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Biological Activities and Potential Applications of Phytotoxins

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 19986

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Special Issue Editor

Dr. Marco Masi

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Guest Editor

Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
Interests: natural products; secondary metabolites; bioactive compounds; spectroscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Plants and microbes are able to produce several specialized (secondary) metabolites belonging to different classes of natural compounds. Among them, phytotoxins are substances which are poisonous or toxic for plants. They seem to play an important role in plant-pathogen interactions when produced by phytopathogenic fungi or bacteria, while plant-produced phytotoxins—including allelochemicals—seem to be involved in plant-plant interactions. Thus, the determination of their chemical structure or their identification are fundamental for chemical ecology and for understanding their function. However, most of these compounds have already shown other interesting biological activities and potential applications in fields such as agriculture or medicine. In fact, some phytotoxins have already been proposed for the development of biopesticides, cosmetics, and drugs.

The present Special Issue will collect studies on the isolation and characterization of new bioactive phytotoxins or on the evaluation of the biological activities of known phytotoxins for their potential application in different fields.

Dr. Marco Masi
Guest Editor

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Keywords

natural products
bioactive secondary metabolites
novel structures
chemical ecology
biopesticides
antibiotics

Published Papers (11 papers)

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Research

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17 pages, 1783 KiB

Open AccessArticle

Comparative Analysis of Secondary Metabolites Produced by Ascochyta fabae under In Vitro Conditions and Their Phytotoxicity on the Primary Host, Vicia faba, and Related Legume Crops

by Eleonora Barilli, Pierluigi Reveglia, Francisco J. Agudo-Jurado, Vanessa Cañete García, Alessio Cimmino, Antonio Evidente and Diego Rubiales

Toxins 2023, 15(12), 693; https://doi.org/10.3390/toxins15120693 - 09 Dec 2023

Viewed by 1859

Abstract

Ascochyta blight, caused by Ascochyta fabae, poses a significant threat to faba bean and other legumes worldwide. Necrotic lesions on stems, leaves, and pods characterize the disease. Given the economic impact of this pathogen and the potential involvement of secondary metabolites in symptom development, a study was conducted to investigate the fungus’s ability to produce bioactive metabolites that might contribute to its pathogenicity. For this investigation, the fungus was cultured in three substrates (Czapek-Dox, PDB, and rice). The produced metabolites were analyzed by NMR and LC-HRMS methods, resulting in the dereplication of seven metabolites, which varied with the cultural substrates. Ascochlorin, ascofuranol, and (R)-mevalonolactone were isolated from the Czapek-Dox extract; ascosalipyrone, benzoic acid, and tyrosol from the PDB extract; and ascosalitoxin and ascosalipyrone from the rice extract. The phytotoxicity of the pure metabolites was assessed at different concentrations on their primary hosts and related legumes. The fungal exudates displayed varying degrees of phytotoxicity, with the Czapek-Dox medium’s exudate exhibiting the highest activity across almost all legumes tested. The species belonging to the genus Vicia spp. were the most susceptible, with faba bean being susceptible to all metabolites, at least at the highest concentration tested, as expected. In particular, ascosalitoxin and benzoic acid were the most phytotoxic in the tested condition and, as a consequence, expected to play an important role on necrosis’s appearance. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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15 pages, 2494 KiB

Open AccessArticle

Effects of Sesquiterpene Lactones on Primary Cilia Formation (Ciliogenesis)

by Marina Murillo-Pineda, Juan M. Coto-Cid, María Romero, Jesús G. Zorrilla, Nuria Chinchilla, Zahara Medina-Calzada, Rosa M. Varela, Álvaro Juárez-Soto, Francisco A. Macías and Elena Reales

