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PubMed1994

Cloning and molecular analysis of structural genes involved in flavonoid and stilbene biosynthesis in grape (Vitis vinifera L.).

Genes involved in flavonoid and stilbene biosynthesis were isolated from grape (Vitis vinifera L.). Clones coding for phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3-hydroxylase (F3H), dihydroflavonol 4-reductase (DFR), leucoanthocyanidin dioxygenase (LDOX) and UDP glucose:flavonoid 3-O-glucosyl transferase (UFGT), were isolated by screening a cDNA library, obtained from mRNA from seedlings grown in light for 48 h using snapdragon (Antirrhinum majus) and maize heterologous probes. A cDNA clone coding for stilbene synthase (StSy) was isolated by probing the library with a specific oligonucleotide. These clones were sequenced and when the putative products were compared to the published amino acid sequence for corresponding enzymes, the percentages of similarity ranged from 65% (UFGT) to 90% (CHS and PAL). The analysis of the genomic organization and expression of these genes in response to light shows that PAL and StSy genes belong to large multigene families, while the others are present in one to four copies per haploid genome. The steady-state level of mRNAs encoded by the flavonoid biosynthetic genes as determined in young seedlings is coordinately induced by light, except for PAL and StSy, which appear to be constitutively expressed.

Anthocyanins↗
PubMed1989

The nonselective cation channel in the basolateral membrane of rat exocrine pancreas. Inhibition by 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC) and activation by stilbene disulfonates.

Nonselective Ca2+-sensitive cation channels in the basolateral membrane of isolated cells of the rat exocrine pancreas were investigated with the patch clamp technique. With 1.3 mmol/l Ca2+ on the cytosolic side, the mean open-state probability Po of one channel was about 0.5. In inside-out oriented cell-excised membrane patches the substances diphenylamine-2-carboxylic acid (DPC), 5-nitro-2-(3-phenelpropylamino)-benzoic acid (NPPB) and 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC) were applied to the cytosolic side. These compounds inhibited the nonselective cation channels by increasing the mean channel closed time (slow block). 100 mumol/l of NPPB or DPC decreased Po from 0.5 (control conditions) to 0.2 and 0.04, respectively, whereas 100 mumol/l of DCDPC blocked the channel completely. All effects were reversible. 1 mmol/l quinine also reduced Po, but in contrast to the above mentioned substances, it induced fast flickering. Ba2+ (70 mmol/l) and tetraethylammonium (TEA+; 20 mmol/l) had no effects. We investigated also the stilbene disulfonates 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and 4,4'-dinitro-2,2'-stilbenedisulfonate (DNDS). 10 mumol/l SITS applied to the cytosolic side increased Po from 0.5 to 0.7 and with 100 mumol/l SITS the channels remained nearly permanently in its open state (Po approximately equal to 1). A similar activation of the channels was also observed with DIDS and DNDS. These effects were poorly reversible. The stilbene disulfonates acted by increasing the channel mean open time. When the channel was inactivated by decreasing bath Ca2+ concentration to 0.1 mumol/l, addition of 100 mumol/l of SITS had no effect. Similarly, reducing bath Ca2+ concentration from 1.3 mmol/l in presence of 100 mumol/l SITS (channels are maximally activated) to 0.1 mumol/l, inactivated the channels completely. These results demonstrate, that SITS can only activate the channels in the presence of Ca2+. SITS had no effects, when applied to the extracellular side in out-side out patches.(ABSTRACT TRUNCATED AT 400 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1984

Effect of bicarbonate, pH, methazolamide and stilbenes on the intracellular potentials of cultured bovine corneal endothelial cells.

