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At least 667 records · Page 37Linked to original sources
PubMed1977

Antiviral activities of 4'-(9-acridinylamino)-methanesulfon-M-aniside (SN11841).

SN11841 [4'-(9-acridinylamino)-methanesulfon-m-aniside] is an antitumor compound discovered by B.F. Cain. The LD50 for BALB/c mice with single intraperitoneal dosage is approximately 25 mg/kg. RLV-(Rauscher leukemia virus)-induced splenomegaly, a disease indicator in BALB/c mice, is inhibited at SN11841 doses not causing acute mortality. The life span of RLV-infected mice increases at some SN11841 doses. SN11841 does not have direct, or virolytic effects on RLV under conditions approximating those of antiviral effectiveness. SN11841 is cytotoxic for cells in tissue culture, as measured by inhibition of growth rate or vital dye uptake. At nontoxic concentrations SN11841 has no effect on RLV infectivity for murine cells, as determined by XC-cell induced syncytium formation. SN11841 has antiviral activity against vaccinia virus in tissue culture but is inactive against herpes simplex (Type 1), vesicular stomatitis, encephalomyocarditis, or reoviruses. SN11841 apparently does not act by inducing interferon. SN11841 is chemically labile, particularly in the presence of sulfhydryl compounds, but the degradation products resulting from prolonged storage in media are neither cytotoxic nor antiviral.

Acridines↗
PubMed1997

Quantitative determination of BMS186716, a thiol compound, in dog plasma by high-performance liquid chromatography-positive ion electrospray mass spectrometry after formation of the methyl acrylate adduct.

As it is extremely unstable in blood, the thiol compound BMS186716 was stabilized by the addition of methyl acrylate (MA) to blood samples. The blood samples were then kept in ice for 10-15 min for completion of the Michael addition reaction to occur between the thiol group of BMS186716 and MA, after which the plasma was separated by centrifugation under refrigeration. For sample analysis, the standard and quality control samples were prepared by spiking blank plasma with the BMS186716-MA adduct. After addition of the internal standard, BMS 188035-MA, each sample was acidified with HCI and then extracted with methyl tert.-butyl ether. Each reconstituted extract was injected into a high-performance liquid chromatography-positive ion electrospray ionization mass spectrometric system. The electrospray condition was chosen to enhance the [M+NH4]+ signal at the expense of the [M+H]+ signal. Monitoring the [M+NH4]+ signal, a lower limit of quantitation of 2.5 ng/ml was achieved, with 0.5 ml plasma. We have thus shown that a sulfhydryl compound (BMS186716) in blood can successfully be stabilized by reacting it with MA and that the adduct produced is adequately stable in blood and plasma to allow the development of a rugged quantitative bioanalytical method.

Acrylates↗
PubMedDate not supplied

Inhibition of colony formation of Hela cells by naturally occurring and synthetic agents.

The present study compared the effects of naturally occurring extracts or compound in combination with synthetic selenium compounds on the colony formation and nucleic acid synthesis of cultured human cervical epitheloid carcinoma cells (Hela). Crude extract of bean (Phaseolus vulgaris) or purified lectin from red kidney bean (Phaseolus vulgaris) in combination with selenomethionine were more effective in inhibiting the colony formation of Hela cells than when these cells were treated with these agents alone. Extracts of saffron (Crocus sativus) and selenite have previously been shown to inhibit the colony formation and nucleic acid synthesis by Hela cells in vitro. In the present study we examined the effects of saffron extract in combination with selenite on the colony formation and DNA and RNA synthesis in Hela cells. We found that the treatment of tumor Hela cells with saffron extract in combination with selenite increased the level of inhibition of the colony formation and nucleic acid synthesis in comparison with cells that were treated with only one of these agents. The inhibitory effect of saffron extract in combination with selenite was modified by intracellular sulfhydryl compounds.

Cell Division↗
PubMed1993

N-acetylcysteine inhibits angiotensin converting enzyme in vivo.

