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Stress levels, hematological condition, and productivity of plasma-producing horses used for snake antivenom manufacture: A comparison of two industrial bleeding methods 用于制造蛇毒血清的产血马的应激水平、血液状况和生产率:两种工业化放血方法的比较
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-21 DOI: 10.1016/j.toxcx.2024.100212
Ana Margarita Arias-Esquivel , Edwin Moscoso , Deibid Umaña , Mauricio Arguedas , Daniela Solano , Gina Durán , Aarón Gómez , José María Gutiérrez , Guillermo León
The immunization and industrial bleeding of horses are essential stages for producing snake antivenoms. In Costa Rica, the traditional method involves stimulating the antibody response of horses by periodically injecting venoms, collecting hyperimmune plasma over three consecutive bleeding days, and repeating this process every eight weeks. While this method does not cause major physical or hematological issues in horses, the associated stress has not been evaluated. We compared this traditional method with an alternative method that involves injecting venoms, collecting hyperimmune plasma in a single bleeding day, and repeating the process every two weeks. We assessed stress (via serum and fecal cortisol levels and an ethological study), hematological parameters (hematocrit and hemoglobin concentration), and plasma productivity over eight months. Serum cortisol levels remained within the normal range for both methods throughout the immunization/bleeding cycle. However, serum and fecal cortisol levels were significantly higher in horses subjected to the traditional method compared to those in the alternative method. Neither method caused significant hematological alterations. Notably, the alternative method yielded a higher volume of plasma. We concluded that adopting the alternative method ensures horse welfare while improving industrial bleeding productivity. This approach may reduce costs and improve the availability of this essential treatment for vulnerable populations.
对马进行免疫和工业化放血是生产蛇类抗蛇毒血清的重要阶段。在哥斯达黎加,传统方法是通过定期注射毒液来刺激马匹的抗体反应,在连续三个放血日内收集高免疫血浆,并每八周重复这一过程。虽然这种方法不会对马的身体或血液造成大的影响,但相关的压力尚未得到评估。我们将这种传统方法与另一种方法进行了比较,后者包括注射毒液,在一个出血日内收集高免疫血浆,并每两周重复一次。我们评估了八个月内的压力(通过血清和粪便皮质醇水平以及伦理研究)、血液学参数(血细胞比容和血红蛋白浓度)以及血浆生产率。在整个免疫/放血周期中,两种方法的血清皮质醇水平都保持在正常范围内。然而,采用传统方法的马匹血清和粪便皮质醇水平明显高于采用替代方法的马匹。两种方法都没有引起明显的血液学变化。值得注意的是,替代方法产生的血浆量更高。我们的结论是,采用替代方法既能确保马匹的福利,又能提高工业出血的生产率。这种方法可以降低成本,改善弱势人群获得这种基本治疗的机会。
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引用次数: 0
Diagnosis of human envenoming by terrestrial venomous animals: Routine, advances, and perspectives 陆生有毒动物致人类中毒的诊断:常规、进展和前景
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-10 DOI: 10.1016/j.toxcx.2024.100211
Joeliton S. Cavalcante , Sabrina Santana Toledo Arruda , Pedro Marques Riciopo , Manuela Pucca , Rui Seabra Ferreira Junior
Despite the development of new and advanced diagnostic approaches, monitoring the clinical evolution of accidents caused by venomous animals is still a challenge for science. In this review, we present the state of the art of laboratory tests that are routinely used for the diagnosis and monitoring of envenomings by venomous animals, as well as the use of new tools for more accurate and specific diagnoses. While a comprehensive range of tools is outlined, comprising hematological, biochemical, immunoassays, and diagnostic imaging tools, it is important to acknowledge their limitations in predicting the onset of clinical complications, since they provide an overview of organic damage after its development. Thus, the need for discovery, validation, and use of biomarkers that have greater predictive power, sensitivity and specificity is evident. This will help in the diagnosis, monitoring, and treatment of patients envenomated by venomous animals, consequently reducing the global burden of morbidity and mortality.
