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Apoptosis and Oxidative Stress in Human Intestinal Epithelial Caco-2 Cells Caused by Marine Phycotoxin Azaspiracid-2 海洋植物毒素 Azaspiracid-2 引起的人肠道上皮细胞 Caco-2 细胞凋亡和氧化应激
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-31 DOI: 10.3390/toxins16090381
Liye Zhao, Jiangbing Qiu, Jingrui Zhang, Aifeng Li, Guixiang Wang
When humans consume seafood contaminated by lipophilic polyether phycotoxins, such as azaspiracids (AZAs), the toxins are mainly leached and absorbed in the small intestine, potentially causing intestinal damage. In this study, human intestinal epithelial Caco-2 cells were used to investigate the adverse effects of azaspiracid-2 (AZA-2) on human intestinal epithelial cells. Cell viability, apoptosis, oxidative damage and mitochondrial ultrastructure were investigated, and ribonucleic acid sequence (RNA-seq) analysis was applied to explore the potential mechanisms of AZA-2 toxicity to Caco-2 cells. Results showed that AZA-2 significantly reduced the proliferation of Caco-2 cells in a concentration-dependent response, and the 48 h EC50 of AZA-2 was 12.65 nmol L−1. AZA-2 can induce apoptosis in Caco-2 cells in a dose-dependent manner. Visible mitochondrial swelling, cristae disintegration, membrane rupture and autophagy were observed in Caco-2 cells exposed to AZA-2. Reactive oxygen species (ROS) and malondialdehyde (MDA) content were significantly increased in Caco-2 cells after 48 h of exposure to 1 and 10 nmol L−1 of AZA-2. Transcriptome analysis showed that KEGG pathways related to cellular oxidative damage and lipid metabolism were affected, mainly including mitophagy, oxidative phosphorylation, cholesterol metabolism, vitamin digestion and absorption, bile secretion and the peroxisome proliferator-activated receptor signaling pathway. The cytotoxic effects of AZA-2 on Caco-2 cells may be associated with ROS-mediated autophagy and apoptosis in mitochondrial cells. Results of this study improve understanding of the cytotoxicity and molecular mechanisms of AZA-2 on Caco-2 cells, which is significant for protecting human health.
当人类食用被亲脂性聚醚藻毒素(如氮杂螺螨毒素(AZAs))污染的海产品时,毒素主要在小肠中浸出和吸收,可能会造成肠道损伤。本研究利用人体肠道上皮细胞 Caco-2 来研究氮杂吡啶-2(AZA-2)对人体肠道上皮细胞的不良影响。研究了细胞活力、凋亡、氧化损伤和线粒体超微结构,并应用核糖核酸序列(RNA-seq)分析探讨了AZA-2对Caco-2细胞毒性的潜在机制。结果表明,AZA-2能明显降低Caco-2细胞的增殖,且呈浓度依赖性,48 h的EC50为12.65 nmol L-1。AZA-2 能以剂量依赖性方式诱导 Caco-2 细胞凋亡。在暴露于 AZA-2 的 Caco-2 细胞中观察到线粒体明显肿胀、嵴解体、膜破裂和自噬。Caco-2 细胞暴露于 1 nmol L-1 和 10 nmol L-1 的 AZA-2 48 小时后,活性氧(ROS)和丙二醛(MDA)含量显著增加。转录组分析表明,与细胞氧化损伤和脂质代谢相关的 KEGG 通路受到了影响,主要包括有丝分裂、氧化磷酸化、胆固醇代谢、维生素消化吸收、胆汁分泌和过氧化物酶体增殖激活受体信号通路。AZA-2 对 Caco-2 细胞的细胞毒性作用可能与 ROS 介导的线粒体细胞自噬和凋亡有关。这项研究的结果加深了人们对AZA-2对Caco-2细胞的细胞毒性和分子机制的认识,对保护人类健康具有重要意义。
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引用次数: 0
Aligning Post-Column ESI-MS, MALDI-MS, and Coagulation Bioassay Data of Naja spp., Ophiophagus hannah, and Pseudonaja textillis Venoms Chromatographically to Assess MALDI-MS and ESI-MS Complementarity with Correlation of Bioactive Toxins to Mass Spectrometric Data 对 Naja spp.、Ophiophagus hannah 和 Pseudonaja textillis 毒液的柱后 ESI-MS、MALDI-MS 和凝血生物测定数据进行色谱比对,以评估 MALDI-MS 和 ESI-MS 与生物活性毒素与质谱数据相关性的互补性
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-29 DOI: 10.3390/toxins16090379
Haifeng Xu, Susan El-Asal, Hafsa Zakri, Rama Mutlaq, Natascha T. B. Krikke, Nicholas R. Casewell, Julien Slagboom, Jeroen Kool
