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PubMed2004

Role of chemopreventive agents in cancer therapy.

Tumorigenesis or carcinogenesis is a multi-step process that is induced primarily by carcinogens leading to the development of cancer. Extensive research in the last few years has revealed that regular consumption of certain fruits and vegetables can reduce the risk of acquiring specific cancers. Phytochemicals derived from such fruits and vegetables, referred to as chemopreventive agents include genistein, resveratrol, diallyl sulfide, S-allyl cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins and eugenol. Because these agents have been shown to suppress cancer cell proliferation, inhibit growth factor signaling pathways, induce apoptosis, inhibit NF-kappaB, AP-1 and JAK-STAT activation pathways, inhibit angiogenesis, suppress the expression of anti-apoptotic proteins, inhibit cyclooxygenase-2, they may have untapped therapeutic value. These chemopreventive agents also have very recently been found to reverse chemoresistance and radioresistance in patients undergoing cancer treatment. Thus, these chemopreventive agents have potential to be used as adjuncts to current cancer therapies.

Anticarcinogenic Agents↗

PubMed2004

Nrf2 as a novel molecular target for chemoprevention.

One of the rational and effective strategies for chemoprevention is the blockade of DNA damage caused by carcinogenic insult. This can be achieved either by reducing the formation of reactive carcinogenic species or stimulating their detoxification. A wide spectrum of xenobiotic metabolizing enzymes catalyze both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions involved in carcinogen activation and/or deactivation. Several antioxidant-response element (ARE)-regulated gene products such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, UDP-glucuronosyltransferase, gamma-glutamate cysteine ligase, and hemeoxygenase-1 are known to mediate detoxification and/or to exert antioxidant functions thereby protecting cells from genotoxic damage. The transcription of ARE-driven genes is regulated, at least in part, by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2), which is sequestered in cytoplasm by Kelch-like ECH-associated protein 1 (Keap1). Exposure of cells to ARE inducers results in the dissociation of Nrf2 from Keap1 and facilitates translocation of Nrf2 to the nucleus, where it heterodimerizes with small Maf protein, and binds to ARE, eventually resulting in the transcriptional regulation of target genes. The Nrf2-Keap1-ARE signaling pathway can be modulated by several upstream kinases including phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases. Selected Nrf2-Keap1-ARE activators, such as oltipraz, anethole dithiolethione, sulforaphane, 6-methylsulphinylhexyl isothiocyanate, curcumin, caffeic acid phenethyl ester, 4'-bromoflavone, etc. are potential chemopreventive agents. This mini-review will focus on a chemopreventive strategy directed towards protection of DNA and other important cellular molecules by inducing de novo synthesis of phase II detoxifying or antioxidant genes via the Nrf2-ARE core signaling pathway.

Antioxidants↗

PubMed2005

Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations.

OBJECTIVE: Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Na(v)1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS. METHODS: Four male patients with typical BrS ST-segment elevation in V1-V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. The sodium currents (I(Na)) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments. RESULTS: Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Na(v)1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 degrees C, we observed a pronounced acceleration of Na(v)1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced I(Na), fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever. CONCLUSIONS: The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specific.

Action Potentials↗

PubMed2005

Design, synthesis and biological evaluation of heteroaryl diketohexenoic and diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity.

Highly active anti-retroviral therapy (HAART) using reverse transcriptase (RT) and protease (PR) inhibitors and, more recently, inhibitors of the fusion is currently the best clinical approach in combating acquired immunodeficiency syndrome (AIDS), caused by infection from human immunodeficiency virus type 1 (HIV-1). However, this therapy does not completely eradicate the virus, so that resistant strains easily emerge. The above problem calls urgently for research on inhibitors of further viral targets such as integrase (IN), the third enzyme produced by HIV. Recently, our research group was engaged in studies on conformationally restrained cinnamoyl compounds related to curcumin as anti-IN agents. Compounds containing both a 3,4,5-trihydroxyphenyl group and a carboxylic acid function were potent IN inhibitors active against viral replication. More recently, a promising new class of inhibitors synthesized by Merck Company has emerged, which contain aryldiketoacid (ADK) functionality. The ADKs selectively inhibited the stand transfer (ST) step of integration and were proven to be effective IN inhibitors in vivo. Our interest in the field of IN inhibitors led us to design pyrrole and indole derivatives containing both a cinnamoyl moiety and a diketoacid group. A number of the cited derivatives were proven potent IN inhibitors, which selectively inhibited the ST step at submicromolar concentrations and were effective against virus replication in HIV-1 infected cells.