Micropuncture of cultured bovine corneal endothelial cells led to registrations stable for hours. Intracellular potentials were mainly in the range of -40 to -55 mV, average 46.3 +/- 0.6 mV (SEM). Changes of extracellular [HCO-3] led to voltage transients, their amplitude depending logarithmically on [HCO-3] with a mean slope of 37.3 +/- 8.8 (SD) mV. After removal of bicarbonate/CO2, a steady-state depolarization was seen. This steady-state depolarization, but not the voltage transients, could be reduced by 1 mM Ba++. After removal of bicarbonate, the voltage response to changes of extracellular potassium was reduced. Alteration of pHi induced by permeable buffers (butyrate, glycodiazine and ammonium) also resulted in voltage transients, internal acidification being correlated with a hyperpolarization, and internal alkalinization with a depolarization. Also changes of external pH caused voltage responses, alkalinization causing a hyperpolarization, acidification a depolarization. Methazolamide, an inhibitor of carbonic anhydrase, as well as stilbenes (SITS or DIDS) caused a reduction of the voltage response to HCO-3 and pH. Their effects were additive. It is suggested that corneal endothelial cells possess one or two electrogenic transporters for HCO-3 or related species, one of which is inhibitable by stilbenes.

Animals↗
PubMed1989

Identification of the trans-stilbene oxide-active glutathione transferase in human mononuclear leukocytes and in liver as GST1.

A glutathione transferase from human mononuclear leukocytes with a high activity toward trans-stilbene oxide (GT-tSBO) has been studied in liver and blood from fetus and adults and in blood from neonates. Using starch gel electrophoresis, different phenotypes of GST1 have been determined, GST1 0, GST1 1, and GST1 2. As judged from activity measurements and the fact that only those individuals who express the null allele of GST1, the GST1 0, which has a low activity toward trans-stilbene oxide, it is concluded that the hepatic transferase GST1 is identical to GT-tSBO, as well as to hepatic transferase mu. In addition, it has been shown that the different genotypes of GST1 1 (GST1 1-1, GST1 1-0) and GST1 2 (GST1 2-2, GST1 2-0) can be separated by measuring the GT-tSBO activity in whole blood from the same individual. It is also demonstrated that GT-tSBO activity is much lower in fetal liver, approximately 10 times, compared with adult liver, while this activity seems to be unchanged in the blood from fetus and adults, as well as in neonates.

Adult↗
PubMed2002

The radical scavenging effects of stilbene glucosides from Polygonum multiflorum.

The extract of the root of Polygonum multiflorum exhibited a significant antioxidant activity assessed by the DPPH radical scavenging activity in vitro. The bioassay-guided fractionation of the extract yielded a stilbene glucoside, (E)-2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucopyranoside (1) as an active constituent responsible for the antioxidant property. Compound 1 demonstrated a moderate DPPH radical scavenging activity (IC50, 40 microM), while the corresponding deglucosylated stilbene 2 exhibited a much higher activity (IC50, 0.38 microM).

Free Radical Scavengers↗
PubMed1984

Rat liver DT-diaphorase: regulation of functional mRNA levels by 3-methylcholanthrene, trans-stilbene oxide, and phenobarbital.

Total liver poly(A+)-RNA isolated from untreated, and 3-methylcholanthrene-, trans-stilbene oxide-, and phenobarbital-treated rats has been translated in the rabbit reticulocyte lysate system in order to determine the effect of these xenobiotics on the level of translationally active DT-diaphorase mRNA. The in vitro translation systems were subjected to immunoprecipitation with rabbit IgG raised against purified DT-diaphorase and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The identity of the radiolabeled, immunoprecipitated product as DT-diaphorase was confirmed by limited peptide mapping using Staphylococcus aureus V-8 protease. These quantitation results demonstrate that 3-methylcholanthrene leads to an eight-fold elevation in functional DT-diaphorase mRNA at 8 h after a single administration of 3-methylcholanthrene; whereas, trans-stilbene oxide and phenobarbital produced only a modest elevation, two- to three-fold, in the functional DT-diaphorase mRNA level. These data indicate that the increase in the level of DT-diaphorase after 3-methylcholanthrene administration noted previously [B. Höjeberg, K. Blomberg, S. Stenberg, and C. Lind (1981) Arch. Biochem. Biophys. 207, 205-216] can be totally accounted for by an elevation in the mRNA level specific for this protein.

