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Antibodies (Basel, Switzerland) Feb 2020Abrin and ricin are potent AB toxins, which are considered biological threats. To date, there are no approved treatments against abrin or ricin intoxications....
Abrin and ricin are potent AB toxins, which are considered biological threats. To date, there are no approved treatments against abrin or ricin intoxications. Previously, we showed that the administration of polyclonal anti-abrin antibodies to mice that were intranasally exposed to abrin, even very late post-exposure, conferred an exceedingly high-level of protection, while following ricin intoxication, similar treatment with anti-ricin antibodies resulted in negligible survival rates. To probe this unexpected difference in protection ability, we first examined whether the efficient anti-abrin-induced protection was due to neutralization of the A-subunit responsible for the catalytic effect, or of the B-subunit, which enables binding/internalization, by evaluating the protection conferred by antibodies directed against one of the two subunits. To this end, we generated and immunized rabbits with chimeric toxins containing a single abrin subunit, AB in which abrin A-subunit was linked to ricin B-subunit, and AB in which ricin A-subunit is linked to abrin B-subunit. Here, we show that antibodies raised against either AB or AB conferred exceptionally high protection levels to mice following intranasal exposure to a a lethal dose of abrin, suggesting that the high level of protection conferred by anti-abrin antibodies is not related to the neutralization of a particular subunit.
PubMed: 32041179
DOI: 10.3390/antib9010004 -
Asian Pacific Journal of Tropical... May 2014Medicinal plants are being widely used, either as a single drug or in combination in health care delivery system. Medicinal plants can be important source of previously... (Review)
Review
Medicinal plants are being widely used, either as a single drug or in combination in health care delivery system. Medicinal plants can be important source of previously unknown chemical substances with potential therapeutic effects. Abrus precatorius L. is commonly known as Gunja or Jequirity and abundantly found all throughout the plains of India, from Himalaya down to Southern India and Ceylon. This plant is having medicinal potential to cure various diseases. The roots, leaves and seeds of this plant are used for different medicinal purpose. It principally contains flavonoids, triterpene glycosides, abrin and alkaloids. The plant have been reported for neuromuscular effects, neuro-protective, abortifacient, antiepileptic, anti-viral, anti-malarial, antifertility, nephroprotective, immunomodulator, immunostimulatory properties, anti-inflammatory activity, antidiabetic effect, etc. As this is a potential medicinal plant, present review reveals chemical constituents of leaf, root and seeds of Abrus precatorius. The plant is considered as a valuable source of unique natural products for development of medicines against various diseases and also for the development of industrial products.
PubMed: 25183095
DOI: 10.12980/APJTB.4.2014C1069 -
Acta Biochimica Et Biophysica Sinica May 2016To explore the cytotoxic mechanism of abrin P2 on human colon cancer HCT-8 cells, abrin P2 was isolated from the seed of Abrus precatorius L. It was found that abrin P2...
To explore the cytotoxic mechanism of abrin P2 on human colon cancer HCT-8 cells, abrin P2 was isolated from the seed of Abrus precatorius L. It was found that abrin P2 exhibited cytotoxicity toward 12 different human cancer cell lines. Our results demonstrated that abrin P2 suppressed the proliferation of human colon cancer cells (HCT-8 cells) and induced cell cycle arrest at the S and G2/M phases. The mechanism by which abrin P2 inhibited cell proliferation was via the down-regulation of cyclin B1, proliferating cell nuclear antigen and Ki67, as well as the up-regulation of P21. In addition, abrin P2 induced a dose- and time-dependent increase in the rate of HCT-8 cell apoptosis. Treatment with both Z-VAD-FMK, a broad-spectrum caspase inhibitor, and abrin P2 demonstrated that abrin P2 induced HCT-8 cell apoptosis via the activation of caspases. Together, our results revealed that abrin P2-induced apoptosis in HCT-8 cells was associated with the activation of caspases-3/-8/-9, the reduction in the Bcl-2/Bax ratio, the loss of mitochondrial membrane potential, and the increase in cytochrome c release. We further showed that abrin P2 administration effectively suppressed the growth of colon cancer xenografts in nude mice. This is the first report that abrin P2 effectively inhibits colon cancer cell growth in vivo and in vitro by suppressing proliferation and inducing apoptosis.
