Effects of Functional and Nutraceutical Foods in the Context of the Mediterranean Diet in Patients Diagnosed with Breast Cancer.

Several studies report that breast cancer survivors (BCS) tend to have a poor diet, as fruit, vegetable, and legume consumption is often reduced, resulting in a decreased intake of nutraceuticals. Moreover, weight gain has been commonly described among BCS during treatment, increasing recurrence rate and mortality. Improving lifestyle and nutrition after the diagnosis of BC may have important benefits on patients' general health and on specific clinical outcomes. The Mediterranean diet (MD), known for its multiple beneficial effects on health, can be considered a nutritional pool comprising several nutraceuticals: bioactive compounds and foods with anti-inflammatory and antioxidant effects. Recent scientific advances have led to the identification of nutraceuticals that could amplify the benefits of the MD and favorably influence gene expression in these patients. Nutraceuticals could have beneficial effects in the postdiagnostic phase of BC, including helping to mitigate the adverse effects of chemotherapy and radiotherapy. Moreover, the MD could be a valid and easy-to-follow option for managing excess weight. The aim of this narrative review is to evaluate the recent scientific literature on the possible beneficial effects of consuming functional and nutraceutical foods in the framework of MD in BCS.

Perioperative Nutritional Management in Enhanced Recovery after Bariatric Surgery.

Obesity is a crucial health problem because it leads to several chronic diseases with an increased risk of mortality and it is very hard to reverse with conventional treatment including changes in lifestyle and pharmacotherapy. Bariatric surgery (BS), comprising a range of various surgical procedures that modify the digestive tract favouring weight loss, is considered the most effective medical intervention to counteract severe obesity, especially in the presence of metabolic comorbidities. The Enhanced Recovery After Bariatric Surgery (ERABS) protocols include a set of recommendations that can be applied before and after BS. The primary aim of ERABS protocols is to facilitate and expedite the recovery process while enhancing the overall effectiveness of bariatric procedures. ERABS protocols include indications about preoperative fasting as well as on how to feed the patient on the day of the intervention, and how to nourish and hydrate in the days after BS. This narrative review examines the application, the feasibility and the efficacy of ERABS protocols applied to the field of nutrition. We found that ERABS protocols, in particular not fasting the patient before the surgery, are often not correctly applied for reasons that are not evidence-based. Furthermore, we identified some gaps in the research about some practises that could be implemented in the presence of additional evidence.

Mitochondrial Aging and Senolytic Natural Products with Protective Potential.

Living organisms do not disregard the laws of thermodynamics and must therefore consume energy for their survival. In this way, cellular energy exchanges, which aim above all at the production of ATP, a fundamental molecule used by the cell for its metabolisms, favor the formation of waste products that, if not properly disposed of, can contribute to cellular aging and damage. Numerous genes have been linked to aging, with some favoring it (gerontogenes) and others blocking it (longevity pathways). Animal model studies have shown that calorie restriction (CR) may promote longevity pathways, but given the difficult application of CR in humans, research is investigating the use of CR-mimetic substances capable of producing the same effect. These include some phytonutrients such as oleuropein, hydroxytyrosol, epigallo-catechin-gallate, fisetin, quercetin, and curcumin and minerals such as magnesium and selenium. Some of them also have senolytic effects, which promote the apoptosis of defective cells that accumulate over the years (senescent cells) and disrupt normal metabolism. In this article, we review the properties of these natural elements that can promote a longer and healthier life.

Weight Maintenance after Dietary Weight Loss: Systematic Review and Meta-Analysis on the Effectiveness of Behavioural Intensive Intervention.