Snakebite is a serious health issue in tropical and subtropical areas of the world and results in various pathologies, such as hemotoxicity, neurotoxicity, and local swelling, blistering, and tissue necrosis around the bite site. These pathologies may ultimately lead to permanent morbidity and may even be fatal. Understanding the chemical and biological properties of individual snake venom toxins is of great importance when developing a newer generation of safer and more effective snakebite treatments. Two main approaches to ionizing toxins prior to mass spectrometry (MS) analysis are electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). In the present study, we investigated the use of both ESI-MS and MALDI-MS as complementary techniques for toxin characterization in venom research. We applied nanofractionation analytics to separate crude elapid venoms using reversed-phase liquid chromatography (RPLC) and high-resolution fractionation of the eluting toxins into 384-well plates, followed by online LC-ESI-MS measurements. To acquire clear comparisons between the two ionization approaches, offline MALDI-MS measurements were performed on the nanofractionated toxins. For comparison to the LC-ESI-MS data, we created so-called MALDI-MS chromatograms of each toxin. We also applied plasma coagulation assaying on 384-well plates with nanofractionated toxins to demonstrate parallel biochemical profiling within the workflow. The plotting of post-column acquired MALDI-MS data as so-called plotted MALDI-MS chromatograms to directly align the MALDI-MS data with ESI-MS extracted ion chromatograms allows the efficient correlation of intact mass toxin results from the two MS-based soft ionization approaches with coagulation bioassay chromatograms. This facilitates the efficient correlation of chromatographic bioassay peaks with the MS data. The correlated toxin masses from ESI-MS and/or MALDI-MS were all around 6–8 or 13–14 kDa, with one mass around 20 kDa. Between 24 and 67% of the toxins were observed with good intensity from both ionization methods, depending on the venom analyzed. All Naja venoms analyzed presented anticoagulation activity, whereas pro-coagulation was only observed for the Pseudonaja textillis venom. The data of MALDI-MS can provide complementary identification and characterization power for toxin research on elapid venoms next to ESI-MS.
蛇咬伤是世界热带和亚热带地区的一个严重健康问题,会导致各种病症,如血液中毒、神经中毒以及咬伤部位周围的局部肿胀、水疱和组织坏死。这些病变最终可能导致永久性发病,甚至致命。在开发新一代更安全、更有效的蛇咬伤治疗方法时,了解各种蛇毒毒素的化学和生物特性非常重要。在质谱分析之前电离毒素的两种主要方法是电喷雾电离(ESI)和基质辅助激光解吸电离(MALDI)。在本研究中,我们调查了在毒液研究中使用 ESI-MS 和 MALDI-MS 作为毒素表征的互补技术的情况。我们采用纳米分馏分析法,使用反相液相色谱法(RPLC)分离粗伶仃毒液,并在 384 孔板中对洗脱出的毒素进行高分辨率分馏,然后进行在线 LC-ESI-MS 测量。为了明确比较两种电离方法,对纳米分馏毒素进行了离线 MALDI-MS 测量。为了与 LC-ESI-MS 数据进行比较,我们为每种毒素绘制了所谓的 MALDI-MS 图谱。我们还在 384 孔板上使用纳米分馏毒素进行血浆凝固测定,以展示工作流程中的并行生化分析。将柱后获得的 MALDI-MS 数据绘制成所谓的 MALDI-MS 色谱图,将 MALDI-MS 数据与 ESI-MS 提取的离子色谱图直接对齐,可将两种基于 MS 的软电离方法得出的完整质量毒素结果与凝血生物测定色谱图进行有效关联。这有助于将色谱生物测定峰与质谱数据有效地关联起来。从 ESI-MS 和/或 MALDI-MS 中得到的相关毒素质量都在 6-8 或 13-14 kDa 左右,其中一种质量在 20 kDa 左右。根据所分析毒液的不同,两种离子化方法都能观察到 24% 至 67% 的毒素具有良好的强度。分析的所有 Naja 毒液都具有抗凝活性,而只有 Pseudonaja textillis 毒液具有促凝活性。与 ESI-MS 相比,MALDI-MS 的数据可为麋鹿毒液毒素研究提供补充鉴定和表征能力。
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引用次数: 0
Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway 细胞外囊泡抑制剂通过调节 JNK 依赖性通路增强胆碱酯酶诱导的细胞死亡
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-29 DOI: 10.3390/toxins16090380
Kazuya Ozaki, Hiyo Nagahara, Asaka Kawamura, Takashi Ohgita, Sachika Higashi, Kohei Ogura, Hiroyasu Tsutsuki, Sunao Iyoda, Atsushi Yokotani, Toshiyuki Yamaji, Joel Moss, Kinnosuke Yahiro
Vibrio cholerae is an important foodborne pathogen. Cholix cytotoxin (Cholix), produced by V. cholerae, is a novel eukaryotic elongation factor 2 (eEF2) adenosine diphosphate ribosyltransferase that causes host cell death by inhibiting protein synthesis. However, the role of Cholix in the infectious diseases caused by V. cholerae remains unclear. Some bacterial cytotoxins are carried by host extracellular vesicles (EVs) and transferred to other cells. In this study, we investigated the effects of EV inhibitors and EV-regulating proteins on Cholix-induced hepatocyte death. We observed that Cholix-induced cell death was significantly enhanced in the presence of EV inhibitors (e.g., dimethyl