Animals↗
PubMed1995

Induction of metallothionein synthesis by glutathione depletion after trans- and cis-stilbene oxide administration in rats.

To investigate the relationship between glutathione (GSH) depletion and metallothionein (MT) synthesis, the effects of substrates and an inhibitor of GSH S-transferases on concentrations of hepatic GSH, zinc (Zn) and MT were studied in rats. Trans-stilbene oxide (TSO) is an inducer of drug metabolizing enzymes and also a substrate of GSH S-transferase, whereby it covalently reacts with and depletes GSH. The hepatic GSH level was decreased to 25% of the control 2 h after injection of TSO, and returned to the control level by 24 h. TSO significantly increased hepatic concentrations of Zn and MT in a dose-dependent manner. Two isoforms of MT (MT-I and MT-II) were increased by TSO; MT-II was the dominant form. Pretreatment with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, enhanced MT synthesis itself as well as that induced by TSO and cis-stilbene oxide (CSO). On the contrary, infection into rats of perfluorodecanoic acid (PFDA), an inhibitor of GSH S-transferase, resulted in a decrease in basal levels of Zn, and prevented the increase in MT synthesis by TSO and CSO. These results suggest that the decrease of GSH concentration in the liver which causes oxidative stress conditions may be related to MT induction.

Animals↗
PubMed1993

Selective interaction of valinomycin/K+ with the cytochrome bf complex of chloroplasts. Synergistic effect with MOA stilbene on extent of cytochrome b563 reduction in continuous light.

Valinomycin/K+ is shown to selectively interact at sub-micromolar concentrations with the cytochrome bf complex in thylakoid membranes, inducing a red shift of the ferrohaem b absorbance alpha-band, a slow down of post-illumination b-reoxidation and a corresponding increase of b-reduction level in continuous light. These effects of valinomycin/K+ are not related to its field dissipating action, as they are not affected by nonactin. Presence of K+ is required. Phenomenologically the valinomycin/K+ effects are similar to those caused by 10 times higher MOA stilbene nonactin. Presence of K+ is required. Phenomenologically the valinomycin/K+ effects are similar to those caused by 10 times higher MOA stilbene concentrations. However, synergism is observed between the two inhibitors, suggesting different modes of action. When both inhibitors are combined more than one haem b can be reduced by illumination.

Chloroplasts↗
PubMed1983

Variations in induction of drug-metabolizing enzymes by trans-Stilbene oxide in rodent species.

Trans-Stilbene oxide (400 mg/kg) produced a 500% increase in the microsomal epoxide hydratase activity in rat and mouse with little change in the soluble enzyme activity. However, in guinea pig, the soluble epoxide hydratase activity increased by about 33% with only a small increase (47.6%) in the microsomal enzyme activity. The soluble glutathione S-transferase activities were also induced in both rat and mouse, with little change in that of the guinea pig. Increasing dosage of trans-stilbene oxide from 400 mg/kg to 1000 mg/kg had little effect on the above enzyme activities. That the guinea pig was not relatively refractory to all inducing agents was shown by the fact that phenobarbital (100 mg/kg) and 3-methylcholanthrene (25 mg/kg) produced relatively similar increases in the activities of aniline hydroxylase and P-aminopyrine N-demethylase in rat, mouse and guinea pig. However, these inducers produced only a 15-20% stimulation in the soluble glutathione S-transferase and microsomal epoxide hydratase activities in guinea pig, when compared to a 50-80% increase in rat and mouse, suggesting a general resistance to induction by the phase II enzymes in guinea liver. In all three animal models, the inducer markedly increased the microsomal total phospholipid content, although the sphingomyelin content itself was decreased. In both rat and mouse, the microsomal cholesterol content was significantly decreased while that in guinea pig was unaffected. Possible factors responsible for the observed species differences are discussed.

