Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biocompatibility of two polymers for potential use as orthopaedic implant materials in an isoelastic hip prosthesis was investigated. The interactions of polyetheretherketone (PEEK) and epoxy resin polymers (with and without carbon fibre reinforcement) with both fibroblasts and osteoblasts were tested using cell protein, intracellular reduced glutathione (GSH), leakage of lactate dehydrogenase and the MTT assay as indices of cellular cytotoxicity. The epoxy resin polymer was slightly cytotoxic to and inhibited the growth rate of fibroblasts (as assessed by total cell protein), and depleted GSH in both cell types. In contrast, the PEEK material did not display overt signs of cytotoxicity and, in fact, increased osteoblast cell protein content. This suggests that, of these two materials, PEEK would be the one of choice for development of an isoelastic implant and, in view of its stimulatory effect on osteoblast protein content, it may encourage ingrowth of bone around the prosthesis and thus minimize joint loosening.
 ...
PMID:In vitro biocompatibility testing of polymers for orthopaedic implants using cultured fibroblasts and osteoblasts. 858 Feb 62

Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. Multidrug resistance (MDR) is one of the involved mechanisms. In this work we have studied the MDR1 gene expression in five MTC human cell lines that we have isolated and we have compared this expression to that of normal thyroid tissue. We have also tried to reverse the resistance to doxorubicin with verapamil (VRP) and ciclosporin A (CSA). MDR1 ARNm expression was studied and quantified by polymerase chain reaction (PCR) in normal and pathological thyroid tissues. The doxorubicin-induced cytotoxicity was evaluated with the 3,-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total glutathione (GSH) or intracellular lactate dehydrogenase (LDH) measurements. We found an increase of MDR1 ARNm in MTC as compared with normal tissues. Doxorubicin was cytotoxic after a 48-h coincubation with the cells. Three microM CSA and 10 microM VRP reversed the doxorubicin resistance only after a 48-h coincubation, generally followed with a 24 h-post-incubation. In these conditions, the GSH levels were decreased only by VRP in all the five cell lines. In conclusion, a chemoresistance related to the MDR1 gene overexpression was found in the five human MTC lines tested. VRP and CSA reversed the resistance to doxorubicin in all the MTC cell lines tested.
 ...
PMID:[Expression of the MDR1 gene in five human cell lines of medullary thyroid cancer and reversion of the resistance to doxorubicine by ciclosporin A and verapamil]. 867 55

1. Procaine has previously been shown to diminish the nephrotoxicity of cisplatin and the nephrotoxic effects of cisplatin and a new cisplatin complex (cis-diamminechloro-[2-(diethylamino) ethyl-4-aminobenzoate, N4]-chlorideplatinum (II) monohydrochloride monohydrate; DPR), that contains procaine hydrochloride were compared with rat renal cortical slices. 2. Cisplatin at 1 mM caused toxicity to the slices, as shown by an increase in the leakage of aspartate aminotransferase and lactate dehydrogenase from the slices into the incubation medium and a decrease in the reduction of a tetrazolium dye (MTT assay). Addition of procaine (1 mM) protected against cisplatin-induced toxicity. DPR either at 1 mM or at 4 mM had no effect either on the enzyme leakage or MTT reduction by the renal slices, but DPR at 10 mM produced a similar magnitude of enzyme leakage to cisplatin (1 mM). 3. DPR lowered the concentration of ATP and glutathione (GSH) in the slices but was less potent than cisplatin. Thiobarbituric acid reactive substances, indicators of lipid peroxidation, released into the medium were increased by the highest concentration of DPR (10 mM), which suggests that DPR has the potential to cause oxidative stress. 4. The results suggest that DPR was far less toxic than either cisplatin alone or a mixture of cisplatin and procaine.
 ...
PMID:Comparison of the toxicities of cisplatin and a new cisplatin-procaine complex to rat renal cortical slices. 884 12

Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. In this work, we have studied the effect of cisdiamminedichloroplatinum (II) (CDDP) in six MTC human cell lines and we have tried to reverse the resistance to CDDP with amphotericin B (AmB). We also studied the metabolism of glutathione (GSH) and the presence of the glutathione-sulfotransferase pi (GST pi) mRNA in the MTC cell lines. The cisplatin-induced cytotoxicity was evaluated with the 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total GSH measurement in six cell lines, TT cell line and five cell lines that we isolated. The cultures were performed with or without AmB (5 micrograms/mL). Intracellular GSH was measured in TMC cells and compared to the levels obtained in six normal thyroid tissues. The expression of GST pi mRNA was evaluated by Northern blotting in the different cell lines. A CDDP-induced cytotoxicity was obtained in the six cell lines at doses inhibiting 50% of the cellular proliferation (IC50) varying from 6 to 40 micrograms according to the tests and the cells tested. A low concentration of AmB (5 micrograms/mL) potentiated the cisplatin toxicity after a 48-h coincubation of TMC in all cases. GSH levels in TMC cell lines were identical to those found in normal cells. GST pi mRNA was detected in all the TMC lines, except in TT cell line. In conclusion, CDDP was toxic for all the TMC cell lines and AmB potentiated this antitumoral effect. On the contrary, GSH and GST pi do not seem to be involved in the mechanisms of the resistance in these cell lines.
 ...
PMID:[Modulation of cisplatin cytotoxicity by amphotericin B in six human cell lines of medullary thyroid cancer]. 886 41