尽管开发出了新的先进诊断方法,但监测由毒液动物引起的事故的临床演变仍是科学界面临的一项挑战。在这篇综述中,我们介绍了常规用于诊断和监测毒液动物咬伤的实验室检测技术的现状,以及使用新工具进行更准确、更具体诊断的情况。虽然概述了一系列全面的工具,包括血液学、生化、免疫测定和诊断成像工具,但必须承认这些工具在预测临床并发症的发生方面存在局限性,因为它们提供的是有机损害发生后的概况。因此,显然需要发现、验证和使用具有更强预测能力、灵敏度和特异性的生物标志物。这将有助于诊断、监测和治疗被毒液动物咬伤的患者,从而减轻全球发病率和死亡率的负担。
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引用次数: 0
Supplementation of polyclonal antibodies, developed against epitope-string toxin-specific peptide immunogens, to commercial polyvalent antivenom, shows improved neutralization of Indian Big Four and Naja kaouthia snake venoms 在商用多价抗蛇毒血清中添加针对表位串毒素特异性多肽免疫原开发的多克隆抗体,可提高对印度大四斑和 Naja kaouthia 蛇毒的中和效果
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.toxcx.2024.100210
Abhishek Chanda , Nitin C. Salvi , Pravin V. Shelke , Bhargab Kalita , Aparup Patra , Upasana Puzari , Milind V. Khadilkar , Ashis K. Mukherjee
Snakebites profoundly impact the rural population of tropical nations, leading to significant socio-economic repercussions. Polyvalent antivenom (PAV) therapy faces several limitations, including intra-specific variations and poor efficacy against some major toxins and low molecular mass, poorly immunogenic toxins, which contribute to increased mortality and morbidity rates. Innovative strategies for developing novel antivenoms are continuously explored to address these challenges. The present study focuses on designing of 17 epitope-string toxin-specific peptide immunogens from pharmacologically active major and/or poorly immunogenic toxins (snake venom metalloprotease, Kunitz-type serine protease inhibitor, phospholipase A2, three-finger toxin) from the venom of the ‘Big Four’ venomous snakes and Naja kaouthia (NK) in India. These custom peptide antibodies demonstrated robust immuno-reactivity against the venoms ‘Big Four’ and NK. When these antibodies were supplemented with commercial PAV at a defined ratio (formulated polyvalent antivenom or FPAV), it significantly enhanced the neutralization of snake venom enzymes and in vivo neutralization of lethality and pharmacological activities such as haemorrhage, necrosis, pro-coagulant, defibrinogenation, and myotoxicity of ‘Big Four’ and NK venoms compared to PAV in mice. The present study highlights a promising strategy for developing next-generation antivenoms using synthetic peptide-based immunogens, offering a targeted approach to address the limitations of current antivenom therapy.
