Toxicon最新文献

{"title":"Modelling long-term outcomes in patients with post-stroke spasticity with or without BoNT-A treatment on all-cause mortality and secondary cardiovascular events","authors":"Klemens Fheodoroff","doi":"10.1016/j.toxicon.2025.108409","DOIUrl":"10.1016/j.toxicon.2025.108409","url":null,"abstract":"<div><div>App. 25 % of stroke survivors develop post-stroke spasticity (PSS) over the first year after a stroke, and they also experience motor weakness, which may prevent effective recovery by restricting mobility and participating in exercise programmes. Patients generally experience rapid improvement with Botulinum Toxin Type A (BoNT-A) therapy for PSS. Unfortunately, clinical trials demonstrating benefits from BoNT-A treatment are of short duration. Consequently, it is not known if treatment-related improvements in mobility could also contribute to lowering the risks of secondary cardiovascular (CV) events and all-cause death.</div><div>To assess if BoNT-A injections could also have an impact on long-term outcomes, we developed a 10-year survival model comparing the effects of AbobotulinumtoxinA (aboBoNT-A) injections and rehabilitation therapy (aboBoNT-A+RT) with rehabilitation therapy (RT) alone. The Functional Independence Measure (FIM) appeared to be the only functional outcome allowing us to model the effect of aboBoNT-A injections on all-cause mortality. Stroke survivors who reported better improvement in FIM score during rehabilitation had lower risk of all-cause mortality during follow-up. Patients treated with aboBoNT-A injections + RT showed better improvement in FIM score than patients treated without aboBoNT-A injections. Our modelling results showed that the addition of aboBoNT-A injections to RT led to a reduction of 8.8 % in the risk of all-cause mortality, and a relative increase of 12.8 % in discounted life-years.</div><div>The addition of aboBoNT-A injections to RT led to an increase in total costs of £42.329 over 10 years (based on National Health Service (NHS) UK cost collection 2018/2019). In the base-case scenario, incremental costs were driven by the increased number of hours of home care and RT for patients treated with aboBoNT-A injections compared with RT alone. Assuming an incremental cost-effectiveness ratio (ICER) threshold of £30.000, the probabilistic sensitivity analysis found a 73 % likelihood that aboBoNT-A + RT demonstrated cost-effectiveness compared with RT alone.</div><div>Our work advocates for the need to consider and to capture the impact of BoNT-A injections on all-cause mortality and secondary events, such as CV events and recurrent stroke, which are prevalent in stroke survivors.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"263 ","pages":"Article 108409"},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079738","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":"Kraits of Indian subcontinent: Natural history, risks, venom variation, lethality and treatment strategies – A comprehensive review","authors":"Amit Talukdar ,&nbsp;Surajit Giri ,&nbsp;Robin Doley","doi":"10.1016/j.toxicon.2025.108406","DOIUrl":"10.1016/j.toxicon.2025.108406","url":null,"abstract":"<div><div>The World Health Organization (WHO) has re-classified “Snakebite” as a Neglected Tropical Disease in 2017, and estimated that as many as 5.4 million people suffer from snakebites every year. Out of this large number of snakebites, envenoming occurs in about 50 % of the cases, and the number of resulting deaths could be as high as 138,000. The genus <em>Bungarus</em> commonly known as kraits are medically important elapid snakes widely distributed in the Indian subcontinent, southern China and the Southeast Asian countries (except Philippines). The Indian subcontinent (India, Bangladesh, Bhutan, Nepal, Pakistan, Sri Lanka and Maldives) is home to 8–9 krait species, among which <em>B. caeruleus</em> and <em>B. niger</em> are highly venomous. This review presents the current state of knowledge on krait bites in the Indian subcontinent. The risk of envenomation by kraits, the venom lethality and krait bite management in the Indian subcontinent have been critically analyzed. Moreover, the issue of dry bites from kraits and their management has also been reviewed. Furthermore, critical aspects, such as knowledge of snakebite management among healthcare workers, clinical symptoms of snakebite patients, and treatment in healthcare facilities including antivenom administration and their clinical efficacy, have helped us in identifying the critical knowledge gaps. Proposed preventive measures will help to reduce krait bite associated mortality and morbidity. Moreover, development and accessibility to affordable treatment options may help in the effective management of krait bites.