Citrinin (CIT), a polyketide mycotoxin produced by Penicillium, Aspergillus, and Monascus species, is a contaminant that has been found in various food commodities and was also detected in house dust. Several studies showed that CIT can impair the kidney, liver, heart, immune, and reproductive systems in animals by mechanisms so far not completely elucidated. In this study, we investigated the CIT mode of action on two human tumor cell lines, HepG2 (hepatocellular carcinoma) and A549 (lung adenocarcinoma). Cytotoxic concentrations were determined using an MTT proliferation assay. The genotoxic effect of sub-IC50 concentrations was investigated using the alkaline comet assay and the impact on the cell cycle using flow cytometry. Additionally, the CIT effect on the total amount and phosphorylation of two cell-cycle-checkpoint proteins, the serine/threonine kinase Chk2 and Fanconi anemia (FA) group D2 (FANCD2), was determined by the cell-based ELISA. The data were analyzed using GraphPad Prism statistical software. The CIT IC50 for HepG2 was 107.3 µM, and for A549, it was >250 µM. The results showed that sensitivity to CIT is cell-type dependent and that CIT in sub-IC50 and near IC50 induces significant DNA damage and cell-cycle arrest in the G2/M phase, which is related to the increase in total and phosphorylated Chk2 and FANCD2 checkpoint proteins in HepG2 and A549 cells.
{"title":"Citrinin Provoke DNA Damage and Cell-Cycle Arrest Related to Chk2 and FANCD2 Checkpoint Proteins in Hepatocellular and Adenocarcinoma Cell Lines","authors":"Darija Stupin Polančec, Sonja Homar, Daniela Jakšić, Nevenka Kopjar, Maja Šegvić Klarić, Sanja Dabelić","doi":"10.3390/toxins16070321","DOIUrl":"https://doi.org/10.3390/toxins16070321","url":null,"abstract":"Citrinin (CIT), a polyketide mycotoxin produced by Penicillium, Aspergillus, and Monascus species, is a contaminant that has been found in various food commodities and was also detected in house dust. Several studies showed that CIT can impair the kidney, liver, heart, immune, and reproductive systems in animals by mechanisms so far not completely elucidated. In this study, we investigated the CIT mode of action on two human tumor cell lines, HepG2 (hepatocellular carcinoma) and A549 (lung adenocarcinoma). Cytotoxic concentrations were determined using an MTT proliferation assay. The genotoxic effect of sub-IC50 concentrations was investigated using the alkaline comet assay and the impact on the cell cycle using flow cytometry. Additionally, the CIT effect on the total amount and phosphorylation of two cell-cycle-checkpoint proteins, the serine/threonine kinase Chk2 and Fanconi anemia (FA) group D2 (FANCD2), was determined by the cell-based ELISA. The data were analyzed using GraphPad Prism statistical software. The CIT IC50 for HepG2 was 107.3 µM, and for A549, it was >250 µM. The results showed that sensitivity to CIT is cell-type dependent and that CIT in sub-IC50 and near IC50 induces significant DNA damage and cell-cycle arrest in the G2/M phase, which is related to the increase in total and phosphorylated Chk2 and FANCD2 checkpoint proteins in HepG2 and A549 cells.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
María Jesús Antón Andrés, Ernesto Domingo Candau Pérez, María Pilar Bermejo de la Fuente
Hyperhidrosis (HH) is defined as the production of more sweat than is necessary for its thermoregulatory function, negatively affecting patients’ quality of life and interfering with their social, work and family life. In this context, the aim of thisstudy was to evaluate the efficacy of two different doses of botulinum toxin type A (50 or 100 units) in each axilla in severe primary axillary hyperhidrosis. A descriptive, observational, cross-sectional and post-authorisation study was conducted onpatients referred to our department.Thirty-one patients with severe primary axillary hyperhidrosis were included, some of whom received more than one infiltration during the follow-up period, performing a total of 82 procedures. They were assigned by simple random sampling to two types of treatment: infiltration of 50 or 100 units (U) of botulinum toxin A per axilla.Hyperhidrosis severity was assessed using the Hyperhidrosis Disease Severity Scale (HDSS), and quality of life was assessed using the Dermatology Life Quality Index (DLQI) questionnaire. Onabotulinum toxin A infiltration reduced the severity of hyperhidrosis and improved the quality of life of the treated patients, with no significant differences between the two groups.
