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Phenylethanoid triglycoside acylated with caffeic acid was isolated from the inflorescences of V, lychnitis and identified as verbascoside 6'-0-beta-D-apiofuranoside (forsythoside B). It has also been found, that forsythoside B is one of the major constituents in the inflorescences of V. lychnitis and V. nigrum, whereas in the flowers of V. phlomoides and V. densiflorum it was hardly detectable.
The activation of microglial cells is involved in the pathogenesis of a variety of neurodegenerative diseases, stroke and traumatic brain injuries. Recent studies suggest that protein acetylation can affect the extent of inflammatory responses. Our aim was to elucidate whether histone deacetylase inhibitors, inducers of protein hyperacetylation, regulate the inflammatory response in neural models of inflammation in vitro and whether neurone-glia interactions affect this regulation. Interestingly, we observed that histone deacetylase inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid, strongly potentiated the lipopolysaccharide (LPS)-induced inflammatory response in murine N9 and rat primary microglial cells as well in neural co-cultures and hippocampal slice cultures. TSA clearly potentiated the LPS-induced expression of interleukin (IL)-6 and inducible nitric oxide synthase mRNAs, as well as the secretion of cytokines IL-6, tumour necrosis factor-alpha and macrophage inflammatory protein (MIP)-2, and nitric oxide (NO). Co-culture and slice culture experiments showed that the presence of astrocytes and neurones did not stimulate or prevent the pro-inflammatory potentiation induced by histone deacetylase inhibitor in microglial cells. The potentiation of cytokine and NO responses was blocked by the nuclear factor kappa B (NF-kappa B) inhibitors caffeic acid phenethyl ester and helenalin, demonstrating that the NF-kappa B signalling pathway is involved. The DNA-binding activity of the NF-kappa B complex was strongly increased by LPS treatment but not enhanced by TSA. This suggests that potentiation of the inflammatory response is not dependent on the level of cytoplasmic NF-kappa B activation or DNA-binding activity but that site of action may be at the level of transcriptional regulation. Our results suggest that environmental stresses, ageing, diet and diseases that regulate protein acetylation status may also affect the inflammatory response.
Propolis is a beehive product with a very complex chemical composition, widely used in folk medicine because of its several therapeutic activities. Its biological properties and chemical composition may vary according to the geographic location and to the different plant sources. The possible mechanism of action of propolis as well as of its active compounds has been the subject of researchers in recent years. In this work, first we reported the results of our study on the seasonal effect of the immunomodulatory action of propolis on antibody production in bovine serum albumin (BSA)-immunized rats. Then, we compared the effect of Brazilian and Bulgarian propolis, some isolated compounds and Baccharis extract on anti-BSA antibody levels. Based on the results, we conclude that propolis stimulates antibody production, independently of the season and geographic origin. Caffeic acid, quercetin and Baccharis extract had no effect on antibody production, although the importance of isolated compounds is well reported in other biological assays. Propolis action is a consequence of plant-derived products with synergic effects, while isolated compounds or extracts from its plant sources had no effect in this assay.
Keratinocytes not only produce vitamin D3 in response to ultraviolet B light (UVB) and convert 25-hydroxyvitamin D3 to 1 alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D) but also possess the vitamin D receptor (VDR) and respond to 1,25(OH)2D. We characterized the regulation of the expression of the VDR gene in primary human keratinocytes following UVB irradiation. We report a marked dose-dependent down-regulation of the VDR mRNA and protein within a few hours after irradiation. This occurs independently of de novo protein synthesis and is not due to a change in the half-life of the VDR mRNA. Interestingly, treatment of the cells with sodium salicylate, caffeic acid phenethyl ester and tosylphenylchloromethylketone inhibited this down-regulation. Our results strongly suggest the existence of a feedback mechanism in that UVB initiates vitamin D synthesis in keratinocytes and at the same time limits VDR abundance. They also provide a rational explanation for the reported lack of any additive effect between 1,25(OH)2D and UVB phototherapy in the treatment of psoriasis.