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108406"},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080649","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 double-banded false coralsnake Erythrolamprus bizona (Dipsadidae, Xenodontinae, Xenodontini) has a metalloproteinase-rich venom with proteolytic activity towards azocasein and α-fibrinogen","authors":"Kristian A. Torres-Bonilla ,&nbsp;Juan D. Bayona-Serrano ,&nbsp;Paula A. Sáenz-Suarez ,&nbsp;Luis M. Muñoz-Gómez ,&nbsp;Manuel H. Bernal-Bautista ,&nbsp;Stephen Hyslop","doi":"10.1016/j.toxicon.2025.108407","DOIUrl":"10.1016/j.toxicon.2025.108407","url":null,"abstract":"<div><div>The venom of the double-banded false coralsnake, <em>Erythrolamprus bizona</em>, is proteolytic and attenuates neuromuscular contractile activity <em>in vitro</em>. Here, we examined the Duvernoy's venom gland histology and general composition of <em>E. bizona</em> venom using a combination of chromatographic, electrophoretic, enzymatic and proteomic analyses. Histologically, the venom gland consisted of serous epithelium-lined secretory tubules and a supralabial gland that stained positively for mucopolysaccharide. SDS-PAGE showed that the venom had a simple composition, with proteins in the range of 15–60 kDa. This simple composition was confirmed by RP-HPLC that revealed 15 main protein peaks. The venom (1–10 μg) was highly proteolytic towards azocasein, but was devoid of esterase, phospholipase (PLA₂), and L-amino acid oxidase activities. The venom also degraded casein and gelatin in zymographic assays, with activity towards gelatin being particularly potent and detected over the range of 18.7 ng–30 μg of venom; gelatinolytic activity was also detected in four of the RP-HPLC peaks. The venom (10 μg) selectively degraded the α-chain of fibrinogen. All proteolytic activity was inhibited by EDTA (metalloproteinase inhibitor) but not by AEBSF (serine proteinase inhibitor). SDS-PAGE followed by in-gel digestion of the main electrophoretic bands coupled with LC-MS/MS analysis revealed the presence of five toxin families: C-type lectin-like proteins (CTL), cysteine-rich secretory proteins (CRiSP), phospholipase B (PLB), snake venom matrix metalloproteinases (svMMP), and snake venom metalloproteinases (SVMP). These findings extend our knowledge of the toxinology of <em>E. bizona</em> and suggest that the local manifestations (pain, edema, erythema, and ecchymosis) seen in human envenomation by this species are probably mediated by venom metalloproteinases.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"263 ","pages":"Article 108407"},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079828","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":"Widespread occurrence of botulinum and tetanus neurotoxin genes in ancient DNA","authors":"Shyan Mascarenhas ,&nbsp;Harold P. Hodgins ,&nbsp;Andrew C. Doxey","doi":"10.1016/j.toxicon.2025.108405","DOIUrl":"10.1016/j.toxicon.2025.108405","url":null,"abstract":"<div><h3>Background</h3><div>Ancient DNA collected from archaeological specimens not only provides a window into ancient human genetic diversity but also contains a rich mixture of associated microbial DNA including potential pathogens. In recent work, we identified <em>C. tetani</em> and tetanus neurotoxin (TeNT) genes in ancient DNA datasets collected from human archaeological specimens. However, the reasons underlying the occurrence of these toxin genes and the extent to which other toxin genes are present in ancient DNA is unclear.</div></div><div><h3>Methods</h3><div>Here, we performed a large-scale analysis of 6435 ancient DNA (aDNA) sequencing datasets including human and non-human sources, searching for 49 clostridial neurotoxin types and subtypes, and 3 additional unrelated toxins.</div></div><div><h3>Results</h3><div>Our search identified a total of 105 ancient DNA datasets (1.6 %) containing significant matches to one or more neurotoxin genes. Consistent with our earlier work, TeNT genes were most common, found in 50 ancient DNA datasets. In addition, we identified sequences encoding diverse botulinum neurotoxins including BoNT/C (40 samples), BoNT/D (6 samples), BoNT/B (4 samples), BoNT/E (1 sample), and the <em>Enterococcus</em>-associated BoNT/En (10 samples). TeNT genes were detected in a broad range of ancient samples including human and animal (horse, wild bear, chimpanzee, gorilla, dog) remains, whereas the largest diversity of toxins was detected in aDNA from Egyptian mummies. Phylogenetic and sequence analysis of the identified matches revealed close identity to modern forms of these toxins. Damage analysis revealed several toxin genes with hallmarks of ancient DNA associated damage, indicative of an ancient origin.