IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-08 DOI: 10.1016/j.toxicon.2024.108162

Dujian Yan , Mengru Zhou , Tian Tian , Chenchen Wu

To analysis repair function of mucin-2(MUC2) and glycoprotein particles on the tight junction protein of uterus under bacterial endotoxins. In this experiment, we showed that the thicker mucus layer of the uterus is used to prevent the translocation of endotoxin at 21d postdelivery. When endotoxin acts on the uterus to thin its mucous layer, the cells in the lamina propria of the uterus secrete a large number of glycoprotein particles at 27d postdelivery. Due to a significantly decrease in the expression of glycosyltransferase, the glycoprotein particles are incompletely glycosylation MUC2, which can interact with the cell membrane and are released in large quantities in the form of exocytosis. These glycoprotein particles can significantly repair tight junction proteins in the inter-cellular space and significantly increase the expression of Claudin-1, JAM (Junction adhesion molecule-A), E-cadherin, ZO-1(Zonula occludens-1) and desmosome proteins after endotoxin treatment. The results of the present study show that endotoxins can thin the uterine mucus layer and accelerate the release of incompletely glycosylated MUC2 from lamina propria cells. In inter-cellular spaces, MUC2 can increase its expression levels and distribution area to repair the tight junction structure of cells with larger gaps. Further strengthening of the barrier prevents endotoxin translocation by repairing the tight junction structure of uterine epithelial cells.

分析粘蛋白-2（MUC2）和糖蛋白颗粒在细菌内毒素作用下对子宫紧密连接蛋白的修复功能。本实验表明，在分娩后 21 天，较厚的子宫粘液层可用于阻止内毒素的转运。当内毒素作用于子宫使其粘液层变薄时，子宫固有层细胞会在分娩后 27 天分泌大量糖蛋白颗粒。由于糖基转移酶的表达明显减少，糖蛋白颗粒中的MUC2糖基化不完全，可与细胞膜相互作用，并以外渗的形式大量释放。这些糖蛋白颗粒能明显修复细胞间隙的紧密连接蛋白，经内毒素处理后，Claudin-1、JAM（连接粘附分子-A）、E-cadherin、ZO-1（Zonula occludens-1）和脱绒毛蛋白的表达明显增加。本研究结果表明，内毒素可使子宫粘液层变薄，加速固有层细胞释放未完全糖基化的 MUC2。在细胞间隙中，MUC2 可增加其表达水平和分布面积，以修复间隙较大的细胞的紧密连接结构。通过修复子宫上皮细胞的紧密连接结构，进一步加强屏障，防止内毒素转运。

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引用次数: 0

Unusual paralytic shellfish poisoning toxins in Cayuga Lake, New York 纽约卡尤加湖中的异常麻痹性贝类中毒毒素。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-07 DOI: 10.1016/j.toxicon.2024.108165

Zacharias J. Smith , Gregory L. Boyer

Cyanobacteria blooms were detected in 2017 and 2018 in Cayuga Lake, New York, with paralytic shellfish poisoning toxins (PSPTs) the primary toxin detected. Analysis of these samples by HPLC with chemical oxidation, receptor binding assay, ELISA, and LC-MS/MS confirmed the presence of PSPTs but each method gave highly unusual results based on the theory establishing each method. The structures of the toxins could not be identified and may be ‘unusual’ or unelucidated PSPTs.

2017 年和 2018 年，纽约州卡尤加湖检测到蓝藻藻华，其中麻痹性贝类中毒毒素（PSPTs）是检测到的主要毒素。通过 HPLC 化学氧化法、受体结合测定法、ELISA 和 LC-MS/MS 对这些样本进行分析，证实了 PSPTs 的存在，但根据每种方法的理论基础，每种方法都得出了极不寻常的结果。这些毒素的结构无法确定，可能是 "不常见的 "或未阐明的 PSPT。

引用次数: 0

Bee venom and melittin: Potent key enzyme inhibitors with promising therapeutic potential 蜂毒和美乐汀：具有治疗潜力的强效关键酶抑制剂。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-05 DOI: 10.1016/j.toxicon.2024.108164