蛇咬伤对热带国家的农村人口造成了严重影响,导致了重大的社会经济后果。多价抗蛇毒血清(PAV)疗法面临着一些局限性,包括特异性内变异、对一些主要毒素和低分子质量、免疫原性差的毒素疗效不佳,这些都是导致死亡率和发病率上升的原因。为应对这些挑战,人们不断探索开发新型抗蛇毒血清的创新战略。本研究的重点是从印度 "四大毒蛇 "和 Naja kaouthia(NK)毒液中具有药理活性的主要和/或免疫原性差的毒素(蛇毒金属蛋白酶、Kunitz 型丝氨酸蛋白酶抑制剂、磷脂酶 A2、三指毒素)中设计出 17 种表位串毒素特异性多肽免疫原。这些定制的多肽抗体对 "四大毒蛇 "和 NK 毒液具有很强的免疫反应性。与 PAV 相比,当这些抗体按一定比例加入商用 PAV(配制多价抗蛇毒血清或 FPAV)时,可显著增强对蛇毒酶的中和作用,并在小鼠体内中和 "四大 "和 NK 毒液的致死性和药理活性,如出血、坏死、促凝血、去纤维蛋白原和肌毒性。本研究强调了利用基于合成肽的免疫原开发下一代抗蛇毒血清的前景广阔的战略,为解决目前抗蛇毒血清疗法的局限性提供了一种有针对性的方法。
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引用次数: 0
Bioprospection of rattlesnake venom peptide fractions with anti-adipose and anti-insulin resistance activity in vitro 具有体外抗脂肪和抗胰岛素抵抗活性的响尾蛇毒肽组分的生物研究
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.toxcx.2024.100209
David Meléndez-Martínez , Erika Ortega-Hernández , Edwin Estefan Reza-Zaldívar , Alejandro Carbajal-Saucedo , Gustavo Arnaud-Franco , Ana Gatica-Colima , Luis Fernando Plenge-Tellechea , Marilena Antunes-Ricardo , Daniel A. Jacobo-Velázquez , Karla Mayolo-Deloisa , Omar Lozano , Marco Rito-Palomares , Jorge Benavides
Animal venoms are natural products that have served as a source of novel molecules that have inspired novel drugs for several diseases, including for metabolic diseases such as type-2 diabetes and obesity. From venoms, toxins such as exendin-4 (Heloderma suspectum) and crotamine (Crotalus durissus terrificus) have demonstrated their potential as treatments for obesity. Moreover, other toxins such as Phospholipases A2 and Disintegrins have shown their potential to modulate insulin secretion in vitro. This suggests an unexplored diversity of venom peptides with a potential anti-obesogenic in Mexican rattlesnake venoms. For that reason, this study explored the in vitro effect of Crotalus venom peptide-rich fractions on models for insulin resistance, adipocyte lipid accumulation, antioxidant activity, and inflammation process through nitric oxide production inhibition. Our results demonstrated that the peptide-rich fractions of C. aquilus, C. ravus, and C. scutulatus scutulatus were capable of reverting insulin resistance, enhancing glucose consumption to normal control; C. culminatus, C. molossus oaxacus, and C. polystictus diminished the lipid accumulation on adipocytes by 20%; C. aquilus, C. ravus, and C. s. salvini had the most significant cellular antioxidant activity, having nearly 80% of ROS inhibition. C. aquilus, C. pyrrhus, and C. s. salvini inhibited nitric oxide production by about 85%. We demonstrated the potential of these peptides from Crotalus venoms to develop novel drugs to treat type-2 diabetes and obesity. Moreover, we described for the first time that Crotalus venom peptide fractions have antioxidant and inflammatory properties in vitro models.
动物毒液是天然产品,是新型分子的来源,为治疗多种疾病(包括 2 型糖尿病和肥胖症等代谢性疾病)的新型药物提供了灵感。从毒液中提取的毒素,如exendin-4(Heloderma suspectum)和crotamine(Crotalus durissus terrificus)已证明具有治疗肥胖症的潜力。此外,磷脂酶 A2 和崩解素等其他毒素也显示出在体外调节胰岛素分泌的潜力。这表明墨西哥响尾蛇毒液中具有潜在抗致肥性的毒肽种类还未被开发。因此,本研究通过抑制一氧化氮的产生,探讨了富含多肽的响尾蛇毒液对胰岛素抵抗、脂肪细胞脂质积累、抗氧化活性和炎症过程模型的体外效应。我们的研究结果表明,C. aquilus、C. ravus和C. scutulatus scutulatus的多肽富集部分能够恢复胰岛素抵抗,将葡萄糖消耗量提高到正常控制水平;C. culminatus、C. molossus oaxacus和C.c.s.salvini具有最显著的细胞抗氧化活性,对 ROS 的抑制率接近 80%。C.aquilus、C. pyrrhus 和 C. s. salvini 对一氧化氮产生的抑制率约为 85%。我们证明了这些来自克罗特鲁斯毒液的多肽在开发治疗 2 型糖尿病和肥胖症的新型药物方面的潜力。此外,我们首次在体外模型中描述了黄颡鱼毒多肽组分具有抗氧化和抗炎特性。
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引用次数: 0
A probabilistic hazard assessment for cyanobacterial toxins accounting for regional geography and water body trophic status 考虑区域地理和水体营养状况的蓝藻毒素概率危害评估
