Showing papers on "Theobromine published in 2021"

Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin.

Abstract: Natural products have been studied to reveal new therapies against human dysfunctions since they present several medicinal properties. Caffeine, theobromine and (+)-catechin are remarkable natural agents in the class of methylxanthines and flavonoids. These bioactive molecules have several biological activities, for instance, antioxidant, anti-inflammatory, and antitumor capacity. In this sense, studies focusing on these molecules have been performed to discover new treatments against diseases, such as cancer. Cancer is a serious public health problem worldwide responsible for more than 70% of all deaths globally. Industrialized products associated with a sedentary lifestyle and a diet low in antioxidants are related to neoplasms development. Unfortunately, many types of cancers are extremely aggressive and untreatable since, in many cases, they are resistant to chemotherapy. Therefore, revealing new strategies to block cancer growth is one of the biggest challenges to science. In this context, despite the known anticancer actions of caffeine, theobromine and (+)-catechin, it is still essential to elucidate the causal antitumor mechanism of these molecules by analyzing the dysfunctional cancer pathways associated with the hallmarks of cancer. Hence, this review aims to describe the anticancer activity of caffeine, theobromine, and (+)-catechin against the different hallmarks and enabling characteristics of cancer.

Theobromine ameliorates nonalcoholic fatty liver disease by regulating hepatic lipid metabolism via mTOR signaling pathway in vivo and in vitro

Abstract: Theobromine, a methylxanthine present in cocoa, has been shown to possess many beneficial pharmacological properties such as anti-oxidative stress, anti-inflammatory property, and anti-microbial ac...

Degradation of synthetic coffee wastewater using induced cells of Pseudomonas sp. NCIM 5235

Abstract: Coffee wastewater contains a high amount of caffeine, which causes adverse effects on the environment. Current treatment strategies focus majorly on overall chemical oxygen demand (COD) reduction and do not focus on caffeine degradation in wastewater. Though several techniques are available to degrade caffeine, biological methods are preferred as they are economical and eco-friendly. In this study, Pseudomonas strain NCIM 5235 was evaluated for its potential to degrade caffeine in synthetic coffee wastewater. Uninduced cells degraded caffeine completely in 36 h. Sucrose in the medium did not affect caffeine degradation and remain unconsumed by the bacteria. Under optimal cell loading of 10 × 1011 CFU/L, complete degradation of caffeine was achieved in 2 h. Traces of theaflavin and thearubigin were degraded, whereas other polyphenols remain unaffected and were monitored by UV-visible spectrophotometer. Induced cells also displayed the ability of simultaneous degradation of theobromine present in wastewater. Results showed that caffeine degradation is unaffected at adverse pH, indicating its effectiveness in industrial waste treatment where complete reduction of caffeine and its metabolite theobromine can be achieved by induced cells.

Quantitative analysis and response surface modeling of important bitter compounds in chocolate made from cocoa beans with eight roast profiles across three origins.

Abstract: Eight different roast profiles for each of the three origins of cacao were prepared and made into unsweetened chocolate based upon an I-Optimal response-surface design for minimizing prediction variance. Quantitative chemical analysis of all chocolate treatments was performed with HPLC-DAD on six important bitter compounds (i.e., theobromine, caffeine, epicatechin, catechin, procyanidin B2, and cyclo(Proline-Valine)). Least-squares linear modeling was then performed. Using derived linear models, response-surface contour plots were produced to show predicted changes in the six bitter compounds over the entire experimental region. Significant and large decreases in concentration of epicatechin and procyanidin B2 were observed as roasting progressed, whereas for catechin and cyclo(Proline-Valine), significant increases were observed. Small yet significant theobromine and caffeine concentration increases were also observed with roasting, likely due to moisture loss. Some significant differences were also found between the cacao origins for all bitter compound concentrations except for cyclo(Proline-Valine), suggesting the importance of a survey encompassing a greater number of cacao origins in the future to obtain a more complete picture of the variation in bitter compounds in cacao due to origin. PRACTICAL APPLICATION: This research describes how roasting can be used to alter the concentration of bitter and sometimes astringent chemicals for several origins of cacao, which may be used to improve the sensory characteristics of dark chocolate.

