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PubMed2002

Inhibitory activity of the white wine compounds, tyrosol and caffeic acid, on lipopolysaccharide-induced tumor necrosis factor-alpha release in human peripheral blood mononuclear cells.

The objective of this study was to assess whether tyrosol and caffeic acid are able to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release. TNF is one of the most important cytokines involved in inflammatory reactions. The results show that both tyrosol and caffeic acid are able to inhibit LPS-induced TNF-alpha release from human monocytes, even at low doses. Their mechanisms of action are discussed and we conclude that high doses of the two compounds are not required to achieve effective inhibition of inflammatory reactions due to TNF-alpha release.

Caffeic Acids↗
PubMed2001

Novel biomarkers of the metabolism of caffeic acid derivatives in vivo.

The purpose of this study was to investigate biomarkers of the bioavailability and metabolism of hydroxycinnamate derivatives through the determination of the pharmacokinetics of their urinary elimination and identification of the metabolites excreted. Coffee was used as a rich source of caffeic acid derivatives and human supplementation was undertaken. The results show a highly significant increase in the excretion of ferulic, isoferulic, dihydroferulic acid (3-(4-hydroxy-3-methoxyphenyl)-propionic acid), and vanillic acid postsupplementation relative to the levels presupplementation. Thus, ferulic, isoferulic, and dihydroferulic acids are specific biomarkers for the bioavailability and metabolism of dietary caffeic acid esters. Isoferulic acid is a unique biomarker as it is not a dietary component, however, dihydroferulic acid may well derive from other flavonoids with a structurally related B-ring. 3-Hydroxyhippuric acid has also been identified as an indicator for bioavailability and metabolism of phenolic compounds, and shows a highly significant excretion increase postsupplementation. The results reveal isoferulic acid (and possibly dihydroferulic acid) as novel markers of caffeoyl quinic acid metabolism.

Adult↗
PubMed2004

Microbial metabolites of ingested caffeic acid are absorbed by the monocarboxylic acid transporter (MCT) in intestinal Caco-2 cell monolayers.

It was previously reported that m-coumaric acid, m-hydroxyphenylpropionic acid (mHPP), and 3,4-dihydroxyphenylpropionic acid (DHPP) are major metabolites of ingested caffeic acid formed by gut microflora and would be transported by the monocarboxylic acid transporter (MCT). We have directly measured their absorption characteristics in Caco-2 cells using a coulometric detection method involving HPLC-ECD. The proton-coupled directional transport of m-coumaric acid, mHPP, and DHPP was observed, and the transport was inhibited by an MCT substrate. The permeation of m-coumaric acid and mHPP was concentration-dependent and saturable: The Michaelis constant for m-coumaric acid and mHPP was 32.5 and 12.9 mM, respectively, and the maximum velocity for m-coumaric acid and mHPP was 204.3 and 91.2 nmol (min)(-1) (mg protein)(-1), respectively. By contrast, the permeation of DHPP was nonsaturable even at 30 mM and was inversely correlated with the paracellular permeability of Caco-2 cells. Our results demonstrate that these compounds are absorbed by the MCT, although DHPP is mainly permeated across Caco-2 cells via the paracellular pathway. MCT-mediated absorption of phenolic compounds per se and their colonic metabolites would exert significant impact on human health.

Biological Transport↗
PubMed2004

Caffeic acid phenethyl ester ameliorated ototoxicity induced by cisplatin in rats.