The acute anti-oxidant and protective effect of American ginseng berry extract (AGBE) has been demonstrated in cultured cardiomyocytes in our previous study. In the current study we evaluated if a chronic pretreatment of cultured cardiomyocytes with AGBE can alter the cellular antioxidant potential. Chick embryo cardiomyocytes were treated with AGBE (0.5-2.5 mg/ml) for up to 72 h. The treated cells were then exposed to exogenously added hydrogen peroxide (H(2)O(2); 500 microM). The oxidant-mediated injury was measured using a fluorescent probe 2',7'-dichlorofluorescin diacetate (DCFH/DA) while cell death was measured using propidium iodide (PI) staining. The non-treated (control) cells exposed to H(2)O(2) showed significant increase in DCF- and PI-mediated fluorescence suggesting significant oxidative injury and cell death. Pretreatment with AGBE demonstrated a significant attenuation of DCF fluorescence (p<0.005) with AGBE 0.5 mg/ml showing a 17% decrease, AGBE 1.0 mg/ml showing a 26% decrease, and AGBE 2.5 mg/ml showing a 49% decrease from control DCF fluorescence following a 72 h pretreatment. Cell death caused by H(2)O(2) was also significantly attenuated in AGBE-pretreated cells in a concentration- and time-dependent manner (p<0.005). We also demonstrated that active polyphenolic constituents in AGBE, caffeic acid and chlorogenic acid, appear to contribute significantly to AGBE's protective effects. Finally, catalase inhibition resulted in a significantly increased fluorescence in AGBE-treated cells compared to the control. The results suggest that pretreatment with AGBE upregulates peroxide detoxifying mechanisms, which could affect intracellular oxidant dynamics in cardiomyocytes.
The inhibitory effects of Perilla frutescens and its phenolic constituents on cytokine-induced proliferation of murine cultured mesangial cells were investigated. DNA synthesis of mesangial cells stimulated by platelet derived growth factor (PDGF, 10 ng/ml) or tumor necrosis factor (TNF)-alpha (100 U/ml) was inhibited by the extract of P. frutescens (IC50 values, 3.3 and 1.4 micrograms/ml, respectively). The strength of the anti-proliferative activity was nearly equal in various chemotypes of P. frutescens. Caffeic acid, methyl caffeate, rosmarinic acid, and luteolin 7-O-glucuronide-6"-methyl ester were isolated as active constituents from the extract of the typical strain of P. frutescens, and their IC50 values for PDGF-induced mesangial cell proliferation were estimated as 26 microM, 2.6 microM, 1.8 microM, and 4.1 microM, respectively. We also compared the activities of related flavonoids previously isolated from P. frutescens, and luteolin had the highest anti-proliferative activity.
Six different cultural media (corn meal agar, rice extract agar, chlamydospore agar, PCB, Tween 80-oxgall-caffeic acid and diluted milk) were compared for chlamydospore production by 224 yeastlike fungi isolates. Candida albicans formed chlamydospores to a variable degree in all of the media, as did C. stellatoidea to a lesser extent. C. tropicalis, C. parasilopsis, C. guilliermondii and C. krusei did no produce chlamydospores in any of the media tested. Statistically, the most productive media were the milk and TOC media. Milk medium is particularly useful because of its simplicity and economy.
OBJECTIVE: Serotonin via serotonin 2B receptors (SR2BR) regulates cardiac embryonic development and adult heart functions. However, the role of SR2BR in the failing heart due to pressure overload is not well understood. METHODS: Wistar rats of aortic banding and neonatal cardiomyocyte with mechanical stretch were used as cardiomyopathy models. RESULTS: After two weeks of aortic banding surgery, serum serotonin, mRNA and protein expression of SR2BR increased significantly. The selective SR2BR antagonist, SB215505 (SB), significantly reduced the increase in heart weight, decreased heart wall thickness, left ventricular mass and the expression of the brain natriuretic peptide (BNP) but did not attenuate the up-regulation of SR2BR protein expression in rats after aortic banding for three weeks. After following in vitro mechanical stretch of cardiomyocytes and incubation with serotonin 1 muM, the level of SR2BR and BNP protein increased time-dependently. When transfected by specific siRNA of SR2BR or pretreated with caffeic acid phenethyl ester in cardiomyocytes, the increase of nuclear factor-kappaB (NF-kappaB) translocation and BNP protein induced by serotonin incubation plus mechanical stretch were both reversed. CONCLUSIONS: SR2BR expression is involved in pressure-induced cardiomyopathy and its downstream signaling may involve NF-kappaB to modulate BNP expression in cardiomyocyte.
Some N-(hydroxycinnamoyl)-L-tyrosine and L-DOPA alkyl esters were synthesized and evaluated as a variation of the clovamide (N-caffeoyl-L-3,4-dihydroxyphenylalanine) structure, a known antioxidant found in red clover. The amides were prepared in good yields starting from methyl and dodecylesters of L-tyrosine and L-DOPA by reacting with the N-hydroxysuccinimidyl esters of ferulic, sinapic, and acetyl-protected caffeic acid, respectively. In the DPPH* (2,2-diphenyl-1-picrylhydrazyl) and superoxide radical quencher assays they showed radical scavenging activity equal to or higher than those of the standard antioxidants ascorbic acid and tocopherol. The antioxidative potentials of the clovamide derivatives against bulk lipid oxidation, as determined by the accelerated autoxidation of oils, were equal to or higher than those of the standard antioxidants; some of the compounds were able to protect an emulsion of linoleic acid/beta-carotene against oxidation. N-Caffeoyl L-tyrosine methyl ester and the N-cinnamoyl L-DOPA alkyl esters especially were potent antioxidants in bulk lipids and moderate protectants in emulsions.
