Dietary flavonoids: Nano delivery and nanoparticles for cancer therapy.

Application of nanotechnologies to cancer therapy might increase solubility and/or bioavailability of bioactive compounds of natural or synthetic origin and offers other potential benefits in cancer therapy, including selective targeting. In the present review we aim to evaluate in vivo studies on the anticancer activity of nanoparticles (NPs) obtained from food-derived flavonoids. From a systematic search a total of 60 studies were identified. Most of the studies involved the flavanol epigallocatechin-3-O-gallate and the flavonol quercetin, in both delivery and co-delivery (with anti-cancer drugs) systems. Moreover, some studies investigated the effects of other flavonoids, such as anthocyanins aglycones anthocyanidins, flavanones, flavones and isoflavonoids. NPs inhibited tumor growth in both xenograft and chemical-induced animal models of cancerogenesis. Encapsulation improved bioavailability and/or reduced toxicity of both flavonoids and/or co-delivered drugs, such as doxorubicin, docetaxel, paclitaxel, honokiol and vincristine. Moreover, flavonoids have been successfully applied in molecular targeted nanosystems. Selectivity for cancer cells involves pH- and/or reactive oxygen species-mediated mechanisms. Furthermore, flavonoids are good candidates as drug delivery for anticancer drugs in green synthesis systems. In conclusion, although human studies are needed, NPs obtained from food-derived flavonoids have promising anticancer effects in vivo.

Camellia sinensis in asymptomatic hyperuricemia: A meta-analysis of tea or tea extract effects on uric acid levels.

Flavanols of Camellia sinensis exhibit uric acid (UA) lowering effect, through the modulation of both xanthine oxidase and urate excretion. In order to investigate the potential benefit of Camellia Sinenis products in asymptomatic hyperuricemia, a meta-analysis of long-term Randomized Controlled Trials (RCT) with tea or tea extract has been conducted. From 20 human intervention studies selected only 5 RCT (13 interventions) were suitable for meta-analysis (n = 472). The current "normal" range set for hyperuricemia fails to identify patients with potential metabolic disorders. Therefore on the basis of the literature data, we fixed cut-off limits for UA baseline levels of 4.5 mg/dl for women, 6.1 mg/dl for men, and 5.5 mg/dl for studies involving mixed populations. Statistically significant effects were not found, but subgroup analysis revealed that the Pooled Estimate effect was different in subjects with baseline levels under [MD (95% CI): 0.1078 (-0.0528 to 0.2684)] and over the cut-off [MD (95% CI): -0.0239 (0.3311 to 0.2833)]. However, due to the low number of RCT and to the lack of data on bioavailability, it is difficult to draw any firm conclusion and more studies are needed to establish if tea flavanols could be useful in asymptomatic hyperuricemia treatment.

Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 µg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. SIGNIFICANCE STATEMENT: Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.

Plasma total antioxidant capacity and peroxidation biomarkers in psoriasis.

Systemic biomarkers of oxidative stress can be relevant for assessment of psoriasis severity, for prediction of the outcome of therapy and of the development of comorbidities. In this review we aimed to evaluate the relationship between plasma total antioxidant capacity (TAC) and peroxidation biomarkers, as well as their association with dyslipidemia and systemic inflammation in psoriasis. The review of 59 case-control comparisons (from 41 studies) and 17 interventions (from 13 studies) suggests that peroxidation markers are more sensitive than TAC in the evaluation of oxidative stress in psoriasis. Although few studies investigated the effect of treatment on oxidative stress, it seems that biological drugs could be the better choice in the treatment of psoriasis. However, considering the limitations of TAC and plasma peroxidation markers, this review suggests that new methods should be developed in order to evaluate systemic oxidative stress in psoriasis.

Green Tea and Bone Marrow Transplantation: From Antioxidant Activity to Enzymatic and Multidrug-resistance Modulation.