Toxins 2023, 15(11), 632; https://doi.org/10.3390/toxins15110632 - 27 Oct 2023

Cited by 2 | Viewed by 1346

Abstract

Sesquiterpene lactones (SLs), plant-derived metabolites with broad spectra of biological effects, including anti-tumor and anti-inflammatory, hold promise for drug development. Primary cilia, organelles extending from cell surfaces, are crucial for sensing and transducing extracellular signals essential for cell differentiation and proliferation. Their life cycle is linked to the cell cycle, as cilia assemble in non-dividing cells of G₀/G₁ phases and disassemble before entering mitosis. Abnormalities in both primary cilia (non-motile cilia) and motile cilia structure or function are associated with developmental disorders (ciliopathies), heart disease, and cancer. However, the impact of SLs on primary cilia remains unknown. This study evaluated the effects of selected SLs (grosheimin, costunolide, and three cyclocostunolides) on primary cilia biogenesis and stability in human retinal pigment epithelial (RPE) cells. Confocal fluorescence microscopy was employed to analyze the effects on primary cilia formation (ciliogenesis), primary cilia length, and stability. The effects on cell proliferation were evaluated by flow cytometry. All SLs disrupted primary cilia formation in the early stages of ciliogenesis, irrespective of starvation conditions or cytochalasin-D treatment, with no effect on cilia length or cell cycle progression. Interestingly, grosheimin stabilized and promoted primary cilia formation under cilia homeostasis and elongation treatment conditions. Thus, SLs have potential as novel drugs for ciliopathies and tumor treatment. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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13 pages, 2888 KiB

Open AccessArticle

Biological Activity of Naphthoquinones Derivatives in the Search of Anticancer Lead Compounds

by Alexandra G. Durán, Nuria Chinchilla, Ana M. Simonet, M. Teresa Gutiérrez, Jorge Bolívar, Manuel M. Valdivia, José M. G. Molinillo and Francisco A. Macías

Toxins 2023, 15(5), 348; https://doi.org/10.3390/toxins15050348 - 20 May 2023

Cited by 2 | Viewed by 1416

Abstract

Naphthoquinones are a valuable source of secondary metabolites that are well known for their dye properties since ancient times. A wide range of biological activities have been described highlighting their cytotoxic activity, gaining the attention of researchers in recent years. In addition, it is also worth mentioning that many anticancer drugs possess a naphthoquinone backbone in their structure. Considering this background, the work described herein reports the evaluation of the cytotoxicity of different acyl and alkyl derivatives from juglone and lawsone that showed the best activity results from a etiolated wheat coleoptile bioassay. This bioassay is rapid, highly sensitive to a wide spectrum of activities, and is a powerful tool for detecting biologically active natural products. A preliminary cell viability bioassay was performed on cervix carcinoma (HeLa) cells for 24 h. The most promising compounds were further tested for apoptosis on different tumoral (IGROV-1 and SK-MEL-28) and non-tumoral (HEK-293) cell lines by flow cytometry. Results reveal that derivatives from lawsone (particularly derivative 4) were more cytotoxic on tumoral than in non-tumoral cells, showing similar results to those obtained with of etoposide, which is used as a positive control for apoptotic cell death. These findings encourage further studies on the development of new anticancer drugs for more directed therapies and reduced side effects with naphthoquinone skeleton. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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14 pages, 1844 KiB

Open AccessArticle

Harzianic Acid Activity against Staphylococcus aureus and Its Role in Calcium Regulation

by Alessia Staropoli, Paola Cuomo, Maria Michela Salvatore, Gaetano De Tommaso, Mauro Iuliano, Anna Andolfi, Gian Carlo Tenore, Rosanna Capparelli and Francesco Vinale

Toxins 2023, 15(4), 237; https://doi.org/10.3390/toxins15040237 - 24 Mar 2023

Viewed by 1291

Abstract

Staphylococcus aureus is a Gram-positive bacterium, which can be found, as a commensal microorganism, on the skin surface or in the nasal mucosa of the human population. However, S. aureus may become pathogenic and cause severe infections, especially in hospitalized patients. As an opportunistic pathogen, in fact, S. aureus interferes with the host Ca²⁺ signaling, favoring the spread of the infection and tissue destruction. The identification of novel strategies to restore calcium homeostasis and prevent the associated clinical outcomes is an emerging challenge. Here, we investigate whether harzianic acid, a bioactive metabolite derived from fungi of the genus Trichoderma, could control S. aureus-induced Ca²⁺ movements. First, we show the capability of harzianic acid to complex calcium divalent cations, using mass spectrometric, potentiometric, spectrophotometric, and nuclear magnetic resonance techniques. Then, we demonstrate that harzianic acid significantly modulates Ca²⁺ increase in HaCaT (human keratinocytes) cells incubated with S. aureus. In conclusion, this study suggests harzianic acid as a promising therapeutical alternative against diseases associated with Ca²⁺ homeostasis alteration. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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10 pages, 1475 KiB