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.toxcx.2024.100208
Diane A. Mielewczyk , Chris N. Glover , Gavin N. Saari

Under climate change scenarios freshwater eutrophication is expected to increase, and with it the occurrence of cyanobacterial toxin-producing harmful algal blooms. In the current study, microcystin toxin occurrence data from literature sources and a long-term provincial monitoring program were used to conduct a probabilistic hazard assessment for Alberta, Canada. The large temporal and spatial range of data makes Alberta a model system for identifying regional geography and water body trophic status factors driving toxin concentrations. Environmental exposure distributions of microcystin concentrations were plotted and used to identify the likelihood of a given sample exceeding water guideline values as a function of regional geography, total phosphorus and chlorophyll-a concentration. This process identified regions with intensive cultivation and those most prone to water deficits associated with climate change to be most associated with exceedances of regulatory guideline values. Elevated phosphorus and chlorophyll-a concentrations were also drivers of toxin occurrence. This assessment can be used to identify water bodies of greatest risk to human and animal populations from cyanotoxins and thereby inform regulators as to most effective monitoring strategies.

在气候变化的情况下,淡水富营养化预计会加剧,产生蓝藻毒素的有害藻华也会随之增加。在当前的研究中,利用文献来源和省级长期监测计划中的微囊藻毒素发生数据,对加拿大艾伯塔省进行了概率危害评估。大量的时间和空间数据使艾伯塔省成为确定区域地理和水体营养状态因素驱动毒素浓度的示范系统。绘制了微囊藻毒素浓度的环境暴露分布图,并根据区域地理、总磷和叶绿素-a 浓度的函数,确定了特定样本超过水指导值的可能性。这一过程确定了密集种植地区和最容易因气候变化而缺水的地区与监管指导值超标的关系最为密切。磷和叶绿素-a 浓度的升高也是毒素发生的驱动因素。该评估可用于确定蓝藻毒素对人类和动物群体造成最大风险的水体,从而为监管机构提供最有效的监测策略。
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引用次数: 0
Plug and play virus-like particles for the generation of anti-toxin antibodies 用于生成抗毒素抗体的即插即用病毒样颗粒
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.toxcx.2024.100204
Rebecca J. Edge , Amy E. Marriott , Emma L. Stars , Rohit N. Patel , Mark C. Wilkinson , Lloyd D.W. King , Julien Slagboom , Choo Hock Tan , Kavi Ratanabanangkoon , Simon J. Draper , Stuart Ainsworth

Snakebite is a major global health concern, for which antivenom remains the only approved treatment to neutralise the harmful effects of the toxins. However, some medically important toxins are poorly immunogenic, resulting in reduced efficacy of the final product. Boosting the immunogenicity of these toxins in the commercial antivenom immunising mixtures could be an effective strategy to improve the final dose efficacy, and displaying snake antigens on Virus-like particles (VLPs) is one method for this. However, despite some applications in the field of snakebite, VLPs have yet to be explored in methods that could be practical at an antivenom manufacturing scale. Here we describe the utilisation of a “plug and play” VLP system to display immunogenic linear peptide epitopes from three finger toxins (3FTxs) and generate anti-toxin antibodies. Rabbits were immunised with VLPs displaying individual consensus linear epitopes and their antibody responses were characterised by immunoassay. Of the three experimental consensus sequences, two produced antibodies capable of recognising the consensus peptides, whilst only one of these could also recognise native whole toxins. Further characterisation of antibodies raised against this peptide demonstrated a sub-class specific response, and that these were able to elicit partially neutralising antibody responses, resulting in increased survival times in a murine snakebite envenoming model.

