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PubMed1992

Human fibroblasts lacking trans-stilbene oxide active glutathione transferase exhibit increased cell death when exposed to polycyclic aromatic hydrocarbons.

Glutathione transferases (GST) are detoxifying enzymes who act with many endogenous and exogenous substances such as polycyclic aromatic hydrocarbons (PAH). The GST activity towards trans-stilbene oxide (GST-tSBO) is inherited in an autosomal dominant fashion and can be separated in high (GST-positive) and low (GST-negative) phenotypes when measured in blood. Human fibroblast cultures were established from males matched for age, smoking habits and clinical manifestations of atherosclerosis. Matched pairs of GST-negative and GST-positive fibroblasts were studied. There was a very strong correlation between the levels of GST-tSBO in peripheral blood and in cultured fibroblasts within the same individual. When fibroblasts were exposed to benzo(a)pyrene (BP) or dimethylbenzanthracene (DMBA) GST-negative cells produced relatively more collagen than GST-positive cells. GST-negative fibroblasts showed a greater cell death than GST-positive fibroblasts as well among controls as after exposure to PAH. It is concluded that lack of GST-tSBO is easily discriminated in cultured skin fibroblasts. GST-negative and GST-positive fibroblasts showed different susceptibility towards some toxic stimuli that might be of importance in atherogenesis.

Aged↗
PubMed1979

The effects of a disulphonic stilbene on chloride and bicarbonate transport in the turtle bladder.

1. In turtle bladders bathed by Na-free media containing Cl and HCO3, the mucosa is electropositive to the serosa. Serosally applied 4-acetamido-4'-isothiocyano-2,2'-disulphonic stilbene (SITS) reduces the p.d. and Isc by 100%, and reduces the rate of net Cl reabsorption in some bladders but not in others. 2. In the absence of exogenous HCO2 (Cl present), SITS reduces the p.d. and Isc by 100%, and reduces the rate of mucosal acidification by 80%; net Cl reabsorption is not detectable under these HCO3-free bathing conditions. 3. In the absence of exogenous Cl (HCO3, present), the mucosa is also electropositive to the serosa and serosally applied SITS reverses the orientation of the p.d. and Isc so that the mucosa becomes electronegative to the serosa. 4. This constitutes sufficient evidence for the active, electrogenic secretion of an anion, probably HCO3. These data are explained by an analogue of discrete, electrogenic pumps and paths for the reabsorption of Na, Cl, and HCO3, and the secretion of HCO3.

Animals↗
PubMed1983

Uptake and action of a disulphonic stilbene (SITS) in the perfused guinea-pig liver: a comparison with bromsulphthalein.

1. Livers were perfused with a Krebs-Ringer bicarbonate buffer in a single-pass perfusion system. Bile secretion was maintained by infusion of secretin. 4-Acetamido-4'-isothiocyano-2,2'-stilbene disulphonic acid (SITS) was added to the perfusate to give concentrations ranging between 5 x 10(-6) and 10(-4) M. 2. SITS was extracted from the perfusate by the liver (V, 0 . 15 mumol/min per g liver; Km 8 . 6 x 10(-5) M) and excreted in bile in a modified form (bile/plasma ratio: 50-170; maximum rate of excretion: 25 nmol/min per g liver wet wt). 3. The rates of uptake and excretion of bromsulphthalein (BSP) were similar to those for SITS, with the exception that the affinity of BSP for hepatic uptake was greater (Km 1 . 8 x 10(-5) M). 4. Both SITS and BSP decreased the rate of bile flow. A 50% reduction in bile flow was attained in each case at an estimated drug content of the liver of 1 . 5 mumol/g wet wt. 5. Unlike other cells the hepatocyte appears to be readily penetrated by SITS, and it is suggested that SITS inhibits bile secretion by inhibiting an intracellular mechanism which could be mitochondrial in location.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1988

Inhibition of chloride self-exchange with stilbene disulphonates in depolarized skeletal muscle of Rana temporaria.

