RESUMO
Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.
Assuntos
Pirazóis , Trypanosoma cruzi , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Humanos , Trypanosoma cruzi/efeitos dos fármacos , Antiparasitários/farmacologia , Antiparasitários/síntese química , Antiparasitários/química , Desenho de Fármacos , Leishmania infantum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/químicaRESUMO
BACKGROUND: Benznidazole is an effective drug in the trypanocidal treatment of acute and chronic indeterminate Chagas' disease (CD). However, adverse drug reactions (ADR) are common and frequently cause patients to discontinue treatment. OBJECTIVES: We hypothesized that antioxidant supplementation could mitigate benznidazole-induced toxicity. METHODS: We co-supplemented an adult traveller with chronic indeterminate CD who experienced benznidazole ADR with ascorbic acid (AA), 1000â mg/day. We measured selected serum biomarkers of oxidative stress [total antioxidant status (TAS), total oxidative status (TOS), nuclear factor erythroid 2-related factor 2 (Nrf2), malondialdehyde (MDA), extracellular glutathione peroxidase (GPX3), catalase (CAT) and total superoxide dismutase (T-SOD)] at timepoints before and throughout benznidazole treatment and after AA co-supplementation. RESULTS: AA co-supplementation effectively mitigated benznidazole-induced ADR during the aetiological treatment of chronic indeterminate CD. The kinetics of serum biomarkers of oxidative stress suggested significantly decreased oxidative insult in our patient. CONCLUSIONS: We hypothesize that the key pathophysiological mechanism of benznidazole-associated toxicity is oxidative stress, rather than hypersensitivity. AA co-supplementation may improve adherence to benznidazole treatment of chronic indeterminate (or acute) CD. Oxidative stress biomarkers have the potential to guide the clinical management of CD. Prospective studies are needed to establish the benefit of antioxidant co-supplementation to benznidazole treatment of CD in reducing benznidazole toxicity, parasite clearance and the prevention of end-organ damage.
Assuntos
Doença de Chagas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nitroimidazóis , Adulto , Antioxidantes/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Biomarcadores , Doença de Chagas/tratamento farmacológico , Suplementos Nutricionais , Humanos , Nitroimidazóis/efeitos adversos , Estresse OxidativoRESUMO
It is well known that biotransformation processes in the human body are crucial to form potentially bioactive metabolites from particular classes of natural products. However, little research has been conducted concerning the bioavailability of polyphenols, especially in the colon. The gastrointestinal stability and colonic biotransformation of the crude extract of the leaves of Cecropia obtusifolia, rich in flavone C-glycosides, was investigated under in vitro conditions, and the processing and interpretation of results were facilitated by using an automated machine learning model. This investigation revealed that flavone C-glycosides and flavonolignans from C. obtusifolia were stable throughout their passage in the simulated gastrointestinal tract including the colon phase. On the other hand, the colon bacteria extensively metabolized chlorogenic acid, flavonol, and triterpenoid O-glycosides. This investigation revealed that the colonic microbiota has an important role in the biotransformation of some chemical constituents of this extract.