Epigallocatechin-3-gallate (EGCG), the main flavonoid of green tea (GT), could play an active role in the prevention of oxidative-stress-related diseases, such as hematologic malignancies. Some effects of EGCG are not imputable to antioxidant activity, but involve modulation of antioxidant enzymes and uric acid (UA) levels. The latter is the major factor responsible of the plasma non-enzymatic antioxidant capacity (NEAC). However, hyperuricemia is a frequent clinical feature caused by tumor lysis syndrome or cyclosporine side effects, both before and after bone marrow transplantation (BMT). Besides this, food-drug interactions could be associated with GT consumption and could have clinical implications. The molecular mechanisms involved in the redox and drug metabolizing/transporting pathways were discussed, with particular reference to the potential role of GT and EGCG in BMT. Moreover, on reviewing data on NEAC, isoprostanes, uric acid, and various enzymes from human studies on GT, its extract, or EGCG, an increase in NEAC, without effect on isoprostanes, and contrasting results on UA and enzymes were observed. Currently, few and contrasting available evidences suggest caution for GT consumption in BMT patients and more studies are needed to better understand the potential impact of EGCG on oxidative stress and metabolizing/transporting systems.

Effects of red wine on postprandial stress: potential implication in non-alcoholic fatty liver disease development.

INTRODUCTION: Red wine consumption is considered to be protective against oxidative stress. Diet strongly influences non-alcoholic fatty liver disease, which is associated with oxidative stress and is considered the hepatic manifestation of the metabolic syndrome. METHODS: We reviewed the available evidence that investigated the effects of red wine on the postprandial-induced metabolic and oxidative stress in humans. RESULTS: After red wine consumption with meal, despite the improvement in non-enzymatic antioxidant capacity and lipoperoxidation markers, the influence of confounding factors such as uric acid should be taken into account. Both uric acid and triglycerides increases, induced by ethanol, could cause liver damage. On the other hand, further researches are required in order to understand the meaning of the induction of antioxidant enzymes by red wine and red wine polyphenols in the context of non-alcoholic fatty liver disease. CONCLUSION: In conclusion, inconsistent and contrasting findings exist regarding the potential benefits of red wine consumption against postprandial stress.

Interference of flavonoids with fluorescent intracellular probes: methodological implications in the evaluation of the oxidative burst by flow cytometry.

The evaluation of oxidative burst is particularly relevant in many pathological and subclinical conditions. Flow cytometry provides quick and accurate measures of the reactive oxygen species production by leukocytes in most situations. However, spurious results, related to probes' efflux may be observed in several instances. Many factors affect the evaluation of the oxidative burst with fluorescent probes that require intracellular deacetylation and could be substrate of the multidrug resistance proteins (MDR). After discussing the implications of the efflux of fluorophores in the normalization strategies in flow cytometry assays, we have pointed out the possible interference of flavonoids with fluorescet probes' staining and signal. We have also reviewed the results from human intervention studies regarding the evaluation of oxidative burst with these probes. In vitro, at concentrations close to post-ingestion circulating levels, some flavonoids and their metabolites could interfere with probes' staining and fluorescence signal through different mechanisms, such as the inhibition of esterases, the modulation of the MDR-mediate efflux of probe and the inhibition of the oxidation of probe. These effects may explain the contrasting results obtained by human intervention studies. Finally, also inflammatory state or the use of drugs substrate of MDR proteins could affect the evaluation of the oxidative burst with intracellular probes.

Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention?

The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment.

CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors.

Cocaine exposure triggers molecular events that lead to long-lasting changes in brain structure and function. These changes can lead to the development of persistent and robust behavioral adaptations that characterize addiction. Recent evidence suggests the regulation of transcription via chromatin modification, such as histone acetylation, has an important role in the development of addictive behavior. Histone acetylation is regulated by histone acetyltransferases (HATs), which acetylate histones and promote transcription, and histone deacetylases (HDACs), which remove acetyl groups and silence transcription. Studies have demonstrated that HDACs may negatively regulate cocaine-induced behaviors, but very little is known about the role of specific HATs in long-lasting drug-induced plasticity. The histone acetyltransferase CREB-binding protein (CBP) mediates transcriptional activation by recruiting basal transcription machinery and acetylating histones. CBP is a critically important chromatin-modifying enzyme involved in regulating gene expression required for long-term plasticity and memory. However, the role of CBP in cocaine-induced behaviors remains largely unknown. We examined the role of CBP in drug-induced plasticity using CBP-FLOX genetically modified mice in combination with adeno-associated virus expressing Cre-recombinase to generate focal homozygous deletions of Cbp in the nucleus accumbens (NAc). A complete loss of CBP in NAc neurons results in decreased histone acetylation and significantly altered c-fos expression in response to cocaine. Furthermore, the deletion of CBP in the NAc correlates with significant impairments in cocaine sensitivity and context-cocaine associated memory. This is the first study to demonstrate a definitive role for CBP in modulating gene expression that may subserve drug-seeking behaviors.