1. The inhibition of 36Cl efflux with stilbene disulphonates, SD, has been studied under conditions of chloride equilibrium in depolarized fibre bundles from frog semitendinosi. The chosen probes were the aminoreactive derivative SITS and the derivative DNDS with no aminoreactive group. SD were added to the medium during 36Cl efflux allowing the estimation of fractional inhibition after a single 36Cl loading. 2. Both probes inhibited chloride self-exchange reversibly within the pH range 5.5-9.5 under study. 3. At SD concentrations above the half-inhibition concentration the inhibition reached a steady level with a time lag equal to that required for extracellular fluid change. The time constant for reversibility upon the removal of SD increased with decreasing pH, but rapid reversibility always appeared upon an increase of pH to 7.2. These findings suggest that SD may enter the membrane at low pH, but that the inhibitory action is confined to superficial membrane sites. 4. The inhibitory power of both probes showed a pronounced pH dependence, pK approximately 7. The half-inhibition concentration increased about 6-7 times when pH was lowered one unit from the pK value. 5. The apparent affinity of SITS to the transport system was about 5 times higher than that of DNDS. The apparent dissociation constants at neutral pH were 8.5 x 10(-5) M (SITS) and 4.5 x 10(-4) M (DNDS). Both probes showed a maximal inhibition close to 100% at neutral pH and approximately 85% at pH 5.5. 6. The inhibition depended on the chloride concentration in a way consistent with competitive inhibition in both neutral and acid media. 7. The results are consistent with the classical model of anion transport in frog muscle, suggesting that SD and chloride may compete for binding to a site with increasing anion affinity upon protonation; the results do not, however, exclude that the conductive and the non-conductive chloride transport modes in frog muscle are mediated by separate SD-sensitive transport pathways.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2006

Induction of genes for metabolism and transport by trans-stilbene oxide in livers of Sprague-Dawley and Wistar-Kyoto rats.

trans-Stilbene oxide (TSO) is a synthetic proestrogen that induces phase I and II drug-metabolizing enzymes in rat liver. The purpose of this study was to determine whether TSO also induces transporter expression in rat liver and whether gene induction in rat liver after TSO occurs in a constitutive androstane receptor (CAR)-dependent manner. Total RNA was isolated from male rat livers after treatment with TSO for up to 4 days (200 mg/kg, i.p., twice daily), and the mRNA levels for each gene were quantified. CYP2B1/2, CYP3A1, epoxide hydrolase, heme oxygenase-1, UGT1A6, UGT2B1, multiple drug resistance protein (Mdr) 1a and 1b, as well as multidrug resistance-associated protein (Mrp) 2, 3, and 4 mRNA were increased in livers after TSO treatment. To determine whether TSO activates gene expression in a CAR-dependent manner, male and female Wistar-Kyoto (WKY) rats were treated with TSO for 3 days. TSO induced CYP2B1/2, UGT2B1, and Mdr1b in males more than in females, suggesting that TSO could increase their expression via CAR. Conversely, TSO induced CYP3A1, epoxide hydrolase, UGT1A6, and Mrp3 similarly in both genders, indicating that induction of these genes occurs independently of CAR. TSO treatment also increased the activity of a CAR binding element luciferase reporter construct in HepG2 cells transfected with rat CAR and in mouse liver. Additionally, TSO increased antioxidant response element/electrophile response element luciferase reporter construct activity in HepG2 cells. In conclusion, in WKY rat liver, TSO increases CYP2B1/2, UGT2B1, and Mdr1b mRNA expression in a gender-dependent manner and CYP3A1, epoxide hydrolase, UGT1A6, and Mrp3 in a gender-independent manner.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Suramin and disulfonated stilbene derivatives stimulate the Ca2+-induced Ca2+ -release mechanism in A7r5 cells.

We have described previously a novel Ca2+-induced Ca2+-release (CICR) mechanism in permeabilized A7r5 cells (embryonic rat aorta) and 16HBE14o-cells (human bronchial mucosa) cells (J Biol Chem 278:27548-27555, 2003). This CICR mechanism was activated upon the elevation of the free cytosolic calcium concentration [Ca2+]c and was not inhibited by pharmacological inhibitors of the inositol-1,4,5-trisphosphate (IP3) receptor nor of the ryanodine receptor. This CICR mechanism was inhibited by calmodulin (CaM)1234, a Ca2+-insensitive CaM mutant, and by different members of the superfamily of CaM-like Ca2+-binding proteins. Here, we present evidence that the CICR mechanism that is expressed in A7r5 and 16HBE14o-cells is strongly activated by suramin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). We found several indications that both activation mechanisms are indeed two different modes of the same release system. Suramin/DIDS-induced Ca2+ release was only detected in cells that displayed the CICR mechanism, and cell types that do not express this type of CICR mechanism did not exhibit suramin/DIDS-induced Ca2+ release. Furthermore, we show that the suramin-stimulated Ca2+ release is regulated by Ca2+ and CaM in a similar way as the previously described CICR mechanism. The pharmacological characterization of the suramin/DIDS-induced Ca2+ release further confirms its properties as a novel CaM-regulated Ca2+-release mechanism. We also investigated the effects of disulfonated stilbene derivatives on IP3-induced Ca2+ release and found, in contrast to the effect on CICR, a strong inhibition by DIDS and 4'-acetoamido-4'-isothiocyanostilbene-2',2'-disulfonic acid.

