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Toxicity and Therapeutic Potential of Plant Alkaloid

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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 (25 August 2022) | Viewed by 8721

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Special Issue Editors

Prof. Dr. Zhiling Yu

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Guest Editor

Hong Kong Baptist University, 224 Waterloo Rd, Kowloon Tong, Hong Kong
Interests: herbal pharmacology; anticancer; anti-inflammation

Prof. Dr. Duncan Chung-Hang Leung

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Guest Editor

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
Interests: transition metal-based probes; metallodrugs; structure-based drug discovery; luminescent oligonucleotide-based biosensors
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Elaine Lai-Han Leung

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Guest Editor

State Key Laboratory for Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macao
Interests: natural products; cancer; pharmacology; treatment mechanisms

Special Issue Information

Dear Colleagues,

Plant-derived alkaloids are natural compounds that contain at least one nitrogen atom. Researchers have long studied the beneficial and toxic effects of plant alkaloids. These compounds have been found to possess anticancer, analgesic, cholinomimetic, antimalarial, antiasthmatic, antibacterial, vasodilatory, antiarrhythmic, and hypoglycemic properties, and exert other pharmacological effects. Some plant alkaloids, such as homoharringtonine, morphine and galantamine, have been developed into clinical drugs. However, some plant alkaloids, e.g., aconitine and tubocurarine, are toxic. The aim of this Special Issue of Toxins is to discuss the toxicity and therapeutic potential of plant alkaloids. Pharmacological research papers and review articles are all welcome.

Prof. Dr. Zhiling Yu
Prof. Dr. Duncan Chung-Hang Leung
Prof. Dr. Elaine Lai-Han Leung
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pharmacological activity
toxicity
plant alkaloid
old drug repurposing
compound combination effects

Published Papers (4 papers)

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Research

15 pages, 3349 KiB

Open AccessArticle

Integrative Metabolomics and Proteomics Detected Hepatotoxicity in Mice Associated with Alkaloids from Eupatorium fortunei Turcz.

by Ke Zan, Wei Lei, Yaolei Li, Ying Wang, Lina Liu, Tiantian Zuo, Hongyu Jin and Shuangcheng Ma

Toxins 2022, 14(11), 765; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14110765 - 05 Nov 2022

Cited by 1 | Viewed by 1477

Abstract

The traditional Chinese herbal medicine Eupatorium fortunei Turcz. (E. fortunei) has been widely adopted to treat nausea, diabetes, siriasis, and poor appetite. However, E. fortunei contains multiple pyrrolizidine alkaloids (PAs). This study aimed to investigate the hepatotoxicity of total alkaloids in E. fortunei (EFTAs) and identify the toxic mechanisms of EFTAs on hepatocytes. Liquid chromatography with a tandem mass spectrometry assay with reference standards indicated that EFTAs mainly consisted of eight PAs whose content accounted for 92.38% of EFTAs. EFTAs markedly decreased mouse body and liver weights and increased the contents of AST and ALT. The histopathological assays demonstrated that, after exposition to EFTAs, the structures of hepatocytes were damaged and the fibrosis and apoptosis in hepatocytes were accelerated. Moreover, EFTAs increased the serum level of inflammatory cytokines and aggravated circulating oxidative stress. A combination of hepatic proteomics and metabolomics was used to investigate the toxic mechanisms of EFTAs. The study revealed that EFTAs seriously disrupted glycerophospholipid metabolism by upregulating the contents of lysophosphatidylglycerol acyltransferase 1 and phosphatidylinositol and downregulating the contents of choline/ethanolamine kinase beta, choline-ethanolamine phosphotransferase 1, phospholipase D4, 1-acylglycerophosphocholine, phosphatidylcholine, and dihydroxyacetone phosphate in the liver, resulting in detrimental inflammation, fibrosis, and apoptosis. This study revealed that EFTAs induced severe hepatotoxicity by disrupting glycerophospholipid metabolism. Full article

(This article belongs to the Special Issue Toxicity and Therapeutic Potential of Plant Alkaloid)

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19 pages, 6082 KiB

Open AccessArticle

Combined Hepatotoxicity and Toxicity Mechanism of Intermedine and Lycopsamine

by Ziqi Wang, Liang Qiao, Qinqin Zheng, Haolei Han, Zuguang Li, Xiangchun Zhang and Hongping Chen

Toxins 2022, 14(9), 633; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14090633 - 13 Sep 2022

Cited by 3 | Viewed by 1901

Abstract

Pyrrolizidine alkaloids (PAs) are common constituents of plants and have serious hepatotoxicity. Intermedine (Im) and lycopsamine (La) are two monoesters of PAs that frequently coexist in the PA-containing plants (e.g., comfrey and tea). The present study aimed to explore the combined hepatotoxicity and toxicity mechanism of the Im and La mixture. In vitro, the combined cytotoxicity of the Im and La mixture on human hepatocytes (HepD) was examined by CCK-8, colony formation, wound healing, and Annexin V/PI staining assays. The combination of Im and La inhibited the ability of HepD cells to proliferate, colonize, and migrate and induced hepatocytes apoptosis in a dose-dependent manner. In addition to significantly causing a burst of intracellular reactive oxygen species (ROS), mitochondrial apoptosis, and endoplasmic reticulum (ER) stress, the Im and La mixture can also cause an increase in intracellular Ca²⁺, triggering the PERK/eIF2α/ATF4/CHOP apoptosis pathway. This study provided the first direct evidence that the combined PAs induced hepatotoxicity through ER-mediated apoptosis. These results supplemented the basic toxicity data for the combined PAs and provided a new perspective for the risk assessment of combined PA toxicity. Full article

(This article belongs to the Special Issue Toxicity and Therapeutic Potential of Plant Alkaloid)

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Graphical abstract

12 pages, 1553 KiB

Open AccessArticle

Insights into the Cardiotoxic Effects of Veratrum Lobelianum Alkaloids: Pilot Study

by Amir Taldaev, Roman P. Terekhov, Elizaveta V. Melnik, Maria V. Belova, Sergey V. Kozin, Andrey A. Nedorubov, Tatyana Ya. Pomerantseva and Galina V. Ramenskaya

Toxins 2022, 14(7), 490; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14070490 - 15 Jul 2022

Cited by 3 | Viewed by 1938

Abstract

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel Na_V1.5, and machine learning-based structure–activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (−10.8 kcal/mol), logP value (4.188), and pK_a value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC₅₀. In general, all three analyzed alkaloids show the affinity to Na_V1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by Na_V1.5 inhibition. Full article

(This article belongs to the Special Issue Toxicity and Therapeutic Potential of Plant Alkaloid)

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14 pages, 2048 KiB

Open AccessArticle

Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole–Protein Adducts

by Jiang Ma, Mi Li, Na Li, Wood Yee Chan and Ge Lin

Toxins 2021, 13(10), 723; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13100723 - 13 Oct 2021

Cited by 8 | Viewed by 2618

Abstract

Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole–protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of Crotalaria sessiliflora (containing one PA: monocrotaline) and Gynura japonica (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole–protein adducts formed in the rats’ livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole–protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole–protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole–protein adducts—which directly correlated with the elevation of serum ALT activity—was a common insult leading to PA-ILI, suggesting a potential for using pyrrole–protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures. Full article

(This article belongs to the Special Issue Toxicity and Therapeutic Potential of Plant Alkaloid)

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