多汗症（HH）的定义是出汗量超过其体温调节功能所需的量，对患者的生活质量产生负面影响，并干扰其社交、工作和家庭生活。因此，本研究旨在评估在每个腋窝注射两种不同剂量的 A 型肉毒毒素（50 或 100 单位）对严重原发性腋窝多汗症的疗效。研究对象为转诊至我科的31名严重原发性腋窝多汗症患者，其中一些患者在随访期间接受了不止一次浸润治疗，共进行了82次治疗。多汗症的严重程度采用多汗症疾病严重程度量表（HDSS）进行评估，生活质量采用皮肤科生活质量指数（DLQI）问卷进行评估。奥那保妥适A浸润疗法减轻了多汗症的严重程度，改善了患者的生活质量，两组之间无显著差异。
{"title":"Treatment of Primary Axillary Hyperhidrosis with Two Doses of Botulinum Toxin A—Observational Study","authors":"María Jesús Antón Andrés, Ernesto Domingo Candau Pérez, María Pilar Bermejo de la Fuente","doi":"10.3390/toxins16070320","DOIUrl":"https://doi.org/10.3390/toxins16070320","url":null,"abstract":"Hyperhidrosis (HH) is defined as the production of more sweat than is necessary for its thermoregulatory function, negatively affecting patients’ quality of life and interfering with their social, work and family life. In this context, the aim of thisstudy was to evaluate the efficacy of two different doses of botulinum toxin type A (50 or 100 units) in each axilla in severe primary axillary hyperhidrosis. A descriptive, observational, cross-sectional and post-authorisation study was conducted onpatients referred to our department.Thirty-one patients with severe primary axillary hyperhidrosis were included, some of whom received more than one infiltration during the follow-up period, performing a total of 82 procedures. They were assigned by simple random sampling to two types of treatment: infiltration of 50 or 100 units (U) of botulinum toxin A per axilla.Hyperhidrosis severity was assessed using the Hyperhidrosis Disease Severity Scale (HDSS), and quality of life was assessed using the Dermatology Life Quality Index (DLQI) questionnaire. Onabotulinum toxin A infiltration reduced the severity of hyperhidrosis and improved the quality of life of the treated patients, with no significant differences between the two groups.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tenuazonic acid (TeA), usually found in cereals, fruits, vegetables, oil crops, and their products, was classified as one of the highest public health problems by EFSA as early as 2011, but it has still not been regulated by legislation due to the limited toxicological profile. Moreover, it has been reported that the coexistence of TeA and patulin (PAT) has been found in certain agricultural products; however, there are no available data about the combined toxicity. Considering that the gastrointestinal tract is the physiological barrier of the body, it would be the first target site at which exogenous substances interact with the body. Thus, we assessed the combined toxicity (cell viability, ROS, CAT, and ATP) in Caco-2 cells using mathematical modeling (Chou-Talalay) and explored mechanisms using non-targeted metabolomics and molecular biology methods. It revealed that the co-exposure of TeA + PAT (12.5 μg/mL + 0.5 μg/mL) can induce enhanced toxic effects and more severe oxidative stress. Mechanistically, the lipid and amino acid metabolisms and PI3K/AKT/FOXO signaling pathways were mainly involved in the TeA + PAT-induced synergistic toxic effects. Our study not only enriches the scientific basis for the development of regulatory policies but also provides potential targets and treatment options for alleviating toxicities.