Animals↗
PubMed2005

Mechanistic differences in inhibition of ubiquinol cytochrome c reductase by the proximal Qo-site inhibitors famoxadone and methoxyacrylate stilbene.

Famoxadone (FAM) is a newly commercialized antibiotic for use against plant pathogenic fungi. It inhibits mitochondria ubiquinol:cytochrome c oxidoreductase (EC 1.10.2.2, bc(1) complex) function by binding to the proximal niche of the quinol oxidation site on the enzyme. FAM has effects on the enzyme characteristic of both type Ia (E-beta-methoxyacrylates) and type Ic (stigmatellin) inhibitors. Steady-state and tight-binding inhibition kinetics; as well as direct binding measurements with famoxadone (FAM) and methoxyacrylate stilbene (MOAS), indicated that FAM is a non-competitive inhibitor of the enzyme while methoxyacrylate stilbene (MOAS) is better described as a mixed-competitive inhibitor with respect to substrate. Mixed-competitive and non-competitive inhibition kinetics predicts a ternary enzyme-substrate-inhibitor (ESI) intermediate in the reaction sequence. Current views of the Qo domain architecture propose substrate binding niches in both distal and proximal regions of the domain. Since both inhibitors bind within the proximal niche, the formation of an ESI complex implicates substrate binding within the distal niche near the iron-sulfur protein (ISP) and cytochrome c(1) (C1). In the presence of saturating FAM, addition of substrate led to a slow, nearly stoichiometric reduction of C1 that was enzyme dependent, and independent of O(2)(-) production. Similar experiments with saturating MOAS led to a slow, sub-stoichiometric reduction of C1 by substrate. A comparison of the stoichiometries of reduction, and the apparent second order rate constants (K(cat)/K(m)) indicated that saturating MOAS elicits two distinct enzyme-inhibitor (EI) intermediates. One form does not bind substrate, but the other does. In contrast, saturating FAM leads to a predominant EI form capable of binding substrate. We suggest that these differences can be correlated to the respective effects of each inhibitor on the position of the ISP, and the integrity of a distal substrate binding site. The results also indicate that binding of these inhibitory substrate analogues to the proximal niche of the Qo domain significantly increases the DeltaG(double dagger) for reduction of C1.

Animals↗
PubMed2004

FADD-dependent apoptosis induction in Jurkat leukemia T-cells by the resveratrol analogue, 3,4,5-trihydroxy-trans-stilbene.

The plant-produced compound, resveratrol (3,5,4'-trihydroxy-trans-stilbene, 3,4,5-THS), induces apoptosis in various human leukemia cell types in vitro, and thus appears to be a promising anti-leukemia agent. In this study, we observed that treatment of resveratrol-resistant Jurkat cells with the resveratrol analogue, 3,4,5-trihydroxy-trans-stilbene (3,4,5-THS), rapidly induced extensive apoptosis, indicating that the apoptotic activity of the analogue differed from that of the parental compound resveratrol. Indeed, we found that treatment of Jurkat cells with 3,4,5-THS, unlike treatment with resveratrol, induced activation of caspase-8 and apoptosis by a Fas-associated death domain (FADD) protein-dependent mechanism without involving the known death ligands CD95 ligand (CD95L), tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL). Therefore, 3,4,5-THS induced activation of a FADD-dependent apoptotic mechanism that was unresponsive to the parental compound resveratrol. Therefore, the ability of 3,4,5-THS, but not resveratrol, to induce apoptosis demonstrates a structure-associated apoptotic activity of the resveratrol analogue.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro.

