Review on toxicology and activity of tomato glycoalkaloids in immature tomatoes.

Owing to the lack of selection and limited intelligence in mechanical picking, some immature tomatoes that contain alkaloids are thrown away. Tomatine alkaloids are steroidal alkaloids naturally present in Solanaceae plants, which are distributed in small amounts in immature tomato fruits and decrease as the fruits ripen. Tomato glycoalkaloids are harmful to human health. However, in small quantities, there is some evidence that these compounds might be beneficial, as other non-antioxidant bioactivities. This article considers recent research on the biological effects of tomato glycoalkaloids in immature tomatoes, providing reference value for the potential development of these compounds.

Exploring toxicological interactions in a changing sea: The case of the alkaloids caffeine and caulerpin.

The bisindolic alkaloid caulerpin (CAU) is a bioactive compound isolated from green algae of the genus Caulerpa that are highly invasive in the Mediterranean Sea. On the other side, the purine alkaloid caffeine (CAF) is one of the most globally consumed psychoactive substances and a widespread anthropogenic water pollutant. Both compounds display a large panel of biological properties and are well known to accumulate in the tissues of aquatic organisms and, in certain circumstances, co-occur in the human diet. On this premise, the present study aimed to investigate possible synergistic interactions between CAU and CAF by using the bivalve Mytilus galloprovincialis as a model organism. Mussels were exposed to CAF via medium while they were fed with food enriched with CAU. After treatments, biochemical analysis confirmed the toxic potential of CAF, with increased AChE activity and lipid peroxidation. Also, histopathological alterations were observed in the gills and digestive tubules. The NMR-based metabolomics analysis detected higher levels of free amino acids under CAF treatments. Conversely, the food administration of CAU did not affect the above toxicological biomarkers. In addition, we did not observe any cumulative effect between CAF and CAU toward increased cellular damage and neurotoxicity. On the other hand, a possible action of CAU in decreasing CAF toxicity could be hypothesized based on our results. This hypothesis is supported by the activity of CAU as an agonist of peroxisome proliferator-activated receptors (PPARs). PPARs mediate xenobiotic detoxification via cytochromes P450, which is involved in CAF metabolism. Overall, the results obtained not only rule out any cumulative adverse effects of CAF and CAU but also encourage further research to evaluate the possible use of CAU, a compound easily obtained through the valorization of biomass from invasive species, as a food additive to improve the clearance of xenobiotics.

Matrine and Oxymatrine: evaluating the gene mutation potential using in silico tools and the bacterial reverse mutation assay (Ames test).

The quinolizidine alkaloids matrine and its N-oxide oxymatrine occur in plants of the genus Sophora. Recently, matrine was sporadically detected in liquorice products. Morphological similarity of the liquorice plant Glycyrrhiza glabra with Sophora species and resulting confusion during harvesting may explain this contamination, but use of matrine as pesticide has also been reported. The detection of matrine in liquorice products raised concern as some studies suggested a genotoxic activity of matrine and oxymatrine. However, these studies are fraught with uncertainties, putting the reliability and robustness into question. Another issue was that Sophora root extracts were usually tested instead of pure matrine and oxymatrine. The aim of this work was therefore to determine whether matrine and oxymatrine have potential for causing gene mutations. In a first step and to support a weight-of-evidence analysis, in silico predictions were performed to improve the database using expert and statistical systems by VEGA, Leadscope (Instem®), and Nexus (Lhasa Limited). Unfortunately, the confidence levels of the predictions were insufficient to either identify or exclude a mutagenic potential. Thus, in order to obtain reliable results, the bacterial reverse mutation assay (Ames test) was carried out in accordance with OECD Test Guideline 471. The test set included the plate incorporation and the preincubation assay. It was performed with five different bacterial strains in the presence or absence of metabolic activation. Neither matrine nor oxymatrine induced a significant increase in the number of revertants under any of the selected experimental conditions. Overall, it can be concluded that matrine and oxymatrine are unlikely to have a gene mutation potential. Any positive findings with Sophora extracts in the Ames test may be related to other components. Notably, the results also indicated a need to extend the application domain of respective (Q)SAR tools to secondary plant metabolites.

