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15 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

Extracts Prepared from a Canadian Toxic Plant Induce Light-Dependent Perinuclear Vacuoles in Human Cells

by Jan M. Tuescher, Chad R. Beck, Locke Spencer, Benjamin Yeremy, Yutong Shi, Raymond J. Andersen and Roy M. Golsteyn

Toxins 2021, 13(2), 138; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020138 - 12 Feb 2021

Viewed by 2656

Abstract

We are investigating plant species from the Canadian prairie ecological zone by phenotypic cell assays to discover toxins of biological interest. We provide the first report of the effects of extracts prepared from the shrub Symphoricarpos occidentalis in several human cell lines. S. [...] Read more.

We are investigating plant species from the Canadian prairie ecological zone by phenotypic cell assays to discover toxins of biological interest. We provide the first report of the effects of extracts prepared from the shrub Symphoricarpos occidentalis in several human cell lines. S. occidentalis (Caprifoliaceae) extracts are cytotoxic, and, strikingly, treated cells undergo light-dependent vacuolation near the nucleus. The range of irradiation is present in standard ambient light and lies in the visible range (400-700 nm). Vacuolization in treated cells can be induced with specific wavelengths of 408 or 660 nm at 1 J/cm² energies. Vacuolated cells show a striking phenotype of a large perinuclear vacuole (nuclear associated vacuole, NAV) that is distinct from vesicles observed by treatment with an autophagy-inducing agent. Treatment with S. occidentalis extracts and light induces an intense lamin A/C signal at the junction of a nuclear vacuole and the nucleus. Further study of S. occidentalis extracts and vacuolation provide chemical tools that may contribute to the understanding of nuclear envelope organization and human cell biology. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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12 pages, 2247 KiB

Open AccessArticle

Toxicity and Sublethal Effects of Autumn Crocus (Colchicum autumnale) Bulb Powder on Red Imported Fire Ants (Solenopsis invicta)

by Sukun Lin, Deqiang Qin, Yue Zhang, Qun Zheng, Liupeng Yang, Dongmei Cheng, Suqing Huang, Jianjun Chen and Zhixiang Zhang

Toxins 2020, 12(11), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110731 - 21 Nov 2020

Cited by 11 | Viewed by 3103

Abstract

Autumn crocus (Colchicum autumnale L.) is a medicinal plant as it contains high concentrations of colchicine. In this study, we reported that the ground powder of autumn crocus bulb is highly toxic to invasive Solenopsis invicta Buren, commonly referred to as red [...] Read more.

Autumn crocus (Colchicum autumnale L.) is a medicinal plant as it contains high concentrations of colchicine. In this study, we reported that the ground powder of autumn crocus bulb is highly toxic to invasive Solenopsis invicta Buren, commonly referred to as red imported fire ants (RIFAs). Ants fed with sugar water containing 5000 mg/L of bulb powder showed 54.67% mortality in three days compared to 45.33% mortality when fed with sugar water containing 50 mg/L of colchicine. Additionally, the effects of short-term feeding with sugar water containing 1 mg/L of colchicine and 100 mg/L of autumn crocus bulb powder were evaluated for RIFAs’ colony weight, food consumption, and aggressiveness, i.e., aggregation, grasping ability, and walking speed. After 15 days of feeding, the cumulative colony weight loss reached 44.63% and 58.73% due to the sublethal concentrations of colchicine and autumn crocus bulb powder, respectively. The consumption of sugar water and mealworm (Tenebrio molitor L.) was substantially reduced. The aggregation rates decreased 48.67% and 34.67%, grasping rates were reduced to 38.67% and 16.67%, and walking speed decreased 1.13 cm/s and 0.67 cm/s as a result of the feeding of the two sublethal concentrations of colchicine and autumn crocus bulb powder, respectively. Our results for the first time show that powder derived from autumn crocus bulbs could potentially be a botanical pesticide for controlling RIFAs, and application of such a product could be ecologically benign due to its rapid biodegradation in the environment. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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15 pages, 2499 KiB

Open AccessArticle

Production of Recombinant Gelonin Using an Automated Liquid Chromatography System

by Maria E. B. Berstad, Lawrence H. Cheung and Anette Weyergang

Toxins 2020, 12(8), 519; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080519 - 13 Aug 2020

Cited by 1 | Viewed by 2892

Abstract

Advances in recombinant DNA technology have opened up new possibilities of exploiting toxic proteins for therapeutic purposes. Bringing forth these protein toxins from the bench to the bedside strongly depends on the availability of production methods that are reproducible, scalable and comply with [...] Read more.

