Toxins

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Open AccessEditorial

Introduction to the Toxins Special Issue “Ricin Toxins”

by Nilgun E. Tumer

Toxins 2020, 12(1), 13; https://doi.org/10.3390/toxins12010013 - 27 Dec 2019

Cited by 4 | Viewed by 3017

Abstract

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known [...] Full article

(This article belongs to the Special Issue Ricin Toxins)

Research

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15 pages, 3665 KiB

Open AccessArticle

TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

by Alexa L. Hodges, Cody G. Kempen, William D. McCaig, Cory A. Parker, Nicholas J. Mantis and Timothy J. LaRocca

Toxins 2019, 11(8), 450; https://doi.org/10.3390/toxins11080450 - 1 Aug 2019

Cited by 14 | Viewed by 4236

Abstract

Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides [...] Read more.

Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule’s known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL. Full article

(This article belongs to the Special Issue Ricin Toxins)

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10 pages, 1400 KiB

Open AccessArticle

Characterization of MicroRNA and Gene Expression Profiles Following Ricin Intoxication

by Nir Pillar, Danielle Haguel, Meitar Grad, Guy Shapira, Liron Yoffe and Noam Shomron

Toxins 2019, 11(5), 250; https://doi.org/10.3390/toxins11050250 - 2 May 2019

Cited by 7 | Viewed by 3741

Abstract

Ricin, derived from the castor bean plant, is a highly potent toxin, classified as a potential bioterror agent. Current methods for early detection of ricin poisoning are limited in selectivity. MicroRNAs (miRNAs), which are naturally occurring, negative gene expression regulators, are known for [...] Read more.

Ricin, derived from the castor bean plant, is a highly potent toxin, classified as a potential bioterror agent. Current methods for early detection of ricin poisoning are limited in selectivity. MicroRNAs (miRNAs), which are naturally occurring, negative gene expression regulators, are known for their tissue specific pattern of expression and their stability in tissues and blood. While various approaches for ricin detection have been investigated, miRNAs remain underexplored. We evaluated the effect of pulmonary exposure to ricin on miRNA expression profiles in mouse lungs and peripheral blood mononuclear cells (PBMCs). Significant changes in lung tissue miRNA expression levels were detected following ricin intoxication, specifically regarding miRNAs known to be involved in innate immunity pathways. Transcriptome analysis of the same lung tissues revealed activation of several immune regulation pathways and immune cell recruitment. Our work contributes to the understanding of the role of miRNAs and gene expression in ricin intoxication. Full article

(This article belongs to the Special Issue Ricin Toxins)

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21 pages, 2035 KiB

Open AccessArticle

A New Method for Extraction and Analysis of Ricin Samples through MALDI-TOF-MS/MS

by Roberto B. Sousa, Keila S. C. Lima, Caleb G. M. Santos, Tanos C. C. França, Eugenie Nepovimova, Kamil Kuca, Marcos R. Dornelas and Antonio L. S. Lima

Toxins 2019, 11(4), 201; https://doi.org/10.3390/toxins11040201 - 3 Apr 2019

Cited by 11 | Viewed by 6868

Abstract

We report for the first time the efficient use of accelerated solvent extraction (ASE) for extraction of ricin to analytical purposes, followed by the combined use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and MALDI-TOF [...] Read more.

We report for the first time the efficient use of accelerated solvent extraction (ASE) for extraction of ricin to analytical purposes, followed by the combined use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and MALDI-TOF MS/MS method. That has provided a fast and unambiguous method of ricin identification for in real cases of forensic investigation of suspected samples. Additionally, MALDI-TOF MS was applied to characterize the presence and the toxic activity of ricin in irradiated samples. Samples containing ricin were subjected to ASE, irradiated with different dosages of gamma radiation, and analyzed by MALDI-TOF MS/MS for verification of the intact protein signal. For identification purposes, samples were previously subjected to SDS-PAGE, for purification and separation of the chains, followed by digestion with trypsin, and analysis by MALDI-TOF MS/MS. The results were confirmed by verification of the amino acid sequences of some selected peptides by MALDI-TOF MS/MS. The samples residual toxic activity was evaluated through incubation with a DNA substrate, to simulate the attack by ricin, followed by MALDI-TOF MS/MS analyses. Full article

(This article belongs to the Special Issue Ricin Toxins)

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13 pages, 1051 KiB

Open AccessArticle

Generation of Highly Efficient Equine-Derived Antibodies for Post-Exposure Treatment of Ricin Intoxications by Vaccination with Monomerized Ricin

by Reut Falach, Anita Sapoznikov, Ron Alcalay, Moshe Aftalion, Sharon Ehrlich, Arik Makovitzki, Avi Agami, Avishai Mimran, Amir Rosner, Tamar Sabo, Chanoch Kronman and Yoav Gal

Toxins 2018, 10(11), 466; https://doi.org/10.3390/toxins10110466 - 12 Nov 2018

Cited by 9 | Viewed by 3980

Abstract

Ricin, a highly lethal toxin derived from the seeds of Ricinus communis (castor beans) is considered a potential biological threat agent due to its high availability, ease of production, and to the lack of any approved medical countermeasure against ricin exposures. To date, [...] Read more.

