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At least 919 records · Page 51Linked to original sources
PubMed1981

Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.

The recent finding that retinoic acid induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line, HL-60, prompted an investigation of the sensitivity to this inducer of human myelocytic leukemia cells in primary suspension culture. Of the 21 leukemic specimens, only cells from the two patients with acute promyelocytic leukemia differentiated in response to retinoic acid. After an incubation period of 5--7 days in 1 microM retinoic acid, the cells from these two patients showed extensive morphological and functional maturation. Thus, because it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes, this compound may have therapeutic utility in the treatment of acute promyelocytic leukemia.

Adolescent↗
PubMed2001

Curcumin, a medicinal herbal compound capable of inducing the heat shock response.

OBJECTIVE: There is interest in developing pharmacologic inducers of the heat shock response as a means to confer cytoprotection in the clinical setting. We propose that a potential strategy for screening novel pharmacologic inducers of the heat shock response is to examine known inhibitors of the transcription factor nuclear factor-kappaB. Curcumin, derived from the tropical herb Curcuma longa, is a recently described inhibitor of nuclear factor-kappaB and is widely used in Eastern medicinal practices. We tested the hypothesis that curcumin can induce expression of heat shock protein 70. DESIGN: Experimental. SETTING: University laboratory. SUBJECTS: HeLa cells. INTERVENTIONS: HeLa cells were exposed to varying concentrations of curcumin and analyzed for expression of heat shock protein 70 by Western blot. MEASUREMENTS AND MAIN RESULTS: Activation of the transcription factor, heat shock factor-1, was analyzed by electromobility shift assays. Curcumin-mediated inhibition of nuclear factor-kappaB activation was measured by transiently transfecting cells with a nuclear factor-kappaB luciferase reporter plasmid. The role of heat shock factor-1 in curcumin-mediated expression of heat shock protein 70 was tested in embryonic fibroblasts derived from heat shock factor-1 knockout mice. Induction of the heat shock response was quantified by transiently transfecting cells with a heat shock protein 70 promoter-luciferase reporter plasmid. Cell viability was measured by using the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Curcumin induced expression of heat shock protein 70, the major inducible heat shock protein in cells undergoing the heat shock response, in a dose-dependent and time-dependent manner. Curcumin induced specific nuclear translocation and activation of heat shock factor-1. Curcumin-mediated expression of heat shock protein 70 was reduced substantially in fibroblasts having genetic ablation of heat shock factor-1. The extent of induction of the heat shock response correlated, in part, with cellular toxicity. CONCLUSIONS: Curcumin, a widely used medicinal compound, induces the heat shock response in vitro as measured by expression of heat shock protein 70. The mechanism of heat shock protein 70 induction depends on activation of heat shock factor-1. Examining known inhibitors of nuclear factor-kappaB for their ability to induce heat shock protein 70 may be a valid screening method to discover novel pharmacologic inducers of the heat shock response.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Ethionine toxicity in vitro: the correlation of data from rat hepatocyte suspensions and monolayers with in vivo observations.

The hepato-steatogenic compound ethionine has been used to investigate the correlations between in vivo and in vitro toxicity data. The aim was to find a suitable model of toxicity in hepatocyte suspensions or monolayers in vitro, which could predict the known toxicity of ethionine in vivo and which could be implemented in screening compounds of unknown toxicity. Thus a variety of markers of cytotoxicity, metabolic competence and liver-specific functions were investigated in rat hepatocyte suspensions and monolayers and compared with in vivo data in the rat. The following markers were measured in the appropriate system: (1) Neutral red uptake; 3-(4,5 dimethyl)thiazol-2-yl,-2,5-diphenyl tetrazolium bromide (MTT) reduction; lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) leakage (cytotoxicity). (2) ATP levels, protein synthesis and glutathione (GSH) levels (metabolic competence). (3) Urea and triglyceride synthesis and beta-oxidation (liver specific functions). Ethionine (0-30 mM) did not affect the markers of direct cytotoxicity, except neutral red uptake, which was reduced by 18 and 30 mM ethionine after 20 h in culture. ATP and GSH depletion occurred in hepatocyte suspensions at the highest concentrations of ethionine (20 and 30 mM) after 1 h. In monolayers, GSH levels were reduced after 4 h, but not 20 h. Urea synthesis was increased in hepatocyte suspensions from 1 to 3 h by 10-30 mM ethionine and reduced after 20 h in cultured hepatocytes (18-30 mM). Protein synthesis was reduced and beta-oxidation was increased in ethionine-treated hepatocyte suspensions. Unfortunately, there was no measurable effect on triglyceride accumulation within cells (the major biochemical change in vivo) in either system. Ethionine treated hepatocytes in suspension showed the same rate of triglyceride synthesis and transportation out of cells as control cells. Thus, hepatocyte suspensions were able to mimic the early biochemical effects of ethionine in vivo (ATP and GSH depletion, inhibition of protein synthesis) and some effects on urea synthesis, but monolayer cultures appeared to be less sensitive to the toxicity of ethionine. However, neither in vitro system was able to model the effects of ethionine on the accumulation of triglycerides in vivo.

