Publications by authors named "Rosaria Meccariello"

63 Publications

Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview.

Antioxidants (Basel) 2021 Mar 24;10(4). Epub 2021 Mar 24.

Department of Movement Sciences and Wellbeing, University of Naples Parthenope, 80133 Naples, Italy.

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.
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http://dx.doi.org/10.3390/antiox10040507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064059PMC
March 2021

Microplastics: A Threat for Male Fertility.

Int J Environ Res Public Health 2021 03 1;18(5). Epub 2021 Mar 1.

Department of Movement Sciences and Wellbeing, University of Naples Parthenope, 80133 Naples, Italy.

Much of the planet is swimming in discarded plastic, which is harming animal and possibly human health. Once at sea, sunlight, wind, and wave action break down plastic waste into small particles: the microplastics (MPs). Currently, particular attention has been drawn to their effects on aquatic environments but the health risks, especially in mammals, are poorly known. These non-biodegradable materials can act as a vector for environmental pollutants, can be ingested by humans in food and water, and can enter and accumulate in human tissues with a possible risk for heath. Recent studies revealed the deleterious effects of MPs exposure in male reproduction and sperm quality, making them a potential hazard to reproductive success. This manuscript summarizes the main changes in sperm quality along the lifespan and the upcoming studies on the effects of MPs in male fertility in mammals.
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http://dx.doi.org/10.3390/ijerph18052392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967748PMC
March 2021

Sirt1 Activity in the Brain: Simultaneous Effects on Energy Homeostasis and Reproduction.

Int J Environ Res Public Health 2021 01 30;18(3). Epub 2021 Jan 30.

Department of Movement Sciences and Wellbeing, University of Naples Parthenope, 80133 Napoli, Italy.

Diet deeply impacts brain functions like synaptic plasticity and cognitive processes, neuroendocrine functions, reproduction and behaviour, with detrimental or protective effects on neuronal physiology and therefore consequences for health. In this respect, the activity of metabolic sensors within the brain is critical for the maintenance of health status and represents a possible therapeutic target for some diseases. This review summarizes the main activity of Sirtuin1 (Sirt1), a metabolic sensor within the brain with a focus on the link between the central control of energy homeostasis and reproduction. The possible modulation of Sirt1 by natural phytochemical compounds like polyphenols is also discussed.
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http://dx.doi.org/10.3390/ijerph18031243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908627PMC
January 2021

The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery.

Int J Mol Sci 2021 Jan 19;22(2). Epub 2021 Jan 19.

Department of Movement Sciences and Wellbeing, Parthenope University of Naples, 80133 Naples, Italy.

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer.
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http://dx.doi.org/10.3390/ijms22020972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835826PMC
January 2021

Kisspeptins, new local modulators of male reproduction: A comparative overview.

Gen Comp Endocrinol 2020 12 18;299:113618. Epub 2020 Sep 18.

Dipartimento di Medicina Sperimentale, Università degli Studi della Campania "L. Vanvitelli", Napoli, Italy.

Spermatogenesis is a complex process that leads to the production of male gametes within the testis through the coordination of mitotic, meiotic and differentiation events, under a deep control of endocrine, paracrine and autocrine modulators along the Hypothalamus-pituitary-gonad (HPG) axis. The kisspeptin system plays a fundamental role along the HPG axis as it is the main positive modulator upstream of the hypothalamic neurons that secrete the Gonadotropin Releasing Hormone (GnRH), the decapeptide that supports pituitary gonadotropins and the production of gonadal sex steroid. Currently, kisspeptins and their receptor, KISS1R, have a recognized activity in the central control of puberty onset, sex maturation, reproduction and sex-steroid feedback mechanisms in both animal models and human. However, kisspeptin signaling has been widely reported in peripheral tissues, particularly in the testis of mammalian and non-mammalian vertebrates, with functions related to Leydig cells physiology and steroid biosynthesis, spermatogenesis progression and spermatozoa functions, but its mandatory role within the testis is still a matter of discussion. This review provides a summary of the main intratesticular effects of kisspeptin in vertebrates, via a comparative approach. Particular emphasis was devoted to data from the anuran amphibian Pelophylax esculentus, the first animal model in which the direct intratesticular activity of kisspeptin was reported.
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http://dx.doi.org/10.1016/j.ygcen.2020.113618DOI Listing
December 2020

ω-3 and ω-6 Polyunsaturated Fatty Acids, Obesity and Cancer.