Advances in recombinant DNA technology have opened up new possibilities of exploiting toxic proteins for therapeutic purposes. Bringing forth these protein toxins from the bench to the bedside strongly depends on the availability of production methods that are reproducible, scalable and comply with good manufacturing practice (GMP). The type I ribosome-inhibiting protein, gelonin, has great potential as an anticancer drug, but is sequestrated in endosomes and lysosomes. This can be overcome by combination with photochemical internalization (PCI), a method for endosomal drug release. The combination of gelonin-based drugs and PCI represents a tumor-targeted therapy with high precision and efficiency. The aim of this study was to produce recombinant gelonin (rGel) at high purity and quantity using an automated liquid chromatography system. The expression and purification process was documented as highly efficient (4.4 mg gelonin per litre induced culture) and reproducible with minimal loss of target protein (~50% overall yield compared to after initial immobilized metal affinity chromatography (IMAC)). The endotoxin level of 0.05–0.09 EU/mg was compatible with current standards for parenteral drug administration. The automated system provided a consistent output with minimal human intervention and close monitoring of each purification step enabled optimization of both yield and purity of the product. rGel was shown to have equivalent biological activity and cytotoxicity, both with and without PCI-mediated delivery, as rGel_ref produced without an automated system. This study presents a highly refined and automated manufacturing procedure for recombinant gelonin at a quantity and quality sufficient for preclinical evaluation. The methods established in this report are in compliance with high quality standards and compose a solid platform for preclinical development of gelonin-based drugs. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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20 pages, 7541 KiB

Open AccessEditor’s ChoiceArticle

The Cytotoxicity Effect of Resveratrol: Cell Cycle Arrest and Induced Apoptosis of Breast Cancer 4T1 Cells

by Hong Wu, Liang Chen, Feifei Zhu, Xu Han, Lindan Sun and Keping Chen

Toxins 2019, 11(12), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120731 - 13 Dec 2019

Cited by 109 | Viewed by 10562

Abstract

Resveratrol, a natural polyterpenoid, can scavenge reactive oxygen species in vivo to carry out the functions of antioxidation and antiaging. Resveratrol’s anti-cancer capability has attracted widespread attention, but its molecular mechanism has not been systematically explained. In this study, by comparing the activity [...] Read more.

Resveratrol, a natural polyterpenoid, can scavenge reactive oxygen species in vivo to carry out the functions of antioxidation and antiaging. Resveratrol’s anti-cancer capability has attracted widespread attention, but its molecular mechanism has not been systematically explained. In this study, by comparing the activity of normal cell lines and cancer cell lines after treating with resveratrol, it was found that resveratrol has more significant cytotoxicity in cancer cell lines. Resveratrol could play a toxic role through inducing apoptosis of the cancer cell in a time- and concentration-dependent manner. A total of 330 significantly differential genes were identified through large-scale transcriptome sequencing, among which 103 genes were upregulated and 227 genes were downregulated. Transcriptome and qRT-PCR data proved that a large number of genes related to cell cycle were differentially expressed after the treatment of resveratrol. The changes of cell cycle phases at different time points after treating with resveratrol were further detected, and it was found that the cells were arrested in the S phase because of the percentage of cells in S phase increased and cells in G1/G0 phase decreased. In conclusion, resveratrol can inhibit the proliferation of 4T1 cancer cells by inhibiting cell cycle and inducing apoptosis. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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19 pages, 3319 KiB

Open AccessEditor’s ChoiceArticle

Chemical Composition, Phytotoxic, Antimicrobial and Insecticidal Activity of the Essential Oils of Dracocephalum integrifolium

by Shixing Zhou, Caixia Wei, Chi Zhang, Caixia Han, Nigora Kuchkarova and Hua Shao

Toxins 2019, 11(10), 598; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11100598 - 13 Oct 2019

Cited by 37 | Viewed by 4229

Abstract

The present investigation studied the chemical composition of the essential oils extracted from Dracocephalum integrifolium Bunge growing in three different localities in northwest China and evaluated the phytotoxic, antimicrobial and insecticidal activities of the essential oils as well as their major constituents, i.e., [...] Read more.