Biphasic regulation of the acute µ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum.

The cloning of the opioid-receptor-like receptor (ORL-1) and the identification of the orphaninFQ/nociceptin (OFQ/N) as its endogenous agonist has revealed a new G-protein-coupled receptor signalling system. The structural and functional homology of ORL-1 to the opioid receptor systems has posed a number of challenges in the understanding the often competing physiological responses elicited by these G-protein-coupled receptors. We had previously shown that in guinea pig ileum (GPI), the acute µ-withdrawal response is under the inhibitory control of several systems. Specifically, we found that the exposure to a µ-opioid receptor agonist activates indirectly the κ-opioid, the A(1)-adenosine and the cannabinoid CB(1) systems, that in turn inhibit the withdrawal response. The indirect activation of these systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated whether the ORL-1 system is also involved in the regulation of the acute µ-withdrawal response. Interestingly, we found that in GPI preparation, the ORL-1 system is not indirectly activated by the µ-opioid receptor stimulation, but instead the system is able by itself to directly regulate the acute µ-withdrawal response. Moreover, we have demonstrated that the ORL-1 system behaves both as anti-opioid or opioid-like system based on the level of activation. The same behaviour has also been observed in presence of CCk-8. Furthermore, in GPI, the existence of an endogenous tone of the ORL-1 system has been demonstrated. We concluded that the ORL-1 system acts as a neuromodulatory system, whose action is strictly related to the modulation of excitatory neurotrasmitters released in GPI enteric nervous system.

Propofol enhances memory formation via an interaction with the endocannabinoid system.

BACKGROUND: Propofol is associated with postoperative mood alterations and induces a higher incidence of dreaming compared with other general anesthetics. These effects might be mediated by propofol's inhibitory action on fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid anandamide. Because propofol is also associated with a higher incidence of traumatic memories from perioperative awareness and intensive care unit treatment and the endocannabinoid system is involved in regulating memory consolidation of emotional experiences, the authors investigated whether propofol, at anesthetic doses, modulates memory consolidation via an activation of the endocannabinoid system. METHODS: Male Sprague-Dawley rats were trained on an inhibitory avoidance task in which they received an inescapable foot shock upon entering the dark compartment of the apparatus. Drugs were administered intraperitoneally immediately or 30, 90, or 180 min after training. On the retention test 48 h later, the latency to reenter the dark compartment was recorded and taken as a measure of memory retention. RESULTS: The anesthetic doses of propofol administered after training significantly increased latencies of 48-h inhibitory avoidance performance (483.4 ± 181.3, 432.89 ± 214.06, 300 and 350 mg/kg, respectively; mean ± SD) compared with the corresponding vehicle group (325.33 ± 221.22, mean ± SD), which is indicative of stronger memory consolidation in propofol treated rats. Administration of a nonimpairing dose of the cannabinoid receptor antagonist rimonabant blocked the memory enhancement induced by propofol (123.39 ± 133.10, mean ± SD). Delayed administration of propofol 90 and 180 min after training or immediate posttraining administration of the benzodiazepine midazolam or the barbiturate pentobarbital did not significantly alter retention. CONCLUSIONS: These findings indicate that propofol, in contrast to other commonly used sedatives, enhances emotional memory consolidation when administered immediately after a stressful event by enhancing endocannabinoid signaling.

Modulation of anxiety through blockade of anandamide hydrolysis.