Assuntos
Flavonolignanos , Saponinas , Triterpenos , Biotransformação , Ácido Clorogênico/metabolismo , Flavonoides/metabolismo , Flavonolignanos/metabolismo , Trato Gastrointestinal/metabolismo , Saponinas/metabolismo , Triterpenos/metabolismoRESUMO
In this study, we critically review the literature concerning the relation of Mg, Fe, Zn, Cu and Se and attention-deficit/hyperactivity disorder (ADHD). Elemental status is estimated using peripheral blood parameters, hair, urine, daily intake and response to supplementation. The observed associations between concentration levels of the elements Mg, Fe, Zn, Cu and Se and ADHD symptoms are contradictory. This is partly due to the heterogeneity and complexity of the disorder. As a trend, lower ferritin and zinc levels can be observed. However, this correlation is not causative, as illustrated by placebo-controlled trials reporting conflicting evidence on the efficacy of supplementation. Well-defined studies on changes in concentration levels of the elements in relation to ADHD symptoms before and after treatment with therapeutics it will be possible to shed more light on the significance of these elements in this behavioral disorder. The discussion on whether a change in concentration of an element is cause or consequence of ADHD is not within the scope of this article.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Cobre , Ferro , Magnésio , Selênio , Zinco , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Cobre/metabolismo , Cobre/uso terapêutico , Humanos , Ferro/metabolismo , Ferro/uso terapêutico , Magnésio/metabolismo , Magnésio/uso terapêutico , Selênio/metabolismo , Selênio/uso terapêutico , Zinco/metabolismo , Zinco/uso terapêuticoRESUMO
Nuclear Magnetic Resonance (NMR) spectroscopy is, together with liquid chromatography-mass spectrometry (LC-MS), the most established platform to perform metabolomics. In contrast to LC-MS however, NMR data is predominantly being processed with commercial software. Meanwhile its data processing remains tedious and dependent on user interventions. As a follow-up to speaq, a previously released workflow for NMR spectral alignment and quantitation, we present speaq 2.0. This completely revised framework to automatically analyze 1D NMR spectra uses wavelets to efficiently summarize the raw spectra with minimal information loss or user interaction. The tool offers a fast and easy workflow that starts with the common approach of peak-picking, followed by grouping, thus avoiding the binning step. This yields a matrix consisting of features, samples and peak values that can be conveniently processed either by using included multivariate statistical functions or by using many other recently developed methods for NMR data analysis. speaq 2.0 facilitates robust and high-throughput metabolomics based on 1D NMR but is also compatible with other NMR frameworks or complementary LC-MS workflows. The methods are benchmarked using a simulated dataset and two publicly available datasets. speaq 2.0 is distributed through the existing speaq R package to provide a complete solution for NMR data processing. The package and the code for the presented case studies are freely available on CRAN (https://cran.r-project.org/package=speaq) and GitHub (https://github.com/beirnaert/speaq).
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Algoritmos , Cromatografia Líquida/métodos , Imageamento por Ressonância Magnética/métodos , Software , Fluxo de TrabalhoRESUMO
The objective of this study is to compare oxidative stress and immune biomarkers between attention-deficit/hyperactivity disorder (ADHD) patients and controls without ADHD. A case-control comparison between 57 paediatric (6-12 years) untreated ADHD patients from the Antwerp University Hospital and 69 controls without ADHD from random schools in Flanders, Belgium, was conducted. Erythrocyte glutathione (GSH) and plasma lipid-soluble antioxidants (retinol, α-tocopherol, γ-tocopherol, retinyl palmitate, ß-carotene, and co-enzyme Q10) were determined by HPLC with electrochemical detection, plasma malondialdehyde (MDA) by HPLC with fluorescence detection, plasma cytokines (interleukin (IL)-1ß, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF) and interferon (INF)-γ) and immunoglobulins (IgE, IgG and IgM) by flow cytometry and urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels by ELISA assay. Dietary habits were determined by a food frequency questionnaire. Plasma MDA levels were on average 0.031 µM higher in patients than in controls (p < 0.05), and a trend for higher urinary 8-OHdG was observed. Erythrocyte GSH and plasma retinyl palmitate levels, as well as IgG and IgE levels, were higher in patients than in controls as well (on average 93.707 µg/ml, 0.006 µg/ml, 301.555 µg/ml and 125.004 µg/ml, resp., p < 0.05). Finally, a trend for lower plasma IL-5 levels was observed. After Bonferroni correction for multiple testing, the difference in GSH levels remained statistically significant (nominally significant for retinyl palmitate), while significance was lost for MDA, IgG and IgE levels. Dietary habits do not appear to cause the observed differences. These results point at the potential involvement of slight oxidative stress and immune disturbances in ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Dieta/métodos , Imunidade/imunologia , Estresse Oxidativo/imunologia , Estudos de Casos e Controles , Criança , Feminino , Humanos , MasculinoRESUMO
Iron, zinc and vitamin A deficiencies are serious public health problems in sub-Saharan Africa, which can be alleviated by dietary diversification. The effects of adding cowpea leaf (CL) and orange-fleshed sweet potato (OFSP) relishes to sorghum and maize porridges on iron, zinc and ß-carotene contents and bioaccessibilities were determined. Despite the high iron content of the CL relish (14.59 mg/100 g), the vegetable relishes had little effect on the iron bioaccessibility from the cereal porridges. Importantly, the addition of the CL relish increased the percentage and amount of bioaccessible zinc 2- and 3-fold, respectively. Addition of CL and OFSP relishes resulted in ß-carotene contents of 10-13 mg/100 g. The ß-carotene from the OFSP relish meals was double as bioaccessible than that from the CL relish meals. Addition of the vegetable relishes has real potential to improve especially the vitamin A and zinc nutritive value of cereal diets.