Polymerization of the amyloid beta-peptide (Abeta) has been identified as one of the major characteristics of Alzheimer's disease (AD). Thus, finding molecules to prevent the aggregation of Abeta could be of therapeutic value in AD. We describe an original routine in vitro assay to search for inhibitors of Abeta(25-35) fibril formation which uses UV-visible measurements and electron microscopy (EM). In particular, this routine assay was used to examine the effects of stilbenes, a well-known polyphenol class, as inhibitors of Abeta fibril formation. The inhibitory properties of resveratrol (RES), piceid (PIC), resveratrol diglucoside (DIG), piceatannol (PIA), astringine (AST), and viniferin (VIN) were characterized and compared. RES and PIC effectively and dose-dependently inhibited Abeta polymerization while other polyphenols exerted less inhibition. Although the mechanism of anti-amyloidogenic activity is still unknown, these results support the hypothesis that stilbenes could be of therapeutic value in AD.

Algorithms↗
PubMed2006

Stilbene-based anticancer agents: resveratrol analogues active toward HL60 leukemic cells with a non-specific phase mechanism.

Several stilbenes, related to known resveratrol, have been synthesized and tested for their anticancer effect on HL60 leukemia cell line, taking particular care of the cell cycle analysis. The most potent compound was the known (Z)-3,4',5-trimethoxystilbene (6b) which was active as apoptotic agent at 0.24 microM. Differently from other stilbenes (including resveratrol) that induced a prevalent recruitment of cells in S phase of cell cycle, we found a peculiar behavior of 6b that caused a decrease of cells in all phases of cell cycle (G0-G1, S, and G2-M) and a proportional increase of apoptotic cells. The potent pro-apoptotic activity shown by compound 6b and its effects on cell cycle make this compound of great interest for further investigations.

Antimony↗
PubMed2006

Anti-HIV activity of stilbene-related heterocyclic compounds.

Viral transcription has not been routinely targeted in the development of new antiviral drugs. This crucial step of the viral cycle depends on the concerted action of cellular and viral proteins such as NF-kappaB and Tat. In the present study, stilbene-related heterocyclic compounds including benzalphthalide, phthalazinone, imidazoindole and pyrimidoisoindole derivatives are tested for their anti-HIV activity. Original assays based on recombinant viruses were used to evaluate HIV replication inhibition and stably transfected cell lines were used to evaluate inhibition of Tat and NF-kappaB proteins. Some of the stilbene-related heterocyclic compounds analysed displayed anti-HIV activity through interference with NF-kappaB and Tat function. Moreover, compounds inhibiting both targets displayed a stronger activity on viral replication.

Anti-HIV Agents↗
PubMed2006

Design, microwave-assisted synthesis, and spasmolytic activity of 2-(alkyloxyaryl)-1H-benzimidazole derivatives as constrained stilbene bioisosteres.

A simple, fast, and efficient method for the preparation of several 2-(alkyloxyaryl)-1H-benzimidazole derivatives is reported. Compounds were synthesized through a rapid one-pot three component reaction via microwave irradiation, starting from commercially available aldehydes and o-phenylenediamine, in the presence of Na(2)S(2)O(5) and solvent-free conditions. The design of these compounds explore the hypothesis that the stilbene framework could be mimicked with an appropriate 2-(Alkyloxyphenyl)benzimidazole scaffold. This framework has a similar structural motif as the 6-phenylnaphthalene and behaves like stilbene bioisosteres. The spasmolytic activity of these compounds was recorded using isolated rat ileum test. Compound 12 was the most active of the series, showing an IC(50) of 1.19 microM.

Aldehydes↗
PubMed2004

An aldol switch discovered in stilbene synthases mediates cyclization specificity of type III polyketide synthases.

