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Alkaloids: Toxicology and Health Effects
Abstract
Alkaloids are produced by many plants as defense chemicals not only mainly against herbivores but also against microbial pathogens. Many alkaloids exhibit a pronounced toxicity in animal models and humans. A major target in animals is the nervous system and many alkaloids structurally resemble neurotransmitters. Because of structural similarity, they can interfere with neurotransmitter receptors or ion channels and thus modulate neuronal signal transduction. Also, other organs can be affected by toxic alkaloids, such as the liver, kidneys, heart and circulation, gastrointestinal tract, and reproductive organs. At a molecular level, alkaloids can interfere with membrane permeability, membrane proteins (ion channels and receptors), enzymes and other proteins, DNA, RNA and corresponding proteins, electron chain, and the cytoskeleton. Because of these pharmacological properties, some alkaloids can be used in medicine to treat infections, health disorders, and even cancer.
... [1][2][3][4] In daily life, Sweet cherries are not only widely used in fresh food, but also in the production of jams, jellies, syrups and a variety of soft drink products. 5 The limited life span does not exceed 21days, which greatly limits its shelf life. 6 Cherry wine is becoming more and more popular in China. ...
... 6 Cherry wine is becoming more and more popular in China. [5][6][7] Among them, the cherry is made into cherry wine, which not only prolongs its shelf life, but also greatly preserves the active ingredients of the fruit, thereby fully developing the cherry resources. In addition, cherry wine has a unique flavor and health function due to its rich antioxidants. ...
This paper took cherry wine lees as the main raw material, and used three extraction methods (ultrasound-assisted enzymatic method, microwave extraction method, condensation reflux extraction method) to extract anthocyanin. The result showed that the extraction number of anthocyanins by ultrasonic-assisted enzymatic method was the highest. On the basis of single factor experiment, the response surface method was used for optimization. The impacts of experimental factors on extraction amount were successively the enzymolysis time, enzymolysis temperature, pH value, ultrasonic power, amount of enzyme added and solid-liquid ratio. Through polynomial regression analysis, the regression model of anthocyanin extraction rate was established, and according to the actual production condition, the following optimal process parameters were determined: enzyme addition: 1.5%; solid-liquid ratio: 1:32; pH value: 4.30; enzymolysis temperature: 54 °C; enzymolysis time: 55 min, and the ultrasonic power: 300 W. Under this condition, the extraction amount of anthocyanin from Cherry Wine lees was 4.19 mg/g.
... Alkaloid's stimulant the central nervous system in human body, that's why alkaloids are used as stimulants and psychoactive drugs. [3] Alkaloids are very important in pharmacological activities and Indole containing alkaloids are well known alkaloids for their importance in medicinal chemistry. Among all alkaloids, Indole containing alkaloids are one of the most promising pharmacological active molecules, Due to their chemical reactivity. ...
... [7] In nature, there are many toxic alkaloids are also present which are very toxic in nature even in very small dose like pyrrolizidine alkaloids, nicotine, Piperine, tropane, cocaine alkaloids which directly affects liver, kidneys, lungs, heart, gastrointestinal tract in human body. [3,9] (Figure 1) This review work is carried out mainly in the context to provide information about different alkaloids which are mainly present in food stuffs. This review work concludesabout different alkaloids which are taken by human in daily life and their desired and adverse effects on human health. ...
Alkaloids are a huge class of natural occurring organic molecules, which contain nitrogen atom or atoms (amino or amido in some cases) in their structures. Alkaloids are extremely divergent chemical structures including heterocyclic ring systems and encompass more than 20,000 different molecules in organisms. They are present not only in human daily life, in food and drinks but also as stimulant drugs, medicines, narcotics, insecticides and in many physiological activities. They showed strong biological effects on animal and human organisms even in very small doses. Alkaloids show several pharmacological activities on human healthsuch as anti-cancer, anti-inflammatory, Anti-malarial, Anti-microbial, Anti-hypertensive, Anti-diabetic, Anti-oxidant. Alkaloids directly act on the central nervous system in the human body and also affect nucleic acid, DNA (Deoxy Ribonucleic acid), RNA (Ribonucleic acid), membrane permeability and proteins. In this review article we aimed to investigate the pharmacological activities of different alkaloids, their importance in medicinal science and their toxicity on human health.
... Many alkaloids exhibit a pronounced toxicity in animal models and humans. A major target in animals is the nervous system and many alkaloids structurally resemble neurotransmitters (Wink, 2016) [22] . Pyrrolidine alkaloids from Epipremnum aureum had shown antitermite effect against Odontotermes obesus, with SEM studies supporting the neurological effect of botanicals over synthetic pesticides (Meshram et al., 2017) [18] . ...
... Many alkaloids exhibit a pronounced toxicity in animal models and humans. A major target in animals is the nervous system and many alkaloids structurally resemble neurotransmitters (Wink, 2016) [22] . Pyrrolidine alkaloids from Epipremnum aureum had shown antitermite effect against Odontotermes obesus, with SEM studies supporting the neurological effect of botanicals over synthetic pesticides (Meshram et al., 2017) [18] . ...
... However, in the medicinal area, alkaloids are used as anesthetics, narcotics, analgesics, respiratory stimulants, to dilate pupils, to relax the skeletal muscles, as well as to treat infections, health disorder and cancers. Caffeine is one of the alkaloids that can modulate receptors of neurotransmitters, that is, it is used as an stimulant in medicinal applications (Wink, 2016), which perhaps explains the use of monguba seeds as a tonic by indigenous healers. Nevertheless, depending on the concentration, this compound can cause toxicological effects due to binding to neurotransmitter receptors and neurotransmitter-degrading enzymes (Wink, 2016). ...