After a low-calorie diet, only 25% of patients succeed in maintaining the result of weight loss for a long time. This systematic review and meta-analysis aims to explore whether patients undergoing intensive intervention during the maintenance phase have a greater preservation of the weight achieved during the previous slimming phase than controls. A bibliographic search was conducted using PubMed, Scopus, and Cochrane databases for clinical trials and randomised, controlled trials investigating the role of choice in weight-loss-maintenance strategies. Only studies with a follow-up of at least 12 months were considered. A total of eight studies, for a total of 1454 patients, was identified, each comparing a group that followed a more intensive protocol to a control group. Our metanalysis highlighted that an intensive approach even in the maintenance phase could be important to ensure greater success in the phase following the weight-loss period. However, it should be pointed out that the improvement was not so different from the trend of the respective controls, with a non-statistically significant mean difference of the effect size (0.087; 95% CI -0.016 to 0.190 p = 0.098). This finding, along with the observation of a weight regain in half of the selected studies, suggests this is a long work that has to be started within the weight-loss phase and reinforced during the maintenance phase. The problem of weight control in patients with obesity should be understood as a process of education to a healthy lifestyle and a balanced diet to be integrated in the context of a multidisciplinary approach.

Repeated exposure to JWH-018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlates.

BACKGROUND AND PURPOSE: Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in the NAc shell. Here, we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopaminergic transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype. EXPERIMENTAL APPROACH: Rats were administered with JWH-018 once a day for 14 consecutive days. We then performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation. KEY RESULTS: Repeated JWH-018 exposure (i) induced anxious and aversive behaviours, transitory attentional deficits, and withdrawal signs; (ii) decreased spontaneous activity and number of dopamine neurons in the VTA; and (iii) reduced stimulation of dopaminergic transmission in the NAc shell while potentiating that in the NAc core, in response to acute JWH-018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to a first chocolate exposure; conversely, after a second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB1 receptors (mPFC, NAc shell and core). CONCLUSION AND IMPLICATIONS: Repeated exposure to JWH-018 may provide a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex.

Previous results indicate that dopamine (DA) release in the medial prefrontal cortex (mPFC) is modified by α2 adrenoceptor- but not D2 DA receptor- agonists and antagonists, suggesting that DA measured by microdialysis in the mPFC originates from noradrenergic terminals. Accordingly, noradrenergic denervation was found to prevent α2-receptor-mediated rise and fall of extracellular DA induced by atipamezole and clonidine, respectively, in the mPFC. The present study was aimed to determine whether DA released by dopaminergic terminals in the mPFC is not detected by in vivo microdialysis because is readily taken up by norepinephrine transporter (NET). Accordingly, the D2-antagonist raclopride increased the electrical activity of DA neurons in the ventral tegmental area (VTA) and enhanced extracellular DOPAC but failed to modify DA in the mPFC. However, in rats whose NET was either inactivated by nisoxetine or eliminated by noradrenergic denervation, raclopride still elevated extracellular DOPAC and activated dopaminergic activity, but also increased DA. Conversely, the D2-receptor agonist quinpirole reduced DOPAC but failed to modify DA in the mPFC in control rats. However, in rats whose NET was eliminated by noradrenergic denervation or inhibited by locally perfused nisoxetine, quinpirole maintained its ability to reduce DOPAC but acquired that of reducing DA. Moreover, raclopride and quinpirole, when locally perfused into the mPFC of rats subjected to noradrenergic denervation, were able to increase and decrease, respectively, extracellular DA levels, while being ineffective in control rats. Transient inactivation of noradrenergic neurons by clonidine infusion into the locus coeruleus, a condition where NET is preserved, was found to reduce extracellular NE and DA in the mPFC, whereas noradrenergic denervation, a condition where NET is eliminated, almost totally depleted extracellular NE but increased DA. Both transient inactivation and denervation of noradrenergic neurons were found to reduce the number of spontaneously active DA neurons and their bursting activity in the VTA. The results indicate that DA released in the mPFC by dopaminergic terminals is not detected by microdialysis unless DA clearance from extracellular space is inactivated. They support the hypothesis that noradrenergic terminals are the main source of DA measured by microdialysis in the mPFC during physiologically relevant activities.

Noradrenergic terminals are the primary source of α2-adrenoceptor mediated dopamine release in the medial prefrontal cortex.