Assuntos
Grão Comestível/química , Ferro/análise , Valor Nutritivo , Verduras/química , Zinco/análise , beta Caroteno/análise , África Subsaariana , Disponibilidade Biológica , Dieta , Humanos , Mucosa Intestinal/metabolismo , Ipomoea batatas/química , Refeições , Fenol/análise , Ácido Fítico/análise , Sorghum/química , Vigna/química , Vitamina A/análise , Zea mays/químicaRESUMO
There is a rapid increase in the percentage of elderly people in Europe. Consequently, the prevalence of age-related diseases will also significantly increase. Therefore, the main goal of MediHealth, an international research project, is to introduce a novel approach for the discovery of active agents of food plants from the Mediterranean diet and other global sources that promote healthy ageing. To achieve this goal, a series of plants from the Mediterranean diet and food plants from other origins are carefully selected and subjected to in silico, cell-based, in vivo (fly and mouse models), and metabolism analyses. Advanced analytical techniques complement the bio-evaluation process for the efficient isolation and identification of the bioactive plant constituents. Furthermore, pharmacological profiling of bioactive natural products, as well as the identification and synthesis of their metabolites, is carried out. Finally, optimization studies are performed in order to proceed to the development of innovative nutraceuticals, dietary supplements or herbal medicinal products. The project is based on an exchange of researchers between nine universities and four companies from European and non-European countries, exploiting the existing complementary multidisciplinary expertise. Herein, the unique and novel approach of this interdisciplinary project is presented.
Assuntos
Produtos Biológicos/química , Dieta Mediterrânea , Suplementos Nutricionais/análise , Envelhecimento Saudável/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Plantas Comestíveis/química , Animais , Disponibilidade Biológica , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/fisiologia , Envelhecimento Saudável/fisiologia , Humanos , Comunicação Interdisciplinar , Cooperação Internacional , Camundongos , Camundongos Endogâmicos C57BL , Ciências da Nutrição/instrumentação , Ciências da Nutrição/métodos , Compostos Fitoquímicos/química , Plantas Medicinais/químicaRESUMO
Hymenocardine is a cyclopeptide alkaloid present in the root bark of Hymenocardia acida. In traditional African medicine, the leaves and roots of this plant are used to treat malaria, and moderate in vitro antiplasmodial activity has been reported for hymenocardine. However, in view of its peptide-like nature, potential metabolisation after oral ingestion has to be taken into account when considering in vivo experiments. In this study, the stability and small intestinal absorption of hymenocardine was assessed using an in vitro gastrointestinal dialysis model. In addition, potential liver metabolisation was investigated in vitro by incubation with a human S9 fraction. Moreover, hymenocardine was administered to rats per os, and blood and urine samples were collected until 48 and 24 h after oral administration, respectively. All samples resulting from these three experiments were analyzed by LC-MS. Analysis of the dialysate and retentate, obtained from the gastrointestinal dialysis model, indicated that hymenocardine is absorbed unchanged from the gastrointestinal tract, at least in part. After S9 metabolisation, several metabolites of hymenocardine could be identified, the major ones being formed by the reduction and/or the loss of an N-methyl group. The in vivo study confirmed that hymenocardine is absorbed from the gastrointestinal tract unchanged, since it could be identified in both rat plasma and urine, together with hymenocardinol, its reduction product.