Pharmacological and toxicological effects of Amaryllidaceae.

The Amaryllidaceae family is widely distributed in the tropics, presenting biological activity attributed mostly to alkaloids, such as an important inhibitory activity of acetylcholinesterase (AChE), antifungal, antibacterial, and cytotoxic activities. The present study aims to review the spectrum of action of the main biological activities and toxicity of secondary metabolites found in Amaryllidaceae through a literature review, using Prisma and the descriptors "Pharmacological effects of Amaryllidaceae" and "Amaryllidaceae family" and "Pharmacological actions of Amaryllidaceae", used in English and Portuguese. The literature search was done in March and May 2023. Original works published from 2012 to 2023, available in full, and presenting experimental and clinical studies were included. After the selection considering the inclusion and exclusion criteria, 60 articles fulfilled the defined criteria. From a pharmacological point of view, the highlight is due to the alkaloid galantamine, which has the potential- and is already used - for treating Alzheimer's. The toxicological aspect must be considered and evaluated carefully, as alkaloids have been associated with adverse effects such as nausea, vomiting, diarrhea, abdominal pain, and cardiovascular, neurological, and respiratory changes. Furthermore, some studies indicate that consuming these plants in significant quantities can lead to hepatic and renal toxicity. Therefore, the therapeutical use of this family's plant drugs and derivatives requires further studies to elucidate its effects and point out metabolites with therapeutic potential.

UPLC-Q-TOF-MS/MS-based urine metabolomics studies on the toxicity and detoxication of Tripterygium wilfordii Hook. f. after roasting.

Tripterygium wilfordii (TW), a well-known traditional Chinese medicine, was widely used in the treatment of autoimmune disorders and inflammatory diseases. However, the clinical use of TW was limited by severe toxicities, such as hepatotoxicity and nephrotoxicity. Our previous studies indicated that roasting was an effective approach for reducing TW-induced toxicity. After roasting, celastrol was completely decomposed, partially converted into 1-hydroxy-2,5,8-trimethyl-9-fluorenone and the total alkaloids content were significantly reduced. However, the detoxication mechanisms of roasting on TW were poorly unknown. This study aimed to explore the toxicity and detoxification mechanisms of TW after roasting based on urine metabolomics. Promising biomarkers were evaluated by multiple comparison analyses. Sixteen toxicity biomarkers were identified between control group and total extract group. Twelve toxicity biomarkers were identified between control group and total alkaloids group. Eight toxicity biomarkers were identified between control group and celastrol group. These metabolites were mainly involved in seven metabolic pathways, summarized as pentose and glucuronate interconversions, lipid metabolism (sphingolipid metabolism, glycerophospholipid metabolisms, fatty acid biosynthesis and steroid hormone biosynthesis) and amino acid metabolism (taurine and hypotaurine metabolism, tryptophan metabolism). After roasting, the toxicities of total extract, total alkaloids and celastrol were relieved by ameliorative serum parameters and pathological changes in hepatic and renal tissues which revealed that the reduction of celastrol and total alkaloids played important roles in the detoxification of roasting on TW. Furthermore, roasting regulated the levels of fourteen potential biomarkers in the total extract group, ten potential biomarkers in the total alkaloids group and seven candidate biomarkers in the celastrol group to normal levels. Biological pathway analysis revealed that roasting may ameliorate TW-induced metabolic disorders in pentose and glucuronate interconversions, lipid metabolism and amino acid metabolism. This study provided evidence for the application of roasting in TW.

Phytochemical screening and allelopathic potential of phytoextracts of three invasive grass species.