... Caffeine is one of the alkaloids that can modulate receptors of neurotransmitters, that is, it is used as an stimulant in medicinal applications (Wink, 2016), which perhaps explains the use of monguba seeds as a tonic by indigenous healers. Nevertheless, depending on the concentration, this compound can cause toxicological effects due to binding to neurotransmitter receptors and neurotransmitter-degrading enzymes (Wink, 2016). ...
The monguba (Pachira aquatica Aubl.) tree is distributed from southern Mexico to South America. This plant has a variety of applications, including handicraft works, the consumption of its seeds as an alternative to coffee consumption, and the use of monguba bark and seeds in the treatment of vaginal infections in folk medicine. This review aims to draw the attention of researchers to the nutraceutical potential, physicochemical and nutritional composition, and bioactive compounds in the monguba plant for applications in the food, and other industries. After searching for publications containing ‘Pachira aquatica’, ‘monguba’ or ‘munguba’ in titles and abstracts from 1878 to 2020 in six databases, the resulting publications were analyzed, and 50 full-text articles were included in this review. We observed that monguba has not been much explored and it is not widely known, though it is a novel oilseed with nutritional potential since it is rich in oils, proteins, minerals, fibers and phytochemicals. However, in vivo studies are required to verify the current uses of monguba in folk medicine by analyzing potential effects of the fruit, in addition to the compounds related to such bioactivity.
... To alleviate the discomforts that arise during pregnancy, many pregnant women seek alternative treatment in medicinal plants, as they believe that, because they are natural, they are free of harmful effects on pregnancy, despite the lack of robust data on their safety and efficacy [ , Brunfelsia uniflora (Manacá), and Camellia sinensis (Chá-verde) are rich in these metabolites, which makes the consumption of these plants during pregnancy a high-risk practice since the literature reports that in addition to being teratogenic, these secondary metabolites of plants can determine embryotoxic and abortifacient effects [25][26][27][28][29]. Some morphological characteristics of plants rich in alkaloids in their constitution and commonly found in different regions of different Brazilian states are shown in Figure 1. ...
During fetal organogenesis, exposure to natural and/or synthetic chemical agents can have devastating effects on the developing fetus, including congenital malformations, embryotoxicity, and fetal death. Despite contraindications to the use of certain chemicals during pregnancy, many pregnant women use medicinal plants to alleviate unwanted symptoms inherent to the development of the gestational period, such as nausea, vomiting, and abdominal pain, among others. This practice is unfortunately supported by the false idea that the use of natural substances is incapable of causing harm to the health of the pregnant woman or the fetus. This study aims to systematically identify medicinal plants commonly used in South America and their secondary metabolites that may pose risks to fetal development if consumed during pregnancy. By investigating these plants and their secondary metabolites, we aim to improve the understanding of their potential embryotoxic effects and provide valuable insights for clinical practices related to herbal remedies during pregnancy. The search for articles was carried out in the databases PubMed (NCBI), Virtual Health Library (VHL), Scientific Online Electronic Library (SciELO), Medical Literature Analysis and Retrieval System Online-MedLine (PubMed), Scientific Electronic Library-SciELO and Latin American and Caribbean Literature in Health Sciences-LILACS. Although the use of medicinal plants to relieve discomfort related to the development of pregnancy is an ancient practice, the use of the medicinal plants presented in this work should be avoided by pregnant women, as they are plants endowed with secondary metabolites that can cause embryotoxic, teratogenic and abortifacient effects.
... For example, alkaloids such as lupanine and sparteine inhibit sodium and potassium channels, thus blocking the signal transduction in the nerve cells at a second critical point. Also, some alkaloids like lupanine, cytisine and sparteine exhibit antimicrobial properties against a wide range of microorganisms [26,27]. ...
Anagyris foetida is a genus of legumes belonging to the Fabaceae family, considered as a good source of medications to treat various ailments. In order to determine the biological potential of this plant, the present work deals for the first time with the extraction and identification of alkaloids from leaves, stems and seeds of Algerian A. foetida species and evaluation of their antioxidant effects. The extraction was performed by three different methods to compare the influence of many factors (extraction temperature, nature and polarity of solvents) on the yield and chemical composition of extracts. Capillary GC-MS analyses of the obtained fractions allowed the identification of six alkaloids in the leaves and stems and five in the seeds, with a significant difference in the percentage content of identified compounds. The identified alkaloids include sparteine, N-methylcytisine, cytisine, 5,6-dehydrolupanine, lupanine and anagyrine. In vitro antioxidant activity of the alkaloids extracts was assessed by DPPH free radical scavenging test. Results showed that different parts of A. foetida exhibited relatively moderate scavenging of DPPH radicals. Extracts obtained by method III presented the highest antioxidant activity with IC50 = 108.7 ± 9.0 μg/mL for the leaves and stems and 92.9 ± 6.2 μg/mL for the seeds. These results suggested that cytisine, which was extracted only by method III in both samples, presented the highest antiradical activity.
... Aggravation is important for a complex organic cycle which expects to reestablish homeostasis to the body later it has been upset by actual harm, synthetic aggravations, pathogenic miniature creatures, or harmed tissues. [30] It is ostensibly the body's major defensive framework, and works intimately with the invulnerable framework in checking obsessive action and starting the recuperating system. It is regulated by connecting with both the endocrine and the sensory systems. ...
