertuzumab/trastuzumab formulation, including severe systemic reactions and anaphylaxis, although the overall incidence is low. We describe a patient with metastatic HER2-positive breast cancer who developed an immediate hypersensitivity reaction during intravenous pertuzumab administration followed by recurrent delayed cutaneous manifestations after anti-HER2 treatment and, subsequently, after subcutaneous PHESGO® administration. Diagnostic work-up revealed selective intradermal reactivity to pertuzumab, whereas trastuzumab remained consistently negative. A CFSE-based lymphocyte proliferation assay demonstrated increased CD3⁺ T-cell and CD19⁺ B-cell proliferation predominantly after stimulation with the combined pertuzumab/trastuzumab formulation. These findings, together with the clinical history, identified pertuzumab as the most likely culprit and were consistent with a mixed immediate/delayed hypersensitivity phenotype. A simplified 9-step subcutaneous desensitization protocol enabled administration of the full therapeutic dose of PHESGO® without breakthrough reactions and was successfully repeated in subsequent cycles. This case highlights the value of combining skin testing with functional cellular assays to improve immune characterization and supports the feasibility of simplified subcutaneous desensitization for fixed-dose anti-HER2 biologics.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112254","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":"A multi-omics and machine-learning framework reveals shared druggable targets for Alzheimer's disease and periodontitis and identifies amentoflavone and taraxerone as potential dual-action natural products.","authors":"Yeke Wu, Shuang Li, Ximei Zhang, Qianrong Xu, Bingjun Chen, Wenbin Yang, Min Liu, Jiawei Li, Xiang He, Juan Li, Wenbin Wu","doi":"10.1007/s00210-026-05953-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05953-y","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Alzheimer's disease (AD) and periodontitis (PD) are highly prevalent chronic disorders in ageing populations and share multiple pathological features, particularly persistent inflammatory and immune dysregulation. Despite increasing evidence supporting an association between the two diseases, the shared druggable molecular mechanisms underlying their comorbidity remain incompletely understood, and effective therapeutic strategies capable of simultaneously targeting shared disease-related processes are limited. This study aimed to identify shared druggable molecular candidates associated with AD and PD and to evaluate the potential biological effects of the natural products amentoflavone (AF) and taraxerone (TA) in AD-PD-related inflammatory cell models. An integrative strategy combining Mendelian randomisation (MR), transcriptomic profiling, machine learning, and structure-based virtual screening was used to identify and prioritise shared molecular candidates associated with AD and PD. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate the predicted binding modes and interaction stability of AF and TA with selected core proteins. In vitro experiments were conducted using LPS-induced mouse BV2 microglia and mouse primary gingival fibroblasts (MGFs) to assess the effects of AF and TA, alone and in combination, on core-gene expression, inflammatory mediator secretion, oxidative stress, apoptosis, and iNOS/CD206-defined microglial activation states. MR, transcriptomic, and machine-learning analyses prioritised six shared key genes, including FCGRT, LTBP1, CD59, SPRED1, SURF2, and ZDHHC2, with FCGRT, SPRED1, and SURF2 selected for subsequent structural and cellular investigations. Molecular docking and MD simulations suggested stable predicted interactions of AF and TA with these three proteins. AF formed persistent hydrogen-bond networks, particularly in the SPRED1 and SURF2 complexes, whereas TA interactions were predominantly hydrophobic. MM-PBSA analysis yielded favourable binding free energies ranging from - 62.4 to - 99.7 kJ/mol. AF at 10 µM and TA at 20 µM were selected as non-cytotoxic working concentrations for subsequent cellular experiments. Both compounds partially restored LPS-associated alterations in FCGRT, SPRED1, and SURF2 expression, reduced TNF-α, IL-1β, and IL-6 secretion, increased IL-10 production, attenuated oxidative stress by reducing ROS, MDA, and NO levels while increasing SOD activity, decreased apoptosis, and shifted the iNOS/CD206-defined microglial activation profile away from an LPS-induced pro-inflammatory state toward an anti-inflammatory or repair-associated response. AF + TA co-treatment produced greater combined effects than either single treatment in several assays; however, quantitative combination analyses are required to determine whether these effects represent pharmacological synergy or additive interactions. This study identified FCGRT, SPRED1, and SURF2 as prioritised","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081456","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":"Aflatoxin-associated hepatocarcinogenesis in a changing climate: the gut microbiome as a missing link in the One Health framework.","authors":"Precious Adeoye Oyedokun, Victor Pelumi Owolabi, Marvelous Dasola Oyedokun, James Ajigasokoa Ndako, Peter Ifeoluwa Adegbola, Nicodemus Adeyemi Oyedokun","doi":"10.1007/s00210-026-05921-6","DOIUrl":"https://doi.org/10.1007/s00210-026-05921-6","url":null,"abstract":"<p><p>Global anthropogenic climate change is restructuring the thermohygric parameters that govern Aspergillus flavus and Aspergillus parasiticus ecology, expanding the geographic range and contamination intensity of aflatoxin in staple food crops worldwide. Aflatoxin B1, a Group 1 IARC carcinogen and the most potent naturally occurring hepatocarcinogen, undergoes CYP3A4/CYP1A2-mediated bioactivation to the exo-8,9-epoxide, which alkylates N7-guanine residues in DNA, generating AFB1-N7-guanine adducts that produce G → T transversions culminating in the TP53 R249S gain-of-function mutation, a molecular fingerprint of aflatoxin-driven hepatocellular carcinoma. Beyond direct genotoxicity, AFB1 drives mitochondrial dysfunction through oxidative phosphorylation impairment, glutathione depletion, cardiolipin peroxidation, and mitochondrial membrane potential collapse. It activates NF-κB, STAT3, and TGF-β inflammatory signaling; and engages hepatic stellate cells in fibrogenesis culminating in cirrhosis. Critically, AFB1 also disrupts the gut microbiome, depleting butyrateproducing Ruminococcaceae, Faecalibacterium prausnitzii, and Akkermansia muciniphila while expanding pro-inflammatory Proteobacteria and Enterobacteriaceae. These dysbiotic changes compromise tight junction integrity, increase intestinal permeability, elevate portal LPS, and activate hepatic TLR4/MyD88/NF-κB and NLRP3 inflammasome cascades that amplify the carcinogenic consequences of direct AFB1 genotoxicity. This review integrates mechanistic evidence from molecular toxicology, microbiome biology, immunometabolism, and systems oncology to establish a unified framework positioning gut dysbiosis as a modifiable intermediate pathway in climate-sensitive aflatoxin-driven carcinogenesis.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075436","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}