Omega-3 polyunsaturated fatty acids and ventricular fibrillation: the possible involvement of eicosanoids

Increased dietary omega-3 polyunsaturated fatty acids (PUFAs) reduce the incidence and severity of ventricular fibrillation (VF) in laboratory animals subjected to partial ischaemia and reduce the risk of cardiac arrest in humans after myocardial infarction. In whole animals there is considerable evidence which suggests that incorporation of these fatty acids into cardiac membrane phospholipids influences the production of a variety of eicosanoids having opposing arrhythmogenic or anti-arrhythmogenic properties, and that the balance of these actions is shifted in favour of an anti-arrhythmogenic state by feeding fish oil dietary supplements rich in omega-3 PUFA. However, differences in eicosanoid biosynthesis between species, between tissues of the same species and even between different intracellular sites within cells of the same tissue could influence experimental outcomes. The importance of further studies with the most appropriate whole animal models or tissues is emphasized, as is the difference between the structural integrity of cardiac muscle and cardiomyocytes in vitro.     

Age-dependent effect of static magnetic field on brain tissue hydration

Age-dependent effect of Static Magnetic Field (SMF) on rats in a condition of active and inactive Na⁺/K⁺ pump was studied for comparison of brain tissues hydration state changes and magnetic sensitivity. Influence of 15?min 0, 2 Tesla (T) SMF on brain tissue hydration of three aged groups of male albino rats was studied. Tyrode’s physiological solution and 10^?4?M ouabain was used for intraperitoneal injections. For animal immobilization, the liquid nitrogen was used and the definition of tissue water content was performed by tissue drying method. Initial water content in brain tissues of young animals is significantly higher than in those of adult and aged ones. SMF exposure leads to decrease of water content in brain tissues of young animals and increase in brain tissues of adult and aged ones. In case of ouabain-poisoned animals, SMF gives reversal effects on brain tissue’s hydration both in young and aged animals, while no significant effect on adults is observed. It is suggested that initial state of tissue hydration could play a crucial role in animal age-dependent magnetic sensitivity and the main reason for this could be age-dependent dysfunction of Na⁺/K⁺ pump.     

Systemic overexpression of antizyme 1 in mouse reduces ornithine decarboxylase activity without major changes in tissue polyamine homeostasis

Polyamines, spermidine, spermine and their precursor putrescine, are ubiquitous cell components essential for normal cell growth. Increased polyamine levels and enhanced biosynthesis have been associated with malignant transformation and tumor formation, and thus, the polyamines have been considered to be a meaningful target to cancer therapies. However, clinical cancer treatment trials using inhibitors of polyamine synthesis have been unsuccessful probably due to compensatory uptake of polyamines from extracellular sources. The antizyme proteins regulate both polyamine biosynthesis and transport, and thus, the antizymes could provide an efficient approach to control cellular proliferation compared to the mere inhibition of biosynthesis. To define the role of antizymes in proliferative processes associated with the whole animal, we have generated transgenic mice overexpressing mouse antizyme 1 gene under its own regulatory sequences. Antizyme 1 protein was abundantly expressed in various organs and the expressed antizyme protein was functional as ornithine decarboxylase activity was significantly reduced in all tissues analyzed. However, antizyme 1 overexpression caused only minor changes in tissue polyamine levels demonstrating the challenges in using the “antizyme approach” to deplete polyamines in a living animal. Neither were there any changes in cellular proliferation in the proliferative tissues of transgenic animals. Interestingly though, there was occurrence of abnormally high level of apoptosis in the non-proliferating part of the colon epithelia. Otherwise, the transgenic founder mice appeared healthy and out of seven founders six were fertile. However, none of the founders could transmit the transgene suggesting that the antizyme 1 overexpression may be deleterious to transgenic gametes.     

A new human pathology with visceral accumulation of long-chain n-alkanes; tissue distribution of the stored compounds and pathophysiological hypotheses

This report deals with a new human disorder characterized by the accumulation of plant long-chain n-alkanes in viscera of a human patient. Lipid analysis of tissues from an adult male after sudden death (affected with diffuse visceral granuloma containing lipophilic crystallized material) showed the presence of abnormal compounds identified as long-chain n-alkanes with 29 (n-nonacosane), 31 (n-hentriacontane) and 33 carbons (n-tritriacontane). Study of n-alkane distribution in patient tissues showed a major accumulation in lumbo-aortic lymph nodes, adrenal glands, lung (the highest levels were found in lung granulomas) and liver; significantly lower amounts were detected in myocardium and kidney, whereas no detectable level was found in brain. On the basis of the structural composition and of the tissue distribution of the accumulated n-alkanes, their dietary (plant) origin and the pathophysiological mechanism of the storage are discussed.     