Coffee toxicology, processing of the coffee and liver diseases (is it a miracle of nature?)

Abstract: The present study aimed to investigate the beneficial effects of coffee on the liver. The results show that coffee has beneficial effects on the liver and can reduce liver disease progression due to its antioxidant properties. Coffee contains antioxidant capacities of chlorogenic acid, hydrophilic components, hydrophobic components, lactones, and diterpenes. There are also rich amounts of potassium and magnesium in coffee. Roasting of the green coffee beans at high temperatures will make unique components due to the chemical reactions between carbohydrates and amino acids as Maillard reactions. Caffeine with a purine derivative is found in several dietary sources, including tea, chocolate bars, coffee, cocoa beverages, energy, and soft drinks. Caffeine can pass all biological membranes due to the hydrophobic properties of caffeine. Three primary metabolites, such as theophylline, theobromine, and paraxanthine, are caused by metabolizing caffeine in the liver. Caffeine at normal consumption doses mainly acts among humans as an antagonist of adenosine receptors. Two cups of coffee per day should be consumed to show its beneficial effects. Coffee drinkers experience a lower incidence of advanced cirrhosis and fibrosis. There are also differences between males and females in their responses to caffeine due to changes in circulating steroid hormones. PRACTICAL APPLICATIONS: This article investigates the beneficial effects of coffee on the liver and summarizes the potential preventive or positive effects of coffee on the liver. Coffee has beneficial effects on the liver and can reduce the progression of liver disease due to its antioxidant properties.

Substrate promiscuity of the NdmCDE N7-demethylase enzyme complex

Abstract: Methylxanthines, including caffeine and theophylline, are a class of natural and synthetic compounds with important roles in food, cosmetics, and medicine. These compounds are metabolized by bacteria using five enzymes from the Rieske non-heme iron oxygenase family, NdmABCDE. The NdmCDE complex is responsible for the N7-demethylation of 7-methylxanthine to xanthine and was originally described as being highly specific for 7-methylxanthine. Here, we report that the NdmCDE complex is also active toward theobromine, producing 3-methylxanthine due to N7-demethylation. Minimal activity was observed when the enzyme complex was tested with caffeine or paraxanthine, indicating that the presence of the N1-methyl group significantly inhibits N7-demethylase activity by NdmCDE. We also demonstrated positional promiscuity in the N3-demethylase, NdmB, which is able to carry out N1-demethylation of paraxanthine. The N1-demethylation by NdmB is limited to paraxanthine and was not observed when caffeine or theophylline were assayed. These newly discovered activities were observed when enzymes were overexpressed in E. coli and differ from results with purified enzymes assayed in vitro, indicating that they may behave differently in vivo. Furthermore, these results reveal promiscuity of bacterial N-demethylase enzymes that can be used to engineer new enzymes and bacterial strains for production of high-value methylxanthines.

Simultaneous determination of caffeine and its metabolites in rat plasma by UHPLC-MS/MS.

Abstract: Caffeine is a widely consumed psychostimulant with several mechanisms of action and various positive and negative effects on organisms. Caffeine undergoes extensive hepatic metabolism to form main metabolites such as theobromine, theophylline, paraxanthine, and 1,3,7-trimethyluric acid. However, interspecies diversities have been observed in caffeine metabolism. In the present study, we developed a sensitive and straightforward ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify caffeine and its primary metabolites, namely theobromine, theophylline, paraxanthine, and 1,3,7-trimethyluric acid in rat plasma. After extraction of analytes using micro solid-phase extraction plate, analytes were separated by elution gradient on the Acquity UPLC HSS T3 (50 × 2.1 mm, 1.8 μm) column over 4 min. The detection was done on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring modes using a positive electrospray ionization interface. The method was successfully validated according to the European Medicine Agency guideline over a concentration range of 5-1500 ng/ml for caffeine, 5-1200 ng/mL for theobromine, and 2.5-1200 ng/mL for theophylline, paraxanthine, and 1,3,7-trimethyluric acid. The developed method was applied to analyze samples from animal experiments focusing on the metabolism and effects of caffeine and caffeine-containing beverages.