Nitrate tolerance has been explained by 1) a direct loss of pharmacological effect due to reduced bioconversion and 2) an indirect effect due to activation of the renin/angiotensin system and counter-regulatory vasoconstriction. The sulfhydryl compound N-acetylcysteine (NAC) has been shown to attenuate and partly counteract tolerance to nitrates, and this effect has been attributed to a nitrate/sulfhydryl interaction and increased production of vasoactive intermediates. The effect of NAC on counter-regulatory mechanisms is, however, unknown. This study examined whether NAC modulates the function of the renin/angiotensin system in normal rats and in nitrate-tolerant healthy volunteers. Animal study: Conscious rats received NAC (5 mmol/kg/hr i.v., n = 8) or placebo (N-acetylserine, n = 8). Two hours of NAC infusion significantly reduced the pressor effect of angiotensin I (ANG I) by 39 +/- 14% (mean +/- SEM) and reduced angiotensin converting enzyme activity by 31% in plasma (N-acetylserine: 74 +/- 9 nmol/min/mg, NAC: 51 +/- 7) and 43% in kidney (N-acetylserine: 0.9 +/- 0.3, NAC: 0.5 +/- 0.1 nmol/min/mg protein) (P < .05). Clinical study: Isosorbide dinitrate (5 mg/hr) was infused into six male volunteers for 48 hr. NAC (2 g i.v. followed by 5 mg/kg/hr) was co-infused from 24 to 48 hr. Plasma angiotensin II (ANG II) increased during the first 24 hr of isosorbide dinitrate infusion and decreased from 28 +/- 4 to 14 +/- 2 ng/l after 2 hr of NAC infusion (P < .05). The results suggest that sulfhydryl supplementation modifies the function of the renin/angiotensin system in vivo, an effect probably mediated by inhibition of angiotensin converting enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1981

Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.

This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

Acetylcysteine↗
PubMed1987

Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis.

Comparative investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 (vinyl oxirane, the primary reactive intermediate of butadiene) revealed major differences in metabolism of this compound between rats and mice. Whereas in rats no indication of saturation kinetics of epoxybutene metabolism could be observed up to exposure concentrations of 5000 ppm, in mice saturation of epoxybutene metabolism becomes apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate (Vmax) in mice for epoxybutene was only 350 mumol X h-1 X kg-1 (rats: greater than 2600 mumol X h-1 X kg-1). In the lower concentration range where first order metabolism applies (up to about 500 ppm) epoxybutene is metabolized by mice at higher rates compared to rats (metabolic clearance per kg body weight, mice: 24,900 ml X h-1, rats: 13,400 ml X h-1). Under these conditions the steady state concentration of epoxybutene in the mouse is about 10 times that in the rat. When mice are exposed to high concentrations of butadiene (greater than 2000 ppm; conditions of saturation of butadiene metabolism; closed exposure system) epoxybutene is exhaled by the animals, and its concentration in the gas phase increases with exposure time. At about 10 ppm epoxybutene signs of acute toxicity are observed. When rats are exposed to butadiene under similar conditions, the epoxybutene concentration reaches a plateau at about 4 ppm. Under these conditions hepatic non-protein sulfhydryl compounds are virtually depleted in mice but not in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed2005

Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage.

AIM: This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 micromol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 micromol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 micromol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 micromol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 micromol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which is also responsible for an increment of sulfhydryl radical bioavailability. It is also suggested that lansoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. In clinical settings, proton pump inhibitors have proven to be effective in preventing and healing NSAID-induced gastroduodenal lesions. The present study investigates the mechanisms of protection afforded by pantoprazole against gastric injury induced by different NSAIDs in rats. Animals were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals received pantoprazole 6 or 60 micromol/kg orally. Four hours after NSAIDs, the following parameters were assessed: histomorphometric evaluation of gastric mucosal damage; gastric mucosal levels of myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione as an index of non-proteic sulfhydryl compounds (GSH), and prostaglandin E2 (PGE2); mucosal cyclooxygenase-1 and -2 (COX-1, COX-2) mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Separate experiments were carried out to assay the effects of pantoprazole on gastric acid secretion in pylorus-ligated rats. The in vitro influence of pantoprazole (1-10 microM) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate was also examined. All NSAIDs elicited mucosal necrotic lesions associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels, were detected in the gastric mucosa of indomethacin-, piroxicam- or ketoprofen-treated animals. Indomethacin enhanced mucosal COX-2 expression, while not affecting COX-1. At the oral dose of 6 micromol/kg pantoprazole did not affect NSAID-induced mucosal damage, whereas at 60 micromol/kg it markedly reduced injuries provoked by all test NSAIDs. Pantoprazole 60 micromol/kg also reversed the effects of NSAIDs on MPO, MDA, and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced COX-2 expression. However, at both doses, pantoprazole inhibited acid secretion in pylorus-ligated rats. Furthermore, pantoprazole concentration dependently reduced the in vitro oxidation of LDLs. Our results suggest that besides inhibiting acid secretion, the protection afforded by pantoprazole against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which may also account for an increment of sulfhydryl radical mucosal bioavailability. It is also suggested that pantoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Involvement of a sperm protein sensitive to sulfhydryl-depleting reagents in mouse sperm-egg fusion.