Bayram Alparslan , Murat Şentürk , Cengiz Erkan

Bee venom (BV) is a versatile product with extensive applications, boasting antibacterial and anticancer properties. Within this study, we focused on isolating melittin (Mel) from Apis mellifera L. venom and exploring the influence of both BV and Mel on specific enzymes, namely carbonic anhydrase (CA) I, CA II, CA IX, glutathione reductase (GR), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and neuraminidase (NA). The rationale for selecting these enzymes is that their inhibitors have a particular interest in medicinal chemistry in the treatment of several diseases. BV was obtained using a poison collection apparatus, and Mel was isolated by means of High-Performance Liquid Chromatography (HPLC). All enzymes, except for CA I and CA II, were commercially sourced and of high purity, and the enzyme assays were carried out spectrophotometrically.

Our findings showed that BV inhibited the enzymes with IC₅₀ values of 0.583–3.32 ng/mL, and Mel showed an inhibition range of 0.528–3.2 ng/mL. These results underscore the potential therapeutic promise of BV and Mel as robust enzyme inhibitors, offering prospects for addressing diverse health conditions.

蜂毒（BV）是一种用途广泛的产品，具有抗菌和抗癌特性。在这项研究中，我们重点从蜜蜂毒液中分离 Melittin（Mel），并探索 BV 和 Mel 对特定酶的影响，即碳酸酐酶 (CA) I、CA II、CA IX、谷胱甘肽还原酶 (GR)、乙酰胆碱酯酶 (AChE)、丁酰胆碱酯酶 (BChE) 和神经氨酸酶 (NA)。之所以选择这些酶，是因为它们的抑制剂在治疗多种疾病的药物化学中具有特殊的意义。BV 是通过毒物收集装置获得的，而 Mel 则是通过高效液相色谱法（HPLC）分离的。除 CA I 和 CA II 外，所有酶的来源均为高纯度的商用酶，酶测定采用分光光度法进行。我们的研究结果表明，BV 对酶的抑制作用 IC50 值为 0.583-3.32 纳克/毫升，而 Mel 的抑制作用范围为 0.528-3.2 纳克/毫升。这些结果凸显了 BV 和 Mel 作为强效酶抑制剂的潜在治疗前景，为解决各种健康问题提供了可能。

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引用次数: 0

Corrigendum to “Distribution mapping of deadly scorpions in Iran” [Toxicon 250 (2024) 108109] "伊朗致命蝎子分布图 "更正[毒物学 250 (2024) 108109]

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-04 DOI: 10.1016/j.toxicon.2024.108158

Masoumeh Baradaran , Sedigheh Mohajer , Seyed Mahdi Kazemi

引用次数: 0

Snakebite-induced reversible cerebral vasoconstriction syndrome: Report of three cases 蛇咬伤诱发的可逆性脑血管收缩综合征：三例病例报告。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-02 DOI: 10.1016/j.toxicon.2024.108161

Subramanian Senthilkumaran , Jarred Williams , José R. Almeida , Harry F. Williams , Ketan Patel , Ponniah Thirumalaikolundusubramanian , Sakthivel Vaiyapuri

Envenomings from Russell's viper typically result in local tissue damage and bleeding complications, but the bites from common krait and cobra primarily cause neurotoxic effects. While most symptoms can be treated with appropriate antivenom, additional support is necessary for several snakebite victims to tackle a broad range of unusual complications that they develop following bites. Reversible vasoconstriction syndrome (RCVS), characterised by the constriction of cerebral arteries, is a rare but serious issue, presenting with severe headaches and, in extreme cases, haemorrhagic/ischaemic stroke. This report presents three cases of RCVS in snakebite victims following Russell's viper, krait and cobra bites. The patients were admitted to the hospital with neurological and/or haematological complications, and they were treated with polyvalent antivenom. After two days of antivenom treatment, all the patients developed intense headaches that lasted for several hours and failed to respond to commonly used analgesics. While the physical, laboratory and computed tomography examinations were normal, the RCVS was diagnosed with multimodal magnetic resonance angiography. All patients were successfully treated with oral nimodipine, and during their follow-ups, physical and laboratory examinations were unremarkable, and the magnetic resonance imaging confirmed the reversal of RCVS. To achieve positive outcomes in patients, clinicians must swiftly identify such rare complications and make accurate diagnoses to provide prompt treatments. Overall, this report presents an unusual complication of RCVS in snakebite patients and appropriate diagnosis and treatment approaches to tackle this condition.