The present investigation studied the chemical composition of the essential oils extracted from Dracocephalum integrifolium Bunge growing in three different localities in northwest China and evaluated the phytotoxic, antimicrobial and insecticidal activities of the essential oils as well as their major constituents, i.e., sabinene and eucalyptol. GC/MS analysis revealed the presence of 21–24 compounds in the essential oils, representing 94.17–97.71% of the entire oils. Monoterpenes were the most abundant substances, accounting for 85.30–93.61% of the oils; among them, sabinene (7.35–14.0%) and eucalyptol (53.56–76.11%) were dominant in all three oils, which occupied 67.56–83.46% of the total oils. In general, phytotoxic bioassays indicated that the IC₅₀ values of the oils and their major constituents were below 2 μL/mL (1.739–1.886 mg/mL) against Amaranthus retroflexus and Poa annua. Disc diffusion method demonstrated that the oils and their major constituents possessed antimicrobial activity against Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Saccharomyces cerevisiae, and Candida albicans, with MIC values ranging from 5–40 μL/mL (4.347–37.712 mg/mL). The oils, sabinene and eucalyptol also exhibited significant pesticidal activity, with the mortality rates of Aphis pomi reaching 100% after exposing to 10 μL oil/petri dish (8.694–9.428 mg/petri dish) for 24 h. To the best of our knowledge, this is the first report on the chemical composition, phytotoxic, antimicrobial and insecticidal activity of the essential oils extracted from D. integrifolium; it is noteworthy to mention that this is also the first report on the phytotoxicity of one of the major constituents, sabinene. Our results imply that D. integrifolium oils and sabinene have the potential value of being further exploited as natural pesticides. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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14 pages, 5246 KiB

Open AccessArticle

Gallic Acid Triggers Iron-Dependent Cell Death with Apoptotic, Ferroptotic, and Necroptotic Features

by Ho Man Tang and Peter Chi Keung Cheung

Toxins 2019, 11(9), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090492 - 26 Aug 2019

Cited by 30 | Viewed by 5417

Abstract

Gallic acid (GA) is a natural anti-cancer compound that can be found in many food sources, including edible mushrooms, fruits, and vegetables. Studies generally attribute the anti-cancer activity of GA to the induction of apoptosis. Here, we reported that GA activated iron-dependent cell [...] Read more.

Gallic acid (GA) is a natural anti-cancer compound that can be found in many food sources, including edible mushrooms, fruits, and vegetables. Studies generally attribute the anti-cancer activity of GA to the induction of apoptosis. Here, we reported that GA activated iron-dependent cell death mechanisms with apoptotic, ferroptotic, and necroptotic features. Our time-lapse live-cell microscopy study demonstrated that GA could induce coexistence of multiple types of cell death pathways, including apoptosis characterized by mitochondrial cytochrome c release and caspase-3 activation, ferroptosis characterized by lipid peroxidation, and necroptosis characterized by the loss of plasma membrane integrity. This GA-induced cell death could be completely suppressed by exposure to an iron chelator deferoxamine, indicating that it is an iron-dependent cell death process. Importantly, MLKL (mixed lineage kinase domain-like protein) inhibitor necrosulfonamide exerted a synergistic effect by increasing the sensitivity of cancer cells to GA. Taken together, our results provide new mechanistic insights, and also suggest new strategies to enhance the efficacy of this natural anti-cancer compound by identifying the agents that can promote or suppress the GA-induced cell death process. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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Review

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23 pages, 5483 KiB

Open AccessReview

Quo vadis Cardiac Glycoside Research?

by Jiří Bejček, Michal Jurášek, Vojtěch Spiwok and Silvie Rimpelová

Toxins 2021, 13(5), 344; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13050344 - 11 May 2021

Cited by 17 | Viewed by 6365

Abstract

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG’s [...] Read more.

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG’s toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG’s toxicity is inhibition of Na⁺/K⁺-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca²⁺ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG’s chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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24 pages, 1280 KiB

Open AccessReview

Saporin from Saponaria officinalis as a Tool for Experimental Research, Modeling, and Therapy in Neuroscience

by Alexey P. Bolshakov, Mikhail Yu. Stepanichev, Yulia V. Dobryakova, Yulia S. Spivak and Vladimir A. Markevich

Toxins 2020, 12(9), 546; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12090546 - 25 Aug 2020

Cited by 8 | Viewed by 4234

Abstract

Saporin, which is extracted from Saponaria officinalis, is a protein toxin that inactivates ribosomes. Saporin itself is non-selective toxin but acquires high specificity after conjugation with different ligands such as signaling peptides or antibodies to some surface proteins expressed in a chosen [...] Read more.

Saporin, which is extracted from Saponaria officinalis, is a protein toxin that inactivates ribosomes. Saporin itself is non-selective toxin but acquires high specificity after conjugation with different ligands such as signaling peptides or antibodies to some surface proteins expressed in a chosen cell subpopulation. The saporin-based conjugated toxins were widely adopted in neuroscience as a convenient tool to induce highly selective degeneration of desired cell subpopulation. Induction of selective cell death is one of approaches used to model neurodegenerative diseases, study functions of certain cell subpopulations in the brain, and therapy. Here, we review studies where saporin-based conjugates were used to analyze cell mechanisms of sleep, general anesthesia, epilepsy, pain, and development of Parkinson’s and Alzheimer’s diseases. Limitations and future perspectives of use of saporin-based toxins in neuroscience are discussed. Full article

(This article belongs to the Special Issue Basic Research for the Potential Use of Plant Toxins)

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