Caffeic acid phenethyl ester (CAPE), an active component of propolis, exhibits antioxidant properties. This experimental study was designed to determine the effect of CAPE on ototoxicity induced with cisplatin. Twenty-four adult Wistar albino rats were divided into four groups: cisplatin (n=6), saline (n=6), CAPE (n=6), and cisplatin plus CAPE (n=6). Rats were tested before and 5 days after cisplatin treatment with or without chemo protection. The Distortion Product Otoacoustic Emissions (DPOAEs) were elicited from the control and experimental animals utilizing the standard commercial Otoacoustic Emission (OAEs) apparatus. The animals in all groups were sacrificed under general anesthesia on the fifth day following last OAE measurements. For biochemical investigations, the blood samples were drawn from inferior vena cava. On day 0, the initial baseline DPOAEs measurement results presented similar values while comparing the groups in drug free phase (p>0.05). On day 5, intrasubject measurement parameters of DPgrams and I/O functions of cisplatin group were significantly deteriorated (p<0.05). The second measurements of the other groups revealed no significant differences between their DPgrams and I/O functions in all frequencies (p>0.05). Among the biochemical parameters, plasma xanthine oxidase (XO) activity was found to be more elevated in the cisplatin group than the saline group (p<0.05). CAPE led to more decreased XO activity than cisplatin (p<0.05). The results of this study show that prophylactic administration of CAPE for cisplatin ototoxicity ameliorated hearing deterioration in rats.

Analysis of Variance↗
PubMed2003

Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells.

Caffeic acid phenethyl ester (CAPE), an active component of propolis, has many biological and pharmacological activities including antioxidant, anti-inflammation, antiviral action, and anticancer effect. Our previous studies showed that CAPE exhibited significant cytotoxicity in oral cancer cells. Herein we further investigated the cytotoxicity potential of CAPE and the mechanism of its action in C6 glioma cells. The data exhibited that C6 glioma cells underwent internucleosomal DNA fragmentation 24 hr after the treatment of CAPE (50 microM). The proportion of C6 glioma cells with hypodiploid nuclei was increased to 24% at 36 hr after the exposure. Further results showed that CAPE induced the release of cytochrome c from mitochondria into cytosol, and the activation of CPP32. CAPE application also enhanced the expression of p53, Bax, and Bak. Finally, the potential signaling components underlying CAPE induction of apoptosis were elucidated. We found that CAPE activated extracellular signal-regulated kinase (ERKs) and p38 mitogen-activated protein kinase (p38 MAPK) in C6 glioma cells. More importantly, p38 kinase formed a complex with p53 after the treatment of CAPE for 0.5 hr. The expression of p53, phospho-serine 15 of p53, and Bax, and inactivate form of CPP32 was suppressed by a pretreatment of a specific p38 MAPK inhibitor, SB203580. The resultant data suggest that p38 MAPK mediated the CAPE-induced p53-dependent apoptosis in C6 glioma cells.

Animals↗
PubMed1997

Dose response for the stimulation of cell division by caffeic acid in forestomach and kidney of the male F344 rat.

Caffeic acid (CA, 3,4-dihydroxycinnamic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by immunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.40 and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1. 8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.

Animal Feed↗
PubMed1999

[Studies on caffeic acid derivatives in medicinal plants].

The components of Artemisia and Labiatae species were isolated and their chemical structures were determined. These compounds were found to have tannic activity for the first time. The activity of the compounds comes from the caffeic acid moiety in their molecules, not from structural features of usual tannins (hydrolyzable and condensed tannins). These also showed several other biological activities. Furthermore, the research on dimerization of caffeic acid derivatives was performed.

Antioxidants↗
PubMed1998

Developmental expression and substrate specificities of alfalfa caffeic acid 3-O-methyltransferase and caffeoyl coenzyme A 3-O-methyltransferase in relation to lignification.