被罗素蝰蛇咬伤通常会导致局部组织损伤和出血并发症，但被普通甲蛇和眼镜蛇咬伤主要会导致神经中毒。虽然大多数症状都可以通过适当的抗蛇毒血清来治疗，但一些被蛇咬伤的患者还需要额外的支持，以应对咬伤后出现的各种异常并发症。以脑动脉收缩为特征的可逆性血管收缩综合征（RCVS）是一种罕见但严重的问题，表现为剧烈头痛，极端情况下还会导致出血性/缺血性中风。本报告介绍了三例被罗素蝰、眼镜蛇和乌梢蛇咬伤的蛇伤患者的 RCVS 病例。患者因神经系统和/或血液系统并发症入院，并接受了多价抗蛇毒血清治疗。抗蛇毒血清治疗两天后，所有患者都出现了持续数小时的剧烈头痛，且对常用镇痛药无效。虽然体格检查、实验室检查和计算机断层扫描检查均正常，但通过多模态磁共振血管造影术确诊为 RCVS。所有患者均成功接受了口服尼莫地平治疗，在随访期间，体格检查和实验室检查均无异常，磁共振成像证实 RCVS 已逆转。为了使患者获得良好的治疗效果，临床医生必须迅速识别这种罕见的并发症，并做出准确诊断，提供及时治疗。总之，本报告介绍了蛇咬伤患者罕见的 RCVS 并发症，以及应对这种情况的适当诊断和治疗方法。

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引用次数: 0

Intramuscular injection of Bothrops jararaca venom provoked acute kidney injury (AKI): Underpinned by impaired renal filtration, Na+ handling, and tissue damage 肌肉注射箭毒导致急性肾损伤（AKI）：肾过滤、Na+处理和组织损伤受损。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-01 DOI: 10.1016/j.toxicon.2024.108159

Taissa Nunes Guerrero , Mayara Amorim Romanelli , Dayene Santos Gomes , Russolina Benedeta Zingali , Lucienne da Silva Lara

Globally, about 2.5 million people are victims of snakebites annually. In Brazil, the most clinically relevant snake is the Bothrops jararaca. The symptoms of envenomation are acute inflammation at the bite site and bleeding disorders. Despite kidney failure being the main cause of death after envenomation, kidney damage is not completely understood, and there are no clinically representative in vivo models. This work aimed to characterize the acute kidney injury (AKI) induced by intramuscular injection (IM) of Bothrops jararaca (Bjc) venom in male Wistar rats. The control group received 0.9% saline solution. Three doses of venom (3.5, 6.0, and 8.0 mg/kg) were administered IM into the posterior region of the right knee. After the injection, the rats were kept in metabolic cages. The following parameters were analyzed after 24 h: the extent of muscle damage and kidney damage (urinary creatinine, proteinuria, plasma creatinine, and renal tissue histology). All rats presented a hemorrhagic lesion at the injection site in a dose-dependent manner. Biochemical parameters indicated kidney damage: plasma creatinine accumulation, decreased glomerular filtration rate, albuminuria and proteinuria, and disturbance in Na⁺ homeostasis. Histological analyses showed glomerular injury, tissue discontinuity more evident in the cortex and tubular dilatation, and collagen deposition. The decline in renal function and tissue damage indicated the occurrence of AKI. Therefore, a Bjc venom-induced in vivo model of renal injury has been established for future studies.