Adenosine Triphosphate↗
PubMed1997

Induction of differentiation of U-937 cells by 2-chloro-3-amino-1,4-naphthoquinone.

Naphthoquinone compounds have various pharmacological effects such as antiviral, antifungal and anticancer activities. We demonstrated the differentiation of the inducing effect of a naphthoquinone derivative, 2-chloro-3-amino-1,4-nahpthoquinone (NQCA) on the human leukemia cell line U-937. When U-937 cells were treated with NQCA for 4 days, phenotypes indicative of differentiation such as nitroblue tetrazolium (NBT)-reducing activity and phagocytosis were induced. To evaluate the route of differentiation of U-937 cells induced by NQCA, we determined naphthol AS-D chloroacetate esterase and alpha-naphthyl acetate esterase activities. Four days treatment of U-937 cells with NQCA increased alpha-naphthyl acetate esterase activity about 63.5% but naphthol AS-D chloroacetate esterase was not detected. These results indicate that NQCA caused differentiation of U-937 cells into macrophage-like cells. Since protein kinase C (PKC) and protein kinase A (PKA) have important roles in cell-differentiation and proliferation, we employed a PKC inhibitor NA-382 and a PKA inhibitor H-89 to examine the effects of each kinase on the differentiation of U-937 cells. The PKC inhibitor NA-382 decreased the effect of NQCA on U-937 cells, while the PKA inhibitor H-89 did not. Also glutathione (GSH) inhibited the effect of NQCA. It is concluded that the differentiation-inducing effect of NQCA on U-937 cells may be attributed to PKC activation followed by production of free radicals.

Alkaloids↗
PubMed1999

Cu(III)-polypeptide complexes exhibiting SOD-like activity.

The SOD-like activity of Cu(III)-complexes with polypeptides poly-L-lysine and poly-L-glutamic acid respectively was investigated. The Cu(II)-polypeptide complexes were first oxidized by K2IrCl6 to give the corresponding Cu(III)-compounds. The oxidation of Cu(II) and the corresponding Cu(II)/Cu(III) potential was evaluated by cyclic voltammetry (c.v.), UV-Vis and EPR spectroscopic (r.t.) experiments. Spin trapping EPR spectra were also conducted to confirm the formation of the superoxide radical. The SOD-like activity of each Cu(III)-complex was proved using the nitro blue tetrazolium (NBT) method slightly modified.

Copper↗
PubMed1991

Postanoxic Injury in Soybean (Glycine max) Seedlings.

The postanoxic injury, also known as reperfusion injury, is associated with the returning of anoxic tissues to normal atmosphere. Using tetrazolium chloride staining, ATP content, and seedling growth rate as indicators, we found that postanoxic injuries in soybean (Glycine max) seedlings were more severe after 1 and 2 hours of anoxia than after longer anoxic durations (3 to 5 hours). Anaerobic incubation of root tips in the presence of 100 mm ascorbate, an antioxidant and free radical-scavenging compound, alleviated the postanoxic injury associated with the short durations of anoxia. Extracts from soybean seedling roots returned to air from 1 hour of anoxia had an elevated capacity to produce superoxide radicals over extracts from postanoxic roots stressed for 3 or 5 hours. Activity of superoxide dismutase in soybean roots returned to air from 1 and 2 hours of anoxia was 30 to 50% lower than activities in roots returned to air from 5 hours of anoxia. Superoxide dismutase-specific transcripts were also lower in postanoxic roots stressed for 1 hour than in roots stressed for longer anoxic durations. The evidence suggested that the postanoxic injury of soybean roots after a short anoxic stress was associated with an increased superoxide radicals production capacity coupled with a reduced superoxide dismutase activity. Periods of anoxia of at least 3 hours were necessary for soybean seedlings to develop the ability to cope with postanoxic stress.