Topics: Abrin; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Enzyme Activation; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; RNA, Messenger; RNA, Neoplasm; Xenograft Model Antitumor Assays
PubMed: 27055473
DOI: 10.1093/abbs/gmw023 -
Journal of Analytical Toxicology Nov 2018Ricin and abrin are toxic ribosome-inactivating proteins found in plants. Exposure to these toxins can be detected using the biomarkers ricinine and abrine, which are...
Ricin and abrin are toxic ribosome-inactivating proteins found in plants. Exposure to these toxins can be detected using the biomarkers ricinine and abrine, which are present in the same plant sources as the toxins. The concentration of the biomarkers in urine and blood will be dependent upon the purification of abrin or ricin, the route of exposure, and the length of time between exposure and sample collection. Here, we present the first diagnostic assay for the simultaneous quantification of both ricinine and abrine in blood matrices. Furthermore, this is the first-ever method for the detection of abrine in blood products. Samples were processed by isotope-dilution, solid-phase extraction, protein precipitation and quantification by HPLC-MS-MS. This analytical method detects abrine from 5.00 to 500 ng/mL and ricinine from 0.300 to 300 ng/mL with coefficients of determination of 0.996 ± 0.003 and 0.998 ± 0.002 (n = 22), respectively. Quality control material accuracy was determined to have <10% relative error, and precision was within 19% relative standard deviation. The assay's time-to-first result is three hours including sample preparation. Furthermore, the method was applied for the quantification of ricinine in the blood of a patient who had intentionally ingested castor beans to demonstrate the test was fit-for-purpose. This assay was designed to support the diagnosis of ricin and abrin exposures in public health investigations.
Topics: Abrin; Alkaloids; Biomarkers; Calibration; Forensic Toxicology; Humans; Indole Alkaloids; Limit of Detection; Poisoning; Pyridones; Reproducibility of Results; Ricin; Specimen Handling
PubMed: 29931062
DOI: 10.1093/jat/bky040 -
Toxins Jan 2021The toxin abrin found in the seeds of has attracted much attention regarding criminal and terroristic misuse over the past decade. Progress in analytical methods for a...
The toxin abrin found in the seeds of has attracted much attention regarding criminal and terroristic misuse over the past decade. Progress in analytical methods for a rapid and unambiguous identification of low abrin concentrations in complex matrices is essential. Here, we report on the development and evaluation of a MALDI-TOF mass spectrometry approach for the fast, sensitive and robust abrin isolectin identification, differentiation and quantification in complex food matrices. The method combines immunoaffinity-enrichment with specific abrin antibodies, accelerated trypsin digestion and the subsequent MALDI-TOF analysis of abrin peptides using labeled peptides for quantification purposes. Following the optimization of the workflow, common and isoform-specific peptides were detected resulting in a ~38% sequence coverage of abrin when testing ng-amounts of the toxin. The lower limit of detection was established at 40 ng/mL in milk and apple juice. Isotope-labeled versions of abundant peptides with high ionization efficiency were added. The quantitative evaluation demonstrated an assay variability at or below 22% with a linear range up to 800 ng/mL. MALDI-TOF mass spectrometry allows for a simple and fast (<5 min) analysis of abrin peptides, without a time-consuming peptide chromatographic separation, thus constituting a relevant alternative to liquid chromatography-tandem mass spectrometry.
Topics: Abrin; Abrus; Food Contamination; Immunoassay; Isotope Labeling; Plant Proteins; Seeds; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Toxins, Biological
PubMed: 33450857
DOI: 10.3390/toxins13010052 -
Biomedicine & Pharmacotherapy =... Nov 2021The efficacy of small molecule inhibitors (SMIs) against the enzymatic activity of Shiga toxin prompted the evaluation of their efficacy on related toxins viz. ricin and... (Comparative Study)
Comparative Study
The efficacy of small molecule inhibitors (SMIs) against the enzymatic activity of Shiga toxin prompted the evaluation of their efficacy on related toxins viz. ricin and abrin. Ricin, like Shiga toxin, is listed as a category B bioweapon and belongs to the type II family of ribosome inactivating proteins (RIPs). Abrin though structurally and functionally similar to ricin, is considerably more toxic. In the present study, 35 compounds were evaluated in A549 cells in in vitro assays, of which 5 offered protection against abrin and 2 against ricin, with IC values ranging between 30.5-1379 μM and 300-341 μM, respectively. These findings are substantiated by fluorescence based thermal shift assay. Moreover, the binding of the promising compounds to the toxin components has been validated by Surface Plasmon Resonance assay and in vitro protein synthesis assay. In vivo studies reveal complete protection of mice with compound 4 E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide against orally administered lethal doses of, both, abrin and ricin. The present study thus proposes the emergence of E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide as a lead compound against RIPs.
