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Biological Activities of Alkaloids: From Toxicology to Pharmacology
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Biological Activities of Alkaloids: From Toxicology to Pharmacology

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 93258

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Sabino Aurelio Bufo

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Guest Editor
Department of Science, University of Basilicata, Potenza, Italy
Interests: pharmaceuticals from plants and microorganisms; chemistry of natural substances in vegetables and soil; secondary plant metabolites; protection and recovery of ecosystems
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Linda L. Blythe

E-Mail Website
Guest Editor
Department of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
Interests: Veterinary Pharmacology, Toxicology and Pharmaceutics Environmental Science, Agricultural and Biological Sciences, Immunology and Microbiology
Dr. Zbigniew Adamski

E-Mail Website
Guest Editor
Assistant Professor, Department of Animal Physiology and Development, Electron and Confocal Microscope Laboratory, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
Interests: lethal and sub-lethal effects of plant-derived substances and their possible application as insecticides and nematicides; effects of alkaloids at cell and tissue level; alkaloid-procured lethality, altered fecundity, fertility, and morphological malformations of tested organisms
Special Issues, Collections and Topics in MDPI journals
Dr. Luigi Milella

E-Mail Website
Guest Editor
Department of Science, University of Basilicata, Potenza, Italy
Interests: secondary metabolite isolation; structural determination; oxidative stress; nutraceuticals; bioactive molecules; cholinesterase inhibitory activity; Alzheimer’s disease; cytotoxic effects
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Plants produce many substances, the so-called secondary metabolites, which have biological activity. They are distinct from the components of the primary metabolism as they are generally not essential for the basic metabolic processes of the plant. However, they often have the character of physiologically active compounds that makes them applicable in different fields, for instance medicine or agriculture.

A broad spectrum of physiological activity is demonstrated by alkaloids. Their rich diversity results in part from an evolutionary process driven by selection for the acquisition of an improved defense against microbial attacks or the predation of herbivores. A positive aspect is that their main role in plants is to protect them from diseases caused by pests. However, some alkaloids are of concern to veterinary toxicology because of their occurrence in plant species involved in animal poisoning, which usually occurs when plants contaminate hay or silage or when forage alternatives are not available. At times, some toxicity effects have also been highlighted in human nutrition. Other components of this class of compounds have been proved to exhibit antioxidant, anti-inflammatory, anti-aggregation, hypo-cholesteric, immunostimulant or anticancer properties. In fact, the effects of toxicity can be both harmful and beneficial depending on the ecological or pharmacological context, and, as often pointed out, are dose-dependent.

The interest of researchers in the study of the bioactivity of plant alkaloids is still very keen. In this Special Issue, ecological, biological, pharmacological and toxicological effects as well as structural and analytical aspects of plant alkaloids will be collected. Reviews and original research contributions are expected on, but not limited to, the biological activity of natural alkaloids against pathogens, herbivores and cancerous cells, or unwanted physiological conditions, including metabolism and accumulation. Studies on alkaloid biosynthesis and action mechanisms are welcome to improve the selection and production of biologically active molecules, to discover new substances, and to exploit them in a sustainable way against targets of concern.

Prof. Dr. Sabino Aurelio Bufo
Prof. Dr. Linda L. Blythe
Prof. Dr. Zbigniew Adamski
Dr. Luigi Milella
Guest Editors

Manuscript Submission Information

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Keywords

  • plant secondary metabolites
  • alkaloids
  • biological activity
  • toxicity
  • biopesticides
  • natural pharmaceuticals

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review

4 pages, 225 KiB  
Editorial
Biological Activities of Alkaloids: From Toxicology to Pharmacology
by Zbigniew Adamski, Linda L. Blythe, Luigi Milella and Sabino A. Bufo
Toxins 2020, 12(4), 210; https://doi.org/10.3390/toxins12040210 - 26 Mar 2020
Cited by 63 | Viewed by 6397
Abstract
Plants produce many secondary metabolites, which reveal biological activity [...] Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)