In various psychiatric disorders, deficits in dopaminergic activity in the prefrontal cortex (PFC) are implicated. Treatments involving selective augmentation of dopaminergic activity in the PFC primarily depend on the inhibition of α2-adrenoreceptors singly or in combination with the inhibition of the norepinephrine transporter (NET). We aimed to clarify the relative contribution of dopamine (DA) release from noradrenergic and dopaminergic terminals to DA output induced by blockade of α2-adrenoreceptors and NET. To this end, we assessed whether central noradrenergic denervation modified catecholamine output in the medial PFC (mPFC) of rats elicited by atipamezole (an α2-adrenoreceptor antagonist), nisoxetine (an NET inhibitor), or their combination. Intraventricular administration of anti-dopamine-beta-hydroxylase-saporin (aDBH) caused a loss of DBH-positive fibers in the mPFC and almost total depletion of tissue and extracellular NE level; however, it did not reduce tissue DA level but increased extracellular DA level by 70% in the mPFC. Because noradrenergic denervation should have caused a loss of NET and reduced NE level at α2-adrenoceptors, the actual effect of an aDBH-induced lesion on DA output elicited by blockade of α2-adrenoceptors and NET was evaluated by comparing denervated and control rats following blockade of α2-adrenoceptors and NET with atipamezole and nisoxetine, respectively. In the control rats, extracellular NE and DA levels increased by approximately 150% each with 3 mg/kg atipamezole; 450% and 230%, respectively, with 3 mg/kg nisoxetine; and 2100% and 600%, respectively, with combined atipamezole and nisoxetine. In the denervated rats, consistent with the loss of NET, nisoxetine failed to modify extracellular DA level, whereas atipamezole, despite the lack of NE-induced stimulation of α2-adrenoceptors, increased extracellular DA level by approximately 30%. Overall, these results suggest that atipamezole-induced DA release mainly originated from noradrenergic terminals, possibly through the inhibition of α2-autoreceptors. Furthermore, while systemic and local administration of the α2-adrenoceptor agonist clonidine into the mPFC of the controls rats reduced extracellular NE level by 80% and 60%, respectively, and extracellular DA level by 50% and 60%, respectively, it failed to reduce DA output in the denervated rats, consistent with the loss of α2-autoreceptors. To eliminate the possibility that denervation reduced DA release potential via the effects at dopaminergic terminals in the mPFC, the effect of systemic administration of the D2-DA antagonist raclopride (0.5 mg/kg IP) on DA output was analyzed. In the control rats, raclopride was found to be ineffective when administered alone, but it increased extracellular DA level by 380% following NET inhibition with nisoxetine. In the denervated rats, as expected due to the loss of NET, raclopride-alone or with nisoxetine-increased DA release to approximately the same level as that observed in the control rats after NET inhibition. Overall, these results suggest that noradrenergic terminals in the mPFC are the primary source of DA released by blockade of α2-adrenoreceptors and NET and that α2-autoreceptors, and not α2-heteroreceptors, mediate DA output induced by α2-adrenoceptor blockade.

Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

INTRODUCTION: Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. METHODS: Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. RESULTS: Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. CONCLUSIONS: This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.

Nitrergic system and plasmatic methylarginines: Evidence of their role in the perinatal programming of cardiovascular diseases.

Atherosclerosis, in turn preceded by endothelial dysfunction, underlies a series of important cardiovascular diseases. Reduced bioavailability of endothelial nitric oxide, by increasing vascular tone and promoting platelet aggregation, leukocyte adhesion, and smooth muscle cell proliferation, plays a key role in the onset of the majority of cardiovascular diseases. In addition, high blood levels of asymmetric dimethylarginine, a potent inhibitor of nitric oxide synthesis, are associated with future development of adverse cardiovascular events and cardiac death. Recent reports have demonstrated that another methylarginine, i.e., symmetric dimethylarginine, is also involved in the onset of endothelial dysfunction and hypertension. Almost a decade ago, prematurity at birth and intrauterine growth retardation were first associated with a potential negative influence on the cardiovascular apparatus, thus constituting risk factors or leading to early onset of cardiovascular diseases. This condition is referred to as cardiovascular perinatal programming. Accordingly, cardiovascular morbidity and mortality are higher among former preterm adults than in those born at term. The aim of this paper was to undertake a comprehensive literature review focusing on cellular and biochemical mechanisms resulting in both reduced nitric oxide bioavailability and increased methylarginine levels in subjects born preterm. Evidence of the involvement of these compounds in the perinatal programming of cardiovascular risk are also discussed.