amiloride, and desipramine) and Rab27a-knockdown cells, but it did not involve a sphingomyelin-dependent pathway. RNA sequencing analysis revealed that desipramine, imipramine, and EV inhibitors promoted the Cholix-activated c-Jun NH2-terminal kinase (JNK) pathway. Furthermore, JNK inhibition decreased desipramine-enhanced Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage. In addition, suppression of Apaf-1 by small interfering RNA further enhanced Cholix-induced PARP cleavage by desipramine. We identified a novel function of desipramine in which the stimulated JNK pathway promoted a mitochondria-independent cell death pathway by Cholix.
霍乱弧菌是一种重要的食源性病原体。霍乱弧菌产生的 Cholix 细胞毒素(Cholix)是一种新型真核细胞延伸因子 2(eEF2)二磷酸腺苷核糖转移酶,可通过抑制蛋白质合成导致宿主细胞死亡。然而,Cholix 在霍乱弧菌引起的传染病中的作用仍不清楚。一些细菌细胞毒素由宿主胞外囊泡(EVs)携带并转移到其他细胞。在本研究中,我们研究了EV抑制剂和EV调节蛋白对Cholix诱导的肝细胞死亡的影响。我们观察到,在EV抑制剂(如二甲基氨苯蝶啶和地西泮)和Rab27a敲除细胞存在的情况下,Cholix诱导的细胞死亡明显增强,但这并不涉及鞘磷脂依赖途径。RNA 测序分析表明,地西泮、丙咪嗪和 EV 抑制剂促进了 Cholix 激活的 c-Jun NH2 端激酶(JNK)通路。此外,抑制 JNK 可减少去甲丙咪嗪增强的 Cholix 诱导的多(ADP-核糖)聚合酶(PARP)裂解。此外,通过小干扰 RNA 抑制 Apaf-1 进一步增强了去甲丙咪嗪诱导 Cholix 的 PARP 分裂。我们发现了去甲丙咪嗪的一种新功能,即刺激的 JNK 通路促进了 Cholix 的线粒体依赖性细胞死亡通路。
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引用次数: 0
New Report of Cyanobacteria and Cyanotoxins in El Pañe Reservoir: A Threat for Water Quality in High-Andean Sources from PERU 关于 El Pañe 水库中蓝藻和蓝藻毒素的新报告:秘鲁安第斯高水源地水质面临的威胁
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-28 DOI: 10.3390/toxins16090378
Victor Hugo Rodriguez Uro, Joana Azevedo, Mário Jorge Araújo, Raquel Silva, Jürgen Bedoya, Betty Paredes, Cesar Ranilla, Vitor Vasconcelos, Alexandre Campos
Cyanobacteria are cosmopolitan organisms; nonetheless, climate change and eutrophication are increasing the occurrence of cyanobacteria blooms (cyanoblooms), thereby raising the risk of cyanotoxins in water sources used for drinking, agriculture, and livestock. This study aimed to determine the presence of cyanobacteria, including toxigenic cyanobacteria and the occurrence of cyanotoxins in the El Pañe reservoir located in the high-Andean region, Arequipa, Peru, to support water quality management. The study included morphological observation of cyanobacteria, molecular determination of cyanobacteria (16S rRNA analysis), and analysis of cyanotoxins encoding genes (mcyA for microcystins, cyrJ for cylindrospermopsins, sxtl for saxitoxins, and AnaC for anatoxins). In parallel, chemical analysis using Liquid Chromatography coupled with Mass Spectrometry (LC-MS/MS) was performed to detect the presence of cyanotoxins (microcystins, cylindrospermopsin, saxitoxin, and anatoxin, among others) and quantification of Microcystin-LR. Morphological data show the presence of Dolichospermum sp., which was confirmed by molecular analysis. Microcystis sp. was also detected through 16S rRNA analysis and the presence of mcyA gene related to microcystin production was found in both cyanobacteria. Furthermore, microcystin-LR and demethylated microcystin-LR were identified by chemical analysis. The highest concentrations of microcystin-LR were 40.60 and 25.18 µg/L, in May and November 2022, respectively. Microcystins were detected in cyanobacteria biomass. In contrast, toxins in water (dissolved) were not detected. Microcystin concentrations exceeded many times the values established in Peruvian regulation and the World Health Organization (WHO) in water intended for human consumption (1 µg/L). This first comprehensive report integrates morphological, molecular, and chemical data and confirms the presence of two toxigenic cyanobacteria and the presence of microcystins in El Pañe reservoir. This work points out the need to implement continuous monitoring of cyanobacteria and cyanotoxins in the reservoir and effective water management measures to protect the human population from exposure to these contaminants.