全球每年约有 250 万人被蛇咬伤。在巴西，临床上最常见的蛇是 Bothrops jararaca。毒蛇咬伤的症状是咬伤部位急性发炎和出血性疾病。尽管肾功能衰竭是毒蛇咬伤后死亡的主要原因，但人们对肾脏损伤的了解还不全面，也没有具有临床代表性的体内模型。本研究旨在描述雄性 Wistar 大鼠肌肉注射 Bothrops jararaca（Bjc）毒液诱发急性肾损伤（AKI）的特征。对照组接受 0.9% 生理盐水。对照组接受 0.9% 的生理盐水，雄性 Wistar 大鼠的右膝盖后部肌肉注射三种剂量的毒液（3.5、6.0 和 8.0 mg/kg）。注射后，大鼠被关在代谢笼中。24 小时后分析以下参数：肌肉损伤程度和肾脏损伤（尿肌酐、蛋白尿、血浆肌酐和肾组织学）。所有大鼠的注射部位都出现了出血病变，其程度与剂量有关。生化指标显示肾脏受损：血浆肌酐累积、肾小球滤过率下降、白蛋白尿和蛋白尿以及 Na+ 平衡紊乱。组织学分析显示肾小球损伤、皮质组织间断、肾小管扩张和胶原沉积。肾功能下降和组织损伤表明发生了 AKI。因此，我们建立了一个 Bjc 毒液诱导的体内肾损伤模型，供今后研究使用。

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引用次数: 0

Quercetin protects the liver of broiler chicken against oxidative stress and apoptosis induced by ochratoxin A 槲皮素可保护肉鸡肝脏免受赭曲霉毒素 A 诱导的氧化应激和细胞凋亡的影响。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-11-01 DOI: 10.1016/j.toxicon.2024.108160

Abdel Azeim A. Khalaf , Mohamed A. Elhady , Marwa A. Ibrahim , Eman I. Hassanen , Rehab E. Abdelrahman , Peter A. Noshy

Ochratoxin A (OTA) is a mycotoxin that causes major health concerns in human and animals. Quercetin (QUE) is a flavonoid that possesses antioxidant, anti-inflammatory and anti-apoptotic properties. This report aims to investigate the ameliorative effects of QUE against OTA-induced hepatotoxicity in broiler chicken. Forty broiler chicks were equally allocated into 4 groups: Group I (control), Group II (OTA), Group III (QUE) and Group IV (OTA + QUE). OTA (0.5 mg/kg) and QUE (0.5 g/kg) were incorporated into the chicken feed for 42 days. The results presented a significant decrease in body weight and elevation in feed conversion ratio, and a significant elevation of the activities of serum alanine aminotransferase and aspartate aminotransferase enzymes in the OTA birds. Additionally, there was a significant decrease in catalase activity and reduced glutathione content and a significant elevation in malondialdehyde level in the liver of OTA-exposed birds. Various hepatocellular lesions were also noticed in the OTA-exposed birds. OTA exposure up-regulated the phosphatase and tensin homologue (PTEN) and the pro-apoptotic genes and down-regulated the anti-apoptotic genes in the liver. The addition of QUE ameliorated most of the hepatotoxic effects of OTA.

赭曲霉毒素 A（OTA）是一种霉菌毒素，对人类和动物的健康造成严重危害。槲皮素（QUE）是一种类黄酮，具有抗氧化、抗炎和抗细胞凋亡的特性。本报告旨在研究槲皮素对 OTA 引起的肉鸡肝中毒的改善作用。将 40 只肉鸡平均分为 4 组：第一组（对照组）、第二组（OTA）、第三组（QUE）和第四组（OTA+QUE）。在鸡饲料中添加 OTA（0.5 毫克/千克）和 QUE（0.5 克/千克），持续 42 天。结果显示，OTA 组鸡的体重明显下降，饲料转化率明显提高，血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶的活性明显升高。此外，受 OTA 影响的禽类肝脏中过氧化氢酶活性和还原型谷胱甘肽含量显著下降，丙二醛含量显著升高。暴露于 OTA 的鸟类还出现了各种肝细胞病变。暴露于 OTA 会上调肝脏中的磷酸酶和天丝同源物（PTEN）以及促凋亡基因，下调抗凋亡基因。添加 QUE 可改善 OTA 的大部分肝毒性效应。