Research

Jump to: Editorial, Review

12 pages, 4056 KiB  
Article
Curine Inhibits Macrophage Activation and Neutrophil Recruitment in a Mouse Model of Lipopolysaccharide-Induced Inflammation
by Jaime Ribeiro-Filho, Fagner Carvalho Leite, Andrea Surrage Calheiros, Alan de Brito Carneiro, Juliana Alves Azeredo, Edson Fernandes de Assis, Celidarque da Silva Dias, Márcia Regina Piuvezam and Patrícia T. Bozza
Toxins 2019, 11(12), 705; https://doi.org/10.3390/toxins11120705 - 3 Dec 2019
Cited by 9 | Viewed by 6222
Abstract
Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects [...] Read more.
Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects of curine on macrophage activation and neutrophil recruitment. Using a murine model of lipopolysaccharide (LPS)-induced pleurisy, we demonstrated that curine significantly inhibited the recruitment of neutrophils in association with the inhibition of cytokines tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-6, monocyte chemotactic protein (CCL2/MCP-1) as well as leukotriene B4 in the pleural lavage of mice. Curine treatment reduced cytokine levels and the expression of iNOS in in vitro cultures of macrophages stimulated with LPS. Treatment with a calcium channel blocker resulted in comparable inhibition of TNF-α and IL-1β production, as well as iNOS expression by macrophages, suggesting that the anti-inflammatory effects of curine may be related to the inhibition of calcium-dependent mechanisms involved in macrophage activation. In conclusion, curine presented anti-inflammatory effects that are associated with inhibition of macrophage activation and neutrophil recruitment by inhibiting the production of inflammatory cytokines, LTB4 and nitric oxide (NO), and possibly by negatively modulating Ca2+ influx. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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18 pages, 2412 KiB  
Article
Determination of Selected Isoquinoline Alkaloids from Mahonia aquifolia; Meconopsis cambrica; Corydalis lutea; Dicentra spectabilis; Fumaria officinalis; Macleaya cordata Extracts by HPLC-DAD and Comparison of Their Cytotoxic Activity
by Anna Petruczynik, Tomasz Plech, Tomasz Tuzimski, Justyna Misiurek, Barbara Kaproń, Dorota Misiurek, Małgorzata Szultka-Młyńska, Bogusław Buszewski and Monika Waksmundzka-Hajnos
Toxins 2019, 11(10), 575; https://doi.org/10.3390/toxins11100575 - 2 Oct 2019
Cited by 32 | Viewed by 4580
Abstract
Alkaloids have protective functions for plants and can play an important role in living organisms. Alkaloids may have a wide range of pharmacological activities. Many of them have cytotoxic activity. Nowadays, cancer has become a serious public health problem. Searching for effective drugs [...] Read more.
Alkaloids have protective functions for plants and can play an important role in living organisms. Alkaloids may have a wide range of pharmacological activities. Many of them have cytotoxic activity. Nowadays, cancer has become a serious public health problem. Searching for effective drugs with anticancer activity is one of the most significant challenges of modern scientific research. The aim of this study was the investigation of cytotoxic activity of extracts obtained from Corydalis lutea root and herb, Dicentra spectabilis root and herb, Fumaria officinalis, Macleaya cordata leaves and herb, Mahonia aquifolia leaves and cortex, Meconopsis cambrica root and herb on FaDu, SCC-25, MCF-7, and MDA-MB-231 cancer cell lines. The cytotoxic activity of these extracts has not been previously tested for these cell lines. The aim was also to quantify selected alkaloids in the investigated extracts by High Performance Liquid Chromatography (HPLC). The analyses of alkaloid content were performed using HPLC in reversed phase (RP) mode using Polar RP column and mobile phase containing acetonitrile, water and ionic liquid (IL). Cytotoxic effect of the tested plant extracts and respective alkaloid standards were examined using human pharyngeal squamous carcinoma cells (FaDu), human tongue squamous carcinoma cells (SCC-25), human breast adenocarcinoma cell line (MCF-7), human triple-negative breast adenocarcinoma cell line (MDA-MB-231). All investigated plant extracts possess cytotoxic activity against tested cancer cell lines: FaDu, SCC-25, MCF-7, and MDA-MB-231. The highest cytotoxic activity against FaDu, SCC-25, and MCF-7 cell lines was estimated for Macleaya cordata leaf extract, while the highest cytotoxic activity against MDA-MB-231 cell line was obtained for Macleaya cordata herb extract. Differences in cytotoxic activity were observed for extracts obtained from various parts of investigated plants. In almost all cases the cytotoxic activity of investigated plant extracts, especially at the highest concentration against tested cell lines was significantly higher than the activity of anticancer drug etoposide. Our investigations exhibit that these plant extracts can be recommended for further in vivo experiments to confirm their anticancer activity. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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12 pages, 1802 KiB  