蓝藻是一种世界性生物;然而,气候变化和富营养化正在增加蓝藻藻华(蓝藻花)的发生率,从而提高了饮用、农业和畜牧业水源中蓝藻毒素的风险。本研究旨在确定位于秘鲁阿雷基帕高安第斯地区的 El Pañe 水库中是否存在蓝藻(包括毒性蓝藻)以及蓝藻毒素的发生情况,从而为水质管理提供支持。该研究包括蓝藻形态观察、蓝藻分子测定(16S rRNA 分析)和蓝藻毒素编码基因分析(mcyA 表示微囊藻毒素,cyrJ 表示圆筒孢囊藻毒素,sxtl 表示沙西毒素,AnaC 表示锐毒素)。与此同时,还利用液相色谱-质谱联用技术(LC-MS/MS)进行了化学分析,以检测蓝藻毒素(微囊藻毒素、圆柱孢藻毒素、鲑鱼毒素和锐毒素等)的存在以及微囊藻毒素-LR 的定量。形态学数据显示存在 Dolichospermum sp.通过 16S rRNA 分析还检测到了微囊藻,并在这两种蓝藻中发现了与产生微囊藻毒素有关的 mcyA 基因。此外,还通过化学分析鉴定了微囊藻毒素-LR 和去甲基化的微囊藻毒素-LR。2022 年 5 月和 11 月,微囊藻毒素-LR 的最高浓度分别为 40.60 微克/升和 25.18 微克/升。在蓝藻生物量中检测到了微囊藻毒素。相比之下,在水中(溶解的)未检测到毒素。微囊藻毒素浓度超过秘鲁法规和世界卫生组织(WHO)规定的供人类饮用的水体中微囊藻毒素浓度值(1 µg/L)的许多倍。这份首次综合报告整合了形态、分子和化学数据,证实了 El Pañe 水库中存在两种致毒蓝藻和微囊藻毒素。这项工作表明,有必要对水库中的蓝藻和蓝藻毒素进行持续监测,并采取有效的水管理措施,以保护人类免受这些污染物的危害。
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引用次数: 0
Cardiotoxic Effects of Lachesis acrochorda Snake Venom in Anesthetized Wistar Rats 蛇毒对麻醉 Wistar 大鼠心脏的毒性作用
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-28 DOI: 10.3390/toxins16090377
Karen Leonor Ángel-Camilo, Mary Luz Bueno-Ospina, Ivonne Carolina Bolaños Burgos, Santiago Ayerbe-González, José Beltrán-Vidal, Ana Acosta, Jaime Álvarez-Soler, Jimmy Alexander Guerrero-Vargas
Ophidism is a public health problem in tropical countries, occurring predominantly in rural areas. In Colombia, among the species responsible for snakebite envenomation, inflicting high mortality, is the Chocoan bushmaster, Lachesis acrochorda, better known locally by the names “verrugosa (warty)” and “pudridora (rot-causing)”. In this research, the cardiotoxic effect of the venom of L. acrochorda in male Wistar rats weighing 230 ± 20 g was evaluated. A statistical design of randomized blocks was implemented with three treated groups, injected with lyophilized venom (doses of 3.22 μg/g, 6.43 μg/g, 12.86 μg/g), and a control group injected with 0.9% saline solution. Electrocardiographic (ECG) recordings were taken from the anesthetized animals, revealing an increase in the amplitude of the P and T waves and an increase in the duration of the QT intervals in the electrocardiographic recordings. These increases were not observed in the control biomodels. In the analysis of the CK and CK-MB enzyme levels, increases were also observed in the levels of cardiac isoenzymes in the injected animals, but none in the control animals. The histopathological analyses carried out reveal that the injected animals showed effects such as interfibrillar and perivascular edema, cellular shortening of the cardiomyocytes, foci with tissue destructuring, and necrosis with contraction bands. In conclusion, the venom of the Lachesis acrochorda snake increases the P and T waves and the QT interval and increases the CK and CK-MB enzymes in the blood. Additionally, it causes interfibrillar and perivascular edema in the cardiac tissue, cardiocytolysis, and contraction bands.