A solitary traditional medication by and large has one predominant pharmacological method of activity which represents its restorative viability, though a home grown cure on account of the different dynamic specialists it contains, for the most part impacts a few biochemical and additionally physiological frameworks present in the body.It analyzes a significant class of sub positions, the adaptogens, and the different synthetic structures it embraces, like the saponins and triterpenes. The Herbs with adjust the invulnerable framework, for example garlic, turmeric and St John's Wort, are moreover reviewed, just like the alkaloids and organic calming specialists. Herbs which apply pharmacological activity by means of their nitric oxide administrative properties are recorded, similar to those which give fundamental miniature supplements, like nutrients and certain minerals. The survey closes with remark on the significance of understanding home grown cure methods of activity as a positive advance to their more extensive reception in the cutting edge restorative armamentarium.
... At and Sc have been used throughout history in medicine, generally administered at low doses as drugs in the form of salts, such as atropine sulfate, or as semi-synthetic derivatives such as homatropine bromide or N-butylscopolamine bromide [1]. Their use has served to treat multiple symptoms and pathologies such as nausea, vomiting, heart or respiratory problems and also as an antispasmodic in gastrointestinal problems, as antiallergic drugs, as a treatment against organophosphate compounds and even as a pupil dilator for ophthalmic treatment [7][8][9][10]. However, and despite their great use, these compounds have been implicated in numerous intoxications due to the consumption of TA-containing plants or foods contaminated with these plants. ...
Tropane alkaloids (TAs) are natural toxins produced by different plants, mainly from the Solanaceae family. The interest in TAs analysis is due to the serious cases of poisoning that are produced due to the presence of TA-producing plants in a variety of foods. For this reason, in recent years, different analytical methods have been reported for their control. However, the complexity of the matrices makes the sample preparation a critical step for this task. Therefore, this review has focused on (a) collecting the available data in relation to the occurrence of TAs in foods for human consumption and (b) providing the state of the art in food sample preparation (from 2015 to today). Regarding the different food categories, cereals and related products and teas and herbal teas have been the most analyzed. Solid–liquid extraction is still the technique most widely used for sample preparation, although other extraction and purification techniques such as solid-phase extraction or QuEChERS procedure, based on the use of sorbents for extract or clean-up step, are being applied since they allow cleaner extracts. On the other hand, new materials (molecularly imprinted polymers, mesostructured silica-based materials, metal–organic frameworks) are emerging as sorbents to develop effective extraction and purification methods that allow lower limits and matrix effects, being a future trend for the analysis of TAs.
... In this work a dilution of ethanol in water was used, varying the polarity for the extraction of saponin. This was important in this work since the polar and apolar behavior is a structural characteristic of this glycoside, which is made up of a sugar and an aglycone (Wink, 2016). Regarding the ultrasonic extraction time for saponins, it is lower compared to other extraction methods. ...
... In this work a dilution of ethanol in water was used, varying the polarity for the extraction of saponin. This was important in this work since the polar and apolar behavior is a structural characteristic of this glycoside, which is made up of a sugar and an aglycone (Wink, 2016). Regarding the ultrasonic extraction time for saponins, it is lower compared to other extraction methods. ...
Background:
Quinoa grain has a bitter tasting layer in the pericarp called saponin, a triterpenoid glycoside with industrial potential. Traditionally, quinoa saponins are extracted with a large amount of water, which is why ultrasound technology constitutes an emerging technological alternative which is considered efficient and profitable compared to traditional extraction methods. The objective of this research was to determine the amplitude, time, and concentration of ethanol that guarantee a higher content of saponin through extraction assisted by ultrasound.
Methods:
To find the optimal extraction conditions, the response surface methodology was used using the Box Behnken design with 5 central points, taking as a response the content of saponins (expressed in oleanolic acid as it is the most abundant sapogenin).
Results:
According to the results obtained, the R2 values were in agreement with the adjusted R2, showing that the data fit the model well. The results showed that ethanol concentration has a significant effect (p < 0.05) on the saponin content in the extract. Optimization showed that the optimal extraction conditions were 70% ethanol, 59% amplitude and an exposure time of 12 min. These values were obtained experimentally to compare theoretical values and found residual error percentages less than 3%. The emulsifying activity was evaluated, reporting a value of 52,495 units of emulsion activity per milliliter (UAE/mL), and the foaming stability indicated that 87.54% of the initial foam was maintained after 5 min, indicating high stability.
Conclusions:
The parameters of ethanol concentration, amplitude and time were optimized in the extraction of saponins, assisted by ultrasound. Furthermore, the extract obtained had good foaming and emulsifying characteristics, suggesting its suitability for use in industry.
... The elevated serum urea levels may be an indication of early kidney damage and this is supported by the result of histological examination of the kidneys which showed slight tubular necrosis at all the extract treated doses and this will likely affect the efficient reabsorption of minerals and fluids from urine as it forms. The toxic effect on the liver and kidneys may be due to the presence of alkaloids in the extracts which can interfere with membrane permeability, membrane proteins (ion channels and receptors), enzymes and other proteins, DNA, RNA and corresponding proteins, electron chain and the cytoskeleton (Wink, 2016). The result of this study is in contrast to that of Ezejiofor et al., 2013 who reported non-toxicity of the aqueous leaf extract of Costus afer on the kidneys of male albino Wistar rats in both biochemical and histological examination of the kidneys and this may be due to differences in phytochemical constituents. ...