The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.

Dietary Habits and Musculoskeletal Pain in Statin and Red Yeast Rice Users: A Pilot Study.

(1) Background: Diet and statins are commonly used to treat high cholesterol (CHOL) levels. (2) Aim: To compare adherence to Mediterranean diet (Med-D), orthorexia nervosa (ON), and musculoskeletal pain in individuals in treatment with statins metabolized by CYP3A4, not metabolized by CYP3A4 or red yeast rice (RYR, containing monacolin K: MON-K). (3) Methods: starting from 80 individuals, after the exclusion of those with other causes of possible pain, 56 individuals were selected and divided into three groups according to the type of statin (CYP3A4, NO-CYP3A4 and MON-K). Adherence to the Med-D was evaluated with the MEDScore and a sub-score was calculated for fruit and vegetables consumption (MEDScore-FV). ON and musculoskeletal pain were assessed with the ORTO-15 and with the Nordic Musculoskeletal questionnaires, respectively. A retrospective analysis of CHOL decrease after treatment was conducted. (4) Results: CHOL levels were lower in CYP3A4 and NO-CYP3A4 after treatment (182.4 ± 6.3 and 177.0 ± 7.8 mg/dL, respectively), compared with MON-K (204.2 ± 7.1 mg/dL, p < 0.05). MON-K and CYP3A4 groups had a high prevalence of reported knee pain (33.3% and 18.8%, respectively) than NO-CYP3A4 group (0%, p < 0.05). A high percentage of individuals in MON-K take supplements and nutraceuticals (87.5%), whereas MEDScore-FV was higher in CYP3A4 (9.4 ± 0.2) compared to NO-CYP3A4 (7.6 ± 0.5, p < 0.05). (5) Conclusions: This study suggests that individuals receiving treatment with statins and RYR should be monitored from the perspective of plant foods' consumption and nutraceutical use, to prevent musculoskeletal pain.

Cannabinoid CB1 receptor elevation of intracellular calcium in neuroblastoma SH-SY5Y cells: interactions with muscarinic and delta-opioid receptors.

Although coupled to G(i/o) proteins, cannabinoid CB(1) receptors can also activate intracellular Ca(2+) ([Ca(2+)](i)) accumulation through not fully understood mechanisms. We report that in, human neuroblastoma SH-SY5Y cells, CB(1) activation with the specific agonist arachidonoylchloroethanolamide (ACEA), weakly elevates [Ca(2+)](i) and that this effect, when using low (1-100 nM) concentrations of ACEA, is enhanced by the previous activation of G(q/11)-coupled M(3) muscarinic receptors with carbachol, dose-dependently and up to approximately 8-fold. A similar behaviour was also observed with carbachol and the G(i/o)-coupled delta-opioid receptor. Furthermore, stimulation of CB(1) receptors produced a concentration-dependent leftward shift of the elevation of [Ca(2+)](i) by delta-opioid receptors. These stimulatory effects were variedly attenuated by selective antagonists of each receptor, pertussis toxin, inhibitors of phospholipase C (U73122 and D609), and, when assessed in the presence of extracellular Ca(2+), by the block of voltage-activated calcium channels. Cholera toxin only slightly inhibited the G(q/11)-G(i/o)-mediated cross-talk, but induced a stronger inhibition of the G(i/o)-G(i/o)-mediated interaction. These findings suggest that activation of M(3) muscarinic receptors might produce a qualitative alteration of the signaling associated with G(i/o)-coupled receptors, and that sequential activation of CB(1) and delta-opioid receptors, both coupled to G(i/o), produces instead synergistic effects on [Ca(2+)](i) elevation.

Entomophagy: A Narrative Review on Nutritional Value, Safety, Cultural Acceptance and A Focus on the Role of Food Neophobia in Italy.