蛇毒是热带国家的一个公共卫生问题,主要发生在农村地区。在哥伦比亚,造成毒蛇咬伤并导致高死亡率的物种包括乔科安丛林蛇,Lachesis acrochorda,当地人称之为 "verrugosa(疣)"和 "pudridora(致烂)"。在这项研究中,我们评估了尖吻鲈毒液对体重为 230 ± 20 克的雄性 Wistar 大鼠的心脏毒性作用。研究采用随机区组统计设计,分为三个处理组,分别注射冻干毒液(剂量分别为 3.22 μg/g、6.43 μg/g、12.86 μg/g),以及注射 0.9% 生理盐水的对照组。麻醉动物的心电图记录显示,P 波和 T 波的振幅增大,心电图记录中 QT 间期的持续时间延长。在对照组生物模型中没有观察到这些增加。在对 CK 和 CK-MB 酶水平的分析中,也观察到注射动物的心脏同工酶水平升高,而对照组动物则没有。组织病理学分析表明,注射动物表现出纤维间和血管周围水肿、心肌细胞缩短、组织重组灶和带有收缩带的坏死等效应。总之,尖吻蝮蛇毒会增加 P 波、T 波和 QT 间期,增加血液中的 CK 和 CK-MB 酶。此外,它还会导致心脏组织纤维间和血管周围水肿、心脏溶解和收缩带。
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引用次数: 0
Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model 针对表皮生长因子受体和uPAR的双特异性配体靶向毒素eBAT在小鼠和临床犬模型中的毒性概况
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-26 DOI: 10.3390/toxins16090376
Rose H. Dicovitsky, Jill T. Schappa, Ashley J. Schulte, Haeree P. Lang, Ellen Kuerbitz, Sarah Roberts, Taylor A. DePauw, Mitzi Lewellen, Amber L. Winter, Kathy Stuebner, Michelle Buettner, Kelly Reid, Kelly Bergsrud, Sara Pracht, Andrea Chehadeh, Caitlin Feiock, M. Gerard O’Sullivan, Tim Carlson, Alexandra R. Armstrong, Danielle Meritet, Michael S. Henson, Brenda J. Weigel, Jaime F. Modiano, Antonella Borgatti, Daniel A. Vallera
EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated Pseudomonas toxin. Its purpose was to simultaneously target tumors and their vasculature in the tumor microenvironment. In prior studies on mice and dogs, the drug proved efficacious. Here, we report the safety of eBAT in normal wildtype, uPAR knockout, and immunoreplete and immunodeficient tumor-bearing mice, as well as in dogs with spontaneous sarcoma that more closely mirror human cancer onset. In immunocompetent mice, tumor-bearing mice, uPAR knockout mice, and mice receiving species-optimized eBAT, toxicities were mild and self-limiting. Likewise, in dogs with life-threatening sarcoma given dosages found to be biologically active, eBAT was well tolerated. In mice receiving higher doses, eBAT was associated with dose-dependent evidence of liver injury, including portal biliary hyperplasia, oval cell proliferation, lymphoplasmacytic inflammation, periportal hepatocellular microvesicular change, hemorrhage, necrosis, and apoptosis. The results support continuing the clinical development of eBAT as a therapeutic agent for individuals with sarcoma and other cancers.
