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Cvill6 and Cvill7: Potent and Selective Peptide Blockers of Kv1.2 Ion Channel Isolated from Mexican Scorpion Centruroides villegasi. Cvill6和Cvill7:墨西哥蝎Kv1.2离子通道强效和选择性肽阻断剂
IF 3.9 3区 医学
Toxins Pub Date : 2025-06-04 DOI: 10.3390/toxins17060279
Kashmala Shakeel, Muhammad Umair Naseem, Timoteo Olamendi-Portugal, Fernando Z Zamudio, Lourival Domingos Possani, Gyorgy Panyi
{"title":"Cvill6 and Cvill7: Potent and Selective Peptide Blockers of Kv1.2 Ion Channel Isolated from Mexican Scorpion <i>Centruroides villegasi</i>.","authors":"Kashmala Shakeel, Muhammad Umair Naseem, Timoteo Olamendi-Portugal, Fernando Z Zamudio, Lourival Domingos Possani, Gyorgy Panyi","doi":"10.3390/toxins17060279","DOIUrl":"10.3390/toxins17060279","url":null,"abstract":"<p><p>Scorpion venoms are a rich source of peptides that modulate the activity of ion channels and can serve as a new drug for channelopathies. Cvill6 and Cvill7 are two new peptides isolated from the venom of <i>Centruroides villegasi</i> with MW of 4277 Da and 4287 Da and they consist of 38 and 39 amino acids, respectively, including six cysteines. Sequence alignment revealed high similarity with members of the α-KTx2 subfamily of potassium channel toxins. In electrophysiology, Cvill7 potently inhibited Kv1.2 ion channels with an IC<sub>50</sub> of 16 pM and Kv1.3 with an IC<sub>50</sub> of 7.2 nM. In addition, it exhibited partial activity on KCa3.1 and Kv1.1, with ~16% and ~34% inhibition at 100 nM, respectively. In contrast, Cvill6 blocked Kv1.2 with low affinity (IC<sub>50</sub> of 3.9 nM) and showed modest inhibition of Kv1.3 (~11%) and KCa3.1 (~27%) at 100 nM concentration. Neither peptide showed any activity against other K<sup>+</sup> channels tested in this study (Kv1.5, Kv11.1, KCa1.1, and KCa2.2). Notably, Cvill7 has a remarkable affinity for Kv1.2 and high selectivity of 450-fold over Kv1.3 and 12,000-fold over Kv1.1. These pharmacological properties make Cvill7 a potential candidate to target Kv1.2 gain of function (GOF)-related channelopathies such as epilepsy.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single Tri-Epitopic Antibodies (TeAbs) to Botulinum Neurotoxin Serotypes B, E, and F Recapitulate the Full Potency of a Combination of Three Monoclonal Antibodies in Toxin Neutralization. 针对肉毒杆菌神经毒素血清型B、E和F的单一三表位抗体(TeAbs)再现了三种单克隆抗体组合在毒素中和中的全部效力。
IF 3.9 3区 医学
Toxins Pub Date : 2025-06-04 DOI: 10.3390/toxins17060281
Jianlong Lou, Wei Hua Wen, Fraser Conrad, Christina C Tam, Consuelo Garcia-Rodriguez, Shauna Farr-Jones, James D Marks
{"title":"Single Tri-Epitopic Antibodies (TeAbs) to Botulinum Neurotoxin Serotypes B, E, and F Recapitulate the Full Potency of a Combination of Three Monoclonal Antibodies in Toxin Neutralization.","authors":"Jianlong Lou, Wei Hua Wen, Fraser Conrad, Christina C Tam, Consuelo Garcia-Rodriguez, Shauna Farr-Jones, James D Marks","doi":"10.3390/toxins17060281","DOIUrl":"10.3390/toxins17060281","url":null,"abstract":"<p><p>Recombinant monoclonal antibody (mAb) botulinum neurotoxin (BoNT) antitoxins, consisting of three mAbs that bind non-overlapping epitopes, are highly potent. However, the three-mAb mixtures pose unique development and manufacturing challenges. Combining even more mAbs to create multivalent antitoxin drugs multiplies those challenges. We previously reported that a single tri-epitopic IgG1-based mAb (TeAb) containing the variable domains of the three parental BoNT/A mAbs and an Fc was as potent as the combination of three IgGs in the mouse neutralization assay (MNA). Here, we