The reductive release of ferritin iron by several naturally occurring o-diphenols was studied. The initial rate of iron release was quantified by spectrophotometric measurement of the Fe(ferrozine)3(2+) complex, which absorbs maximally at 562 nm. The initial rate of iron release was dependent upon o-diphenol concentration, but not on the concentration of the chromophoric chelating agent, ferrozine, Stoichiometric measurements resulted in a ratio of 2Fe(II) released per molecule of o-diphenol. The series of o-diphenols studied included, caffeic acid, chlorogenic acid, dihydrocaffeic acid, 3,4-dihydroxybenzoic acid, and several analogs. These reductants represent an oxidation reduction potential range of 0.38 volts. A direct correlation between reducing power of the o-diphenols and rate of ferritin iron release was observed. Superoxide dismutase, catalase, mannitol, or general radical traps had no effect on the rate of iron removal; however, EDTA and oxalate inhibited iron release. A mechanism for ferritin iron reduction and release by o-diphenols consistent with the experimental observations is discussed.
It is unknown whether IL-4 induces apoptosis in oral cavity cancer (OCC) cells and, if so, what the mediator of this apoptosis is. Therefore, this study investigated whether apoptosis of OCC cells is induced by IL-4 and whether 15-lipoxygenase-1 (15-LO-1), induced by IL-4, is the mediator of this apoptosis. SCC 1483 oral cavity cancer cells were used in these experiments, and flow cytometry and PARP cleavage were used to examine apoptosis. At an IL-4 dosage that inhibited 50% of cell proliferation, apoptosis was observed, and this apoptosis was inhibited by 2.2 microM caffeic acid (CA). 15-LO-1 mRNA expression was observed beginning at 8 h after treatment with IL-4, and apoptosis increased after 24 h treatment with IL-4. In this apoptosis, the caspase cascade was not involved. In summary, IL-4 induced apoptosis in SCC 1483 OCC cells, and 15-LO-1, induced by IL-4, may mediate this apoptotic pathway.
The altitudinal variation on the contents of secondary metabolites in flowering heads of Arnica montana was assessed. Plants of A. montana cultivar ARBO were grown in nine experimental plots at altitudes between 590 and 2230m at Mount Patscherkofel near Innsbruck/Austria. The total contents of sesquiterpene lactones and flavonoids were not positively correlated with the altitude of the growing site. However, the proportion of flavonoids with vicinal free hydroxy groups in ring B to flavonoids lacking this feature significantly increased with elevation. Additionally, the level of caffeic acid derivatives also positively correlated with the altitude of the growing site. In particular amounts of 1-methoxyoxaloyl-3,5-dicaffeoylquinic acid significantly increased in higher sites and samples from the summit region contained 85% more of this compound than samples from valley sites. These results are discussed with regards to chemosystematic studies comparing samples collected in different altitudes as well as in the light of a UV-B protective and radical scavenging function of phenolics and their significance for plant life in environments with elevated UV-B radiation.
Propolis, obtained from honeybee hives, has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, and immunomodulatory agent. There is considerable evidence suggesting that angiogenesis and chronic inflammation are codependent. Blockage of angiogenesis results in an anti-inflammatory effect. Ethanol (EEP) and ether extracts of propolis (REP), and caffeic acid phenethyl ester (CAPE), an active component of propolis, were examined for their anti-angiogenic activities using the chick embryo chorioallantoic membrane (CAM), and the calf pulmonary arterial endothelial (CPAE) cell proliferation, assays. The presence of EEP, REP and CAPE inhibited angiogenesis in the CAM assay and the proliferation of CPAE cells. The results suggest that anti-angiogenic activities of EEP, REP and CAPE are also responsible for their anti-inflammatory effect.
At non-toxic concentrations, 2 naturally occurring phenolic compounds, caffeic acid and chlorogenic acid, suppressed the mutagenic activity of the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Salmonella typhimurium strain TA1535. The inhibitory effect was observed only when the phenolic compound and the mutagen were administered concurrently. The interaction between phenolic compounds and MNNG was also studied in a cell-free system using a colorimetric method. The results are consistent with the assumption that phenolic compounds scavenge reactive electrophilic MNNG degradation products, thereby preventing their action on critical cellular targets.
