Is there a link between depression, neurochemical asymmetry and cardiovascular function?

Although at present depression is one of the most disabling disorders in our social environment, the understanding of its pathogenesis and the resources for its treatment are still unsatisfactory. The importance of brain asymmetry in the pathogenesis of disorders in brain function, including mood disorders such as depression, is a highly unexplored, sometimes underrated, and even ignored topic. It is important to note that the basal and pathological functional lateralization must have an underlying neurochemical substrate. It is also necessary to indicate that the brain asymmetry extends to a neurovisceral integration whose behavior may also be lateralized. One of the most studied axis from the functional point of view is the brain-heart connection, in whose operation there are observations that suggest an asymmetric behavior in basal conditions that is modified by central and peripheral changes, as well as by pharmacological treatments. There are evidences that connect cardiovascular function, neurochemical asymmetries, and depression. A deep understanding of the bilateral behavior of the brain following pathophysiological changes in blood pressure as well as pharmacologically induced, can provide us with therapeutic suggestions for the treatment of depression. In this article, we analyze remarkable results of some representative selected contributions, with which we discuss our proposal on the relationship between hypertension, depression and neurochemical asymmetry.

Asymmetrical influence of a standard light/dark cycle and constant light conditions on the alanyl-aminopeptidase activity of the left and right retinas in adult male rats.

The retina acts as an independent clock informing the central pacemaker, the suprachiasmatic nucleus, under environmental light conditions, with consequences of such inputs for the central and peripheral nervous system. Differences in the behavior of the left and right retinas depending on environmental light conditions may influence the information projected to the brain hemispheres. The retina possesses neuropeptides that act as neurotransmitters or neuromodulators. Alanyl-aminopeptidase (AlaAP, EC 3.4.11.2) activity regulates some of these neuropeptides and therefore reflects their function. We analyzed AlaAP activity in the left and right retinas of adult male rats at successive time points under standard (12/12 h light/dark cycle) and nonstandard (constant light) conditions. AlaAP activity was measured fluorometrically using alanyl-beta-naphthylamide as the substrate. Under standard conditions, there were no differences in the left or right retina between time points, with the left retina predominating, particularly in the light period. In contrast, under constant light, no left versus right differences were observed, but significant differences between time points appeared. In comparison with standard conditions, constant conditions led to significantly higher AlaAP activity. Considering all the left retina data in comparison with all the right retina data, no correlation was found between the left and right retinas under standard conditions, but a significant positive correlation was observed under constant light. These results demonstrate an asymmetrical response of retinal AlaAP activity to changes in environmental light conditions, which may affect the functions in which the substrates of AlaAP are involved and the information projected to the brain hemispheres.

Angiotensin II, dopamine and nitric oxide. An asymmetrical neurovisceral interaction between brain and plasma to regulate blood pressure.

Vital functions, such as blood pressure, are regulated within a framework of neurovisceral integration in which various factors are involved under normal conditions maintaining a delicate balance. Imbalance of any of these factors can lead to various pathologies. Blood pressure control is the result of the balanced action of central and peripheral factors that increase or decrease. Special attention for blood pressure control was put on the neurovisceral interaction between Angiotensin II and the enzymes that regulate its activity as well as on nitric oxide and dopamine. Several studies have shown that such interaction is asymmetrically organized. These studies suggest that the neuronal activity related to the production of nitric oxide in plasma is also lateralized and, consequently, changes in plasma nitric oxide influence neuronal function. This observation provides a new aspect revealing the complexity of the blood pressure regulation and, undoubtedly, makes such study more motivating as it may affect the approach for treatment.

Cystinyl and pyroglutamyl-beta-naphthylamide hydrolyzing activities are modified coordinately between hypothalamus, liver and plasma depending on the thyroid status of adult male rats.