毒蛇咬伤是全球关注的主要健康问题,抗蛇毒血清仍是唯一获准用于中和毒素有害影响的治疗方法。然而,一些在医学上很重要的毒素免疫原性很差,导致最终产品的疗效降低。在商用抗蛇毒血清免疫混合物中增强这些毒素的免疫原性,可能是提高最终剂量疗效的有效策略,而在病毒样颗粒(VLPs)上显示蛇类抗原则是其中一种方法。然而,尽管在蛇咬伤领域有一些应用,VLPs 仍有待于在抗蛇毒血清生产规模的实用方法中进行探索。在这里,我们介绍了利用 "即插即用 "VLP系统来显示三指毒素(3FTx)的免疫原线性肽表位并产生抗毒素抗体的方法。用显示单个共识线性表位的 VLP 对兔子进行免疫,并用免疫测定法鉴定兔子的抗体反应。在三个实验性共识序列中,有两个产生的抗体能够识别共识肽,而其中只有一个还能识别原生的整个毒素。对针对这种多肽产生的抗体进行的进一步鉴定表明,这种抗体具有亚类特异性反应,能够引起部分中和抗体反应,从而延长小鼠蛇咬伤模型的存活时间。
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引用次数: 0
Design, development and preclinical assessment of MENAVip-ICP, a new snake antivenom with potential coverage of species in the Middle East and North Africa regions 新型蛇类抗蛇毒血清 MENAVip-ICP 的设计、开发和临床前评估,可能覆盖中东和北非地区的物种
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.toxcx.2024.100206
Álvaro Segura, Edwin Moscoso, Deibid Umaña, Mariángela Vargas, Andrés Sánchez, Andrés Hernández, Gina Durán, Mauren Villalta, Aarón Gómez, María Herrera, Mauricio Arguedas, José María Gutiérrez, Guillermo León

Snakebite in the Middle East and North Africa (MENA) is a public health problem whose magnitude is not fully known. Several antivenoms are available in these regions, but these formulations are designed for restricted geographical settings. Many countries do not have local production of antivenoms and must access products whose clinical performance has not been demonstrated. We hypothesize that it is possible to unify the treatment for viperid snakebites of MENA in a single antivenom formulation. Hereby we describe the design, development and preclinical evaluation of an antivenom of broad geographical coverage for this region (MENAVip-ICP). We produced this antivenom from the plasma of horses immunized with eight medically important venoms of viperid snake species from MENA. For this, we used a strategy based on two stages: first, immunization of horses with North African (NA) venoms, followed by a second immunization stage, on the same horses, with MENA venoms. We purified antivenoms from both stages: the Anti-NA and the final product Anti-MENA (MENAVip-ICP). Anti-NA was considered as intermediate formulation and was purified with the intention to study the progression of the immunoglobulin immune response of the horses. Antivenoms from both stages neutralized lethal, hemorrhagic, and procoagulant activities of homologous venoms. Compared to Anti-NA, MENAVip-ICP improved the neutralization profile of intravenous lethality and in vitro procoagulant activities of venoms. A notable finding was the difference in the neutralization of lethality when MENAVip-ICP was assessed intraperitoneally versus intravenously in the murine model. Intraperitoneally, MENAVip-ICP appears more effective in neutralizing the lethality of all venoms. Furthermore, MENAVip-ICP neutralized the lethal activity of venoms of species from other regions of MENA, Central/East Asia, and Sub-Saharan Africa that were not included in the immunization protocol. Our results showed that MENAVip-ICP neutralizes the main toxic activities induced by viperid MENA venoms at the preclinical level. Consequently, it is a promising product that could be clinically assessed for the treatment of snakebite envenomings in this region.