{"title":"Metabolome and Its Mechanism Profiling in the Synergistic Toxic Effects Induced by Co-Exposure of Tenuazonic Acid and Patulin in Caco-2 Cells","authors":"Yuxian Qin, Hongyuan Zhou, Yulian Yang, Ting Guo, Ying Zhou, Yuhao Zhang, Liang Ma","doi":"10.3390/toxins16070319","DOIUrl":"https://doi.org/10.3390/toxins16070319","url":null,"abstract":"Tenuazonic acid (TeA), usually found in cereals, fruits, vegetables, oil crops, and their products, was classified as one of the highest public health problems by EFSA as early as 2011, but it has still not been regulated by legislation due to the limited toxicological profile. Moreover, it has been reported that the coexistence of TeA and patulin (PAT) has been found in certain agricultural products; however, there are no available data about the combined toxicity. Considering that the gastrointestinal tract is the physiological barrier of the body, it would be the first target site at which exogenous substances interact with the body. Thus, we assessed the combined toxicity (cell viability, ROS, CAT, and ATP) in Caco-2 cells using mathematical modeling (Chou-Talalay) and explored mechanisms using non-targeted metabolomics and molecular biology methods. It revealed that the co-exposure of TeA + PAT (12.5 μg/mL + 0.5 μg/mL) can induce enhanced toxic effects and more severe oxidative stress. Mechanistically, the lipid and amino acid metabolisms and PI3K/AKT/FOXO signaling pathways were mainly involved in the TeA + PAT-induced synergistic toxic effects. Our study not only enriches the scientific basis for the development of regulatory policies but also provides potential targets and treatment options for alleviating toxicities.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141645594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maize plays a significant global role as a food source, feed, and as a raw material in industry. However, it is affected by toxin-producing fungi, mainly Fusarium graminearum, Fusarium verticillioides, and Aspergillus flavus, which compromise its quality. This study, conducted in 2022 and 2023 at the Látókép long-term research site of the University of Debrecen, Hungary, investigated the effects of different nitrogen fertilization rates (0, 90 and 150 Kgha−1 N) on mycotoxin contamination (DON vs. FB vs. AFB1) in the kernels of three (3) maize hybrids: DKC4590 (tolerant), GKT376 (sensitive), and P9610 (undefined). The results showed a significant (p = 0.05) influence of nitrogen fertilization and maize genotype on mycotoxin levels. Sole nitrogen impacts were complex and did not define a clear trend, contrary to the hybrids selected, which followed superiority to resistance. Increased nitrogen fertilization was associated with higher DON production, while hybrid selection demonstrated a clearer trend in resistance to mycotoxins. Therefore, to maximize yield and minimize mycotoxin contamination., future research should focus on optimizing nitrogen application rates and breeding for resistance to balance yield and mycotoxin management. These results suggest that while nitrogen fertilization is crucial for maximizing yield, selecting less susceptible maize hybrids remains vital for minimizing mycotoxin contamination.
玉米作为食物来源、饲料和工业原料，在全球发挥着重要作用。然而，玉米受到产毒真菌（主要是禾谷镰刀菌、疣孢镰刀菌和黄曲霉）的影响，质量受到损害。本研究于 2022 年和 2023 年在匈牙利德布勒森大学拉托凯普长期研究基地进行，调查了不同氮肥施用量（0、90 和 150 Kgha-1 N）对三（3）种玉米杂交种籽粒中霉菌毒素污染（DON vs. FB vs. AFB1）的影响：DKC4590（耐受）、GKT376（敏感）和 P9610（未确定）。结果表明，氮肥和玉米基因型对霉菌毒素含量有明显影响（p = 0.05）。单氮的影响是复杂的，没有明确的趋势，这与所选杂交种的抗性优越性相反。氮肥的增加与较高的 DON 产量有关，而杂交种的选择则在抗霉菌毒素方面表现出更明显的趋势。因此，为了实现产量最大化和霉菌毒素污染最小化，未来的研究应侧重于优化氮肥施用量和抗性育种，以平衡产量和霉菌毒素管理。这些结果表明，虽然氮肥对最大限度地提高产量至关重要，但选择抗性较低的玉米杂交种对最大限度地减少霉菌毒素污染仍然至关重要。
{"title":"Aspergillus and Fusarium Mycotoxin Contamination in Maize (Zea mays L.): The Interplay of Nitrogen Fertilization and Hybrids Selection","authors":"Muhoja Sylivester Nyandi, Péter Pepó","doi":"10.3390/toxins16070318","DOIUrl":"https://doi.org/10.3390/toxins16070318","url":null,"abstract":"Maize plays a significant global role as a food source, feed, and as a raw material in industry. However, it is affected by toxin-producing fungi, mainly Fusarium graminearum, Fusarium verticillioides, and Aspergillus flavus, which compromise its quality. This study, conducted in 2022 and 2023 at the Látókép long-term research site of the University of Debrecen, Hungary, investigated the effects of different nitrogen fertilization rates (0, 90 and 150 Kgha−1 N) on mycotoxin contamination (DON vs. FB vs. AFB1) in the kernels of three (3) maize hybrids: DKC4590 (tolerant), GKT376 (sensitive), and P9610 (undefined). The results showed a significant (p = 0.05) influence of nitrogen fertilization and maize genotype on mycotoxin levels. Sole nitrogen impacts were complex and did not define a clear trend, contrary to the hybrids selected, which followed superiority to resistance. Increased nitrogen fertilization was associated with higher DON production, while hybrid selection demonstrated a clearer trend in resistance to mycotoxins. Therefore, to maximize yield and minimize mycotoxin contamination., future research should focus on optimizing nitrogen application rates and breeding for resistance to balance yield and mycotoxin management. These results suggest that while nitrogen fertilization is crucial for maximizing yield, selecting less susceptible maize hybrids remains vital for minimizing mycotoxin contamination.