In recent years, the consumption of insects, or entomophagy, has produced an increasing interest amongst scientists and ecologists as a potential source of animal protein. Eating insects is also interesting in terms of low greenhouse gas emissions and low land use. In contrast to tropical countries, where most of the 2000 edible insect species are traditionally consumed, the concept of eating insects is still new to Western culture and diet. Culture and eating habits exert a great influence on what is considered edible in the Mediterranean area, especially in Italy, where the preservation of culinary traditions is a predominant factor affecting dietary behaviour. The purpose of this narrative paper is to provide an overview of the main topics related to entomophagy. The introduction presents some information about the nutrient content and safety aspects, the second part summarises the cultural acceptance of insect in the world, while the role of food neophobia on the intention to consume insects in Italy is focused on in part three. The discussion displays important viewpoints of previously published studies and based on these perspectives it can be concluded that the Italian diet is still clearly influenced by local tradition. In conclusion, in order to introduce insects into the Italian diet, psychological motivation has to be enhanced.

Diurnal trajectories of salivary cortisol and α-amylase and psychological profiles in patients with central serous chorioretinopathy.

It has been hypothesized that the occurrence of central serous chorioretinopathy (CSC) might be associated with stress. Therefore, our purpose was to investigate the diurnal trajectories of salivary cortisol and α-amylase (α-Amy) - markers of hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary (SAM) system activity, respectively - and psychological profiles in idiopathic acute CSC. This cross-sectional observational case-control study, which included self-reported psychometric questionnaires, was formally approved by the Ethics Committee. Written informed consent was obtained from all participants. Home diurnal saliva collection was scheduled at several timepoints: at awakening, 30 and 60 min later, and at approximately 13:00 h and 20:00 h. Twenty consecutive male subjects with first-episode CSC attending the outpatient clinic of the Retina Medical Service at the Bietti Foundation were enrolled in the study. Twenty age-matched subjects were recruited as controls. After their initial enrollment, 3 subjects per group were excluded. The production of cortisol and α-Amy and the scores on the negative subscale of the Positive/Negative Affect Schedule, the Daily Hassles and Stress Scale and the Beck Depression Inventory were higher in the CSC group than in the control group. To estimate the diurnal trends in the production of salivary cortisol and α-Amy, an equation was derived for each group of the study population. The equations describing the interpolated regression lines gave salivary cortisol and salivary α-Amy slopes that were determined to be significantly different by Student's t-test (cortisol: t = 3.533, p < .001; α-Amy: t = 2.382, p = .018). Furthermore, the area under the curve with respect to the ground (AUCG) was calculated to summarize repeated salivary biomarker measurements from 07:00 h to 08:00 h for assessment of the cortisol awakening response (CAR) and the α-Amy awakening response (AR). The diurnal cortisol AUCG and diurnal α-Amy AUCG were calculated from 07:00 h to 20:00 h. The CAR AUCG values of the CSC patients were significantly higher than those of the controls. No differences between the two groups were detected for the α-Amy AR AUCG. The present study adds novel information to the growing body of data suggesting that abnormal diurnal activity of the HPA axis and the SAM system is associated with CSC in susceptible individuals, providing ophthalmologists with a new chronobiological approach for these patients.

Investigating the Hypothesis of Stress System Dysregulation as a Risk Factor for Central Serous Chorioretinopathy: A Literature Mini-Review.

Background: This mini-review addressed the question "what do we know about the association between the dysregulation of stress systems (HPA axis and SAM) and the onset and prognosis of CSC in adult populations?" Methods: The literature mini-review was conducted through electronic searches using the PubMed, Web of Science, and Scopus databases. All published human and animal studies with both observational and experimental designs from 1966 to October 2018 were included. Results: Our search identified 229 reports, of which 32 articles were ultimately identified to be reviewed in this paper. Among these key articles, twenty-three were related to exogenous and/or endogenous high glucocorticoids as risk factors for CSC, seven were related to Type-A behavior and chronic psychological distress as risk factors for idiopathic CSC, and two were related to stress-induced animal models of CSC. Nineteen out of twenty-three studies in the first group reported a consistent association between high circulating corticosteroids and the onset and prognosis of CSC. Six out of seven studies in the second group reported a consistent association between stress-induced allostatic (over)load and the appearance of more- or less-severe CSC disorders, assuming that elevated circulating steroids may constitute a kind of risk factor for the eye through dysregulation of the HPA axis. All the selected studies reported HPA axis dysregulation as a possible common factor to explain the association between high circulating corticosteroids and CSC. In contrast, the involvement of the SAM system is only indirectly taken into consideration through the PA and HR measures and/or plasma and 24-h urinary catecholamine levels. Therefore, information regarding the involvement of SAM system dysregulation in the onset and prognosis of CSC is lacking. This observation is particularly relevant in view of the fact that animal models of CSC in monkeys are primarily induced by adrenergic hypertonia and that the course of experimental CSC is not further exacerbated by the administration of corticosteroids.