The liver and the kidneys are two very important organs in the body and they are responsible for the metabolism and excretion of drugs respectively amongst several other functions. Severe adverse effects on these organs can lead to organ dysfunction or failure and a consequential effect on wellbeing and can even be life-threatening. This study investigated the effects of hydromethanolic stem extract of Costus afer Ker Gawl. (Costaceae) on liver and kidney function indices and the histopathology of the organs in Wistar rats. Serum liver enzymes which include: alanine amino transferase (ALT), aspartate amino transferase (AST) and alkaline phosphatase (ALP), total protein and albumin as well as serum urea, creatinine, sodium ions, potassium ions, chloride ions, bicarbonate ions were evaluated in biochemical studies. Sections of the liver and kidneys appropriately treated were examined microscopically for pathological lesions.There were decreased serum levels of ALT and ALP, but serum levels of AST increased at 500 and 1000 mg/kg doses. Serum levels of total protein (TP) and albumin concentration as well as urea and creatinine serum levels were not significantly (p>0.05) affected. However, histological examination of the liver and kidneys revealed slight to moderate hepatic necrosis and slight tubular necrosis respectively especially at 500 and 100 mg/kg doses of the extract. The results showed that the extract may be harmful to the liver and to a lesser extent the kidneys on prolonged administration and therefore it should be used with caution in such instances.
... During the processing of fruits and vegetables by the food industries, high rates of loss of nearly 90 million tons of food waste are expelled each year. And in addition to the direct consumption of fruits, these food industries produce large quantities of canned fruit, juice, jam, jelly, compotes, marmalade, syrup and several types of soft drinks (Ferretti et al., 2010;Wink, 2016) at the expense of large amounts of waste in the form of stones and kernels. Some of which are already used as edible oil sources in oil mixtures, in paint and varnish formulation, in surface coatings and as cosmetic oils (Helmy, 1990), while others are still presenting a serious problem of elimination. ...
Four varieties of Prunus avium ( Burlat , Napoleon , Coeur de pigeon , Van ) kernel oils were extracted using a soxhlet apparatus with n-hexane as solvent. These oils composition was compared amongst them, with fatty acids, phytosterols and tocopherols identification and physicochemical characterization of said oils. Several differences, such as in oil yield were observed, “ Coeur de pigeon ” variety being the highest with a 23.5% yield. Twelve fatty acids were identified in all the varieties with linoleic and oleic fatty acids being the most abundant. β-sitosterol, Campesterol and Δ5-Avenasterol were the major compounds in the sterols assay performed. Also, total tocopherols ranged from 352.22 mg/kg ( Var. Coeur de pigeon ) to 2072.55 mg/kg ( Var. Napoleon ), with γ-tocopherol being the dominant one. These results suggest that these oils have numerous active compounds that can be further exploited.
... Os polifenóis são fitoquímicos presentes em elevados teores no morango (200 mg 100 g -1 a 300 mg 100 g -1 ) , sendo as antocianinas os fenóis mais predominantes, contudo os polifenóis apresentam um teor de absorção pelo organismo de apenas 1% (WINK, 2016). São metabolizados na microbiota intestinal após atingir o ceco, resultando em uma menor biodisponibilidade. ...
Objetivou-se realizar uma revisão de literatura sobre os potenciais efeitos do
consumo de morango e seus compostos em patologias como câncer, diabete
mellitus, doenças cardiovasculares, síndrome metabólica, doenças neurológicas e
sistema imunológico. Trata-se de uma revisão de literatura de estudos publicados
entre 2000 e 2019, indexados nas bases de dados BVS, SciELO, Lilacs, PubMed e
ScienceDirect. O potencial anticarcinogênico do morango está associado à
capacidade de seus compostos antioxidantes no bloqueio do ciclo celular envolvido
na progressão do câncer. No diabetes mellitus, os compostos fenólicos e a vitamina
C atuam da redução dos níveis de glicose circulante, devido à capacidade de
estimular a secreção de insulina pelas células β pancreáticas. Os compostos
fenólicos do morango atuam na redução dos níveis de colesterol total, LDL e
triglicerídeos. Assim, conclui-se que o morango é um fruto com elevado potencial
preventivo e terapêutico em diversas patologias, o que ressalta a relevância desta
revisão para a ciência e comunidade em geral. Ademais, sugere-se a produção de
novos ensaios clínicos controlados com humanos, uma vez que observou-se maior
número de publicações com testes realizados em animais.
... Alkaloide Besonders in der Gruppe der Alkaloide findet man viele wichtige Arzneistoffe, wie z. B. das aus Papaver somniferum gewonnene Schmerzmittel Morphin oder die aus Camptotheca acuminata (Camptothecin) oder Catharanthus roseus (Vinblastin und Vincristin) isolierten Chemotherapeutika (Wink, 2016b). ...