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The characteristic accumulation of circulating uremic toxins, such as indoxyl sulfate (IS), in chronic kidney disease (CKD) further exacerbates the disease progression. The gut microbiota, particularly gut bacterial-specific enzymes, represents a selective and attractive target for suppressing uremic toxin production and slowing the progression of renal failure. This study investigates the role of 4-phenylbutyrate (PB) and structurally related compounds, which are speculated to possess renoprotective properties in suppressing IS production and slowing or reversing renal failure in CKD. In vitro enzyme kinetic studies showed that 7-phenylheptanoic acid (PH), a PB homologue, suppresses the tryptophan indole lyase (TIL)-catalyzed decomposition of tryptophan to indole, the precursor of IS. A hydroxypropyl β-cyclodextrin (HPβCD) inclusion complex formulation of PH was prepared to enhance its biopharmaceutical properties and to facilitate in vivo evaluation. Prophylactic oral administration of the PH-HPβCD complex formulation reduced circulating IS and attenuated the deterioration of renal function and tubulointerstitial fibrosis in adenine-induced CKD mice. Additionally, treatment of moderately advanced adenine-induced CKD mice with the formulation ameliorated renal failure, although tissue fibrosis was not improved. These findings suggest that PH-HPβCD can slow the progression of renal failure and may have implications for preventing or managing CKD, particularly in early-stage disease.
{"title":"7-Phenylheptanoic Acid-Hydroxypropyl β-Cyclodextrin Complex Slows the Progression of Renal Failure in Adenine-Induced Chronic Kidney Disease Mice","authors":"Kindness Lomotey Commey, Airi Enaka, Ryota Nakamura, Asami Yamamoto, Kenji Tsukigawa, Koji Nishi, Masaki Otagiri, Keishi Yamasaki","doi":"10.3390/toxins16070316","DOIUrl":"https://doi.org/10.3390/toxins16070316","url":null,"abstract":"The characteristic accumulation of circulating uremic toxins, such as indoxyl sulfate (IS), in chronic kidney disease (CKD) further exacerbates the disease progression. The gut microbiota, particularly gut bacterial-specific enzymes, represents a selective and attractive target for suppressing uremic toxin production and slowing the progression of renal failure. This study investigates the role of 4-phenylbutyrate (PB) and structurally related compounds, which are speculated to possess renoprotective properties in suppressing IS production and slowing or reversing renal failure in CKD. In vitro enzyme kinetic studies showed that 7-phenylheptanoic acid (PH), a PB homologue, suppresses the tryptophan indole lyase (TIL)-catalyzed decomposition of tryptophan to indole, the precursor of IS. A hydroxypropyl β-cyclodextrin (HPβCD) inclusion complex formulation of PH was prepared to enhance its biopharmaceutical properties and to facilitate in vivo evaluation. Prophylactic oral administration of the PH-HPβCD complex formulation reduced circulating IS and attenuated the deterioration of renal function and tubulointerstitial fibrosis in adenine-induced CKD mice. Additionally, treatment of moderately advanced adenine-induced CKD mice with the formulation ameliorated renal failure, although tissue fibrosis was not improved. These findings suggest that PH-HPβCD can slow the progression of renal failure and may have implications for preventing or managing CKD, particularly in early-stage disease.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chemical pesticides help reduce crop loss during production and storage. However, the carbon footprints and ecological costs associated with this strategy are unsustainable. Here, we used three in vitro models to characterize how different Trichoderma species interact with two aflatoxin producers, Aspergillus flavus and Aspergillus parasiticus, to help develop a climate-resilient biological control strategy against aflatoxigenic Aspergillus species. The growth rate of Trichoderma species is a critical factor in suppressing aflatoxigenic strains via physical interactions. The dual plate assay suggests that Trichoderma mainly suppresses A. flavus via antibiosis, whereas the suppression of A. parasiticus occurs through mycoparasitism. Volatile organic compounds (VOCs) produced by Trichoderma inhibited the growth of A. parasiticus (34.6 ± 3.3%) and A. flavus (20.9 ± 1.6%). The VOCs released by T. asperellum BTU and T. harzianum OSK-34 were most effective in suppressing A. flavus growth. Metabolites secreted by T. asperellum OSK-38, T. asperellum BTU, T. virens OSK-13, and T. virens OSK-36 reduced the growth of both aflatoxigenic species. Overall, T. asperellum BTU was the most effective at suppressing the growth and aflatoxin B1 production of both species across all models. This work will guide efforts to screen for effective biological control agents to mitigate aflatoxin accumulation.