Neutrophil-to-Lymphocyte Ratio, Mediterranean Diet, and Bone Health in Coeliac Disease Patients: A Pilot Study.

Neutrophil-to-lymphocyte ratio (NLR) has been proposed as a bone loss index in postmenopausal women and as a marker of inflammation in coeliac patients. The aims of this work were to evaluate the effect of gluten-free diet (GFD) on NLR retrospectively and study the relationship between NLR and Mediterranean diet adherence and selected food groups (fruits, vegetables, red meat, potatoes, and unrefined and refined cereals). Adult individuals (n = 50), who had been on a strict GFD by at least 6 months, were recruited. The degree of adherence to the Mediterranean diet was calculated with two different scores: the Mediterranean Diet Score (MDS-14), assessed through the validated 14-item questionnaire of the PREDIMED study, and the MEDScore (Score-55) proposed by Panagiotakos. The latter includes the consumption of unrefined cereals (UC). High percentages of osteopenia and osteoporosis were found within the recruited subjects, who furnished the reports of bone mineral density (BMD), in particular in postmenopausal (Post-M) women. Recent NLR was higher in subjects with osteoporosis compared to osteopenia and normal BMD. However, retrospective analysis showed both increase and decrease in NLR after GFD, with no significant differences between Marsh grade, anemia, and BMD status. Moreover, premenopausal previous pregnancy (Pre-MPP) and Post-M had higher NLR at diagnosis compared to Men and premenopausal (Pre-M), but higher differences were observed in recent NLR between Pre-MPP and Men only. Chocolate consumption was associated with lower recent NLR, whereas the latter was correlated with Score-55, but not with MDS-14. Moreover, refined cereal consumption was correlated with recent NLR. Although large prospective studies are needed in order to clarify the relationship between UC and NLR in coeliac patients, in this pilot study, we have investigated for the first time the relationship between NLR, dietary habit, and osteoporosis in coeliac disease.

Anandamide modulation of circadian- and stress-dependent effects on rat short-term memory.

The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges. CB1 receptors are highly expressed within cortico-limbic brain areas, where they modulate stress effects on memory processes. Glucocorticoid and endocannabinoid release is influenced by circadian rhythm. Here, we investigated how different stress intensities immediately after encoding influence rat short-term memory in an object recognition task, whether the effects depend on circadian rhythm and if exogenous augmentation of anandamide levels could restore any observed impairment. Two separate cohorts of male adult Sprague-Dawley rats were tested at two different times of the day, morning (inactivity phase) or afternoon (before the onset of the activity phase) in an object recognition task. The anandamide hydrolysis inhibitor URB597 was intraperitoneally administered immediately after the training trial. Rats were thereafter subjected to a forced swim stress under low or high stress conditions and tested 1 h after training. Control rats underwent the same experimental procedure except for the forced swim stress (no stress). We further investigated whether URB597 administration might modulate corticosterone release in rats subjected to the different stress conditions, both in the morning or afternoon. The low stressor elevated plasma corticosterone levels and impaired 1 h recognition memory performance when animals were tested in the morning. Exposure to the higher stress condition elevated plasma corticosterone levels and impaired memory performance, independently of the testing time. These findings show that stress impairing effects on short-term recognition memory are dependent on the intensity of stress and circadian rhythm. URB597 (0.3 mg kg-1) rescued the altered memory performance and decreased corticosterone levels in all the impaired groups yet leaving memory unaltered in the non-impaired groups.