extended the tri-epitopic strategy to three other BoNT serotypes. Each TeAb (TeAb-B for BoNT/B, TeAb-E for BoNT/E, and TeAb-F for BoNT/F) binding was measured using fluorescence-activated cell sorting and flow fluorimetry, and the potency was tested in the MNA. The three TeAbs displayed binding affinities that were the same within error of the parental IgGs for each epitope, and all had higher avidity to each serotype of BoNT than that of the parental mAbs. The potency of the BoNT/B, BoNT/E, and BoNT/F TeAbs was similar to the combinations of the three parental IgGs binding BoNT/B, BoNT/E, and BoNT/F in the MNA. We now have four examples of a single TeAb recapitulating the affinity and in vivo potency of a three-mAb antitoxin. The tri-epitopic strategy could be applied to streamline the production and bioanalytics of antibody drugs where three-mAb binding is required for activity.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Combination of Rhamnetin and RXP03 Mitigates Venom-Induced Toxicity in Murine Models: Preclinical Insights into Dual-Target Antivenom Therapy. 鼠李素和RXP03联合使用可减轻小鼠模型中蛇毒诱导的毒性:双靶点抗蛇毒治疗的临床前研究
IF 3.9 3区 医学
Toxins Pub Date : 2025-06-04 DOI: 10.3390/toxins17060280
Jianqi Zhao, Guangyao Liu, Xiao Shi, Chunhong Huang
{"title":"Combination of Rhamnetin and RXP03 Mitigates Venom-Induced Toxicity in Murine Models: Preclinical Insights into Dual-Target Antivenom Therapy.","authors":"Jianqi Zhao, Guangyao Liu, Xiao Shi, Chunhong Huang","doi":"10.3390/toxins17060280","DOIUrl":"10.3390/toxins17060280","url":null,"abstract":"<p><p>Snakebite is a significant global public health challenge, and the limited application of antivenom has driven the exploration of novel therapies. Combination therapy using small-molecule drugs targeting phospholipases A<sub>2</sub> (PLA2) and metalloproteinases (SVMP) in venom shows great potential. Although Rhamnetin and RXP03 exhibit notable anti-phospholipase and anti-metalloproteinase activities, respectively, their antiophidic potential remains poorly explored. This study aims to evaluate the inhibitory effects of Rhamnetin and RXP03 on snake venom toxicity. Methodologically, we conducted in vitro enzymatic assays to quantify PLA<sub>2</sub>/SVMP inhibition, murine models of envenomation (subcutaneous/intramuscular venom injection) to assess local tissue damage and systemic toxicity, and histopathological/biochemical analyses. In vitro experiments demonstrated that Rhamnetin effectively inhibited PLA<sub>2</sub> activity while RXP03 showed potent suppression of SVMP activity, with their combination significantly reducing venom-induced hemorrhagic activity. In murine models, the combined therapy markedly alleviated venom-triggered muscle toxicity and ameliorated oxidative stress. Furthermore, the combination enhanced motor performance and survival rate in mice, improved serum biochemical parameters, corrected coagulation disorders, and attenuated pathological damage in liver, kidney, heart, and lung tissues. This research demonstrates that dual-targeted therapy against metalloproteinases and phospholipases in snake venom can effectively prevent a series of injuries caused by snake venom. Collectively, the combined application of Rhamnetin and RXP03 exhibits significant inhibitory effects on a variety of venom-induced toxicities, providing pharmacological evidence for the development of antivenom therapies. However, the efficacy validation in this study was limited to murine models, and there is a discrepancy with clinical needs for delayed treatment in real-world envenomation scenarios. Despite these limitations, the findings provide robust preclinical evidence supporting the Rhamnetin-RXP03 combination therapy as a cost-effective, broad-spectrum antivenom strategy. Future studies are required to optimize dosing regimens and evaluate clinical translatability.