RESUMO
AIM: This systematic review and meta-analysis evaluated theobromine's (Theobroma cacao) potential in remineralizing white spot lesions in dental enamel. Methods: This study is reported according to the PRISMA checklist and was registered in PROSPERO (CRD42023414371). In vitro tests that evaluated the remineralizing potential of theobromine compared to fluoride ion after demineralization for the formation of white spot lesions on enamel were selected, with no limitation on the year of publication. Electronic searches were performed in PubMed/MEDLINE, Scopus, and Web of Science by two independent researchers. Thirty articles were received of which six were selected according to the inclusion criteria. RESULTS: The selected studies evaluated the Enamel Surface Microhardness (SMH), Vickers or Knoop, before and after treatment with theobromine and fluoride solutions. For the SMH Vickers, there were no differences between groups at baseline (p=1.00; mean difference: -0.00; CI: -11.36 to 11.36) and after treatment (p=0.51; mean difference: 4.12; CI: -8.16 to 16.41). The results of SMH Knoop showed differences between groups at baseline, favoring the experimental group (p=0.002; mean difference: 9.84; CI: 3.65 to 16.02) and after treatment favoring the control group (p=0.00001; mean difference: -5.45; CI: -7.62 to -3.27). CONCLUSION: The use of theobromine increases the microhardness of dental enamel subjected to a demineralization process, thus being effective in the remineralization of this tissue with success equivalent to that obtained with the use of fluoride.
Assuntos
Esmalte Dentário , Teobromina , Remineralização Dentária , Remineralização Dentária/métodos , Humanos , Teobromina/uso terapêutico , Teobromina/farmacologia , Esmalte Dentário/efeitos dos fármacos , Cárie Dentária , Fluoretos/uso terapêutico , Cariostáticos/uso terapêuticoRESUMO
Coffee is one of the three most consumed beverages in the world. It is made by first roasting coffee beans, and then grinding and boiling or steeping the roasted beans in water (brewing). The process of roasting and brewing produces a complex mix of bioactive compounds, including methylxanthines (caffeine, theobromine, theophylline), diterpenes, chlorogenic acid, trigonelline, flavonoids, and hydroxycinnamic acid. In the body, these compounds may be metabolized to produce other bioactive compounds. For example, caffeine is primarily (80%) broken down by demethylation to produce paraxanthine. In the post-ingestion period, levels of paraxanthine may be higher than caffeine due to its slower elimination. Hence, while paraxanthine is not found in coffee itself, it has many of the same properties as caffeine and may be a major contributor to its metabolic effects. The impacts of caffeine and paraxanthine on metabolism relate to their impact on adenosine receptors (notably the A2A receptor). It has been known for almost 100 years that intake of coffee stimulates metabolism by between 5% and 20% for at least 3 h. About half of the increase in metabolic rate after drinking coffee is due to caffeine and derivatives, but the source of the other half is unclear. There are large differences in the response to the same amount of coffee in different individuals, which may be related to caffeine clearance rates, effects of other unknown pathways, genetic polymorphism, age, sex, and body composition.
Assuntos
Cafeína , Café , Café/metabolismo , Café/química , Cafeína/metabolismo , Humanos , Teofilina/metabolismo , Xantinas/metabolismo , Teobromina/metabolismo , AnimaisRESUMO
This study undertakes a comprehensive examination of the intricate link between diet nutrition, age, and metabolic syndrome (MetS), utilizing advanced artificial intelligence methodologies. Data from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018 were meticulously analyzed using machine learning (ML) techniques, specifically extreme gradient boosting (XGBoost) and the proportional hazards model (COX). Using these analytic methods, we elucidated a significant correlation between age and MetS incidence and revealed the impact of age-specific dietary patterns on MetS. The study delineated how the consumption of certain dietary components, namely retinol, beta-cryptoxanthin, vitamin C, theobromine, caffeine, lycopene, and alcohol, variably affects MetS across different age demographics. Furthermore, it was revealed that identical nutritional intakes pose diverse pathogenic risks for MetS across varying age brackets, with substances such as cholesterol, caffeine, and theobromine exhibiting differential risks contingent on age. Importantly, this investigation succeeded in developing a predictive model of high accuracy, distinguishing individuals with MetS from healthy controls, thereby highlighting the potential for precision in dietary interventions and MetS management strategies tailored to specific age groups. These findings underscore the importance of age-specific nutritional guidance and lay the foundation for future research in this area.