The hypothalamus determinates metabolic processes in liver through endocrine and autonomic control. Hypothalamic neuropeptides, such as thyrotropin releasing hormone or vasopressin, have been involved in liver metabolism. The thyroid status influences metabolic processes including liver metabolism in modulating those hypothalamic peptides whose functional status is regulated in part by aminopeptidase activities. In order to obtain data for a possible coordinated interaction between hypothalamus, plasma and liver, of some aminopeptidase activities that may partially reflect the hydrolysis of those peptides, pyroglutamyl- (pGluAP) and cystinyl- (CysAP) beta-naphthylamide hydrolyzing activities were determined fluorimetrically, both in their soluble and membrane-bound forms, in eu- hypo- and hyperthyroid adult male rats. Hyperthyroidism and hypothyroidism were induced with daily subcutaneous injections of tetraiodothyronine (300 µg/kg/day) or with 0.03% methimazole in drinking water for 6 weeks. Results demonstrated significant changes depending on the type of enzyme and the thyroid status. The most striking changes were observed for CysAP in liver where it was reduced in hypothyroidism and increased in hyperthyroidism. Significant intra- and inter-tissue correlations were observed. While there were positive inter-tissue correlations between liver, plasma and hypothalamus in eu-and hypothyroid rats, a negative correlation between hypothalamus and liver was observed in hyperthyroidism. These results suggest the influence of thyroid hormones and an interactive role for these activities in the control of liver metabolism. The present data also suggest a role for CysAP and pGluAP activities in liver function linked to their activities in hypothalamus.

Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights.

The cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized.

Effect of virgin and refined olive oil consumption on gut microbiota. Comparison to butter.

There is increasing evidence of the health benefits of olive oil consumption in the diet. Some authors have studied the effect of high fat/high calorie diets and have detected changes on the microbiota. However, these studies are mainly based on saturated fats. Here we present a study on the specific effect on gut bacterial populations of extra virgin olive oil, rich in monounsaturated fatty acids and phenolic compounds, in comparison to refined olive oil, rich in monounsaturated fatty acids but low in phenolic compounds, and to butter, rich in saturated fatty acids and cholesterol. Four groups of animals were studied: one group of mice received a standard chow diet, and the other received three high fat diets, rich in extra virgin olive oil, refined olive oil or butter. Evolution of symbiont population in feces was studied using culture-dependent and culture-independent methods. In the latter, the V3 region of 16S rDNA was amplified and separated by denaturing gradient gel electrophoresis; followed by sequencing of the most representative bands. Culture-dependent studies and comparison of the different DGGE profiles throughout the experiment demonstrated that different dietary fats had different effects on gut microbial composition. Butter-induced changes in the microbial counts resembled those previously described in obese individuals. Interestingly, a different behavior between extra virgin and refined olive oil was also observed, extra virgin olive oil being most different from butter. To our knowledge, no studies have analyzed gut microbiota depending on diets with different fatty acid saturations including different types of olive oil. This may offer new data supporting the benefits for health of extra virgin olive oil, so important in the Mediterranean diet.

The profile of fatty acids in frontal cortex of rats depends on the type of fat used in the diet and correlates with neuropeptidase activities.

The kind of fat in the diet modifies the profile of fatty acids in brain and also affects aminopeptidase activities in tissues. Although modifications in brain fatty acids, neurotransmitters, or enzymes due to dietary fat composition have been reported, no direct relationship has yet been described between specific brain fatty acid changes and neuropeptide metabolism following the fat composition of the diet. We investigated the lipid profile and some neuropeptidase activities in the frontal cortex of adult male rats after a period in which diets were supplemented with fatty acids differing in their degrees of saturation such as fish oil (rich in polyunsaturated fatty acids, PUFAs), olive oil (rich in monounsaturated fatty acids, MUFAs), and coconut oil (rich in saturated fatty acids, SAFAs). It is observed that the diet composition affects fatty acid distribution in the brain. Although there is no change of global aminopeptidase/neuropeptidase, their activities in the brain correlate positively or negatively with the dietary fat composition. It is hypothesized that fatty acid in the diet modifies membrane fluidity, peptidases tertiary structure, and therefore, the availability and function of neuropeptides. The present results support the notion that cognitive functions may be modulated depending on the type of fat used in the diet.

Safety and potential risks of enterococci isolated from traditional fermented capers.