The effects of acute ethanol and acetaldehyde treatment on cell proliferation, cell adhesion capacity, neutral red incorporation into lysosomes, glutathione content, protein sulfhydryl compounds, lipid peroxidation, inner mitochondrial membrane integrity (MTT test), lactate dehydrogenase activity (LDH) and ultrastructural alterations were investigated in a human fetal hepatic cell line (WRL-68 cells). WRL-68 cells were used, due to the fact that, although this cell line expresses some hepatic characteristics, it does not express alcohol dehydrogenase or cytochrome P450 activity, so it could be a good model to study the effect of the toxic agents per se. Cells were exposed during 120 min with 200 mM ethanol or 10 mM acetaldehyde. Under these conditions, cells presented 100% viability and no morphological alteration was observed by light microscopy. Acetaldehyde-treated cells reduced their proliferative capacity drastically while the ethanol-treated ones presented no difference with control cells. Cell adhesion to substrate, measured as time required to adhere to the substrate and time required to detach from the substrate, was diminished in acetaldehyde WRL-68-treated cells. Cytotoxicity measures as neutral red and MTT test showed that acetaldehyde-treated cells presented more damage than ethanol-treated ones. Cellular respiratory capacity was compromised by acetaldehyde treatment due to 40% less oxygen consumption than control cells. Lipid peroxidation values, measured as malondialdehyde production, were higher in ethanol-treated WRL-68 cells (127%) than in acetaldehyde-treated ones (60%) to control cell values. Lactate dehydrogenase activity (LDH) in extracellular media of ethanol-treated cells presented the highest values. GSH content was reduced 95% and thiol protein content was diminished severely in acetaldehyde-treated cells. Transmission electron microscopy showed more ultrastructural alterations in cells treated with acetaldehyde. The results indicate that acetaldehyde, like ethanol, produced damage at cellular level, although more damage could be observed in acetaldehyde WRL-68-treated cells.
 ...
PMID:Comparative study of the damage produced by acute ethanol and acetaldehyde treatment in a human fetal hepatic cell line. 918

Primary rat hepatocyte cultures exposed to tert-butylhydroperoxide (t-BHP) or cumene hydroperoxide were used to assess the antioxidative and protective potential of water-soluble extracts of artichoke leaves. Both hydroperoxides stimulated the production of malondialdehyde (MDA), particularly when the cells were pretreated with diethylmaleate (DEM) in order to diminish the level of cellular glutathione (GSH). Addition of artichoke extracts did not affect basal MDA production, but prevented the hydroperoxide-induced increase of MDA formation in a concentration-dependent manner when presented simultaneously or prior to the peroxides. The effective concentrations (down to 0.001 mg/ml) were well below the cytotoxic levels of the extracts which started above 1 mg/ml. The protective potential assessed by the LDH leakage assay and the MTT assay closely paralleled the reduction in MDA production and largely prevented hepatocyte necrosis induced by the hydroperoxides. The artichoke extracts did not affect the cellular level of glutathione (GSH), but diminished the loss of total GSH and the cellular leakage of GSSG resulting from exposure to t-BHP. Chlorogenic acid and cynarin accounted for only part of the antioxidative principle of the extracts which was resistant against tryptic digestion, boiling, acidification, and other treatments, but was slightly sensitive to alkalinization. These results demonstrate that artichoke extracts have a marked antioxidative and protective potential. Primary hepatocyte cultures seem suitable for identifying the constituents responsible for these effects and for elucidating their possible mode of action.
 ...
PMID:Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes. 919 11

