Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation

Knowing threshold changes in brain lipids and lipid enzymes during dietary n-3 polyunsaturated fatty acid deprivation may elucidate dietary regulation of brain lipid metabolism. To determine thresholds, rats were fed for 15 weeks DHA-free diets having graded reductions of α-linolenic acid (α-LNA). Compared with control diet (4.6% α-LNA), plasma DHA fell significantly at 1.7% dietary α-LNA while brain DHA remained unchanged down to 0.8% α-LNA, when plasma and brain docosapentaenoic acid (DPAn-6) were increased and DHA-selective iPLA₂ and COX-1 activities were downregulated. Brain AA was unchanged by deprivation, but AA selective-cPLA₂, sPLA₂ and COX-2 activities were increased at or below 0.8% dietary α-LNA, possibly in response to elevated brain DPAn-6. In summary, homeostatic mechanisms appear to maintain a control brain DHA concentration down to 0.8% dietary DHA despite reduced plasma DHA, when DPAn-6 replaces DHA. At extreme deprivation, decreased brain iPLA₂ and COX-1 activities may reduce brain DHA loss.     

Antiplatelet pyrazolopyridines derivatives: pharmacological,biochemical and toxicological characterization

Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N′-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3?h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE₂ and TXB₂ through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.     

Biophotons from stressed and dying organisms: toxicological aspects

Cells and organisms exposed to detrimental and toxic substances show different responses in photon emission dependent on amount, kind and exposure time of toxin as well as on the organism investigated. Radical reaction-generating substances and dehydrating, lipid dissolving and protein denaturating toxins which do not induce direct chemiluminescence resulting from reactive oxygen species were applied. Lethal doses of toxins and stress factors such as osmotics and temperature evoke increase in the intensity of photon emission resulting from a rapid and irreversible perturbation of homeostasis. Bacterial and fungal toxins that elicit hypersensitive death of plant cells or defense response correlated with photon emission are also briefly discussed. Collective molecular interactions contribute to the photon-generating degradative processes in stressed and dying organisms. The measurements of biophoton signals and analysis of their parameters are used to elucidate the possible mechanisms of the toxin-organism interaction and the resistance of organisms. Toxicological perspectives of the use of these sensitive and rapid measurements as a part of direct toxicity assessment are discussed.     

Human aldehyde dehydrogenases: potential pathological,pharmacological, and toxicological impact

Aldehyde dehydrogenases catalyze the pyridine nucleotide-dependent oxidation of aldehydes to acids. Seventeen enzymes are currently viewed as belonging to the human aldehyde dehydrogenase superfamily. Summarized herein, insofar as the information is available, are the structural composition, physical properties, tissue distribution, subcellular location, substrate specificity, and cofactor preference of each member of this superfamily. Also summarized are the chromosomal locations and organization of the genes that encode these enzymes and the biological consequences when enzyme activity is lost or substantially diminished. Broadly, aldehyde dehydrogenases can be categorized as critical for normal development and/or physiological homeostasis (1). even when the organism is in a friendly environment or (2). only when the organism finds itself in a hostile environment. The primary, if not sole, evolved raison d'être of first category aldehyde dehydrogenases appears to be to catalyze the biotransformation of a single endobiotic for which they are relatively specific and of which the resultant metabolite is essential to the organism. Most of the human aldehyde dehydrogenases for which the relevant information is available fall into this category. Second category aldehyde dehydrogenases are relatively substrate nonspecific and their evolved raison d'être seems to be to protect the organism from potentially harmful xenobiotics, specifically aldehydes or xenobiotics that give rise to aldehydes, by catalyzing their detoxification. Thus, the lack of a fully functional first category aldehyde dehydrogenase results in a gross pathological phenotype in the absence of any insult, whereas the lack of a functional second category aldehyde dehydrogenase is ordinarily of no consequence with respect to gross phenotype, but is of consequence in that regard when the organism is subjected to a relevant insult.     

L-Tryptophan: Biochemical,nutritional and pharmacological aspects

Summary Tryptophan is important both for protein synthesis and as a precursor of niacin, serotonin and other metabolites. Tryptophan is an unusual amino acid because of the complexity of its metabolism, the variety and importance of its metabolites, the number and diversity of the diseases it is involved in, and because of its use in purified form as a pharmacological agent. This review covers the metabolism of tryptophan, its presence in the diet, the disorders associated with low tryptophan levels due to low dietary intake, malabsorption, or high rates of metabolism, the therapeutic effects of tryptophan and the side effects of tryptophan when it is used as a drug including eosinophilia myalgia syndrome.     

Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects

In previous minireviews in this journal, we discussed work on induction of tetrahydrobiopterin biosynthesis by cytokines and its significance for nitric oxide (NO) production of intact cells as well as functions of H4-biopterin identified at this time for NO synthases (Proc Soc Exp Biol Med 203: 1-12, 1993; Proc Soc Exp Biol Med 219: 171-182, 1998). Meanwhile, the recognition of the importance of tetrahydrobiopterin for NO formation has led to new insights into complex biological processes and revealed possible novel pharmacological strategies to intervene in certain pathological conditions. Recent work could also establish that tetrahydrobiopterin, in addition to its allosteric effects, is redox-active in the NO synthase reaction. In this review, we summarize the current view of how tetrahydrobiopterin functions in the generation of NO and focus on pharmacological aspects of tetrahydrobiopterin availability with emphasis on endothelial function.     

Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects

Cytosolic sulphotransferases transfer the sulpho moiety from the cofactor 5'-phosphoadenosine-3'-phosphosulphate (PAPS) to nucleophilic groups of xenobiotics and small endogenous compounds (such as hormones and neurotransmitters). This reaction often leads to products that can be excreted readily. However, other sulpho conjugates are strong electrophiles and may covalently bind with DNA and proteins. All known cytosolic sulphotransferases are members of an enzyme/gene superfamily termed SULT. In humans, 10 SULT genes are known. One of these genes encodes two different enzyme forms due to the use of alternative first exons. Different SULT forms substantially differ in their substrate specificity and tissue distribution. Genetic polymorphisms have been described for three human SULTs. Several allelic variants differ in functional properties, including the activation of promutagens. Only initial results are available from the analysis of SULT allele frequencies in different population groups, e.g. subjects suffering from specific diseases and corresponding controls.     

GABA-benzodiazepine interactions: physiological, pharmacological and developmental aspects

Many of the pharmacological actions of the benzodiazepines can be attributed to their actions on gamma-aminobutyric acid (GABA) systms in the brain. Electrophysiological studies on dorsal raphe neurons indicate that the benzodiazepines act postsynaptically to potentiate GABAergic inhibition in this midbrain nucleus. Direct binding studies have shown that both in vitro and in vivo binding of [3H]diazepam to a specific high affinity benzodiazepine binding site in cerebral cortical tissue are enhanced by the direct in vitro addition of GABA and GABA agonists or by pretreatment of animals with GABA analogs and agents that elevate GABA levels in brain. Ontogenic development of [3H]diazepam binding in brain parallels the development of the sodium-independent [3H]GABA binding. The ability of GABA to enhance benzodiazepine binding is present throughout development and inversely related to age. These data suggest that there is a functionally significant interaction between the benzodiazepines and GABA throughout development and at maturity. A model is proposed to relate these interactions to conformational changes in a benzodiazepine/GABA/Cl- ionophore complex.     

Swertia (Gentianaceae): chemical and pharmacological aspects

A compilation of the constituents isolated from Swertia species covering the literature up to December 2003 is presented. The botanical classification and ethno-pharmacology of Swertia plants, as well as the biological activities and pharmacological applications of both distinct phytochemicals and medicinally active plant materials (formulations, extracts, etc.) are discussed in detail.     

膳食多不饱和脂肪酸对骨细胞功能的调节

骨骼是体内唯一可以同时提供支持、运动及矿物质平衡的组织。有三种细胞参与软骨及骨骼的形成,即：软骨细胞、成骨细胞和破骨细胞。这些细胞在多种功能因子的调节下,使骨骼保持最佳的质量状态。体内内平衡机制的紊乱,尤其在老年时期,常会导致骨质的丢失或软骨损伤。为此,常采用药物方法来防止和减轻这些症状,然而,有一点常被忽略但却非常重要,那就是膳食调节的作用。本文主要讨论的是膳食多不饱和脂肪酸对骨细胞功能的调节作用。     

Analytical method for determination of nitric oxide in zebrafish larvae: toxicological and pharmacological applications

Zebrafish are currently used at various stages of the drug discovery process and can be a useful and cost-effective alternative to some mammalian models. Nitric oxide (NO) plays an important role in physiology of zebrafish. The availability of appropriate analytical techniques to quantify the NO is crucial for studying its role in physiological and pathological conditions. This work aimed at establishing a high-performance liquid chromatography method for determination of NO levels in zebrafish larvae. Attempts were also made to assess the normal levels of NO at the first days postfertilization and the possible changes under pathological conditions. The method validation was quantitatively evaluated in terms of sensitivity, specificity, precision, accuracy, linearity, and recovery. NO levels from zebrafish larvae at the first days postfertilization and larvae challenged to N(G)-nitro-L-arginine methyl ester, sodium nitroprusside, Escherichia coli lipopolysaccharide, and copper sulfate were analyzed. The samples were derivatized with 2,3-diaminonaphthalene, and fluorescence detection was used for the indirect determination of NO. The method showed a good performance for all validation parameters evaluated and was efficient to monitor changes in NO concentration under physiological and pathophysiological conditions. This method might represent a powerful tool to be applied in NO studies with zebrafish larvae.     