Undoubtedly, it is important to remain vigilant and manage invasive grasses to prevent their spread and mitigate their negative impact on the environment. However, these aggressive plants can also play a beneficial role in certain contexts. For example, several invasive grasses provide valuable forage for livestock and have disease control potential. Therefore, a research experiment was conducted to explore the pros and cons of this approach, not only for surrounding vegetation but also for human and animal disease control. The study is primarily focused on developing livestock feed, plant-derived herbicides, and an understanding of the phytotoxic effects of invasive species. All plant parts of Cenchrus ciliaris L., Polypogon monspeliansis L., and Dicanthium annulatum (Forssk.) Stapf, were tested for their phyto-chemical screening, proximate, and toxicity analysis which was caused by the methanolic extract of these grass species. Qualitative phytochemical screening tests were performed for proximate composition analysis and toxicity assessment essays. The phytochemical analysis revealed the positive results for alkaloids, flavonoids, coumarins, phenols, saponins, and glycosides, while negative for tannins. Comparison of proximate analysis intimated maximum moisture (10.8%) and crude fat (4.1%) in P. monspeliensis, whereas maximum dry matter (84.1%), crude protein (13.95%), crude fiber (11%), and ash (7.2%) in D. annulatum. Five (10, 100, 500, 100, 10,000 ppm) and three (10, 1000, 10,000 ppm) different concentrations of methanolic extract prepared from C. ciliaris, P. monspeliansis, and D. annulatum were used respectively for root inhibition and seed germination essay. Furthermore, three different concentrations (10, 30, 50 mg) of plant fine powder were used for sandwich method test. There was a significant decline in the growth rate of experimental model radish seeds (P > 0.005), and results from sandwich method tests showed suppressed growth of root hairs, inhibiting the anchoring of the radish seed. In comparison, results manifest that; P. monspeliansis indicated an upsurge of inhibition (66.58% at 10,000 ppm), D. annulatum revealed soar germination (75.86% in controlled conditions), and C. ciliaris exhibited dramatic shoot up of inhibition because of sandwich method test (14.02% at 50 mg). In conclusion, although grasses are toxic, it is important to consider the beneficiary account.

Toxicity of House Plants to Pet Animals.

Cases of ingestion of indoor poisonous plants are relatively common among animals and lead to both acute cases of poisoning and long-term exposure to harmful substances and chronic damage to the animal's health. Plants produce a large number of secondary metabolites, which serve to protect the plant from attacks by insects, parasitic plants, fungi or, for example, during reproduction. However, these metabolites can be toxic if ingested by animals or humans. Toxicologically effective components found in plants are mainly alkaloids, glycosides, saponins, terpenes and others. This review article describes in detail the most common and popular indoor poisonous plants grown in Europe, the mechanisms of action of their active substances and clinical signs of the respective poisonings. This manuscript is supplemented with rich photographic documentation of these plants not found in similar articles, and also includes a description of the treatment of individual types of poisoning.

Exploration of Synergistic Pesticidal Activities, Control Effects and Toxicology Study of a Monoterpene Essential Oil with Two Natural Alkaloids.

With the increasing development of pest resistances, it is not easy to achieve satisfactory control effects by using only one agrochemical. Additionally, although the alkaloid matrine (MT) isolated from Sophora flavescens is now utilized as a botanical pesticide in China, in fact, its pesticidal activities are much lower in magnitude than those of commercially agrochemicals. To improve its pesticidal activities, here, the joint pesticidal effects of MT with another alkaloid oxymatrine (OMT) (isolated from S. flavescens) and the monoterpene essential oil 1,8-cineole (CN) (isolated from the eucalyptus leaves) were investigated in the laboratory and greenhouse conditions. Moreover, their toxicological properties were also studied. Against Plutella xylostella, when the mass ratio of MT and OMT was 8/2, good larvicidal activity was obtained; against Tetranychus urticae, when the mass ratio of MT and OMT was 3/7, good acaricidal activity was obtained. Especially when MT and OMT were combined with CN, the significant synergistic effects were observed: against P. xylostella, the co-toxicity coefficient (CTC) of MT/OMT (8/2)/CN was 213; against T. urticae, the CTC of MT/OMT (3/7)/CN was 252. Moreover, the activity changes over time of two detoxification enzymes, carboxylesterase (CarE) and glutathione S-transferase (GST) of P. xylostella treated with MT/OMT (8/2)/CN, were observed. In addition, by scanning electron microscope (SEM), the toxicological study suggested that the acaricidal activity of MT/OMT (3/7)/CN may be related to the damage of the cuticle layer crest of T. urticae.

Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine.