Measurement of carnitine biosynthesis enzyme activities by tandem mass spectrometry: differences between the mouse and the rat

Although the mouse frequently is used to study metabolism and deficiencies therein, little is known about carnitine biosynthesis in this animal. To this point, only laborious procedures have been described to measure the activity of carnitine biosynthesis enzymes using subcellular fractions as the enzyme source. We developed two simple tandem mass spectrometry-based methods to determine the activity of three carnitine biosynthesis enzymes (6-N-trimethyllysine dioxygenase, 4-trimethylaminobutyraldehyde dehydrogenase, and 4-trimethylaminobutyric acid dioxygenase) in total homogenates that can be prepared from frozen tissue. The new assays were used to characterize these enzymes in mouse liver homogenate. Because carnitine biosynthesis has been studied extensively in the rat, we compared the mouse tissue distribution of carnitine biosynthesis enzyme activities and levels of the biosynthesis metabolites with those in the rat to determine which tissues contribute to carnitine biosynthesis in these species. Surprisingly, large differences in enzyme activities were found between the rat and the mouse, whereas carnitine biosynthesis metabolite levels were very similar in both species, possibly due to the different kinetic properties of the first enzyme of carnitine biosynthesis. Also, muscle carnitine levels were found to vary considerably between these two species, suggesting that there is a metabolic dissimilarity between the mouse and the rat.     

Oxygen and the connective tissues.

Avascular connective tissues (cartilage, discs, cornea) change with maturation and aging, particularly in large animals, where diffusion paths are longest. It is suggested that the changes in such tissues are responses to increasing difficulties in obtaining oxygen. Two almost identical structural polymers are made in these tissues: chondroitin sulphate, which requires large amounts of oxygen for biosynthesis and keratan sulphate, which requires relatively little. The observed balance of these polymers in the tissue is proposed to depend on the control of biosynthesis by the ambient oxygen tension, and/or selective breakdown.     

Expression of CA III in rodent models of obesity

To achieve a better understanding of the biochemical basis of obesity, we have undertaken comparative analyses of adipose tissue of lean and obese mice. By two-dimensional gel analysis, carbonic anhydrase-III (CA III) has been identified as a major constituent of murine adipose tissue. Quantitative comparisons of CA III protein and mRNA levels indicate that this enzyme is expressed at lower levels in adipose tissue from animals that were either genetically obese or had experimentally induced obesity compared to levels in the corresponding lean controls. This decrease in CA III expression was unique to adipose tissue, since other CA III-containing organs and tissues did not show a change when lean and obese animals were compared. Additionally, levels of CA III in adipose tissue from obese animals responded to acute changes in energy balance of the animal. These results are discussed in light of possible metabolic roles for CA III.     

Variants of effective coefficients of oxygen diffusion in the tissues of rats of different age in relation to alimentary factors

A method intended to record and analyze kinetics of decrease in the initial part of current on platinum diffusion oxygen sensor has been used to estimate efficient oxygen diffusivities (DO2) to the working surface of sensor in the muscular tissue and in tissue of the subcutaneous area of posterior extremities in anesthetized rats of different age in control and after addition of plant fats with various content of saturated fatty acids to their usual ration. It is shown that average value of DO2 in the muscular tissue of young animals is higher than in the muscle of adult animals. In adult animals DO2 of the subcutaneous area is higher than that of the muscle. There are no significant differences of coefficients in the examined tissues of young animals. Addition of plant fats to the basal food ration causes differently directed changes of DO2 in tissues of young and adult animals. These changes depend on the tissue of animal and saturation of fats. A problem on the existence of translation transfer of substances parallel with diffusion one in live tissues is under discussion.     

Beta-1,4-galactosylation of N-glycans is a complex process

Most beta-1,4-galactosyltransferase (beta-1,4-GalT)-knockout mice die after birth. Although several defects were found transiently in these animals, the primary cause of death is obscure. Not only beta-1,4-linked galactose residues on N-glycans, but also beta-1, 4-GalT activities were found in some of the tissues. Recently, five human genes which encode beta-1,4-GalTs have been cloned, and the possible presence of such novel beta-1,4-GalTs in mice is considered to bring about survival of the mutant animal beyond birth. In order to understand the semi-lethal nature of this animal, it is inevitable to clarify how individual novel beta-1,4-GalTs are involved in the biosynthesis of glycoconjugates based on their acceptor-substrate specificities.     