</div></div><div><h3>Conclusions</h3><div>Our work reveals that clostridial neurotoxin genes occur frequently in aDNA samples, including human and animal-associated toxin variants. We conclude that the frequent association of these genes with aDNA likely reflects a strong ecological association of pathogenic clostridia with decaying human and animal remains and possible post-mortem colonization of these samples.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108405"},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080008","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":"Integrating postsynaptic morphology and dynamics to evaluate neuromuscular synapse status: Insights from α-bungarotoxin","authors":"Juan Pablo Henríquez ,&nbsp;Francisca Bermedo-García ,&nbsp;Diego Zelada ,&nbsp;Jessica Mella","doi":"10.1016/j.toxicon.2025.108404","DOIUrl":"10.1016/j.toxicon.2025.108404","url":null,"abstract":"<div><div>The neuromuscular junction (NMJ) is a crucial peripheral synapse that controls muscle contraction. It consists of a presynaptic motor terminal, a postsynaptic muscle domain, and associated cells, such as terminal Schwann cells and kranocytes. Its larger size compared to central synapses has allowed detailed analyses of NMJ morphology that have been widely used as a reliable parameter of synaptic formation, maturation, function, and decline. Due to its high affinity for postsynaptic acetylcholine receptors (AChRs), the snake venom-derived α-bungarotoxin (BTX) has been pivotal in advancing our understanding of NMJ organization, enabling a detailed mapping of postsynaptic morphologies associated to distinct functional outcomes. Although certain morphological features are often associated with NMJ worsening, some of these cellular changes also occur in biological contexts where synaptic function remains intact. In this review, we draw on previous studies and our recent findings using BTX-based pulse-chase assays to suggest that combining morphological analyses with assessments of postsynaptic stability offers a more comprehensive understanding of NMJ function and regenerative potential. We propose that integrating diverse BTX-based tools into studies of NMJ morphology and stability will provide particularly valuable insights in contexts such as aging, injury, and neuromuscular diseases, where these combined parameters may serve as robust predictors of functional outcomes.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108404"},"PeriodicalIF":2.6,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935534","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":"Investigation of natural diphtheria toxin as a potential anticancer agent in colorectal cancer: An in vitro analysis on HT-29 cells","authors":"Tugba Yalcinkaya ,&nbsp;Ahmet Carhan","doi":"10.1016/j.toxicon.2025.108386","DOIUrl":"10.1016/j.toxicon.2025.108386","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the fourth most common cancer worldwide and the second leading cause of cancer-related deaths. The limited efficacy of conventional treatments underscores the need for alternative strategies. Among emerging candidates, diphtheria toxin (DT) has gained attention for its selective cytotoxicity, apoptosis induction, and inhibition of cancer cell proliferation with minimal harm to healthy cells. However, studies on DT's anticancer effects in CRC remain scarce. This study evaluated the cytotoxic and apoptotic effects of DT on HT-29 colorectal cancer cells. MTT assays confirmed DT's selective cytotoxicity, showing stronger effects on HT-29 cells than on normal Vero cells. Flow cytometry revealed DT-induced G1-phase cell cycle arrest. DNA fragmentation and qRT-PCR analyses demonstrated apoptosis activation, with upregulation of pro-apoptotic genes (Bax, FasL) and downregulation of Bcl-2. Additionally, qRT-PCR assessed key molecules in apoptosis, cell cycle regulation, and DNA damage response, including GADD45α, PARP1, p38α, p53, FoxO3a, and RbL2. Our findings suggest that DT inhibits HT-29 cell proliferation, induces apoptosis, and impacts DNA damage response, highlighting its potential as a therapeutic agent requiring further investigations.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108386"},"PeriodicalIF":2.