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Time-Resolved Visualization of Cyanotoxin Synthesis via Labeling by the Click Reaction in the Bloom-Forming Cyanobacteria Microcystis aeruginosa and Planktothrix agardhii. 通过点击反应标记蓝藻绿微囊藻和浮藻藻中蓝藻毒素合成的时间分辨可视化。
IF 3.9 3区 医学
Toxins Pub Date : 2025-06-03 DOI: 10.3390/toxins17060278
Rainer Kurmayer, Rubén Morón Asensio
{"title":"Time-Resolved Visualization of Cyanotoxin Synthesis via Labeling by the Click Reaction in the Bloom-Forming Cyanobacteria <i>Microcystis aeruginosa</i> and <i>Planktothrix agardhii</i>.","authors":"Rainer Kurmayer, Rubén Morón Asensio","doi":"10.3390/toxins17060278","DOIUrl":"10.3390/toxins17060278","url":null,"abstract":"<p><p>In non-ribosomal peptide synthesis of cyanobacteria, promiscuous adenylation domains allow the incorporation of clickable non-natural amino acids into peptide products-namely into microcystins (MCs) or into anabaenopeptins (APs): 4-azidophenylalanine (Phe-Az), <i>N</i>-propargyloxy-carbonyl-L-lysine (Prop-Lys), or <i>O</i>-propargyl-L-tyrosine (Prop-Tyr). Subsequently, chemo-selective labeling is used to visualize the clickable cyanopeptides using Alexa Fluor 488 (A488). In this study, the time-lapse build up or decline of azide- or alkyne-modified MCs or APs was visualized during maximum growth, specifically MC biosynthesis in <i>Microcystis aeruginosa</i> and AP biosynthesis in <i>Planktothrix agardhii</i>. Throughout the time-lapse build up or decline, the A488 signal occurred with heterogeneous intracellular distribution. There was a fast increase or decrease in the A488 signal for either Prop-Tyr or Prop-Lys, while a delayed or unobservable A488 signal for Phe-Az was related to increased cell size as well as a reduction in growth and autofluorescence. The proportion of clickable MC/AP in peptide extracts as recorded by a chemical-analytical technique correlated positively with A488 labeling intensity quantified via laser-scanning confocal microscopy for individual cells or via flow cytometry at the population level. It is concluded that chemical modification of MC/AP can be used to track intracellular dynamics in biosynthesis using both analytical chemistry and high-resolution imaging.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative Ecotoxicological Effects of Cyanobacterial Crude Extracts on Native Tropical Cladocerans and Daphnia magna. 蓝藻粗提物对原生热带枝大洋和大水蚤的生态毒理学比较研究。
IF 3.9 3区 医学
Toxins Pub Date : 2025-06-02 DOI: 10.3390/toxins17060277
Cesar Alejandro Zamora-Barrios, Marcos Efrén Fragoso Rodríguez, S Nandini, S S S Sarma
{"title":"Comparative Ecotoxicological Effects of Cyanobacterial Crude Extracts on Native Tropical Cladocerans and <i>Daphnia magna</i>.","authors":"Cesar Alejandro Zamora-Barrios, Marcos Efrén Fragoso Rodríguez, S Nandini, S S S Sarma","doi":"10.3390/toxins17060277","DOIUrl":"10.3390/toxins17060277","url":null,"abstract":"<p><p>Freshwater cyanobacterial harmful algal blooms (FCHABs) alter zooplankton communities, often adversely, through the production of cyanotoxins. While <i>Daphnia magna</i> is frequently used to evaluate the impact of toxicants, it is not commonly found in tropical waters; cladocerans from tropical and subtropical waterbodies should be used in bioassays. Here, we evaluated the impact of crude