Patterning the C. elegans embryo: moving beyond the cell lineage.

The Caenorhabditis elegans embryo undergoes a series of stereotyped cell cleavages that generates the organs and tissues necessary for an animal to survive. Here we review two models of embryonic patterning, one that is lineage-based, and one that focuses on domains of organ and tissue precursors. Our evolving view of C. elegans embryogenesis suggests that this animal develops by mechanisms that are qualitatively similar to those used by other animals.     

Inflammation reduces physiological tissue tolerance in the development of work-related musculoskeletal disorders.

Work-related musculoskeletal disorders (MSDs) cause substantial worker discomfort, disability and loss of productivity. Due to the difficulty in analyzing the tissues of patients in the early stages of work-related MSD, there is controversy concerning the pathomechanisms of the development of these disorders. The pathophysiology of work-related MSD can be studied more easily in animal models. The purpose of this review is to relate theories of the development of tissue injury due to repeated motion to findings of recent investigations in animals that address the role of the inflammatory response in propagating tissue injury and contributing to chronic or recurring tissue injury. These tissue effects are related to behavioral indicators of discomfort and movement dysfunction with the aim of clarifying key time points for specific intervention approaches. The results from animal models of MSD are discussed in the light of findings in patients, whose tissues are examined at a much later phase of MSD development. Finally, a conceptual model of the potentially negative impact of inflammation on tissue tolerance is proposed along with suggestions for future research directions.     

Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography

A high-performance liquid chromatographic method has been developed for the simultaneous determination of the new anti-psychotic risperidone and its major metabolite 9-hydroxyrisperidone in plasma, urine and animal tissues. The alkalinized plasma samples were extracted with ethyl acetate and further purified prior to reversed-phase chromatography with ultraviolet detection at 280 nm. The method could also be applied to urine samples and animal tissue homogenates. Quantification limits were 2 ng/ml for plasma and urine and 10 ng/g for animal tissue. The method was applied to pharmacokinetic studies in experimental animals, human volunteers and patients.     

Species and tissue distribution of the 4S carcinogen binding protein and its possible role in cytochrome P-450 induction

A carcinogen binding protein (CBP) that is implicated in controlling the expression of rat cytochrome P-450c which is closely associated with aryl hydrocarbon hydroxylase (AHH) was examined in hepatic and extrahepatic tissues of the neonatal and adult New Zealand White (NZW) rabbits, the hepatic tissue of the BALB/cJ and DBA/2J mice, Brown Norway rat, Golden Syrian hamster and Hartley guinea pig. These animals and tissues were examined in order to determine whether there was a correlation of CBP levels and the reported presence or absence of inducibility of AHH in these tissues. The CBP was found in hepatic and extrahepatic tissue of the NZW rabbit and the hepatic tissues of all animals except the Hartley guinea pig. The Hartley guinea pig may provide a useful animal with which to further examine the role of CBP in cytochrome induction. Since the CBP is not a tissue specific protein and because it is found in both neonatal and adult NZW rabbit tissue, the data suggests that the CBP is not the limiting factor in the tissue specific induction of cytochromes nor in developmentally controlled induction of cytochromes previously reported in the rabbit.     

An epithelial tissue in Dictyostelium challenges the traditional origin of metazoan multicellularity

We hypothesize that aspects of animal multicellularity originated before the divergence of metazoans from fungi and social amoebae. Polarized epithelial tissues are a defining feature of metazoans and contribute to the diversity of animal body plans. The recent finding of a polarized epithelium in the non-metazoan social amoeba Dictyostelium discoideum demonstrates that epithelial tissue is not a unique feature of metazoans, and challenges the traditional paradigm that multicellularity evolved independently in social amoebae and metazoans. An alternative view, presented here, is that the common ancestor of social amoebae, fungi, and animals spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. Some descendants of this ancestor retained multicellularity, while others reverted to unicellularity. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution. Editor's suggested further reading in BioEssays Searching for Eve: Basal metazoans and the evolution of multicellular complexity Abstract.     

