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Quantitative proteomics reveals common and unique molecular mechanisms underlying beneficial effects of caffeine and trigonelline on human hepatocytes

ABSTRACT: Caffeine and trigonelline are the major bioactive compounds in coffee. Caffeine alone or combined with other coffee compounds shows hepatoprotective effects. However, molecular mechanisms underlying such hepatoprotective effects remain unclear. We therefore addressed molecular effects of caffeine and trigonelline on human hepatocytes using quantitative proteomics followed by bioinformatic analyses to obtain topological and functional significance. HepG2 cells were treated with 100 μM caffeine or trigonelline for 24-h and evaluated by quantitative proteomics using nanoLC-ESI-LTQ-Orbitrap MS/MS. A total of 27 and 26 significantly altered proteins were identified in caffeine-treated and trigonelline-treated cells, respectively, compared with control cells. Topological analyses revealed that ribosomal and translation regulatory proteins predominantly served as the hub proteins associated with protein clusters. Functional analyses also revealed that these two bioactive compounds shared some molecular mechanisms via induction of translational processes. There were also other unique molecular functions and biological processes triggered or suppressed by either caffeine or trigonelline. These data highlight common and unique molecular mechanisms underlying the hepatoprotective effects of caffeine and trigonelline that may be useful for future clinical applications.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Visith Thongboonkerd

LAB HEAD: Prof. Visith Thongboonkerd

PROVIDER: PXD037553 | Pride | 2023-12-05

REPOSITORIES: Pride

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Quantitative proteomics reveals common and unique molecular mechanisms underlying beneficial effects of caffeine and trigonelline on human hepatocytes.

Peerapen Paleerath P Chanthick Chanettee C Thongboonkerd Visith V

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20221213

Caffeine and trigonelline are the major bioactive compounds in coffee. Caffeine alone or combined with other coffee compounds shows hepatoprotective effects. However, molecular mechanisms underlying such hepatoprotective effects remain unclear. We therefore addressed molecular effects of caffeine and trigonelline on human hepatocytes using quantitative proteomics followed by bioinformatic analyses to obtain topological and functional significance. HepG2 cells were treated with 100 μM caffeine or ...[more]

PMID: 36521247

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Project description:described in: Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects Shi J, Benowitz NL, Denaro CP and Sheiner LB. ;Clin. Pharmacol. Ther. 1993 Jan;53(1):6-14. PMID:8422743; Abstract: We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90 percent reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine. Caffeine intake in this version is modelled as cups of coffee drunk at regular intervals (parameter t_interval). The amount of caffeine per cup is determined by the parameter cupsize. The body weight of the person drinking is given by the parameter bodyweight. The even coffee cup occures delayed to the drinking of each cup, as the availability of the caffeine in the digestive tract is assumed to be delayed to the ingestion by the time t_lag. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Our previous research demonstrated that caffeine exposure on embryonic day (E) 8.5 increased body weight, altered cardiac morphology and function in adult male mice. However, these adverse effects were not observed in adenosine A1 receptor knockout (A1AR-/-) mice. Our hypothesis is that A1AR action mediates changes in DNA methylation patterns in mice exposed in utero to caffeine and that these changes in methylation lead to long-term effects in adult mice. To test this hypothesis, DNA Methylation 2.1M Deluxe Promoter Arrays (NimbleGen) were used to examine the methylation patterns of DNA isolated from adult left ventricles of the A1AR knockout line exposed to 20 mg/kg caffeine at E8.5 in utero. In A1AR+/+ mice, 4,896 hypermethylated and 2,823 hypomethylated regions were discovered in the left ventricles of the caffeine group compared to the normal saline group. In A1AR-/- mice, 1,024 hypermethylated and 1,757 hypomethylated regions were found in the caffeine group. The differentially methylated regions (DMRs) in the caffeine treated A1AR+/+ hearts mapped to 6,148 genes, 4,853 promoters, 4,111 primary transcripts, 816 CpG islands, and 98 miRNAs. Functional annotation clustering of genes revealed that many genes were involved in the development of hypertrophic cardiomyopathy and other heart diseases, which may explain our earlier findings of thickening of the left ventricular wall after in utero caffeine treatment. The methylation changes in several DMRs, mef2c, ins2, tnnt2, and myh6, were validated by bisulfite sequencing. In summary, in utero caffeine exposure caused DNA methylation changes in adult left ventricles and that these changes may be mediated by A1ARs. Pregnant mice were injected at embryonic day 8.5 with 0.9% NaCl (vehicle) or 20 mg/kg caffeine in vehicle i.p. Pups were born and raised until 8-10 weeks of age. Analysis was performed on the following groups vehicle A1AR+/+ (veh+/+), vehicle A1AR-/- (veh-/-), caffeine A1AR+/+ (caff+/+), and caffeine A1AR-/- (caff-/-). Genomic DNA from left ventricles of adult male mice was used. Two biological replicates were measured for each group.

Project description:A summary of the work associated to these microarrays is the following: Background: Phenolic compounds present in coffee are antioxidants in vitro that might protect against cardiovascular disease and certain types of cancer in humans. Objective: Our aim was to identify differentially expressed genes upon incubation of HT-29 human colon cancer cells with instant caffeinated coffee (ICC) or caffeic acid (CA) using microarrays. Results: In HT-29 cells incubated with ICC, 77 genes were overexpressed whereas 162 were underexpressed. Upon incubation with CA, 12 genes were overexpressed whereas 33 were underexpressed. A list of five overexpressed genes and eleven underexpressed genes were found in common between the two conditions and was use to construct a biological association network. In the generated network, STAT5B and ATF-2 appeared as highly interconnected nodes. STAT5B overexpression was confirmed at the mRNA and protein levels. For ATF-2, the changes in mRNA levels were confirmed for both ICC and CA, whereas the decrease in protein levels was only observed in CA-treated cells. The levels of cyclin D1, a target gene for both STAT5B and ATF-2 transcription factors, decreased dramatically in breast cancer cells treated with CA or ICC. Conclusions: Coffee polyphenols are able to affect gene expression in cancer cells through the modulation of STA5B and ATF-2 transcription factors. The aim of our study was to evaluate, by using whole genome microarrays, the effects of one cup of coffee, either regular caffeinated coffee or a coffee polyphenol, such as caffeic acid, on HT-29 gene expression, Three experimental approaches were conducted to assess the effects of coffee on HT29 cells. I) Incubation with non cytotoxic concentrations of ICC (7 Âµg/mL) for 24h. (Group ICC); II) Incubation with non cytotoxic concentrations of CA (1.68 Âµg/mL) for 24h. (Group CA); III) non treatment of HT-29 to refered as a control (Group CNT). Triplicate samples were hybridized for each experimental condition (9 samples in total). The samples provided were analyzed using the specific software GeneSpring GX.

			Action	DRS
	Annotated_MSMS_spectra.pptx	Other
	CAF_1-2.raw	Raw
	CAF_1-3.raw	Raw
	CAF_1_1.raw	Raw
	Control_1_1.raw	Raw