In Vitro Free Radical Scavenging Properties and Anti-Inflammatory Activity of Ilex paraguariensis (Maté) and the Ability of Its Major Chemical Markers to Inhibit the Production of Proinflammatory Mediators.

Abstract: Ilex paraguariensis A. St. Hil. (Aquifoliaceae), popularly known as "yerba mate," has great economic and social significance for the population of Southern Latin America. This study was conducted (1) to investigate the phytochemical composition of four different standardized extracts, (2) to investigate its free radical scavenging properties, and (3) to investigate the anti-inflammatory action of I. paraguariensis and its major chemical markers. The chemical profile was achieved by Folin-Ciocalteu, by LC/DAD, and by LC/MS assays, while the antioxidant and anti-inflammatory properties were investigated, respectively, by DPPH assay and by inhibition of nitric oxide (Griess reaction) and TNF-α (ELISA). Our results demonstrated that the IA (aqueous infusion extract) showed higher amounts of total phenolic contents (266.62 ± 10.85 mg CAE·g-1 DE), the highest amounts of all six chemical markers (theobromine, 5-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, caffeine, and rutin), and stronger antioxidant activity (EC50 = 54.4 ± 5.14 μg · mL-1). The IA extract also showed the lowest inhibition of NOx secretion (50.10 ± 8.97%) as well as inhibition of TNF-α (83.33 ± 4.01%). Regarding the chemical markers, all compounds showed strong inhibition of NOx secretion, especially theobromine, which was 200x more potent than dexamethasone. Furthermore, TNF-α secretion was also significantly decreased by THEO at 0.033 μM (22.15 ± 6.49%), NCA at 1.97 μM (27.46 ± 3.98%), CCA at 0.35 μM (39.76 ± 5.73%), CGA at 0.56 μM (23.58 ± 5.79%), CAF at 0.52 μM (26.45 ± 5.34%), and RUT at 0.16 μM (40.18 ± 3.70%). Our results suggest that I. paraguariensis and its major chemical markers have strong free radical scavenging properties as well as showed important anti-inflammatory activity and that these compounds in a plant extract may work based on several different mechanisms synergistically, resulting in moderating the immune system.

Simultaneous quantitation of serum caffeine and its metabolites by ultra-high-performance liquid chromatography-tandem mass spectrometry for CYP1A2 activity prediction in premature infants.

Abstract: Caffeine is accepted as a probe of cytochrome P450 1A2 enzyme (CYP1A2) activity and is commonly used in premature infants with great interindividual variability of metabolism. To evaluate the change characteristics of CYP1A2 activity in premature infants, an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and optimized for the simultaneous quantitation of serum caffeine (CA) and its major metabolites, including paraxanthine (PX), theophylline (TP) and theobromine (TB) in premature infants. A C18 column and gradient elution with 0.1% formic acid in methanol and 0.1% formic acid in water at a flow rate of 0.3 mL/min were used for compound separation. The mass spectrometer monitored the transitions of CA (m/z 195.0→138.0), CA-d9 (m/z 204.0→144.1), PX (m/z 181.0→124.1), TP (m/z 181.0→123.9) and TB (m/z 181.0→138.0) using multiple reaction monitoring in positive ion mode. CYP1A2 activity was evaluated by serum molar concentration ratios of CA and its metabolites. The results showed that CYP1A2 has a significant positive correlation with the clearance of CA, and was affected by current weight (CW) and CYP1A2*1C. The results suggested that the serum concentration ratios of caffeine metabolic could be used to predict the changes in CYP1A2 enzyme activity in premature infants.

