Evaluation of Cytotoxicity and Cytoprotection. Effects of Natural Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Mycotoxins".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 22329

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Guest Editor
Laboratory of Food Chemistry and Toxicology, Faculty of Pharmacy, University of Valencia, E-46100 Valencia, Spain
Interests: toxicological effects of food contaminants, specifically mycotoxins; risk assessment of food contaminants with a focus on human’s health; factors that influence intestinal bioavailability and investigation of methods to decrease mycotoxins’ effects; new advanced techniques in elucidating mycotoxins’ toxicological effects implementing the 3R’s principle
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Special Issue Information

Dear Colleagues,

The lifestyle associated with good quality of food is well known for its widely recognized health benefits, especially when rich in bioactive compounds.  Reduced risks of some types of cancer and other diseases have been associated with the adoption of such a diet, as have increased antioxidants, inhibitors of lipid peroxidation, decrease of pro-inflammatory cytokine production, etc. Their classification is very wide, including lycopenes, carotenoids, and polyphenols (flavonoids and non-flavonoids). Nevertheless, the presence of natural toxins in food usually happens due to a lack in harvesting, storage or packaging, or climate changes and atmospheric conditions. Such toxins can have different origins, as from plants, fungi, algae, bacteria, marine biotoxins including mycotoxins, lectins, furocoumarins, shiga toxin, ciguatoxins, etc. Studies at the cellular level attributed to natural toxins precede those toxins detected in organs and systems. Evaluation of the effects of natural toxins and biologically active compounds of extracts from the plant kingdom constitute a potential to combat various diseases thanks to its rich content. The focus of this Special Issue of Toxins is to gather the most recent advances related to the cytotoxicity of natural toxins and the potential for the cytoprotection of natural compounds present in food, thus, papers dealing with cellular systems are welcome. In this context, omics data are also encouraged. Both research papers and review articles proposing novelties or overviews, respectively, are welcome.

Prof. Dr. Ana Juan-García
Guest Editor

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Keywords

  • mycotoxins
  • cells
  • in vitro
  • alternative methods
  • cytometry
  • mass cytometry
  • metabolomics
  • cytotoxicity
  • cytoprotection
  • biological systems

Published Papers (9 papers)

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Editorial

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3 pages, 230 KiB  
Editorial
Introduction to the Toxins’ Special Issue on Evaluation of Cytotoxicity and Cytoprotection Effects of Natural Toxins
by Ana Juan-García
Toxins 2022, 14(2), 114; https://doi.org/10.3390/toxins14020114 - 02 Feb 2022
Viewed by 1240
Abstract
The lifestyle associated with good nutritional quality of food is well known for its widely recognized health benefits, especially when rich in bioactive compounds [...] Full article

