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13 pages, 2612 KiB

Open AccessArticle

Modulation of Ricin Intoxication by the Autophagy Inhibitor EACC

by Kirsten Sandvig, Simona Kavaliauskiene, Anne Grethe Myrann, Tore Geir Iversen and Tore Skotland

Toxins 2022, 14(5), 360; https://doi.org/10.3390/toxins14050360 - 22 May 2022

Cited by 3 | Viewed by 2897

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. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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18 pages, 11777 KiB

Open AccessArticle

Kirkiin: A New Toxic Type 2 Ribosome-Inactivating Protein from the Caudex of Adenia kirkii

by Massimo Bortolotti, Stefania Maiello, José M. Ferreras, Rosario Iglesias, Letizia Polito and Andrea Bolognesi

Toxins 2021, 13(2), 81; https://doi.org/10.3390/toxins13020081 - 22 Jan 2021

Cited by 13 | Viewed by 3587

Abstract

Ribosome-inactivating proteins (RIPs) are plant toxins that irreversibly damage ribosomes and other substrates, thus causing cell death. RIPs are classified in type 1 RIPs, single-chain enzymatic proteins, and type 2 RIPs, consisting of active A chains, similar to type 1 RIPs, linked to lectin B chains, which enable the rapid internalization of the toxin into the cell. For this reason, many type 2 RIPs are very cytotoxic, ricin, volkensin and stenodactylin being the most toxic ones. From the caudex of Adenia kirkii (Mast.) Engl., a new type 2 RIP, named kirkiin, was purified by affinity chromatography on acid-treated Sepharose CL-6B and gel filtration. The lectin, with molecular weight of about 58 kDa, agglutinated erythrocytes and inhibited protein synthesis in a cell-free system at very low concentrations. Moreover, kirkiin was able to depurinate mammalian and yeast ribosomes, but it showed little or no activity on other nucleotide substrates. In neuroblastoma cells, kirkiin inhibited protein synthesis and induced apoptosis at doses in the pM range. The biological characteristics of kirkiin make this protein a potential candidate for several experimental pharmacological applications both alone for local treatments and as component of immunoconjugates for systemic targeting in neurodegenerative studies and cancer therapy. Full article

(This article belongs to the Special Issue Biological Activities of Ribosome-Inactivating Proteins)

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18 pages, 8423 KiB

Open AccessArticle

Primary Sequence and 3D Structure Prediction of the Plant Toxin Stenodactylin

by Rosario Iglesias, Letizia Polito, Massimo Bortolotti, Manuela Pedrazzi, Lucía Citores, José M. Ferreras and Andrea Bolognesi

Toxins 2020, 12(9), 538; https://doi.org/10.3390/toxins12090538 - 21 Aug 2020

Cited by 6 | Viewed by 3830

Abstract

Stenodactylin is one of the most potent type 2 ribosome-inactivating proteins (RIPs); its high toxicity has been demonstrated in several models both in vitro and in vivo. Due to its peculiarities, stenodactylin could have several medical and biotechnological applications in neuroscience and cancer treatment. In this work, we report the complete amino acid sequence of stenodactylin and 3D structure prediction. The comparison between the primary sequence of stenodactylin and other RIPs allowed us to identify homologies/differences and the amino acids involved in RIP toxic activity. Stenodactylin RNA was isolated from plant caudex, reverse transcribed through PCR and the cDNA was amplificated and cloned into a plasmid vector and further analyzed by sequencing. Nucleotide sequence analysis showed that stenodactylin A and B chains contain 251 and 258 amino acids, respectively. The key amino acids of the active site described for ricin and most other RIPs are also conserved in the stenodactylin A chain. Stenodactylin amino acid sequence shows a high identity degree with volkensin (81.7% for A chain, 90.3% for B chain), whilst when compared with other type 2 RIPs the identity degree ranges from 27.7 to 33.0% for the A chain and from 42.1 to 47.7% for the B chain. Full article

(This article belongs to the Special Issue Toxin and Immunotoxin Based Therapeutic Approaches)

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11 pages, 1422 KiB

Open AccessReview

The Phytochemical Composition of Melia volkensii and Its Potential for Insect Pest Management

by Victor Jaoko, Clauvis Nji Tizi Taning, Simon Backx, Jackson Mulatya, Jan Van den Abeele, Titus Magomere, Florence Olubayo, Sven Mangelinckx, Stefaan P.O. Werbrouck and Guy Smagghe

Plants 2020, 9(2), 143; https://doi.org/10.3390/plants9020143 - 22 Jan 2020

Cited by 16 | Viewed by 6866

Abstract

Due to potential health and environmental risks of synthetic pesticides, coupled with their non-selectivity and pest resistance, there has been increasing demand for safer and biodegradable alternatives for insect pest management. Botanical pesticides have emerged as a promising alternative due to their non-persistence, high selectivity, and low mammalian toxicity. Six Meliaceae plant species, Azadirachta indica, Azadirachta excelsa, Azadirachta siamens, Melia azedarach, Melia toosendan, and Melia volkensii, have been subject to botanical pesticide evaluation. This review focuses on Melia volkensii, which has not been intensively studied. M. volkensii, a dryland tree species native to East Africa, has shown activity towards a broad range of insect orders, including dipterans, lepidopterans and coleopterans. Its extracts have been reported to have growth inhibiting and antifeedant properties against Schistocerca gregaria, Trichoplusia ni, Pseudaletia unipuncta, Epilachna varivestis, Nezara viridula, several Spodoptera species and other insect pests. Mortality in mosquitoes has also been reported. Several limonoids with a wide range of biological activities have been isolated from the plant, including volkensin, salannin, toosendanin, trichilin-class limonoids, volkendousin, kulactone among others. This paper presents a concise review of published information on the phytochemical composition and potential of M. volkensii for application in insect pest management. Full article

(This article belongs to the Special Issue Pesticidal Plants: From Smallholder Use to Commercialisation)

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