Ricin, a highly lethal toxin derived from the seeds of Ricinus communis (castor beans) is considered a potential biological threat agent due to its high availability, ease of production, and to the lack of any approved medical countermeasure against ricin exposures. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this work was to generate anti-ricin antitoxin that confers high level post-exposure protection against ricin challenge. Due to safety issues regarding the usage of ricin holotoxin as an antigen, we generated an inactivated toxin that would reduce health risks for both the immunizer and the immunized animal. To this end, a monomerized ricin antigen was constructed by reducing highly purified ricin to its monomeric constituents. Preliminary immunizing experiments in rabbits indicated that this monomerized antigen is as effective as the native toxin in terms of neutralizing antibody elicitation and protection of mice against lethal ricin challenges. Characterization of the monomerized antigen demonstrated that the irreversibly detached A and B subunits retain catalytic and lectin activity, respectively, implying that the monomerization process did not significantly affect their overall structure. Toxicity studies revealed that the monomerized ricin displayed a 250-fold decreased activity in a cell culture-based functionality test, while clinical signs were undetectable in mice injected with this antigen. Immunization of a horse with the monomerized toxin was highly effective in elicitation of high titers of neutralizing antibodies. Due to the increased potential of IgG-derived adverse events, anti-ricin F(ab’)₂ antitoxin was produced. The F(ab’)₂-based antitoxin conferred high protection to intranasally ricin-intoxicated mice; ~60% and ~34% survival, when administered 24 and 48 h post exposure to a lethal dose, respectively. In line with the enhanced protection, anti-inflammatory and anti-edematous effects were measured in the antitoxin treated mice, in comparison to mice that were intoxicated but not treated. Accordingly, this anti-ricin preparation is an excellent candidate for post exposure treatment of ricin intoxications. Full article

(This article belongs to the Special Issue Ricin Toxins)

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13 pages, 1472 KiB

Open AccessArticle

Peptide Mimics of the Ribosomal P Stalk Inhibit the Activity of Ricin A Chain by Preventing Ribosome Binding

by Xiao-Ping Li, Jennifer N. Kahn and Nilgun E. Tumer

Toxins 2018, 10(9), 371; https://doi.org/10.3390/toxins10090371 - 13 Sep 2018

Cited by 14 | Viewed by 3728

Abstract

Ricin A chain (RTA) depurinates the sarcin/ricin loop (SRL) by interacting with the C-termini of the ribosomal P stalk. The ribosome interaction site and the active site are located on opposite faces of RTA. The interaction with P proteins allows RTA to depurinate [...] Read more.

Ricin A chain (RTA) depurinates the sarcin/ricin loop (SRL) by interacting with the C-termini of the ribosomal P stalk. The ribosome interaction site and the active site are located on opposite faces of RTA. The interaction with P proteins allows RTA to depurinate the SRL on the ribosome at physiological pH with an extremely high activity by orienting the active site towards the SRL. Therefore, if an inhibitor disrupts RTA–ribosome interaction by binding to the ribosome binding site of RTA, it should inhibit the depurination activity. To test this model, we synthesized peptides mimicking the last 3 to 11 amino acids of P proteins and examined their interaction with wild-type RTA and ribosome binding mutants by Biacore. We measured the inhibitory activity of these peptides on RTA-mediated depurination of yeast and rat liver ribosomes. We found that the peptides interacted with the ribosome binding site of RTA and inhibited depurination activity by disrupting RTA–ribosome interactions. The shortest peptide that could interact with RTA and inhibit its activity was four amino acids in length. RTA activity was inhibited by disrupting its interaction with the P stalk without targeting the active site, establishing the ribosome binding site as a new target for inhibitor discovery. Full article

(This article belongs to the Special Issue Ricin Toxins)

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Review

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37 pages, 2584 KiB

Open AccessEditor’s ChoiceReview

Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin

by Natalia Sowa-Rogozińska, Hanna Sominka, Jowita Nowakowska-Gołacka, Kirsten Sandvig and Monika Słomińska-Wojewódzka

Toxins 2019, 11(6), 350; https://doi.org/10.3390/toxins11060350 - 18 Jun 2019

Cited by 65 | Viewed by 12602

Abstract

Ricin can be isolated from the seeds of the castor bean plant (Ricinus communis). It belongs to the ribosome-inactivating protein (RIP) family of toxins classified as a bio-threat agent due to its high toxicity, stability and availability. Ricin is a typical [...] Read more.