Anti-Retroviral Agents↗

PubMed2004

Do aberrant crypt foci have predictive value for the occurrence of colorectal tumours? Potential of gene expression profiling in tumours.

The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2% curcumin (CUR), 4% rutin (RUT) or 0.04% benzyl isothiocyanate (BIT) for 8 months. ACF were counted after 7, 15 and 26 weeks. Tumours were scored after 26 weeks and 8 months. We found that the WB and CUR diets inhibited the development of colorectal tumours. In contrast, the RUT and BIT diets rather enhanced (although not statistically significantly) colorectal carcinogenesis. In addition, the various compounds caused different effects on the development of ACF. In most cases the number or size of ACF was not predictive for the ultimate tumour yield. The expression of some tumour-related genes was significantly different in tumours from the control group as compared to tumours from the treated groups. It was concluded that WB and CUR, as opposed to RUT and BIT, protects against colorectal cancer and that ACF are unsuitable as biomarker for colorectal cancer. Effects of the different dietary compounds on metalloproteinase 1 (TIMP-1) expression correlated well with the effects of the dietary compounds on the ultimate tumour yield.

Animals↗

PubMed2004

Hepatopoietin interacts directly with COP9 signalosome and regulates AP-1 activity.

Hepatopoietin (HPO)/augmenter of liver regeneration (ALR) is a specific hepatotrophic growth factor, which plays a key role in liver regeneration. Our previous study indicated that HPO executes its function by an inter-reactive network of the autocrine, paracrine and endocrine pathways. Recently, we have demonstrated that intracellular HPO interacts with Jun activation domain-binding protein 1 (JAB1) and leads to potentiation of activating protein-1 (AP-1) activity in a MAPK independent fashion. JAB1 is the fifth subunit of the COP9 signalosome (CSN), which is first identified as a suppressor of plant morphogenesis. A protein complex kinase activity associated with the CSN has been reported but not identified yet. In this report, we investigated further the association of HPO with the whole CSN. HPO exists in a complex with the eight-component CSN, both when purified from glycerol gradient centrifugation and when reciprocal immunoprecipitated from the lysates of transfected COS-7 cells. Intracellular HPO colocalizes with endogenous CSN in nucleus of hepatic cells. In addition, intracellular function of HPO that increases the phosphorylation of c-Jun leading to potentiate the AP-1 activity is inhibited by curcumin, a potent inhibitor of CSN-associated kinase. Taken together, these results elucidate a novel relationship of intracellular growth factor, HPO with large protein complex, CSN, which suggests a possible linkage between CSN and liver regeneration.

Animals↗

PubMed2005

Interleukin-17--induced interleukin-8 release in human airway smooth muscle cells: role for mitogen-activated kinases and nuclear factor-kappaB.

BACKGROUND: It has recently become clear that interleukin (IL)-8 plays a role in chronic neutrophilic inflammatory disorders, such as chronic rejection after lung transplantation. We have shown that IL-17--stimulated human airway smooth muscle cells (HASMC) are able to produce IL-8. The aim of this study was to determine whether p38 mitogen-activated protein kinase (MAPK), c-Jun amino-terminal kinase (JNK), p42/p44 extracellular signal-related kinase (ERK) and nuclear factor-kappaB (NF-kappaB) are involved in IL-17--induced IL-8 production in HASMC in vitro. METHODS: We used human airway smooth muscle cells in culture. Western blotting was done to obtain data regarding activation of MAPK. Furthermore, we used specific inhibitors of MAPK to investigate their involvement in IL-17--induced IL-8 release, which was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Western blotting clearly demonstrated that p38 MAPK, JNK and p42/p44 ERK were activated by IL-17 in HASMC. Using SB203580, a specific inhibitor of p38 MAPK, we detected a concentration-dependent inhibition of IL-17--induced IL-8 production with a maximal decrease of 63 +/- 5% (n=8, p<0.01). Curcumin, a specific inhibitor of JNK, also concentration-dependently reduced IL-17--induced IL-8 production, with a maximal decrease of 82+/-4% (n=8, p<0.01). U0126, a specific inhibitor of p42/p44 ERK, induced a maximal decrease of 84+/-5% (n=8, p<0.001). Pyrrolydine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, caused a 70+/-5% (n=8, p<0.01) decrease in IL-17--induced IL-8 production. CONCLUSIONS: We found that IL-17 induces activation of p38MAPK, JNK and p42/p44ERK in HASMC. We also found that p38MAPK, JNK, p42/p44 ERK and NF-kappaB play an important role in IL-17--induced IL-8 production in HASMC in vitro. This may open up new opportunities for further treatment of this disease.