Article
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties
by Dmitry I. Osmakov, Sergey G. Koshelev, Victor A. Palikov, Yulia A. Palikova, Elvira R. Shaykhutdinova, Igor A. Dyachenko, Yaroslav A. Andreev and Sergey A. Kozlov
Toxins 2019, 11(9), 542; https://doi.org/10.3390/toxins11090542 - 18 Sep 2019
Cited by 14 | Viewed by 3703
Abstract
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation [...] Read more.
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of Laurus nobilis L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel’s response to physiologically-relevant stimuli of pH 6.5–6.85 with IC50 range 150–9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund’s adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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26 pages, 8963 KiB  
Article
Nigritanine as a New Potential Antimicrobial Alkaloid for the Treatment of Staphylococcus aureus-Induced Infections
by Bruno Casciaro, Andrea Calcaterra, Floriana Cappiello, Mattia Mori, Maria Rosa Loffredo, Francesca Ghirga, Maria Luisa Mangoni, Bruno Botta and Deborah Quaglio
Toxins 2019, 11(9), 511; https://doi.org/10.3390/toxins11090511 - 1 Sep 2019
Cited by 44 | Viewed by 5386
Abstract
Staphylococcus aureus is a major human pathogen causing a wide range of nosocomial infections including pulmonary, urinary, and skin infections. Notably, the emergence of bacterial strains resistant to conventional antibiotics has prompted researchers to find new compounds capable of killing these pathogens. Nature [...] Read more.
Staphylococcus aureus is a major human pathogen causing a wide range of nosocomial infections including pulmonary, urinary, and skin infections. Notably, the emergence of bacterial strains resistant to conventional antibiotics has prompted researchers to find new compounds capable of killing these pathogens. Nature is undoubtedly an invaluable source of bioactive molecules characterized by an ample chemical diversity. They can act as unique platform providing new scaffolds for further chemical modifications in order to obtain compounds with optimized biological activity. A class of natural compounds with a variety of biological activities is represented by alkaloids, important secondary metabolites produced by a large number of organisms including bacteria, fungi, plants, and animals. In this work, starting from the screening of 39 alkaloids retrieved from a unique in-house library, we identified a heterodimer β-carboline alkaloid, nigritanine, with a potent anti-Staphylococcus action. Nigritanine, isolated from Strychnos nigritana, was characterized for its antimicrobial activity against a reference and three clinical isolates of S. aureus. Its potential cytotoxicity was also evaluated at short and long term against mammalian red blood cells and human keratinocytes, respectively. Nigritanine showed a remarkable antimicrobial activity (minimum inhibitory concentration of 128 µM) without being toxic in vitro to both tested cells. The analysis of the antibacterial activity related to the nigritanine scaffold furnished new insights in the structure–activity relationships (SARs) of β-carboline, confirming that dimerization improves its antibacterial activity. Taking into account these interesting results, nigritanine can be considered as a promising candidate for the development of new antimicrobial molecules for the treatment of S. aureus-induced infections. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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19 pages, 1184 KiB  
Article
Cytotoxic and Proapoptotic Activity of Sanguinarine, Berberine, and Extracts of Chelidonium majus L. and Berberis thunbergii DC. toward Hematopoietic Cancer Cell Lines
by Anna Och, Daniel Zalewski, Łukasz Komsta, Przemysław Kołodziej, Janusz Kocki and Anna Bogucka-Kocka
Toxins 2019, 11(9), 485; https://doi.org/10.3390/toxins11090485 - 23 Aug 2019
Cited by 42 | Viewed by 6433
Abstract
Isoquinoline alkaloids belong to the toxic secondary metabolites occurring in plants of many families. The high biological activity makes these compounds promising agents for use in medicine, particularly as anticancer drugs. The aim of our study was to evaluate the cytotoxicity and proapoptotic [...] Read more.