Thermal behavior of different cocoa powder varieties and their physicochemical, phytochemical and microbiological characteristics

Abstract: Four cocoa powder varieties processed in different European countries (Germany, Poland, Romania and Bulgaria) were subjected to physicochemical, phytochemical and microbiological analysis. The cocoa powders were extensively characterized by recording their pH and titratable acidity, respectively, the polyphenols and also the methylxantine derivatives content (theobromine and caffeine). The cocoa powders pH ranged between 5.37 and 8.23, while the titratable acidity was 3.2–4.3 miliequivalent (100 g)−1 of cocoa powder. Their total polyphenols content ranged between 0.986 ÷ 2.003 g GAE/(100 g)−1. The methylxanthine derivatives (theobromine and caffeine) were analyzed by the HPLC method and ranges of 0.992–1.174% for theobromine and 0.096–0.369% for caffeine were obtained. Thermal analysis (TG–DTA) combined with mass spectrometry (MS) elucidated the decomposition processes and the volatile substances (CO, CO2, H2O, NO, theobromine, caffeine). The thermal analysis revealed transformations in the cocoa powders composition: drying and water loss; decomposition of pectic polysaccharides; lipids, amino acids and proteins, crystalline phase transformations and carbonizations. The microbiological analysis tested the degree of preservation of the cocoa powders across time, specifically immediately after unwrapping and after 14 days.

Pharmacokinetics of caffeine: A systematic analysis of reported data for application in metabolic phenotyping and liver function testing

Abstract: Caffeine is by far the most ubiquitous psychostimulant worldwide found in tea, coffee, cocoa, energy drinks, and many other beverages and food. Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products theobromine and theophylline. Besides its stimulating properties, two important applications of caffeine are metabolic phenotyping of cytochrome P450 1A2 (CYP1A2) and liver function testing. An open challenge in this context is to identify underlying causes of the large inter-individual variability in caffeine pharmacokinetics. Data is urgently needed to understand and quantify confounding factors such as lifestyle (e.g. smoking), the effects of drug-caffeine interactions (e.g. medication metabolized via CYP1A2), and the effect of disease. Here we report the first integrative and systematic analysis of data on caffeine pharmacokinetics from 148 publications and provide a comprehensive high-quality data set on the pharmacokinetics of caffeine, caffeine metabolites, and their metabolic ratios in human adults. The data set is enriched by meta-data on the characteristics of studied patient cohorts and subjects (e.g. age, body weight, smoking status, health status), the applied interventions (e.g. dosing, substance, route of application), measured pharmacokinetic time-courses, and pharmacokinetic parameters (e.g. clearance, half-life, area under the curve). We demonstrate via multiple applications how the data set can be used to solidify existing knowledge and gain new insights relevant for metabolic phenotyping and liver function testing based on caffeine. Specifically, we analyzed (i) the alteration of caffeine pharmacokinetics with smoking and use of oral contraceptives; (ii) drug-drug interactions with caffeine as possible confounding factors of caffeine pharmacokinetics or source of adverse effects; (iii) alteration of caffeine pharmacokinetics in disease; and (iv) the applicability of caffeine as a salivary test substance by comparison of plasma and saliva data. In conclusion, our data set and analyses provide important resources which could enable more accurate caffeine-based metabolic phenotyping and liver function testing.

Effects of Theophylline and Theobromine on exercise performance and implications for competition sport: A systematic review

Abstract: A systematic review was undertaken to evaluate studies on the effects of theophylline and theobromine on exercise performance in normal (healthy) subjects. Theophylline was found to have been studied on eight occasions and theobromine on one, the number of subjects per study ranging from seven to 15. In two exercise investigations, theophylline was superior to placebo at a p < 0.05 level and no different in four including one that was conducted in artificial hypoxia. In a treadmill time trial over 3 km, theobromine was superior to placebo and equal to caffeine, at the <0.05 level. In strength studies, theophylline increased wrist strength in one and showed a slight but not statistically significant increase in limb strength in four of the seven subjects in the other. Theophylline caused adverse effects in six participants. There were no adverse effects in the theobromine investigation. Although the studies showed contradicting results and/or insufficient data to draw solid conclusions, it appears both drugs have potential to enhance performance and could be considered for inclusion on the WADA banned list.