Blotting, Western↗

PubMed2006

Mechanism of macrophage activation by (1,4)-alpha-D-glucan isolated from Tinospora cordifolia.

The signaling mechanism of the novel (1,4)-alpha-D-glucan (RR1) isolated from the medicinal plant Tinospora cordifolia was investigated in macrophages to evaluate its immunostimulating properties. When RAW264.7 macrophages were incubated with RR1 at 4 degrees C, the novel glucan inhibited the phagocytosis of unopsonized zymosan A bioparticles in a dose-dependent manner. RR1 also inhibited the binding and internalization of opsonized zymosan A bioparticles, although at a lower level than laminarin. Incubation of macrophages with anti-CD11b mAb followed by RR1 failed to show any inhibitory effect on RR1-induced TNF-alpha synthesis confirming that complement receptor 3 (CR3) is not involved in the opsonic binding and internalization of RR1 in macrophages unlike zymosan A. The anti-CD11b mAb has significant inhibitory effect on the zymosan A-induced tumor necrosis factor (TNF)-alpha synthesis. RR1 induced TNF-alpha synthesis in macrophages in a dose-dependent manner which can be completely inhibited by the NF-kappaB inhibitor caffeic acid phenethyl ester (CAPE) or curcumin. RR1 activated NF-kappaB in a time- and dose-dependent manner and this modulation of nuclear NF-kappaB activity is associated with the degradation of I-kappaB alpha thus facilitating the translocation of NF-kappaB into the nucleus. RR1-induced NF-kappaB activity peaks at 8 h of RR1 stimulation while I-kappaB alpha degradation occurred within 1 h of stimulation. RR1-induced NF-kappaB activation occurred through TLR6 signaling as evidenced by the synthesis of IL-8 in TLR6-transfected HEK293 cells. These results show that the novel (1,4)-alpha-D-glucan from Tinospora cordifolia activates the immune system through the activation of macrophages that occurs through TLR6 signaling, NF-kappaB translocation and cytokine production.

Animals↗

PubMed2006

Chemoprevention of nonmelanoma skin cancer.

UNLABELLED: Skin cancer is the most common cancer in human beings. The increased incidence of skin cancer has brought much attention to the process by which these tumors develop and how they can be prevented. Efforts have been made to educate the public about the importance of protecting skin from excessive ultraviolet light. Despite this work, the incidence of skin cancer continues to increase. Available compounds may be useful in the chemoprevention of skin cancer. Chemoprevention is defined as oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer. Potential agents included are the retinoids; difluoromethylornithine; T4 endonuclease V; polyphenolic antioxidants, such as (-)-epigallocatechin gallate, found in green tea and grape seed extract; silymarin; isoflavone genestein; nonsteroidal anti-inflammatory drugs; curcumin; lycopene; vitamin E; beta-carotene; and selenium. Many of these agents are available over the counter as topical or oral preparations. LEARNING OBJECTIVE: At the conclusion of this activity, participants should be familiar with the chemopreventive agents and their efficacy, as well as any significant side effects associated with them.

Animals↗

PubMed2026

Selective monitoring of trace-level catechin and myricetin in herbal and aqueous matrices using magnetic MIP-DSPME: Optimization via design of experiments.