Assuntos
Aprendizado de Máquina , Síndrome Metabólica , Inquéritos Nutricionais , Humanos , Síndrome Metabólica/epidemiologia , Adulto , Pessoa de Meia-Idade , Masculino , Feminino , Adulto Jovem , Idoso , Fatores Etários , Adolescente , Dieta/estatística & dados numéricos , Nutrientes/administração & dosagem , Nutrientes/análise , Criança , Modelos de Riscos Proporcionais , Teobromina/administração & dosagemRESUMO
The incidence of non-alcoholic fatty liver disease (NAFLD) tends to be younger. And the role of theobromine in fatty liver disease remains unclear. The purpose of this study was to investigate the relationship between dietary theobromine intake and degree of hepatic steatosis in individuals aged 45 and below, using data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and liver ultrasonography transient elastography. A total of 1796 participants aged below 45 years were included from NHANES 2017-2020 data after applying exclusion criteria. Multivariate regression and subgroup analyses were conducted to examine the associations between theobromine intake and controlled attenuation parameter (CAP), adjusting for potential confounders. Generalized additive models and two-piecewise linear regression were used to analyze nonlinear relationships. In the unadjusted Model 1 and preliminarily adjusted Model 2, there was no significant correlation between theobromine intake and CAP values. However, in Models 3 and 4, which accounted for confounding factors, a higher intake of theobromine was significantly associated with lower CAP values. Subgroup analyses in the fully adjusted Model 4 revealed a significant negative correlation among individuals aged 18-45, women, and white populations. Nonlinear analysis revealed a U-shaped relationship in black Americans, with the lowest CAP values at 44.5 mg/day theobromine. This study provides evidence that higher theobromine intake is correlated with lower degree of hepatic steatosis in young people, especially those aged 18-45 years, women, and whites. For black Americans, maintaining theobromine intake around 44.5 mg/day may help minimize liver steatosis. These findings may help personalize clinical nutritional guidance, prevent the degree of hepatic steatosis, and provide pharmacological approaches to reverse fatty liver disease in young people.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Inquéritos Nutricionais , Teobromina , Humanos , Teobromina/administração & dosagem , Feminino , Masculino , Adulto , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Fígado/diagnóstico por imagem , Fígado/patologia , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/diagnóstico por imagemRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Dopamina , Memória de Curto Prazo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Teobromina , Animais , Masculino , Ratos , Teobromina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Dopamina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Lobo Frontal/metabolismo , Lobo Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Modelos Animais de Doenças , Proteína 25 Associada a Sinaptossoma/metabolismoRESUMO
Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.
Assuntos
Simulação por Computador , Esvaziamento Gástrico , Modelos Biológicos , Período Pós-Prandial , Solubilidade , Esvaziamento Gástrico/fisiologia , Período Pós-Prandial/fisiologia , Humanos , Febuxostat/farmacocinética , Febuxostat/química , Teobromina/farmacocinética , Teobromina/química , Cafeína/farmacocinética , Cafeína/química , Cafeína/administração & dosagem , Citrato de Sildenafila/farmacocinética , Citrato de Sildenafila/química , Liberação Controlada de Fármacos , Aspirina/farmacocinética , Aspirina/química , Aspirina/administração & dosagemRESUMO
Coffee plants contain well-known xanthines as caffeine. Three Coffea species grown in a controlled greenhouse environment were the focus of this research. Coffea arabica and C. canephora are two first principal commercial species and commonly known as arabica and robusta, respectively. Originating in Central Africa, C. anthonyi is a novel species with small leaves. The xanthine metabolites in flower, fruit and leaf extracts were compared using both targeted and untargeted metabolomics approaches. We evaluated how the xanthine derivatives and FQA isomers relate to the expression of biosynthetic genes encoding N- and O-methyltransferases. Theobromine built up in leaves of C. anthonyi because caffeine biosynthesis was hindered in the absence of synthase gene expression. Despite this, green fruits expressed these genes and they produced caffeine. Given that C. anthonyi evolved successfully over time, these findings put into question the defensive role of caffeine in leaves. An overview of the histolocalisation of xanthines in the different flower parts of Coffea arabica was also provided. The gynoecium contained more theobromine than the flower buds or petals. This could be attributed to increased caffeine biosynthesis before fructification. The presence of theophylline and the absence of theobromine in the petals indicate that caffeine is catabolized more in the petals than in the gynoecium.