表皮生长因子受体靶向疗法疗效显著,但毒性也很常见,而且可能很严重。尿激酶型纤溶酶原激活物受体(uPAR)靶向药物才刚刚出现,因此其疗效和毒性都尚未完全确定。重组 eBAT 是将细胞因子 EGF 和 uPA 与截短的假单胞菌毒素结合在同一单链分子上而制成的。其目的是在肿瘤微环境中同时靶向肿瘤及其血管。在之前对小鼠和狗进行的研究中,这种药物被证明是有效的。在此,我们报告了 eBAT 在正常野生型小鼠、uPAR 基因敲除小鼠、免疫缺陷小鼠和免疫缺陷肿瘤小鼠以及患有自发性肉瘤的狗体内的安全性。在免疫功能健全的小鼠、肿瘤携带小鼠、uPAR基因敲除小鼠和接受物种优化eBAT的小鼠中,毒性都很轻微,而且是自限性的。同样,在患有危及生命的肉瘤的狗身上,服用具有生物活性的剂量后,eBAT的耐受性也很好。在接受较高剂量治疗的小鼠中,eBAT 与剂量依赖性肝损伤相关,包括门静脉胆管增生、卵圆形细胞增殖、淋巴浆细胞炎症、肝细胞周围微囊变、出血、坏死和细胞凋亡。这些结果支持继续将 eBAT 作为肉瘤和其他癌症患者的治疗药物进行临床开发。
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引用次数: 0
Combining Multiple Omics with Molecular Dynamics Reveals SCP2-Mediated Cytotoxicity Effects of Aflatoxin B1 in SW480 Cells 将多种全息技术与分子动力学相结合,揭示黄曲霉毒素 B1 在 SW480 细胞中由 SCP2 介导的细胞毒性效应
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-24 DOI: 10.3390/toxins16090375
Mengting Chen, Jiaxin Wen, Yiyan Qiu, Xinyue Gao, Jian Zhang, Yifan Lin, Zekai Wu, Xiaohuang Lin, An Zhu
Aflatoxins belong to a class of mycotoxins, among which aflatoxin B1 (AFB1) has detrimental effects on the health of both animals and humans. It is associated with long-term exposure-induced carcinogenicity, hepatotoxicity, renal toxicity, neurotoxicity, and immunosuppressive properties, resulting in a variety of diseases. The intestine is the first barrier for human exposure to AFB1, but limited investigations have been conducted to clarify the underlying mechanisms of intestinal cytotoxicity. The mechanism of AFB1-induced cytotoxicity was investigated in this study using an integrated approach combining transcriptome, proteome, and metabolome analysis along with molecular dynamics simulation. After exposing SW480 cells to 50 μM AFB1 for 72 h, the transcriptome, proteome, and metabolome exhibited significant enrichment in pathways associated with oxidative stress, fatty acid and lipid metabolism, and glutathione metabolism. The experimental results demonstrated that AFB1 significantly reduces SW480 cells viability, and induces oxidative stress, calcium overload, mitochondrial damage, and lipid metabolism disorders.
黄曲霉毒素属于霉菌毒素的一种,其中黄曲霉毒素 B1(AFB1)对动物和人类的健康都有不利影响。长期接触会引起致癌、肝中毒、肾中毒、神经中毒和免疫抑制,导致多种疾病。肠道是人类暴露于 AFB1 的第一道屏障,但目前为阐明肠道细胞毒性的基本机制而进行的研究十分有限。本研究采用转录组、蛋白质组和代谢组分析与分子动力学模拟相结合的综合方法研究了 AFB1 诱导细胞毒性的机制。将 SW480 细胞暴露于 50 μM AFB1 72 小时后,转录组、蛋白质组和代谢组中与氧化应激、脂肪酸和脂质代谢以及谷胱甘肽代谢相关的通路出现了显著的富集。实验结果表明,AFB1 能显著降低 SW480 细胞的活力,并诱导氧化应激、钙超载、线粒体损伤和脂质代谢紊乱。
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引用次数: 0
Cyanobacterial Cyclic Peptides Can Disrupt Cytoskeleton Organization in Human Astrocytes—A Contribution to the Understanding of the Systemic Toxicity of Cyanotoxins 蓝藻环肽能破坏人类星形胶质细胞的细胞骨架组织--对理解蓝藻毒素的全身毒性的贡献
IF 4.2 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-23 DOI: 10.3390/toxins16090374
Anja Bubik, Robert Frangež, Monika C. Žužek, Ion Gutiérrez-Aguirre, Tamara T. Lah, Bojan Sedmak
The systemic toxicity of cyclic peptides produced by cyanobacteria (CCPs) is not yet completely understood. Apart from the most known damages to the liver and kidneys, symptoms of their neurotoxicity have also been reported. Hepatotoxic CCPs, like microcystins, as well as non-hepatotoxic anabaenopeptins and planktopeptins, all exhibit cytotoxic and cytostatic effects on mammalian cells. However, responses of different cell types to CCPs depend on their specific modes of interaction with cell membranes. This study demonstrates that non-hepatotoxic planktopeptin BL1125 and anabaenopeptins B and F, at concentrations up to 10 µM, affect normal and tumor human astrocytes (NHA and U87-GM) in vitro by their almost immediate insertion into the lipid monolayer. Like microcystin-LR (up to 1 µM), they inhibit Ser/Thr phosphatases and reorganize cytoskeletal elements, with modest effects on their gene expression. Based on the observed effects on intermediate filaments and intermediate filament linkage elements, their direct or indirect influence on tubulin cytoskeletons via post-translational modifications, we conclude that the basic mechanism of CCP toxicities is the induction of inter- and intracellular communication failure. The assessed inhibitory activity on Ser/Thr phosphatases is also crucial since the signal transduction cascades are modulated by phosphorylation/dephosphorylation processes.