The biosynthesis of monolignols can potentially occur via two parallel pathways involving free acids or their coenzyme A (CoA) esters. Caffeic acid 3-O-methyltransferase (COMT) and caffeoyl CoA 3-O-methyltransferase (CCOMT) catalyze functionally identical reactions in these two pathways, resulting in the formation of mono- or dimethoxylated lignin precursors. The activities of the two enzymes increase from the first to the sixth internode in stems of alfalfa (Medicago sativa L.), preceding the deposition of lignin. Alfalfa CCOMT is highly similar at the amino acid sequence level to the CCOMT from parsley, although it contains a six-amino acid insertion near the N terminus. Transcripts encoding both COMT and CCOMT are primarily localized to vascular tissue in alfalfa stems. Alfalfa CCOMT expressed in Escherichia coli catalyzes O-methylation of caffeoyl and 5-hydroxyferuloyl CoA, with preference for caffeoyl CoA. It has low activity against the free acids. COMT expressed in E. coli is active against both caffeic and 5-hydroxyferulic acids, with preference for the latter compound. Surprisingly, very little extractable O-methyltransferase activity versus 5-hydroxyferuloyl CoA is present in alfalfa stem internodes, in which relative O-methyltransferase activity against 5-hy-droxyferulic acid increases with increasing maturity, correlating with increased lignin methoxyl content.

Amino Acid Sequence↗
PubMed2004

Orally administered rosmarinic acid is present as the conjugated and/or methylated forms in plasma, and is degraded and metabolized to conjugated forms of caffeic acid, ferulic acid and m-coumaric acid.

Rosmarinic acid (RA) is contained in various Lamiaceae herbs used commonly as culinary herbs. Although RA has various potent physiological actions, little is known on its bioavailability. We therefore investigated the absorption and metabolism of orally administered RA in rats. After being deprived of food for 12 h, RA (50 mg/kg body weight) or deionized water was administered orally to rats. Blood samples were collected from a cannula inserted in the femoral artery before and at designated time intervals after administration of RA. Urine excreted within 0 to 8 h and 8 to 18 h post-administration was also collected. RA and its related metabolites in plasma and urine were measured by LC-MS after treatment with sulfatase and/or beta-glucuronidase. RA, mono-methylated RA (methyl-RA) and m-coumaric acid (COA) were detected in plasma, with peak concentrations being reached at 0.5, 1 and 8 h after RA administration, respectively. RA, methyl-RA, caffeic acid (CAA), ferulic acid (FA) and COA were detected in urine after RA administration. These components in plasma and urine were present predominantly as conjugated forms such as glucuronide or sulfate. The percentage of the original oral dose of RA excreted in the urine within 18 h of administration as free and conjugated forms was 0.44 +/- 0.21% for RA, 1.60 +/- 0.74% for methyl-RA, 1.06 +/- 0.35% for CAA, 1.70 +/- 0.45% for FA and 0.67 +/- 0.29% for COA. Approximately 83% of the total amount of these metabolites was excreted in the period 8 to 18 h after RA administration. These results suggest that RA was absorbed and metabolized as conjugated and/or methylated forms, and that the majority of RA absorbed was degraded into conjugated and/or methylated forms of CAA, FA and COA before being excreted gradually in the urine.

Administration, Oral↗
PubMed1996

Inhibitory effects of caffeic acid ethyl ester on H2O2-induced cytotoxicity and DNA single-strand breaks in Chinese hamster V79 cells.

Cytotoxicity and DNA single-strand breaks caused by H2O2 were assessed by a colony formation assay and a DNA precipitation assay, respectively, with Chinese hamster V79 cells. In both assays, caffeic acid ethyl ester showed protective effects. The structure-activity relationship showed that the o-dihydroxy structure of caffeic acid ethyl ester was essential for the protective effects.

Animals↗
PubMed1995

Redox intermediates of flavonoids and caffeic acid esters from propolis: an EPR spectroscopy and cyclic voltammetry study.