A collection of 17 enterococci isolates obtained from fermentations of capers (the fruits of Capparis sp.) were investigated for incidence of known virulence determinants, antibiotic resistance and production of biogenic amines. Molecular identification revealed the presence of Enterococcus faecium (nine isolates), Enterococcus faecalis (4), E. avium (3) and Enterococcus casseliflavus/flavescens (1). Alpha-haemolytic activity was detected in two E. avium and one E. faecalis isolates, and beta-haemolytic activity was detected in E. casseliflavus/flavescens. The haemolytic component cylB was detected by PCR amplification in three non-haemolytic isolates and in E. casseliflavus/flavescens. The collagen adhesin ace gene and the endocarditis associated antigen gene efaA(fm) were detected in two isolates each. Genes encoding sex pheromone precursors (cpd, cob, ccf) were detected in E. faecalis and E. casseliflavus/flavescens. Other presumed virulence genes (agg, gelE, cylM, cylA and efaA(fs)) were not detected. All isolates were resistant to rifampicin, erythromycin and ciprofloxacin, and some were also resistant to quinupristin/dalfopristin, tetracycline, levofloxacin, gentamicin and streptomycin. Vancomycin resistance was not detected. Tyrosine decarboxylation was detected in all E. faecium isolates. Given the high resistance of enterococci to environmental conditions, and their implication in opportunistic infections, the incidence of potential virulent enterococci in foods (especially those of a higher risk-like home-made foods) should be carefully studied.

Inhibition of Bacillus licheniformis LMG 19409 from ropy cider by enterocin AS-48.

AIMS: To determine the activity of enterocin AS-48 against ropy-forming Bacillus licheniformis from cider. METHODS AND RESULTS: Enterocin AS-48 was tested on B. licheniformis LMG 19409 from ropy cider in MRS-G broth, fresh-made apple juice and in two commercial apple ciders (A and B). Bacillus licheniformis was rapidly inactivated in MRS-G by 0.5 microg ml(-1)AS-48 and in fresh-made apple juice by 3 microg ml(-1). Concentration-dependent inactivation of this bacterium in two commercial apple ciders (A and B) stored at 4, 15 and 30 degrees C for 15 days was also demonstrated. Counts from heat-activated endospores in cider A plus AS-48 decreased very slowly. Application of combined treatments of heat (95 degrees C) and enterocin AS-48 reduced the time required to achieved complete inactivation of intact spores in cider A to 4 min for 6 microg ml(-1) and to 1 min for 12 microg ml(-1). D and z values also decreased as the bacteriocin concentration increased. CONCLUSION: Enterocin AS-48 can inhibit ropy-forming B. licheniformis in apple cider and increase the heat sensitivity of spores. SIGNIFICANCE AND IMPACT OF THE STUDY: Results from this study support the potential use of enterocin AS-48 to control B. licheniformis in apple cider.

Application of the broad-spectrum bacteriocin enterocin AS-48 to inhibit Bacillus coagulans in canned fruit and vegetable foods.

The enterococcal bacteriocin (enterocin) AS-48 is a broad-spectrum cyclic peptide. Enterocin AS-48 was tested against Bacillus coagulans in three vegetable canned foods: tomato paste (pH 4.64), syrup from canned peaches (pH 3.97), and juice from canned pineapple (pH 3.65). When vegetative cells of B. coagulans CECT (Spanish Type Culture Collection) 12 were inoculated in tomato paste supplemented with 6 microg/ml AS-48 and stored at different temperatures, viable cell counts were reduced by approximately 2.37 (4 degrees C), 4.3 (22 degrees C) and 3.0 (37 degrees C) log units within 24 h storage. After 15-days storage, no viable cells were detected in any sample. Strain B. coagulans CECT 561 showed a poor survival in tomato paste, but surviving cells were also killed by AS-48. The bacteriocin was also very active against B. coagulans CECT 12 vegetative cells in juice from canned pineapple stored at 22 degrees C, and slightly less active in syrup from canned peaches. In food samples supplemented with 1.5% lactic acid, enterocin AS-48 (6 microg/ml) rapidly reduced viable counts of vegetative cells below detection limits within 24 h storage. Addition of glucose and sucrose (10% and 20%) significantly increased bacteriocin activity against vegetative cells of B. coagulans CECT 12. Enterocin AS-48 had no significant effect on B. coagulans CECT 12 spores. However, the combined application of AS-48 and heat (80-95 degrees C for 5 min) significantly increased the effect of thermal treatments on spores.

Bacteriocin production, plasmid content and plasmid location of enterocin P structural gene in enterococci isolated from food sources.