Assuntos
Alcaloides/metabolismo , Embriófitas/química , Absorção Gastrointestinal , Peptídeos Cíclicos/metabolismo , Extratos Vegetais/metabolismo , Alcaloides/sangue , Alcaloides/química , Alcaloides/urina , Animais , Fracionamento Químico , Humanos , Fígado/metabolismo , Masculino , Medicinas Tradicionais Africanas , Estrutura Molecular , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/química , Peptídeos Cíclicos/urina , Extratos Vegetais/sangue , Extratos Vegetais/química , Extratos Vegetais/urina , Ratos , Ratos WistarRESUMO
The impact of the normal whole diet in different countries and of special types of diet on the biomarkers of the metabolic syndrome (MetS) is reviewed. Diet type, specification, risk of MetS and studied biomarkers, as far as could be traced, are included. Critical points in published studies are mentioned. Description of the traditional dietary patterns for the various countries is not always well-defined and numbers of persons in the studied population are sometimes quite limited, which hamper drawing definite conclusions. Since a Nordic diet, a dietary approach to stop hypertension (DASH), and especially a Mediterranean diet are quite promising, due to its health claims, the food pattern is studied more in detail and a large spectrum of vegetarian diets are included as well. Most of the time lipid profile and high sensitive C-reactive protein (hsCRP) are the studied biomarkers in response to diet intake.
Assuntos
Dieta/efeitos adversos , Síndrome Metabólica/metabolismo , Biomarcadores , Saúde Global , HumanosRESUMO
Filipendula ulmaria (meadowsweet) is traditionally used for the treatment of inflammatory diseases and as a diuretic and antirheumatic. Extracts of Filipendulae herba are on the market in the European Union as food supplements. Nevertheless, its active constituents remain to be revealed. During this study, the phytochemical composition of Filipendulae Ulmariae Herba was comprehensively characterised for the first time with two complementary generic ultrahigh-performance liquid chromatography-photodiode array-accurate mass mass spectrometry methods. Selective ion fragmentation experiments with a hybrid quadrupole-orbital trap mass spectrometer significantly contributed to compound identification: a total of 119 compounds were tentatively identified, 69 new to F. ulmaria. A rich diversity of phenolic constituents was detected and only a few non-phenolic phytochemicals were observed. Metabolisation and pharmacological studies should be conducted to investigate which of these constituents or metabolites there of contribute to the activity of F. ulmaria after oral intake.
Assuntos
Cromatografia Líquida/métodos , Filipendula/química , Espectrometria de Massas em Tandem/métodos , Flavonoides/análise , Flavonoides/química , Fenóis/análise , Fenóis/química , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Fitosteróis/análise , Fitosteróis/química , Plantas Medicinais/química , Proantocianidinas/análise , Proantocianidinas/químicaRESUMO
The biological effects of polyphenols depend on their mechanism of action in the body. This is affected by bioconversion by colon microbiota and absorption of colonic metabolites. We developed and validated an in vitro continuous flow dialysis model with colon phase (GastroIntestinal dialysis model with colon phase) to study the gastrointestinal metabolism and absorption of phenolic food constituents. Chlorogenic acid was used as model compound. The physiological conditions during gastrointestinal digestion were mimicked. A continuous flow dialysis system simulated the one-way absorption by passive diffusion from lumen to mucosa. The colon phase was developed using pooled faecal suspensions. Several methodological aspects including implementation of an anaerobic environment, adapted Wilkins Chalgren broth medium, 1.10(8) CFU/mL bacteria suspension as inoculum, pH adaptation to 5.8 and implementation of the dialysis system were conducted. Validation of the GastroIntestinal dialysis model with colon phase system showed a good recovery and precision (CV < 16â%). Availability of chlorogenic acid in the small intestinal phase (37 ± 3â%) of the GastroIntestinal dialysis model with colon phase is comparable with in vivo studies on ileostomy patients. In the colon phase, the human faecal microbiota deconjugated chlorogenic acid to caffeic acid, 3,4-dihydroxyphenyl propionic acid, 4-hydroxybenzoic acid, 3- or 4-hydroxyphenyl acetic acid, 2-methoxy-4-methylphenol and 3-phenylpropionic acid. The GastroIntestinal dialysis model with colon phase is a new, reliable gastrointestinal simulation system. It permits a fast and easy way to predict the availability of complex secondary metabolites, and to detect metabolites in an early stage after digestion. Isolation and identification of these metabolites may be used as references for in vivo bioavailability experiments and for investigating their bioactivity in in vitro experiments.