Open AccessArticle

Alkaline pH, Low Iron Availability, Poor Nitrogen Sources and CWI MAPK Signaling Are Associated with Increased Fusaric Acid Production in Fusarium oxysporum

by Davide Palmieri, David Segorbe, Manuel S. López-Berges, Filippo De Curtis, Giuseppe Lima, Antonio Di Pietro and David Turrà

Toxins 2023, 15(1), 50; https://doi.org/10.3390/toxins15010050 - 06 Jan 2023

Cited by 5 | Viewed by 1777

Abstract

Fusaric acid (FA) is one of the first secondary metabolites isolated from phytopathogenic fungi belonging to the genus Fusarium. This molecule exerts a toxic effect on plants, rhizobacteria, fungi and animals, and it plays a crucial role in both plant and animal pathogenesis. In plants, metal chelation by FA is considered one of the possible mechanisms of action. Here, we evaluated the effect of different nitrogen sources, iron content, extracellular pH and cellular signalling pathways on the production of FA siderophores by the pathogen Fusarium oxysporum (Fol). Our results show that the nitrogen source affects iron chelating activity and FA production. Moreover, alkaline pH and iron limitation boost FA production, while acidic pH and iron sufficiency repress it independent of the nitrogen source. FA production is also positively regulated by the cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) pathway and inhibited by the iron homeostasis transcriptional regulator HapX. Collectively, this study demonstrates that factors promoting virulence (i.e., alkaline pH, low iron availability, poor nitrogen sources and CWI MAPK signalling) are also associated with increased FA production in Fol. The obtained new insights on FA biosynthesis regulation can be used to prevent both Fol infection potential and toxin contamination. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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18 pages, 1373 KiB

Open AccessArticle

In Silico Evaluation of Sesquiterpenes and Benzoxazinoids Phytotoxins against M^pro, RNA Replicase and Spike Protein of SARS-CoV-2 by Molecular Dynamics. Inspired by Nature

by Francisco J. R. Mejías, Alexandra G. Durán, Nuria Chinchilla, Rosa M. Varela, José A. Álvarez, José M. G. Molinillo, Francisco García-Cozar and Francisco A. Macías

Toxins 2022, 14(9), 599; https://doi.org/10.3390/toxins14090599 - 29 Aug 2022

Cited by 2 | Viewed by 1688

Abstract

In the work described here, a number of sesquiterpenes and benzoxazinoids from natural sources, along with their easily accessible derivatives, were evaluated against the main protease, RNA replicase and spike glycoprotein of SARS-CoV-2 by molecular docking. These natural products and their derivatives have previously shown remarkable antiviral activities. The most relevant compounds were the 4-fluoro derivatives of santamarine, reynosin and 2-amino-3H-phenoxazin-3-one in terms of the docking score. Those compounds fulfill the Lipinski’s rule, so they were selected for the analysis by molecular dynamics, and the kinetic stabilities of the complexes were assessed. The addition of the 4-fluorobenzoate fragment to the natural products enhances their potential against all of the proteins tested, and the complex stability after 50 ns validates the inhibition calculated. The derivatives prepared from reynosin and 2-amino-3H-phenoxazin-3-one are able to generate more hydrogen bonds with the M^pro, thus enhancing the stability of the protein–ligand and generating a long-term complex for inhibition. The 4-fluoro derivate of santamarine and reynosin shows to be really active against the spike protein, with the RMSD site fluctuation lower than 1.5 Å. Stabilization is mainly achieved by the hydrogen-bond interactions, and the stabilization is improved by the 4-fluorobenzoate fragment being added. Those compounds tested in silico reach as candidates from natural sources to fight this virus, and the results concluded that the addition of the 4-fluorobenzoate fragment to the natural products enhances their inhibition potential against the main protease, RNA replicase and spike protein of SARS-CoV-2. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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13 pages, 1661 KiB

Open AccessEditor’s ChoiceArticle

Iridoid Glycosides Isolated from Bellardia trixago Identified as Inhibitors of Orobanche cumana Radicle Growth

by Gabriele Soriano, Antonietta Siciliano, Mónica Fernández-Aparicio, Antonio Cala Peralta, Marco Masi, Antonio Moreno-Robles, Marco Guida and Alessio Cimmino