OBJECTIVE: The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products. METHODS: The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products. RESULTS: Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity. CONCLUSION: Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.

Molluscicidal activity of plant alkaloids.

Some snail species pose a serious threat for human health, economy, and the environment due to their widespread distribution and the transmission of dangerous parasites causing, among others, schistosomiasis and fascioliasis. Scientists from around the world have been studying the effects of plant extracts on snails for many years in order to find an alternative to molluscicides of synthetic origin. The main purpose of this study was to collect the results obtained so far on the effect of plant alkaloids on snails in the context of their molluscicidal properties. This work presents the results of publications on the effect of plant alkaloids on snails, which were published in the years 1974-2021. The Solanaceae, Papaveraceae, and Asteraceae are the plant families most frequently cited for containing alkaloids with molluscicidal activity. The alkaloids identified as molluscicidal belonged to various groups, of which the most numerous were pseudoalkaloids and tyrosine-derived alkaloids. Most of the tested alkaloids were characterized by a high mortality rate among the studied groups of snails. Based on the collected research results, it was found that plant alkaloids can be extremely useful in the fight against problematic species of snails and cause much lower harm to the environment than synthetic molluscicides.

Identification of haemanthamine as a phytotoxic alkaloid in Narcissus pseudonarcissus L. (Daffodil) emerging buds.

Emerging buds of Narcissus pseudonarcissus were found to accumulate the alkaloid haemanthamine (1) at high concentrations, exceeding that of narciclasine (2), the most abundant constituent in bulbs of the plant. A phytoactivity screening assay demonstrated the novel phytotoxicity of haemanthamine against Raphanus sativus (radish), Lactuca sativus (lettuce), Triticum aestivum (red wheat), Solanum lycopersicum (tomato), Cucumis sativus (cucumber), Ipomoea (Morning glory), and Lens culinaris (lentil). Haemanthamine (1) phytotoxicity was found to exceed that of the commercial herbicide glyphosate and less toxic than narciclasine (2).

Sensitization of Guinea Pig Skin to Imported Fire Ant Alkaloids and Establishment of an Inflammatory Model.

Imported fire ants (IFAs), Solenopsis invicta, release their venom through multiple stings that induce inflammation, allergies, shock, and even death. Although IFA venom protein sensitization and related subcutaneous immunotherapy have been studied, few studies have examined the potential toxicity or pathogenicity of alkaloids, the main substances in IFA venom. Here, IFA alkaloids were identified and analyzed by gas chromatography-mass spectrometry; we further determined an appropriate extraction method and its effectiveness for extracting high-purity alkaloids through comparative analysis and guinea pig skin sensitivity tests. The alkaloids released from the IFA abdomen included those present in the head and thorax, and the alkaloids in the abdomen accounted for the highest proportion of the total extract. The abdominal extirpation method yielded alkaloids with a purity above 97%, and the skin irritation response score and histopathological diagnosis suggest that intradermal injection of the extracted alkaloids produced symptoms effectively simulating those of IFA stings. The successful establishment of an inflammatory model in guinea pigs stung by IFAs provides a basis for further research on the mechanism of inflammatory diseases caused by IFAs.

Glycoalkaloid Composition and Flavonoid Content as Driving Forces of Phytotoxicity in Diploid Potato.

Despite their advantages, biotechnological and omic techniques have not been applied often to characterize phytotoxicity in depth. Here, we show the distribution of phytotoxicity and glycoalkaloid content in a diploid potato population and try to clarify the source of variability of phytotoxicity among plants whose leaf extracts have a high glycoalkaloid content against the test plant species, mustard. Six glycoalkaloids were recognized in the potato leaf extracts: solasonine, solamargine, α-solanine, α-chaconine, leptinine I, and leptine II. The glycoalkaloid profiles of the progeny of the group with high phytotoxicity differed from those of the progeny of the group with low phytotoxicity, which stimulated mustard growth. RNA sequencing analysis revealed that the upregulated flavonol synthase/flavonone 3-hydroxylase-like gene was expressed in the progeny of the low phytotoxicity group, stimulating plant growth. We concluded that the metabolic shift among potato progeny may be a source of different physiological responses in mustard. The composition of glycoalkaloids, rather than the total glycoalkaloid content itself, in potato leaf extracts, may be a driving force of phytotoxicity. We suggest that, in addition to glycoalkaloids, other metabolites may shape phytotoxicity, and we assume that these metabolites may be flavonoids.