Strictosidin ist der gemeinsame Vorläufer vieler medizinisch relevanter, pflanzlicher Monoterpenindolalkaloide, deren Produktion in der Pflanze häufig nicht ausreicht, um den steigenden Marktbedarf zu decken. Die Produktion dieser Alkaloide bzw. ihres Vorläufers Strictosidin in einem mikrobiellen heterologen System könnte eine Alterna-tive zur Synthese/Produktion in der Pflanze bieten. In dieser Arbeit wurde daher ein System zur Co-Expression von drei Schlüsselgenen der Catharanthus roseus Monoterpenindolalkaloid-Biosynthese entwickelt, das die gleichzeitige funktionelle Expression der Tryptophandecarboxylase (TDC), der Stricto-sidinsynthase (STR) und der Strictosidinglucosidase (SGD) in Escherichia coli ermög-licht. Um dies zu erreichen, wurden zunächst zwei unterschiedliche Expressionssysteme auf ihre Eignung hin untersucht. Zum einen wurde mit Pichia pastoris, ein eukaryotes Sys-tem getestet, zum anderen mit Escherichia coli, ein prokaryotes. Für beide Systeme wurden verschiedene Vektorkonstrukte zur Einzelexpression der Catharanthus-Gene hergestellt und deren Funktionalität im jeweiligen System/Organismus überprüft. Die Gene der STR und SGD wurden für die Expression in E. coli Codon-optimiert. Bei der STR, für die bekannt ist, dass sie in E. coli vermehrt in Form von unlöslichen Inclusion Bodies produziert wird, wurde zusätzlich der Einfluss des Vektors (Kopienzahl) und verschiedener Tag-Sequenzen auf die Expression löslicher, enzymatisch aktiver En-zyme untersucht. Die Aktivität der unterschiedlichen Konstrukte wurde über in vivo Enzymassays in E. coli und anschließendem Nachweis des enzymatischen Produkts Strictosidin mittels HPLC verglichen. Da sich die TDC im P. pastoris System trotz vielfältiger Optimierungsversuche nicht ex-primieren ließ, und die STR trotz nachgewiesener funktioneller Expression nicht aus dem Expressionsmedium gereinigt werden konnte, wurden die Arbeiten mit diesem System eingestellt. Alle Arbeiten zur Produktion der drei Catharanthus-Enzyme erfolg-ten von nun an im E. coli System, in dem sich alle drei Enzyme in löslicher, aktiver Form exprimieren und reinigen ließen. Die gereinigten Enzyme wurden hinsichtlich pH- und Temperaturoptima, kinetischer Parameter Km und Vmax und des Einflusses verschie-dener Aktivatoren und Hemmstoffe charakterisiert. Für die Co-Expression aller drei Gene wurden Doppeltransformanten hergestellt, die zum einen den Vektor pET45b(+)_TDC_C-His und zum anderen den Vektor pCDFDuet1_SGD_STR enthielten. Der Erfolg der Expression wurde über SDS-PAGE, die Funktionalität der gebildeten Enzyme über in vivo Enzymassays mit Tryptophan und Secologanin als Substrate und anschließendem Nachweis der Edukte bzw. Produkte über HPLC bzw. LC-MS überprüft. Als kostengünstigere Alternative wurden auch En-zymassays durchgeführt, bei denen anstelle des reinen Secologanin ein Methanol-Ex-trakt von Symphoricarpos albus Beeren verwendet wurde. Zusätzlich zu den in vivo Klonierungs- und Expressionsarbeiten wurde ein säulenba-siertes System zur in vitro Produktion von Strictosidin mittels rekombinanter STR etabliert. Die Ergebnisse dieser Arbeit liefern einen ersten Beitrag zur heterologen Produktion pharmazeutisch wichtiger Monoterpenindolalkaloide in einem E. coli System.
... In cell cycle analysis, reference drugs colchicine and vinblastine were shown to induce G2/M arrest, which agrees with the literature that they depolymerize microtubules or prevent tubulin assembly by binding to colchicine domain and vinca domain, respectively (Kavallaris, 2010;Wink, 2007;Wink & Schimmer, 2010). Colchicine and vinblastine alter the dynamic of mitotic spindles during mitosis, which triggers the cell cycle checkpoint and thus arrests the cell cycle at G2/M phase (Jordan & Wilson, 2004;Wink, 2016). The actin-binding agent latrunculin B induced G2/M arrest as well. ...
Cucurbitacins, a class of toxic tetracyclic triterpenoids in Cucurbitaceae, modulate many molecular targets. Here we investigated the interactions of cucurbitacin B, E and I with cytoskeletal proteins such as microtubule and actin filaments. The effects of cucurbitacin B, E and I on microtubules and actin filaments were studied in living cells (Hela and U2OS) and in vitro using GFP markers, immunofluorescence staining and in vitro tubulin polymerization assay. Cucurbitacin B, E and I apparently affected microtubule structures in living cells and cucurbitacin E inhibited tubulin polymerization in vitro with IC 50 value of 566.91 ± 113.5 µM. Cucurbitacin E did not affect the nucleation but inhibited the growth phase and steady state during microtubule assembly in vitro . In addition, cucurbitacin B, E and I all altered mitotic spindles and induced the cell cycle arrest at G2/M phase. Moreover, they all showed potent effects on actin cytoskeleton by affecting actin filaments through the depolymerization and aggregation. The interactions of cucubitacin B, E and I with microtubules and actin filaments present new insights into their modes of action.
While food shortages have become an important challenge, providing safe food resources is a point of interest on a global scale. Mycotoxins are secondary metabolites that are formed through various fungi species. They are mainly spread through diets such as food or beverages. About one quarter of the world's food is spoiled with mycotoxins. As this problem is not resolved, it represents a significant threat to global food security. Besides the current concerns regarding the contamination of food items by these metabolites, the lack of knowledge by consumers and their possible growth and toxin production attracted considerable attention. While globalization provides a favorite condition for some countries, food security still is challenging for most countries. There are various approaches to reducing the mycotoxigenic fungi growth and formation of mycotoxins in food, include as physical, chemical, and biological processes. The current article will focus on collecting data regarding consumers' awareness of mycotoxins. Furthermore, a critical overview and comparison among different preventative approaches to reduce risk by consumers will be discussed. Finally, the current effect of mycotoxins on global trade, besides future challenges faced by mycotoxin contamination on food security, will be discussed briefly.