{"title":"Three Ecological Models to Evaluate the Effectiveness of Trichoderma spp. for Suppressing Aflatoxigenic Aspergillus flavus and Aspergillus parasiticus","authors":"Nataliia Voloshchuk, Zilfa Irakoze, Seogchan Kang, Joshua J. Kellogg, Josephine Wee","doi":"10.3390/toxins16070314","DOIUrl":"https://doi.org/10.3390/toxins16070314","url":null,"abstract":"Chemical pesticides help reduce crop loss during production and storage. However, the carbon footprints and ecological costs associated with this strategy are unsustainable. Here, we used three in vitro models to characterize how different Trichoderma species interact with two aflatoxin producers, Aspergillus flavus and Aspergillus parasiticus, to help develop a climate-resilient biological control strategy against aflatoxigenic Aspergillus species. The growth rate of Trichoderma species is a critical factor in suppressing aflatoxigenic strains via physical interactions. The dual plate assay suggests that Trichoderma mainly suppresses A. flavus via antibiosis, whereas the suppression of A. parasiticus occurs through mycoparasitism. Volatile organic compounds (VOCs) produced by Trichoderma inhibited the growth of A. parasiticus (34.6 ± 3.3%) and A. flavus (20.9 ± 1.6%). The VOCs released by T. asperellum BTU and T. harzianum OSK-34 were most effective in suppressing A. flavus growth. Metabolites secreted by T. asperellum OSK-38, T. asperellum BTU, T. virens OSK-13, and T. virens OSK-36 reduced the growth of both aflatoxigenic species. Overall, T. asperellum BTU was the most effective at suppressing the growth and aflatoxin B1 production of both species across all models. This work will guide efforts to screen for effective biological control agents to mitigate aflatoxin accumulation.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Muhammad Babar Shahzad Afzal, Mamuna Ijaz, Naeem Abbas, Sarfraz Ali Shad, José Eduardo Serrão
Bacillus thuringiensis (Bt) toxins are potential alternatives to synthetic insecticides for the control of lepidopteran pests. However, the evolution of resistance in some insect pest populations is a threat and can reduce the effectiveness of Bt toxins. In this review, we summarize the results of 161 studies from 20 countries reporting field and laboratory-evolved resistance, cross-resistance, and inheritance, mechanisms, and fitness costs of resistance to different Bt toxins. The studies refer mainly to insects from the United States of America (70), followed by China (31), Brazil (19), India (12), Malaysia (9), Spain (3), and Australia (3). The majority of the studies revealed that most of the pest populations showed susceptibility and a lack of cross-resistance to Bt toxins. Factors that delay resistance include recessive inheritance of resistance, the low initial frequency of resistant alleles, increased fitness costs, abundant refuges of non-Bt, and pyramided Bt crops. The results of field and laboratory resistance, cross-resistance, and inheritance, mechanisms, and fitness cost of resistance are advantageous for predicting the threat of future resistance and making effective strategies to sustain the effectiveness of Bt crops.