The redox properties of flavonoids: chrysin (1), tectochrysin (2), galangin (3), isalpinin (4), pinostrobin (5), pinobanksin (6), pinobanksin-3-acetate (7), and of caffeic acid ester (8) and diacetylcaffeic acid ester (9), all isolated from propolis, were investigated by cyclic voltammetry in acetonitrile. The choice of aprotic solvent lowered the reactivity of the radical intermediates and made possible to identify redox steps and intermediates not detected so far. The oxidation potentials (vs. saturated calomel electrode) of the investigated compounds were in the region of 1.5 V for 3 and 4; 1.9 V for 1, 2, and 5; 2.0 V for 6 and 7; 1.29 V for 8; and 2.3 V for 9. These oxidation potentials were mainly influenced by the presence of a double bond in 2,3-position and substituent R1 in position 3. Comparison with our earlier data revealed that flavonoids, 1-4, and caffeic acid ester 8 with lower oxidation potentials showed the maximal lipid antioxidant activity, whereas those with higher potentials (5, 6, 7, and 9) are less active. On reduction of 1-9 several one-electron-steps were typically observed in the potential regions: -1.5 V, -1.8 V, and -2 V. where in simultaneous EPR experiments anion radicals of 1 and 3 were observed with the center of unpaired spin density on ring A. Upon oxidation of flavonoids 1-4 carbonyl carbon-centered radicals, .C(O)R, were identified as consecutive products using the EPR spin trapping technique.

Antioxidants↗
PubMed2002

Mechanistic study of the oxidation of caffeic acid by digital simulation of cyclic voltammograms.

The oxidation mechanism of caffeic acid (CAF) has been studied by means of cyclic voltammetry with the plastic formed carbon or glassy carbon electrode. CAF gives a well-developed two-electron reversible wave in acidic media, whereas it shows an irreversible behavior, i.e., a decrease of the rereduction peak, in less acidic media, suggesting that the oxidation of CAF follows an irreversible chemical reaction(s). Digital simulation analyses based on different oxidation mechanisms have been performed for the voltammograms obtained with the GC electrode in 1:1 (v/v) water:ethanol solutions. The results clearly show that the seeming two-electron oxidation of CAF occurs stepwise via one-electron processes, each of which follows an irreversible chemical reaction. It has also been suggested that the semiquinone radical as an intermediate of the one-electron oxidation should play an important role in the oxidation reaction. Evaluations of the rate constants for the chemical reactions have further suggested that the chemical reactions are dimerization reactions.

Caffeic Acids↗
PubMed2000

In vitro inhibition of the activity of phosphorylase kinase, protein kinase C and protein kinase A by caffeic acid and a procyanidin-rich pine bark (Pinus marittima) extract.

Caffeic acid (CA) is a common constituent of human diet while pine bark extract (PBE) is utilized either as nutritional supplement or as phytochemical remedy for different diseases. CA and PBE, are reported as efficient antioxidants and more recently have been described to modulate cellular response to oxidative challenge and to possess many other biological activities, i.e. anti-inflammatory, antimutagenic, antitumoral effects. In order to investigate in depth the mechanism of action of these polyphenols, the effects of CA and PBE on the activity of some protein kinases involved in the regulation of fundamental cellular processes were studied in vitro: phosphorylase kinase (PhK), protein kinase A (PKA), protein kinase C (PKC). PBE at the concentration of 20 microg/ml (corresponding to 69 microM catechin equivalents) inhibited PKA, PhK and PKC by about 90, 59, 57%, respectively, while 100 microM CA inhibited by 37, 52 and 54%, respectively. Considerable inhibitions have been still observed at even lower concentrations of CA and PBE. For PhK and PKA, the inhibition follows a non-competitive mechanism. CA also inhibits PKC activity in a partially purified cellular extract. The results suggest a possible involvement of CA and PBE in modulation of cellular functions.

Caffeic Acids↗
PubMed2005

Effects of caffeic acid phenethyl ester on endotoxin-induced uveitis in rats.