Assuntos
Cafeína , Coffea , Metabolômica , Metiltransferases , Folhas de Planta , Coffea/genética , Coffea/metabolismo , Coffea/enzimologia , Metiltransferases/genética , Metiltransferases/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/genética , Cafeína/metabolismo , Flores/genética , Flores/metabolismo , Perfilação da Expressão Gênica , Xantinas/metabolismo , Frutas/genética , Frutas/metabolismo , Teobromina/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Theobromine is an important quality component in tea plants (Camellia sinensis), which is produced from 7-methylxanthine by theobromine synthase (CsTbS), the key rate-limiting enzyme in theobromine biosynthetic pathway. Our transcriptomics and widely targeted metabolomics analyses suggested that CsMYB114 acted as a potential hub gene involved in the regulation of theobromine biosynthesis. The inhibition of CsMYB114 expression using antisense oligonucleotides (ASO) led to a 70.21% reduction of theobromine level in leaves of the tea plant, which verified the involvement of CsMYB114 in theobromine biosynthesis. Furthermore, we found that CsMYB114 was located in the nucleus of the cells and showed the characteristic of a transcription factor. The dual luciferase analysis, a yeast one-hybrid assay, and an electrophoretic mobility shift assay (EMSA) showed that CsMYB114 activated the transcription of CsTbS, through binding to CsTbS promoter. In addition, a microRNA, miR828a, was identified that directly cleaved the mRNA of CsMYB114. Therefore, we conclude that CsMYB114, as a transcription factor of CsTbS, promotes the production of theobromine, which is inhibited by miR828a through cleaving the mRNA of CsMYB114.
Assuntos
Camellia sinensis , Camellia sinensis/genética , Camellia sinensis/metabolismo , Teobromina/metabolismo , Cafeína/metabolismo , Folhas de Planta/metabolismo , Chá/metabolismo , Fatores de Transcrição/genética , RNA Mensageiro/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
The nosocomial infection outbreak caused by Pseudomonas aeruginosa remains a public health concern. Multi-drug resistant (MDR) strains of P. aeruginosa are rapidly spreading leading to a huge mortality rate because of the unavailability of promising antimicrobials. MurG glycotransferase [UDP-N-acetylglucosamine-N-acetylmuramyl (pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase] is located at the plasma membrane and plays a key role in murein (peptidoglycan) biosynthesis in bacteria. Since MurG is required for bacterial cell wall synthesis and is non-homologous to Homo sapiens; it can be a potential target for the antagonist to treat P. aeruginosa infection. The discovery of high-resolution crystal structure of P. aeruginosa MurG offers an opportunity for the computational identification of its prospective inhibitors. Therefore, in the present study, the crystal structure of MurG (PDB ID: 3S2U) from P. aeruginosa was selected, and computational docking analyses were performed to search for functional inhibitors of MurG. IMPPAT (Indian medicinal plants, phytochemicals and therapeutic) phytomolecule database was screened by computational methods with MurG catalytic site. Docking results identified Theobromine (-8.881 kcal/mol), demethoxycurcumin (-8.850 kcal/mol), 2-alpha-hydroxycostic acid (-8.791 kcal/mol), aurantiamide (-8.779 kcal/mol) and petasiphenol (-8.685 kcal/mol) as a potential inhibitor of the MurG activity. Further, theobromine and demethoxycurcumin were subjected to MDS (molecular dynamics simulation) and free energy (MM/GBSA) analysis to comprehend the physiological state and structural stability of MurG-phytomolecules complexes. The outcomes suggested that these two phytomolecules could act as most favorable natural hit compounds for impeding the enzymatic action of MurG in P. aeruginosa, and thus it needs further validation by both in vitro and in vivo analysis. HIGHLIGHTSThe top phytomolecules such as theobromine, demethoxycurcumin, 2-alpha-hydroxycostic acid, aurantiamide and petasiphenol displayed promising binding with MurG catalytic domain.MurG complexed with theobromine and demethoxycurcumin showed the best interaction and stable by MD simulation at 100 ns.The outcome of MurG binding phytomolecules has expanded the possibility of hit phytomolecules validation.Communicated by Ramaswamy H. Sarma.