The anticancer drugs camptothecin (CPT) and topotecan (TPT) are known DNA topoisomerase I inhibitors which cause DNA damage and lead to cell death. In this study we provide evidence that CPT and TPT also interfere with the elements of cytoskeleton - microtubules and actin filaments which could be partly responsible for their cytotoxic properties. CPT and TPT apparently affected microtubule structures in living cells (Hela and U2OS) and inhibited tubulin polymerization in vitro with IC50 values of 74.57 ± 9.96µM and 121.55 ± 58.68µM, respectively. TPT significantly affected the nucleation and growth phase during the microtubule assembly in vitro, whereas the mode of action of CPT was different in that it specifically affected the 'tread milling' of polymerized microtubules. Cell cycle effects of CPT and TPT varied with their concentrations. CPT and TPT induced G2/M arrest and promoted the population to 76.94 ± 11.20% and 83.91 ± 2.43% at a concentration of 9.4nM and 46.9nM, respectively. As the concentration increased, cells were blocked in S phase with a dose-dependent reduction in G2/M population. In addition, CPT and TPT exhibited a certain effect on actin filaments by reducing the mass of actin filaments. The interactions of CPT and TPT with microtubules and actin filaments present new insights into their modes of action.
Oral hygiene products are usually not classified as dental materials. Their use is at least in part regulated by other laws, such as regulations regarding cosmetics. There is, however, no clear borderline. Oral hygiene products may lead to oral and extra-oral symptoms, which patients or dentists may attribute to dental materials. To assist the dentist in the process of differential diagnostics, a theoretical background and clinical symptoms of adverse effects arising from oral hygiene products are presented in this chapter.
The main objective of this work was to investigate the effect of acid activation on the adsorption ability of synthesized double layered hydroxides (DLH) for fluoride ions present in aqueous solution. Samples of DLH synthesized presented an enhancement of adsorption capacity for fluorides related to their precursors, a consequence of substitution of CO32– anions (after acid degradation) present on the DLH structure by monovalent anions (chloride and formate) that are more easily interchangeable compared to fluoride ions. Both variables evaluated in the activation step (acid concentration and contact time) presented a positive effect on the adsorption capacity for fluoride ions. Results demonstrated the necessity of a rigorous control of these variables to avoid complete degradation of the DLH structure. The adsorption assays permitted the conclusion that an enhancement on adsorption capacity was verified at pH 3.5 (compared to pH 5.0) and temperature of 50 °C (compared to 10 °C), indicating the endothermic nature of the process (ΔS = +28.35 J·K–1·mol–1). The high adsorption capacity of fluoride ions observed in this work (303.54 mg·g–1) demonstrates the potential of these adsorbents toward treatment of water contaminated with this element.
We can safely assume that most alkaloids play an important role in the ecology of plants. In general, alkaloids serve as defense chemicals against herbivores and to a lesser degree against bacteria, fungi, and viruses or provide a means of interaction with other plants (see Chapters 13 and 14). A protective function has also been attributed to those alkaloids that are produced or sequestered by animals (see Chapters 15 and 16). In order to fulfill this function, alkaloids must closely interact with specific targets in herbivores, predators, microorganisms, or competing plants, i.e., they must either inhibit or otherwise deregulate important processes that are vital for these organisms. A thorough understanding of how these capabilities are effected is important for a comprehension of the evolutionary and ecological implications of alkaloids and their rational use in medicine or as natural pesticides in agriculture.
A typical character of plants is the production and storage of usually complex mixtures of secondary metabolites (SM). The main function of secondary metabolites is defense against herbivores and microbes; some SM are signal compounds to attract pollinating and seed dispersing animals or play a role in the symbiotic relationships with plants and microbes. The distribution of SM in the plant kingdom shows an interesting pattern. A specific SM is often confined to a particular systematic unit, but isolated occurrences can occur in widely unrelated taxonomic groups. This review tries to explain the patchy occurrence of SM in plants. It could be due to convergent evolution, but evidence is provided that the genes that encode the biosynthesis of SM appear to have a much wider distribution than the actual secondary metabolite. It seems to be rather a matter of differential gene regulation whether a pathway is active and expressed in a given taxonomic unit or not. It is speculated that the genes of some pathways derived from an early horizontal gene transfer from bacteria, which later became mitochondria and chloroplasts. These genes/pathways should be present in most if not all land plants. About 80% of plants live in close symbiotic relationships with symbiotic fungi (ectomycorrhiza, endophytes). Recent evidence is presented that these fungi can either directly produce SM, which were formerly considered as plant SM or that these fungi have transferred the corresponding pathway gene to the host plant. The fungal contribution could also explain part of the patchy occurrence patterns of several secondary metabolites.
This review summarizes human infections caused by endoparasites, including protozoa, nematodes, trematodes, and cestodes, which affect more than 30% of the human population, and medicinal plants of potential use in their treatment. Because vaccinations do not work in most instances and the parasites have sometimes become resistant to the available synthetic therapeutics, it is important to search for alternative sources of anti-parasitic drugs. Plants produce a high diversity of secondary metabolites with interesting biological activities, such as cytotoxic, anti-parasitic and anti-microbial properties. These drugs often interfere with central targets in parasites, such as DNA (intercalation, alkylation), membrane integrity, microtubules and neuronal signal transduction. Plant extracts and isolated secondary metabolites which can inhibit protozoan parasites, such as Plasmodium, Trypanosoma, Leishmania, Trichomonas and intestinal worms are discussed. The identified plants and compounds offer a chance to develop new drugs against parasitic diseases. Most of them need to be tested in more detail, especially in animal models and if successful, in clinical trials.
Several alkaloids are toxic to insects and vertebrates and, in addition, can inhibit the growth of bacteria and plant seedlings. In vitro assays were established to elucidate their modes of action and to understand their allelochemical properties. Basic molecular targets studied, present in all cells, included DNA intercalation, protein biosynthesis, and membrane stability. The degree of DNA intercalation was positively correlated with inhibition of DNA polymerase I, reverse transcriptase, and translation at the molecular level and with toxicity against insects and vertebrates at an organismic level. Inhibition of protein biosynthesis was positively correlated with animal toxicity. Molecular targets studied, present only in animals, included neuroreceptors (alpha1, alpha2, serotonin, muscarinic, and nicotinic acetylcholine receptors) and enzymes related to acetylcholine (acetylcholine esterase and choline acetyltransferase). The degree of binding of alkaloids to adrenergic, serotonin, and muscarinic acetylcholine receptors was positively correlated in G-protein-coupled receptors. Receptor binding and toxicity was correlated in insects. The biochemical properties of alkaloids are discussed. It is postulated that their structures were shaped in a process termed evolutionary molecular modeling to interact with a single and, more often, with several molecular targets at the same time. Many alkaloids are compounds with a broad activity spectrum that apparently have evolved as multipurpose defense compounds. The evolution of allelochemicals affecting more than one target could be a strategy to counteract adaptations by specialists and to help fight off different groups of enemies.
Chemical protection plays a decisive role in the resistance of plants against pathogens and herbivores. The so-called secondary metabolites, which are a characteristic feature of plants, are especially important and can protect plants against a wide variety of microorganisms (viruses, bacteria, fungi) and herbivores (arthropods, vertebrates). As is the situation with all defense systems of plants and animals, a few specialized pathogens have evolved in plants and have overcome the chemical defense barrier. Furthermore, they are often attracted by a given plant toxin. During domestication of our crop and food plants secondary metabolites have sometimes been eliminated. Taking lupins as an example, it is illustrated that quinolizidine alkaloids are important as chemical defense compounds and that the alkaloid-free varieties (sweet lupins), which have been selected by plant breeders, are highly susceptible to a wide range of herbivores to which the alkaloid-rich wild types were resistant. The potential of secondary metabolites for plant breeding and agriculture is discussed.
Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion.
Plants use complex mixtures of secondary compounds (SM) of different structural classes to protect themselves against herbivores, bacteria, fungi and viruses. These complex mixtures may contain SM, which are specific for a single target (monotarget SM). A majority of SM, however, can interfere with several targets (multitarget SM) in a pleiotropic fashion. The composition of such extracts appears to be optimised, since the components are not only additive but apparently synergistic in their bioactivity. Synergism can be achieved by inhibiting the xenobiotics inactivating activities of animals and microbes (MDR, CYP), by facilitating the uptake of polar SM across biomembranes and/or by affecting several important organs in animals concomitantly. Phytotherapy employs equally complex extracts of medicinal plants. Arguments were put together that the utilisation of complex mixtures with pleiotropic agents presents a unique therapeutic approach with many advantages over monotarget compounds. Mixtures of multitarget SM, used in phytotherapy include phenolics, tannins, mono- and sequiterpenes, saponins, iridoid glucosides and anthraquinones, but only few of them alkaloids or other toxic monotarget SM.Multitarget effects are caused by SM, which can modulate the three-dimensional structure of proteins (and thus their function), by interfering with DNA/RNA (especially gene expression) or membrane permeability. In addition, complex extracts may contain synergists, which can inhibit MDR, cytochrome P450 or enhance absorption and thus bioavailability of active metabolites. The molecular modes of action are reviewed for the main groups of secondary metabolites.
The alkaloids berberine, palmatine and sanguinarine are toxic to insects and vertebrates and inhibit the multiplication of bacteria, fungi and viruses. Biochemical properties which may contribute to these allelochemical activities were analysed. Acetylcholine esterase, butyrylcholinesterase, choline acetyl transferase, alpha 1- and alpha 2-adrenergic, nicotinergic, muscarinergic and serotonin2 receptors were substantially affected. Sanguinarine appears to be the most effective inhibitor of choline acetyl-transferase (IC50 284 nM), while the protoberberines were inactive at this target. Berberine and palmatine were most active at the alpha 2-receptor (binding with IC50 476 and 956 nM, respectively). Furthermore, berberine and sanguinarine intercalate DNA, inhibit DNA synthesis and reverse transcriptase. In addition, sanguinarine (but not berberine) affects membrane permeability and berberine protein biosynthesis. In consequence, these biochemical activities may mediate chemical defence against microorganisms, viruses and herbivores in the plants producing these alkaloids.
Secondary metabolites, at least the major ones present in a plant, apparently function as defence (against herbivores, microbes, viruses or competing plants) and signal compounds (to attract pollinating or seed dispersing animals). They are thus important for the plant's survival and reproductive fitness. Secondary metabolites therefore represent adaptive characters that have been subjected to natural selection during evolution. Molecular phylogenies of the Fabaceae, Solanaceae and Lamiaceae were reconstructed and employed as a framework to map and to interpret the distribution of some major defence compounds that are typical for the respective plant families; quinolizidine alkaloids and non-protein amino acids for legumes; tropane and steroidal alkaloids for Solanaceae, and iridoids and essential oils for labiates. The distribution of the respective compounds appears to be almost mutually exclusive in the families studied, implying a strong phylogenetic and ecological component. However, on a closer look, remarkable exceptions can be observed, in that certain metabolites are absent (or present) in a given taxon, although all the neighbouring and ancestral taxa express (or do not express, respectively) the particular trait. It is argued that these patterns might reflect differential expression of the corresponding genes that have evolved earlier in plant evolution. The inconsistent secondary metabolite profiles mean that the systematic value of chemical characters becomes a matter of interpretation in the same way as traditional morphological markers. Thus, the distribution of secondary metabolites has some value for taxonomy but their occurrence apparently reflects adaptations and particular life strategies embedded in a given phylogenetic framework.