A novel dispersive solid-phase microextraction approach utilizing a magnetic molecularly imprinted polymer (MMIP) integrated with HPLC-UV detection was developed for the concurrent quantification of catechin and myricetin in herbal extracts and aqueous samples. The sorbent was engineered as a core-shell nanocomposite, consisting of a selective polymer layer deposited onto Fe3O4@SiO2-APTMS magnetic nanoparticles. Dual-template imprinting using catechin and myricetin generated complementary binding cavities within the polymer framework. Experimental variables influencing extraction were systematically screened and subsequently optimized. A Plackett-Burman design was first applied to identify the most influential factors, with pH and sorption time identified as the dominant variables. These parameters were subsequently fine-tuned using a central composite design, and the optimization process was completed in only 30 experimental runs. The sorption characteristics of the imprinted sorbent (MMIP) were compared with those of its non-imprinted counterpart (MNIP). The MMIP demonstrated markedly higher maximum binding capacities (Qmax), reaching 119.3 mg g-1 for myricetin and 112.1 mg g-1 for catechin, whereas the corresponding values for the MNIP were 32.55 and 32.08 mg g-1, respectively. Moreover, the affinity constants (KL = 0.760-0.950 L mg-1) were approximately 2.3-fold higher for the MMIP, confirming its stronger and more selective interactions with the target analytes. The selectivity coefficients for the targeted flavonoids relative to structurally related compounds, including ferulic acid, p-coumaric acid, melatonin, and curcumin, exceeded 3.5 for the MMIP, whereas the corresponding values for the MNIP were close to 1.1, demonstrating the high molecular recognition capability of the imprinted sorbent. Method validation demonstrated limits of detection (LODs) of 0.33-0.59 ng mL-1 and limits of quantification (LOQs) of 1.10-1.96 ng mL-1, and excellent linearity over the concentration range of 5.0-5500 ng mL-1 (R2 > 0.998). The method achieved recoveries of 93.96% to 105.69% with RSDs below 5.5%, while the preconcentration factors ranged from 209 to 229. Furthermore, the sorbent retained more than 95% of its extraction efficiency after four consecutive reuse cycles and more than 80% after six cycles, demonstrating excellent stability and reusability. The proposed method was successfully applied to the analysis of six medicinal plant extracts and water samples, showing negligible matrix interference and superior sensitivity, selectivity, and operational simplicity compared with conventional solid-phase extraction methods.

Flavonoids↗

PubMed2006

Combinative method using HPLC quantitative and qualitative analyses for quality consistency assessment of a herbal medicinal preparation.

A selective and efficient quality consistency assessment system was developed for monitoring the manufacturing processes of a Chinese herbal preparation, qingfu guanjieshu (QFGJS) capsule, and for assessing its stability over time. This system is based on quantitative determination of four marker compounds, i.e., sinomenine, paeoniflorin, paeonol, and curcumin, and on qualitative fingerprinting analysis of QFGJS using high-performance liquid chromatography-photodiode array detection (HPLC-DAD) method. The separation was performed on a Phenomenex ODS column by gradient elution with acetonitrile and aqueous phase (containing 0.1% phosphoric acid, adjusted with triethylamine to pH 3.5+/-0.2) at a flow-rate of 1.0 ml/min. In fingerprinting analysis, the chemical characteristics of four herbs present in QFGJS (excluding radix Aconiti Lateralis Preparata) were present in the HPLC chromatographic file. In addition, quantitative determination of hypaconitine was carried out with our published HPLC method as a supplement for quality control of the radix Aconiti Lateralis Preparata in QFGJS. The results showed that the contents of these five marker compounds and HPLC fingerprint profiles of three batches of QFGJS products collected at 3 months after production in the stability testing were relatively consistent. This well-developed method could be used for quality assessment of the complex preparations of herbal medicine.

Aconitine↗

PubMed2006

Dietary supplements and related products: a brief summary.

We were gratified by the interest expressed in publishing a large number of presentations from the NIDA organized Workshop on "Natureceuticals (Natural Products), Nutraceuticals, Herbal Botanicals, Psychoactives: Drug Discovery and Drug-Drug Interactions". The number of manuscripts received necessitated two volumes of proceedings. In this brief summary of the second volume, we present an introduction to the roles of organizations such as National Center for Complementary and Alternate Medicine and Office of Dietary Supplements, both at the National Institutes of Health, and the Food and Drug Administration. These agencies are involved in research and regulation of dietary supplements and related products. Next, a brief summary of each of the fifteen articles is provided. The first four articles are related to regulatory and standardization aspects: issues related to botanicals (Khan); USP and dietary supplements (Srinivasan); dietary supplement reference materials (Sander et al.); and proposed cGMPs and the scientific basis behind the proposed regulations by FDA (Melethil). The next three articles relate to the methodologies employed in research: LC/MS for the pharmacokinetic analysis polyphenols from dietary supplements (Barnes et al.); proteomic analysis of grape seed extract (Kim et al.); and a nematode model, C. elegans, in Alzheimer's and ginkgo biloba extract for mechanistic studies; another model, a hepatocyte tissue culture model for drug herbal interaction, is reviewed later and presented by Venkataramanan. The next four chapters are on specific dietary supplements: green tea and the polyphenolic catechins (Zaveri); curcumin (Maheswari et al.); tocotrienols (alpha-tocotrienol, Sen and Roy), gamma-tocotrienol (Sree Kumar et al.). This topic is followed by drug interaction studies: in vitro and in vivo assessment methodologies (Venkataramanan); flavonoid-drug interactions (Morris); MDR and CYP3A4-mediated drug-herb interaction (Pal and Mitra); and evidence-based examination of drug-herb interaction (Chavez and Chavez).