Topics: A549 Cells; Abrin; Acrylamides; Animals; Antidotes; Cell Survival; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Lethal Dose 50; Lung; Male; Mice, Inbred BALB C; Poisoning; Protein Biosynthesis; Ricin; Mice
PubMed: 34479018
DOI: 10.1016/j.biopha.2021.112134 -
Virulence Nov 2013Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis.... (Review)
Review
Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with other potent toxins that abolish protein synthesis: the fungal ribotoxins which directly cleave the 28S rRNA and the newly discovered Burkholderia lethal factor 1 (BLF1). BLF1 presents additional challenges to the current classification system since, like the ribotoxins, it does not possess RNA N-glycosidase activity but does irreversibly inactivate ribosomes. We further discuss whether the RIP classification should be broadened to include toxins achieving irreversible ribosome inactivation with similar turnovers to RIPs, but through different enzymatic mechanisms.
Topics: Bacterial Toxins; Humans; Poisons; Protein Synthesis Inhibitors; RNA, Ribosomal, 28S; Ribosome Inactivating Proteins
PubMed: 24071927
DOI: 10.4161/viru.26399 -
Toxins May 2022The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in...
The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed.
Topics: Abrin; Autophagy; Lysosomes; Qa-SNARE Proteins; Ricin
PubMed: 35622606
DOI: 10.3390/toxins14050360 -
Interdisciplinary Toxicology Aug 2018Abrin is a highly toxic protein produced by . Exposure to abrin, either through accident or by act of terrorism, poses a significant risk to human health and safety....
Abrin is a highly toxic protein produced by . Exposure to abrin, either through accident or by act of terrorism, poses a significant risk to human health and safety. Abrin functions as a ribosome-inactivating protein by depurinating the 28S rRNA and inhibits protein synthesis. It is a potent toxin warfare agent. There are no antidotes available for abrin intoxication. Supportive care is the only option for treatment of abrin exposure. It is becoming increasingly important to develop countermeasures for abrin by developing pre- and post-exposure therapy. The aim of this study is to screen certain pharmaceutical compounds for their chemoprotective properties against abrin toxicity in BALB/c male mice. Twenty-one compounds having either antioxidant, anti-inflammatory and cyto-protective properties or combination of them, were screened and administered as 1h pre-treatment followed by exposure of lethal dose (2×LD, intraperitoneally) of abrin. To assess the protective efficacy of the compounds, survival and body weight was monitored. Fifteen compounds extended the survival time of animals significantly, as compared to abrin. The following five of these compounds, namely: Epicatechin-3-gallate, Gallic Acid, Lipoic Acid, GSH and Indomethacin extended the life time ranging from 6 to 9 days. These compounds also attenuated the abrin induced inflammation and enzymes associated with liver function, but none of them could prevent abrin induced lethality. The compounds offering extension of life could be useful to provide a time-window for other supportive treatment and could also be used as combinatorial therapy with other medical countermeasures against abrin induced lethality.
PubMed: 31719788
DOI: 10.2478/intox-2018-0013 -
IUBMB Life Feb 2023Ribosome-inactivating proteins (RIPs) are toxic proteins with N-glycosidase activity. RIPs exert their action by removing a specific purine from 28S rRNA, thereby,... (Review)
Review
Ribosome-inactivating proteins (RIPs) are toxic proteins with N-glycosidase activity. RIPs exert their action by removing a specific purine from 28S rRNA, thereby, irreversibly inhibiting the process of protein synthesis. RIPs can target both prokaryotic and eukaryotic cells. In bacteria, the production of RIPs aid in the process of pathogenesis whereas, in plants, the production of these toxins has been attributed to bolster defense against insects, viral, bacterial and fungal pathogens. In recent years, RIPs have been engineered to target a particular cell type, this has fueled various experiments testing the potential role of RIPs in many biomedical applications like anti-viral and anti-tumor therapies in animals as well as anti-pest agents in engineered plants. In this review, we present a comprehensive study of various RIPs, their mode of action, their significance in various fields involving plants and animals. Their potential as treatment options for plant infections and animal diseases is also discussed.
Topics: Animals; Ribosome Inactivating Proteins; Plants; Antiviral Agents; Ribosomes; Plant Proteins
PubMed: 36121739
DOI: 10.1002/iub.2675