Research

Jump to: Editorial

12 pages, 2006 KiB  
Article
Cytotoxicity of an Innovative Pressurised Cyclic Solid–Liquid (PCSL) Extract from Artemisia annua
by Rosanna Culurciello, Andrea Bosso, Giovanni Di Fabio, Armando Zarrelli, Angela Arciello, Francesca Carella, Leonardo Leonardi, Laura Pazzaglia, Gionata De Vico and Elio Pizzo
Toxins 2021, 13(12), 886; https://doi.org/10.3390/toxins13120886 - 11 Dec 2021
Cited by 2 | Viewed by 2304
Abstract
Therapeutic treatments with Artemisia annua have a long-established tradition in various diseases due to its antibacterial, antioxidant, antiviral, anti-malaria and anti-cancer effects. However, in relation to the latter, virtually all reports focused on toxic effects of A. annua extracts were obtained mostly through [...] Read more.
Therapeutic treatments with Artemisia annua have a long-established tradition in various diseases due to its antibacterial, antioxidant, antiviral, anti-malaria and anti-cancer effects. However, in relation to the latter, virtually all reports focused on toxic effects of A. annua extracts were obtained mostly through conventional maceration methods. In the present study, an innovative extraction procedure from A. annua, based on pressurised cyclic solid–liquid (PCSL) extraction, resulted in the production of a new phytocomplex with enhanced anti-cancer properties. This extraction procedure generated a pressure gradient due to compressions and following decompressions, allowing to directly perform the extraction without any maceration. The toxic effects of A. annua PCSL extract were tested on different cells, including three cancer cell lines. The results of this study clearly indicate that the exposure of human, murine and canine cancer cells to serial dilutions of PCSL extract resulted in higher toxicity and stronger propensity to induce apoptosis than that detected by subjecting the same cells to Artemisia extracts obtained through canonical extraction by maceration. Collected data suggest that PCSL extract of A. annua could be a promising and economic new therapeutic tool to treat human and animal tumours. Full article
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11 pages, 6171 KiB  
Article
Protective Effects of the Hydroethanolic Extract of Fridericia chica on Undifferentiated Human Neuroblastoma Cells Exposed to α-Zearalenol (α-ZEL) and β-Zearalenol (β-ZEL)
by Neda Alvarez-Ortega, Karina Caballero-Gallardo, María Taboada-Alquerque, Jackeline Franco, Elena E. Stashenko, Cristina Juan, Ana Juan-García and Jesus Olivero-Verbel
Toxins 2021, 13(11), 748; https://doi.org/10.3390/toxins13110748 - 22 Oct 2021
Cited by 8 | Viewed by 2217
Abstract
Fridericia chica (Bignoniaceae) is a traditional medicinal plant. The aim of this research was to determine the protective effects of the hydroethanolic extract from the F. chica leaves (HEFc) against the cytotoxicity of zearalenone (α-ZEL) and β-ZEL on SH-SY5Y cells. Free radical scavenging [...] Read more.
Fridericia chica (Bignoniaceae) is a traditional medicinal plant. The aim of this research was to determine the protective effects of the hydroethanolic extract from the F. chica leaves (HEFc) against the cytotoxicity of zearalenone (α-ZEL) and β-ZEL on SH-SY5Y cells. Free radical scavenging activity of HEFc was evaluated using the DPPH method. The cytotoxicity of both zearalenone metabolites and HEFc was examined using MTT test, as was the cytoprotective effects of the HEFc on cells treated with these mycotoxins. The chemical composition of HEFc was determined using UPLC-QTOF-MS/MS. HEFc elicited good DPPH radical scavenging activity following a concentration-dependent relationship. Cells exposed to α-ZEL exhibited a viability ˂50% after 48 h of treatment (25 and 50 µM), while those exposed to β-ZEL showed viability ˂50% (100 µM) and ˂25% (25-100 µM) after 24 and 48 h of exposure, respectively. HEFc showed a significant increase in cell viability after exposure to α-ZEL (25 and 50 µM) and β-ZEL (6–100 µM) (p < 0.05). UPLC-QTOF-MS/MS analyses allowed the identification of 10 phytochemical components in the HEFc. In short, the hydroethanolic extract of F. chica grown in Colombian Caribbean can protect against the effects of mycotoxins and it is a valuable source of compounds with antioxidant properties. Full article
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15 pages, 3609 KiB  
Article
N-Acetylcysteine Inhibits Patulin-Induced Apoptosis by Affecting ROS-Mediated Oxidative Damage Pathway
by Jiayu Liu, Qi Liu, Jiahui Han, Jiayu Feng, Tianmin Guo, Zhiman Li, Fenyi Min, Ruyi Jin and Xiaoli Peng
Toxins 2021, 13(9), 595; https://doi.org/10.3390/toxins13090595 - 26 Aug 2021
Cited by 16 | Viewed by 3825
Abstract
Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the present research, we systematically explored the detailed mechanism of ROS production and ROS clearance in PAT-induced HEK293 cell [...] Read more.
Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the present research, we systematically explored the detailed mechanism of ROS production and ROS clearance in PAT-induced HEK293 cell apoptosis. Results showed that PAT treatment (2.5, 5, 7.5, 10 μM) for 10 h could regulate the expression of genes and proteins involved in the mitochondrial respiratory chain complex, resulting in dysfunction of mitochondrial oxidative phosphorylation and induction of ROS overproduction. We further investigated the role of N-acetylcysteine (NAC), an ROS scavenger, in promoting the survival of PAT-treated HEK293 cells. NAC improves PAT-induced apoptosis of HEK293 cells by clearing excess ROS, modulating the expression of mitochondrial respiratory chain complex genes and proteins, and maintaining normal mitochondrial function. In addition, NAC protects the activity of antioxidant enzymes, maintains normal GSH content, and relieves oxidative damage. Additionally, 4 mM NAC alleviated 7.5 μM PAT-mediated apoptosis through the caspase pathway in HEK293 cells. In summary, our study demonstrated that ROS is significant in PAT-mediated cytotoxicity, which provides valuable insight into the management of PAT-associated health issues. Full article
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12 pages, 2549 KiB  
Article
Zearalenone Induces Apoptosis and Cytoprotective Autophagy in Chicken Granulosa Cells by PI3K-AKT-mTOR and MAPK Signaling Pathways
by Yifeng Zhu, Heng Wang, Jianping Wang, Shunshun Han, Yao Zhang, Menggen Ma, Qing Zhu, Keying Zhang and Huadong Yin
Toxins 2021, 13(3), 199; https://doi.org/10.3390/toxins13030199 - 10 Mar 2021
Cited by 30 | Viewed by 2876
Abstract
Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin found in several food commodities worldwide. ZEA causes reproductive disorders, genotoxicity, and testicular toxicity in animals. However, little is known about the functions of apoptosis and autophagy after exposure to ZEA in granulosa cells. This study [...] Read more.
Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin found in several food commodities worldwide. ZEA causes reproductive disorders, genotoxicity, and testicular toxicity in animals. However, little is known about the functions of apoptosis and autophagy after exposure to ZEA in granulosa cells. This study investigated the effects of ZEA on chicken granulosa cells. The results show that ZEA at different doses significantly inhibited the growth of chicken granulosa cells by inducing apoptosis. ZEA treatment up-regulated Bax and downregulated Bcl-2 expression, promoted cytochrome c release into the cytosol, and triggered mitochondria-mediated apoptosis. Consequently, caspase-9 and downstream effector caspase-3 were activated, resulting in chicken granulosa cells apoptosis. ZEA treatment also upregulated LC3-II and Beclin-1 expression, suggesting that ZEA induced a high level of autophagy. Pretreatment with chloroquine (an autophagy inhibitor) and rapamycin (an autophagy inducer) increased and decreased the rate of apoptosis, respectively, in contrast with other ZEA-treated groups. Autophagy delayed apoptosis in the ZEA-treated cells. Therefore, autophagy may prevent cells from undergoing apoptosis by reducing ZEA-induced cytotoxicity. In addition, our results further show that the autophagy was stimulated by ZEA through PI3K-AKT-mTOR and MAPK signaling pathways in chicken granulosa cells. Full article
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21 pages, 8957 KiB  
Article
Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway
by Hyeon-Ju Lee, Se-Young Oh and Inho Jo
Toxins 2021, 13(3), 187; https://doi.org/10.3390/toxins13030187 - 04 Mar 2021
Cited by 16 | Viewed by 2333
Abstract
Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, [...] Read more.
Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, we found that ZEN induced apoptosis of BAECs through increased cleavage of caspase 3 and poly ADP-ribose polymerase (PARP). ZEN also increased phosphorylation of ERK1/2 and p53, and treatment with the ERK1/2 or p53 inhibitor reversed ZEN-induced EC apoptosis. Transfection of BAECs with small interfering RNA against ERK1/2 or p53 revealed ERK1/2 as an upstream target of p53 in ZEN-stimulated apoptosis. ZEN increased the production of reactive oxygen species (ROS), yet treatment with the antioxidant did not prevent EC apoptosis. Similarly, blocking of estrogen receptors by specific inhibitors also did not prevent ZEN-induced apoptosis. Finally, chelation of cytosolic calcium (Ca2+) using BAPTA-AM or inhibition of endoplasmic reticulum (ER) Ca2+ channel using 2-APB reversed ZEN-induced EC apoptosis, but not by inhibiting ER stress using 4-PBA. Together, our findings demonstrate that ZEN induces EC apoptosis through an ERK1/2/p53/caspase 3 signaling pathway activated by Ca2+ release from the ER, and this pathway is independent of ROS production and estrogen receptor activation. Full article
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14 pages, 2384 KiB  
Article
Coffee Silverskin and Spent Coffee Suitable as Neuroprotectors against Cell Death by Beauvericin and α-Zearalenol: Evaluating Strategies of Treatment
by Ana Juan-García, Giovanni Caprioli, Gianni Sagratini, Jordi Mañes and Cristina Juan
Toxins 2021, 13(2), 132; https://doi.org/10.3390/toxins13020132 - 10 Feb 2021
Cited by 11 | Viewed by 1885
Abstract
Coffee silverskin and spent coffee have been evaluated in a neuroblastoma cell line (SH-SY5Y cells) against beauvericin (BEA) and α-zearalenol (α-ZEL)-induced cytotoxicity with different strategies of treatment. First, the direct treatment of mycotoxins and coffee by-products extracts in SH-SY5Y cells was assayed. IC [...] Read more.