蓝藻(CCP)产生的环肽的全身毒性尚未完全明了。除了已知的对肝脏和肾脏的损害外,也有关于其神经毒性症状的报道。肝毒性 CCPs(如微囊藻毒素)以及非肝毒性的anabaenopeptins 和 planktopeptins 都会对哺乳动物细胞产生细胞毒性和细胞抑制作用。然而,不同类型细胞对 CCPs 的反应取决于它们与细胞膜相互作用的特定模式。本研究表明,非肝脏毒性的板蓝根肽 BL1125 和anabaenopeptins B 和 F(浓度高达 10 µM)通过几乎立即插入脂质单层,在体外对正常和肿瘤人类星形胶质细胞(NHA 和 U87-GM)产生影响。与微囊藻毒素-LR(最高 1 µM)一样,它们也会抑制 Ser/Thr 磷酸酶并重组细胞骨架元素,但对其基因表达的影响不大。根据观察到的对中间丝和中间丝连接元件的影响,以及它们通过翻译后修饰对微管蛋白细胞骨架的直接或间接影响,我们得出结论,CCP 毒性的基本机制是诱导细胞间和细胞内的通讯失效。由于信号转导级联受磷酸化/去磷酸化过程的调节,因此评估对 Ser/Thr 磷酸酶的抑制活性也至关重要。
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引用次数: 0
Resistance of Transgenic Maize Cultivars to Mycotoxin Production-Systematic Review and Meta-Analysis. 转基因玉米品种对霉菌毒素产生的抗性--系统综述和元分析。
IF 3.9 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-22 DOI: 10.3390/toxins16080373
Ana Silvia de Lara Pires Batista Gomes, Saulo Henrique Weber, Fernando Bittencourt Luciano

Approximately 25% of cereal grains present with contamination caused by fungi and the presence of mycotoxins that may cause severe adverse effects when consumed. Maize has been genetically engineered to present different traits, such as fungal or insect resistance and herbicide tolerance. This systematic review compared the observable quantities, via meta-analysis, of four mycotoxins (aflatoxins-AFL, fumonisins-FUM, deoxynivalenol-DON, zearalenone-ZEA) between genetically modified (GM) and conventional maize kernels. This study was conducted following the PRISMA guidelines, with searches performed using PubMed, Web of Science, Scopus, Google Scholar, and CAPES journals databases. Analyses were conducted using RevMan v.5.4 software. Transgenic maize showed a 58% reduction in total mycotoxins (p < 0.001) compared to conventional maize. FUM were the most impacted, with a 59% reduction (p < 0.001) in GM maize. AFL and ZEA levels were also lower in GM maize by 49% (p = 0.02) and 51% (p < 0.001), respectively. On the other hand, DON levels increased by 6% (p < 0.001) in GM maize compared to conventional maize. However, results for ZEA and DON were inconclusive due to the limited research and sample sizes. We conclude that transgenic maize reduces total mycotoxins by over 50%, primarily fumonisin and aflatoxin. Most studies presented maize varieties that were resistant to insects or herbicides, not fungal pathogens, showing a positive collateral effect of these genetic alterations. Therefore, transgenic maize appears to be a safer product for animal and human consumption from a toxicological point of view. Further studies with larger sample sizes are needed to confirm our findings for ZEA and DON in transgenic maize.