Endodontic infection and endothelial dysfunction are associated with different mechanisms in men and women.

INTRODUCTION: To investigate the potential link between apical periodontitis (AP) and cardiovascular (CV) function, inflammation markers, endothelial flow reserve (EFR), and levels of asymmetrical dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase (NOS), were measured in young adults with AP aged 20-40 years of both sexes. METHODS: Forty men and 41 women (31 ± 5.71 years) free from periodontal disease, CV disease, and traditional CV risk factors were enrolled in the study. Twenty men and 21 women had AP; 40 healthy individuals matched for age, sex, and physical characteristics were also recruited as controls. All subjects underwent dental and complete physical examination, electrocardiography, conventional and tissue Doppler imaging echocardiography, and measurement of EFR. Interleukin (IL)-2, tumor necrosis factor alpha, reactive oxygen species (ROS), and ADMA were also assessed. Data were analyzed using the 2-tailed Student t test, the Pearson t test (or the Spearman t test for nonparametric variables), and multivariate linear regression analysis. RESULTS: Echocardiography excluded any morphologic and functional cardiac alteration in all the subjects studied. Patients with AP of both sexes showed a significant reduction in EFR (P < .05) and a significant increase in IL-2 (men: P < .01, women: P < .05), whereas ROS were increased significantly only in women (P < .05). ADMA levels were unchanged in women with AP, but they were significantly increased in men (P < .05). A significant direct correlation between ADMA and IL-2 (r = 0.67, P < .001) and an inverse correlation between ADMA and EFR (r = -0.42, P < .05) in men and a significant inverse correlation between ROS and EFR (r = -0.71, P < .01) in female patients were observed. CONCLUSIONS: The presence of chronic inflammation in young adults with AP may cause early endothelial dysfunction documented by the reduced EFR. AP in men may influence the metabolism of NOS, whereas in women it appears to implicate a more direct detrimental mechanism. This difference is sex dependent and may be attributable to the protective action of estrogen in women.

The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex.

The dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex.

Urinary NGAL and hematic ADMA levels: an early sign of cardio-renal syndrome in young adults born preterm?

BACKGROUND: Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. AIMS: (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. METHODS: Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 ± 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. RESULTS: Urinary NGAL levels were higher in ex- ELBW subjects compared to C (p < 0.05), as well as hematic ADMA concentrations (p < 0.05). A statistically significant correlation was found between urinary NGAL and ADMA (r = -0.60, p < 0.04). CONCLUSIONS: Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.

Prematurity and low weight at birth as new conditions predisposing to an increased cardiovascular risk.

Although the survival rate for preterm subjects has improved considerably, due to the progress in the field of perinatal medicine, preterm birth is frequently the cause underlying a series of notorious complications: morphological, neurological, ophthalmological, and renal alterations. In addition, it has recently been demonstrated how low gestational age and reduced foetal growth contribute towards an increased cardiovascular risk in preterm neonates. In fact, cardiovascular mortality is higher among former preterm adults than those born at term. This condition is referred to as cardiovascular perinatal programming. In the light of the above, an early, constant, and prolonged cardiological followup programme should be implemented in former preterm individuals. The aim of this paper was to perform a comprehensive literature review about two new emerging conditions predisposing to an increased cardiovascular risk: prematurity and low weight at birth.

NMDARs mediate the role of monoamine oxidase A in pathological aggression.

Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality.

Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex.