Evaluation of the Local Anesthetic Activity, Acute Toxicity, and Structure-Toxicity Relationship in Series of Synthesized 1-Aryltetrahydroisoquinoline Alkaloid Derivatives In Vivo and In Silico.

Isoquinoline alkaloids constitute one of the most common classes of alkaloids that have shown a pronounced role in curing various diseases. Finding ways to reduce the toxicity of these molecules and to increase their therapeutic margin is an urgent matter. Here, a one-step method for the synthesis of a series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines was performed in 85-98% yield by the Pictet-Spengler reaction. This was accomplished using the reaction between 3,4-dimethoxyphenylethylamine and substituted benzaldehydes boiling in trifluoroacetic acid. Furthermore, 1-(3'-amino-, 4'-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were obtained in 94% and 97% yield by reduction in 1-(3'-nitro-, 4'-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines with SnCl2 × 2H2O. The structures of the substances obtained were confirmed by infrared (IR) and nuclear magnetic resonance (1H and 13C NMR) spectra. ADMET/TOPKAT in silico study concluded that the synthesized compounds exhibited acceptable pharmacodynamic and pharmacokinetic properties without carcinogenic or mutagenic potential but with variable hepatotoxicity. The acute toxicity and structure-toxicity relationship (STR) in the series of 20 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (3a-r, 4a, b) was studied via determination of acute toxicity and resorptive action in white mice employing intragastric step-by-step administration. The first compound, 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a), showed the highest toxicity with LD50 of 280 mg/kg in contrast to 1-(3'-bromo -4'-hydroxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3e) which proved to be the safest of the compounds studied. Its toxicity was 13.75 times lower than that of the parent compound 3a. All compounds investigated showed high local anesthetic activity on rabbit eyes in the concentrations studied. Only 3r, 3n, and 4a caused eye irritation and redness. All investigated derivatives (except 4b) in 1% concentration were more active than lidocaine, providing longer duration of complete anesthesia. Therefore, based on the obtained results of in silico tests, local anesthesia, and acute toxicity, a conclusion can be drawn that the experimental compounds need further extensive future investigations and possible modifications so that they can act as promising drug candidates.

Effect of CYP3A inducer/inhibitor and licorice on hepatotoxicity and in vivo metabolism of main alkaloids of Euodiae Fructus based on UPLC-Q-Exactive-MS.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism, but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing. AIM OF THE STUDY: The poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP). MATERIALS AND METHODS: Rats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and Orthogonal Partial Least Squares Discriminant Analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups. RESULTS: EF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group. CONCLUSION: Licorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity.

Mutagenic potential and structural alerts of phytotoxins.

Toxic plant-produced chemicals, so-called phytotoxins, constitute a category of natural compounds belonging to a diversity of chemical classes. Some of them (e.g., alkaloids, terpenes, saponins) are associated with high toxic potency, while for many of others no toxicological data is available. In this study, the mutagenic potential of 1586 phytotoxins, as obtained from a publicly available database, was investigated applying different in silico approaches. (Q)SAR models (including statistical-based and rule-based systems) were used for the prediction of bacterial in vitro mutagenicity (Ames test) and the results from multiple tools were combined to assign consensus predicted values (i.e., positive, negative, inconclusive). The overall consensus outcome was then employed to investigate relationships between structural features of classes of phytotoxins and potential mutagenicity, allowing the identification of structural alerts raising a specific concern. The results highlighted that about 10% of the screened compounds were predicted to have mutagenic potential and the critical classes of concern, such as alkaloids, were further investigated in terms of subclasses (e.g., indole alkaloids, isoquinoline alkaloids), getting a deeper insight into the mutagenic potential of possible naturally occurring chemicals in plant materials and their structural alerts.

Potential health risk of areca nut consumption: Hazardous effect of toxic alkaloids and aflatoxins on human digestive system.

