Publications by authors named "Natalia Battista"

68 Publications

Dietary Modulation of Oxidative Stress From Edible Insects: A Mini-Review.

Front Nutr 2021 26;8:642551. Epub 2021 Feb 26.

Faculty of Biosciences and Technologies for Agriculture, Food and Environment, University of Teramo, Teramo, Italy.

Edible insects are proposed as a nutritious and environmentally sustainable alternative source to animal proteins, due to their numerous advantages in terms of reduced ecological impact and high nutritional value. However, the novelty for edible insects relies on the content of bioactive ingredients potentially able to induce a functional effect in the body. The present review summarizes the main findings on the antioxidant properties of edible insects available in the literature. A total of 30 studies involving animals, cell cultures, or experimental studies evaluating the antioxidant effect of edible insects are presented in this work. When the antioxidant activity was investigated, using a wide variety of tests and in cellular models, positive results were shown. Dietary supplementation with edible insects was also able to counteract dietary oxidative stress in animal models, restoring the balance of antioxidant enzymes and reducing the formation of oxidation damage markers. On the basis of the reviewed evidences, edible insects might represent a source of novel redox ingredients at low ecological impact able to modulate oxidative stress. However, due to the fact that majority of these evidences have been obtained and in cellular and animal models, dietary intervention trials are needed to assess the efficacy of edible insect consumption to modulate redox status in humans.
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http://dx.doi.org/10.3389/fnut.2021.642551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952304PMC
February 2021

Health-Promoting Role of Isolated from Fermented Foods.

Microorganisms 2021 Feb 10;9(2). Epub 2021 Feb 10.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, 64100 Teramo, Italy.

Fermentation processes have been used for centuries for food production and preservation. Besides the contribution of fermentation to food quality, recently, scientific interest in the beneficial nature of fermented foods as a reservoir of probiotic candidates is increasing. Fermented food microbes are gaining attention for their health-promoting potential and for being genetically related to human probiotic bacteria. Among them, (.) strains, with a long history in the food industry as starter cultures in the production of a wide variety of fermented foods, are being investigated for their beneficial properties which are similar to those of probiotic strains, and they are also applied in clinical interventions. Food-associated showed a good adaptation and adhesion ability in the gastro-intestinal tract and the potential to affect host health through various beneficial activities, e.g., antimicrobial, antioxidative, antigenotoxic, anti-inflammatory and immunomodulatory, in several in vitro and in vivo studies. This review provides an overview of fermented-associated health benefits with evidence from clinical studies. Probiotic criteria that fermented-associated microbes need to fulfil are also reported.
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http://dx.doi.org/10.3390/microorganisms9020349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916596PMC
February 2021

Immunomodulation of J774A.1 Murine Macrophages by Strains Isolated From the Human Gastrointestinal Tract and Fermented Foods.

Front Microbiol 2020 12;11:557143. Epub 2021 Jan 12.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

species (recently re-named subsp. ) can be isolated from both either the mammalian gut or specific fermented foods where they may be present at high concentrations. Whilst strains have been proposed as potential probiotic candidates, the ability of resident strains consumed in fermented foods to interact with the host is unclear. The main objective of this study was to investigate the cellular location and ability of three different food-borne strains isolated from different sources (table olives and cheese) to modulate the immune response of a murine macrophage-like cell line (J774A.1). For that purpose, macrophages were exposed to the three different strains for 24 h and the expression of a panel of genes involved in the immune response, including genes encoding pattern-recognition receptors (TLRs and NLRs) and cytokines was evaluated by qRT-PCR. We also utilized chemical inhibitors of intracellular pathways to gain some insight into potential signaling mechanisms. Results showed that the native food strains of were able to modulate the response of J774A.1 murine macrophages through a predominately NOD signaling pathway that reflects the transient intracellular location of these strains within the macrophage. The data indicate the capacity of food-dwelling strains to influence macrophage-mediated host responses if consumed in sufficient quantities.
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http://dx.doi.org/10.3389/fmicb.2020.557143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835322PMC
January 2021

Bioactive Lipids in Health and Disease.

Biomolecules 2020 12 21;10(12). Epub 2020 Dec 21.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy.

Although the primordial concept of lipids is associated with the role they play as key components of the cell membrane, growing research in the field of bioactive lipids and lipidomic technologies proves the prominent role of these molecules in other biological functions [...].
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http://dx.doi.org/10.3390/biom10121698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767251PMC
December 2020

Food-borne Lactiplantibacillus plantarum protect normal intestinal cells against inflammation by modulating reactive oxygen species and IL-23/IL-17 axis.

Sci Rep 2020 10 1;10(1):16340. Epub 2020 Oct 1.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Food-associated Lactiplantibacillus plantarum (Lpb. plantarum) strains, previously classified as Lactobacillus plantarum, are a promising strategy to face intestinal inflammatory diseases. Our study was aimed at clarifying the protective role of food-borne Lpb. plantarum against inflammatory damage by testing the scavenging microbial ability both in selected strains and in co-incubation with normal mucosa intestinal cells (NCM460). Here, we show that Lpb. plantarum endure high levels of induced oxidative stress through partially neutralizing reactive oxygen species (ROS), whereas they elicit their production when co-cultured with NCM460. Moreover, pre-treatment with food-borne Lpb. plantarum significantly reduce pro-inflammatory cytokines IL-17F and IL-23 levels in inflamed NCM460 cells. Our results suggest that food-vehicled Lpb. plantarum strains might reduce inflammatory response in intestinal cells by directly modulating local ROS production and by triggering the IL-23/IL-17 axis with future perspectives on health benefits in the gut derived by the consumption of functional foods enriched with selected strains.
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http://dx.doi.org/10.1038/s41598-020-73201-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529774PMC
October 2020

CSF Levels of the Endocannabinoid Anandamide are Reduced in Patients with Untreated Narcolepsy Type 1: A Pilot Study.

CNS Neurol Disord Drug Targets 2020 ;19(2):142-147

Campus Bio-Medico University of Rome, Italy.

Background: Endocannabinoids (ECs) modulate both excitatory and inhibitory components in the CNS. There is a growing body of evidence that shows ECs influence both hypothalamic orexinergic and histaminergic neurons involved in narcolepsy physiopathology. Therefore, ECs may influence sleep and sleep-wake cycle.

Objective: To evaluate EC levels in the CSF of untreated narcoleptic patients to test whether ECs are dysregulated in Narcolepsy Type 1 (NT1) and Type 2 (NT2).

Methods: We compared CSF Anandamide (AEA), 2-Arachidonoylglycerol (2-AG) and orexin in narcoleptic drug-naïve patients and in a sample of healthy subjects.

Results: We compared NT1 (n=6), NT2 (n=6), and healthy controls (n=6). We found significantly reduced AEA levels in NT1 patients compared to both NT2 and controls. No differences were found between AEA levels in NT2 versus controls and between 2-AG levels in all groups, although a trend toward a decrease in NT1 was evident. Finally, the CSF AEA level was related to CSF orexin levels in all subjects.

Conclusion: We demonstrated that the EC system is dysregulated in NT1.
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http://dx.doi.org/10.2174/1871527319666200309115602DOI Listing
January 2020

Probiotic antigenotoxic activity as a DNA bioprotective tool: a minireview with focus on endocrine disruptors.

FEMS Microbiol Lett 2020 02;367(3)

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100, Teramo, Italy.

Nowadays, the interest in the role of dietary components able to influence the composition and the activity of the intestinal microbiota and, consequently, to modulate the risk of genotoxicity and colon cancer is increasing in the scientific community. Within this topic, the microbial ability to have a protective role at gastrointestinal level by counteracting the biological activity of genotoxic compounds, and thus preventing the DNA damage, is deemed important in reducing gut pathologies and is considered a new tool for probiotics and functional foods. A variety of genotoxic compounds can be found in the gut and, besides food-related mutagens and other DNA-reacting compounds, there is a group of pollutants commonly used in food packaging and/or in thousands of everyday products called endocrine disruptors (EDs). EDs are exogenous substances that alter the functions of the endocrine system through estrogenic and anti-estrogenic activity, which interfere with normal hormonal function in human and wildlife. Thus, this paper summarizes the main applications of probiotics, mainly lactobacilli, as a bio-protective tool to counteract genotoxic and mutagenic agents, by biologically inhibiting the related DNA damage in the gut and highlights the emerging perspectives to enlarge and further investigate the microbial bio-protective role at intestinal level.
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http://dx.doi.org/10.1093/femsle/fnaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082702PMC
February 2020

-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes.

Biomolecules 2019 12 3;9(12). Epub 2019 Dec 3.

Endocannabinoid Research Group, Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy.

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of -arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different -omics technologies have the merit to have led to the discovery of a huge number of naturally occurring -acyl-amines. Among those mediators, -acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the -acyl amino acids described so far.
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http://dx.doi.org/10.3390/biom9120822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995544PMC
December 2019

Antioxidant Activities of Water and Liposoluble Extracts Obtained by Different Species of Edible Insects and Invertebrates.

Front Nutr 2019 15;6:106. Epub 2019 Jul 15.

Faculty of Biosciences and Technologies for Agriculture, Food, and Environment, University of Teramo, Teramo, Italy.

A new global interest in entomophagy, the practice of eating insects, and invertebrates, arise from the impellent necessity of preserving agriculture resources and to obtain a drastic reduction of the ecological impact of animal food on the planet. The composite nutritional content, direct consequences of a plant-based feeding, associated with the undoubtedly ecological properties, suggest for insects a role as sustainable and functional foods. We aim to investigate the ability of water and liposoluble extracts, obtained by 12 commercially available edible insects and two invertebrates, to display an antioxidant effect . Results show that water-soluble extracts of grasshoppers, silkworm, and crickets display the highest values of antioxidant capacity (TEAC), 5-fold higher than fresh orange juice, while evening cicada, giant water bugs, Thai zebra tarantula, and black scorpions have negligible values. Grasshoppers, African caterpillars, and crickets have the highest levels of reducing power (FRAP), double than fresh orange juice. Grasshoppers, black ants, and mealworms contain the highest levels of total polyphenols, while Thai zebra tarantula, black scorpions, and giant water bugs are positioned at the bottom of the ranking. The liposoluble fraction of silkworm, evening cicada, and African caterpillars shows highest level of TEAC, twice than olive oil, while Thai zebra tarantula, palm worm, and black ants are placed at the bottom of the ranking. Edible insects and invertebrates represent a potential source of antioxidant ingredients with an efficiency related to their taxonomy and eating habits. More evidences are needed in order to understand if the practice of eating insects and invertebrates might contribute to modulate oxidative stress in humans.
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http://dx.doi.org/10.3389/fnut.2019.00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643021PMC
July 2019

Human osteogenic differentiation in Space: proteomic and epigenetic clues to better understand osteoporosis.

Sci Rep 2019 06 6;9(1):8343. Epub 2019 Jun 6.

Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.

In the frame of the VITA mission of the Italian Space Agency (ASI), we addressed the problem of Space osteoporosis by using human blood-derived stem cells (BDSCs) as a suitable osteogenic differentiation model. In particular, we investigated proteomic and epigenetic changes in BDSCs during osteoblastic differentiation induced by rapamycin under microgravity conditions. A decrease in the expression of 4 embryonic markers (Sox2, Oct3/4, Nanog and E-cadherin) was found to occur to a larger extent on board the ISS than on Earth, along with an earlier activation of the differentiation process towards the osteogenic lineage. The changes in the expression of 4 transcription factors (Otx2, Snail, GATA4 and Sox17) engaged in osteogenesis supported these findings. We then ascertained whether osteogenic differentiation of BDSCs could depend on epigenetic regulation, and interrogated changes of histone H3 that is crucial in this type of gene control. Indeed, we found that H3K4me3, H3K27me2/3, H3K79me2/3 and H3K9me2/3 residues are engaged in cellular reprogramming that drives gene expression. Overall, we suggest that rapamycin induces transcriptional activation of BDSCs towards osteogenic differentiation, through increased GATA4 and Sox17 that modulate downstream transcription factors (like Runx2), critical for bone formation. Additional studies are warranted to ascertain the possible exploitation of these data to identify new biomarkers and therapeutic targets to treat osteoporosis, not only in Space but also on Earth.
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http://dx.doi.org/10.1038/s41598-019-44593-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554341PMC
June 2019

Adhesion Properties of Food-Associated Strains on Human Intestinal Epithelial Cells and Modulation of IL-8 Release.

Front Microbiol 2018 8;9:2392. Epub 2018 Oct 8.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Food-associated microbes can reach the gut as viable cells and interact with the human host providing potential health benefits. In this study, we evaluated the impact on cell viability and the adhesion ability of 22 strains, mainly isolated from fermented foods, on a Normal-derived Colon Mucosa cell line. Furthermore, due to the presence of mucus layer on the gut epithelium, we also investigated whether the mucin could affect the microbial adhesion property. Our results demonstrated that all the strains displayed a strong ability to adhere to host cells, showing a strain-dependent behavior with preference for cell edges, that resulted not to be affected by the presence of mucin. Based on interleukin-8 release of intestinal cells induced by some strains, our data suggest a potential cross-talk with the host immune system as unconventional property of these food-associated microbes.
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http://dx.doi.org/10.3389/fmicb.2018.02392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186789PMC
October 2018

Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

PLoS One 2016 18;11(11):e0166827. Epub 2016 Nov 18.

Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.

Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115823PMC
June 2017

Determination of 2-Arachidonoylglycerol by μSPE-LC-MS/MS.

Methods Mol Biol 2016 ;1412:19-26

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Via 1, Teramo, 64023, Italy.

LC-MS/MS is a powerful analytical technique that provides unequivocal identification and reliable quantification of the analytes, using Selected Reaction Monitoring or Multi Reaction Monitoring acquisition mode.2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid, which plays a major role in a wide variety of physiological and pathological processes. Analysis of 2-AG by means of LC-MS/MS allows the detection of very low concentrations in biological samples. Here, we describe how to determine 2-AG levels in tiny samples of tissues and plasma through LC-MS/MS, by using very quick and easy to perform extraction procedures, with reduced solvent consumption.
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http://dx.doi.org/10.1007/978-1-4939-3539-0_3DOI Listing
December 2017

Endocannabinoids and Reproductive Events in Health and Disease.

Handb Exp Pharmacol 2015 ;231:341-65

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy.

The lasting research on the endocannabinoid system (ECS) has now provided solid and convincing evidence that proves the detrimental effects of recreational drug abuse (a growing habit among teenagers) on fertility. Endocannabinoids (eCBs) affect reproductive events from gametogenesis to fertilization, from embryo implantation to the final outcome of pregnancy and, thus, they have been proposed as suitable biomarkers to predict the reproductive potential of male and female gametes in clinical practice. Novel tools for reproductive medicine are highly sought after, and here we report the latest findings on the impact of the ECS on fertility, demonstrating how basic research can be translated into new medical strategies.
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http://dx.doi.org/10.1007/978-3-319-20825-1_12DOI Listing
December 2015

Endocannabinoid Signaling in Autism.

Neurotherapeutics 2015 Oct;12(4):837-47

Center of Integrated Research and School of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy.

Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.
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http://dx.doi.org/10.1007/s13311-015-0371-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604173PMC
October 2015

Active endocannabinoids are secreted on extracellular membrane vesicles.

EMBO Rep 2015 Feb 7;16(2):213-20. Epub 2015 Jan 7.

CNR Institute of Neuroscience, Milano, Italy IRCCS Humanitas, Rozzano, Italy

Endocannabinoids primarily influence neuronal synaptic communication within the nervous system. To exert their function, endocannabinoids need to travel across the intercellular space. However, how hydrophobic endocannabinoids cross cell membranes and move extracellularly remains an unresolved problem. Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells. We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB1), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids.
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http://dx.doi.org/10.15252/embr.201439668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328748PMC
February 2015

Truffles contain endocannabinoid metabolic enzymes and anandamide.

Phytochemistry 2015 Feb 26;110:104-10. Epub 2014 Nov 26.

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy. Electronic address:

Truffles are the fruiting body of fungi, members of the Ascomycota phylum endowed with major gastronomic and commercial value. The development and maturation of their reproductive structure are dependent on melanin synthesis. Since anandamide, a prominent member of the endocannabinoid system (ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that ECS might be present also in truffles. Here, we show the expression, at the transcriptional and translational levels, of most ECS components in the black truffle Tuber melanosporum Vittad. at maturation stage VI. Indeed, by means of molecular biology and immunochemical techniques, we found that truffles contain the major metabolic enzymes of the ECS, while they do not express the most relevant endocannabinoid-binding receptors. In addition, we measured anandamide content in truffles, at different maturation stages (from III to VI), through liquid chromatography-mass spectrometric analysis, whereas the other relevant endocannabinoid 2-arachidonoylglycerol was below the detection limit. Overall, our unprecedented results suggest that anandamide and ECS metabolic enzymes have evolved earlier than endocannabinoid-binding receptors, and that anandamide might be an ancient attractant to truffle eaters, that are well-equipped with endocannabinoid-binding receptors.
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http://dx.doi.org/10.1016/j.phytochem.2014.11.012DOI Listing
February 2015

A functional interplay between 5-lipoxygenase and μ-calpain affects survival and cytokine profile of human Jurkat T lymphocyte exposed to simulated microgravity.

Biomed Res Int 2014 16;2014:782390. Epub 2014 Sep 16.

European Center for Brain Research (CERC), IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy ; Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.

A growing body of evidence strongly indicates that both simulated and authentic weightlessness exert a broad range of effects on mammalian tissues and cells, including impairment of immune cell function and increased apoptotic death. We previously reported that microgravity-dependent activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of apoptosis in human T lymphocytes, suggesting that the upregulation of this enzyme might be (at least in part) responsible for immunodepression observed in astronauts during space flights. Herein, we supplement novel information about the molecular mechanisms underlying microgravity-triggered apoptotic cell death and immune system deregulation, demonstrating that under simulated microgravity human Jurkat T cells increase the content of cytosolic DNA fragments and cytochrome c (typical hallmarks of apoptosis) and have an upregulated expression and activity of µ-calpain. These events were paralleled by the unbalance of interleukin- (IL-) 2 and interferon- (INF-) γ, anti- and proapoptotic cytokines, respectively, that seemed to be dependent on the functional interplay between 5-LOX and µ-calpain. Indeed, we report unprecedented evidence that 5-LOX inhibition reduced apoptotic death, restored the initial IL-2/INF-γ ratio, and more importantly reverted µ-calpain activation induced by simulated microgravity.
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http://dx.doi.org/10.1155/2014/782390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182306PMC
July 2015

Endocannabinoids and reproduction.

Int J Endocrinol 2014 20;2014:378069. Epub 2014 Jan 20.

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

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http://dx.doi.org/10.1155/2014/378069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918352PMC
February 2014

Updates in reproduction coming from the endocannabinoid system.

Int J Endocrinol 2014 16;2014:412354. Epub 2014 Jan 16.

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators-deeply modulated by the activity of biosynthetic and hydrolyzing machineries-regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility.
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http://dx.doi.org/10.1155/2014/412354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914453PMC
June 2014

Endocannabinoids as biomarkers of human reproduction.

Hum Reprod Update 2014 Jul-Aug;20(4):501-16. Epub 2014 Feb 9.

European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy

Background: Infertility is a condition of the reproductive system that affects ∼10-15% of couples attempting to conceive a baby. More than half of all cases of infertility are a result of female conditions, while the remaining cases can be attributed to male factors, or to a combination of both. The search for suitable biomarkers of pregnancy outcome is a challenging issue in human reproduction, aimed at identifying molecules with predictive significance of the reproductive potential of male and female gametes. Among the various candidates, endocannabinoids (eCBs), and in particular anandamide (AEA), represent potential biomarkers of human fertility disturbances. Any perturbation of the balance between synthesis and degradation of eCBs will result in local changes of their tone in human female and male reproductive tracts, which in turn regulates various pathophysiological processes, oocyte and sperm maturation included.

Methods: PubMed and Web of Science databases were searched for papers using relevant keywords like 'biomarker', 'endocannabinoid', 'infertility', 'pregnancy' and 'reproduction'.

Results: In this review, we discuss different studies on the measurements of AEA and related eCBs in human reproductive cells, tissues and fluids, where the local contribution of these bioactive lipids could be critical in ensuring normal sperm fertilizing ability and pregnancy.

Conclusion: Based on the available data, we suggest that the AEA tone has the potential to be exploited as a novel diagnostic biomarker of infertility, to be used in association with assays of conventional hormones (e.g. progesterone, β-chorionic gonadotrophin) and semen analysis. However further quantitative research of its predictive capacity is required.
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http://dx.doi.org/10.1093/humupd/dmu004DOI Listing
September 2014

Analytical approaches for the determination of phytocannabinoids and endocannabinoids in human matrices.

Drug Test Anal 2014 Jan-Feb;6(1-2):7-16. Epub 2013 Nov 11.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; European Center for Brain Research/Santa Lucia Foundation, Rome, Italy.

Over the last two decades, the role played by phytocannabinoids and endocannabinoids in medicine has gained increasing interest in the scientific community. Upon identification of the plant compound Δ(9)-tetrahydrocannabinol (THC) and of the endogenous substance anandamide (AEA), different methodological approaches and innovative techniques have been developed, in order to evaluate the content of these molecules in various human matrices. In this review, we discuss the analytical methods that are currently used for the identification of phytocannabinoids and endocannabinoids, and we summarize the benefits and limitations of these procedures. Moreover, we provide an overview of the main biological matrices that have been analyzed to date for qualitative detection and quantitative determination of these compounds.
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http://dx.doi.org/10.1002/dta.1574DOI Listing
September 2014

The fatty acid amide hydrolase in lymphocytes from sedentary and active subjects.

Med Sci Sports Exerc 2014 Jan;46(1):24-32

1Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, ITALY; 2Department of Movement, Human and Health Sciences, Foro Italico University of Rome, Rome, ITALY; 3Department of Biomedical Sciences, University of Teramo, Teramo, ITALY; 4Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, ITALY; and 5European Center for Brain Research/Santa Lucia Foundation, Rome, ITALY.

Purpose: Endocannabinoids (eCB) and interleukin 6 (IL-6) levels change during physical activity, thus suggesting their involvement in the modulation of exercise-related processes like inflammation and energy homeostasis. To investigate whether lifestyle might affect the activity of the eCB-degrading enzyme fatty acid amide hydrolase (FAAH), active and sedentary subjects were enrolled.

Methods: Plasma IL-6 levels and lymphocyte FAAH activity of eight physically active male subjects (mean ± SEM; age = 39.3 ± 2.9 yr, body mass index = 21.1 ± 0.4 kg·m), usually practicing aerobic exercise (8.1 ± 1.2 h·wk), and eight sedentary subjects (38.8 ± 3.7 yr, body mass index = 23.1 ± 0.8 kg·m) were measured. Also, in vitro effect of IL-6 was tested on FAAH expression and activity and on FAAH promoter activity in lymphocytes from sedentary subjects.

Results: Under resting conditions (at least 12 h from the last exercise), the active group showed plasma IL-6 levels (2.74 ± 0.73 pg·mL) and lymphocyte FAAH activity (215.7 ± 38.5 pmol·min·mg protein) significantly higher than those measured in the sedentary group (0.20 ± 0.02 pg·mL, and 42.0 ± 4.2 pmol·min·mg protein). Increased IL-6 levels paralleled increased FAAH activity, and consistently, the in vitro treatment of lymphocytes from sedentary individuals with 10 ng·mL IL-6 for 48 h significantly increased FAAH expression and activity. Transient transfection experiments showed that IL-6 induced the expression of a reporter gene under the control of a cAMP response element-like region in the human FAAH promoter. A mutation in the same element abolished IL-6 up-regulation, demonstrating that this cytokine regulates FAAH activity at the transcriptional level.

Conclusion: IL-6 leads to activation of the FAAH promoter, thus enhancing FAAH activity that modulates the eCB tone in physically active people.
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http://dx.doi.org/10.1249/MSS.0b013e3182a10ce6DOI Listing
January 2014

In vitro and in vivo models of Huntington's disease show alterations in the endocannabinoid system.

FEBS J 2013 Jul 10;280(14):3376-88. Epub 2013 Jun 10.

Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy.