Nutrients 2020 Sep 10;12(9). Epub 2020 Sep 10.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, via Medina 40, 80133 Napoli, Italy.

Recently, nutraceutical bioactive compounds in foods have been discovered for their potential health benefits regarding the prevention of chronic disorders, such as cancer, and inflammatory, cardiovascular, and metabolic diseases. Dietary omega-3 polyunsaturated fatty acids (ω-3PUFAs), including alpha-linolenic acid, docosapentaenoic acid, and eicosapentaenoic acid, are mostly attractive. They are available for the customers worldwide from commonly used foods and/or as components of commercial food supplements. The anti-inflammatory and hypotriglyceridemic effects of these fatty acids are well known, whereas pro-inflammatory properties have been recognized in their dietary counterparts, the ω-6PUFAs. Both ω-3 and ω-6PUFAs contribute to the production of lipid mediators such as endocannabinoids that are notably involved in control of food intake, energy sensing, and food-related disorders. In this review, we present ω-3 and ω-6PUFAs and their derivatives, endocannabinoids; discuss the anti-obesity effects of ω-3PUFAs; their roles in inflammation and colorectal cancer development; and how their action can be co-preventative and co-therapeutic.
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http://dx.doi.org/10.3390/nu12092751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551151PMC
September 2020

Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives.

Int J Mol Sci 2020 May 18;21(10). Epub 2020 May 18.

Department of Movement Sciences and Wellbeing, University of Naples "Parthenope", Via Medina 40, 80133 Naples, Italy.

The endocannabinoid system (ECS) is a complex signaling system that includes cannabinoid receptors, their endogenous ligands (endocannabinoids), and biosynthetic and hydrolytic enzymes [...].
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http://dx.doi.org/10.3390/ijms21103549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278997PMC
May 2020

Bisphenol A induces DNA damage in cells exerting immune surveillance functions at peripheral and central level.

Chemosphere 2020 Sep 18;254:126819. Epub 2020 Apr 18.

Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy. Electronic address:

Bisphenol A (BPA) is a synthetic xenoestrogen diffused worldwide. Humans are chronically exposed to low doses of BPA from food and drinks, thus BPA accumulates in tissues posing human health risk. In this study, we investigated the effects of BPA on peripheral blood mononuclear cells (PBMC) from human healthy donors, and in glia and microglia of rat offspring at postnatal day 17 (17PND) from pregnant females who received BPA soon after coupling and during lactation and weaning. Results indicated that BPA affected Phytoemagglutinin (PHA) stimulated PBMC proliferation causing an S-phase cell cycle accumulation at nanomolar concentrations while BPA was almost ineffective in resting PBMC. Furthermore, BPA induced chromosome aberrations and the appearance of shattered cells characterized by high number of fragmented and pulverized chromosomes, suggesting that the compound could cause a massive genomic rearrangement by inducing catastrophic events. The BPA-induced DNA damage was observed mainly in TCD4+ and TCD8+ subsets of T lymphocytes and was mediated by the increase of ERK1/2 phosphorylation, p21/Waf1 and PARP1 protein expression. Intriguingly, we observed for the first time that BPA-induced effects were associated to a sex specific modulation of ERα and ERβ in human PBMC. Immunofluorescence analysis of rat hippocampus corroborated in vitro findings showing that BPA induced ɣH2AX phosphorylation in microglia and astrocytosis by decreasing ERα expression within the dentate gyrus. Overall these results suggest that BPA can alter immune surveillance functions at both peripheral and central level with a potential risk for cancer, neuroinflammation and neurodegeneration.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126819DOI Listing
September 2020

The Epigenetics of the Endocannabinoid System.