AIMS: To characterize bacteriocin production, antimicrobial spectrum and plasmid content in bacteriocinogenic enterococci from foods. METHODS AND RESULTS: Bacteriocinogenic Enterococcus faecium (14 isolates) and Enterococcus faecalis (three isolates) showed two different patterns of bacteriocin production in liquid broth: exponential-phase and stationary-phase production. Bacteriocin concentrates from all enterococci were inactivated by trypsin, but seldom by heat (100-117 degrees C), extremes of pH (2.0 to 9.0) or reducing agents (such as dithiothreitol). All bacteriocin concentrates were active against Listeria innocua and Listeria monocytogenes, and most were also active against many Ent. faecalis and Ent. faecium isolates. Enterococci clustered in three main groups according to their plasmid content (which included plasmids from 2.0 to 53 kb). Several isolates from different foods showed almost identical plasmid profiles. The enterocin P structural gene (entP) was detected by hybridization on plasmids of c. 19, 26 and/or 35-38 kb. CONCLUSIONS: Enterococci from food show different patterns of bacteriocin production and different plasmid content in spite of carrying similar bacteriocin-encoding genes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information on the diversity of bacteriocinogenic enterococci from food sources carrying apparently similar enterocin genes.

Control of Alicyclobacillus acidoterrestris in fruit juices by enterocin AS-48.

Alicyclobacillus acidoterrestris is a spoilage-causing bacterium in fruit juices. Control of this bacterium by enterocin AS-48 from Enterococcus faecalis A-48-32 is described. Enterocin AS-48 was active against one A. acidocaldarius and three strains of A. acidoterrestris tested. In natural orange and apple juices incubated at 37 degrees C, vegetative cells of A. acidoterrestris DSMZ 2,498 were inactivated by enterocin AS-48 (2.5 microg/ml) and no growth was observed in 14 days. In commercial fruit juices added of AS-48 (2.5 microg/ml) and inoculated with vegetative cells or with endospores of strain DSMZ 2,498, no viable cells were detected during 90 days of incubation at temperatures of 37 degrees C, 15 degrees C or 4 degrees C, except for apple, peach and grapefruit juices inoculated with vegetative cells and incubated at 37 degrees C which were protected efficiently for up to 60 days. Remarkably, in all commercial fruit juices tested, no viable cells were detected as early as 15 min after incubation with the bacteriocin. Endospores incubated for a very short time (1 min) with increasing bacteriocin concentrations were inactivated by 2.5 microg/ml AS-48. Electron microscopy examination of vegetative cells and endospores treated with enterocin AS-48 revealed substantial cell damage and bacterial lysis as well as disorganization of endospore structure.

Antimicrobial activity of enterocin EJ97 against 'Bacillus macroides/Bacillus maroccanus' isolated from zucchini purée.

AIMS: Activity of the bacteriocin EJ97 produced by Enterococcus faecalis EJ97 against strains of 'Bacillus macroides/B. maroccanus' isolated from spoiled zucchini purée was investigated. METHODS AND RESULTS: The influence of several factors like bacteriocin concentration, incubation temperature, pH, growth medium and chemical perservatives on bacteriocin activity was investigated. Enterocin EJ97 [2 arbitrary units (AU) per millilitre] had a marked bactericidal effect on strain INRA P53-2 after 4 h of incubation at 37 degrees C, 24 h at 15 degrees C or 48 h at 4 degrees C. Activity was markedly reduced at pH values of 5.0 and 9.0, but was potentiated by sodium nitrite, sodium benzoate, sodium lactate and sodium tripolyphosphate. Inhibition of strain INRA P53-2 in a commercial vegetable purée required a 10-fold higher bacteriocin concentration. Strain EJ97 was able to grow and produce bacteriocin on vegetable purée, but no inhibition of strain INRA P53-2 was detected. CONCLUSIONS: The concentration-dependent bactericidal activity of enterocin EJ97 against strain INRA P53-2 was higher at 37 degrees C and neutral pH, and was potentiated by chemical preservatives. Although enterocin EJ97 was less active in vegetable purée, the concentrations providing bactericidal activity in this food matrix are practical for commercial use. SIGNIFICANCE AND IMPACT OF THE STUDY: Enterocin EJ97 may have a potential for use in the prevention of food spoilage caused by 'B. macroides/B. maroccanus'.

mlpB, a gene encoding a new lipoprotein in Myxococcus xanthus.

