The idea of the use of anticancer drugs together with a chemosensitizer emerged as the strategy of reversal of multidrug resistance (MDR) of cancer cells expressing ABC proteins many years ago. The ...approaches relying on the use of a single chemosensitizer have never resulted in a clinical success. Therefore, the application of drug combinations of two or more compounds with different mechanisms of action might be an alternative approach to increase the success rate. In the present study the cytotoxic and NF-κB inhibition potential of the phenothiazine derivative, MAE-TPR, was evaluated. MAE-TPR was demonstrated to be an effective doxorubicin-resistance modulator in human adenocarcinoma cell line LoVo/Dx. In the presence of MAE-TPR cytotoxicity of doxorubicin was elevated, and its intracellular accumulation increased. Strong synergism occurred between MAE-TPR and Dox. MAE-TPR diminished also the expression of ABCB1 transporter (P-glycoprotein) by affecting NF-κB pathway. Theobromine, a phytochemical from cocoa, which was barely active itself, strongly augmented MDR reversal potency of MAE-TPR. The effect of the combination of phenothiazine derivative with theobromine on cancer cells was studied for the first time in the present work. It was concluded that the use of the proposed combination of two modulators might be a promising strategy for MDR reversal since modulators could be used in concentrations much lower than in case of their single application and in that way the risk of intolerable side-effects could be reduced.
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Cacao use and the San Lorenzo Olmec Powis, Terry G; Cyphers, Ann; Gaikwad, Nilesh W ...
Proceedings of the National Academy of Sciences - PNAS,
05/2011, Letnik:
108, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Mesoamerican peoples had a long history of cacao use--spanning more than 34 centuries--as confirmed by previous identification of cacao residues on archaeological pottery from Paso de la Amada on the ...Pacific Coast and the Olmec site of El Manatà on the Gulf Coast. Until now, comparable evidence from San Lorenzo, the premier Olmec capital, was lacking. The present study of theobromine residues confirms the continuous presence and use of cacao products at San Lorenzo between 1800 and 1000 BCE, and documents assorted vessels forms used in its preparation and consumption. One elite context reveals cacao use as part of a mortuary ritual for sacrificial victims, an event that occurred during the height of San Lorenzo's power.
Flavan-3-ols, including the flavan-3-ol monomer (−)-epicatechin, are dietary bioactives known to mediate beneficial cardiovascular effects in humans. Recent studies showed that flavan-3-ols could ...interact with methylxanthines, evidenced by an increase in flavan-3-ol bioavailability with a concomitant increase in flavan-3-ol intake-mediated vascular effects. This study aimed at elucidating flavan-3-ol–methylxanthine interactions in humans in vivo by evaluating the specific contributions of theobromine and caffeine on flavan-3-ol bioavailability. In ileostomists, the effect of methylxanthines on the efflux of flavan-3-ol metabolites in the small intestine was assessed, a parameter important to an understanding of the pharmacokinetics of flavan-3-ols in humans. In a randomized, controlled, triple cross-over study in volunteers with a functional colon (n = 10), co-ingestion of flavan-3-ols and cocoa methylxanthines, mainly represented by theobromine, increased peak circulatory levels (Cmax) of flavan-3-ols metabolites (+21 ± 8%; p < 0.05). Conversely, caffeine did not mediate a statistically significant effect on flavan-3-ol bioavailability (Cmax = +10 ± 8%, p = n.s.). In a subsequent randomized, controlled, double cross-over study in ileostomists (n = 10), cocoa methylxanthines did not affect circulatory levels of flavan-3-ol metabolites, suggesting potential differences in flavan-3-ol bioavailability compared to volunteers with a functional colon. The main metabolite in ileal fluid was (−)-epicatechin-3′-sulfate, however, no differences in flavan-3-ol metabolites in ileal fluid were observed after flavan-3-ol intake with and without cocoa methylxanthines. Taken together, these results demonstrate a differential effect of caffeine and theobromine in modulating flavan-3-ol bioavailability when these bioactives are co-ingested. These findings should be considered when comparing the effects mediated by the intake of flavan-3-ol-containing foods and beverages and the amount and type of methylxanthines present in the ingested matrixes. Ultimately, these insights will be of value to further optimize current dietary recommendations for flavan-3-ol intake.