Isoquinoline alkaloids belong to the toxic secondary metabolites occurring in plants of many families. The high biological activity makes these compounds promising agents for use in medicine, particularly as anticancer drugs. The aim of our study was to evaluate the cytotoxicity and proapoptotic activity of sanguinarine, berberine, and extracts of Chelidonium majus L. and Berberis thunbergii DC. IC10, IC50, and IC90 doses were established toward hematopoietic cancer cell lines using trypan blue staining. Alterations in the expression of 18 apoptosis-related genes in cells exposed to IC10, IC50, and IC90 were evaluated using real-time PCR. Sanguinarine and Chelidonium majus L. extract exhibit significant cytotoxicity against all studied cell lines. Lower cytotoxic activity was demonstrated for berberine. Berberis thunbergii DC. extract had no influence on cell viability. Berberine, sanguinarine, and Chelidonium majus L. extract altered the expression of apoptosis-related genes in all tested cell lines, indicating the induction of apoptosis. The presented study confirmed the substantial cytotoxicity and proapoptotic activity of sanguinarine, berberine, and Chelidonium majus L. extract toward the studied hematopoietic cell lines, which indicates the utility of these substances in anticancer therapy. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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13 pages, 2774 KiB  
Article
The Activity of Isoquinoline Alkaloids and Extracts from Chelidonium majus against Pathogenic Bacteria and Candida sp.
by Sylwia Zielińska, Magdalena Wójciak-Kosior, Magdalena Dziągwa-Becker, Michał Gleńsk, Ireneusz Sowa, Karol Fijałkowski, Danuta Rurańska-Smutnicka, Adam Matkowski and Adam Junka
Toxins 2019, 11(7), 406; https://doi.org/10.3390/toxins11070406 - 12 Jul 2019
Cited by 56 | Viewed by 5380
Abstract
Chelidonium majus (Papaveraceae) extracts exhibit antimicrobial activity due to the complex alkaloid composition. The aim of the research was to evaluate the antimicrobial potential of extracts from wild plants and in vitro cultures, as well as seven major individual alkaloids. Plant [...] Read more.
Chelidonium majus (Papaveraceae) extracts exhibit antimicrobial activity due to the complex alkaloid composition. The aim of the research was to evaluate the antimicrobial potential of extracts from wild plants and in vitro cultures, as well as seven major individual alkaloids. Plant material derived from different natural habitats and in vitro cultures was used for the phytochemical analysis and antimicrobial tests. The composition of alkaloids was analyzed using chromatographic techniques (HPLC with DAD detection). The results have shown that roots contained higher number and amounts of alkaloids in comparison to aerial parts. All tested plant extracts manifested antimicrobial activity, related to different chemical structures of the alkaloids. Root extract used at 31.25–62.5 mg/L strongly reduced bacterial biomass. From the seven individually tested alkaloids, chelerythrine was the most effective against P. aeruginosa (MIC at 1.9 mg/L), while sanguinarine against S. aureus (MIC at 1.9 mg/L). Strong antifungal activity was observed against C. albicans when chelerythrine, chelidonine, and aerial parts extract were used. The experiments with plant extracts, individually tested alkaloids, and variable combinations of the latter allowed for a deeper insight into the potential mechanisms affecting the activity of this group of compounds. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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21 pages, 1653 KiB  
Article
Tissue Accumulations of Toxic Aconitum Alkaloids after Short-Term and Long-Term Oral Administrations of Clinically Used Radix Aconiti Lateralis Preparations in Rats
by Xiaoyu Ji, Mengbi Yang, Ka Hang Or, Wan Sze Yim and Zhong Zuo
Toxins 2019, 11(6), 353; https://doi.org/10.3390/toxins11060353 - 18 Jun 2019
Cited by 24 | Viewed by 4686
Abstract
Although Radix Aconiti Lateralis (Fuzi) is an extensively used traditional Chinese medicine with promising therapeutic effects and relatively well-reported toxicities, the related toxic aconitum alkaloid concentrations in major organs after its short-term and long-term intake during clinical practice are still not known. To [...] Read more.
Although Radix Aconiti Lateralis (Fuzi) is an extensively used traditional Chinese medicine with promising therapeutic effects and relatively well-reported toxicities, the related toxic aconitum alkaloid concentrations in major organs after its short-term and long-term intake during clinical practice are still not known. To give a comprehensive understanding of Fuzi-induced toxicities, current study is proposed aiming to investigate the biodistribution of the six toxic alkaloids in Fuzi, namely Aconitine (AC), Hypaconitine (HA), Mesaconitine (MA), Benzoylaconine (BAC), Benzoylhypaconine (BHA) and Benzoylmesaconine (BMA), after its oral administrations at clinically relevant dosing regimen. A ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for simultaneous quantification of six toxic alkaloids in plasma, urine and major organs of Sprague Dawley rats after oral administrations of two commonly used Fuzi preparations, namely Heishunpian and Paofupian, at their clinically relevant dose for single and 15-days. Among the studied toxic alkaloids and organs, BMA demonstrated the highest concentrations in all studied organs with liver containing the highest amount of the studied alkaloids, indicating their potential hepatotoxicity. Moreover, tissue accumulation of toxic alkaloids after multiple dose was observed, suggesting the needs for dose adjustment and more attention to the toxicities induced by chronic use of Fuzi in patients. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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14 pages, 2322 KiB  