RATIONALE: Disulfiram efficacy in treatment of cocaine addiction is attributed to the inhibition of dopamine-ß-hydroxylase and reduction in brain noradrenaline (NA)/dopamine (DA) ratio. OBJECTIVES: Using microdialysis, we investigated if disulfiram causes DA release from noradrenergic terminals and modifies cocaine-induced DA release. RESULTS: Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei, while it markedly increased DA not only in mPF but also in the occipital cortex, despite its scanty dopaminergic afferences, and modestly increased DA in the accumbens and caudate nuclei, despite their dense dopaminergic innervation. Disulfiram-induced DA accumulation was reversed in both cortices by tetrodotoxin infusion and by systemic administration of the α(2)-adrenoceptor agonist clonidine, but was not modified by the α(2)-adrenoceptor antagonist RS 79948 or the D(2)-like agonist quinpirole. Disulfiram prevented cocaine-induced NA release in the mPF cortex and nucleus accumbens, potentiated cocaine-induced DA release in the mPF cortex but failed to modify cocaine effect in the nucleus accumbens. DA release induced by disulfiram-cocaine combination in the mPF cortex was prevented by clonidine but not by quinpirole. CONCLUSIONS: We suggested that disulfiram, by removing NA-mediated inhibitory control on noradrenergic terminals, causes an unrestrained cocaine-induced DA release from those terminals in the mPF cortex. In the accumbens and caudate nuclei, "allogenic" DA concentration might be clouded by DA originated from dopaminergic terminals. The possible role of "allogenic" DA in disulfiram ability to prevent stress-induced reinstatement of cocaine seeking is discussed.

Inhibition of 5α-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation.

Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25mg/kg, SC) and d-amphetamine (AMPH, 2.5mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10µg/1µl) and in the nucleus accumbens (NAc) shell and core (0.5µg/0.5µl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region.

Association of endodontic infection with detection of an initial lesion to the cardiovascular system.

INTRODUCTION: Dental infections might predispose toward the onset of cardiovascular disease (CVD). To date, only a few studies, yielding inconclusive findings, have investigated the potential correlation between apical periodontitis (AP) and CVD. The aim of this study (as the first part of a prospective study) was to evaluate, in the absence of CV risk factors, whether subjects with AP were more exposed to the pathogenetic indices of an atherosclerotic lesion. METHODS: Forty men between the ages of 20 and 40 years who were free from periodontal disease, CVD, and traditional CV risk factors were enrolled in the study; 20 subjects had AP, and 20 acted as controls. All subjects underwent dental examination and complete cardiac assessment: physical examination, electrocardiogram, conventional and tissue Doppler echocardiography, and measurement of endothelial flow reserve (EFR). The following laboratory parameters were tested: interleukins -1, -2, and -6 (IL-1, IL-2, IL-6), tumor necrosis factor alpha, and asymmetrical dimethylarginine (ADMA). Data were analyzed by using the 2-tailed Student's t test, Pearson t test (or Spearman t test for nonparametric variables), and multivariate linear regression analysis. RESULTS: Echocardiography revealed no abnormalities in any of the subjects studied. ADMA levels were inversely correlated with EFR (P < .05) and directly correlated with IL-2 (P < .001). Patients with AP presented with significantly greater blood concentrations of IL-1 (P < .05), IL-2 (P < .01), IL-6 (P < .05), and ADMA (P < .05) and a significant reduction of EFR (P < .05). CONCLUSIONS: Increased ADMA levels and their relationship with poor EFR and increased IL-2 might suggest the existence of an early endothelial dysfunction in young adults with AP.

Isolation rearing-induced reduction of brain 5α-reductase expression: relevance to dopaminergic impairments.

Isolation rearing (IR), a well-established rat model of early chronic psychosocial stress, engenders marked behavioral alterations related to changes of dopamine (DA) neurotransmission in cortical and subcortical brain regions. Stress-induced shifts in γ-aminobutyric acid (GABA)-ergic signaling have been implicated in the dysregulation of DA release. The neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone/AP), synthesized from progesterone by the action of the rate-limiting enzyme 5α-reductase (5AR), is a potent positive allosteric modulator of GABA(A) receptor function. Thus, alterations of 5AR activity/expression may impact upon DA neurotransmission. We studied the effects of IR on the 5AR expression/function and extracellular concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC). Immediately after weaning, male rats were subjected to either IR or social rearing (SR) conditions for 5-8 weeks. Compared to SR, IR rats exhibited significantly lower protein expression of 5AR isoforms (1 and 2) in both brain regions and reduced brain, but not plasma, content of AP and allotetrahydrodeoxycorticosterone, the 5α-reduced metabolite of deoxycorticosterone. IR-exposed rats also exhibited higher levels of DA and DOPAC in the NAcc shell, but not in mPFC, when compared to SR rats. The 5AR inhibitor finasteride (FIN, 100 mg/kg, i.p.) enhanced DA and DOPAC content in the NAcc shell of SR, but not IR rats. FIN, however, elicited equivalent increases in DA and DOPAC levels in the mPFC of both groups. These results show that IR induces changes in expression/activity of brain 5AR which, in a brain-region specific manner, may partially underlie the alterations in DA signaling induced by this manipulation. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Gating deficits in isolation-reared rats are correlated with alterations in protein expression in nucleus accumbens.