Techniques for pharmacological and toxicological studies with isolated hepatocyte suspensions.

Since its introduction in 1969, the high-yield preparation of isolated hepatocytes has become a frequently used tool for the study of hepatic uptake, excretion, metabolism and toxicity of drugs and other xenobiotics. Basic preparative methods are now firmly established involving perfusion of the liver with a balanced-saline solution containing collagenase. Satisfactory procedures are available for determining cell yields, for expressing cellular activities and for establishing optimal incubation conditions. Gross cellular damage can be detected by means of trypan blue or by measuring enzyme leakage, and damaged cells can be removed from the preparation. Specialized techniques are available for preparing hepatocyte couplets and suspensions enriched with periportal or perivenous hepatocytes. The isolated hepatocyte preparation is particularly convenient for the study of the kinetics of hepatic drug uptake and excretion because the cells can be rapidly separated from the incubation medium. Isolated liver cells have also proved valuable for investigating drug metabolism since they show many of the features of the intact liver. However, they also show important differences such as losses of membrane specialization, some degree of cell polarity and the capacity to form bile. The many consequences of the hepatic toxicity of xenobiotics including lipid peroxidation, free radical formation, glutathione depletion, and covalent binding to macromolecules are also readily studied with the isolated liver cell preparation. A particular advantage is the ease with which morphological changes as a result of drug exposure can be observed in isolated hepatocytes. However, it must be remembered that the isolation procedure inevitably introduces changes that may make the cells more susceptible than the normal liver to damage by xenobiotic agents. Despite its limitations, the isolated hepatocyte preparation is now firmly established in the armamentarium of the investigator examining the interaction of the liver with xenobiotics.     

Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects

Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.     

Hygienic and toxicological aspects of occupational and environmental exposure to beryllium

As the production of missile, nuclear devices and electronics grew and modern industrial technologies emerged the risk of the occupational exposure to beryllium has become increasingly common and widespread. The environmental burden of beryllium is also on the increase, not only as a result of emissions from plants producing and processing beryllium, or its alloys and compounds, but also from burning coal of higher beryllium content in some localities. This article discusses primarily the hygienic and toxicologic aspects of beryllium and its threat to human health. The following topics are included in this review: occurrence, production and uses of beryllium; its metabolism and experimental toxicology; clinical toxicology and pathogenesis of berylliosis; hygienic and epidemiologic aspects of berylliosis; berylliosis treatment and prevention. Berylliosis is here characterized as a disease combining clinical manifestations of pneumosclerosis, allergy to beryllium and, in its granulomatous form, autoimmune reactions. Importantly, the available technical means and measures can ensure that the both occupational and environmental exposure to beryllium can be kept below the established MAC values. If occasionally impossible, special preventive measures should be adopted. It is essential that all persons with allergy be prophylactically excluded from work at risk of exposure to beryllium.     

Hepatoprotective potential of selected medicinally important herbs: evidence from ethnomedicinal,toxicological and pharmacological evaluations

Phytochemistry Reviews - Medicinal herbs are nature’s gift to humanity, contributing crucially to the preservation, maintenance and improvement of our health. In order to explore the...     

Cotinus coggygria Scop.: An overview of its chemical constituents,pharmacological and toxicological potential

The Anacardiaceae Lindl. family comprises of many species which are used in nutrition and in traditional folk medicine for the treatment of several human diseases. Cotinus coggygria Scop. commonly known as “smoke tree”, is a commercial ornamental plant with high medicinal usages, belongs to the family Anacardiaceae. The present review provides a comprehensive report of empirical investigations on important pharmacological activities and phytochemical screening of essential oils and extracts. Relevant information was collected from scientific journals, books, and reports via library and electronic search using Medline, PubMed, Google Scholar, ScienceDirect, Web of Science, and Scopus. The plant has been extensively investigated in a broad range of studies to provide scientific evidence for folklore claims or to find new therapeutic uses. Numerous activities namely antioxidative, antibacterial, antifungal, antiviral, anticancer, antigenotoxic, hepatoprotective and anti-inflammatory have been demonstrated for all parts of these plants by in vivo and in vitro studies. Essential oils and extracts showed various pharmacological and biological properties which make them an effective remedy for various kinds of illnesses. Considering data from the literature, it could be demonstrated that C. coggygria possesses diverse bioactive properties and immense utilization in medicine, health care, cosmetics and as health supplements.