Assuntos
Infecção Hospitalar , Pseudomonas aeruginosa , Humanos , Teobromina , Simulação de Acoplamento Molecular , Simulação de Dinâmica MolecularRESUMO
Caffeine (CF) is a metabolic probe drug used in the determination of the hepatic drug-oxidizing capacity. The aim of this study was to investigate temporal changes in the hepatic drug-oxidizing capacity using plasma metabolite/CF ratios in non-pregnant goats (n = 11) and pregnant goats (n = 23). CF (5 mg/kg, intravenous) was administered in six periods (Period 1-6) with 45 days between two periods. The plasma levels of CF and its metabolites, theophylline (TP), theobromine (TB) and paraxanthine (PX), were determined by HPLC-UV. To evaluate hepatic drug-oxidizing capacity in terms of enzymes that play a role in CF metabolism, the plasma metabolic ratios including TB/CF, PX/CF, TP/CF and TB + PX + TP/CF were determined at 10 h following CF administration. Plasma metabolite/CF ratios were similar between non-pregnant and pregnant goats. However, plasma metabolite/CF ratios in Period 3 (45 days in pregnant goats) were significantly higher than those other periods in both pregnant and non-pregnant goats. The effect of pregnancy may not be observed on drugs that are substrates of enzymes involved in CF metabolism in goats.
Assuntos
Cafeína , Cabras , Animais , Gravidez , Feminino , Preparações Farmacêuticas/metabolismo , Cabras/metabolismo , Fígado/metabolismo , Teofilina , Teobromina/metabolismo , OxirreduçãoRESUMO
Gout is characterized by the formation of monosodium urate crystals in peripheral joints. We carried out laboratory studies to investigate the effect of adding nine different methylxanthines and two different methylated uric acid derivatives on the development of these crystals over the course of 96 h in a medium whose composition was similar to that of synovial fluid. Our results showed that 7-methylxanthine reduced or totally prevented crystal formation; 1-methylxanthine, 3-methylxanthine, 7-methyluric acid, and 1,3-dimethyluric acid had weaker effects, and the other molecules had no apparent effect. The presented results indicate that a 7-methylxanthine concentration of about 6 × 10-5 M (10 mg/L) prevented the formation of crystals for an initial urate concentration of 1.78 × 10-3 M (300 mg/L) in the presence of 0.4 M of Na+ for 96 h at 25 °C and a pH of 7.4. We attribute these results to alterations in thermodynamics, not kinetics. Our results suggest that prevention of crystallization in vivo could be achieved by direct oral administration of 7-methylxanthine or other methylxanthines that are metabolized to 7-methylxanthine. For example, the hepatic metabolism of theobromine leads to significant plasma levels of 7-methylxanthine (14% of the initial theobromine concentration) and 3-methylxanthine (6% of the initial theobromine concentration); however, 7-methyluric acid is present at very low concentrations in the plasma. It is important to consider that several of the specific molecules we examined (theobromine, caffeine, theophylline, dyphylline, etophylline, and pentoxifylline) did not directly affect crystallization.