Assuntos
Ácido Clorogênico/metabolismo , Colo/fisiologia , Microbiota/fisiologia , Polifenóis/metabolismo , Disponibilidade Biológica , Ácidos Cafeicos/metabolismo , Cresóis/metabolismo , Diálise , Digestão , Fezes/microbiologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/fisiologia , Humanos , Ileostomia , Modelos Biológicos , Parabenos/metabolismo , Fenóis/metabolismo , Fenilpropionatos/metabolismoRESUMO
BACKGROUND: Metabolic syndrome (MetS) comprises a spectrum of clinical phenotypes in which dyslipidemia, dysglycemia and hypertension are clustered and where all share a high level of oxidative stress and an increased risk of cardiovascular disease. This study examines the effect of a nutritional supplement combining red yeast rice and olive fruit extract on the lipid profile and on oxidative stress in a population of patients with MetS. METHODS: In a double blind placebo controlled randomized trial, 50 persons with MetS, as defined by the ATPIII criteria, received the study product or placebo for 8 weeks. The study product contained 10.82 mg of monacolins and 9,32 mg of hydroxytyrosol per capsule, and is commercialized as Cholesfytol plus. The primary outcome measure was the difference in LDL reduction between intervention and control groups. Furthermore, differences in changes of CH, HDL, ApoA1, ApoB, HbA1c and oxLDL were measured, as well as side-effects, CK elevation, changes in clinical parameters and in cardiovascular risk. RESULTS: In the intervention group, LDL cholesterol was lowered by 24% whereas it increased by 1% in the control group (p < 0.001). Other effects observed were a change in total cholesterol (-17% in the intervention group vs +2% in the control group, p < 0.001), apolipoprotein B (-15% vs +6%, p < 0.001), and TG (-9% vs + 16%, p = 0.02). Oxidized LDL decreased by 20% vs an increase of 5% in the control group (p < 0.001). Systolic and diastolic arterial blood pressure decreased significantly by 10 mmHg (vs 0% in the control group, p = 0.001) and 7 mmHg (vs 0% in the control group, p = 0.05) respectively. One person in the intervention group, who suffered from Segawa's syndrome, dropped out because of severe muscle ache. CONCLUSIONS: The combination of active products in this study may be an alternative approach to statins in people who do not need, or cannot or do not want to be treated with chemical statins. Side effects, effects on oxidative stress and on glucose metabolism need to be examined more thoroughly. TRIAL REGISTRATION: Clinicaltrials.gov NCT02065180 (February 2014).
Assuntos
Produtos Biológicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Síndrome Metabólica/tratamento farmacológico , Olea/química , Extratos Vegetais/uso terapêutico , Adulto , Produtos Biológicos/farmacologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Colesterol/sangue , LDL-Colesterol/sangue , Suplementos Nutricionais , Método Duplo-Cego , Dislipidemias/tratamento farmacológico , Feminino , Frutas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas LDL/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Fitoterapia , Extratos Vegetais/farmacologia , Fatores de RiscoRESUMO
Both advanced glycation endproducts and advanced lipoxidation endproducts are implicated in many age-related chronic diseases and in protein ageing. In this study, kawain, methysticin, and dihydromethysticin, all belonging to the group of kavalactones, were identified as advanced glycation endproduct inhibitors. With IC50 values of 43.5 ± 1.2 µM and 45.0 ± 1.3 µM for kawain and methysticin, respectively, the compounds inhibited the in vitro protein glycation significantly better than aminoguanidine (IC50 = 231.0 ± 11.5 µM; p = 0.01), an established reference compound. Kawain and methysticin also inhibited the formation of dicarbonyl compounds, which are intermediates in the process of advanced glycation endproduct formation. Similarly, kawain and aminoguanidine prevented the formation of thiobarbituric reactive substances in both low-density lipoprotein and linoleic acid oxidation. Moreover, kawain and aminoguanidine prevented advanced glycation endproduct formation by chelating Fe(3+) and Cu(2+) two to three times better than aminoguanidine. Furthermore, kawain increased the mean life span of Caenorhabditis elegans exposed to high glucose. With glycation inhibiting, lipid peroxidation inhibiting, metal chelating properties, and life span extending ability, kavalactones show a high potential as advanced glycation endproducts and advanced lipoxidation endproduct inhibitors.