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999154","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":"Dissecting oxidative folding of conotoxins using 3D structures of cysteine mutants predicted by AlphaFold 3: A case study of α-conotoxin RgIA, χ-conotoxin CMrVIA and ω-conotoxin MVIIA-Gly","authors":"K. Radhakrishna ,&nbsp;Patil Kanchan Rajshekhar ,&nbsp;R. Arshitha ,&nbsp;Kashibai Patil,&nbsp;Shweta Dhannura,&nbsp;Konkallu Hanumae Gowd","doi":"10.1016/j.toxicon.2025.108402","DOIUrl":"10.1016/j.toxicon.2025.108402","url":null,"abstract":"<div><div>The ability of AlphaFold 3 to accurately predict the 3D structure of polypeptides has been explored to investigate the oxidative folding steps of conotoxins. The peptides α-conotoxin RgIA (α-RgIA) and χ-conotoxin CMrVIA (χ-CMrVIA) share a similar cysteine pattern but differ in their native disulfide connectivity. These short peptides, containing two intramolecular disulfides, may undergo sequential steps of disulfide formation during the oxidative folding process. The current report computed all six possible single disulfide alanine mutants of the peptides and predicted their 3D structures using the AlphaFold 3 server. The potential energy of the conformers derived from the five predicted model structures of the peptides was calculated using the OPLS4 force field in Schrödinger's MacroModel software. The relative potential energy of the single disulfide mutant peptides was computed using the Boltzmann-weighted average energy of the conformers of the corresponding peptides. [C2A,C8A]α-RgIA and [C2A,C11A]χ-CMrVIA are the most stable forms, corresponding to the native single disulfide intermediate analogues. Accordingly, the folding events for α-RgIA are C₃-C₁₂ followed by C₂-C₈, while for χ-CMrVIA, they are C₃-C₈ followed by C₂-C₁₁ connectivity. The current report also explored the native folding steps of an Inhibitory Cystine Knot (ICK) motif peptide ω-conotoxin-MVIIA-Gly using one/two cysteine disulfide alanine mutants. The computation of relative potential energy of the mutant peptides indicates the formation of C₁₅-C₂₅ followed by C₈-C₂₀ and C₁-C₁₆ disulfide bonds. The newly proposed technique that combines AlphaFold 3 with MacroModel conformational sampling tool is allowing to identify the oxidative folding steps of disulfide-rich peptides.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108402"},"PeriodicalIF":2.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942840","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":"Venom composition of Tityus cerroazul (Scorpiones: Buthidae) reveals similarities with venoms of other scorpion species from northern South America","authors":"Cecilia Díaz ,&nbsp;Marcelo Mack-Prado ,&nbsp;Eleodoro Bonilla ,&nbsp;Arturo Chang-Castillo ,&nbsp;Fabián Bonilla ,&nbsp;Natalia Ortiz ,&nbsp;Diego Angulo ,&nbsp;Mahmood Sasa","doi":"10.1016/j.toxicon.2025.108385","DOIUrl":"10.1016/j.toxicon.2025.108385","url":null,"abstract":"<div><div>Several buthid scorpions from Costa Rica and Panama have been extensively characterized for their venom components. One exception is <em>Tityus cerroazul</em>, a peculiar species classified in the subgenus <em>Tityus</em>, separated from the rest of the members of the genus that inhabit this geographic region. Although it has been described as a species that prefers natural areas with low human impact, which could explain the few reported envenomation cases, pre-clinical studies indicate that its venom may be toxic to mammals.</div><div>This analysis describes the venom composition and enzymatic activities of <em>T. cerroazul</em> specimens from Panama. Among the identified venom components, we report the presence of NaTxs TdNa5 and bactridin-1 from <em>T. discrepans</em> from Venezuela, as well as partial sequences corresponding to other putative Na+ and K+ toxins, antimicrobial peptides, protease inhibitors, and secreted proteins, mostly found in the venoms of the <em>T.</em> (<em>Atreus</em>) species. We also confirmed the presence of the four peptides (Tce1-Tce4) identified by previous molecular analyses.</div><div>In conclusion, our study suggests that <em>T. cerroazul</em> does not align closely with the venom of species currently assigned to the subgenus <em>Tityus</em>. Instead, it shows a greater similarity to the venom of the <em>Atreus</em> subgenus, which includes most of the <em>Tityus</em> species that inhabit the region. This finding underscores the need to revise its taxonomic classification based on molecular phylogenetic characters.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108385"},"PeriodicalIF":2.