Article
Differentiated Effects of Secondary Metabolites from Solanaceae and Brassicaceae Plant Families on the Heartbeat of Tenebrio molitor Pupae
by Paweł Marciniak, Angelika Kolińska, Marta Spochacz, Szymon Chowański, Zbigniew Adamski, Laura Scrano, Patrizia Falabella, Sabino A. Bufo and Grzegorz Rosiński
Toxins 2019, 11(5), 287; https://doi.org/10.3390/toxins11050287 - 22 May 2019
Cited by 15 | Viewed by 3900
Abstract
The usage of insects as model organisms is becoming more and more common in toxicological, pharmacological, genetic and biomedical research. Insects, such as fruit flies (Drosophila melanogaster), locusts (Locusta migratoria), stick insects (Baculum extradentatum) or beetles ( [...] Read more.
The usage of insects as model organisms is becoming more and more common in toxicological, pharmacological, genetic and biomedical research. Insects, such as fruit flies (Drosophila melanogaster), locusts (Locusta migratoria), stick insects (Baculum extradentatum) or beetles (Tenebrio molitor) are used to assess the effect of different active compounds, as well as to analyse the background and course of certain diseases, including heart disorders. The goal of this study was to assess the influence of secondary metabolites extracted from Solanaceae and Brassicaceae plants: Potato (Solanum tuberosum), tomato (Solanum lycopersicum), black nightshade (Solanum nigrum) and horseradish (Armoracia rusticana), on T. molitor beetle heart contractility in comparison with pure alkaloids. During the in vivo bioassays, the plants glycoalkaloid extracts and pure substances were injected at the concentration 10−5 M into T. molitor pupa and evoked changes in heart activity. Pure glycoalkaloids caused mainly positive chronotropic effects, dependant on heart activity phase during a 24-h period of recording. Moreover, the substances affected the duration of the heart activity phases. Similarly, to the pure glycoalkaloids, the tested extracts also mainly accelerated the heart rhythm, however S. tuberosum and S. lycopersicum extracts slightly decreased the heart contractions frequency in the last 6 h of the recording. Cardioacceleratory activity of only S. lycopersicum extract was higher than single alkaloids whereas S. tubersoum and S. nigrum extracts were less active when compared to pure alkaloids. The most cardioactive substance was chaconine which strongly stimulated heart action during the whole recording after injection. A. rusticana extract which is composed mainly of glucosinolates did not significantly affect the heart contractions. Obtained results showed that glycoalkaloids were much more active than glucosinolates. However, the extracts depending on the plant species might be more or less active than pure substances. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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11 pages, 1107 KiB  
Article
Toxicity Studies of Chanoclavine in Mice
by Sarah C. Finch, John S. Munday, Jan M. Sprosen and Sweta Bhattarai
Toxins 2019, 11(5), 249; https://doi.org/10.3390/toxins11050249 - 2 May 2019
Cited by 12 | Viewed by 5772
Abstract
Epichloë endophytes have been used successfully in pastoral grasses providing protection against insect pests through the expression of secondary metabolites. This approach could be extended to other plant species, such as cereals, reducing reliance on pesticides. To be successful, the selected endophyte must [...] Read more.
Epichloë endophytes have been used successfully in pastoral grasses providing protection against insect pests through the expression of secondary metabolites. This approach could be extended to other plant species, such as cereals, reducing reliance on pesticides. To be successful, the selected endophyte must express secondary metabolites that are active against cereal insect pests without any secondary metabolite, which is harmful to animals. Chanoclavine is of interest as it is commonly expressed by endophytes and has potential insecticidal activity. Investigation of possible mammalian toxicity is therefore required. An acute oral toxicity study showed the median lethal dose of chanoclavine to be >2000 mg/kg. This allows it to be classified as category 5 using the globally harmonized system of classification and labelling of chemicals, and category 6.1E using the New Zealand Hazardous Substances and New Organisms (HSNO) hazard classes, the lowest hazard class under both systems of classification. A three-week feeding study was also performed, which showed chanoclavine, at a dose rate of 123.9 mg/kg/day, initially reduced food consumption but was resolved by day seven. No toxicologically significant effects on gross pathology, histology, hematology, or blood chemistry were observed. These experiments showed chanoclavine to be of low toxicity and raised no food safety concerns. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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11 pages, 851 KiB  