中东和北非(MENA)的蛇咬伤是一个公共卫生问题,其严重程度尚不完全清楚。这些地区有几种抗蛇毒血清,但这些制剂是为有限的地理环境设计的。许多国家没有本地生产的抗蛇毒血清,因此必须使用临床表现尚未得到证实的产品。我们假设,可以用一种单一的抗蛇毒血清配方来统一治疗中东和北非地区的毒蛇咬伤。在此,我们介绍了一种适用于该地区广泛地域的抗蛇毒血清(MENAVip-ICP)的设计、开发和临床前评估。我们用马匹的血浆生产了这种抗蛇毒血清,马匹免疫了中东和北非地区八种在医学上具有重要意义的毒蛇毒液。为此,我们采用了一种基于两个阶段的策略:首先用北非毒液对马进行免疫,然后再用中东和北非毒液对同样的马进行第二阶段免疫。我们从这两个阶段中提纯了抗蛇毒血清:Anti-NA 和最终产品 Anti-MENA (MENAVip-ICP)。Anti-NA被视为中间配方,纯化的目的是研究马匹免疫球蛋白免疫反应的进展。两个阶段的抗蛇毒血清都能中和同种毒液的致死、出血和促凝血活性。与抗-NA相比,MENAVip-ICP改善了毒液静脉致死性和体外促凝血活性的中和状况。一个值得注意的发现是,在小鼠模型中,腹腔注射 MENAVip-ICP 与静脉注射 MENAVip-ICP 在中和致死率方面存在差异。腹腔注射 MENAVip-ICP 似乎能更有效地中和所有毒液的致死性。此外,MENAVip-ICP 还能中和免疫方案中未包括的来自中东和北非、中亚/东亚以及撒哈拉以南非洲地区的其他物种毒液的致死活性。我们的研究结果表明,MENAVip-ICP 可在临床前水平中和由中东和北非地区毒蛇毒液引起的主要毒性活动。因此,它是一种很有前景的产品,可用于临床评估,以治疗该地区的蛇咬伤。
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引用次数: 0
Stroke as a rare complication of scorpion stings: A systematic review and analysis 中风是蝎子蜇伤的罕见并发症:系统回顾与分析
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.toxcx.2024.100205
Jorge Vasconez-Gonzalez , Karen Delgado-Moreira , Esteban Gamez-Rivera , María Belen Lopez-Molina , Fredy Lizarazo Davila , Juan S. Izquierdo-Condoy , Esteban Ortiz-Prado

Approximately 1 million scorpion stings are recorded annually worldwide, resulting in 3000 deaths. Scorpion venom has various effects on the human body, with neurological complications occurring in about 2% of cases. Among these complications, stroke—whether ischemic or hemorrhagic—is particularly significant. A systematic literature review was conducted through a bibliographic search using key terms in the PubMed, Scopus, Scielo, Latin American and Caribbean Literature in Health Sciences (LILACS) and Google Schoolar databases without date restrictions. Articles related to stroke due to scorpion stings in Spanish, English, and Portuguese were included. Our protocol was registered in PROSPERO. A total of 24 articles met the inclusion criteria for this review. The primary neurological symptoms caused by scorpion stings include hemiplegia, hemiparesis, seizures, and limb weakness. Stroke should be suspected in the presence of these symptoms, as scorpion stings can lead to both hemorrhagic and ischemic strokes in both adults and pediatric populations. While stroke is a rare complication of scorpion stings, it is crucial to consider this diagnosis in patients presenting with neurological symptoms, necessitating the use of computed tomography or magnetic resonance imaging if stroke is suspected.