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引用次数: 0

A simple method to determine proteolytic activity of snake venoms 测定蛇毒蛋白水解活性的简单方法。

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-10-28 DOI: 10.1016/j.toxicon.2024.108157

Federico Camicia , Rocío I. Miguez , Néstor R. Lago , Carlos F. Damin , Adolfo R. de Roodt

In this work, we describe an easy, simple, and cost-effective method to assess the proteolytic activity of snake venoms. The method is based on measuring the hydrolytic halo formed by gelatin radial hydrolysis following the incubation of venoms on a solid gelatin-agarose plate. Venoms from Bothrops (B.) alternatus, B. diporus, B. neuwiedi, B. jararaca, B. jararacussu, Crotalus atrox, and Trimeresurus albolabris were tested. A dose-response relationship was observed for each venom tested, with proteolytic capacity values, determined as GD (gelatinolytic dose, the dose causing a 15 mm hydrolytic halo) ranging from 21 to 222 μg. A correlation between hydrolysis and hemorrhagic activity in rat skin (minimal hemorrhagic dose) was found, with an r² value of 0.8774 (p < 0.0001). The venoms’ hydrolytic activity was significantly, though not completely, inhibited by EDTA. This methodology was also deployed to assess venom neutralization by antivenoms on the hydrolytic activity of the different venoms, demonstrating its usefulness in evaluating antivenom neutralizing capacity. The method presented is simple, cheap and useful for preliminary screening of venom proteolytic activity and its inhibition and may also predict gross differences in hemorrhagic activity, contributing to the reduction of the number of animals used for these determinations.

在这项工作中，我们介绍了一种简便易行、经济高效的方法来评估蛇毒的蛋白水解活性。该方法基于测量明胶-琼脂糖固体平板上的毒液培养后明胶径向水解形成的水解晕。该方法测试了两种蛇（B. alternatus、B. diporus、B. neuwiedi、B. jararaca、B. jararacussu、Crotalus atrox 和 Trimeresurus albolabris）的毒液。对每种毒液的测试都观察到了剂量-反应关系，蛋白水解能力值（以 GD（凝胶溶解剂量，导致 15 毫米水解光晕的剂量）表示）从 21 微克到 222 微克不等。水解作用与大鼠皮肤出血活性（最小出血剂量）之间存在相关性，r2 值为 0.8774（p < 0.0001）。乙二胺四乙酸（EDTA）对毒液的水解活性有明显的抑制作用，但并不完全。该方法还用于评估抗蛇毒血清对不同毒液水解活性的中和作用，证明了其在评估抗蛇毒血清中和能力方面的实用性。所介绍的方法简单、廉价，可用于毒液蛋白水解活性及其抑制作用的初步筛选，还可预测出血活性的显著差异，有助于减少用于这些测定的动物数量。

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引用次数: 0

Environmental determinants of venom variability in captive scorpions: A comprehensive analysis of diet, temperature, and humidity effects 人工饲养蝎子毒液变异性的环境决定因素：对饮食、温度和湿度影响的综合分析

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-10-28 DOI: 10.1016/j.toxicon.2024.108151

Zineb Agourram , Razana Zegrari , Anass Kettani , Bouabid Badaoui , Mouad Mkamel

This study examines the effects of environmental conditions on venom production in four prevalent scorpion species in Morocco: Androctonus amoreuxi, Androctonus mauretanicus, Buthus mardochei, and Scorpio maurus. The research focuses on how climatic factors such as temperature, humidity, and diet—specifically mealworm consumption—affect physical parameters including size and weight, and ultimately venom yield. We conducted a comprehensive investigation involving the capture, acclimatization, and systematic venom extraction from 480 scorpions. Our findings indicate considerable variations in venom volumes, with Scorpio maurus showing a reduced yield compared to Androctonus amoreuxi. Key determinants of venom production were identified as humidity and dietary intake, pointing to significant implications for interspecific diversity and acclimatization processes. These insights have crucial implications for medical and pharmaceutical applications, emphasizing the need for species-specific husbandry protocols to optimize venom extraction for therapeutic use.