cyanobacteria extracts on three common, native species (<i>Daphnia laevis</i>, <i>Ceriodaphnia dubia</i>, and <i>Simocephalus vetulus</i>) based on acute and chronic bioassays. We analyzed the toxicity of cyanobacterial consortium collected from Lake Zumpango, Mexico. The FCHAB was dominated by <i>Planktothrix agardhii</i> (1.16 × 10<sup>6</sup> ind mL<sup>-1</sup>). A series of freeze/thaw/sonification cycles at 20 kHz was used to extract the toxic metabolites and the concentration of dissolved microcystin-LR equivalents was measured using an ELISA immunological kit. <i>S. vetulus</i> was the most sensitive species, with a median lethal concentration of 0.43 compared to 1.19 µg L<sup>-1</sup> of <i>D. magna</i> at 48 h. <i>S. vetulus</i> was also the most sensitive in chronic evaluations, showing a negative rate of population increase (-0.10 d<sup>-1</sup>) in experiments with 20% crude extract.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Elias University Hospital Approach: A Visual Guide to Ultrasound-Guided Botulinum Toxin Injection in Spasticity: Part II-Proximal Upper Limb Muscles. 伊莱亚斯大学医院方法:超声引导肉毒杆菌毒素注射痉挛的视觉指南:第二部分-上肢近端肌肉。
IF 3.9 3区 医学
Toxins Pub Date : 2025-05-31 DOI: 10.3390/toxins17060276
Marius Nicolae Popescu, Claudiu Căpeț, Cristina Beiu, Mihai Berteanu
{"title":"The Elias University Hospital Approach: A Visual Guide to Ultrasound-Guided Botulinum Toxin Injection in Spasticity: Part II-Proximal Upper Limb Muscles.","authors":"Marius Nicolae Popescu, Claudiu Căpeț, Cristina Beiu, Mihai Berteanu","doi":"10.3390/toxins17060276","DOIUrl":"10.3390/toxins17060276","url":null,"abstract":"<p><p>Ultrasound-guided botulinum toxin type A (BoNT-A) injections play a critical role in the management of upper limb spasticity. This is the second part of 'The Elias University Hospital Approach: A Visual Guide to Ultrasound-Guided Botulinum Toxin Injection in Spasticity' and it focuses on the proximal upper limb muscles, complementing the first part, which addressed the distal upper limb muscles. This guide provides a detailed analysis of ultrasound anatomy, clinical relevance, and injection strategies for the latissimus dorsi, teres major, subscapularis, pectoralis major, pectoralis minor, deltoid, triceps brachii, biceps brachii, brachialis, and brachioradialis. Using the Elias University Hospital (EUH) model, it presents a structured approach to BoNT-A administration, ensuring precision, safety, and optimal outcomes in spasticity management. To enhance clinical application, this guide incorporates a wide array of high-quality ultrasound images and dynamic videos, offering a comprehensive and practical understanding of scanning techniques, anatomical structures, and injection procedures. This second part of the series serves as an essential reference for clinicians, aligning with the first installment to provide a complete and systematic approach to ultrasound-guided BoNT-A therapy for upper limb spasticity.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Modulation of the Antioxidant System of Caco-2 Cells in the Presence of Aflatoxin B1, Ochratoxin A, and Ferulic Acid. 黄曲霉毒素B1、赭曲霉毒素A和阿魏酸对Caco-2细胞抗氧化系统的调节
IF 3.9 3区 医学
Toxins Pub Date : 2025-05-30 DOI: 10.3390/toxins17060274
Andreea-Luminița Rădulescu, Roua Gabriela Popescu, Mihaela Balas, George Cătălin Marinescu, Anca Dinischiotu
{"title":"Modulation of the Antioxidant System of Caco-2 Cells in the Presence of Aflatoxin B1, Ochratoxin A, and Ferulic Acid.","authors":"Andreea-Luminița Rădulescu, Roua Gabriela Popescu, Mihaela Balas, George Cătălin Marinescu, Anca Dinischiotu","doi":"10.3390/toxins17060274","DOIUrl":"10.3390/toxins17060274","url":null,"abstract":"<p><p>Food security and food safety are major aspects for human and animal health, yet mycotoxins contaminate 60-80% of food crops before and after harvest, elevating the risk of chronic toxicity and cancer development. This study investigates the potential of ferulic acid (FA) as an antioxidant against mycotoxin-induced oxidative stress in Caco-2 cells exposed to aflatoxin B1 (AFB1) and ochratoxin A (OTA) for 24 and 48 h. The effects on the degree of lipid peroxidation and non-enzymatic and enzymatic mechanisms against oxidative stress were evaluated. FA appears to mitigate oxidative stress by modulating lipid and protein oxidation, decreasing the level of 4-hydroxy-2-nonenal (4-HNE), increasing superoxide dismutase (SOD) activity, and preserving thiol groups by scavenging reactive oxygen species (ROS). Additionally, the reduction in polyubiquitinated Nrf2 level, and higher SOD activity, suggest that FA stabilizes Nrf2, delaying its degradation and reinforcing its antioxidant role. These findings indicate that FA partially counteracts mycotoxin-induced oxidative damage, highlighting the need for further investigation into its long-term effects.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of the IL-6/STAT3 Signaling Axis in the Protective Effect of Selenomethionine Against Zearalenone-Induced Hepatic Inflammatory Injury in Rabbits. IL-6/STAT3信号轴在硒代蛋氨酸对玉米赤霉烯酮诱导兔肝脏炎症损伤的保护作用中的作用
IF 3.9 3区 医学
Toxins Pub Date : 2025-05-30 DOI: 10.3390/toxins17060275
Xiaoguang Chen, Wenjuan Wei, Haonan Li, Wenjing Xu, Qiongxia Lv, Yumei Liu, Ziqiang Zhang
{"title":"Role of the IL-6/STAT3 Signaling Axis in the Protective Effect of Selenomethionine Against Zearalenone-Induced Hepatic Inflammatory Injury in Rabbits.","authors":"Xiaoguang Chen, Wenjuan Wei, Haonan Li, Wenjing Xu, Qiongxia Lv, Yumei Liu, Ziqiang Zhang","doi":"10.3390/toxins17060275","DOIUrl":"10.3390/toxins17060275","url":null,"abstract":"<p><p>Zearalenone (ZEA), a mycotoxin primarily generated by the Fusarium species, constitutes a prevalent contaminant in both human and animal feedstuffs. Chronic exposure to this mycotoxin induces hepatic inflammatory responses in livestock species including rabbits, ultimately leading to organ damage. Selenomethionine (SeMet), an organic selenium source recognized for its antioxidant properties and anti-inflammatory bioactivity, demonstrates protective benefits in animals through its detoxification mechanism and growth promotion. The present study investigated the protective effect of SeMet against ZEA-induced hepatic inflammation and elucidated its underlying mechanisms. Fifty healthy 90-day-old rabbits were randomly divided into five groups: control, ZEA-exposed and three SeMet-supplemented groups receiving 0.2, 0.35 or 0.5 mg/kg via dietary inclusion. After two weeks of SeMet pretreatment, ZEA administration (1.2 mg/kg B.W.) was imitated via oral gavage daily for one week in both the ZEA group and three SeMet-treated groups. As a result, ZEA exposure induced the significant structural disruption of the hepatic lobules, accompanied by increased collagen deposition, elevated pro-inflammatory cytokine profiles (IL-6, IL-1β, TNF-α) and reduced anti-inflammatory mediator levels (IL-10, TGF-β). SeMet supplementation alleviated ZEA-induced histological alterations, including inflammatory cell infiltration and collagen accumulation. Biochemical analysis indicated the restoration of inflammatory markers to near-normal levels when treated with SeMet. Notably, immunohistochemical results showed that SeMet significantly reduced the protein levels of IL-6 and its downstream target STAT3 under ZEA exposure. These findings indicated that SeMet attenuated ZEA-induced hepatic inflammation by modulating the IL-6/STAT3 signaling axis, with dietary supplementation of 0.35 mg/kg SeMet exhibiting the most significant effect on alleviating ZEA-induced hepatic inflammatory injury.