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PubMed1971

Synthesis and oxidation of aminoalkyl-onium compounds by pig kidney diamine oxidase.

1. The preparation of a series of compounds derived from diamines by replacing one amino group by a dimethylsulphonium, isothiuronium, trimethylammonium, NN'-dimethylimidazolium or N-methylpyridinium species is described. 2. The behaviour of these compounds as substrates of pig kidney diamine oxidase is reported. All but the trimethylammonium compounds proved to be substrates. 3. Many of these compounds showed potent inhibition at high substrate concentration and this was studied. 4. On the basis of these and other observations a scheme for enzyme-substrate interaction is suggested.

Alkanes↗
PubMed1975

Effects of reducing and oxidizing agents on the action of bleomycin.

The effects of reducing agents, such as 2-mercaptoethanol, dithiothreitol, L-ascorbic acid, or sodium borohydride, and oxidizing agents, such as hydrogen peroxide or dehydroascorbic acid, on the in vitro action of bleomycin were investigated. After the incubation of DNA with a low concentration of bleomycin and a reducing or oxidizing agent, single strand breaks were mainly caused in the DNA molecules. The degradation of DNA was largely prevented by the removal of oxygen, or by the addition of divalent cations or of S-(2-aminoethyl)isothiuronium bromide hydrobromide, a radical scavenger, to the incubation mixture. Preincubation of bleomycin with these reducing or oxidizing agents reduced the DNA-degrading activity of the antibiotic. However, this reduction in activity was observed even in the absence of oxygen, or in preincubation mixture supplemented with radical scavenger.

Ascorbic Acid↗
PubMed2005

Construction of a reactive surface barrier to reduce fumigant 1,3-dichloropropene emissions.

Halogenated fumigants have been used extensively in production agriculture to control soilborne pests. These types of pesticides are highly volatile and are prone to affect air quality and imperil public health. In the present study, a chemical tarp approach, termed a reactive surface barrier (RSB), was developed to reduce the emission of fumigant 1,3-dichloropropene (1,3-D) from the soil surface. The agrochemicals thiourea and allylthiourea were tested as active reagents for the construction of a RSB, where these soil amendments react with 1,3-D to form nonvolatile isothiuronium ions at the soil surface and, thereby, impede fumigant emission into the atmosphere. The feasibility of the method largely depends on the reactivity of 1,3-D and the RSB agrochemicals in soil as well as on the mobility, persistence, and toxicity of the transformation products. Therefore, the reaction kinetics and transformation mechanism of 1,3-D by thiourea and allylthiourea were studied comprehensively in aqueous solution and soil. A catalytic process occurring at the surface of soil colloids facilitated the reaction between 1,3-D and thiourea in amended soils. The rate of 1,3-D transformation in thiourea-amended soil increased with decreasing soil moisture or increasing thiourea amendment level. In a field trial, a thiourea RSB reduced cumulative 1,3-D emissions by more than 80% relative to that in bare soil surface. The present results clearly indicate that this chemical remediation technology has great potential to control the emissions of volatile halogenated organic contaminants and to mitigate atmospheric pollution.

Allyl Compounds↗
PubMed1992

Radiation protection of male fertility in mouse and rat by a combination of 5-hydroxy-L-tryptophan and a thiol compound (AET).

Sperm abnormalities and fall in total sperm count following different doses (4 Gy, 5 Gy and 6 Gy) of whole body gamma irradiation (WBGR) were studied in adult male Swiss strain A mice. The protecting ability of a combination of 5-hydroxy-L-tryptophan (5-HTP, 100 mg/kg) and 2-aminoethyl isothiuronium bromide hydrobromide (AET, 20 mg/kg) was also investigated. Pretreatment with a 5-HTP+AET formulation i.p., 30 min before irradiation modified the fall in sperm counts significantly. Exposures to 4 Gy, 5 Gy and 6 Gy WBGR caused marked increase of sperm abnormalities which could be significantly reduced by pretreatment with 5-HTP-AET. WBGR with 4 Gy, 5 Gy and 6 Gy produced a short period of sterility associated with oligospermia but these abnormalities were corrected by pretreatment with 5-HTP+AET. This finding was supported by breeding experiments in pretreated adult male Sprague-Dawley rats which showed delivery of normal offsprings in drug-protected irradiated groups in contrast to irradiated controls.