PURPOSE: Caffeic acid phenethyl ester (CAPE) has antimicrobial, anti-inflammatory, antioxidant, immunomodulatory, and carcinostatic properties. In this study, the efficacy of CAPE in endotoxin-induced uveitis (EIU) in rats is investigated. METHODS: EIU was induced by a footpad injection of lipopolysaccharide (LPS). In the treatment group, 10 micromol/kg CAPE was injected intraperitoneally immediately after LPS injection. At 24 hr after LPS injection, the number of infiltrating cells, protein concentration, and levels of myeloperoxidase (MPO) in aqueous humor; malondialdehyde (MDA), MPO, and total antioxidant levels in serum were determined. Eyes were enucleated for histopathologic evaluation, and, counting inflammatory cells in iris-ciliary body (ICB), the efficacy of treatment was determined. RESULTS: CAPE significantly suppressed LPS-induced increase in the number of inflammatory cells (p = 0.0001), protein concentration (p = 0.0001), and MPO levels (p = 0.0001) in aqueous humor as well as MDA (p = 0.001) and MPO (p = 0.0001) levels in serum. Histopathologic evaluation of ICB showed significant reduction in the inflammatory cell counts in the treatment group (p = 0.0001). CONCLUSIONS: CAPE was found efficient in suppressing inflammation and ocular tissue damage induced by LPS in rats.

Animals↗
PubMed2005

Caffeic acid phenethyl ester protects kidneys against carbon tetrachloride toxicity in rats.

Caffeic acid phenethyl ester (CAPE), an active component of propolis produced by honeybees, exhibits antioxidant and anti-inflammatory properties. The aim of this study was to investigate possible protective effects of CAPE on carbon tetrachloride (CCl4)-induced renal damage in rats. A total of 24 animals were divided into three equal groups: the control rats received pure olive oil subcutaneously, rats in the second group were injected with CCl4 (0.5 ml/kg, s.c. in olive oil) and rats in the third group were injected with CCl4 (0.5 ml/kg) plus CAPE (10 micromol/kg, i.p.) every other day for one month. At the end of the experimental period, the animals were sacrificed and blood samples were collected. Serum urea and creatinine levels and renal malondialdehyde (MDA) contents were determined. Histopathological examination of the kidney was also performed using light microscopic methods. It was found that kidney MDA levels were increased significantly following CCl4 exposure and this increase was significantly inhibited by CAPE treatment, while no significant changes were observed in serum urea and creatinine levels. CCl4 administration alone also caused histopathologically prominent damage in the kidney compared to the control group. Glomerular and tubular degeneration, interstitial mononuclear cell infiltration and fibrosis, and vascular congestion in the peritubular blood vessels were observed in the renal cortex. With exception of rare vascular congestions, these histopathological changes were disappeared in rats treated with CCl4 plus CAPE. In view of the present findings, it is suggested that CAPE protects kidneys against CCl4 toxicity.

Animals↗
PubMed2006

Caffeic acid phenethyl ester prevents cadmium-induced cardiac impairment in rat.

Caffeic acid phenethyl ester (CAPE), a flavonoid like compound, is one of the major components of honeybee propolis. It was found to be a potent free radical scavenger and antioxidant recently. The aim of this study was to examine the effect of CAPE on cadmium (Cd)-induced hypertension and cardiomyopathy in rats. In particular, nitric oxide (NO) may contribute to the pathophysiology of Cd induced cardiac impairment. Malondialdehyde (MDA, an index of lipid peroxidation) levels and nitric oxide (NO, a vasodilator) levels were used as markers Cd-induced cardiac impairment and the success of CAPE treatment. Also, the findings have been supported by the histopathologic evidences. The rats were randomly divided into three experimental groups each (12), as follows: the control group, Cd-treated group (Cd) and Cd plus CAPE-treated group (Cd+CAPE). CdCl(2) in 0.9% NaCl was administrated intraperitoneally (i.p.) with a dose of 1mg/kg/day. CAPE was co-administered i.p. a dose of 10 microM/kg for 15 days. Hypertension was found to be induced by intraperitoneal administration of Cd in a dose of 1mg/kg/day on the measurements taken 15 days later. MDA levels were increased (p<0.001) in cardiac tissue and NO levels were decreased (p<0.05) in serum in the Cd group than those of the control group had. On the other hand, there was a slight difference (increase) in MDA levels in the Cd+CAPE group than the ones in the control group (p<0.003). In addition, MDA levels were decreased and NO levels were increased in the Cd+CAPE group compared with the Cd group (p<0.001, p<0.0001, respectively). As a result, treatment with CAPE significantly reversed the increased lipid peroxidation (LPO) product, MDA, and decreased NO levels in Cd treated animals. In the histopathologic examination, a significant hypertrophy in atrial and ventricular myofibrils was observed in only Cd administered group, in comparison with the control group. There was no statistically significant difference between the CAPE given and control groups by means of atrial and ventricular myofibril diameters. In conclusion, the underlying mechanism of the myocardial hypertrophy may be related to hypertension due to inhibition of NO production in the vessels, and CAPE has a protective effect on Cd-induced hypertension mediated cardiac impairment in the rats.