Assuntos
Teobromina , Ácido Úrico , Ácido Úrico/metabolismo , Teobromina/farmacologia , Teobromina/metabolismo , Solubilidade , Cafeína/farmacologiaRESUMO
A computer-assisted drug design (CADD) approach was utilized to design a new acetamido-N-(para-fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T-1-APFPB), following the pharmacophoric features of VEGFR-2 inhibitors. The stability and reactivity of T-1-AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T-1-AFPB's potential to bind with and inhibit VEGFR-2. The precise binding of T-1-AFPB against VEGFR-2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM-GBSA, and PCA studies. Then, T-1-AFPB (4-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamido)-N-(4-fluorophenyl)benzamide) was semi-synthesized and the inâ vitro assays showed its potential to inhibit VEGFR-2 with an IC50 value of 69â nM (sorafenib's IC50 was 56â nM) and to inhibit the growth of HepG2 and MCF-7 cancer cell lines with IC50 values of 2.24±0.02 and 3.26±0.02â µM, respectively. Moreover, T-1-AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T-1-AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2â cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T-1-APFPB providing it as a promising lead VEGFR-2 inhibitor for further development aiming at cancer therapy.
Assuntos
Teobromina , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Células MCF-7 , BenzamidasRESUMO
A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC50 = 0.42 µM) and HepG2 (IC50 = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC50 value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2.
Assuntos
Antineoplásicos , Teobromina , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases , Relação Estrutura-Atividade , Teobromina/química , Teobromina/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Background & aims: The beneficial effects of theobromine (TB) on obesity and features of metabolic syndrome (MetS) have been reported in several studies. However, the findings are equivocal. The present study aimed to investigate the effects of 12 week pure TB supplementation (450 mg day-1) combined with a low-calorie diet on the anthropometric and metabolic syndrome indices in overweight and obese adults with MetS. Methods: In a randomized double-blind parallel controlled trial, 80 participants aged 40-55 years were randomly assigned to take 450 mg day-1 TB or placebo along with a low-calorie diet for 12 weeks. Dietary intake, anthropometric indices, blood pressure, lipid profile and glycemic indices were assessed at the start and end of the intervention. Results: Seventy-two participants completed the study. After 12 weeks, TB supplementation significantly decreased the waist circumference (WC) (-0.86 cm; P = 0.045), LDL-c/HDL-c (-0.26; P = 0.008), TG/HDL-c (-0.41; P = 0.001), TC/HDL-c (-0.38; P = 0.006) and increased HDL-c (1.72 mg dl-1; P = 0.036) compared to the placebo group. There were no significant differences regarding body weight, BMI, hip circumference (HC), hip-to-waist circumference ratio (WHR), systolic and diastolic blood pressure, fasting levels of total cholesterol (TC), triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-c), fasting blood glucose, insulin, homoeostatic model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell function (HOMA-ß) between the two groups (p > 0.05). Conclusion: The results of the current study revealed that TB supplementation along with a low-calorie diet had favorable effects on WC, LDL-c/HDL-c, TG/HDL-c, TC/HDL-c, and serum level of HDL-c in overweight and obese subjects with MetS. Trial registration number: IRCT20091114002709N59. Registration date: 5 March 2022.
Assuntos
Doenças Cardiovasculares , Síndrome Metabólica , Adulto , Humanos , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Teobromina , Restrição Calórica , LDL-Colesterol , Fatores de Risco , Obesidade/complicações , Obesidade/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , HDL-Colesterol , Suplementos NutricionaisRESUMO
Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as added ingredients. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 µg/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 µg/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery.