5-Hydroxytryptophan↗
PubMed1987

Monocyclic beta-lactam antibiotics: synthesis and antibacterial activity of 4-(substituted ethyl)-2-azetidinone-1-sulfonic acid derivatives.

The synthesis and antibacterial activity of sodium (3S,4R)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)acetamido]-2-azetidinone-1-sulfonates having various substituted ethyl groups at the C-4 position are described. Among various substituents explored, the (substituted isothiuronio)ethyl groups were found to have strong antibacterial activity against a variety of Gram-negative bacteria, and moreover, the ethylene isothiuronium derivative exhibited moderate antibacterial activity against Staphylococcus aureus.

Anti-Bacterial Agents↗
PubMedDate not supplied

[NO-inhibiting activity of radioprotectors].

The effect of radioprotectors of different structure on the syntheses of nitric oxide induced by endotoxin in mice was studied. Using ESR-spectroscopy and spin trap techniques, it was shown that compounds of different chemical structure, such as aminothiols, isothiuronium derivatives, thiazolines, indolylalkylamines and others, suppressed the nitric oxide production in a whole body. The analysis of the relevant literature has confirmed the phenomenon described by the authors: radioprotectors show NO-inhibiting activity.

Animals↗
PubMed2005

Structure and activity of NO synthase inhibitors specific to the L-arginine binding site.

Synthesis of compounds containing a fragment similar to the guanidine group of L-arginine, which is a substrate of nitric oxide synthase (NOS), is the main direction in creating NOS inhibitors. The inhibitory effect of such compounds is caused not only by their competition with the substrate for the L-arginine-binding site and/or oxidizing center of the enzyme (heme) but also by interaction with peptide motifs of the enzyme that influence its dimerization, affinity for cofactors, and interaction with associated proteins. Structures, activities, and relative in vitro and in vivo specificities of various NOS inhibitors (amino acid and non-amino acid) with linear or cyclic structure and containing guanidine, amidine, or isothiuronium group are considered. These properties are mainly analyzed by comparison with effects of the inhibitors on the inducible NOS.

Animals↗
PubMed1987

Alterations in monoamine oxidase activity of the mouse brain and liver after mixed neutron-gamma irradiation.

Monoamine oxidase (MAO) plays an important role in the metabolism of neuro-transmitter biogenic amines. Its activity was determined in mouse brain and liver after exposure to different kinds of ionizing radiation and after pretreatment with a radioprotective agent. After a lethal dose of mixed neutron-gamma irradiation the MAO activity decreased in the brain and increased in the liver. In contrast, after a lethal dose of 60Co-gamma irradiation enzyme activity was considerably increased in the brain while in the liver it increased like after mixed neutron-gamma irradiation. AET (S2-aminoethyl-isothiuronium-Br X HBr), when administered in a radio-protective dose, inhibited MAO activity in the brain, while it increased in the liver. Even more marked changes of enzyme activity were observed in both brain and liver after AET pretreatment and mixed neutron-gamma irradiation. On the basis of the results it is suggested that different kinds of ionizing radiation lead to different types of lipid peroxidation in the lipid environment surrounding MAO, an event leading to altered enzyme activity. AET itself inhibited MAO in the brain and increased the activity in the liver but did not prevent the alterations caused by ionizing radiation in enzyme activity.

Animals↗
PubMedDate not supplied

[Use of a manganese citrate complex in the determination of liver enzyme activities in the aging process and following treatment with aminoethylisothiuronium bromide hydrobromide (AET)].

Some oxidation enzyme as well as reductase and dehydrogenases in liver samples were estimated. With the manganese-citrate plus diethylen-p-phenylene-diamine complex method an increases reduction-capacity and succino-dehydrogenase activity was recorded in the liver samples of the 23 month old rat. No differences were found between the 6 and 12 month old rat liver samples. Following a 8-month amino-ethyl-isothiuronium. Br. HBr (AET) treatment (100 mg/kg) of mice both the reduction-capacity and the succino-dehydrogenase activity showed an elevated value in the liver samples of the experimental animals.