Animals↗
PubMed2006

Methotrexate-induced renal oxidative stress in rats: the role of a novel antioxidant caffeic acid phenethyl ester.

The exact mechanisms of methotrexate-induced renal toxicity have not yet been determined. However, several hypotheses have been put forward, including oxidative stress. The aim of this study was to investigate the role of caffeic acid phenethyl ester (Caffeic Ester), a novel antioxidant, on methotrexate-induced renal oxidative stress in rats. Nineteen adult male rats were equally divided into three experimental groups as follows: control group, methotrexate-treated group, and methotrexate+Caffeic Ester-treated group. A single dose of methotrexate (20 mg/kg) was administered intraperitoneally (ip). Caffeic Ester (10 micromol/kg) was administered ip, once daily for seven days. Malondialdehyde (MDA) levels (an index of lipid peroxidation) were used as a marker of oxidative stress-induced renal injury. Similarly, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were determined to evaluate the changes of antioxidant status in renal tissue. Methotrexate administration to control rats increased MDA levels (P<0.0001), but decreased SOD, CAT and GSH-Px activities in renal tissue (P<0.0001). Caffeic Ester+ methotrexate treatment caused a significant decrease in MDA levels (P<0.001), and caused an increase in SOD, CAT and GSH-Px activities when compared with methotrexate treatment alone (P<0.001, <0.05, <0.0001, respectively). In conclusion, methotrexate leads to a reduction in antioxidant enzymatic defense capacity and causes lipid peroxidation in renal tissue. Similarly, Caffeic Ester exhibits protective effects on methotrexate-induced renal oxidative impairment in rats.

Animals↗
PubMed2006

Lithium-induced lung toxicity in rats: the effect of caffeic acid phenethyl ester (CAPE).

AIMS: We aimed to evaluate the effects of caffeic acid phenethyl ester (CAPE) on lithium (Li)-induced lung toxicity. METHODS: Twenty-two adult male Wistar albino rats weighing between 280 and 300 g were used. The rats were randomly divided into three groups: control, Li and Li+CAPE groups. Li and CAPE were co-administered intraperitoneally twice daily for 4 weeks. Control rats were given 0.9% NaCl during the same period. All the rats were allowed to feed ad libitum until midnight after they had received the proposed treatment. RESULTS: In the Li group, peribronchial and intraparenchymal lymphocyte and macrophage infiltration were observed. Atypical type II pneumocytes, alveolar destruction and emphysematous changes were also detected. Lymphocyte and macrophage infiltration was significantly decreased in the Li+CAPE group compared with the Li group. Alveolar destruction, emphysematous changes and intraparenchymal mononuclear cell infiltration were also recovered to a level close to the control group. Malondialdehyde (MDA) levels were increased in the Li group compared with the control group. CAPE administration decreased the MDA levels in the Li+CAPE group. CONCLUSIONS: CAPE was found to associate with histopathological changes recovery in the lungs and oxidative stress due to Li treatment.

Animals↗