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942841","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":"Shining a light on the photochemical stability of peptidic bioinsecticides","authors":"Volker Herzig ,&nbsp;Andrew Ahabh ,&nbsp;Alun Jones ,&nbsp;Glenn F. King","doi":"10.1016/j.toxicon.2025.108381","DOIUrl":"10.1016/j.toxicon.2025.108381","url":null,"abstract":"<div><div>Peptide toxins from spider venoms are being increasingly hailed as environmentally friendly alternatives to market-dominating small-molecule chemical insecticides. While the stability of knotted spider-venom peptides towards enzymatic degradation, temperature changes and varying pH conditions has already been examined, their susceptibility to sunlight remains unclear. Field applications of insecticides demand that the insecticidal component is active for at least a few days to ensure sufficient eradication of the targeted insect pests. We therefore exposed four insecticidal spider-venom peptides (ω-Hv1a, ω/κ-Hv1a, Ta1a and Dc1a) to continuous artificial sunlight for up to 7 days. After certain incubation periods, we quantified the percentage of intact peptide and identified sites of peptide cleavage. We found that after 3 days of continuous exposure (=6 days of 12 h/d sunlight), the amount of remaining intact peptide was 16 % (Ta1a), 21 % (Dc1a), 55 % (ω-Hv1a), and 67 % (ω/κ-Hv1a), whereas bovine serum albumin was completely degraded. Even after 7 days (=14 days of 12 h/d sunlight) exposure, more than 50 % of ω/κ-Hv1a and ω-Hv1a remained intact. Peptides with lower molecular mass tended to be less susceptible to sunlight, while cleavage of peptide bonds involving proline or cysteine were most susceptible to photochemical degradation. The photochemical changes detected by mass spectrometry mainly comprised oxidations, deamidations, and cysteine-targeted modifications.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108381"},"PeriodicalIF":2.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036462","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":"Inhibitory role of arecaidine on PPARγ signaling in oral mucosa: Mechanistic insights from transcriptome and experimental analysis","authors":"Fanzuo Zeng ,&nbsp;Zhenkui Liu ,&nbsp;Jian Yi ,&nbsp;Bowei Chen ,&nbsp;Yin Ouyang ,&nbsp;Wanling Ning ,&nbsp;Jiongwei Tang ,&nbsp;Baiyan Liu","doi":"10.1016/j.toxicon.2025.108403","DOIUrl":"10.1016/j.toxicon.2025.108403","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to elucidate the effects of arecaidine on oral mucosa through RNA sequencing (RNA-Seq) combined with in vivo and in vitro experimental validation.</div></div><div><h3>Methods</h3><div>Based on transcriptomic analysis, we preliminarily explored the molecular targets and mechanisms by which arecaidine influences oral mucosa. Subsequent validation was performed using arecaidine-treated human primary oral mucosal fibroblasts.</div></div><div><h3>Results</h3><div>In vivo experiments revealed that the arecaidine-treated group exhibited significantly restricted oral cavity opening compared to the control group, with markedly reduced mouth-opening values. Histopathological analysis via HE staining and Masson staining demonstrated fibrotic lesions in the arecaidine-treated group. RNA-Seq libraries constructed from oral mucosal tissues identified 100 significantly differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that arecaidine influenced multiple pathways, including autoimmune thyroid disease, allograft rejection, type I diabetes, graft-versus-host disease, and the PPAR-γ signaling pathway. Notably, arecaidine significantly downregulated PPAR-γ, PCK1, pdk4, plin5, Hmgcs2, UCP3, and Angptl4, while upregulating TGF-β1, FOS, and other genes associated with the PPAR pathway. In vitro experiments confirmed that arecaidine induced substantial damage to fibroblasts, suppressing proliferation and promoting the secretion of inflammatory cytokines (e.g., IL-6, TGF-β, TNF-α) after 48 h exposure to high concentrations. Furthermore, arecaidine significantly altered the expression of molecules linked to the PPAR-γ signaling pathway.</div></div><div><h3>Conclusion</h3><div>This study delineates the transcriptomic response of oral mucosa to arecaidine through integrated in vivo and in vitro experiments, confirming its role in inducing submucosal fibrosis. The underlying mechanism is associated with dysregulation of the PPAR-γ signaling pathway.</div></div>","PeriodicalId":23289,"journal":{"name":"Toxicon","volume":"262 ","pages":"Article 108403"},"PeriodicalIF":2.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942842","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}