据记录,全世界每年约有 100 万起蝎子蜇伤事件,造成 3000 人死亡。蝎毒对人体有各种影响,约有 2% 的病例会出现神经系统并发症。在这些并发症中,缺血性或出血性中风尤为严重。通过在 PubMed、Scopus、Scielo、拉丁美洲和加勒比健康科学文献(LILACS)以及 Google Schoolar 数据库中使用关键术语进行文献检索,进行了一次系统的文献综述,没有日期限制。收录了西班牙语、英语和葡萄牙语中与蝎子蜇伤导致中风相关的文章。我们的研究方案已在 PROSPERO 注册。共有 24 篇文章符合本综述的纳入标准。蝎子蜇伤引起的主要神经症状包括偏瘫、偏瘫、癫痫发作和四肢无力。出现这些症状时应怀疑中风,因为蝎子蜇伤可导致成人和儿童出血性和缺血性中风。虽然中风是蝎子蜇伤的罕见并发症,但在出现神经系统症状的患者中考虑这一诊断至关重要,如果怀疑是中风,则有必要使用计算机断层扫描或磁共振成像。
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引用次数: 0
Development of a gold nanoparticle-based novel diagnostic prototype for in vivo detection of Indian red scorpion (Mesobuthus tamulus) venom 开发基于金纳米粒子的新型诊断原型,用于体内检测印度红蝎(Mesobuthus tamulus)毒液
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-08-18 DOI: 10.1016/j.toxcx.2024.100203
Upasana Puzari , Mojibur R. Khan , Ashis K. Mukherjee

Indian red scorpion Mesobuthus tamulus is responsible for substantial mortality in India and Sri Lanka; however, no specific diagnostic method is available to detect the venom of this scorpion in envenomed plasma or body fluid. Therefore, we have proposed a novel, simple, and rapid method for detecting M. tamulus venom (MTV) in the plasma of envenomed animals using polyclonal antibodies (PAb) raised against three modified custom peptides representing the antigenic epitopes of K+ (Tamapin) and Na+ (α-neurotoxin) channel toxins, the two major MTV toxins identified by proteomic analysis. The optimum PAb formulation containing PAb 1, 2, and 3 in proportion (1:1:1, w/w/w) acted synergistically, demonstrating significantly higher immunological recognition of MTV than anti-scorpion antivenom (developed against native toxins) and individual antibodies against peptide immunogens. The PAb formulation could detect MTV optimally in envenomed rat plasma (intravenous and subcutaneous routes) at 30–60 min post-injection. The acetonitrile precipitation method developed in this study to augment the MTV detection sensitivity enriched the low molecular mass peptide toxins in envenomed rat plasma, which was ascertained by mass spectrometry analysis. The gold nanoparticles conjugated PAb formulation, characterised by biophysical techniques such as Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM), demonstrated their interaction with low molecular mass MTV peptide toxins in envenomed rat plasma. This interaction results in the accumulation of the gold nanoparticles, thus leading to signal change in absorbance spectra that can be discerned within 10 min. From a standard curve of MTV spiked plasma, the quantity of MTV in envenomed rat plasma could be determined by gold nanoparticle-PAb formulation conjugate.

印度红蝎(Mesobuthus tamulus)是造成印度和斯里兰卡大量死亡的罪魁祸首;然而,目前还没有特定的诊断方法来检测被毒死动物血浆或体液中的这种蝎子的毒液。因此,我们提出了一种新颖、简单、快速的方法,利用针对三种经修饰的定制肽的多克隆抗体(PAb)来检测被毒杀动物血浆中的蝎毒(MTV),这三种肽分别代表了 K+(Tamapin)和 Na+(α-神经毒素)通道毒素的抗原表位,而这两种毒素是通过蛋白质组分析确定的两种主要的 MTV 毒素。含有 PAb 1、2 和 3 的最佳 PAb 配方按比例(1:1:1, w/w/w)协同作用,对 MTV 的免疫识别率明显高于抗蝎抗血清(针对原生毒素开发)和针对肽免疫原的单个抗体。PAb 制剂可在注射后 30-60 分钟内在被毒死的大鼠血浆(静脉注射和皮下注射)中检测出 MTV。本研究开发的乙腈沉淀法提高了 MTV 的检测灵敏度,富集了被毒杀大鼠血浆中的低分子质量多肽毒素,这一点已通过质谱分析得到证实。通过傅立叶变换红外光谱(FTIR)和透射电子显微镜(TEM)等生物物理技术对金纳米粒子共轭 PAb 制剂进行表征,结果表明它们与被毒杀大鼠血浆中的低分子质量 MTV 多肽毒素发生了相互作用。这种相互作用会导致金纳米粒子的积累,从而导致吸光度光谱的信号变化,这种变化可在 10 分钟内分辨出来。根据添加了 MTV 的血浆的标准曲线,可通过金纳米粒子-PAb 制剂共轭物确定被毒杀大鼠血浆中 MTV 的含量。