Toxins 2022, 14(8), 559; https://doi.org/10.3390/toxins14080559 - 17 Aug 2022

Cited by 4 | Viewed by 1922

Abstract

Orobanche cumana is an obligate holoparasitic plant with noxious effects in sunflower crops. Bellardia trixago is a facultative hemiparasitic plant that infects ruderal plants without noxious significance in agriculture and is known to produce a wide spectrum of bioactive metabolites. The objective of this study was to evaluate the allelopathic effects of B. trixago on the growth of O. cumana seedlings. Three different extracts using solvents of increasing polarity (n-hexane, dichloromethane and ethyl acetate) were prepared from the flowers, aerial green organs and roots of two populations, a white-flowered and a yellow-flowered population of B. trixago, both collected in southern Spain. Each extract was studied using allelopathic screenings on O. cumana which resulted in the identification of allelopathic activity of the ethyl acetate extracts against Orobanche radicles. Five iridoid glycosides were isolated together with benzoic acid from the ethyl acetate extract of aerial green organs by bio-guided purification. These compounds were identified as bartsioside, melampyroside, mussaenoside, gardoside methyl ester and aucubin. Among them, melampyroside was found to be the most abundant constituent in the extract (44.3% w/w), as well as the most phytotoxic iridoid on O. cumana radicle, showing a 72.6% inhibition of radicle growth. This activity of melampyroside was significantly high when compared with the inhibitory activity of benzoic acid (25.9%), a phenolic acid with known allelopathic activity against weeds. The ecotoxicological profile of melampyroside was evaluated using organisms representing different trophic levels of the aquatic and terrestrial ecosystems, namely producers (green freshwater algae Raphidocelis subcapitata and macrophyte Lepidium sativum), consumers (water flea Daphnia magna and nematode Caenorhabditis elegans) and decomposers (bacterium Aliivibrio fischeri). The ecotoxicity of melampyroside differed significantly depending on the test organism showing the highest toxicity to daphnia, nematodes and bacteria, and a lower toxicity to algae and macrophytes. The findings of the present study may provide useful information for the generation of green alternatives to synthetic herbicides for the control of O. cumana. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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12 pages, 2387 KiB

Open AccessArticle

Specialized Metabolites from the Allelopathic Plant Retama raetam as Potential Biopesticides

by Gabriele Soriano, Claudia Petrillo, Marco Masi, Mabrouka Bouafiane, Aminata Khelil, Angela Tuzi, Rachele Isticato, Mónica Fernández-Aparicio and Alessio Cimmino

Toxins 2022, 14(5), 311; https://doi.org/10.3390/toxins14050311 - 28 Apr 2022

Cited by 3 | Viewed by 2087

Abstract

To cope with the rising food demand, modern agriculture practices are based on the indiscriminate use of agrochemicals. Although this strategy leads to a temporary solution, it also severely damages the environment, representing a risk to human health. A sustainable alternative to agrochemicals is the use of plant metabolites and plant-based pesticides, known to have minimal environmental impact compared to synthetic pesticides. Retama raetam is a shrub growing in Algeria’s desert areas, where it is commonly used in traditional medicine because of its antiseptic and antipyretic properties. Furthermore, its allelopathic features can be exploited to effectively control phytopathogens in the agricultural field. In this study, six compounds belonging to isoflavones and flavones subgroups have been isolated from the R. raetam dichloromethane extract and identified using spectroscopic and optical methods as alpinumisoflavone, hydroxyalpinumisoflavone, laburnetin, licoflavone C, retamasin B, and ephedroidin. Their antifungal activity was evaluated against the fungal phytopathogen Stemphylium vesicarium using a growth inhibition bioassay on PDA plates. Interestingly, the flavonoid laburnetin, the most active metabolite, displayed an inhibitory activity comparable to that exerted by the synthetic fungicide pentachloronitrobenzene, in a ten-fold lower concentration. The allelopathic activity of R. raetam metabolites against parasitic weeds was also investigated using two independent parasitic weed bioassays to discover potential activities on either suicidal stimulation or radicle growth inhibition of broomrapes. In this latter bioassay, ephedroidin strongly inhibited the growth of Orobanche cumana radicles and, therefore, can be proposed as a natural herbicide. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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Review