{"title":"Resistance of Lepidopteran Pests to Bacillus thuringiensis Toxins: Evidence of Field and Laboratory Evolved Resistance and Cross-Resistance, Mode of Resistance Inheritance, Fitness Costs, Mechanisms Involved and Management Options","authors":"Muhammad Babar Shahzad Afzal, Mamuna Ijaz, Naeem Abbas, Sarfraz Ali Shad, José Eduardo Serrão","doi":"10.3390/toxins16070315","DOIUrl":"https://doi.org/10.3390/toxins16070315","url":null,"abstract":"Bacillus thuringiensis (Bt) toxins are potential alternatives to synthetic insecticides for the control of lepidopteran pests. However, the evolution of resistance in some insect pest populations is a threat and can reduce the effectiveness of Bt toxins. In this review, we summarize the results of 161 studies from 20 countries reporting field and laboratory-evolved resistance, cross-resistance, and inheritance, mechanisms, and fitness costs of resistance to different Bt toxins. The studies refer mainly to insects from the United States of America (70), followed by China (31), Brazil (19), India (12), Malaysia (9), Spain (3), and Australia (3). The majority of the studies revealed that most of the pest populations showed susceptibility and a lack of cross-resistance to Bt toxins. Factors that delay resistance include recessive inheritance of resistance, the low initial frequency of resistant alleles, increased fitness costs, abundant refuges of non-Bt, and pyramided Bt crops. The results of field and laboratory resistance, cross-resistance, and inheritance, mechanisms, and fitness cost of resistance are advantageous for predicting the threat of future resistance and making effective strategies to sustain the effectiveness of Bt crops.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Botulinum neurotoxin (BNT) injection into the cricopharyngeus muscle (CPM) under ultrasound (US) guidance is a minimally invasive technique performed to relieve cricopharyngeal dysphagia by reducing CPM spasticity. This technique is basically accessible only to both lateral sides of the CPM. This cadaveric study aimed to evaluate whether US-guided injection could effectively deliver BNT to abundant areas of gross nerve endings within the CPM. We utilized a newly modified Sihler’s staining method to identify regions with abundant neural endings within the CPM while preserving the three-dimensional morphology of the muscle in 10 sides of 5 fresh cadavers. A mixture of 0.2 mL dye was injected into the 16 sides of CPM under US guidance in 8 cadavers. Nerve endings were abundant in posterolateral areas of the CPM; the injected dye was identified at the posterolateral area on 12 sides (12/16 side, 75%) without diffusion into the posterior cricoarytenoid muscle. The injection failed on four sides (two sides of the prevertebral fascia and two sides of the esophagus below the CPM). These results suggest that US-guided injection could be a feasible technique as it can deliver BNT to the most abundant nerve distribution areas within the CPM in most cases.
在超声波（US）引导下向环咽肌（CPM）注射肉毒杆菌神经毒素（BNT）是一种微创技术，可通过减轻环咽肌痉挛来缓解环咽吞咽困难。这种技术基本上只能到达环咽肌的两侧。这项尸体研究旨在评估 US 引导注射是否能有效地将 BNT 输送到 CPM 内毛细神经末梢丰富的区域。我们采用了一种新改良的西勒染色法来识别 CPM 内神经末梢丰富的区域，同时保留了 5 具新鲜尸体 10 侧肌肉的三维形态。在 US 引导下，将 0.2 mL 混合染料注入 8 具尸体的 16 侧 CPM。在 CPM 的后外侧区域有大量神经末梢；注射的染料在 12 侧（12/16 侧，75%）的后外侧区域被识别，没有扩散到环状腱膜后肌。四侧注射失败（椎前筋膜两侧和 CPM 下方食管两侧）。这些结果表明 US 引导注射是一种可行的技术，因为它能在大多数情况下将 BNT 注射到 CPM 内最丰富的神经分布区。
{"title":"Ultrasound-Guided Botulinum Neurotoxin Injection for Alleviating Cricopharyngeus Muscle Spasticity: A Cadaveric Feasibility Study with Nerve Ending Analysis","authors":"Ji-Hyun Lee, Hyung-Jin Lee, Bo Hae Kim","doi":"10.3390/toxins16070317","DOIUrl":"https://doi.org/10.3390/toxins16070317","url":null,"abstract":"Botulinum neurotoxin (BNT) injection into the cricopharyngeus muscle (CPM) under ultrasound (US) guidance is a minimally invasive technique performed to relieve cricopharyngeal dysphagia by reducing CPM spasticity. This technique is basically accessible only to both lateral sides of the CPM. This cadaveric study aimed to evaluate whether US-guided injection could effectively deliver BNT to abundant areas of gross nerve endings within the CPM. We utilized a newly modified Sihler’s staining method to identify regions with abundant neural endings within the CPM while preserving the three-dimensional morphology of the muscle in 10 sides of 5 fresh cadavers. A mixture of 0.2 mL dye was injected into the 16 sides of CPM under US guidance in 8 cadavers. Nerve endings were abundant in posterolateral areas of the CPM; the injected dye was identified at the posterolateral area on 12 sides (12/16 side, 75%) without diffusion into the posterior cricoarytenoid muscle. The injection failed on four sides (two sides of the prevertebral fascia and two sides of the esophagus below the CPM). These results suggest that US-guided injection could be a feasible technique as it can deliver BNT to the most abundant nerve distribution areas within the CPM in most cases.