The antioxidative activity of drugs in the liver microsomal system of rats]

The antioxidative properties of drugs--diethylcarbamazine citrate--DECC, dipyridamole-DP, levamisole and labinzarit--have been investigated in various microsomal lipid peroxidation (LPO) models: NADPH-, ascorbate- and CCl4-dependent. The most strong antioxidant of direct action turned out to be DP, DECC exhibited the antioxidative properties as a result of metabolic activity in monooxygenases system of rat liver microsomes. Levamisole and labinzarit turned out to be weak antioxidants. The control of microsomal membrane stability against Fe(2+)-ADP, NADPH-induced LPO, after being isolated from rat liver after the action of CCl4 without and with DECC, showed that DECC protected microsomal membranes from CCl4 in vivo and they remained stable against LPO in vitro.     

New aminophosphonates with antioxidative activity.

The antioxidative activity of some newly synthesized aminomethanephosphonic acid derivatives was studied. The compounds studied differed in their polarity and the hydrophobicity of the electronic substituents at their nitrogen and phosphorus atoms. It was found that all the aminophosphonates studied, both cyclic and acyclic, protected erythrocyte membranes against peroxidation to some extent. The effect was somewhat weaker in the case of cyclic compounds, and for erythrocytes irradiated with UV light. The cyclic compounds provided no protection of erythrocytes illuminated by natural light. The observed differences between the antioxidative activities of cyclic and acyclic compounds are probably related to differences in their ability to incorporate into the lipid phase of erythrocyte membranes. Once incorporated, they change the fluidity of the membranes. The extent of those changes was determined in fluorescence measurements. Generally, they were found to be more pronounced in the case of acyclic aminophosphonates, although as regards other structural differences between particular aminophosphonates, a clear picture of the relationship between structure and effect is more difficult to obtain. No correlation was found between the antioxidative efficiency of the compounds and the fluidity changes they induce.     

Blood antioxidative enzymes during epileptic activity

It has been shown that the development of generalized epileptic activity in rats led to the decrease in superoxide dismutase (SOD) activity without affecting glutathione peroxidase (GP) and glutathione reductase (GR) activity. Long-term examination of 13 patients suffering from generalized forms of epilepsy has shown an about 30% decrease in SOD and GP activity in red blood cells. It is assumed that the functional insufficiency of the antioxidative system plays an essential role in the development of lipid peroxidation disturbances during epilepsy.     

Strigol: biogenesis and physiological activity

The role played by molecules of the strigolactone family in stimulating the germination of seeds of parasitic weeds of the genera Striga, Orobanche and Alectra has never been clearly elucidated. The biogenesis of these unusual terpenoid lactones, originally identified in minute quantities in the root exudates of a small number of host plants and two or three "false hosts", also remains obscure. These lactones, as the chemical signals which initiate the life cycle of Striga, are consequently at the forefront of the Striga research effort. This paper reviews recent key discoveries relating to the biosynthesis and mode of action of strigolactones, and summarises the evidence suggesting that these molecules may be far more widely distributed and have a greater physiological significance than has hitherto been appreciated.     

Xanthine oxidase--xanthines as a system of endogenous regulation of phosphodiesterase activity

The paper is concerned with the data indicating close interaction between xanthinoxidase (Xase) and phosphodiesterase (PDE). PDE activity can be modified by affecting the activity of Xase. This effect is mediated by changes in the concentrations of endogenous xanthines. The action of PDE inhibitors, methylxanthines, is discussed from the point of view of the above effect. The data obtained hold promise for purposeful monitoring of tissue concentrations of the cyclic nucleotides in vivo and in vitro.     

The antioxidative activity of traditional Japanese herbs

The objective of this research was to examine the radical scavenging activity of traditional Japanese herbs. Samples used in the experiments were gennoshoko (Geranium nepalense var. thunbergii), yomogi (Artemisia vulgaris var.indica), senburi (Swertia japonica), iwa-tobacco (Conandron ramondioides), sarunokoshikake (Elfvingia applanata), kanzo (Glycyrrhiza uralensis Fisch) and matatabi (Actinidia polygama). The water-soluble components of the herbs were extracted in boiling water, and the volatile oil was extracted by a distillation apparatus or steeping in some organic solvents such as petroleum ether and ethyl ether. The radical scavenging activity was determined by the decrease of free radicals of DPPH detected by both colorimetric assay and HPLC method at 517 nm. The extracts of gennoshoko, yomogi and iwa-tobacco showed remarkable radical scavenging activity. The volatile oil of yomogi obtained by distillation or steeping in organic solvents had especially strong antioxidative activity.     