Cadmium (Cd) is a highly toxic metal and a known carcinogen. Although the carcinogenic mechanism of action is unknown, Cd will induce transcriptional activation of c-myc and c-jun. We have previously found that the extent of Cd-induced oncogene expression is limited by the presence of cellular metallothionein (MT) in rat L6 myoblasts. Glutathione (GSH) is thought to play an important role in protection against Cd before the onset of MT synthesis. Thus, this study examined the effects of GSH depletion on Cd-induced MT synthesis, cytotoxicity, and proto-oncogene expression in rat L6 myoblasts after pretreatment with L-buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamyl-cysteine synthetase, which effectively depletes GSH. Exposure of L6 cells to BSO (5 or 25 microM) resulted in a dose-dependent decrease in cellular GSH levels. GSH depletion had no effect on Cd- or zinc-induced MT synthesis. Although the depletion of GSH was not itself cytotoxic in L6 cells, BSO pretreatment, particularly at the higher dose (25 microM), resulted in a dose-dependent increase in the sensitivity to Cd cytotoxicity, as assessed by a tetrazolium-based dye (MTT) assay. Low levels of Cd (1 microM) slightly increased the expression of both c-myc and c-jun as assessed by increases in gene-specific mRNA levels, in accordance with previous studies. GSH depletion (5 muM BSO) likewise caused an increase in expression of c-myc and c-jun. However, combined GSH depletion and Cd exposure decreased levels of c-myc and c-jun transcription well below control levels. These results suggest that increased cytotoxicity resulting from exposure to Cd after BSO depletion of cellular GSH abrogates the oncogene activation observed after either treatment alone. Thus proto-oncogene expression induced by Cd appears to be dependent on the absence of over Cd-induced cytotoxicity.
 ...
PMID:Effects of glutathione depletion on cadmium-induced metallothionein synthesis, cytotoxicity, and proto-oncogene expression in cultured rat myoblasts. 924 31

Chronic exposure to low concentrations of the nephrotoxic cysteine conjugate S-(1,2-dichlorovinyl)-l-cysteine (DCVC) causes cataracts in mice. This study explored mechanisms of DCVC-induced cataractogenesis using explanted lenses from male Sprague-Dawley rats. Lenses placed in organ culture were exposed to 2.5 microM-1 mM DCVC for 24 hr. DCVC caused concentration and time-dependent changes in biochemical markers of toxicity (lenticular adenosine 5'-triphosphate (ATP) content, mitochondrial reduction of the tetrazolium dye MTT, and glutathione (GSH) content) at concentrations >/=25 microM. Lens clarity was adversely affected at concentrations >/=50 microM. Within 24 hr, 1 mM DCVC altered lens ATP content (-77 +/- 2%), mitochondrial MTT reduction (-40 +/- 3%), and GSH content (-19 +/- 4%) (percent difference from controls, p < 0.05). ATP was the most sensitive index of DCVC exposure in this model, while lens weight was not altered. The role of lenticular DCVC metabolism was investigated using the beta-lyase inhibitor aminooxyacetic acid (AOA) and the flavin monooxygenase (FMO) inhibitor methimazole (MAZ). AOA (1 mM) provided nearly complete protection from changes in biochemical parameters and lens transparency caused by DCVC, while MAZ (1 mM) provided only partial protection. The mitochondrial Ca2+ uniport inhibitor ruthenium red (30 microM) and the poly(ADP ribosyl)transferase inhibitor 3-aminobenzamide (3 mM) were only partially protective, whereas adverse changes in lens transparency and biochemical markers were not prevented by an antioxidant (2 mM dithiothreitol) or nontoxic transport substrates (200 microM probenecid or 10 mm phenylalanine, S-benzyl-L-cysteine or para-aminohippuric acid). Calpain inhibitors E64d (100 microM) and calpain inhibitor II (1 mM) were ineffective in preventing opacity formation caused by DCVC. In a small separate study, DCVC toxicity to explanted lenses from cynomologus monkeys was also ameliorated by coincubation with AOA. These results indicate that opacity formation by DCVC in rodent and primate lenses in vitro is primarily mediated via lenticular beta-lyase metabolism of DCVC to a reactive metabolite. Metabolism of DCVC by FMO and perturbations in mitochondrial calcium (Ca2+) homeostasis and increased poly(ADP-ribosylation) of nuclear proteins may play a limited role in opacity formation in vitro. However, opacity formation does not appear to be the result of oxidative stress or calpain activation. DCVC toxicity to the lens was not blocked with competitive inhibitors of the amino acid and organic anion transporters of DCVC as is found in the kidney.
 ...
PMID:Mechanistic analysis of S-(1,2-dichlorovinyl)-L-cysteine-induced cataractogenesis in vitro. 929 6