约有 25% 的谷物受到真菌污染并含有霉菌毒素,食用后可能会造成严重的不良影响。经过基因工程改造的玉米具有不同的特性,如抗真菌或抗虫性和耐除草剂性。本系统综述通过荟萃分析比较了转基因玉米粒和传统玉米粒中四种霉菌毒素(黄曲霉毒素-AFL、烟曲霉毒素-FUM、脱氧雪腐镰刀菌烯醇-DON、玉米赤霉烯酮-ZEA)的可观察数量。本研究遵循 PRISMA 准则,使用 PubMed、Web of Science、Scopus、Google Scholar 和 CAPES 期刊数据库进行检索。分析使用 RevMan v.5.4 软件进行。与传统玉米相比,转基因玉米的霉菌毒素总量减少了 58%(p < 0.001)。FUM受到的影响最大,在转基因玉米中减少了59%(p < 0.001)。转基因玉米中的 AFL 和 ZEA 含量也分别降低了 49% (p = 0.02) 和 51% (p < 0.001)。另一方面,与传统玉米相比,转基因玉米的 DON 含量增加了 6% (p < 0.001)。然而,由于研究和样本量有限,ZEA 和 DON 的结果尚无定论。我们的结论是,转基因玉米可减少 50%以上的霉菌毒素总量,主要是伏马菌素和黄曲霉毒素。大多数研究介绍的玉米品种对昆虫或除草剂具有抗性,而不是对真菌病原体具有抗性,这表明这些基因改变产生了积极的附带效应。因此,从毒理学角度来看,转基因玉米似乎是一种更安全的供动物和人类食用的产品。要证实我们对转基因玉米中 ZEA 和 DON 的研究结果,还需要进行样本量更大的进一步研究。
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引用次数: 0
A Multi-Year Study of Mycotoxin Co-Occurrence in Wheat and Corn Grown in Ontario, Canada. 对加拿大安大略省种植的小麦和玉米中霉菌毒素共存情况的多年研究。
IF 3.9 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Pub Date : 2024-08-22 DOI: 10.3390/toxins16080372
Megan J Kelman, J David Miller, Justin B Renaud, Daria Baskova, Mark W Sumarah

Mycotoxin emergence and co-occurrence trends in Canadian grains are dynamic and evolving in response to changing weather patterns within each growing season. The mycotoxins deoxynivalenol and zearalenone are the dominant mycotoxins detected in grains grown in Eastern Canada. Two potential emerging mycotoxins of concern are sterigmatocystin, produced by Aspergillus versicolor, and diacetoxyscirpenol, a type A trichothecene produced by a number of Fusarium species. In response to a call from the 83rd Joint Expert Committee on Food Additives and Contaminants, we conducted a comprehensive survey of samples from cereal production areas in Ontario, Canada. Some 159 wheat and 160 corn samples were collected from farms over a three-year period. Samples were extracted and analyzed by LC-MS/MS for 33 mycotoxins and secondary metabolites. Ergosterol was analyzed as an estimate of the overall fungal biomass in the samples. In wheat, the ratio of DON to its glucoside, deoxynivalenol-3-glucoside (DON-3G), exhibited high variability, likely attributable to differences among cultivars. In corn, the ratio was more consistent across the samples. Sterigmatocystin was detected in some wheat that had higher concentrations of ergosterol. Diacetoxyscirpenol was not detected in either corn or wheat over the three years, demonstrating a low risk to Ontario grain. Overall, there was some change to the mycotoxin profiles over the three years for wheat and corn. Ongoing surveys are required to reassess trends and ensure the safety of the food value chain, especially for emerging mycotoxins.

加拿大谷物中霉菌毒素的出现和共存趋势是动态的,并随着每个生长季节天气模式的变化而不断变化。在加拿大东部种植的谷物中检测到的主要霉菌毒素是脱氧雪腐镰刀菌烯醇和玉米赤霉烯酮。两种新出现的潜在霉菌毒素令人担忧,一种是由多色曲霉产生的固型麦角菌素,另一种是由多种镰刀菌产生的 A 型单端孢霉烯。为响应第 83 届食品添加剂和污染物联合专家委员会的号召,我们对加拿大安大略省谷物产区的样本进行了一次全面调查。在三年时间里,我们从农场收集了约 159 份小麦和 160 份玉米样本。样本经提取后,采用 LC-MS/MS 方法对 33 种霉菌毒素和次级代谢物进行了分析。对麦角甾醇进行了分析,以估算样本中真菌的总体生物量。在小麦中,DON 与其葡萄糖苷--脱氧雪腐镰刀菌烯醇-3-葡萄糖苷(DON-3G)的比率变化很大,这可能是由于不同栽培品种之间的差异造成的。在玉米中,各样本的比率较为一致。在一些麦角甾醇浓度较高的小麦中检测到了麦角甾醇。在这三年中,玉米和小麦中均未检测到二乙酰氧基藨草酚,这表明安大略谷物的风险较低。总体而言,三年来小麦和玉米的霉菌毒素含量发生了一些变化。需要不断进行调查,以重新评估趋势,确保粮食价值链的安全,特别是新出现的霉菌毒素。
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引用次数: 0
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