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20 pages, 10251 KiB

Open AccessReview

Piperine: Chemistry and Biology

by Jin Han, Shaoyong Zhang, Jun He and Tianze Li

Toxins 2023, 15(12), 696; https://doi.org/10.3390/toxins15120696 - 12 Dec 2023

Viewed by 1787

Abstract

Piperine is a plant-derived promising piperamide candidate isolated from the black pepper (Piper nigrum L.). In the last few years, this natural botanical product and its derivatives have aroused much attention for their comprehensive biological activities, including not only medical but also agricultural bioactivities. In order to achieve sustainable development and improve survival conditions, looking for environmentally friendly pesticides with low toxicity and residue is an extremely urgent challenge. Fortunately, plant-derived pesticides are rising like a shining star, guiding us in the direction of development in pesticidal research. In the present review, the recent progress in the biological activities, mechanisms of action, and structural modifications of piperine and its derivatives from 2020 to 2023 are summarized. The structure-activity relationships were analyzed in order to pave the way for future development and utilization of piperine and its derivatives as potent drugs and pesticides for improving the local economic development. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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18 pages, 3217 KiB

Open AccessReview

Defensive Molecules Momilactones A and B: Function, Biosynthesis, Induction and Occurrence

by Hisashi Kato-Noguchi

Toxins 2023, 15(4), 241; https://doi.org/10.3390/toxins15040241 - 25 Mar 2023

Cited by 7 | Viewed by 1714

Abstract

Labdane-related diterpenoids, momilactones A and B were isolated and identified in rice husks in 1973 and later found in rice leaves, straws, roots, root exudate, other several Poaceae species and the moss species Calohypnum plumiforme. The functions of momilactones in rice are well documented. Momilactones in rice plants suppressed the growth of fungal pathogens, indicating the defense function against pathogen attacks. Rice plants also inhibited the growth of adjacent competitive plants through the root secretion of momilactones into their rhizosphere due to the potent growth-inhibitory activity of momilactones, indicating a function in allelopathy. Momilactone-deficient mutants of rice lost their tolerance to pathogens and allelopathic activity, which verifies the involvement of momilactones in both functions. Momilactones also showed pharmacological functions such as anti-leukemia and anti-diabetic activities. Momilactones are synthesized from geranylgeranyl diphosphate through cyclization steps, and the biosynthetic gene cluster is located on chromosome 4 of the rice genome. Pathogen attacks, biotic elicitors such as chitosan and cantharidin, and abiotic elicitors such as UV irradiation and CuCl₂ elevated momilactone production through jasmonic acid-dependent and independent signaling pathways. Rice allelopathy was also elevated by jasmonic acid, UV irradiation and nutrient deficiency due to nutrient competition with neighboring plants with the increased production and secretion of momilactones. Rice allelopathic activity and the secretion of momilactones into the rice rhizosphere were also induced by either nearby Echinochloa crus-galli plants or their root exudates. Certain compounds from Echinochloa crus-galli may stimulate the production and secretion of momilactones. This article focuses on the functions, biosynthesis and induction of momilactones and their occurrence in plant species. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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Graphical abstract

20 pages, 1166 KiB

Open AccessReview

Bioactive Metabolite Production in the Genus Pyrenophora (Pleosporaceae, Pleosporales)

by Marco Masi, Jesús García Zorrilla and Susan Meyer

Toxins 2022, 14(9), 588; https://doi.org/10.3390/toxins14090588 - 27 Aug 2022

Cited by 6 | Viewed by 1811

Abstract

The genus Pyrenophora includes two important cereal crop foliar pathogens and a large number of less well-known species, many of which are also grass pathogens. Only a few of these have been examined in terms of secondary metabolite production, yet even these few species have yielded a remarkable array of bioactive metabolites that include compounds produced through each of the major biosynthetic pathways. There is little overlap among species in the compounds identified. Pyrenophora tritici-repentis produces protein toxin effectors that mediate host-specific responses as well as spirocyclic lactams and at least one anthraquinone. Pyrenophora teres produces marasmine amino acid and isoquinoline derivatives involved in pathogenesis on barley as well as nonenolides with antifungal activity, while P. semeniperda produces cytochalasans and sesquiterpenoids implicated in pathogenesis on seeds as well as spirocyclic lactams with phytotoxic and antibacterial activity. Less well-known species have produced some unusual macrocyclic compounds in addition to a diverse array of anthraquinones. For the three best-studied species, in silico genome mining has predicted the existence of biosynthetic pathways for a much larger array of potentially toxic secondary metabolites than has yet been produced in culture. Most compounds identified to date have potentially useful biological activity. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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