Animals↗
PubMed2006

trans-Stilbene oxide induces expression of genes involved in metabolism and transport in mouse liver via CAR and Nrf2 transcription factors.

trans-Stilbene oxide (TSO) induces drug metabolizing enzymes in rat and mouse liver. TSO is considered a phenobarbital-like compound because it induces Cyp2B mRNA expression in liver. Phenobarbital increases Cyp2B expression in liver via activation of the constitutive androstane receptor (CAR). The purpose of this study was to determine whether TSO induces gene expression in mouse liver via CAR activation. TSO increased CAR nuclear localization in mouse liver, activated the human Cyp2B6 promoter in liver in vivo, and activated a reporter plasmid that contains five nuclear receptor 1 (NR1) binding sites in HepG2 cells. TSO administration increased expression of Cyp2b10, NAD(P)H:quinone oxidoreductase (Nqo1), epoxide hydrolase, heme oxygenase-1, UDP-glucuronosyl-transferase (Ugt) 1a6 and 2b5, and multidrug resistance-associated proteins (Mrp) 2 and 3 mRNA in livers from male mice. Cyp2b10 and epoxide hydrolase induction by TSO was decreased in livers from CAR-null mice, compared with wild-type mice, suggesting CAR involvement. In contrast, TSO administration induced Nqo1 and Mrp3 mRNA expression equally in livers from wild-type and CAR-null mice, suggesting that TSO induces expression of some genes through a mechanism independent of CAR. TSO increased nuclear staining of the transcription factor Nrf2 in liver, and activated an antioxidant/electrophile response element luciferase reporter construct that was transfected into HepG2 cells. In summary, in mice, TSO increases Cyp2b10 and epoxide hydrolase expression in mice via CAR, and potentially induces Nqo1 and Mrp3 expression via Nrf2. Moreover, our data demonstrate that a single compound can activate both CAR and Nrf2 transcription factors in liver.

Animals↗
PubMed1992

The role of guanosine-3',5'-bis-pyrophosphate in mediating antimicrobial activity of the antibiotic 3,5-dihydroxy-4-ethyl-trans-stilbene.

The mode of action of 3,5-dihydroxy-4-ethyl-trans-stilbene (ES), an antibiotic produced by Xenorhabdus luminescens symbiotically associated with an entomopathogenic nematode, was investigated. ES was active against gram-positive and a number of gram-negative bacteria. In susceptible bacteria this antibiotic caused the inhibition of total RNA synthesis and, to a lesser extent, protein synthesis. At or above MICs, ES triggered a substantial accumulation of an intracellular regulatory compound, guanosine-3',5'-bis-pyrophosphate (ppGpp). This response was also noticed in species of bacteria which have previously not been shown to use ppGpp as a regulatory molecule. The involvement of ppGpp in antibiotic action was confirmed by using an isogenic stringent and a relaxed pair of Escherichia coli strains. The fact that the accumulation of ppGpp was correlated with the susceptibility of various gram-positive and gram-negative bacteria to ES suggests that this nucleotide is involved in the regulation of RNA synthesis and growth in all these microorganisms. Thus, inhibition of RNA synthesis via an increase in ppGpp concentrations may represent a mechanism that is prevalent among most bacteria and one that could be exploited for achieving a rapid inhibition of bacterial growth.

Animals↗
PubMed1968

Antifungal activity of isothiocyanates and related compounds. 3. Derivatives of biphenyl, stilbene, azobenzene, and several polycondensed aromatic hydrocarbons.

This paper presents the results of a study on the antifungal activity of isothiocyanates-derivatives of biphenyl (group "A"), of stilbene ("B"), of azobenzene and benzeneazonaphthalene ("C"), of naphthalene ("D"), and of further polycondensed aromatic hydrocarbons ("E"). From a total of 48 investigated compounds, antifungal activity was observed only in A and D group compounds. B, C, and E group derivatives are extremely insoluble in water, and the molecules are very large; as a result, they probably cannot pass into spores or mycelium of fungi. Thus, the -NCS group cannot manifest its reactivity.