Int J Mol Sci 2020 Feb 7;21(3). Epub 2020 Feb 7.

Dipartimento di Medicina Sperimentale, Università della Campania L. Vanvitelli, via Costantinopoli 16, 80138 Cord Napoli, Italy.

The endocannabinoid system (ES) is a cell-signalling system widely distributed in biological tissues that includes endogenous ligands, receptors, and biosynthetic and hydrolysing machineries. The impairment of the ES has been associated to several pathological conditions like behavioural, neurological, or metabolic disorders and infertility, suggesting that the modulation of this system may be critical for the maintenance of health status and disease treatment. Lifestyle and environmental factors can exert long-term effects on gene expression without any change in the nucleotide sequence of DNA, affecting health maintenance and influencing both disease load and resistance. This potentially reversible "epigenetic" modulation of gene expression occurs through the chemical modification of DNA and histone protein tails or the specific production of regulatory non-coding RNA (ncRNA). Recent findings demonstrate the epigenetic modulation of the ES in biological tissues; in the same way, endocannabinoids, phytocannabinoids, and cannabinoid receptor agonists and antagonists induce widespread or gene-specific epigenetic changes with the possibility of trans-generational epigenetic inheritance in the offspring explained by the transmission of deregulated epigenetic marks in the gametes. Therefore, this review provides an update on the epigenetics of the ES, with particular attention on the emerging role in reproduction and fertility.
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http://dx.doi.org/10.3390/ijms21031113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037698PMC
February 2020

A Calorie-Restricted Ketogenic Diet Reduces Cerebral Cortex Vascularization in Prepubertal Rats.

Nutrients 2019 Nov 5;11(11). Epub 2019 Nov 5.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD.
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http://dx.doi.org/10.3390/nu11112681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893715PMC
November 2019

Neuro-toxic and Reproductive Effects of BPA.

Curr Neuropharmacol 2019 ;17(12):1109-1132

Department of Movement Sciences and Wellbeing, Parthenope University of Naples, Naples, Italy.

Background: Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. It has recognized activity as an endocrine-disrupting chemical and has suspected roles as a neurological and reproductive toxicant. It interferes in steroid signaling, induces oxidative stress, and affects gene expression epigenetically. Gestational, perinatal and neonatal exposures to BPA affect developmental processes, including brain development and gametogenesis, with consequences on brain functions, behavior, and fertility.

Methods: This review critically analyzes recent findings on the neuro-toxic and reproductive effects of BPA (and its analogues), with focus on neuronal differentiation, synaptic plasticity, glia and microglia activity, cognitive functions, and the central and local control of reproduction.

Results: BPA has potential human health hazard associated with gestational, peri- and neonatal exposure. Beginning with BPA's disposition, this review summarizes recent findings on the neurotoxicity of BPA and its analogues, on neuronal differentiation, synaptic plasticity, neuroinflammation, neuro-degeneration, and impairment of cognitive abilities. Furthermore, it reports the recent findings on the activity of BPA along the HPG axis, effects on the hypothalamic Gonadotropin Releasing Hormone (GnRH), and the associated effects on reproduction in both sexes and successful pregnancy.

Conclusion: BPA and its analogues impair neuronal activity, HPG axis function, reproduction, and fertility. Contrasting results have emerged in animal models and human. Thus, further studies are needed to better define their safety levels. This review offers new insights on these issues with the aim to find the "fil rouge", if any, that characterize BPA's mechanism of action with outcomes on neuronal function and reproduction.
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http://dx.doi.org/10.2174/1570159X17666190726112101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057208PMC
April 2020

Minireview: The Epigenetic Modulation of in Reproduction and Cancer.

Int J Environ Res Public Health 2019 07 22;16(14). Epub 2019 Jul 22.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, via Medina 40, 80133 Napoli, Italy.

Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions. In this minireview, we summarize the epigenetic modulation of the gene in order to provide an example of epigenetic regulation in health and disease.
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http://dx.doi.org/10.3390/ijerph16142607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679060PMC
July 2019

BPA and Nutraceuticals, Simultaneous Effects on Endocrine Functions.