Stilbene synthase (STS) and chalcone synthase (CHS) each catalyze the formation of a tetraketide intermediate from a CoA-tethered phenylpropanoid starter and three molecules of malonyl-CoA, but use different cyclization mechanisms to produce distinct chemical scaffolds for a variety of plant natural products. Here we present the first STS crystal structure and identify, by mutagenic conversion of alfalfa CHS into a functional stilbene synthase, the structural basis for the evolution of STS cyclization specificity in type III polyketide synthase (PKS) enzymes. Additional mutagenesis and enzymatic characterization confirms that electronic effects rather than steric factors balance competing cyclization specificities in CHS and STS. Finally, we discuss the problematic in vitro reconstitution of plant stilbenecarboxylate pathways, using insights from existing biomimetic polyketide cyclization studies to generate a novel mechanistic hypothesis to explain stilbenecarboxylate biosynthesis.

Acyltransferases↗
PubMed2004

G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4'-bromo-cis-stilbene, in human lung cancer cells.

Stilbenoids, including resveratrol (3,5,4'-trihydroxy-trans-stilbene) which is a naturally occurring phytoalexin abundant in grapes and several plants, have been shown to be active in inhibiting proliferation and inducing apoptosis in human cancer cell lines. Using resveratrol as the prototype, we have synthesized various analogs and evaluated their growth inhibitory effects in cultured human cancer cells. In the present study, we show that one of the stilbenoids, 3,4,5-trimethoxy-4'-bromo-cis-stilbene (BCS), was more effective than its corresponding trans-isomer and resveratrol on the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of BCS (IC50; 0.03 microM) compared to its trans-isomer (IC50; 6.36 microM) and resveratrol (IC50; 33.0 microM) in cultured human lung cancer cells (A549), we investigated its mechanism of action. BCS induced arrest at the G2/M phase cell cycle in the early time and subsequently increased in the sub-G1 phase DNA contents in a time-dependent manner, indicating induction of apoptosis. Morphological observation with round-up shape and DNA fragmentation was also revealed the apoptotic phenomena. BCS treatment elevated the expression levels of the pro-apoptotic protein p53, the cyclin-dependent kinase inhibitor p21, and the release of cytochrome c in the cytosol. The down-regulation of checkpoint protein cyclin B1 by BCS was well correlated with the cell cycle arrest at G2/M. These data suggest the potential of BCS to serve as a cancer chemotherapeutic or chemopreventive agent by virtue of arresting the cell cycle and induction of apoptosis of human lung cancer cells.

Analysis of Variance↗
PubMed2003

Regulation of the calcium release channel from skeletal muscle by suramin and the disulfonated stilbene derivatives DIDS, DBDS, and DNDS.

Activation of skeletal muscle ryanodine receptors (RyRs) by suramin and disulfonic stilbene derivatives (Diisothiocyanostilbene-2',2'-disulfonic acid (DIDS), 4,4'-dibenzamidostilbene-2,2'-disulfonic acid (DBDS),and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS)) was investigated using planar bilayers. One reversible and two nonreversible mechanisms were identified. K(a) for reversible activation (approximately 100 micro M) depended on cytoplasmic [Ca(2+)] and the bilayer composition. Replacement of neutral lipids by negative phosphatidylserine increased K(a) fourfold, suggesting that reversible binding sites are near the bilayer surface. Suramin and the stilbene derivatives adsorbed to neutral bilayers with maximal mole fractions between 1-8% and with affinities approximately 100 micro M but did not adsorb to negative lipids. DIDS activated RyRs by two nonreversible mechanisms, distinguishable by their disparate DIDS binding rates (10(5) and 60 M(-1) s(-1)) and actions. Both mechanisms activated RyRs via several jumps in open probability, indicating several DIDS binding events. The fast and slow mechanisms are independent of each other, the reversible mechanism and ATP binding. The fast mechanism confers DIDS sensitivity approximately 1000-fold greater than previously reported, increases Ca(2+) activation and increases K(i) for Ca(2+)/Mg(2+) inhibition 10-fold. The slow mechanism activates RyRs in the absence of Ca(2+) and ATP, increases ATP activation without altering K(a), and slightly increases activity at pH < 6.5. These findings explain how different types of DIDS activation are observed under different conditions.

Animals↗