Antifungal Agents↗
PubMed1989

Stilbene disulfonate blockade of colonic secretory Cl- channels in planar lipid bilayers.

We studied blockade by 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS) of a secretory Cl- channel from colonic enterocyte plasma membrane vesicles incorporated into planar lipid bilayer membranes. Except for intermittent long-lived closed periods (100 ms to several min), the control channel open probability (Po) was greater than 90%. DNDS, added to the cis or vesicle-containing side, which corresponds to the outer membrane side of the channel, caused a dramatic increase in the number of current transitions from the open-to-closed state. DNDS caused a concentration-dependent decrease in Po with a maximum inhibition of 95 +/- 2.0% and a half-maximal inhibitory concentration of 3.3 +/- 1.4 microM. DNDS added to the trans side of the channel had no effect on either the single-channel conductance or kinetic behavior of the channel. Kinetic analysis revealed that DNDS blockade from the cis side could be explained by a linear, closed-open-blocked, kinetic scheme. The estimated DNDS block rate constants were kon = 3.2 X 10(7) M-1.s-1 and koff = 52 s-1, yielding an equilibrium dissociation constant (KD) of 2.1 +/- 0.38 microM, similar to the Ki for inhibition of Po. The effects of DNDS were fully reversible after perfusion of the cis compartment with DNDS-free solution. In contrast, the covalently reactive 4,4'-diisothiocyano-substituted stilbene disulfonate caused an irreversible blockade of the Cl- channel.

Animals↗
PubMed1986

Concentration-dependent effects of disulfonic stilbenes on colonic chloride transport.

Stripped rabbit colonic mucosa was studied in vitro in Ussing chambers to determine effects of the disulfonic stilbenes 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS) and 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) and the diuretic furosemide on unidirectional and net Cl fluxes. Results from these studies reveal that SITS (1 mM) added to either the serosal or mucosal bathing solution reduced both unidirectional Cl fluxes with no significant change in net Cl flux. The effects of SITS do not appear to be mediated by an effect on the shunt permeability since SITS (1 mM) did not alter either the intercept or slope of the Na concentration dependence of the serosal-to-mucosal Na flux. Furosemide (1 mM) decreased the serosal-to-mucosal Cl flux without altering short-circuit current (Isc) when added to the luminal bathing solution and reduced both unidirectional fluxes and increased Isc when added to the serosal bathing solution. DIDS (0.5 mM) added to the luminal bathing solution did not alter unidirectional Cl fluxes or Isc. However, serosal addition of DIDS produced dose-dependent changes in Cl transport. At 5 microM DIDS reduced the mucosal-to-serosal Cl flux without altering the serosal-to-mucosal flux or Isc. At 50 microM DIDS reduced the mucosal-to-serosal Cl flux and increased Isc, and at 0.5 mM DIDS increased the serosal-to-mucosal Cl flux, reduced the mucosal-to-serosal Cl flux, and increased Isc and transepithelial conductance. The effect of 0.5 mM DIDS on Isc was reduced by Ca removal from the serosal bathing solution and by the loop diuretics furosemide and bumetanide.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors.

PURPOSE: HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1. RESULTS: A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).

Administration, Oral↗
PubMed2005

Unique properties of polyphenol stilbenes in the brain: more than direct antioxidant actions; gene/protein regulatory activity.

The 'French Paradox' has been typically associated with moderate consumption of wine, especially red wine. A polyphenol 3,4',5-trihydroxy-trans-stilbene (a member of the non-flavonoids family), better known as resveratrol, has been purported to have many health benefits. A number of these valuable properties have been attributed to its intrinsic antioxidant capabilities, although the potential level of resveratrol in the circulation is likely not enough to neutralize free radical scavenging. The brain and the heart are uniquely vulnerable to hypoxic conditions and oxidative stress injuries. Recently, evidence suggests that resveratrol could act as a signaling molecule within tissues and cells to modulate the expression of genes and proteins. Stimulation of such proteins and enzymes could explain some the intracellular antioxidative properties. The modulation of genes could suffice as an explanation of some of resveratrol's cytoprotective actions, as well as its influence on blood flow, cell death, and inflammatory cascades. Resveratrol stimulation of the expression of heme oxygenase is one example. Increased heme oxygenase activity has led to significant protection against models of in vitro and in vivo oxidative stress injury. Resveratrol could provide cellular resistance against insults; although more work is necessary before it is prescribed as a potential prophylactic in models of either acute or chronic conditions, such as stroke, amyotrophic lateral sclerosis, Parkinson, Alzheimer, and a variety of age-related vascular disorders.