Aging↗
PubMedDate not supplied

[Mechanism of action of dialkylaminoethylthiol derivatives of pyrimidine and quinazoline].

A study was made of acute toxicity and radioprotective efficiency of some heterocyclic isothiuronium analogues and their ability to change the oxygen uptake by the organism. The rate of hydrolysis of the preparations in vitro was determined. A correlation was found between the above-mentioned indices. On the basis of the data obtained it was concluded that aminothiol, formed as the result of enzymic digestion in the organism, was responsible for the radioprotective effect of the compounds under study since it reduced the oxygen uptake by the organism.

Animals↗
PubMedDate not supplied

[Toxicological and radiobiological characteristics of meprin S-derivatives].

The effect was studied of synthetic thiosulfo- (TSPG), thiophospho- (TPPG), isothiuronium- (ITPG), and diethyldithiocarbamate (DDTKPG) alpha-mercaptopropionylglycine derivatives (alpha-MPG). Their toxicological and radiobiological characteristics were disclosed on mice exposed to gamma rays within a dose range of 9 to 11 Gy. TSPG in a dose of 3500 to 4500 mg/kg provided a 60 to 70% survival at LD100/10. In a dose of 4000 mg/kg the drug favoured a 70% protection of experimental animals when administered 4 hours before exposure to LD60/30. A high degree of protection (90%) was seen after TPPG preadministration (800 mg/kg) and exposure to LD100/10. DDTKPG (1300 mg/kg) also increased the survival of irradiated animals. No protective effect was observed after ITPG administration in doses of 50, 100, 180 and 360 mg/kg. Low toxicity and good enough antiradiation effect of the three compounds tested enabled the authors to proceed to more extensive studies.

Amino Acids, Sulfur↗
PubMed2003

Reversal of the effect of albumin on gut barrier function in burn by the inhibition of inducible isoform of nitric oxide synthase.

HYPOTHESIS: The use of albumin in the early resuscitation formula after major burn has been forbidden because of its damaging effect on the gut barrier function. We hypothesize that inhibition of the inducible isoform of nitric oxide synthase to stabilize endothelial permeability and to retain albumin in the vascular space will ameliorate the major trauma-induced gut barrier dysfunction. DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: In experiment 1, specific pathogen-free rats undergoing 35% total body surface area burn or sham burn were given equal volumes (7.5 mL/kg) of isotonic sodium chloride solution or albumin from femoral veins for fluid resuscitation at 0, 4, or 8 hours after burn. In experiment 2, intraperitoneal S-methylisothiourea sulfate (7.5 mg/kg) was given immediately after burn to rats from different groups, as in experiment 1 (SMT groups). At 24 hours after burn, the intestinal mucosa was assayed for myeloperoxidase activity as an index for neutrophil sequestration, the distribution of fluorescein isothiocyanate-dextran across the lumen of small intestine was determined to evaluate the intestinal permeability, and bacterial translocation (BT) to the mesenteric lymph nodes (MLNs) and histological findings in the ileum were also examined. RESULTS: Compared with sham burn, burn induced significant increases in intestinal mucosa myeloperoxidase activity, intestinal permeability, BT to the MLNs, and villi sloughing in rats. Albumin administration at 0 or 4 hours after burn enhanced the increases in neutrophil sequestration, permeability, and villi sloughing compared with saline injection at the same times. In contrast, injection of albumin in the burn-SMT group did not aggravate these changes in intestinal myeloperoxidase activity, intestinal permeability, BT to the MLNs, and villi edema. Burn-SMT rats with albumin injections at 4 or 8 hours after burn showed significant 35% and 52% decreases, respectively, in intestinal permeability compared with burn-SMT-saline rats. Use of albumin at 8 hours after burn in combination with S-methylisothiourea significantly attenuated BT to the MLNs and reduced villi edema. CONCLUSIONS: Early albumin resuscitation aggravated the burn-induced gut damage. Albumin administration and inhibition of the inducible isoform of nitric oxide synthase in combination decreased burn-induced gut barrier dysfunction and reversed the damaging effect of albumin on gut barrier function and decreased BT.