Cholesterol modification of proteins

The demonstration over 30 years ago that inhibitors of cholesterol biosynthesis disrupt animal development suggested an intriguing connection between fundamental cellular metabolic processes and the more global processes of embryonic tissue patterning. Adding a new dimension to this relationship is the more recent finding that the Hedgehog family of tissue patterning factors are covalently modified by cholesterol. Here we review the mechanism of the Hedgehog autoprocessing reaction that results in this modification, and compare this reaction to that undergone by other autoprocessing proteins. We also discuss the biological consequences of cholesterol modification, in particular the use of cholesterol as a molecular handle in the spatial deployment of the protein signal in developing tissues. Finally, the developmental consequences of chemical and genetic disruption of cholesterol homeostasis are summarized, along with the potential importance of cholesterol-rich lipid rafts in production of and response to the Hh signal.     

Nitric Oxide Synthase Regulates Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration

Mechanisms that coordinate growth during development are essential for producing animals with proper organ proportion. Here we describe a pathway through which tissues communicate to coordinate growth. During Drosophila melanogaster larval development, damage to imaginal discs activates a regeneration checkpoint through expression of Dilp8. This both produces a delay in developmental timing and slows the growth of undamaged tissues, coordinating regeneration of the damaged tissue with developmental progression and overall growth. Here we demonstrate that Dilp8-dependent growth coordination between regenerating and undamaged tissues, but not developmental delay, requires the activity of nitric oxide synthase (NOS) in the prothoracic gland. NOS limits the growth of undamaged tissues by reducing ecdysone biosynthesis, a requirement for imaginal disc growth during both the regenerative checkpoint and normal development. Therefore, NOS activity in the prothoracic gland coordinates tissue growth through regulation of endocrine signals.     

Increased expression of peripheral benzodiazepine receptor (PBR) in dimethylbenz[a]anthracene-induced mammary tumors in rats

Expression of peripheral benzodiazepine receptors (PBR) has been found in every tissue examined; however, it is most abundant in steroid-producing tissues. Although the primary function of PBR is the regulation of steroidogenesis, its existence in nonsteroidogenic tissues as well as in other cellular compartments including the nucleus suggests that there may be other roles for PBR. Our laboratory reported earlier a significant increase of PBR density in the nucleus of DMBA-induced malignant submandibular glands of rats, suggesting a role of PBR in nuclear events of peripheral tissues. Since then numerous studies have demonstrated the abundance of PBR in tumors. Numerous studies implicate a role for cholesterol in the mechanisms underlying cell proliferation and cancer progression. Based on studies with a battery of human breast cancer cell lines and several human tissue biopsies, Hardwick et al. suggested that PBR expression, nuclear localization, and PBR-mediated cholesterol transport into the nucleus are involved in human breast cancer cell proliferation and aggressive phenotype expression. The purpose of the present study is to confirm this hypothesis by developing an animal breast cancer model and correlating the above events with the breast cancer. Weanling rats were maintained on a diet containing animal protein (casein) for 30 days and then a single dose of DMBA in sesame oil (80 mg/kg) was administered by gavage to the animals. Control animals received the vehicle only. After 122 days of DMBA administration, the animals were sacrificed. All tumors were detected by palpation. B_max of PBRs was 52.6% and 128.4% higher in the non-aggressive and aggressive cancer tissues, respectively, than that in normal tissues. Cholesterol uptake into isolated nuclei was found to be higher in both non-aggressive and aggressive tumor breast tissue than that in control tissue. There was also corresponding increase in B_max of PBRs in the nucleus of cancer tissues. Furthermore, the nuclear nucleoside triphosphatase (NTPase) activity was found to be higher in aggressive tumor tissues than that in non-aggressive tumor tissues. In conclusion, these data suggest that PBR ligand binding, and PBR-mediated cholesterol transport into the nucleus may be involved in the development of mammary gland adenocarcinoma, thus participating in the advancement of the disease.     

Insulin resistance at the crossroads of metabolic syndrome: Systemic analysis using microarrays

Recently, it has been suggested that insulin resistance is a better predictor of metabolic syndrome than obesity. Numerous studies have been conducted to identify insulin resistance susceptibility genes in various model systems. This review focuses on recent findings in microarray analyses, which have indicated that (i) in the liver, genes involved in lipid synthesis and gluconeogenesis are increased in an animal model of insulin resistance that leads into liver steatosis and hyperglycemia; (ii) in adipose tissues, genes involved in fatty acid synthesis and adipogenesis are down-regulated both in insulin-resistant humans and in animals; and (iii) in muscle, overall gene expression, including genes involved in fatty acid oxidation and biosynthesis, is either decreased or unresponsive compared to that of insulin-sensitive control human subjects or animals. Considering the multifaceted effects of insulin resistance in various tissues, aiming at multi-targets rather than a single target will be a more promising strategy for the prevention or treatment of insulin resistance.