Ricin can be isolated from the seeds of the castor bean plant (Ricinus communis). It belongs to the ribosome-inactivating protein (RIP) family of toxins classified as a bio-threat agent due to its high toxicity, stability and availability. Ricin is a typical A-B toxin consisting of a single enzymatic A subunit (RTA) and a binding B subunit (RTB) joined by a single disulfide bond. RTA possesses an RNA N-glycosidase activity; it cleaves ribosomal RNA leading to the inhibition of protein synthesis. However, the mechanism of ricin-mediated cell death is quite complex, as a growing number of studies demonstrate that the inhibition of protein synthesis is not always correlated with long term ricin toxicity. To exert its cytotoxic effect, ricin A-chain has to be transported to the cytosol of the host cell. This translocation is preceded by endocytic uptake of the toxin and retrograde traffic through the trans-Golgi network (TGN) and the endoplasmic reticulum (ER). In this article, we describe intracellular trafficking of ricin with particular emphasis on host cell factors that facilitate this transport and contribute to ricin cytotoxicity in mammalian and yeast cells. The current understanding of the mechanisms of ricin-mediated cell death is discussed as well. We also comment on recent reports presenting medical applications for ricin and progress associated with the development of vaccines against this toxin. Full article

(This article belongs to the Special Issue Ricin Toxins)

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16 pages, 11729 KiB

Open AccessEditor’s ChoiceReview

Ricin: An Ancient Story for a Timeless Plant Toxin

by Letizia Polito, Massimo Bortolotti, Maria Giulia Battelli, Giulia Calafato and Andrea Bolognesi

Toxins 2019, 11(6), 324; https://doi.org/10.3390/toxins11060324 - 6 Jun 2019

Cited by 106 | Viewed by 18995

Abstract

The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, [...] Read more.

The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for several biocrimes. This manuscript intends to give the reader an overview of ricin, focusing on the historical path to the current knowledge on this protein. The main steps of ricin research are here reported, with particular regard to its enzymatic activity, structure, and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation between bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been used to develop immunotoxins for the elimination of unwanted cells, mainly cancer cells; some of these immunoconjugates gave promising results in clinical trials but also showed critical limitation. Full article

(This article belongs to the Special Issue Ricin Toxins)

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16 pages, 1759 KiB

Open AccessEditor’s ChoiceReview

How Ricin Damages the Ribosome

by Przemysław Grela, Monika Szajwaj, Patrycja Horbowicz-Drożdżal and Marek Tchórzewski

Toxins 2019, 11(5), 241; https://doi.org/10.3390/toxins11050241 - 27 Apr 2019

Cited by 46 | Viewed by 7308

Abstract

Ricin belongs to the group of ribosome-inactivating proteins (RIPs), i.e., toxins that have evolved to provide particular species with an advantage over other competitors in nature. Ricin possesses RNA N-glycosidase activity enabling the toxin to eliminate a single adenine base from the sarcin-ricin [...] Read more.

Ricin belongs to the group of ribosome-inactivating proteins (RIPs), i.e., toxins that have evolved to provide particular species with an advantage over other competitors in nature. Ricin possesses RNA N-glycosidase activity enabling the toxin to eliminate a single adenine base from the sarcin-ricin RNA loop (SRL), which is a highly conserved structure present on the large ribosomal subunit in all species from the three domains of life. The SRL belongs to the GTPase associated center (GAC), i.e., a ribosomal element involved in conferring unidirectional trajectory for the translational apparatus at the expense of GTP hydrolysis by translational GTPases (trGTPases). The SRL represents a critical element in the GAC, being the main triggering factor of GTP hydrolysis by trGTPases. Enzymatic removal of a single adenine base at the tip of SRL by ricin blocks GTP hydrolysis and, at the same time, impedes functioning of the translational machinery. Here, we discuss the consequences of SRL depurination by ricin for ribosomal performance, with emphasis on the mechanistic model overview of the SRL modus operandi. Full article

(This article belongs to the Special Issue Ricin Toxins)

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