Assuntos
Produtos Finais de Glicação Avançada/antagonistas & inibidores , Guanidinas/farmacologia , Lactonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Piranos/farmacologia , Pironas/farmacologia , Animais , Caenorhabditis elegans , Quelantes/farmacologia , Glucose/administração & dosagem , Glucose/metabolismo , Glicosilação/efeitos dos fármacos , Ácido Linoleico/metabolismo , Lipoproteínas LDL/metabolismo , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Attention-deficit hyperactivity disorder (ADHD) etiology is not completely understood, but common comorbid dysfunction of the gastrointestinal and immune system suggests that these systems may be affected by a common genetic background and molecular mechanisms. For example, increased levels of specific cytokines were observed in ADHD. Moreover, ADHD has a high comorbidity with both Th1- and Th2-mediated disorders like ear infections, eczema and asthma. A common pathophysiological mechanism was suggested to underlie both asthma and ADHD, while several genes that are linked to ADHD have immune functions. Furthermore, immunological recognition of food provoking ADHD-like behavior was suggested. An immune imbalance, probably requiring a predisposing genetic background, is therefore suggested to contribute to ADHD etiology, with immune dysregulation being more likely than a single subcellular defect. However, next to allergic mechanisms, also pharmacological mechanisms (especially in case of food additives) might be involved. In addition, though cellular (cytokine-related) rather than antibody-mediated immune mechanisms seem involved, specific immune-inflammatory markers other than antibodies have not been systematically studied in ADHD. Substantial alterations implicated in ADHD apparently occur in the immune system and epigenetic regulation of gene expression. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation. If immune pathways contribute to ADHD, both its diagnosis and treatment should be reconsidered. Modulation of immune system activity might have potential in ADHD treatment, for example by nutritional approaches providing safe and low-cost ADHD therapy, but further research in these fields is implicated.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/dietoterapia , Transtorno do Deficit de Atenção com Hiperatividade/imunologia , Imunomodulação , Estado Nutricional/imunologia , Criança , HumanosRESUMO
Global aflatoxin contamination of agricultural commodities is of the most concern in food safety and quality. This study investigated the hepatoprotective effect of 80% methanolic leaf extract of Annona senegalensis against aflatoxin B1 (AFB1)-induced toxicity in rats. A. senegalensis has shown to inhibit genotoxicity of aflatoxin B1 in vitro. The rats were divided into six groups including untreated control, aflatoxin B1 only (negative control); curcumin (positive control; 10 mg/kg); and three groups receiving different doses (100 mg/kg, 200 mg/kg, and 300 mg/kg) of A. senegalensis extract. The rats received treatment (with the exception of untreated group) for 7 days prior to intoxication with aflatoxin B1. Serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, and creatinine were measured. Hepatic tissues were analysed for histological alterations. Administration of A. senegalensis extract demonstrated hepatoprotective effects against aflatoxin B1-induced toxicity in vivo by significantly reducing the level of serum aspartate aminotransferase and alanine aminotransferase and regenerating the hepatocytes. No significant changes were observed in the levels of alkaline phosphatase, lactate dehydrogenase, and creatinine for the AFB1 intoxicated group, curcumin+AFB1 and Annona senegalensis leaf extract (ASLE)+AFB1 (100 mg/kg, 200 mg/kg, and 300 mg/kg body weight [b.w.]) treated groups. Annona senegalensis is a good candidate for hepatoprotective agents and thus its use in traditional medicine may at least in part be justified.Contribution: The plant extract investigated in this study can be used in animal health to protect the organism from toxicity caused by mycotoxins.