Quality Parameters, Caffeine and Theobromine Contents and Antioxidant Activity of Artisan and Commercial Chocolate from Brazil

Abstract: Several types of chocolate were analysed: bitter, half-bitter, milk chocolate, 70% cocoa, white chocolate and cocoa seeds. Analysis of fat, insoluble solids, total phenols, theobromine and caffeine contents and antioxidant capacity were carried out to evaluate the quality of artisan and commercial chocolate products in Brazil. Fat contents and insoluble residues were similar to those reported in the literature. We develop a simple method by HPLC-DAD (High-Performance Liquid Chromatography with Diode-Array Detection) to quantify methylxanthines whose identification has been confirmed by UPLC- MS (Ultra performance liquid chromatography—mass spectrometer). The levels of phenols, caffeine and theobromine varied between types. White chocolate had no phenolics nor caffeine or theobromine. The ones with the highest phenolic contents were those with the highest cocoa mass content. The same happened with the antioxidant activity, which is correlated to the amount of phenolics, caffeine and theobromine, shown by the statistical analysis. It is the presence of cocoa that determines the antioxidant activity of chocolates. This work contributed to the confirmation of the properties of the chocolates, highlighting the importance of the artisan product. Chocolates are important for human health and are considered functional foods.

Salts of purine alkaloids caffeine and theobromine with 2,6-dihydroxybenzoic acid as coformer: structural, theoretical, thermal and spectroscopic studies

Abstract: The study of various forms of pharmaceutical substances with specific physicochemical properties suitable for putting them on the market is one of the elements of research in the pharmaceutical industry. A large proportion of active pharmaceutical ingredients (APIs) occur in the salt form. The use of an acidic coformer with a given structure and a suitable pKa value towards purine alkaloids containing a basic imidazole N atom can lead to salt formation. In this work, 2,6-dihydroxybenzoic acid (26DHBA) was used for cocrystallization of theobromine (TBR) and caffeine (CAF). Two novel salts, namely, theobrominium 2,6-dihydroxybenzoate, C7H9N4O2+·C7H5O4- (I), and caffeinium 2,6-dihydroxybenzoate, C8H11N4O2+·C7H5O4- (II), were synthesized. Both salts were obtained independently by slow evaporation from solution, by neat grinding and also by microwave-assisted slurry cocrystallization. Powder X-ray diffraction measurements proved the formation of the new substances. Single-crystal X-ray diffraction studies confirmed proton transfer between the given alkaloid and 26DHBA, and the formation of N-H...O hydrogen bonds in both I and II. Unlike the caffeine cations in II, the theobromine cations in I are paired by noncovalent N-H...O=C interactions and a cyclic array is observed. As expected, the two hydroxy groups in the 26DHBA anion in both salts are involved in two intramolecular O-H...O hydrogen bonds. C-H...O and π-π interactions further stabilize the crystal structures of both compounds. Steady-state UV-Vis spectroscopy showed changes in the water solubility of xanthines after ionizable complex formation. The obtained salts I and II were also characterized by theoretical calculations, Fourier-transform IR spectroscopy (FT-IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elemental analysis.

Investigating the Relations Between Caffeine-Derived Metabolites and Plasma Lipids in 2 Population-Based Studies.

Abstract: Objective To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries. Methods Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines—caffeine, paraxanthine, theobromine, and theophylline—using ultra-high-performance liquid chromatography–tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders. Results In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants. Conclusion Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake.

Biodegradation of methylxanthines by Coniophora puteana

Abstract: The biodegradation of caffeine, theobromine and theophylline by wood destroying fungi Coniophora puteana were analyzed in the present study. Aquatic solution of caffeine (1 g·L−1) was performed and fungal hyphae were put into the solutions for 28 days. Vials with the fungi were stored in a biological incubator at 22 ± 2 °C for 28 days. The same design was used for vials with the fungi without the tested substances and the pure distilled water as a reference. The results of biological tests were evaluated by a liquid chromatography-mass spectrometry method. The fungal samples were analyzed each 7 days. Caffeine concentration increased in the fungal mass during the first 14 days. After that its concentration decreased. Caffeine was also degraded to theophylline and theobromine. Theophylline and theobromine concentrations rapidly increased during the first 7 days and then rapidly decreased fast to zero. The decreasing levels of all substances in fungi indicated their biodegradation during time.