Assuntos
Cafeína , Teobromina , Animais , Ratos , Cafeína/farmacologia , Xantina , Teobromina/farmacologia , Células Endoteliais , FígadoRESUMO
This study aimed to evaluate the efficacy of fluoride-free remineralizing agents in initial enamel caries, with and without combined Er,Cr:YSGG laser application. The remineralization effect of various agents and their combinations on artificial initial caries was investigated using 10 experimental groups (n = 7): NC, negative control; PC, positive control; TM, calcium-phosphate compounds (CPP-ACP); TD, theobromine-containing toothpaste; RG, ROCS® remineralizing gel; L, Er,Cr:YSGG laser (2780 nm; 0.25 W; repetition rate, 20 Hz; pulse duration, 140 µs; tip diameter, 600 µm; without air/water cooling); L + fluoride toothpaste; L + TM; L + TD; and L + RG. The demineralized bovine enamel specimens were subjected to an 8-day pH cycle by daily application of the remineralizing agents and laser therapy once prior to the pH cycle and paste application. The enamel samples underwent the Vickers surface microhardness test, and one sample per group was analyzed with scanning electron microscopy. The Kruskal Wallis test was used to compare the microhardness recovery percentage (SMHR%) for each group, and multiple comparisons were made with the Dunn test. Groups L (p = 0.003), RG (p = 0.019), L + TM (p < 0.001), L + fluoride toothpaste (p = 0.001),and L + RG (p = 0.036) exhibited significant increase in SMHR%. The tested remineralizing agents exhibited no statistically significant difference in effect when used alone and in combination with Er,Cr:YSGG laser. Combined application of Er,Cr:YSGG laser and ROCS® remineralization gel effectively promoted enamel remineralization, while use of CPP-ACP and fluoride toothpaste alone was ineffective. Theobromine-containing toothpaste exhibited the least SMHR%. Long-term evaluation of these agents is recommended.
Assuntos
Fluoretos , Lasers de Estado Sólido , Animais , Bovinos , Fluoretos/farmacologia , Cremes Dentais/farmacologia , Lasers de Estado Sólido/uso terapêutico , Remineralização Dentária , TeobrominaRESUMO
BACKGROUND: This study aimed to assess the impact of theobromine and casein phospho-peptides/amorphous calcium phosphate with fluoride (CPP-ACPF) on the resin-dentine bond strength, microhardness, and dentine morphology. METHODS: A total of 18 sound human molars for micro-tensile bond strength (µTBS), 20 sound human premolars for microhardness, and 30 premolars for Scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDX) were used. Based on the pre-treatment used, teeth were split into six groups; sound dentine, demineralized dentine, and demineralized dentine treated with theobromine (Sigma Aldrich) and MI paste plus (GC International, USA) for two-time intervals; 5 min and 1 month. The bonded teeth were sectioned to produce 1 mm2 resin-dentine sticks which were evaluated for µTBS using a universal testing device (Instron 3365, USA). The dentine microhardness was tested by using the Vickers microhardness tester (Nexus 4000 TM, Netherlands). The pre-treated dentine surface was examined using SEM/EDX (Neoscope JCM-6000 plus Joel benchtop SEM, Japan). µTBS results were analysed with two-way ANOVA. Microhardness and EDX results were analysed with two-way mixed model ANOVA. The significance level was set at (p ≤ 0.05). RESULTS: While both remineralizing materials at the two-time intervals demonstrated µTBS comparable to sound dentine (46.38 ± 12.18), the demineralized group demonstrated statistically the lowest µTBS (p < 0.001). Whether used for 5 min or 1 month, theobromine significantly increased the microhardness (50.18 ± 3.43) and (54.12 ± 2.66) respectively (p < 0.001), whereas MI paste only increased the hardness (51.12 ± 1.45) after 1 month (p < 0.001). CONCLUSIONS: The pre-treatment of demineralized dentine with theobromine for 5 min or 1 month could enhance its bond strength and microhardness while for MI paste plus, only 1-month application was efficient to ensure remineralization.