Journal Article↗
PubMed1990

Human multi-drug-resistant cancer cells exhibit a high degree of selectivity for stereoisomers of verapamil and quinidine.

An in vitro cell proliferation assay was developed to measure the capacity of substances to overcome multi-drug resistance (MDR). The assay is a modification of the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The inclusion of cell titration curves for each concentration of the resistance modifier (RM) allows the IC50 of the RM to be calculated and provides empirical correction of the cell survival curves for the effect of the RM when it is combined with a standard cytotoxic drug, vincristine. The resistance modification index (RMI) is defined as the ratio of the IC50 of vincristine obtained in control cultures divided by that measured in the presence of RM and is linearly related to the dose of RM. The RMI0.1, the RMI at a one-tenth the IC50 of the RM, provides a relative comparison between the activities of different RMs at non-toxic doses. The results obtained using the MDR cell line, KB-8-5, show that l-(-)-verapamil is approximately 4 times more active than d-(+)-verapamil in modifying MDR. The racemic mixture has an intermediate activity. A similar comparison between the epimers quinidine and quinine shows that, at equimolar doses, quinine has a higher RMI but, because it is more toxic, the RMI0.1 is about one-half of that of quinidine. These results demonstrate the importance of comparing the resistance-modifying activities of different compounds at doses relative to their own toxicity.

Cell Line↗
PubMed2006

The protective effects of phenolic constituents from Gastrodia elata on the cytotoxicity induced by KCl and glutamate.

Seven phenolic compounds (1-7) were isolated from the tubers of Gastrodia elata. Their structures were elucidated on the basis of MS and NMR spectral data. p-Ethoxymethyl phenyl-O-beta-D-glucoside (1) was proved to be a new compound, with N-(p-hydroxybenzyl)-adenosine (7) isolated from this plant for the first time. In this study, the protective effects of the six constituents (1-6) on PC12 cells against the cytotoxicity induced by KCl and glutamate were also investigated. The viability of the PC12 cells was significantly enhanced by pretreatment with the six phenolic constituents.

Adenosine↗
PubMed1994

Assessment of long-term effects of transient anoxia on metabolic activity of rat hippocampal slices using triphenyltetrazolium chloride.

Hippocampal slices maintained in an oxygen-rich static interface chamber remained viable, as determined by the mitochondrial marker 2,3,5-triphenyltetrazolium chloride (TTC), for over 20 h in vitro. By contrast, slices exposed, after 1 h in vitro, to an anoxic environment for 25 min and then allowed to recover for 1-18 h, showed an initial slight decrease in TTC staining followed by a dramatic decrease at time points greater than 6.5 h after anoxia. These data are suggestive of delayed neuronal death. Furthermore, the decreases in TTC staining induced by anoxia could be prevented by conditions known to prevent cell death either in vitro or in vivo. For example, pretreatment of the slices with the N-methyl-D-aspartate antagonist 3-((RS)-2-carboxy-piperazin-4-yl)-propyl-1- phosphonic acid dose-dependently prevented the loss of TTC staining induced by 25 min anoxia. In addition, high-intensity TTC staining correlated with normal CA1 synaptic activity, even after more than 20 h in vitro, suggesting that TTC staining reflects functional neuronal activity. These data suggest that the use of TTC staining of in vitro hippocampal slices may represent a novel and convenient screen for anti-ischemic compounds.

Animals↗
PubMed1988

Proteinase inhibitors protect Leishmania amazonensis amastigotes from destruction by amino acid esters.