The investigation of factors that regulate expression of CC-chemokines, the important mediators in immune responses and inflammation processes, has an important significance in understanding the immunopathogenesis of liver diseases. We examined the role of interleukin-1beta (IL-1beta), a multifunctional cytokine, in regulating the expression of macrophage inflammatory protein (MIP)-1beta in human hepatocytes (Huh7 and HepG2). IL-1beta significantly enhanced MIP-1beta expression in these cells at both the mRNA and protein levels. Cytokine-enriched supernatants from monocyte-derived macrophage (MDM) cultures also induced MIP-1beta expression. IL-1beta is responsible for MDM supernatant-mediated up-regulation of MIP-1beta since the antibody to IL-1beta abolished MDM supernatant action. Investigation of the mechanism involved in MIP-1beta induction by IL-1beta showed that IL-1beta activated the nuclear factor kappa B (NF-kappaB) promoter in Huh7 cells. In addition, caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, not only abolished IL-1beta-mediated NF-kappaB promoter activation, but also blocked IL-1beta-induced MIP-1beta expression. These observations suggest that IL-1beta-mediated up-regulation of MIP-1beta production in the hepatic cells may contribute a critical mechanism for continuous recruitment of inflammatory cell to liver and maintenance of inflammation.
BACKGROUND: Rosmarinic acid (RA) is a natural polyphenolic substance contained in many Lamiaceae herbs such as Perilla frutescens. Previous studies have shown RA has antioxidative and anti-inflammatory activity. However, little is known on the absorption, metabolism, degradation and excretion of RA. AIM OF THE STUDY: The aim of this study in healthy humans was to determine the absorption, metabolism, and urinary excretion of RA after a single intake of perilla extract (PE). METHOD: Six healthy men (mean age 37.2 +/- 6.2 y and mean body mass index 22.0 +/- 1.9 kg/m(2)) were enrolled in the study that was a crossover design involving single intakes of PE containing 200 mg RA and placebo with a 10 day interval between treatments. Blood samples were collected before intake and at designated time intervals, while urine samples were collected over the periods 0-6 h, 6-24 h and 24-48 h after intake. RA and its related metabolites in plasma and urine were measured by LC-MS. RESULTS: RA, methylated RA (methyl-RA), caffeic acid (CAA), ferulic acid (FA) and a trace of m-coumaric acid (COA) were detected in the urine after intake of PE. In plasma, RA, methyl-RA and FA were detected, with maximum levels obtained 0.5, 2 and 0.5 h after intake of PE, respectively. The majority of these components in both plasma and urine were present as conjugated forms (glucuronide and/or sulfated). The proportion of RA and its related metabolites excreted in the urine was 6.3 +/- 2.2% of the total dose, with approximately 75% of these components being excreted within 6 h after intake of PE. CONCLUSIONS: RA contained in PE was absorbed, conjugated and methylated following intake, with a small proportion of RA being degraded into various components, such as conjugated forms of CAA, FA and COA. These metabolites were then rapidly excreted in the urine.
Piceatannol (1) was found to be more effective than caffeic acid, an established antinitrosating agent, in inhibiting N-nitrosation of 2,3-diaminonaphthalene. Product analysis of the reaction mixture of 1 (20 microM) with nitrite ions (80 microM) at pH 3.0 and at 37 degrees C showed conversion to a single major nitration product, (E)-3,3',4,5'-tetrahydroxy-beta-nitrostilbene (2) (68% yield). This would result from an unexpected nitration at the double bond sector via the 4-phenoxyl radical, which was analyzed at the unrestricted DFT level.
In this review are presented various lead compounds bearing a polyphenolic moiety and their biological targets. The relevance of these targets to develop the desired compounds as potential anti-cancer agents is discussed. For instance, caffeic acid phenethyl ester (CAPE) has preliminary been studied in our group to hold various biochemical responses. When C6 glioma cells were grown as xenografts in nude mice, treatment with CAPE (1-10 mg/kg; ip) induced a significant dose dependent decrease in tumor growth by evaluating tumor volume and tumor weight. Histochemical and immunohistochemical analysis revealed that CAPE treatment significantly reduced the number of mitotic cells and proliferating cell nuclear antigen (PCNA)-positive cells in C6 glioma. Moreover, the ability of flavonoids to scavenge free-radicals and block lipid peroxidation raises the possibility that they may act as protective factors against carcinogenesis. Furthermore, protocatechuic acid (PCA) seems to be a promising compound regarded as a candidate group for cancer preventive agents. We have isolated and investigated Hibiscus protocatechuic acid from Hibiscus sabdariffa L. Hibiscus PCA showed against oxidative damage induced by t-butyl hydroperoxide in rat primary hepatocytes, and inhibitory effect on tumor promotion in mouse skin. Finally, we review here recent progress with the analogs of natural and synthetic lead compounds in Asiatic folk medicine. Since phenolic dimmers or trimers are significantly more potent than monomer in vitro and in vivo, a large number of phenolic dimmers or trimers with linker lengths and their pharmacological properties have been investigated.