Coffee silverskin and spent coffee have been evaluated in a neuroblastoma cell line (SH-SY5Y cells) against beauvericin (BEA) and α-zearalenol (α-ZEL)-induced cytotoxicity with different strategies of treatment. First, the direct treatment of mycotoxins and coffee by-products extracts in SH-SY5Y cells was assayed. IC50 values for α-ZEL were 20.8 and 14.0 µM for 48 h and 72 h, respectively and, for BEA only at 72 h, it was 2.5 µM. Afterwards, the pre-treatment with spent coffee obtained by boiling water increased cell viability for α-ZEL at 24 h and 48 h from 10% to 16% and from 25% to 30%, respectively; while with silverskin coffee, a decrease was observed. Opposite effects were observed for BEA where an increase for silverskin coffee was observed at 24 h and 48 h, from 14% to 23% and from 25% to 44%, respectively; however, a decrease below 50% was observed for spent coffee. Finally, the simultaneous treatment strategy for the highest concentration assayed in SH-SY5Y cells provided higher cytoprotection for α-ZEL (from 44% to 56% for 24 h and 48 h, respectively) than BEA (30% for 24 h and 48 h). Considering the high viability of coffee silverskin extracts for SH-SY5Y cells, there is a forthcoming promising use of these unexploited residues in the near future against mycotoxins effects. Full article
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15 pages, 2624 KiB  
Article
Polydatin Protects Bovine Mammary Epithelial Cells against Zearalenone-Induced Apoptosis by Inhibiting Oxidative Responses and Endoplasmic Reticulum Stress
by Yurong Fu, Yongcheng Jin, Anshan Shan, Jing Zhang, Hongyu Tang, Jinglin Shen, Changhai Zhou, Hao Yu, Hengtong Fang, Yun Zhao, Junxiong Wang and Yue Tian
Toxins 2021, 13(2), 121; https://doi.org/10.3390/toxins13020121 - 05 Feb 2021
Cited by 13 | Viewed by 2177
Abstract
Zearalenone (ZEA) is a mycotoxin of the Fusarium genus that can cause endoplasmic reticulum (ER) stress and Apoptosis in bovine mammary epithelial cells (MAC-T). Polydatin (PD), a glycoside purified from Polygonum cuspidatum, has antioxidant properties. This study aimed to explore whether PD [...] Read more.
Zearalenone (ZEA) is a mycotoxin of the Fusarium genus that can cause endoplasmic reticulum (ER) stress and Apoptosis in bovine mammary epithelial cells (MAC-T). Polydatin (PD), a glycoside purified from Polygonum cuspidatum, has antioxidant properties. This study aimed to explore whether PD can alleviate ZEA-induced damage on bovine mammary epithelial cells (MAC-T). We found that incasing the concentration of ZEA (0, 7.5, 15, 30, 60, 90, 120, and 240 μM) gradually decreased the cell viability. PD treatment alone at 5, 10, and 20 μM did not affect cell viability. Follow-up studies then applied 30 μM of ZEA and 5 μM of PD to treat cells; the results showed that the ZEA + PD treatment group effectively reduced cell oxidative damage compared with the ZEA treatment group. The qPCR analysis showed that ZEA treatment significantly up-regulated the expression of ER stress-related genes, relative to the control. However, adding PD significantly down-regulated the expression of ER stress-related genes. The cell apoptosis detection results showed that, compared with the ZEA treatment group, the ZEA + PD treatment group down-regulated the Bax gene and up-regulated the Bcl-2 gene expressions, which reduced the cell apoptosis rate and Caspase-3 activity. Taken together, these results indicate that PD reduces ZEA-induced apoptosis by inhibiting oxidative damage and ER stress. Full article
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13 pages, 3484 KiB  
Article
Cytotoxicity Produced by Silicate Nanoplatelets: Study of Cell Death Mechanisms
by Jie-Ting Huang, Ling-Chu Chang, Chung-Ssu Cheng, Jiang-Jen Lin, San-Yuan Huang and Shuen-Ei Chen
Toxins 2020, 12(10), 623; https://doi.org/10.3390/toxins12100623 - 29 Sep 2020
Cited by 7 | Viewed by 2381
Abstract
Nano-silicate platelets (NSP), an exfoliated product from natural clays, have been validated for biosafety and as an effective supplement to alleviate mycotoxicosis. Since NSP induced noticeable cell death, we therefore investigated further the mechanism of cytotoxicity caused by NSP. Exposure to NSP impaired [...] Read more.
Nano-silicate platelets (NSP), an exfoliated product from natural clays, have been validated for biosafety and as an effective supplement to alleviate mycotoxicosis. Since NSP induced noticeable cell death, we therefore investigated further the mechanism of cytotoxicity caused by NSP. Exposure to NSP impaired membrane integrity and caused cell death in a dose-dependent manner. Reactive oxygen species (ROS) generation other than of NADH oxidase origin, and subcellular interactions by internalized NSP also contributed to NSP-induced cell death. NSP persistently provoked receptor-interacting protein 1 Ser/Thr (RIP1) kinase and caspase 6 and 3/7 activation without altering caspase 8 activity and induced evident chromatolysis of necrosis in the later stage. These events proceeded along with increased ER stress and mitochondrial permeability, to final Cyt-C (Cytochrome C) release and AIF (apoptosis inducing factor) translocation, a hallmark of cell necroptosis. Fluorescent probing further manifested NSP traffic, mostly adherence on the cell surfaces, or via internalization, being compartmentalized in the nuclei, cytosols, and mitochondria. Pharmacological approaches with specific inhibitors suggested that endocytosis and particularly RIP1 kinase provocation mediate NSP-induced cell death independent of caspase activation. In conclusion, the necroptotic process contributes to most of the cell death induced by NSP due to membrane interactions/impaired integrity, ROS generation, and subcellular interactions by internalized NSP. Full article
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