Effects of various sulfhydryl (SH)-depleting reagents on sperm-egg fusion were demonstrated. When sperm were treated with three plasma membrane-permeable SH-depleting reagents, N-ethyl-maleimide, sodium tetrathionate and 5,5'-dithiobis (2-nitro-benzoic acid), the rates of cleavage of eggs were significantly lower than those with control sperm. Neither the motility, penetration of the zona pellucida, acrosomal status of the sperm, nor sperm-egg binding was affected by the SH-depleting reagents. Fusion of sperm and zona-free egg was estimated by the sperm nuclear incorporation into the eggs, intracellular calcium mobilization, and cortical granule exocytosis in the eggs. Sperm-egg fusion was blocked dose-dependently when sperm were exposed to membrane-permeable SH-depleting reagents, but was not blocked by a membrane-impermeable SH-depleting reagent, eosin-5-maleimide. Blockage of fusion by sodium tetrathionate was completely reversed by an SH-reductant, dithiothreitol. These results suggest that a protein which is sensitive to SH-depleting reagents may play an important role in mouse sperm-egg fusion and that the functional SH region of the protein may be located at an intracellular site.

Acrosome↗
PubMed2002

Biomimetic studies on iodothyronine deiodinase intermediates: modeling the reduction of selenenyl iodide by thiols.

Enzyme mimetic studies on the crucial intermediate (E-SeI) of the iodothyronine deiodinase cycle have been carried out by using an areneselenenyl iodide stabilized by intramolecular Se.N interactions. Treatment of this compound with aromatic thiols and thiobenzoxazole in the presence of NEt(3) affords areneselenenyl sulfides that are stable towards disproportionation reactions. The structures of three of the areneselenenyl sulfides were determined by X-ray crystallography. In one case, in the absence of NEt(3), a diselenide can be formed rather than the selenenyl sulfide. The areneselenenyl iodide also reacts with a related selenol to produce the corresponding diselenide, and this reaction is found to be much faster than that with thiols. The high reactivity of the selenenyl iodide with the selenol suggests that a reduced selenol group (R'-SeH) may react with the E-SeI intermediate to produce a diselenide (E-Se-Se-R') without any thiol cosubstrate. The intermediacy of selenenyl sulfides during the reduction of selenenyl iodide by thiols and its possible relevance to the iodothyronine deiodinase catalytic cycle is also described.

Binding Sites↗
PubMed2002

Detection of oxidant sensitive thiol proteins by fluorescence labeling and two-dimensional electrophoresis.

Oxidants can activate signaling pathways and modulate a variety of cellular activities. Their action at a molecular level involves the post-translational modification of protein thiols. We have developed a proteomic method to monitor the reduction and oxidation of protein thiols, and identify those thiol proteins most sensitive to oxidation. Cells were disrupted in the presence of N-ethylmaleimide to block the reduced thiol proteins and dithiothreitol was added to reduce the oxidized thiol proteins before labeling with 5-iodoacetamidofluorescein. Two-dimensional (2-D) electrophoresis was used to resolve the labeled samples. We applied the method to Jurkat T lymphocytes and examined the effect of diamide on the oxidized and reduced thiol protein profiles. A small percentage of protein thiols were already oxidized in untreated cells. Exposure of cells to 2 mM diamide for ten minutes led to a dramatic increase in thiol protein oxidation as seen in the oxidized thiol protein map. However, it was difficult to detect any change in the pattern of reduced thiol proteins. Separation of proteins by 2-D electrophoresis revealed approximately 200 thiol proteins that were oxidized by diamide treatment. This method will be valuable in elucidating redox signaling pathways.

Electrophoresis, Gel, Two-Dimensional↗