In this study, we analyzed the components of the endocannabinoid system (ECS) in R6/2 mice, a widely used model of Huntington's disease (HD). We measured the endogenous content of N-arachidonoylethanolamine and 2-arachidonoylglycerol and the activity of their biosynthetic enzymes (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase, respectively) and hydrolytic enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively] and of their target receptors (type 1 cannabinoid receptor, type 2 cannabinoid receptor, and transient receptor potential vanilloid-1) in the brains of wild-type and R6/2 mice of different ages, as well as in the striatum and cortex of 12-week-old animals. In addition, we measured FAAH activity in lymphocytes of R6/2 mice. In the whole brains of 12-week-old R6/2 mice, we found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity and cannabinoid receptor binding, mostly associated with changes in the striatum but not in the cortex, as well as an increase in 2-arachidonoylglycerol content as compared with wild-type littermates, without any other change in ECS elements. Then, our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and noninduced conditions, we demonstrated a fully functional ECS. Overall, our data suggest that the ECS is differently affected in mouse and human HD, and that HD43 cells are suitable for high-throughput screening of FAAH-oriented drugs affecting HD progression.
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http://dx.doi.org/10.1111/febs.12329DOI Listing
July 2013

Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease.

PLoS One 2013 19;8(4):e62078. Epub 2013 Apr 19.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631143PMC
November 2013

Differences in the endocannabinoid system of sperm from fertile and infertile men.

PLoS One 2012 17;7(10):e47704. Epub 2012 Oct 17.

School of Medicine, Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, United Kingdom.

Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS), mainly through the action of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS), mRNA (through quantitative RT-PCR), protein (through Western Blotting and ELISA) expression, and functionality (through activity and binding assays) of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG), as well as of their binding receptors CB(1), CB(2) and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1) and CB(2) receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474715PMC
April 2013

Determination of the two major endocannabinoids in human plasma by μ-SPE followed by HPLC-MS/MS.

Anal Bioanal Chem 2013 Jan 31;405(2-3):785-93. Epub 2012 Jul 31.

Department of Food Sciences, University of Teramo, Teramo, Italy.

Endocannabinoids (ECs) are endogenous compounds that interact with type-1 and type-2 cannabinoid receptors (CB(1) and CB(2)), as well as non-cannabinoid receptors. The multitude of roles attributed to ECs makes them an emerging target of pharmacotherapy for a number of disparate diseases. Here a high-throughput bioanalytical method based on micro SPE (μ-SPE) followed by LC-MS/MS analysis for the simultaneous determination of the two major endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide, AEA) in human plasma is presented. The chromatographic conditions obtained with the fused-core column allowed a good separation in 10 min also of the AG isomers. A very simple and reliable extraction has been optimised by means of C18-modified tips: it requires only 100 μL of plasma and allows the use of minimal volumes of organic solvent. The present method allows a rapid and effective clean-up, which also minimises the isomerisation of 2-AG. The whole procedure has been validated following the FDA guidelines for bioanalytical methods validation: the satisfactory recovery values, the negligible matrix effect and the good values of accuracy and reproducibility make it a simple and high-throughput analytical tool for clinical and biochemical studies on endocannabinoid signaling in humans.
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http://dx.doi.org/10.1007/s00216-012-6273-3DOI Listing
January 2013

The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models.

J Pharmacol Exp Ther 2012 Jul 18;342(1):188-95. Epub 2012 Apr 18.

Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina km. 30,400, 00040 Pomezia, Italy.

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.
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http://dx.doi.org/10.1124/jpet.111.191403DOI Listing
July 2012

The endocannabinoid system: an overview.

Front Behav Neurosci 2012 14;6. Epub 2012 Mar 14.

Department of Biomedical Sciences, University of Teramo Teramo, Italy.

Upon the identification of anandamide (AEA) in the porcine brain, numerous studies contributed to the current state of knowledge regarding all elements that form the "endocannabinoid system (ECS)."How this complex system of receptors, ligands, and enzymes is integrated in helping to regulate fundamental processes at level of central nervous and peripheral systems and how its regulation and dysregulation might counteract disturbances of such functions, is nowadays still under investigation. However, the most recent advances on the physiological distribution and functional role of ECS allowed the progress of various research tools aimed at the therapeutic exploitation of endocannabinoid (eCB) signaling, as well as the development of novel drugs with pharmacological advantages. Here, we shall briefly overview the metabolic and signal transduction pathways of the main eCBs representatives, AEA, and 2-arachidonoylglycerol (2-AG), and we will discuss the therapeutic potential of new ECS-oriented drugs.
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http://dx.doi.org/10.3389/fnbeh.2012.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303140PMC
October 2012