This work was registered at clinicaltrials.gov as NCT03526107 (study part 1, volunteers with functional colon) and NCT03765606 (study part 2, volunteers with an ileostomy).
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•Intake of flavan-3-ols with cocoa methylxanthines but not caffeine increases circulatory flavan-3-ol metabolites levels.•Intake of cocoa methylxanthines and flavan-3-ol does not affect levels of flavan-3-ol metabolites in intestinal lumen.•Circulating flavan-3-ol metabolites levels are strongly influenced by the absence of a functional colon.•There is evidence of a substantial intestinal efflux of (−)-epicatechin-3′-sulfate.
•Develop and validate ASE (accelerated solvent extraction) for Methyl xanthine (MX).•To quantify MX using ultra high performance liquid chromatography (UHPLC-DAD).•To apply the ASE-UHPLC/DAD method ...for quantification of MX in different tea classes.•To establish the method as quality evaluation tool in market available tea samples.
Methyl xanthines (MX), known for its psychostimulant effect, occurs mostly in tea and coffee samples. However most of the market available products does not mention the proper amount and quality of MX present where, its consumption in high amount may pose health risks.
To develop and validate a fast, efficient and reliable method of MX extraction along with a sensitive, rapid and precise method for simultaneous analysis of MX i.e. Theobromine (TB), Theophylline (TH) and Caffeine (C), with application in commercial tea and coffee samples.
Accelerated Solvent Extraction (ASE) was utilized for the first time to extract MX, whereas UHPLC-DAD was applied in order to quantify MX.
ASE resulted a high extract yield (940.22 ± 192.28 mg/g) with optimized conditions of temperature (100 °C) and solvent (MeOH). UHPLC-DAD showed retention time (min) of 1.51 (TB), 1.81 (TH), 2.30 (C) with r2 values (0.980–0.988). Average MX (μg/mL) was as; TB (14.73 ± 20.9), TH (32.05 ± 55.5), C (121.87 ± 32.3). The method application in commercial samples showed a high extract yield with MX concentration (mg/g) as; TB (0.13–0.38), TH (0–0.55), C (7.14–11.20). Temperature and solvent variation showed important correlation with samples in terms of extraction yield.
ASE-UHPLC/DAD revealed a fast and sensitive method of MX extraction, quantification and quality determination in market available tea and coffee samples.
•Integration of biorelevant in vitro methods in mechanistic in silico model.•Dosage form, drug solubility and gastric motility affects rate of gastric emptying.•In vivo study of gastric emptying with ...different meals.•Extrapolation between different prandial states.
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.
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Summary Background & aims Chocolate consumption is associated with a decreased risk for CVD. Theobromine, a compound in cocoa, may explain these effects as it favorably affected fasting serum lipids. ...However, long-term effects of theobromine on postprandial metabolism as well as underlying mechanisms have never been studied. The objective was to evaluate the effects of 4-week theobromine consumption (500 mg/day) on fasting and postprandial lipid, lipoprotein and glucose metabolism, and duodenal gene expression. Methods In a randomized, double-blind crossover study, 44 healthy men and women, with low baseline HDL-C concentrations consumed 500 mg theobromine or placebo daily. After 4-weeks, fasting blood was sampled and subjects participated in a 4-h postprandial test. Blood was sampled frequently for analysis of lipid and glucose metabolism. In a subgroup of 10 men, 5 h after meal consumption duodenal biopsies were taken for microarray analysis. Results 4-weeks theobromine consumption lowered fasting LDL-C (−0.21 mmol/L; P = 0.006), and apoB100 (−0.04 g/L; P = 0.022), tended to increase HDL-C (0.03 mmol/L; P = 0.088) and increased hsCRP (1.2 mg/L; P = 0.017) concentrations. Fasting apoA-I, TAG, FFA, glucose and insulin concentrations were unchanged. In the postprandial phase, theobromine consumption increased glucose (P = 0.026), insulin (P = 0.011) and FFA (P = 0.003) concentrations, while lipids and (apo)lipoproteins were unchanged. In duodenal biopsies, microarray analysis showed no consistent changes in expression of genes, pathways or gene sets related to lipid, cholesterol or glucose metabolism. Conclusions It is not likely that the potential beneficial effects of cocoa on CVD can be ascribed to theobromine. Although theobromine lowers serum LDL-C concentrations, it did not change fasting HDL-C, apoA-I, or postprandial lipid concentrations and duodenal gene expression, and unfavorably affected postprandial glucose and insulin responses. This trial was registered on clinicaltrials.gov under study number NCT02209025.