AIMS: To search for and study the genes involved in the regulation of phosphate in the soil developmental bacterium Myxococcus xanthus. METHODS AND RESULTS: The mlpB gene encoding a 149 residue polypeptide was identified while screening for genes with products related to phosphate metabolism. The amino terminal 19 residues of MlpB encode a typical prokaryotic signal sequence with a putative lipoprotein cleavage site. CONCLUSIONS: In this study, a new myxobacterial putative lipoprotein is reported. The data suggest that MlpB may be involved in the secretion of phosphate-related proteins. SIGNIFICANCE AND IMPACT OF THE STUDY: Soil bacteria have complex regulatory systems for using inorganic phosphate. This nutrient is limiting in the environment, and has a critical importance for growth and in the initiation of differentiation for developmental bacteria. A number of proteins are involved in all these processes, including membrane lipoproteins, which are being increasingly studied in M. xanthus.

MlpA, a lipoprotein required for normal development of Myxococcus xanthus.

The mlpA gene encoding a 236-residue polypeptide has been identified immediately downstream of the oar gene of Myxococcus xanthus (M. Martinez-Canamero, J. Munoz-Dorado, E. Farez-Vidal, M. Inouye, and S. Inouye, J. Bacteriol. 175:4756-4763, 1993). The amino-terminal 21 residues of MlpA encode a typical prokaryotic signal sequence with a putative lipoprotein cleavage site. When expressed in Escherichia coli in the presence of [2-3H]glycerol, 3H-labeled MlpA had a molecular mass of 33 kDa and was found to be associated with the membrane fraction. Globomycin, an inhibitor of signal peptidase II, caused a shift in the mobility of E. coli-expressed MlpA to 35 kDa. Subsequently, a mlpA disruption strain (oar+) was constructed and found to have delayed fruiting body formation (by approximately 36 h), with significantly larger fruiting bodies being produced compared with those of the wild-type strain. Nevertheless, spore yields for the two strains were identical after 120 h of development. These data indicate that MlpA, the lipoprotein identified in M. xanthus, is required for normal fruiting body formation.

Oar, a 115-kilodalton membrane protein required for development of Myxococcus xanthus.

Myxococcus xanthus is a developmental gram-negative bacterium which forms multicellular fruiting bodies upon nutrient starvation. This bacterium was found to contain a 115-kDa membrane protein which separated with the inner membrane fraction by sucrose density gradient centrifugation. The gene for this protein was cloned, and its DNA sequence was determined. The deduced amino acid sequence consists of 1,061 residues. This protein contains a putative signal sequence and many short segments, found scattered throughout the entire protein, that have sequence similarities with OmpA, a major outer membrane protein of Escherichia coli. Thus, the gene was designated oar (OmpA-related protein). A second open reading frame was found 36 bases downstream of the oar termination codon. This open reading frame encodes a protein of 236 residues and contains a putative lipoprotein signal sequence. An aor disruption mutation (delta oar) showed no effect on vegetative growth but caused abnormal morphogenesis during development and reduced myxospore formation. When examined with a light microscope, delta oar cells were unable to aggregate on developmental agar, indicating that Oar is required for cellular adhesiveness during development.

Deoxyribonuclease activities in Myxococcus coralloides D.

Myxococcus coralloides D produced cell-bound deoxyribonucleases (DNases) during the exponential phase of growth in liquid medium. DNase activity was much higher than that detected in other myxobacterial strains and was fractionated into three different peaks by filtration through Sephadex G-200. The DNases were named G, M and P. The optimum temperatures were 37 degrees C, 33 degrees C and 25 degrees C respectively, although high activities were recorded over the temperature range 20-45 degrees C. The pH range of high activity was between 6.0 and 9.0, with an optimum for each DNase at 8.0. DNases M and P were strongly inhibited by low concentrations of NaCl, but activity of DNase G was less affected by NaCl. The three activities required divalent metal ions as cofactors (especially Mg2+ and Mn2+); however, other metal ions (Fe2+, Ni2+, Zn2+) were inhibitors. The molecular weights were estimated by gel filtration chromatography and SDS-PAGE as 44 kDa (DNase G), 49 kDa (DNase M) and 39 kDa (DNase P).