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lan Xiao, Li Luo, Jia Liu, Luyao Liu, Han Han, Rui Xiao, Lei Guo, Jianwei Xie, Li Tang
Abrin and ricin, both type II ribosome-inactivating proteins, are toxins of significant concern and are under international restriction by the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. The development of a rapid and sensitive detection method for these toxins is of the utmost importance for the first emergency response. Emerging rapid detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and lateral flow assay (LFA), have garnered attention due to their high sensitivity, good selectivity, ease of operation, low cost, and disposability. In this work, we generated stable and high-affinity nanotags, via an efficient freezing method, to serve as the capture module for SERS-LFA. We then constructed a sandwich-style lateral flow test strip using a pair of glycoproteins, asialofetuin and concanavalin A, as the core affinity recognition molecules, capable of trace measurement for both abrin and ricin. The limit of detection for abrin and ricin was 0.1 and 0.3 ng/mL, respectively. This method was applied to analyze eight spiked white powder samples, one juice sample, and three actual botanic samples, aligning well with cytotoxicity assay outcomes. It demonstrated good inter-batch and intra-batch reproducibility among the test strips, and the detection could be completed within 15 min, indicating the suitability of this SERS-LFA method for the on-site rapid detection of abrin and ricin toxins.
{"title":"A Glycoprotein-Based Surface-Enhanced Raman Spectroscopy–Lateral Flow Assay Method for Abrin and Ricin Detection","authors":"Lan Xiao, Li Luo, Jia Liu, Luyao Liu, Han Han, Rui Xiao, Lei Guo, Jianwei Xie, Li Tang","doi":"10.3390/toxins16070312","DOIUrl":"https://doi.org/10.3390/toxins16070312","url":null,"abstract":"Abrin and ricin, both type II ribosome-inactivating proteins, are toxins of significant concern and are under international restriction by the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. The development of a rapid and sensitive detection method for these toxins is of the utmost importance for the first emergency response. Emerging rapid detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and lateral flow assay (LFA), have garnered attention due to their high sensitivity, good selectivity, ease of operation, low cost, and disposability. In this work, we generated stable and high-affinity nanotags, via an efficient freezing method, to serve as the capture module for SERS-LFA. We then constructed a sandwich-style lateral flow test strip using a pair of glycoproteins, asialofetuin and concanavalin A, as the core affinity recognition molecules, capable of trace measurement for both abrin and ricin. The limit of detection for abrin and ricin was 0.1 and 0.3 ng/mL, respectively. This method was applied to analyze eight spiked white powder samples, one juice sample, and three actual botanic samples, aligning well with cytotoxicity assay outcomes. It demonstrated good inter-batch and intra-batch reproducibility among the test strips, and the detection could be completed within 15 min, indicating the suitability of this SERS-LFA method for the on-site rapid detection of abrin and ricin toxins.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141610833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natalie D. King-Lyons, Aryana S. Bhati, John C. Hu, Lorrie M. Mandell, Gautam N. Shenoy, Hugh J. Willison, Terry D. Connell