Animals↗
PubMed1978

Inhibition of the bicarbonate exit step in urinary acidification by a disulfonic stilbene.

Acidification of the luminal solution by the isolated turtle bladder involves H(+) secretion by a pump at the luminal membrane. The OH(-) dissociated in this process reacts with CO(2) and forms HCO(3) (-) which moves passively out of the cell across the serosal cell membrane. In the present study, this exit step for HCO(3) (-) was inhibited by serosal addition of the disulfonic stilbene, SITS, an agent which is thought to bind to a transport protein at the serosal cell membrane. 90 min after serosal addition of 0.5 mM SITS, H(+) secretion decreased by > 80%. In contrast, luminal addition of SITS had no effect. During inhibition of H(+) secretion by serosal SITS, overall cell pH, measured by the 5, 5-dimethyl-2, 3-oxazolidinedione method, increased from 7.48+/-0.03 to 7.61+/-0.02. This increase of 0.13+/-0.02 pH U was associated with a much larger regional pH increase as judged from the decrement in the attainable pH gradient across the epithelium. After serosal SITS, this gradient was reduced from 2.88+/-0.06 to 2.09+/-0.11 pH U. In the absence of evidence for increased H(+) permeability or a change in the force of the H(+) pump, the gradient decrement of 0.79+/-0.08 U reflects a similar pH increment on the cytoplasmic side of the pump.SITS inhibits the exit of bicarbonate across the serosal cell membrane and, thereby, creates a compartment of high alkalinity in series with the pump. The increased electrochemical gradient across the active transport pathway is the primary factor in the inhibition of urinary acidification.

Acid-Base Equilibrium↗
PubMed2002

(+)-Alpha-viniferin, a stilbene trimer from Caragana chamlague, inhibits acetylcholinesterase.

In the course of screening natural products for anti-acetylcholinesterase (AChE) activity, we found that a total methanolic extract of the underground parts of Caragana chamlague (Leguminosae) had significant inhibition towards AChE. Bioactivity-guided fractionation of the total methanolic extract resulted in the isolation and identification of two active stilbene oligomers, (+)-alpha-viniferin (1) and kobophenol A (2). Both 1 and 2 inhibited AChE activity in a dose-dependent manner, and the IC50 values of 1 and 2 were 2.0 and 115.8 microM, respectively. The AChE inhibitory activity of 1 was specific, reversible and noncompetitive.

Acetylcholinesterase↗
PubMed2002

(4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene as a potent inhibitor of melanin production.

The current study was carried out to investigate in vitro the effects of (4-methoxy-benzylidene)-(3-methoxyphenyl)-amine on melanin biosynthesis which is closely related to hyper-pigmentation. (4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene, was synthesized by a single step process. This compound inhibited the tyrosinase activity, which converts dopa to dopachrome in the biosynthetic process of melanin, and showed a UV-blocking effect at UV-B band. The compound also exhibited SOD-like activity, which is involved in the protection against auto-oxidation and inhibited melanin production in melan-a cell line. Our results suggest the possibility that (4-methoxy-benzylidene)-(3-methoxy-phenyl)-amine might be used as a skin whitening agent.

Animals↗
PubMed2002

Stilbene derivatives from two species of Gnetaceae.

Five new stilbene oligomers (gnemonols A, B and C, gnemonoside E and gnetal) were isolated together with 2b-hydroxyampelopsin F and gnetin E from Gnetum gnemon and G. gnemonoides. The structures of the compounds were elucidated on the basis of spectral evidence.

Benzofurans↗
PubMed2002

Stilbene and 2-arylbenzofuran glucosides from the rhizomes of Schoenocaulon officinale.

Two stilbene glucosides, oxyresveratrol 2-O-beta-glucopyranoside and resveratrol 3,4'-O,O'-di-beta-D-glucopyranoside, and a 2-arylbenzofuran glucoside, schoenoside, were isolated from the rhizomes of Schoenocaulon officinale, along with five known compounds, oxyresveratrol 3'-O-beta-D-glucopyranoside, oxyresveratrol, resveratrol 3-O-beta-D-glucopyranoside, mulberroside A and moracin M 3'-O-beta-D-glucopyranoside. The structural elucidations were based on analyses of both physical and spectroscopic data.

Benzofurans↗