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Role of a Conserved Arg-Asp Pair in the Structure and Function of Tetanus Neurotoxin. 一个保守的精氨酸- asp对在破伤风神经毒素结构和功能中的作用。
IF 3.9 3区 医学
Toxins Pub Date : 2025-05-30 DOI: 10.3390/toxins17060273
Elizabeth A Wilson, Ashtyn N Bevans, Michael R Baldwin
{"title":"The Role of a Conserved Arg-Asp Pair in the Structure and Function of Tetanus Neurotoxin.","authors":"Elizabeth A Wilson, Ashtyn N Bevans, Michael R Baldwin","doi":"10.3390/toxins17060273","DOIUrl":"10.3390/toxins17060273","url":null,"abstract":"<p><p>Tetanus, a severe and life-threatening illness caused by <i>Clostridium tetani</i>, produces symptoms such as muscle spasms, muscle stiffness and seizures caused by the production of tetanus neurotoxin (TeNT). TeNT causes spastic paralysis through the inhibition of neurotransmission in spinal inhibitory interneurons. This is achieved, in part, through pH-triggered membrane insertion of the translocation (HCT) domain, which delivers the catalytic light-chain (LC) domain to the cytosol. While the function of HCT is well defined, the mechanism by which it accomplishes this task is largely unknown. Based on the crystal structure of tetanus neurotoxin, we identified potential polar interactions between arginine 711, tryptophan 715 and aspartate 821 that appear to be evolutionarily conserved across the clostridial neurotoxin family. We show that the disruption of the Asp-Arg pair in a beltless HCT variant (bHCT) results in changes in thermal stability without significant alterations to the overall secondary structure. ANS (1-anilino-8-napthalene sulfonate) binding studies, in conjunction with liposome permeabilization assays, demonstrate that mutations at R711 or D821 trigger interactions with the membrane at higher pH values compared to wildtype bHCT. Interestingly, we show that the introduction of the D821N mutation into LH<sub>N</sub>T (LC-HCT only), but not the holotoxin, resulted in the increased cleavage of VAMP 2 in cortical neurons relative to the wildtype protein. This suggests that, as observed for botulinum toxin A, the receptor-binding domain is not necessary for LC translocation but rather helps determine the pH threshold of membrane insertion. The mutation of W715 did not result in detectable changes in the activity of either bHCT or the holotoxin, suggesting that it plays only a minor role in stabilizing the structure of the toxin. We conclude that the protonation of D821 at low pH disrupts interactions with R711 and W715, helping to drive the conformational refolding of HCT needed for membrane insertion and the subsequent translocation of the LC.</p>","PeriodicalId":23119,"journal":{"name":"Toxins","volume":"17 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dietary Supplementation of Zinc Oxide Quantum Dots Protective Against Clostridium perfringens Induced Negative Effects in Broilers. 饲粮中添加氧化锌量子点对肉仔鸡产气荚膜梭菌诱导的负面影响。
IF 3.9 3区 医学
Toxins Pub Date : 2025-05-29 DOI: 10.3390/toxins17060272
Lei Shi, Qin-Jian Niu, Hao-Hua Xu, Yu-Xuan Huang, Yu-Wei Zhao, Alainaa Refaie, Lv-Hui Sun, Zhang-Chao Deng
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