Complementary Therapies↗

PubMed2004

Cell signaling pathways altered by natural chemopreventive agents.

Epidemiological studies have indicated a significant difference in the incidence of cancers among ethnic groups, who have different lifestyles and have been exposed to different environmental factors. It has been estimated that more than two-thirds of human cancers, which are contributed by mutations in multiple genes, could be prevented by modification of lifestyle including dietary modification. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers. The in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), apigenin, etc., have shown inhibitory effects on human and animal cancers, suggesting that they may serve as chemopreventive agents. Experimental studies have also revealed that these components regulate the molecules in the cell signal transduction pathways including NF-kappaB, Akt, MAPK, p53, AR, and ER pathways. By modulating cell signaling pathways, these components, among other mechanisms, activate cell death signals and induce apoptosis in precancerous or cancer cells, resulting in the inhibition of cancer development and/or progression. This article reviews current studies regarding the effects of natural chemopreventive agents on cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of chemopreventive agents in cancer cells.

Animals↗

PubMed2003

Bacterial antimutagenesis by hydroxycinnamic acids from plant cell walls.

We have determined the abilities of (E)-ferulic acid, (E)-p-coumaric acid and (E,E)-5-5-dehydrodiferulic acid to protect against different types of mutation in a simple bacterial model. These antimutagenic properties were compared with those of the related compound curcumin, and also with those of an extract containing hydroxycinnamic acids obtained by the saponification of the cell walls of wheat coleoptiles. Three known mutagens, bleomycin, hydrogen peroxide and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were used to chemically induce reversion mutation, while the known antimutagen Trolox was used as a positive control. Both the pure hydroxycinnamic acids and the extract from the cell walls showed antimutagenic properties. It is known that hydroxycinnamic acids ester-linked to plant cell walls can be released in the human colon by the action of microbial esterases. Providing the current data extrapolate to mammalian cells, they suggest that antimutagenic properties of hydroxycinnamic acids released from plant cell walls could play a role in dietary fibre protection against cancer.

Antimutagenic Agents↗

PubMed2005

Acrolein produces nitric oxide through the elevation of intracellular calcium levels to induce apoptosis in human umbilical vein endothelial cells: implications for smoke angiopathy.

Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde, the levels of which are increased in the blood of smokers. To determine if acrolein is involved in the pathology of smoke angiopathy, the effect of acrolein on human umbilical vein endothelial cells (HUVEC) was examined. Intracellular nitric oxide (NO) levels, determined using diaminofluorescein-2 diacetate (DAF-2 DA), an NO sensitive fluorescent dye, were found to be increased after treatment in HUVEC with 10 microM acrolein. The measurement of nitrite with 2,3-diaminonaphthalene and a Western blot analysis revealed that nitrite and S-nitroso-cysteine levels were increased in a dose-dependent manner, confirming that NO production is increased by acrolein. The increase was not reduced by treatment with 10mM N-acetyl-l-cysteine (NAC), an anti-oxidant, but was reduced with 10 microM of the intracellular calcium chelator, 1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester. Acrolein-stimulated NO production was significantly reduced by pretreatment with 1mM N(G)-nitro-l-arginine-methyl ester (L-NAME), an NO synthase inhibitor. The cytotoxicity of acrolein was reduced by pretreatment with 10 microM 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO), an intracellular NO scavenger, or 1mM L-NAME, whereas it was not reduced by 10mM NAC, 20 microM Curcumin, another peroxide scavenger, or 100 microM Mn(III)TMPyP, a superoxide dismutase mimic. Nuclear staining and a Western blot analysis using an anti-cleaved caspase 3 antibody revealed that the reduced viability of HUVEC by acrolein was due to apoptosis, which was reversed after pretreatment with 0.1mM carboxy-PTIO or 1mM L-NAME. Thus, acrolein increases intracellular calcium production to induce intracellular NO production by a calcium-dependent NO synthase, possibly eNOS, and the excess and rapid increase in NO might lead to the apoptosis of HUVEC. These data suggest that acrolein might be involved in the pathology of smoke angiopathy through the NO-induced apoptosis of endothelial cells.