The isolation-rearing (IR) paradigm, consisting of the social deprivation for 6-9 weeks after weaning, induces a spectrum of aberrant behaviors in adult rats. Some of these alterations such as sensorimotor gating deficits are reminiscent of the dysfunctions observed in schizophrenia patients. Although gating impairments in IR rats have been linked to impairments in the cortico-mesolimbic system, the specific molecular mechanisms underlying this relation are unclear. To elucidate the neurochemical modifications underlying the gating disturbances exhibited by IR rats, we compared their pre-pulse inhibition (PPI) of the acoustic startle reflex with that of socially reared (SR) controls, and correlated this index to the results of proteomic analyses in prefrontal cortex and nucleus accumbens from both groups. As expected, IR rats exhibited significantly lower startle amplitude and PPI than their SR counterparts. Following behavioral testing, IR and SR rats were killed and protein expression profiles of their brain regions were examined using two-dimensional electrophoresis based proteomics. Image analysis in the Coomassie blue-stained gel revealed that three protein spots were differentially expressed in the nucleus accumbens of IR and SR rats. Mass spectrometry (matrix-assisted laser desorption ionization-time of flight and MS/MS) identified these spots as heat shock protein 60 (HSP60), alpha-synuclein (alpha-syn), and 14-3-3 protein zeta/delta. While accumbal levels of HSP60 was decreased in IR rats, alpha-syn and 14-3-3 proteins were significantly increased in IR in comparison with SR controls. Notably, these two last alterations were significantly correlated with different loudness intensity-specific PPI deficits in IR rats. In view of the role of these proteins in synaptic trafficking and dopaminergic regulation, these findings might provide a neurochemical foundation for the gating alterations and psychotic-like behaviors in IR rats.

Differential distribution of VGF-derived peptides in the adrenal medulla and evidence for their selective modulation.

While vg f gene knockout mice are hyperactive and hypermetabolic, surprisingly the TLQP-21 brain VGF peptide increased energy consumption, suggesting that opposing regulatory effects could be exerted by peptides alternatively cleaved from the VGF precursor. Using antisera to the VGF precursor C-terminus and three cleavage products, we revealed a distinct differential distribution in adrenal, certain peptides (VGF(422-430): PGH peptides) being found throughout bovine and swine medulla, while C-terminus and TLQP peptides were confined to adrenaline cells in the above species and in rat and C-terminally shortened forms (VGF(604-612): HVLL peptides) to nor-adrenaline cells. Random abattoir samples of bovine and swine adrenal contained 520+/-40 and 450+/-60 pmol/g (mean+/-s.e.m. respectively) of C-terminus peptides and similar or lower amounts of others. Upon gel chromatography, bona fide VGF precursor, approximately 7.5 and approximately 3.5 kDa forms were revealed by C-terminus assays, HVLL peptides being limited to small fragments. TLQP peptides included ~7.5 kDa form and peaks accounting for TLQP-21 and predicted TLQP-30 and TLQP-42. Low molecular weight (MW) PGH peptides were revealed, together with a high MW form possibly encompassing the VGF precursor N-terminus. In acutely stressed swine, a striking increase was seen for C-terminus and TLQP peptides, with no significant differences for PGH peptides. A similar response was found in rat TLQP peptides showing a major increase upon an acute swimming stress and 30 min thereafter. A differential processing of the VGF precursor encompassing many areas of its primary sequence and selective modulations of its derived peptides occur in adrenal medullary cells, possibly relevant to adaptive homeostatic responses.