Article
Palmatine from Unexplored Rutidea parviflora Showed Cytotoxicity and Induction of Apoptosis in Human Ovarian Cancer Cells
by Okiemute Rosa Johnson-Ajinwo, Alan Richardson and Wen-Wu Li
Toxins 2019, 11(4), 237; https://doi.org/10.3390/toxins11040237 - 25 Apr 2019
Cited by 13 | Viewed by 4454
Abstract
Ovarian cancer ranks amongst the deadliest cancers in the gynaecological category of cancers. This research work aims to evaluate in vitro anti-ovarian cancer activities and identify phytochemical constituents of a rarely explored plant species—Rutidea parviflora DC. The aqueous and organic extracts of [...] Read more.
Ovarian cancer ranks amongst the deadliest cancers in the gynaecological category of cancers. This research work aims to evaluate in vitro anti-ovarian cancer activities and identify phytochemical constituents of a rarely explored plant species—Rutidea parviflora DC. The aqueous and organic extracts of the plant were evaluated for cytotoxicity using sulforhodamine B assay in four ovarian cancer cell lines and an immortalized human ovarian epithelial (HOE) cell line. The bioactive compounds were isolated and characterized by gas/liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. Caspase 3/7 activity assay, western blotting and flow cytometry were carried out to assess apoptotic effects of active compounds. The extracts/fractions of R. parviflora showed promising anti-ovarian cancer activities in ovarian cancer cell lines. A principal cytotoxic alkaloid was identified as palmatine whose IC50 was determined as 5.5–7.9 µM. Palmatine was relatively selective towards cancer cells as it was less cytotoxic toward HOE cells, also demonstrating interestingly absence of cross-resistance in cisplatin-resistant A2780 cells. Palmatine further induced apoptosis by increasing caspase 3/7 activity, poly-ADP-ribose polymerase cleavage, and annexin V and propidium iodide staining in OVCAR-4 cancer cells. Our studies warranted further investigation of palmatine and R. parviflora extracts in preclinical models of ovarian cancer. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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18 pages, 2545 KiB  
Article
A Complete Survey of Glycoalkaloids Using LC-FTICR-MS and IRMPD in a Commercial Variety and a Local Landrace of Eggplant (Solanum melongena L.) and their Anticholinesterase and Antioxidant Activities
by Filomena Lelario, Susanna De Maria, Anna Rita Rivelli, Daniela Russo, Luigi Milella, Sabino Aurelio Bufo and Laura Scrano
Toxins 2019, 11(4), 230; https://doi.org/10.3390/toxins11040230 - 19 Apr 2019
Cited by 35 | Viewed by 6584
Abstract
Eggplant contains glycoalkaloids (GAs), a class of nitrogen-containing secondary metabolites of great structural variety that may have both adverse and beneficial biological effects. In this study, we performed a complete survey of GAs and their malonylated form, in two genotypes of eggplants: A [...] Read more.
Eggplant contains glycoalkaloids (GAs), a class of nitrogen-containing secondary metabolites of great structural variety that may have both adverse and beneficial biological effects. In this study, we performed a complete survey of GAs and their malonylated form, in two genotypes of eggplants: A commercial cultivated type, Mirabella (Mir), with purple peel and bitter taste and a local landrace, named Melanzana Bianca di Senise (Sen), characterized by white peel with purple strip and a typical sweet aroma. Besides the analysis of their morphological traits, nineteen glycoalkaloids were tentatively identified in eggplant berry extracts based upon LC-ESI-FTICR-MS analysis using retention times, elution orders, high-resolution mass spectra, as well as high-resolution fragmentation by IRMPD. The relative signal intensities (i.e., ion counts) of the GAs identified in Mir and Sen pulp extracts showed as solamargine, and its isomers are the most abundant. In addition, anticholinesterase and antioxidant activities of the extracts were evaluated. Pulp tissue was found to be more active in inhibiting acetylcholinesterase enzyme than peel showing an inhibitory effect higher than 20% for Mir pulp. The identification of new malonylated GAs in eggplant is proposed. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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14 pages, 2686 KiB  
Article