Assuntos
Annona , Curcumina , Ratos , Animais , Aflatoxina B1/toxicidade , Curcumina/farmacologia , Alanina Transaminase/farmacologia , Fosfatase Alcalina/farmacologia , Creatinina/farmacologia , Fígado , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Aspartato Aminotransferases/farmacologia , Lactato DesidrogenasesRESUMO
The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol's role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE-/- fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features, such as large necrotic cores, high levels of inflammation, and intraplaque neovascularization, that resemble the unstable phenotype of human plaques. ApoE-/- Fbn1C1039G+/- mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE-/- Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.
RESUMO
Ferroptosis is a type of regulated necrosis that is associated with iron-dependent accumulation of lipid hydroperoxides. Given that iron deposition and lipid peroxidation initiate ferroptosis in atherosclerosis and contribute to further plaque development, we hypothesized that inhibition of ferroptosis could be of value in the treatment of atherosclerosis. Glutathione peroxidase 4 (GPX4) is the only enzyme known capable of reducing lipid hydroperoxides. Previous studies have demonstrated that inactivation of GPX4 results in ferroptosis, while overexpression of GPX4 confers resistance to ferroptosis. In the present study, we examined the impact of GPX4 overexpression on the development of atherosclerotic plaques. GPX4-overexpressing mice (GPX4Tg/+) were crossbred with ApoE-/- mice and fed a western-type diet for 16 weeks. Atherosclerotic plaques of GPX4Tg/+ ApoE-/- mice showed increased GPX4 expression and a reduced amount of lipid hydroperoxides. However, plaque size and composition were not different as compared to control animals. Similarly, GPX4-overexpressing vascular smooth muscle cells and bone marrow-derived macrophages were not protected against lipid peroxidation and cell death triggered by the ferroptosis inducers erastin and 1S,3R-RSL3. We concluded that GPX4 overexpression reduces lipid peroxidation in plaques of ApoE-/- mice, yet GPX4 overexpression is not sufficiently powerful to change plaque size or composition.
RESUMO
Catechins have proven to have several health benefits, yet a huge interindividual variability occurs. The metabolic potency of the colonic microbiota towards catechin is a key determinant of this variability. Microbiota from two donors - previously characterized as a fast and a slow converter- were incubated with (+)-catechin in vitro. The robustness of in vitro metabolic profiles was verified by well-fitted human trials. The colon region-dependent and donor-dependent patterns were reflected in both metabolic features and colonic microbiota composition. Upstream and downstream metabolites were mainly detected in the proximal and distal colons, respectively, and were considered important explanatory variables for microbiota clustering in the corresponding colon regions. Higher abundances of two catechin-metabolizing bacteria, Eggerthella and Flavonifractor were found in the distal colon compared to the proximal colon and in slow converter than fast converter. Additionally, these two bacteria were enriched in treatment samples compared to sham treatment samples.
Assuntos
Catequina , Microbioma Gastrointestinal , Microbiota , Humanos , Catequina/metabolismo , Colo/microbiologia , Bactérias/genética , Bactérias/metabolismo , MetabolomaRESUMO
Saponin-rich sea cucumber extracts have shown antidiabetic effects in a few reports. Although the triterpene glycosides of sea cucumbers are commonly isolated from their Cuvierian tubules, these are absent in Holothuria atra Jaeger. Therefore, this study intended to investigate the saponin profile in the body wall of H. atra, as well as to assess the α-glucosidase inhibitory activity of the H. atra extracts. The chemical profiling of sea cucumber extracts was conducted by UPLC-HRMS analysis. This resulted in the tentative identification of 11 compounds, 7 of which have not been reported in the H. Atra body wall before. Additionally, two triterpene glycosides were purified and their structures were elucidated based on HRMS and NMR data: desholothurin B (1), and a novel epimer, 12-epi-desholothurin B (2). Moreover, the fatty acid profile of the H. atra body wall was investigated by GC-MS. It was found that the Me90 fraction of the H. atra body wall showed the strongest α-glucosidase inhibitory activity (IC50 value 0.158 ± 0.002 mg/mL), thus making it more potent than acarbose (IC50 value 2.340 ± 0.044 mg/mL).