Not since the late 1970s has a single work presented the biology of this heterogenous group of secondary alkaloids in such depth. Alkaloids, a unique treatise featuring leaders in the field, presents both the historical use of alkaloids and the latest discoveries in
• the biochemistry of alkaloid production in plants
• alkaloid ecology, including marine invertebrates, animal and plant parasites, and
• alkaloids as antimicrobial and current medicinal use
. Highlights include chapters on the chemical ecology of alkaloids in host-predator interactions, and on the compartmentation of alkaloids synthesis, transport, and storage. Extensive cross-referencing in tabular format makes this volume an excellent reference.
Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.
The production of plant secondary metabolites by means of large-scale culture of plant cells in bioreactors is technically feasible. The economy of such a production is the major bottleneck. For some costly products it is feasible, but unfortunately some of the most interesting products are only in very small amounts or not all produced in plant cell cultures. Screening, selection and medium optimization may lead to 20- to 30-fold increase in case one has producing cultures. In case of phytoalexins, elicitation will lead to high production. But for many of the compounds of interest the production is not inducible by elicitors. The culture of differentiated cells, such as (hairy) root or shoot cultures, is an alternative, but is hampered by problems in scaling up of such cultures. Metabolic engineering offers new perspectives for improving the production of compounds of interest. This approach can be used to improve production in the cell culture, in the plant itself or even production in other plant species or organisms. Studies on the production of terpenoid indole alkaloids have shown that the overexpression of single genes of the pathway may lead for some enzymes to an increased production of the direct product, but not necessarily to an increased alkaloid production. On the other hand feeding of such transgenic cultures with early precursors showed an enormous capacity for producing alkaloids, which is not utilized without feeding precursors. Overexpression of regulatory genes results in the upregulation of a series of enzymes in the alkaloid pathway, but not to an improved flux through the pathway, but feeding loganin does result in increased alkaloid production if compared with wild-type cells. Indole alkaloids could be produced in hairy root cultures of Weigelia by overexpression of tryptophan decarboxylase and strictosidine synthase. Alkaloids could be produced in transgenic yeast overexpressing strictosidine synthase and strictosidine glucosidase growing on medium made out the juice of Symphoricarpus albus berries to which tryptamine is added. Metabolic engineering thus seems a promising approach to improve the production of a cell factory.
Alkaloids represent one of the largest classes of natural products produced not only by plants but also by marine animals and amphibia, certain bacteria and fungi. Their general function in plants and animals seems to be chemical defence against herbivorous and predating animals. In order to fulfil this function alkaloids had to be shaped during evolution (by a process termed “evolutionary molecular modelling”) in such a way that they can interfere with important molecular targets of animals. Neuronal signal transduction, especially interference with neuroreceptors, enzymes of neurotransmitter metabolism and signal transduction, and with ion channels represent such animal specific targets. This review summarizes the experimental data on the molecular interactions of more than 300 alkaloids with neuroreceptors and ion channels and interprets these results under evolutionary and applied aspects, such as their exploitation as medicinal compounds or biorational pesticides for agriculture.
Recent advances in the cell, developmental, and molecular biology of alkaloid biosynthesis have heightened our appreciation for the complexity and importance of plant secondary pathways. Several biosynthetic genes involved in the formation of tropane, benzylisoquinoline, and terpenoid indole alkaloids have now been isolated. The early events of signal perception, the pathways of signal transduction, and the function of gene promoters have been studied in relation to the regulation of alkaloid metabolism. Enzymes involved in alkaloid biosynthesis are associated with diverse subcellular compartments including the cytosol, vacuole, tonoplast membrane, endoplasmic reticulum, chloroplast stroma, thylakoid membranes, and perhaps unique "biosynthetic" or transport vesicles. Localization studies have shown that sequential alkaloid biosynthetic enzymes can also occur in distinct cell types, suggesting the intercellular transport of pathway intermediates. Isolated genes have also been used to genetically alter the accumulation of specific alkaloids and other plant secondary metabolites. Metabolic modifications include increased indole alkaloid levels, altered tropane alkaloid accumulation, elevated serotonin synthesis, reduced indole glucosinolate production, redirected shikimate metabolism, and increased cell wall-bound tyramine formation. This review discusses the biochemistry, cell biology, molecular regulation, and metabolic engineering of alkaloid biosynthesis in plants.
This chapter discusses the molecular mode of action of cytotoxic alkaloids. Alkaloids comprise a class of secondary metabolites. Alkaloids have evolved in plants as powerful defence compounds against herbivores. Although many of them interfere with neuroreceptors and neuronal signal transduction, several others have cytotoxic properties, directed against animal and microbial cells. The chapter summarizes some of the molecular targets that are involved in this process. Alkaloids that interfere with microtubules, with DNA (intercalation, topoisomerase inhibition), with protein biosynthesis, and with membrane stability, apparently induce apoptosis, thus leading to cell death. Because of the evolutionary selection processes, one can conclude that alkaloids and other SM produced by plants, animals, and microbes could be relevant molecules when searching for bioactive compounds against new drug targets. Many cytotoxic compounds, such as pyrroles, pyrazines, imidazoles, and other N-heterocyclic alkaloids, have been discovered in marine organisms, such as sponges, ascidians, tunicates, and molluscs; several have been tested as novel antitumor agents. In order to discover interesting active compounds from nature, one only have to search by selecting the appropriate organisms and using intelligent screening assays, including high throughput procedures.
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