本研究探讨了环境条件对摩洛哥四种常见蝎子毒液分泌的影响：Androctonus amoreuxi、Androctonus mauretanicus、Buthus mardochei 和 Scorpio maurus。研究的重点是温度、湿度等气候因素和食物（特别是黄粉虫的食用量）如何影响体型和重量等物理参数，并最终影响毒液产量。我们对 480 只蝎子进行了全面调查，包括捕捉、适应环境和系统提取毒液。我们的研究结果表明，蝎子的毒液量存在很大差异，蝎尾蝎的毒液产量比蝎尾蝎低。毒液产量的主要决定因素是湿度和食物摄入量，这对种间多样性和适应过程具有重要影响。这些见解对医疗和制药应用具有重要意义，强调需要制定针对特定物种的饲养规程，以优化用于治疗的毒液提取。

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引用次数: 0

Effective production of snake antivenom by targeting epidermal dendritic cells via the ‘low dose, low volume, multi-site’ immunization 通过 "低剂量、小体积、多部位 "免疫，以表皮树突状细胞为目标，有效生产蛇毒抗蛇毒血清

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon

Pub Date : 2024-10-28 DOI: 10.1016/j.toxicon.2024.108156

Kavi Ratanabanangkoon

Snakebite envenomation (SBE) is a serious neglected tropical disease that affects about 3 million people every year and causes over 100,000 deaths annually, mostly in developing countries. WHO has pledged to cut in half the morbidity and mortality due to SBE by 2030. Animal plasma-derived antivenoms, produced mostly in horses and sheep, are the main treatment modality. However, for over a century, equine plasma antivenom production has faced many problems. These include: low neutralizing potency, failure of horses to develop a satisfactory immune response, and a long immunization period. These problems have led to antivenom shortages and higher costs resulting in otherwise avoidable morbidity and mortality in snake bite victims. Attempts have been made to improve the antivenom production process. For example, a number of adjuvants designed to improve the immune response have been tested. In 1997, an immunization protocol involving the use of multi-site, low-volume and venom doses was developed and is currently used in antivenom production. This protocol constituted a significant innovation that has resulted in highly potent antivenoms within much shortened immunization periods, with all the immunized horses responding and with much less venom immunogen used. It has resulted in an ample antivenom supply for use in Thailand and neighboring countries and has led to no reported deaths from snakebite in Thailand in the past few years. The effectiveness of this immunization protocol was the result of a strategy based on targeting dendritic cells which play a pivotal role in the immune response process. This communication summarizes the basis and results of this immunization strategy.

蛇咬伤（SBE）是一种严重的被忽视的热带疾病，每年约有 300 万人受到影响，每年造成 10 多万人死亡，其中大部分发生在发展中国家。世卫组织承诺到 2030 年将 SBE 的发病率和死亡率减半。动物血浆衍生抗蛇毒血清主要由马和羊生产，是主要的治疗方式。然而，一个多世纪以来，马血浆抗蛇毒血清的生产面临着许多问题。这些问题包括：中和效力低、马匹无法产生令人满意的免疫反应以及免疫期长。这些问题导致抗蛇毒血清短缺和成本上升，造成蛇咬伤患者本可避免的发病率和死亡率。人们一直在尝试改进抗蛇毒血清的生产工艺。例如，对一些旨在改善免疫反应的佐剂进行了测试。1997 年，制定了一项涉及使用多部位、低剂量和毒液剂量的免疫方案，目前正用于抗蛇毒血清的生产。该方案是一项重大创新，在大大缩短免疫期的情况下生产出了强效抗蛇毒血清，所有接受免疫的马匹都做出了反应，而且使用的毒液免疫原大大减少。该方案为泰国和周边国家提供了充足的抗蛇毒血清，在过去几年中，泰国没有发生过因被蛇咬伤而死亡的报告。这种免疫方案之所以有效，是因为采取了一种以树突状细胞为目标的策略，树突状细胞在免疫反应过程中发挥着关键作用。这篇通讯总结了这一免疫策略的基础和结果。

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引用次数: 0

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