Neutrophils were intra-cellularly "loaded" with the chemotherapeutic agent, doxorubicin applying a variety of incubation conditions in order to identify parameters which maximize chemotherapeutic incorporation, while simultaneously preserving optimal viability and chemotactic responsiveness. Doxorubicin "loaded" neutrophils (DLN) were produced in triplicate at different combinations of incubation conditions such as temperature (4 degrees C, 37 degrees C); duration (0, 1, 2 hours); and doxorubicin concentration (20, 40, 60 micrograms/ml). Chemotactic responsiveness of rinsed DLN preparations was subsequently assessed against the neutrophil peptide chemotactic agent, formyl methionyl leucyl phenylalanine (fMLP, 10(-6) M) utilizing a modified 96-well Boyden chemotactic chamber apparatus. Viable, fMLP-responsive DLN preparations were subsequently detected with MTT vitality staining reagent. At sub-physiological incubation temperatures (4 degrees C), profound declines in the viability of DLN preparations were detected when simultaneously incubated with doxorubicin formulated at concentrations greater than 10 micrograms/ml. In contrast, DLN preparations incubated at 37 degrees C displayed diminished viability only when incubated with doxorubicin formulated at a concentration of 60 micrograms/ml. Viable DLN populations were subsequently evaluated to determine their ability to exert in vitro cytotoxic activity against monolayer populations of human mammary carcinoma (HTB-19) propagated in a tissue culture environment. The lethal effect which DLN preparations inflicted towards HTB-19 populations was substantially greater than was observed with an equivalent population of untreated neutrophils. Maximal in vitro cytotoxic activity was detected with DLN preparations produced at 37 degrees C in the presence of doxorubicin formulated at a concentration of 40 micrograms/ml. In contrast, DLN preparations produced at an incubation temperature of 37 degrees C, and a doxorubicin concentration of 20 micrograms/ml displayed relatively lower levels of in vitro cytotoxic activity against HTB-19 monolayer populations. The degree of in vitro cytotoxic activity exerted against HTB-19 monolayer populations by DLN preparations was directly influenced by the duration of the challenge period. Maximal in vitro cytotoxic activity was observed when HTB-19 monolayer populations were challenged with DLN preparations for a period of 96-hours duration at 37 degrees C. Challenge periods of 48-hours duration produced levels of in vitro cytotoxic activity which were substantially lower than those observed for challenge periods of 96-hours duration. Optimal in vitro cytotoxic activity was recognized when DLN preparations were allowed to establish direct contact with HTB-19 monolayer populations at an estimated DLN:HTB-19 cellular ratio of approximately 5:1 (37 degrees C, CO2, 6%). Significantly less in vitro cytotoxic activity was recognized when DLN preparations were only permitted indirect cellular contact with HTB-19 monolayer populations which was achieved through the application of a semi-permeable 3 microM pore membrane partition. In vitro cytotoxic activity of DLN populations was not inhibited by the anti-oxidant agent, dimethyl sulfoxide (DMSO), but was inhibited in the presence of glutathione (GSH), superoxide dismutase (SOD), and vitamin E (alpha-tocopherol). Similarly, in vitro cytotoxic activity of DLN populations was also inhibited in the presence of sodium heparin (serine esterase inhibitor), and dexamethasone (inhibitor of neutrophil activation-degranulation phenomenon). Experimental results observed in these investigations collectively imply that the in vitro cytotoxic activity exerted by DLN preparations against HTB-19 populations is in part attributable to neutrophil-mediated cytotoxic immunity. This innate property of neutrophil populations involves their capacity to generate highly reactive oxygen "free" radical species (O2, HO, H2O2), and synthes
 ...
PMID:Cytotoxic activity of doxorubicin "loaded" neutrophils against human mammary carcinoma (HTB-19). 937 37

Aflatoxin M1 (AFM1) is the principal hydroxylated aflatoxin metabolite present in the milk of dairy cows fed a diet contaminated with aflatoxin B1, (AFB1) and the metabolite is also present in the milk of human nursing mothers consuming foodstuffs containing the toxin. AFM1 is usually considered to be a detoxification product of AFB1 and this appears warranted if the biological endpoints involved are carcinogenicity and mutagenicity. However, it may not be a valid conclusion in the case of cytotoxicity. The metabolism of AFM1 and AFB1 have been studied in vitro using human liver microsomes. Formation of primary metabolites associated with metabolic activation to the respective epoxides reflected the differences between the carcinogenic potentials of the two toxins and, similar to AFB1, the conjugation of AFM1 epoxide with reduced GSH was catalyzed by mouse, but not human liver cytosol. Although the majority of the binding of [3H]AFB1 to microsomal protein was dependent on metabolic activation, a high level of retention of [3H]AFM1 by microsomes, nonextractable in methanol and unrelated to metabolic activation, was observed. It appears possible that this property is related to the high cytotoxicity of AFM1. Experiments using human cell line cells either expressing or not expressing human cytochrome P450 enzymes in assays of acute toxicity (MTT assays) have demonstrated a directly toxic potential of AFM1 in the absence of metabolic activation, in contrast to AFB1. Caution therefore needs to be exercised in designating the formation of AFM1 as essentially detoxification when considering a biological response in which cytotoxicity may play a significant role, e.g., immunotoxicity.
 ...
PMID:Metabolism and toxicity of aflatoxins M1 and B1 in human-derived in vitro systems. 970 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>