Carnosine and cancer: a perspective

The application of carnosine in medicine has been discussed since several years, but many claims of therapeutic effects have not been substantiated by rigorous experimental examination. In the present perspective, a possible use of carnosine as an anti-neoplastic therapeutic, especially for the treatment of malignant brain tumours such as glioblastoma is discussed. Possible mechanisms by which carnosine may perform its anti-tumourigenic effects are outlined and its expected bioavailability and possible negative and positive side effects are considered. Finally, alternative strategies are examined such as treatment with other dipeptides or β-alanine.     

Significance of melatonin in antioxidative defense system: reactions and products

Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(.)), nitric oxide (NO(.)), peroxynitrite anion (ONOO(-)), hypochlorous acid (HOCl), singlet oxygen ((1)O(2)), superoxide anion (O(2)(-).) and peroxyl radical (LOO(.)), although the validity of its ability to scavenge O(2)(-). and LOO(.) is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO. Also, its secondary and tertiary metabolites, for example, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.     

Coronatine alleviates salinity stress in cotton by improving the antioxidative defense system and radical-scavenging activity

Coronatine (COR) is a chlorosis-inducing phytotoxin that mimics some biological activities of methyl jasmonate. This study investigated whether COR confers salinity tolerance to cotton and whether such tolerance is correlated with changes in the activity of antioxidant enzymes. COR at 0.01muM was applied hydroponically to cotton seedlings at the two-leaf stage for 24h. A salinity stress of 150mM NaCl was imposed after completion of COR treatment for 15d. Salinity stress reduced biomass of seedlings and increased leaf superoxide radicals, hydrogen peroxide, lipid peroxidation, and electrolyte leakage. Activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione reductase (GR), and of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), scavenging activity were altered by salinity to varying degrees. Pretreatment with COR increased the activities of CAT, POD, GR, and DPPH scavenging activity in leaf tissues of salinity-stressed seedlings. Thus, COR might reduce the production of reactive oxygen species by activating antioxidant enzymes and DPPH-radical scavenging, thereby preventing membrane peroxidation and denaturation of bio-molecules.     

Carnosine: from exercise performance to health

Carnosine was first discovered in skeletal muscle, where its concentration is higher than in any other tissue. This, along with an understanding of its role as an intracellular pH buffer has made it a dipeptide of interest for the athletic population with its potential to increase high-intensity exercise performance and capacity. The ability to increase muscle carnosine levels via β-alanine supplementation has spawned a new area of research into its use as an ergogenic aid. The current evidence base relating to the use of β-alanine as an ergogenic aid is reviewed here, alongside our current thoughts on the potential mechanism(s) to support any effect. There is also some emerging evidence for a potential therapeutic role for carnosine, with this potential being, at least theoretically, shown in ageing, neurological diseases, diabetes and cancer. The currently available evidence to support this potential therapeutic role is also reviewed here, as are the potential limitations of its use for these purposes, which mainly focusses on issues surrounding carnosine bioavailability.     

Carnosine derivatives: new multifunctional drug-like molecules

Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely and abundantly distributed in the muscle and nervous tissues of several animal species. Many functions have been proposed for this compound because of its antioxidant and metal ion-chelator properties. Many potential therapeutic properties have been recognized especially related to the antioxidant activity, but the therapeutic uses are strongly limited by the mechanism governing its homeostasis. This fact has been the main reason for developing the synthesis of carnosine derivatives with interesting potentiality, but until now there have been very few applications. These derivatives could represent the future drugs for many pathologies related to oxidative stress and metal ion dyshomeostasis.     

Determination of the antioxidative activity of substituted 5-aminopyrimidines

The aminopyrimidine structural motif can be found in diverse biologically active compounds. This study aimed to describe the antioxidant activity of a series of di- and tri-substituted 5-aminopyrimidines using in vitro (TEAC, LPO) and cell-based assays. 2,4,6-trisubstituted 5-aminopyrimidines displayed the highest activity in the TEAC and LPO assays whereas compounds with protected 5-aminogroup were active in the cellular assay. This is most likely because of their better membrane permeability and intracellular metabolic activation. In summary, we have identified the antioxidant activity of a series of substituted 5-aminopyrimidines and their potential prodrugs which may have implications in the treatment of oxidative stress-related diseases.     

Determination of the antioxidative activity of substituted 5-aminopyrimidines

The aminopyrimidine structural motif can be found in diverse biologically active compounds. This study aimed to describe the antioxidant activity of a series of di- and tri-substituted 5-aminopyrimidines using in vitro (TEAC, LPO) and cell-based assays. 2,4,6-trisubstituted 5-aminopyrimidines displayed the highest activity in the TEAC and LPO assays whereas compounds with protected 5-aminogroup were active in the cellular assay. This is most likely because of their better membrane permeability and intracellular metabolic activation. In summary, we have identified the antioxidant activity of a series of substituted 5-aminopyrimidines and their potential prodrugs which may have implications in the treatment of oxidative stress-related diseases.     

Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

Abstract

New catechol-containing chemical entities have been investigated as matrix metalloproteinase inhibitors as well as antioxidant molecules. The combination of the two properties could represent a useful feature due to the potential application in all the pathological processes characterized by increased proteolytic activity and radical oxygen species (ROS) production, such as inflammation and photoaging. A series of catechol-based molecules were synthesized and tested for both proteolytic and oxidative inhibitory activity, and the detailed binding mode was assessed by crystal structure determination of the complex between a catechol derivative and the matrix metalloproteinase-8. Surprisingly, X-ray structure reveals that the catechol oxygens do not coordinates the zinc atom.     

Retinoic acid: an endogenous compound of human blood. Unequivocal demonstration of endogenous retinoic acid in normal physiological conditions.

The occurrence of retinoic acid (vitamin A acid) as a normal constituent of the vitamin A reserve from the body is demonstrated. Improved methodologies based on selected peak monitoring (spm) and high-performance liquid chromatography (hplc) are used for the detection of retinoic acid in EDTA-plasma. After extensive cleanup by double-phase extraction and chromatography on Sephadex LH-20, retinoic acid is determined as its methyl derivative by spm. A different approach using double-phase extraction combined with a preextraction step and hplc is used to confirm the findings of the spm experiments. Both techniques proved the presence of retinoic acid in human plasma at a concentration of 1 to 3 ng/ml.     

Retina contains endogenous heparinase activity

Heparin binding growth factors (HBGF), a major component of retinal endothelial cell growth factor activity, have been located particularly to a storage site in the vascular basement membrane, where they are bound to heparan sulphate in a relatively inactive state. It has been suggested that angiogenic activity in the retina may be released, during basement membrane degradation, by heparinase enzymes. We now report that mitogenic saline extracts of retina contain heparinase-like activity, whereas non-mitogenic retinal homogenate does not. However, heparinase-like activity may only account for part of the mitogenic activity in retinal extract. In previous studies we have shown that the absence of mitogenic activity in retinal homogenate is due to a heat-labile inhibitor. Heat-treatment of retinal homogenate is due to a heat-labile inhibitor. Heat-treatment of retinal homogenate restored mitogenic activity to 60% of that in retinal extract, but this heat-treated homogenate still lacked heparinase activity.     

Mammalian lignans: possible involvement in endogenous digitalis activity

Lignans are natural products, some of which were recently discovered in animal urines, semen and blood plasma. We investigated the actions of animal lignans obtained by total synthesis or extracted from urines of pregnant women on Na+, K+-ATPase in human red cells and human and guinea-pig heart cell membranes. Some of the tested lignans (enterolactone, prestegane B and 3-O-methyl enterolactone) inhibited Na+, K+-pump activity in human red cells with IC50 ranging from 5 to 9 X 10(-4) M. The IC50 for ouabain (7 X 10(-7) M) was not modified by addition of lignans. Enterolactone inhibited Na+, K+-ATPase activity in human and guinea pig heart membranes. It also displaced [3H]-ouabain binding from human heart with IC50 = 1.5 X 10(-4) M. The apparent dissociation rate constants (kd) of [3H]-ouabain were not different in presence of digoxin or enterolactone. Enterolactone exhibited a poor cross reactivity against antidigoxin antibodies. The aglycones of the lignans studied here were slight inhibitors of the Na+, K+-ATPase. However, we cannot exclude that a glycosyl- (and/or butenolide-) derivative of enterolactone could be one "endogenous ouabain-like" factor.     

Inhibition of the antioxidative activity of plasma by sodium azide

Powerful antioxidant activity of human plasma was demonstrated by measuring the thiobarbituric acid reaction and Fe+2-induced chemiluminescence. Inhibition of lipid peroxidation was shown both for plasma lipids and for the suspension of egg lipoproteins, which was taken as a model system. The inhibitory effect of plasma peroxidation was removed by azide Na taken in the concentration of 0.5 mg/ml, but caeroplasmin activity in the plasma was completely suppressed at NaN3 concentration equal to 0.1 mg/ml. A low correlation (r = 0.75) between caeruloplasmin activity in the blood plasma and extent of chemiluminescence activation obtained in the presence of NaN3 was found. The presented data led to an assumption that only a part of lipid peroxidation inhibitors in the plasma can be attributed with caeruloplasmin.