Assuntos
Caseínas , Fluoretos , Humanos , Caseínas/farmacologia , Teobromina , Peptídeos , DentinaRESUMO
Background: VEGFR-2 is one of the most effective targets in cancer treatment. Aim: The design and semi-synthesis of new theobromine derivatives as potential VEGFR-2 inhibitors. Methods: In vitro and in silico evaluation of the synthesized compounds. Results: Compound 5b demonstrated excellent antiproliferative and VEGFR-2 inhibitory effects with significant apoptotic activity. It modulated the immune response by increasing IL-2 and reducing TNF-α levels. Docking and molecular dynamics simulations revealed the compound's binding affinity with VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion and toxicity studies indicated the high potential of compound 5b for drug development. Conclusion: Compound 5b could be a promising anticancer agent targeting VEGFR-2.
Assuntos
Antineoplásicos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Teobromina/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Inibidores de Proteínas Quinases/farmacologia , Proliferação de Células , Antineoplásicos/química , Simulação de Acoplamento Molecular , Desenho de FármacosRESUMO
PURPOSE: To investigate the production and physical stability of coamorphous materials (CAM) of naringenin (NAR) and coformers-caffeine, theophylline or theobromine (CAF/THY/THE, respectively). We independently assessed the impact of moisture and temperature on the physical stability of CAMs, and transformation products after destabilization were examined. METHODS: Neat grinding, liquid assisted grinding and water slurry were selected to prepare multi-component materials with NAR and CAF, THY or THE. The physical stability of CAMs was investigated at 65°C/<10%RH, 21°C/85% RH and 21°C/<10% RH. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for recrystallization during the stability studies. Glass forming ability of amorphous NAR was assessed to understand CAM formation and physical stability. RESULTS: NAR:THY and NAR:THE CAMs showed physical stability for approximately nine months, under 21°C/<10% RH while NAR:CAF CAMs destabilized in 2.5 weeks. All CAMs recrystallized within a week at 65°C/<10%RH, and the physical stability at 21°C/85% RH was in the order of - NAR:THY > NAR:THE > NAR:CAF. NAR:THY produced 1:1 cocrystal under all storage conditions, while NAR:CAF destabilized to a 1:1 cocrystal at high RH but a physical mixture at high temperature. NAR:THE was found to recrystallize as a physical mixture in all conditions. NAR was found to be strong glass, with moderate kinetic fragility and good glass forming ability. CONCLUSION: Five naringenin-based multi-component solids were generated in this study: 3 new CAMs, 1 new cocrystal, and 1 previously reported cocrystal. Destabilization of CAMs was found to be exposure specific and coformer dependent.
Assuntos
Cafeína , Teofilina , Teofilina/química , Teobromina , Cristalização , Varredura Diferencial de Calorimetria , Difração de Raios X , Estabilidade de Medicamentos , SolubilidadeRESUMO
Uric acid lithiasis accounts for about 10% of all types of renal lithiasis. The most common causes of uric acid lithiasis are low urinary pH, followed by high concentration of urinary uric acid, and low diuresis. Treatment of patients consists of alkalinization of urine, reducing the consumption of purine-rich foods, and administration of xanthine oxidase inhibitors, because there are no established therapeutic inhibitors of uric acid crystallization. We recently found that theobromine inhibited uric acid crystallization in vitro, and that the increased urinary level of theobromine following its oral consumption was associated with the prevention of uric acid crystallization. In this study, we evaluated the inhibitory effects of theobromine metabolites and other methylxanthine-related compounds on uric acid crystallization. We also measured the urinary concentrations of theobromine and its metabolites in samples from healthy individuals and patients with uric acid stones and compared the extent of uric acid supersaturation and uric acid crystal formation in these different samples. Theobromine and other methylxanthines that lacked a substituent at position 1 inhibited uric acid crystallization, but other methylxanthines did not have this effect. Individuals with clinical parameters that favored uric acid crystallization did not develop uric acid crystals when theobromine and its metabolites were in the urine at high levels. Thus, theobromine and its metabolites reduced the risk of uric acid lithiasis.