Lysosomotropic amino acid esters and amides kill Leishmania amazonensis amastigotes by a mechanism which probably involves enzymatic hydrolysis of the compounds and rapid accumulation of less permeant amino acid within the parasites. We show here that, in agreement with this model, the proteinase inhibitors antipain and chymostatin prevented the killing of intracellular and isolated parasites by L-leucine methyl ester (Leu-OMe). Survival of Leishmania within macrophages was assessed microscopically, and that of isolated amastigotes was measured by tetrazolium (MTT) reduction. Near maximal protection of intracellular parasites was obtained after 24 h incubation of macrophage cultures with 50 micrograms ml-1 antipain or chymostatin. Incubation for greater than 1 h with chymostatin or greater than 4 h with antipain alone resulted in loss of viability of the parasites. Protective activity was only slightly diminished by 20 h chase of isolated parasites in inhibitor-free medium. Two synthetic chymostatin analogues, Z-Val-Phe-Sc and Z-Ile-Phe-Sc, protected isolated amastigotes at 4 or 10 micrograms ml-1. With the exception of Trp-NH2, the toxicity of which was only minimally inhibited, antipain and chymostatin also prevented parasite destruction by other amino acid derivatives. Finally, in concentration-dependent fashion, the inhibitors reduced the accumulation of [3H]leucine in isolated amastigotes incubated with [3H]Leu-OMe. Since uptake of labelled ester was unaffected, we postulate that protection involves inhibition of the parasite enzymes which hydrolyse the amino acid derivatives.

Amino Acids↗
PubMed2005

Speciation study of an imidazolate-bridged copper(II)-zinc(II) complex in aqueous solution.

The solution equilibrium and the binding mode of the species in the five-component system containing two metal ions (copper(II) and zinc(II)) and three ligands (A=diethylenetriamine, B=imidazole, C=tris(2-aminoethyl)amine) were investigated by pH-potentiometric titration, UV-visible spectrophotometry and EPR (electron paramagnetic resonance) spectroscopic titration in aqueous solution in the 2-11 pH range. An imidazolate-bridged heterobinuclear complex (ACuBH(-1)ZnC) was found to evolve above pH=7 and was stable between pH 7 and 11. The existence of the ACuBH(-1)ZnC complex (by determination of its molecular weight) was proved by mass spectrometry (ESI-MS (electrospray ionization mass spectrometry) and MALDI (matrix-assisted laser desorption/ionization) techniques). The electrochemical behaviour and the superoxide dismutase activity of this complex were also tested by cyclic voltammetry and the Riboflavin/NBT (nitro blue tetrazolium) assay, respectively.

Binding Sites↗
PubMed1996

Modulation of sensitivity to cis-diamminedichloroplatinum (II) by thromboxane A2 receptor antagonists in non-small-cell lung cancer cell lines.

We examined the effect of selective thromboxane A2 (TXA2) receptor antagonists, calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) and +/- -7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)-7-phenylhaptanoic acid (AA-2414), on sensitivity to cis-diamminedichloroplatinum (II) (CDDP) in non-small-cell lung cancer cell lines. IC50 values to CDDP using MTT assay were decreased 2.1- and 4.6-fold respectively by treatment with 250 or 500 microM S-1452, for a 2 h simultaneous drug exposure, and those of PC-9/CDDP, a CDDP-resistant cell line, were decreased 3.1- and 6.1-fold. Sensitivity to carboplatin was also enhanced by the treatment with S-1452. IC50 values to CDDP and carboplatin were decreased by treatment with AA-2414 in a dose-dependent manner. Isobologram analysis showed that the combination of CDDP with S-1452 or AA-2414 produced supra-additive or additive effects in each cell line. Neither glutathione content nor glutathione S-transferase activity was changed in either cell line by treatment with 500 microM S-1452. Accumulation of platinum into PC-9 and PC-9/CDDP was increased by the treatment in a dose-dependent manner. Na+, K+-ATPase activity of PC-9 and PC-9/CDDP was enhanced by the treatment of S-1452 in a dose-dependent manner. These data show that the TXA2 receptor antagonists may enhance the sensitivity of non-small-cell lung cancer cell lines to platinum agents. Increase in Na+, K+-ATPase activity induced by S-1452 may be the mechanism of its sensitising effect through increase in platinum accumulation.

Adenocarcinoma↗
PubMed2001

Mechanism of inhibitory effect of NCC164 on replication of human immunodeficiency virus.

The effect of a novel anti-HIV (human immunodeficiency virus) compound, designated NCC164, has been studied with HIV infected cultures. The agent exhibited concentration-dependent inhibition of HIV replication in primary infected cultures of H9 cell line and PBMCs. Substantial inhibition of viral replication was observed at concentration of NCC164 that showed little cytotoxicity. The ratio of IC50 values for the MTT (3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide) to RT (reverse transcriptase) assays means the selectivity index was more than 100. In attempting to define the inhibitory mechanism of NCC164, we investigated its effect on each step of HIV replication. This agent was highly effective against HIV replication regardless of the addition period during early stages of infection (adsorption to integration) but did not inhibit reverse transcriptase activity directly. The agent efficiently blocked virus maturation without side effect and the number of progeny produced by NCC164-treated cells was markedly reduced.