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.
The alteration of the intestinal barrier function is currently believed to be involved in the pathogenesis of gut diseases mainly associated with the activation of inflammation processes.
Diet plays ...an important role in the control of human gut integrity. Theobromine is a natural methylxanthine present in dark chocolate particularly abundant in cocoa bean shell. This is a polyphenol rich by-product generated in cocoa industrial processing, which is gaining value as a functional ingredient. This study aims to highlight for the first time the capability of theobromine in protecting the intestinal cell monolayer from a mixture of dietary oxysterols showing an inflammatory action in terms of IL-8 and MCP-1 overproduction. Differentiated CaCo-2 cells were treated with 60 μM oxysterol mixture and pre-incubated with 10 μM theobromine. Intestinal barrier damage was investigated in terms of tight junction claudin 1, occludin and JAM-A protein levels, matrix metalloproteinase (MMP) −2 and −9 activation and anti/pro-apoptotic protein changes.
The observed cell monolayer permeability protection by theobromine may be due to its ability to inhibit the production of cytokines and MMPs that can be responsible for tight junction loss and apoptosis in intestinal cells. Our findings provide additional mechanistic hints on the healthy effect of theobromine cocoa component as an attractive natural molecule in the prevention of inflammatory gut diseases.
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•Theobromine (TB), other than polyphenols, is the main cocoa bean shell component.•TB prevents intestinal inflammation induced by a mixture of dietary oxysterols.•TB protects CaCo-2 cell monolayer from oxysterol-dependent tight junction loss and matrix metalloproteinase activation.•TB inhibits oxysterol-induced apoptosis by restoring Bax/Bcl-xL protein level changes.•TB can be partly responsible for the benefits associated with cocoa consumption.
This study substantially synthesized the β-type MnO2 nano-flowers assembled by the hierarchical nano-sheets using a simplified hydro-thermal procedure. According to the FESEM images, MnO2 nano-flower ...exhibited diameter of ∼800 nm and fabricated with a lot of irregular sheets as a petal-like structure with thickness of several nano-meters. Therefore, the study focused on the construction of an electro-chemical sensor to simultaneously determine theobromine (ThB), theophylline (ThP), as well as caffeine (CaF) on the basis of the β-type hierarchical structure of the MnO2 nano-flowers (βH-MnO2-NF) modified electrode (βH-MnO2-NF/GCE). Analysis showed an acceptable linear association between the oxidation peak current and ThB, ThP and CaF concentration within the ranges between 0.01 and 320.0 μM with a limit of detection (LOD) equal to 8.7, 5.9, and 10.1 nM (S/N = 3), respectively. Additionally, this study intended to investigate ThB, Thp and CaF bio-availability in the five commercially available brands of the chocolate products and drug.
Electrochemical sensor based on β-MnO2 nanoflower modified glassy carbon electrode for simultaneous detecting theobromine, theophylline and caffeine was fabricated. Display omitted
•Petal-like MnO2 nanostructure were synthesized and characterized by EDX, XRD and SEM.•Petal-like MnO2 nanostructure was used for modified carbon paste electrode.•This modified electrode was used for the simultaneous determination of 3 methylxanthines.
Uric acid (UA) renal lithiasis has a high rate of recurrence and a prevalence ranging from 10% and 15%, depending on the population. The most important etiological factor is persistence of urinary pH ...below 5.5 and one of the most common treatments is alkalization with citrate. Recent studies demonstrated that theobromine, which is abundant in chocolate and cocoa, is a potent inhibitor of UA crystallization.
The aim was to compare the efficacy of citrate versus citrate + theobromine as treatment for UA lithiasis.
This randomized cross-over trial investigated the efficacy of two treatments in 47 patients with UA renal lithiasis. Urine volume, pH, UA excretion, theobromine excretion, and risk of UA crystallization (RUAC) at baseline and at the end of each intervention period were measured.
Each treatment significantly reduced the risk of UA crystallization compared to basal values. The RUAC after citrate + theobromine was lower than the RUAC after citrate, although this difference was not statistically significant.
The combined consumption of citrate and theobromine may be a promising strategy for the prevention of UA kidney stones.
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