Triple-negative breast cancer (TNBC), which constitutes 10–20 percent of all breast cancers, is aggressive, has high metastatic potential, and carries a poor prognosis due to limited treatment options. LT-IIc, a member of the type II subfamily of ADP-ribosylating—heat-labile enterotoxins that bind to a distinctive set of cell-surface ganglioside receptors—is cytotoxic toward TNBC cell lines, but has no cytotoxic activity for non-transformed breast epithelial cells. Here, primary TNBC cells, isolated from resected human tumors, showed an enhanced cytotoxic response specifically toward LT-IIc, in contrast to other enterotoxins that were tested. MDA-MB-231 cells, a model for TNBC, were used to evaluate potential mechanisms of cytotoxicity by LT-IIc, which induced elevated intracellular cAMP and stimulated the cAMP response element-binding protein (CREB) signaling pathway. To dissect the role of ADP-ribosylation, cAMP induction, and ganglioside ligation in the cytotoxic response, MDA-MB-231 cells were exposed to wild-type LT-IIc, the recombinant B-pentamer of LT-IIc that lacks the ADP-ribosylating A polypeptide, or mutants of LT-IIc with an enzymatically inactivated A1-domain. These experiments revealed that the ADP-ribosyltransferase activity of LT-IIc was nonessential for inducing the lethality of MDA-MB-231 cells. In contrast, a mutant LT-IIc with an altered ganglioside binding activity failed to trigger a cytotoxic response in MDA-MB-231 cells. Furthermore, the pharmacological inhibition of ganglioside expression protected MDA-MB-231 cells from the cytotoxic effects of LT-IIc. These data establish that ganglioside ligation, but not the induction of cAMP production nor ADP-ribosyltransferase activity, is essential to initiating the LT-IIc-dependent cell death of MDA-MB-231 cells. These experiments unveiled previously unknown properties of LT-IIc and gangliosides in signal transduction, offering the potential for the targeted treatment of TNBC, an option that is desperately needed.
{"title":"A Novel Cytotoxic Mechanism for Triple-Negative Breast Cancer Cells Induced by the Type II Heat-Labile Enterotoxin LT-IIc through Ganglioside Ligation","authors":"Natalie D. King-Lyons, Aryana S. Bhati, John C. Hu, Lorrie M. Mandell, Gautam N. Shenoy, Hugh J. Willison, Terry D. Connell","doi":"10.3390/toxins16070311","DOIUrl":"https://doi.org/10.3390/toxins16070311","url":null,"abstract":"Triple-negative breast cancer (TNBC), which constitutes 10–20 percent of all breast cancers, is aggressive, has high metastatic potential, and carries a poor prognosis due to limited treatment options. LT-IIc, a member of the type II subfamily of ADP-ribosylating—heat-labile enterotoxins that bind to a distinctive set of cell-surface ganglioside receptors—is cytotoxic toward TNBC cell lines, but has no cytotoxic activity for non-transformed breast epithelial cells. Here, primary TNBC cells, isolated from resected human tumors, showed an enhanced cytotoxic response specifically toward LT-IIc, in contrast to other enterotoxins that were tested. MDA-MB-231 cells, a model for TNBC, were used to evaluate potential mechanisms of cytotoxicity by LT-IIc, which induced elevated intracellular cAMP and stimulated the cAMP response element-binding protein (CREB) signaling pathway. To dissect the role of ADP-ribosylation, cAMP induction, and ganglioside ligation in the cytotoxic response, MDA-MB-231 cells were exposed to wild-type LT-IIc, the recombinant B-pentamer of LT-IIc that lacks the ADP-ribosylating A polypeptide, or mutants of LT-IIc with an enzymatically inactivated A1-domain. These experiments revealed that the ADP-ribosyltransferase activity of LT-IIc was nonessential for inducing the lethality of MDA-MB-231 cells. In contrast, a mutant LT-IIc with an altered ganglioside binding activity failed to trigger a cytotoxic response in MDA-MB-231 cells. Furthermore, the pharmacological inhibition of ganglioside expression protected MDA-MB-231 cells from the cytotoxic effects of LT-IIc. These data establish that ganglioside ligation, but not the induction of cAMP production nor ADP-ribosyltransferase activity, is essential to initiating the LT-IIc-dependent cell death of MDA-MB-231 cells. These experiments unveiled previously unknown properties of LT-IIc and gangliosides in signal transduction, offering the potential for the targeted treatment of TNBC, an option that is desperately needed.","PeriodicalId":23119,"journal":{"name":"Toxins","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141586059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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