Acrolein↗

PubMed2005

Piceatannol upregulates endothelial heme oxygenase-1 expression via novel protein kinase C and tyrosine kinase pathways.

Piceatannol is an anti-inflammatory and anti-proliferative plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme to activate by various phytochemicals. In this study, we examined the ability of piceatannol to upregulate HO-1 expression in endothelial cells. We found piceatannol at micromolar (10-50 microM) concentrations dramatically increased HO-1 protein levels in a time-dependent manner. Piceatannol was similarly potent in the induction of HO-1 as hemin, arsenate, and 15d-PGJ2, and was more potent than some other phytochemicals including curcumin, EGCG, baicalein, and quercetin. In contrast, the similar chemical structure compounds, trans-stilbene, stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting a critical role for the hydroxyl groups in HO-1 induction. No cytotoxicity and superoxide production was observed after 10-50 microM piceatannol treatments. Piceatannol-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine and glutathione, but not by other antioxidants. Induction of HO-1 by piceatannol was further enhanced by using buthionine sulfoximine. In addition, we determined that tyrosine kinase was involved in the induction of HO-1 by using tyrosine kinase inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no significant changes in the pretreatment of PI3 kinase or MAP kinase inhibitors was determined. HO-1 induction was blocked by the protein kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment, whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM, had no effect. Elevated HO-1 protein levels were associated with the inhibition of tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Treating ECs with zinc protoporphyrin, an HO-1 inhibito blocked the anti-inflammatory effect of piceatannol. In summary, this study identified piceatannol as a novel phytochemical inducer of HO-1 expression and identified the mechanisms involved in this process.

Animals↗

PubMed2005

Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals.

Transcriptomics, proteomics and metabolomics are genomics technologies with great potential in toxicological sciences. Toxicogenomics involves the integration of conventional toxicological examinations with gene, protein or metabolite expression profiles. An overview together with selected examples of the possibilities of genomics in toxicology is given. The expectations raised by toxicogenomics are earlier and more sensitive detection of toxicity. Furthermore, toxicogenomics will provide a better understanding of the mechanism of toxicity and may facilitate the prediction of toxicity of unknown compounds. Mechanism-based markers of toxicity can be discovered and improved interspecies and in vitro-in vivo extrapolations will drive model developments in toxicology. Toxicological assessment of chemical mixtures will benefit from the new molecular biological tools. In our laboratory, toxicogenomics is predominantly applied for elucidation of mechanisms of action and discovery of novel pathway-supported mechanism-based markers of liver toxicity. In addition, we aim to integrate transcriptome, proteome and metabolome data, supported by bioinformatics to develop a systems biology approach for toxicology. Transcriptomics and proteomics studies on bromobenzene-mediated hepatotoxicity in the rat are discussed. Finally, an example is shown in which gene expression profiling together with conventional biochemistry led to the discovery of novel markers for the hepatic effects of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole.

Animals↗

PubMed2006

Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses.

Diets rich in vegetables and fruits are associated with reduced risk of several major diseases, including neurodegenerative disorders. Although some beneficial phytochemicals might function solely as antioxidants, it is becoming clear that many of the beneficial chemicals in vegetables and fruits evolved as toxins (to dissuade insects and other predators) that, at subtoxic doses, activate adaptive cellular stress-response pathways in a variety of cells including neurons. Examples of such 'preconditioning' or 'neurohormesis' pathways include those involving cell-survival signaling kinases, the transcription factors NRF2 and CREB, and histone deacetylases of the sirtuin family. In these ways, neurohormetic phytochemicals such as resveratrol, sulforaphanes and curcumin might protect neurons against injury and disease by stimulating the production of antioxidant enzymes, neurotrophic factors, protein chaperones and other proteins that help cells to withstand stress. Thus, as we discuss in this review, highly conserved longevity and survival pathways in neurons are the targets of many phytochemicals.

Animals↗