Albumins↗
PubMed1996

S-methylisothiourea inhibits inducible nitric oxide synthase and improves left ventricular performance after acute myocardial infarction.

The contribution of increased inducible nitric oxide synthase (iNOS) activity to the development of left ventricular dysfunction after acute myocardial infarction (MI) was investigated New Zealand rabbits (n = 24) were randomly treated with either saline, S-methylisothiourea sulfate (SMT; selective iNOS inhibitor) or N-omega-nitro-L-arginine (NOLA; non-isoform selective NOS inhibitor). Left ventricular hemodynamics and myocardial blood flow were measured before coronary occlusion and on postoperative day 3 (POD 3). MI resulted in left ventricular dysfunction and increased myocardial iNOS activity. SMT and NOLA significantly inhibited iNOS activity; SMT, but not NOLA, significantly improved left ventricular maximum +dP/dt and decreased LVEDP; myocardial blood flow in the remote myocardium significantly increased after SMT. Induction of myocardial iNOS after MI on POD 3 contributes to the development of left ventricular dysfunction; modulation of iNOS activity by SMT improves left ventricular performance and may be beneficial after acute MI.

Animals↗
PubMed1997

Evidence for the presence of an unusual nitric oxide- and citrulline-producing enzyme in rat kidney.

We have found an enzymatic activity obtained from rat kidney capable of producing citrulline and NOx. (nitrate and nitrite) which was resistant to inhibition by conventional arginine analogues. This enzyme activity does not require any calcium or calmodulin and was found to be induced during pregnancy. This unique enzyme was found to be tissue and species specific. Another unique feature of this enzyme is that it did not bind to 2'5'-ADP-sepharose under standard conditions. Western blot analysis of the 100,000 g kidney supernatant using monoclonal antibody for macrophage inducible nitric oxide synthase failed to produce a band for inducible nitric oxide synthase. HPLC and capillary ion analysis for nitrate and nitrite (NOx) showed clear peaks for [3H] L-citrulline and NOx, respectively, which were not changed either in the absence of calcium and calmodulin or in the presence of 300 microM S-ethylisothiourea, which has been shown to be a very potent and selective inhibitor of inducible nitric oxide synthase with a Ki of about 14.7 nM. These results suggest the possible existence of another isoform of nitric oxide synthase with very distinct properties from the known isoforms.

Animals↗
PubMed1996

Nitric oxide regulates wound healing.

Nitric oxide (NO) synthesis occurs during wound healing, but its role has not been defined. To study the effect of NO on wound repair, S-methyl isothiouronium (MITU, a competitive inhibitor of NO synthase) was administered at a dose of 10, 50, and 100 mg/kg body weight/day, using intraperitoneally implanted miniosmotic pumps. Groups of 10 male Balb/C mice underwent a dorsal skin incision and polyvinyl alcohol sponges were inserted subcutaneously. The animals were sacrificed 10 days postwounding and wound breaking strength and hydroxyproline content of sponges, an index of reparative collagen deposition, were determined. Some sponges were used to harvest wound fluid and infiltrating cells, which were then incubated overnight with or without 1 mM MITU. Nitrite and nitrate, stable end products of NO, were measured in wound fluid and in wound cell culture supernatants. Continuous intraperitoneal infusion of MITU significantly decreased wound fluid nitrite/nitrate concentrations in a dose dependent manner (P < 0.01). Inhibition of wound NO synthesis by 100 mg MITU/kg/day was paralleled by lowered wound collagen accumulation (P < 0.01) and wound breaking strength (P < 0.01). In vitro NO synthesis by wound cells obtained from animals treated with 100 mg MITU/kg/day was not significantly different from controls (12.6 +/- 1.2 vs 10.7 +/- 0.6 nmole NO2 + NO3/microgram DNA), reflecting the reversible inhibition of NO synthase by MITU. However, NO production was equally inhibited in wound infiltrating cells by the in vitro addition of MITU (83% vs 85%, respectively). These data suggest that nitric oxide synthesis is critical to wound collagen accumulation and acquisition of mechanical strength.