Dehydrocrenatidine Inhibits Voltage-Gated Sodium Channels and Ameliorates Mechanic Allodia in a Rat Model of Neuropathic Pain
by Fang Zhao, Qinglian Tang, Jian Xu, Shuangyan Wang, Shaoheng Li, Xiaohan Zou and Zhengyu Cao
Toxins 2019, 11(4), 229; https://doi.org/10.3390/toxins11040229 - 18 Apr 2019
Cited by 15 | Viewed by 4090
Abstract
Picrasma quassioides (D. Don) Benn, a medical plant, is used in clinic to treat inflammation, pain, sore throat, and eczema. The alkaloids are the main active components in P. quassioides. In this study, we examined the analgesic effect of dehydrocrenatidine (DHCT), a [...] Read more.
Picrasma quassioides (D. Don) Benn, a medical plant, is used in clinic to treat inflammation, pain, sore throat, and eczema. The alkaloids are the main active components in P. quassioides. In this study, we examined the analgesic effect of dehydrocrenatidine (DHCT), a β-carboline alkaloid abundantly found in P. quassioides in a neuropathic pain rat model of a sciatic nerve chronic constriction injury. DHCT dose-dependently attenuated the mechanic allodynia. In acutely isolated dorsal root ganglion, DHCT completely suppressed the action potential firing. Further electrophysiological characterization demonstrated that DHCT suppressed both tetrodotoxin-resistant (TTX-R) and sensitive (TTX-S) voltage-gated sodium channel (VGSC) currents with IC50 values of 12.36 μM and 4.87 µM, respectively. DHCT shifted half-maximal voltage (V1/2) of inactivation to hyperpolarizing direction by ~16.7 mV in TTX-S VGSCs. In TTX-R VGSCs, DHCT shifted V1/2 of inactivation voltage to hyperpolarizing direction and V1/2 of activation voltage to more depolarizing potential by ~23.9 mV and ~12.2 mV, respectively. DHCT preferred to interact with an inactivated state of VGSCs and prolonged the repriming time in both TTX-S and TTX-R VGSCs, transiting the channels into a slow inactivated state from a fast inactivated state. Considered together, these data demonstrated that the analgesic effect of DHCT was likely though the inhibition of neuronal excitability. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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15 pages, 4338 KiB  
Article
Arecoline Promotes Migration of A549 Lung Cancer Cells through Activating the EGFR/Src/FAK Pathway
by Chih-Hsiang Chang, Mei-Chih Chen, Te-Huan Chiu, Yu-Hsuan Li, Wan-Chen Yu, Wan-Ling Liao, Muhammet Oner, Chang-Tze Ricky Yu, Chun-Chi Wu, Tsung-Ying Yang, Chieh-Lin Jerry Teng, Kun-Yuan Chiu, Kun-Chien Chen, Hsin-Yi Wang, Chia-Herng Yue, Chih-Ho Lai, Jer-Tsong Hsieh and Ho Lin
Toxins 2019, 11(4), 185; https://doi.org/10.3390/toxins11040185 - 28 Mar 2019
Cited by 24 | Viewed by 5704
Abstract
Arecoline is the primary alkaloid in betel nuts, which are known as a risk factor for oral submucosal fibrosis and oral cancer. Lung cancer is a severe type of carcinoma with high cell motility that is difficult to treat. However, the detailed mechanisms [...] Read more.
Arecoline is the primary alkaloid in betel nuts, which are known as a risk factor for oral submucosal fibrosis and oral cancer. Lung cancer is a severe type of carcinoma with high cell motility that is difficult to treat. However, the detailed mechanisms of the correlation between Arecoline and lung cancer are not fully understood. Here, we investigated the effect of Arecoline on migration in lung cancer cell lines and its potential mechanism through the muscarinic acetylcholine receptor 3 (mAChR3)-triggered EGFR/Src/FAK pathway. Our results indicate that different concentrations of Arecoline treatment (10 µM, 20 µM, and 40 µM) significantly increased the cell migration ability in A549 and CL1-0 cells and promoted the formation of the filamentous actin (F-actin) cytoskeleton, which is a crucial element for cell migration. However, migration of H460, CL1-5, and H520 cell lines, which have a higher migration ability, was not affected by Arecoline treatment. The EGFR/c-Src/Fak pathway, which is responsible for cell migration, was activated by Arecoline treatment, and a decreased expression level of E-cadherin, which is an epithelial marker, was observed in Arecoline-treated cell lines. Blockade of the EGFR/c-Src/Fak pathway with the inhibitors of EGFR (Gefitinib) or c-Src (Dasatinib) significantly prevented Arecoline-promoted migration in A549 cells. Gefitinib or Dasatinib treatment significantly disrupted the Arecoline-induced localization of phospho-Y576-Fak during focal adhesion in A549 cells. Interestingly, Arecoline-promoted migration in A549 cells was blocked by a specific mAChR3 inhibitor (4-DAMP) or a neutralizing antibody of matrix metalloproteinase (MMP7 or Matrilysin). Taken together, our findings suggest that mAChR3 might play an essential role in Arecoline-promoted EGFR/c-Src/Fak activation and migration in an A549 lung cancer cell line. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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Review