Adenosine↗
PubMed1992

Oxygen free radicals and the cerebral arteriolar response to group B streptococci.

We used a cranial window preparation to observe the effects of direct application of group B streptococci to the surface of the brain in the adult rat. Continuous exposure to group B streptococci at concentrations of 10(3) and 10(5) organisms/mL caused progressive dilation of surface (pial) cerebral arterioles that became statistically significant (p less than 0.05) after 2.5 h. These results were reproduced with heat-killed organisms at the same concentration, but not with a bacteria-free filtrate of the growth medium. In separate studies, we found that infusion of alkaline cerebrospinal fluid (pH = 7.8) into the window did not reverse vasodilation, suggesting that it was not due to progressive cerebrospinal fluid acidosis. A solution of nitroblue tetrazolium infused into the window at the end of a 3-h exposure to the organism was promptly reduced, suggesting the presence of oxygen free radicals. Treatment with i.v. polyethylene glycol-superoxide dismutase and polyethylene glycol-catalase in doses of 10,000 and 20,000 U/kg, respectively, was itself without effect on pial arterioles, but treatment with these compounds before exposure to group B streptococci eliminated the vasodilation. These data support a role for oxygen free radicals in the pathogenesis of pial arteriolar dysfunction induced by exposure to group B streptococci.

Animals↗
PubMed2003

Optimisation of a microbial bioassay for contaminated soil monitoring: bacterial inoculum standardisation and comparison with Microtox assay.

This work represents the first step to set up a toxicity testing procedure and to evaluate the sensitivity of the test microorganism to several classes of environmental pollutants. First, three different techniques were employed to standardise the microbial inoculum, then two different toxicity assessment protocols have been compared: Microtox and a dehydrogenase (DHase) activity inhibition test. The main goal was the optimisation of a microbial bioassay based on the dehydrogenase activity (DHase) inhibition in Pseudomonas fluorescens bacterial strain ATCC 13525. Triphenyl tetrazolium chloride (TTC) was used as electron acceptor and its reduction produces Triphenyl formazane (TPF). The P. fluorescens DHase inhibition bioassay was investigated for being a reliable and rapid method for assessing toxicity. The optimisation of the operating conditions resulted in a repeatable bioassay. Then, P. fluorescens and Vibrio fischeri sensitivity were firstly compared by testing Zn++, one of the reference compounds for Microtox test. In addition, other compounds (Ni++, Cd++, Cu++, phenol) were also tested with both bioassays. A high statistical significance of data was obtained with the logistic curve. The present work has demonstrated that P. fluorescens is as sensitive as Microtox culture (V. fischeri), for some of the metal ions. With reference to organic compounds, the lower sensitivity of P. fluorescens to phenol makes its use difficult in organic polluted samples.

Biological Assay↗
PubMedDate not supplied

Effects of 1,3,5-Trinitrobenzene on cytotoxicity and metabolic activity of type I astrocytes of rats.

1,3,5-Trinitrobenzene (TNB) is a munitions chemical that causes gliovascular lesions in the brain stem of rats similar to those produced by thiamine deficiency and nitroaromatic compounds, including m-dinitrobenzene. To identify neuropathic indices of toxicity, the effects of varying concentrations (0 to 2 mM) of TNB on cytotoxicity and cellular metabolic activity were examined using cultured astrocytes from Fischer-344 rats. The cytotoxicity was assessed by lactate dehydrogenase (LDH) leakage into the culture medium. Astrocyte metabolic activity was assessed by measuring the conversion of a tetrazolium salt to a formazan product. Additionally, the effects of oxidative stress on cellular metabolic activity were determined by varying oxygen tension via alteration of culture media depth. In vitro, the toxic concentration 50% (TC50) of TNB, which induced cell death, was 16 microM following a 24-h exposure. The concentration of TNB that reduced cellular metabolic activity by 50% was 29 microM following a 24-h exposure. Varying the depth of the culture media did not influence the cellular metabolic activity in control or TNB-treated astrocytes. These results support the hypothesis that TNB induced neurotoxicity could partially be mediated via injury to astrocytes, a major component of the blood-brain barrier.

Animals↗