Animals↗
PubMed2001

A novel method of studying wound healing.

In order to study wound healing, it is often necessary to administer various wound-active substances by the systemic route. It is unclear whether the observed effects are the result of local or systemic influence of the agent administered. Furthermore, high systemic doses are often required to achieve activity at the wound level. Direct intrawound administration of substances is traumatic and disruptive to the fragile wound environment and increases the risk of infection. We devised a system for continuous atraumatic delivery of substances directly to subcutaneously implanted polyvinyl alcohol sponges, an adaptation of a well-established model of wound healing. Sponge-catheter constructs were fashioned by feeding identical lengths of silicone catheters through two 40-mg sponge disks (on edge). The distal sponge was fixed 0.5 cm from the distal, ligated end of the catheter and centered over two 1-mm holes in the catheter tubing. The proximal sponge was fixed over nonperforated catheter with its edge 2 cm proximal from the close edge of the distal sponge. Each construct was connected to a mini-osmotic pump (infusion rate 1 microl/h) loaded with an appropriate infusate and inserted subcutaneously on the dorsum of anesthetized male Sprague-Dawley rats. Hydroxyproline (OHP) content of sponges, a measure of collagen deposition, was determined at 7 days postwounding. Infusion of India ink confirmed selective delivery to the distal sponge. Saline infusion alone significantly elevated OHP content compared to noninfused sponges (450 +/- 43 vs 328 +/- 36 microg OHP/100 mg sponge, P < 0.05). Infusion of S-methylisothiourea (a selective iNOS inhibitor, 84 microg/sponge/24 h) successfully inhibited NO production (35.9 +/- 3.1 vs 49.6 +/- 3.6 microM, P < 0.05) and decreased sponge OHP content (385 +/- 60 vs 568 +/- 70 microg OHP/100 mg sponge, P < 0.05) without the toxic side effect (i.e., weight loss) seen with systemic administration. Infusion of an adenoviral solution containing mouse iNOS cDNA resulted in successful transduction of wound cells demonstrating the ability to deliver genes to a healing wound model. The data demonstrate that manipulation of wound physiology is possible by local delivery of low doses of wound-active compounds to the wound site. This promises to be a powerful tool for the study of both normal and impaired wound healing.

Adenoviridae↗
PubMed2001

High levels of nitric oxide production decrease early but increase late survival of Brucella abortus in macrophages.

Nitric oxide (NO), produced by the iNOS protein, is known as a defense mechanism against various pathogens and an apoptotic inducer of cells. Apoptosis can also be a host protective mechanism against intracellular bacteria. The intracellular survival of Brucella abortus in RAW264.7 macrophages was examined under conditions of the apoptotic inducer, NO. Since B. abortus does not induce high output of NO, Escherichia coli LPS and IFN-gamma, as potential therapeutic modalities, were added to increase the expression of iNOS, and thus NO. Using 10 ng/ml E. coli LPS and 25 U/ml IFN-gamma, nitrite production was as high as 140 microM by 72 h. However, when macrophages were infected with B. abortus, the nitrite concentration was 60 microM after 72 h post infection, greater than a two-fold decrease. The number of surviving bacteria decreased, from 6 to 24 h, in the presence of nitrite accumulation. In the absence of B. abortus there was an increase in apoptotic cells at 72 h with high nitrite accumulation. In contrast, the number of macrophage apoptotic bodies decreased in the presence of B. abortus. The data suggest that: (i) NO accelerates the killing of intracellular B. abortus, but not to completion during the first 24 h of infection; (ii) B. abortus can prevent apoptosis as an advantage for bacterial survival inside macrophages and (iii) surviving intracellular bacteria then replicate steadily after 24 h. B. abortus probably expresses genes that counteract the effect of a high NO environment or activates genes to utilize NO as a nitrogen source, as the Brucella genome codes for nitric and nitrous oxide reductase genes.

Animals↗