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Toxins May 2020RTX-Toxins (Repeats in ToXin) are members of a rapidly expanding family of proteins [...].
RTX-Toxins (Repeats in ToXin) are members of a rapidly expanding family of proteins [...].
Topics: Animals; Humans; Protein Conformation; Ricin; Structure-Activity Relationship
PubMed: 32486155
DOI: 10.3390/toxins12060359 -
PloS One 2023The continuing emergence of SARS-CoV-2 variants has highlighted the need to identify additional points for viral inhibition. Ribosome inactivating proteins (RIPs), such...
The continuing emergence of SARS-CoV-2 variants has highlighted the need to identify additional points for viral inhibition. Ribosome inactivating proteins (RIPs), such as MAP30 and Momordin which are derived from bitter melon (Momordica charantia), have been found to inhibit a broad range of viruses. MAP30 has been shown to potently inhibit HIV-1 with minimal cytotoxicity. Here we show that MAP30 and Momordin potently inhibit SARS-CoV-2 replication in A549 human lung cells (IC50 ~ 0.2 μM) with little concomitant cytotoxicity (CC50 ~ 2 μM). Both viral inhibition and cytotoxicity remain unaltered by appending a C-terminal Tat cell-penetration peptide to either protein. Mutation of tyrosine 70, a key residue in the active site of MAP30, to alanine completely abrogates both viral inhibition and cytotoxicity, indicating the involvement of its RNA N-glycosylase activity. Mutation of lysine 171 and lysine 215, residues corresponding to those in Ricin which when mutated prevented ribosome binding and inactivation, to alanine in MAP30 decreased cytotoxicity (CC50 ~ 10 μM) but also the viral inhibition (IC50 ~ 1 μM). Unlike with HIV-1, neither Dexamethasone nor Indomethacin exhibited synergy with MAP30 in the inhibition of SARS-CoV-2. From a structural comparison of the two proteins, one can explain their similar activities despite differences in both their active-sites and ribosome-binding regions. We also note points on the viral genome for potential inhibition by these proteins.
Topics: Humans; COVID-19; Lysine; SARS-CoV-2; Alanine; HIV Seropositivity; HIV-1; Momordica charantia; Ribosome Inactivating Proteins; Ribosomes; COVID-19 Drug Treatment
PubMed: 37384752
DOI: 10.1371/journal.pone.0286370 -
Journal of Neurology, Neurosurgery, and... Jun 2020We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on...
OBJECTIVES
We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.
METHODS
A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.
RESULTS
Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years).
CONCLUSIONS
There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.
Topics: Humans; Nervous System Diseases; Outcome Assessment, Health Care
PubMed: 32111637
DOI: 10.1136/jnnp-2019-322180 -
Toxins Jan 2021Ricin, a highly toxic protein from , is considered a potential biowarfare agent. Despite the many data available, no specific treatment has yet been approved. Due to... (Comparative Study)
Comparative Study
Ricin, a highly toxic protein from , is considered a potential biowarfare agent. Despite the many data available, no specific treatment has yet been approved. Due to their ability to provide immediate protection, antibodies (Abs) are an approach of choice. However, their high specificity might compromise their capacity to protect against the different ricin isoforms (D and E) found in the different cultivars. In previous work, we have shown the neutralizing potential of different Abs (43RCA-G1 (anti ricin A-chain) and RB34 and RB37 (anti ricin B-chain)) against ricin D. In this study, we evaluated their protective capacity against both ricin isoforms. We show that: (i) RB34 and RB37 recognize exclusively ricin D, whereas 43RCA-G1 recognizes both isoforms, (ii) their neutralizing capacity in vitro varies depending on the cultivar, and (iii) there is a synergistic effect when combining RB34 and 43RCA-G1. This effect is also demonstrated in vivo in a mouse model of intranasal intoxication with ricin D/E (1:1), where approximately 60% and 40% of mice treated 0 and 6 h after intoxication, respectively, are protected. Our results highlight the importance of evaluating the effectiveness of the Abs against different ricin isoforms to identify the treatment with the broadest spectrum neutralizing effect.
Topics: Animals; Antibodies, Neutralizing; Antibody Specificity; Antidotes; Cell Survival; Drug Therapy, Combination; Female; Humans; Jurkat Cells; Lethal Dose 50; Mice, Inbred BALB C; Poisoning; Protein Isoforms; Ricin; Ricinus; Mice
PubMed: 33573016
DOI: 10.3390/toxins13020100 -
Toxins Jan 2023Ricin toxin is a disulfide-linked glycoprotein (AB toxin) comprising one enzymatic A chain (RTA) and one cell-binding B chain (RTB) contained in the castor bean, a... (Review)
Review
Ricin toxin is a disulfide-linked glycoprotein (AB toxin) comprising one enzymatic A chain (RTA) and one cell-binding B chain (RTB) contained in the castor bean, a species. Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, resulting in apoptosis, inflammation, oxidative stress, and DNA damage, in addition to the classically known rRNA damage. Ricin has been used in traditional medicine throughout the world since prehistoric times. Because ricin toxin is highly toxic and can be readily extracted from beans, it could be used as a bioweapon (CDC B-list). Due to its extreme lethality and potential use as a biological weapon, ricin toxin remains a global public health concern requiring specific countermeasures. Currently, no specific treatment for ricin intoxication is available. This review focuses on the drugs under development. In particular, some examples are reviewed to demonstrate the proof of concept of antibody-based therapy. Chemical inhibitors, small proteins, and vaccines can serve as alternatives to antibodies or may be used in combination with antibodies.
Topics: Antibodies, Neutralizing; Medical Countermeasures; Ricin; Toxins, Biological; Vaccines
PubMed: 36828415
DOI: 10.3390/toxins15020100 -
Glycoconjugate Journal Oct 2020Lectins are proteins with diverse molecular structures that share the ability to recognize and bind specifically and reversibly to carbohydrate structures without... (Review)
Review
Lectins are proteins with diverse molecular structures that share the ability to recognize and bind specifically and reversibly to carbohydrate structures without changing the carbohydrate moiety. The history of lectins started with the discovery of ricin about 130 years ago but since then our understanding of lectins has dramatically changed. Over the years the research focus was shifted from 'the characterization of carbohydrate-binding proteins' to 'understanding the biological function of lectins'. Nowadays plant lectins attract a lot of attention especially because of their potential for crop improvement and biomedical research, as well as their application as tools in glycobiology. The present review aims to give an overview of plant lectins and their applications, and how the field evolved in the last decades.
Topics: Biomedical Research; Carbohydrates; Glycomics; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Plant Lectins
PubMed: 32860551
DOI: 10.1007/s10719-020-09942-y