Jump to: Editorial, Research

28 pages, 4225 KiB  
Review
The Biological Activity of Natural Alkaloids against Herbivores, Cancerous Cells and Pathogens
by Amin Thawabteh, Salma Juma, Mariam Bader, Donia Karaman, Laura Scrano, Sabino A. Bufo and Rafik Karaman
Toxins 2019, 11(11), 656; https://doi.org/10.3390/toxins11110656 - 11 Nov 2019
Cited by 187 | Viewed by 12495
Abstract
The growing incidence of microorganisms that resist antimicrobials is a constant concern for the scientific community, while the development of new antimicrobials from new chemical entities has become more and more expensive, time-consuming, and exacerbated by emerging drug-resistant strains. In this regard, many [...] Read more.
The growing incidence of microorganisms that resist antimicrobials is a constant concern for the scientific community, while the development of new antimicrobials from new chemical entities has become more and more expensive, time-consuming, and exacerbated by emerging drug-resistant strains. In this regard, many scientists are conducting research on plants aiming to discover possible antimicrobial compounds. The secondary metabolites contained in plants are a source of chemical entities having pharmacological activities and intended to be used for the treatment of different diseases. These chemical entities have the potential to be used as an effective antioxidant, antimutagenic, anticarcinogenic and antimicrobial agents. Among these pharmacologically active entities are the alkaloids which are classified into a number of classes, including pyrrolizidines, pyrrolidines, quinolizidines, indoles, tropanes, piperidines, purines, imidazoles, and isoquinolines. Alkaloids that have antioxidant properties are capable of preventing a variety of degenerative diseases through capturing free radicals, or through binding to catalysts involved indifferent oxidation processes occurring within the human body. Furthermore, these entities are capable of inhibiting the activity of bacteria, fungi, protozoan and etc. The unique properties of these secondary metabolites are the main reason for their utilization by the pharmaceutical companies for the treatment of different diseases. Generally, these alkaloids are extracted from plants, animals and fungi. Penicillin is the most famous natural drug discovery deriving from fungus. Similarly, marines have been used as a source for thousands of bioactive marine natural products. In this review, we cover the medical use of natural alkaloids isolated from a variety of plants and utilized by humans as antibacterial, antiviral, antifungal and anticancer agents. An example for such alkaloids is berberine, an isoquinoline alkaloid, found in roots and stem-bark of Berberis asculin P. Renault plant and used to kill a variety of microorganisms. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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16 pages, 559 KiB  
Review
Impact of Ergot Alkaloids on Female Reproduction in Domestic Livestock Species
by Rebecca K. Poole and Daniel H. Poole
Toxins 2019, 11(6), 364; https://doi.org/10.3390/toxins11060364 - 21 Jun 2019
Cited by 21 | Viewed by 4945
Abstract
Fescue toxicosis is a multifaceted syndrome that elicits many negative effects on livestock consuming ergot alkaloids produced by endophyte-infected tall fescue. The economic losses associated with fescue toxicosis are primarily due to reproductive failure including altered cyclicity, suppressed hormone secretion, reduced pregnancy rates, [...] Read more.
Fescue toxicosis is a multifaceted syndrome that elicits many negative effects on livestock consuming ergot alkaloids produced by endophyte-infected tall fescue. The economic losses associated with fescue toxicosis are primarily due to reproductive failure including altered cyclicity, suppressed hormone secretion, reduced pregnancy rates, agalactia, and reduced offspring birth weights. For decades, a multitude of research has investigated the physiological and cellular mechanisms of these reproductive failures associated with fescue toxicosis. This review will summarize the various effects of ergot alkaloids on female reproduction in grazing livestock species. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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