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引用次数: 0
Pilot-scale evaluation of a dynamic body-feed filtration system for primary clarification of snake antivenoms produced by the caprylic acid method 对用于初级澄清用辛酸法生产的蛇毒血清的动态主体进料过滤系统进行试验性评估
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.toxcx.2024.100202
Andrés Sánchez, Maykel Cerdas, Jairo Gutiérrez, Mariángela Vargas, Álvaro Segura, María Herrera, Stephanie Chaves-Araya, Ronald Sánchez, Mauren Villalta, Gina Durán, Adriana Sánchez, Gabriela Solano, Daniel Cordero, Paola Sánchez, José María Gutiérrez, Guillermo León

The performance of dynamic body-feed filtration (DBF) in the removal of bulky solids produced during the manufacturing of snake antivenoms using the caprylic acid method was evaluated. For this purpose, diatomites with different filterability properties were compared in a bench-scale study to assess their effectiveness in removing the precipitated material formed after the addition of caprylic acid to equine hyperimmune plasma. C1000 diatomite at a concentration of 90 g/L of precipitated plasma showed the best performance. Then, the process was scaled up to three batches of 50 L of hyperimmune horse plasma. At this pilot scale, 108 ± 4% of the immunoglobulins present following plasma precipitation were recovered after DBF. The antivenoms generated using this procedure met quality specifications. When compared to open filtration systems commonly used at an industrial scale by many antivenom manufacturers, DBF has a similar yield and produces filtrates with comparable physicochemical characteristics. However, DBF ensures the microbiological quality of the primary clarification in a way that open systems cannot. This is because: 1) DBF is performed in a single-use closed device of depth filters which prevents microbial contamination, and 2) DBF removes bulky material in few minutes instead of the more than 24 h needed by open filtration systems, thus reducing the risk of contamination. It was concluded that DBF is a cost-effective, easily validated, and GMP-compliant alternative for primary clarification following caprylic acid precipitation of plasma in snake antivenom production.

我们评估了动态给体过滤(DBF)在去除使用辛酸法生产蛇毒血清过程中产生的大块固体物质方面的性能。为此,在一项台式研究中对具有不同过滤特性的硅藻土进行了比较,以评估它们在去除向马高免疫血浆中添加辛酸后形成的沉淀物方面的效果。沉淀血浆浓度为 90 克/升的 C1000 硅藻土表现最佳。然后,将该工艺放大到三批 50 升高免疫马血浆。在这一试验规模中,血浆沉淀后的免疫球蛋白有 108 ± 4% 在 DBF 后被回收。使用该程序生成的抗蛇毒血清符合质量规格。与许多抗蛇毒血清生产商在工业规模上常用的开放式过滤系统相比,DBF 的产量相似,生产的滤液理化特性也相当。不过,DBF 能确保初级澄清的微生物质量,而开放式系统则无法做到这一点。这是因为1) DBF 是在深度过滤器的一次性封闭装置中进行的,可防止微生物污染,以及 2) DBF 可在几分钟内去除大块物质,而开放式过滤系统则需要 24 小时以上,因此降低了污染风险。结论是,DBF 是一种成本效益高、易于验证且符合 GMP 标准的替代方法,可用于蛇毒抗蛇毒血清生产中血浆的辛酸沉淀后的初级澄清。
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引用次数: 0
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Toxicon: X
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