Contemporarily, there has been a growing consumption rate of areca nut (AN) products worldwide, despite the fact that both fresh and processed AN contain various hazardous ingredients, including toxic alkaloids and carcinogenetic aflatoxins. However, there is a dearth of toxicity and potential cancer risk information regarding toxic alkaloids and aflatoxins via consuming AN products. The present study conducted a comprehensive assessment of the combined hazardous effects of AN alkaloids and aflatoxins towards human digestive system, by methods of HPLC analysis, cell study and in vitro digestive system study. The results revealed a synergetic effect of arecoline and aflatoxins was on human gingival normal fibroblast cell of HGF-1 and a proliferation effect on human tongue squamous carcinoma cell of CAL-27. Specifically, the residual arecoline was as high as 91.08 µg·ml-1 in oral phase and 72.41 µg·ml-1 in gastric phase, which could be an evidence of oral cancer. More importantly, 25.93 % of AN products were contaminated with aflatoxins and the maximum value was three times the MRLs. Under these circumstances, the cytotoxic and MOE values raised a considerable health concern in terms of malignancy risk for children that consume processed AN product, especially compared to scenarios that involve adults and/or fresh AN samples. This study would give rise to a better understanding of the hazards associated with AN alkaloids and aflatoxins towards digestive system, and thus to predict the potential carcinogenic risk of AN products.

Endogenous Synthesis of Tetrahydroisoquinoline Derivatives from Dietary Factors: Neurotoxicity Assessment on a 3D Neurosphere Culture.

Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume that an acute or chronic exposure to some THIQs might lead to neurodegenerative diseases including essential tremor (ET). We developed a method to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to study their reactivity with endogenous amines and identify the reaction products. Then, we predicted in silico their pharmacokinetic and toxicological properties toward the central nervous system. Finally, their possible neurological effects on a novel in vitro 3D neurosphere model were assessed. The obtained data indicate that meat is an alkaloid precursor, and we identified the alkaloid 1-benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol (1-benz-6,7-diol THIQ) as the condensation product of phenylacetaldehyde with dopamine; in silico study of 1-benz-6,7-diol-THIQ reveals modulation of dopamine receptor D1 and D2; and in vitro study of 1-benz-6,7-diol-THIQ for cytotoxicity and oxidative stress induction does not show any difference after 24 h contact for all tested concentrations. To conclude, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol-THIQ.

Evaluation of Acute and Subacute Toxicity and LC-MS/MS Compositional Alkaloid Determination of the Hydroethanolic Extract of Dysphania ambrosioides (L.) Mosyakin and Clemants Flowers.

Dysphania ambrosioides (L.) Mosyakin and Clemants is a medicinal plant that has traditionally been used to cure a range of diseases. There has been no thorough investigation of the potential toxicity of this plant. The objective of this study is to assess the acute and subacute toxicity of D. ambrosioides hydroethanolic extract (DAHE), as well as it alkaloids composition, utilizing LC-MS/MS analysis. An in silico approach was applied to determine pharmacokinetic parameters and to predict the toxicity of D. ambrosioides identified alkaloids. A 14-day treatment with a single oral dose of 1-7 g/kg was carried out to investigate acute toxicity. DAHE was given orally at dosages of 5, 50, and 500 mg/kg for 15 days in the subacute toxicity investigation, and body weight and biochemical parameters were evaluated. Livers, kidneys, lungs, and heart were examined histologically. Chromatographic investigation revealed the existence of nine alkaloids, with N-formylnorgalanthamine being the most prevalent. The oral LD50 value of DAHE was found to be 5000 mg/kg in an acute toxicity study. No variations were observed with respect to food intake, water consumption, mortality, or body and organ weight in the subacute toxicity study. On the other hand, DAHE (500 mg/kg) significantly enhanced alanineaminotransferase, aspartate aminotransferase, and urea. Liver and kidney histological examinations revealed modest infiltration of hepatocyte trabeculae by inflammatory cells in the liver and slight alteration in the kidney histoarchitecture. According to our findings, DAHE exhibits low to moderate toxicity.

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

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure-activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (-10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition.