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At least 811 records · Page 45Linked to original sources
PubMed1982

Synthetic prostaglandin1 analogue: in vitro studies on human neutrophils.

Prostaglandin (PG) E1 and chemically related compounds 15 alpha-11-deoxy-8-azaPGE1 and 15 epi-11-deoxy-8-azaPGE1 were examined in vitro for their capacity to modulate some physiological functions of human polymorphonuclear leukocytes (PMN). PGE1 was completely devoid of chemotactic activity and did not affect leukocyte phagocytosis. On the contrary, 15 alpha-11-deoxy-8-azaPGE1 showed a potent leukotactic activity. In addition, this synthetic substance significantly depressed the phagocytic activity and the concomitant NBT reduction by leukocytes. The analogue 15 epi-11-deoxy-8-azaPGE1 did not exert any of these effects. From these results it appeared that the substitution of the carbon-8 by the nitrogen and the lack of hydroxyl group at the position 11 into the PGE1 structure, make the compound active towards human neutrophils.

Alprostadil↗
PubMed1998

Radical releasing properties of nitric oxide donors GEA 3162, SIN-1 and S-nitroso-N-acetylpenicillamine.

The nitric oxide (NO)-, superoxide anion (O2.-)- and peroxynitrite (ONOO-)-releasing properties of 1,2,3,4-oxatriazolium,5-amino-3-(3,4-dichlorophenyl)-chloride (GEA 3162) were characterized and compared with the known NO-donors 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine. All the three compounds released NO in aqueous solutions in a dose-dependent manner as measured by ozone-chemiluminescence. GEA 3162 produced more NO than SIN-1, but less than S-nitroso-N-acetylpenicillamine during a 45 min incubation time. SIN-1 reduced nitro blue tetrazolium and the effect was inhibitable by superoxide dismutase. Reduction of nitro blue tetrazolium was not detected in the solutions of GEA 3162 and S-nitroso-N-acetylpenicillamine suggesting that SIN-1 but not GEA 3162 and S-nitroso-N-acetylpenicillamine release O2.- in their decomposition process. Formation of ONOO- in solutions of GEA 3162, SIN-1 and S-nitroso-N-acetylpenicillamine was estimated indirectly by measuring the formation of nitrotyrosine. The data indicate that ONOO- was produced in the presence of SIN-1 but not in solutions of GEA 3162 and S-nitroso-N-acetylpenicillamine. The results suggest that GEA 3162 produces negligible amounts of O2.- and ONOO- as compared to SIN-1. This adds the value of GEA 3162 as an useful tool in NO research and could well explain the earlier findings on the superior NO-like biological activity of oxatriazole derivatives as compared to SIN-1.

Molsidomine↗
PubMed2006

Virgin olive oil phenols inhibit proliferation of human promyelocytic leukemia cells (HL60) by inducing apoptosis and differentiation.

Although epidemiologic evidence and animal studies suggest that olive oil may prevent the onset of cancer, the components responsible for such an effect and their mechanisms of action remain largely unknown. In the present study, we investigated the effect of a virgin olive oil phenol extract (PE) on proliferation, the cell cycle distribution profile, apoptosis, and differentiation of the human promyelocytic cell line HL60. PE inhibited HL60 cell proliferation in a time- and concentration-dependent manner, as demonstrated by the viable cell count and 3-[4,5-dimethyl(thiazol-2-yl)]-3,5-diphenyltetrazolium bromide (MTT) metabolism. Cell growth was completely blocked at a PE concentration of 13.5 mg/L; apoptosis was also induced as detected by fluorescence microscopy and flow cytometry. Determination of the cell cycle distribution by flow cytometry revealed an accumulation of cells in the G(0)/G(1) phase. Two compounds isolated from PE, the dialdehydic forms of elenoic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) and to tyrosol (pHPEA-EDA), were shown to possess properties similar to those of PE; they account for a part of the powerful effects exerted by the complex mixture of compounds present in PE. The concentrations of the different compounds in PE were determined by HPLC, and the purity of 3,4-DHPEA-EDA and pHPEA-EDA was ascertained by NMR. Treatment with PE induced a differentiation in HL60 cells, which subsequently acquired the ability to produce superoxide ions and reduce nitroblue tetrazolium to formazan. These results support the hypothesis that polyphenols play a critical role in the anticancer activity of olive oil.

Apoptosis↗
PubMed1991

Circumvention of multidrug resistance mediated by P-170 glycoprotein using calcium antagonists in primary human renal cell carcinoma.

In experimental cell lines and in some human tumors, calcium antagonists reversed multidrug resistance mediated by P-170 glycoprotein in vitro. So far, clinical trials have not been very rewarding as intrinsic cardiovascular activities of these compounds impeded sufficient dosage. Renal cell carcinomas are considered to be good models for the evaluation of this new therapeutic concept. In 35 primary human renal cell carcinomas, the potency of 7 different calcium antagonists in combination with vinblastine monotherapy was examined in a tetrazolium-based microculture assay (MTT test) in order to circumvent chemoresistance. Concomitantly, P-170 glycoprotein expression was traced immunohistochemically using moab C 219. Substances derived from piperazine (flunarizine) showed only minor effects in this respect. The calcium antagonists of the papaverine type such as verapamil etc. revealed the strongest reversal of chemoresistance. Derivatives of benzothiazepine (diltiazem) or of dihydropyridine (nifedipine etc.) acted similarly and reached about 70% of the verapamil activity. All calcium antagonists lead to a significant enhancement of vinblastine cytotoxicity. An obvious link of P-170 glycoprotein to vinblastine chemoresistance was demonstrated. This particular resistance characteristic was detected in 19 of 27 resistant cases, but in none of the tumors displaying a chemoresponse. In particular, the new stereoisomer R-verapamil, which showed strong reversal of chemoresistance but which exerts 10 times lower cardiovascular side effects than racemic verapamil, seems to be suitable for further evaluation with regard to the clinical application.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Development of a new isogenic cell-xenograft system for evaluation of NAD(P)H:quinone oxidoreductase-directed antitumor quinones: evaluation of the activity of RH1.

PURPOSE: The purpose of our study was to develop and validate an isogenic cell line pair that differs only in the expression of NAD(P)H:quinone oxidoreductase (NQO1) that can be used to examine the in vitro and in vivo role of NQO1 in the bioactivation of the antitumor quinone RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), a compound currently in Phase I clinical trials. EXPERIMENTAL DESIGN: MDA-MB-468 (MDA468) human breast adenocarcinoma cells, homozygous for a polymorphism in NQO1 (NQO1*2/*2) and with low levels of NQO1 activity, were stably transfected with human NQO1 to generate a clone (NQ16) expressing very high NQO1 activity. We examined levels of other reductases and looked at biochemical systems that might influence response to antitumor quinones to validate that the isogenic cell line pair differed only in the expression of NQO1. The 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium (MTT) assay was used to determine the differential toxicity of various quinones, including the most recent NQO1-directed antitumor quinone, RH1, between the two cell lines. Human tumor xenografts were established from both MDA468 and NQ16 cells, and the antitumor activity of RH1 was evaluated. RESULTS: Levels of cytochrome P450 reductase, cytochrome b(5) reductase, soluble thiols, and superoxide dismutase in the NQ16 line were unchanged from the parental line. The functional significance of wild-type NQO1 expression was confirmed by measurement of the differential toxicity of compounds activated or deactivated by NQO1 in the two cell lines. The toxicity of the NQO1-directed antitumor quinones RH1 and streptonigrin were markedly greater and the toxicity of menadione, which is detoxified by NQO1, was ameliorated in the NQ16 line. High levels of NQO1 expression were observed throughout xenograft tumors established from the NQ16 cell line. RH1 treatment was effective at statistically reducing tumor volume in NQ16 xenografts at all of the doses tested (0.1, 0.2, 0.4 mg/kg every day for 5 days), whereas only the highest dose of RH1 resulted in a significant reduction in tumor volume in MDA468 xenografts. CONCLUSIONS: The MDA468/NQ16 isogenic cell line pair is a useful model system for evaluating the role of NQO1 in the bioactivation of antitumor quinones in both cell lines and xenografts. In addition, our data demonstrate that the novel antitumor quinone RH1, is effectively activated by NQO1 both in vitro and in vivo.

Animals↗
PubMed1990

Indoxyl alfa-D-galactoside as the temporarily last substrate for glycosidase histochemistry. The present state of the art in histochemical glycosidase research using indoxyl glycosidas.

Initiated by the recently published histochemical method for the investigation of alfa-D-galactosidas with an indoxyl substrate, the current state of this group of synthetic compounds in light and electron microscopic histochemical glycosidase research is evaluated whereby historical, functional, methodological and applied aspects are considered. Beginning with the introduction of indoxyl acetate for non-specific esterase in 1951 and 1952 numerous other indoxyl substrates and mostly substituted in the 5- and 4-position of the indol ring by Br and Cl were developed to study histochemically non-specific phosphatases and glycosidases and frequently used in indigogenic, azoidoxyl, tetrazolium salts and metal salt techniques for catalytic (activity) histochemical and less often for immunohistochemical, affinity histochemical and hybridohistochemical purposes. The last substrate which became available and was validated for activity histochemistry was 5-Br-4-Cl-3-indoxyl alfa-1-galactoside for alfa-1-galactosidase. At present, the indoxyl glycosides are more widely used than 5-Br-4-Cl-3-indoxyl acetates and phosphates when compared with the alternative synthetic (artificial) naphthol, 6-Br-2-naphthol or ternative synthetic (artificial) naphthol, 6-Br-2-naphthol AS substrates, and among the indoxyl glycosides those for the oxoglycosidases lactase, maltase-glucoamylase, glucoamylase, acid beta-D-galactosidase, neuroaminidase and alfa-D-galactosidase are superior to other artificial compounds. When one considers in addition, electron microscopic catalytic glicosidase histochemistry (ultracytochemistry, 5-Br-4-Cl-3-indoxyl is the only suitable moiety for this purpose. These glycosidase can mostly be localized in plasma membranes or lysosomes and also measured there in tissue sections but are also found in secretion granules, endoplasmic reticulum and organ lumina.

Animals↗
PubMed1977

Effects of nitroblue tetrazolium and vitamin E on platelet ultrastructure, aggregation, and secretion.

All agents capable of triggering the platelet release reaction also stimulate prostaglandin biosynthesis in these cells. Information concerning the endoperoxides, thromboxanes, and more stable metabolites generated by the action of cyclooxygenase and lipoxygenase on arachidonic acid has accumulated rapidly, but little is known about the preliminary steps in the cleavage and preparation of arachidonic acid for insertion into the enzymatic pathways of prostaglandin synthesis. Studies in this laboratory have shown that the combination of nitroblue tetrazolium (NBT) and vitamin E which prevents oxygenation of arachidonic acid to a free radical also blocks platelet prostaglandin biosynthesis. The present study has evaluated the influence of NBT, vitamin E, and the combination of NBT and vitamin E on the fine structure and biochemistry of platelets during incubation, and the effects of these compounds on the aggregation and secretion of platelets stimulated by collagen, thrombin, epinephrine, and ADP. Results of the study demonstrate that NBT and vitamin E, rather than injuring platelets, appear to protect them during incubation. Together NBT and vitamin E blocked aggregation by epinephrine, collagen, and thrombin, but permitted a small first wave stimulated by ADP. Both ADP and thrombin induced shape change, pseudopod formation, and limited degrees of internal contraction in vitamin E-NBT-treated platelets, whereas epinephrine and collagen failed to significantly alter discoid form. This pattern of response to aggregating agents was identical to reactions observed in platelets pretreated with aspirin and indomethacin, both potent inhibitors of platelet prostaglandin synthesis. In addition, NBT-vitamin E virtually blocked the first wave of aggregation which is not affected by aspirin and indomethacin. The findings support the concept that conversion of arachidonic acid to an activated state is an important step in prostaglandin synthesis and that electron transfer or oxidation-reduction reactions are intimately involved in the development of platelet stickiness.

Adenosine Diphosphate↗
PubMed2002

Spectrophotometric assay of superoxide anion formed in Maillard reaction based on highly water-soluble tetrazolium salt.

A novel highly water-soluble tetrazolium salt, WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt), can be reduced to water-soluble formazan with a superoxide anion. Here, the WST-1 assay was applied to detect the superoxide anion generated during the Maillard reaction. A sample solution containing carbonyl compounds such as glyceraldehyde and glycolaldehyde (5 mM) and Na-acetyl-L-lysine (10 mM) was incubated for 2 days at 37 degrees C. The detection of a superoxide anion generated in the sample was performed by the WST-1 assay, and the result was compared with the cytochrome c assay. The reduction of WST-1 was almost perfectly (86-96%) inhibited by the addition of the superoxide dismutase (SOD). On the contrary, the reduction of cytochrome c was slightly (20-25%) inhibited by the addition of SOD. A similar result was observed for the addition of 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). These results mean that the specificity of WST-1 to the superoxide anion was superior to that of cytochrome c. It was also possible to continuously monitor superoxide anion generation during the Maillard reaction by the coexistence of WST-1 in the reaction solution.

Acetaldehyde↗
PubMed1998

The role of glutathione S-transferases as a defense against reactive electrophiles in the blood vessel wall.

The glutathione transferases (GSTs) are a family of ubiquitous enzymes that catalyze the conjugation of reduced glutathione (GSH) with reactive electrophiles. Rat vascular tissue contains GST isoforms that represent a major cellular defense mechanism against atherogenic alpha,beta-unsaturated aldehydes (Misra et al., Toxicol. Appl. Pharmacol. 133, 27-33, 1995). In this study we examined the role of GSTs in providing protection to cultured neonatal vascular smooth muscle cells (VSMCs) from the alpha,beta-unsaturated carbonyl cardiovascular toxins, allylamine and its metabolite, acrolein. Confluent cultured cells were exposed to 2 to 10 microM allylamine (a cardiovascular toxin that is metabolized in vivo and in vitro by VSMCs to the reactive aldehyde, acrolein) or to acrolein (2-10 microM) for 48 h; dose-cytotoxicity curves were generated utilizing a tetrazolium-dependent cytotoxicity assay. Concommittant treatment with sulfasalazine, an established inhibitor of GST, was found to markedly increase allylamine- or acrolein-induced cytotoxicity, decreasing the LC50 by two- to threefold at 50 to 100 microM sulfasalazine. A clonogenic survival assay in VSMCs exposed to these compounds for 4 h confirmed lethal toxicity and enhanced toxicity following cotreatment with sulfasalazine. Isobologram analysis (which statistically defines the limits of additivity of two independent treatments) showed that the sulfasalazine effect on both allylamine and acrolein cytotoxicity was supraadditive, or synergistic. Sulfasalazine was not cytotoxic to VSMCs in the range of concentrations that augmented acrolein or allylamine cytoxicity; total GST activity was inhibited, however, in a dose-dependent manner in that range. GST purified by GSH-affinity chromatography from pelleted untreated cells gave specific activities and kinetic constants consistent with those previously reported for rat aorta total GSTs. The catalytic efficiency (Kcat/Vm) was found to be much greater for 4-hydroxy-2-nonenal than for 1-chloro-2,4-dinitrobenzene (0.058 vs 0.4 s-1 mM-1). Western blot of purified total GSTs using antibodies against rec-mGSTA4-4 revealed a single band at 25 kDa, confirming the presence of a GST isozyme immunologically similar to rat GST8-8, which is known to utilize alpha,beta-unsaturated carbonyls as preferred substrates. Our data indicate that GSTs are an important defense in the vascular media, protecting blood vessels against alpha,beta-unsaturated carbonyl cardiovascular toxins that are involved in initiating atherosclerotic lesions.

Acrolein↗
PubMed2004

Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia.

We determined the roles of reactive oxygen species (ROS) in the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated microglia. LPS treatment increased intracellular ROS in rat microglia dose-dependently. Pre-treatment with superoxide dismutase (SOD)/catalase, or SOD/catalase mimetics that can scavenge intracellular ROS, significantly attenuated LPS-induced release in PGE2. Diphenylene iodonium (DPI), a non-specific NADPH oxidase inhibitor, decreased LPS-induced PGE2 production. In addition, microglia from NADPH oxidase-deficient mice produced less PGE2 than those from wild-type mice following LPS treatment. Furthermore, LPS-stimulated expression of COX-2 (determined by RT-PCR analysis of COX-2 mRNA and western blot for its protein) was significantly reduced by pre-treatment with SOD/catalase or SOD/catalase mimetics. SOD/catalase mimetics were more potent than SOD/catalase in reducing COX-2 expression and PGE2 production. As a comparison, scavenging ROS had no effect on LPS-induced nitric oxide production in microglia. These results suggest that ROS play a regulatory role in the expression of COX-2 and the subsequent production of PGE2 during the activation process of microglia. Thus, inhibiting NADPH oxidase activity and subsequent ROS generation in microglia can reduce COX-2 expression and PGE2 production. These findings suggest a potential therapeutic intervention strategy for the treatment of inflammation-mediated neurodegenerative diseases.

Animals↗
PubMed1995

Involvement of protein kinase C in the delayed cytoprotection following sublethal ischaemia in rabbit myocardium.

Rabbit hearts were preconditioned with four 5 min coronary artery occlusions 24 h before 30 min coronary occlusion with 120 min reperfusion. Preconditioning significantly reduced the percentage of myocardium infarcting within the risk zone from 49.1 +/- 4.3% to 31.8 +/- 3.5% (P < 0.05). When the protein kinase C (PKC) inhibitor, chelerythrine, was administered just before preconditioning, the delayed protection against infarction 24 h later was abolished. We conclude that the delayed cytoprotective response associated with ischaemic preconditioning of myocardium is likely to involve the early activation of one or more PKC subtypes.

Alkaloids↗
PubMed2006

Phenolic constituents of Malus doumeri var. formosana in the field of skin care.

Plant phenolic compounds isolated from a 70% aqueous acetone extract of the leaves of Malus doumeri A. CHEV. var. formosana (KAWAK. & KOIDZ.) S. S. YING, a type of Taiwanese indigenous plant, were evaluated for potential application in the field of skin care. A phytochemical investigation of the active fractions resulted in the isolation of seven compounds of which the structures were identified by spectroscopic characterization. In the present study, the isolated phenolic compounds were evaluated for their free radical-scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the superoxide radicals, anti-elastase, and for their anti-matrix metalloproteinase-1 (MMP-1) activity in human skin fibroblast cells. Of these compounds, 3-hydroxyphloridzin (2), 3-hydroxyphloretin (6), and quercetin (7) exhibited the strongest DPPH and superoxide radical-scavenging activities. The IC50 values of these compounds were 9.2, 7.7, and 15.4 microM, respectively, for the DPPH radical, and 25.0, 19.6, and 42.6 microM, respectively, for the superoxide radical. 3-Hydroxyphloridzin (2) and 3-hydroxyphloretin (6) also showed xanthine oxidase inhibitory activity, with IC(50) values of 52.1 and 22.4 muM, respectively. In the test for elastase inhibitory activity, phloretin (5) and 3-hydroxyphloretin (6) were the most potent compounds. Phloretin (5), 3-hydroxyphloretin (6), and quercetin (7) showed better inhibition of MMP-1 production in fibroblast cells. To the best of our knowledge, this is the first time that the active phenolic compounds from M. doumeri var. formosana have been isolated, reported, and described. The above results suggest that the extract of M. doumeri var. formosana containing phenolic compounds could be suitable naturally occurring active constituents for use in anti-aging or cosmetic products.

Biphenyl Compounds↗
PubMed1990

[Role of calcium antagonists in the treatment of chemoresistant cancer of the kidney].

In experimental cell lines and in some human tumors, calcium antagonists reversed multidrug resistance in vitro. So far, clinical trials have not been very rewarding as intrinsic cardiovascular activities of these compounds impeded a sufficient dosage. Renal cell carcinomas are considered to be good models for the evaluation of this new therapeutic concept. In 35 primary human renal cell carcinomas, the potency of 7 different calcium antagonists in combination with vinblastine monotherapy was examined in a tetrazolium-based microculture assay (MTT test) in order to circumvent chemoresistance. Substances derived from piperazine (flunarizine) showed only minor effects in this respect. The calcium antagonists of the papaverine type such as Verapamil etc. revealed the strongest reversal of chemo-resistance. Derivatives of benzothiazepine (diltiazem) or of dihydropyridine (nifedipine etc.) acted similarly and reached about 70% of the Verapamil activity. All calcium antagonists tested lead to significant enhancement of vinblastine cytotoxicity. In particular, the new stereoisomer R-Verapamil, which showed strong reversal of resistance but which exerts 10 times lower cardiovascular side effects than racemic Verapamil, seems to be suitable for further evaluation with regard to the clinical application.

ATP Binding Cassette Transporter, Subfamily B, Mem↗