Endocr Metab Immune Disord Drug Targets 2019 ;19(5):594-604

Dipartimento di Scienze Motorie e del Benessere, Universita di Napoli Parthenope, Napoli, Italy.

Background: Bisphenol A (BPA) is worldwide diffused as a monomer of epoxy resins and polycarbonate plastics and has recognized activity as Endocrine Disruptor (ED). It is capable to interfere or compete with endogenous hormones in many physiological activities thus having adverse outcomes on health. Diet highly affects health status and in addition to macronutrients, provides a large number of substances with recognized pro-heath activity, and thus called nutraceuticals.

Objective: This mini-review aims at summarizing the possible opposite and simultaneous effects of BPA and nutraceuticals on endocrine functions. The possibility that diet may represent the first instrument to preserve health status against BPA damages has been discussed.

Methods: The screening of recent literature in the field has been carried out.

Results: The therapeutic and anti-oxidant properties of many nutraceuticals may reverse the adverse health effects of BPA.

Conclusion: In vitro and in vivo studies provided evidence that nutraceuticals can preserve the health. Thus, the use of nutraceuticals can be considered a support for clinical treatment. In conclusion, dietary remediation may represent a successful therapeutic approach to maintain and preserve health against BPA damage.
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http://dx.doi.org/10.2174/1871530319666190101120119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360909PMC
January 2020

Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems.

Front Endocrinol (Lausanne) 2018 3;9:727. Epub 2018 Dec 3.

Department of Movement Sciences and Wellbeing, Parthenope University of Naples, Naples, Italy.

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http://dx.doi.org/10.3389/fendo.2018.00727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286967PMC
December 2018

A novel experimental approach for liver analysis in rats exposed to Bisphenol A by means of LC-mass spectrometry and infrared spectroscopy.

J Pharm Biomed Anal 2019 Feb 10;165:207-212. Epub 2018 Dec 10.

Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via S. M. di Costantinopoli, 16, 80138, Naples, Italy.

An innovative complementary approach using a liquid chromatographic-mass spectrometer method and infrared spectroscopy is proposed for measuring internal biological exposure to dangerous chemical contaminants and for monitoring biochemical changes in target organs. The proposed methodologies were validated and applied in the case of rats exposed to low-doses of Bisphenol A (BPA). A liquid chromatographic method coupled to a tandem mass spectrometer was used in order to measure BPA concentration in rat livers. BPA was detected at different levels in all liver samples from BPA-treated rats, although the exposure dose was the same in all treated animals, and also from control rats, highlighting the difficulties in eliminating external uncontrolled exposure and the need for internal biological monitoring. Fourier Transform Infrared analysis was applied to detect structural changes occurring in several molecules (lipids, proteins, carbohydrates and nucleic acids) as well as the presence of specific metabolic processes. The spectroscopic analyses clearly demonstrated a different lipid composition more than an evident lipid accumulation and a glycogen accumulation decrease, revealing a metabolic disturbance in livers with a normal histological aspect. These results demonstrated the potential of an integrated approach based on mass spectrometry and infrared spectroscopy to evaluate at an early stage the hepatotoxic effect of BPA exposure in an animal model. This approach can be usefully exploited in all the investigations aimed to provide better information concerning the interrelationships between contaminant exposure, dose, and health effects.
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http://dx.doi.org/10.1016/j.jpba.2018.12.011DOI Listing
February 2019

Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells.

Oncotarget 2018 Apr 10;9(27):19273-19282. Epub 2018 Apr 10.

Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Purpose: Kisspeptin signaling, its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown.

Experimental Design: The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT).

Results: Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP-9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components.

Conclusion: Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma.
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http://dx.doi.org/10.18632/oncotarget.25018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922395PMC
April 2018

Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation.

Sci Rep 2018 02 13;8(1):2961. Epub 2018 Feb 13.

Department of Movement Sciences and Wellbeing, University of Naples "Parthenope", Via Medina 40, 80133, Naples, Italy.

Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD-dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53, γH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis.
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http://dx.doi.org/10.1038/s41598-018-21076-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811609PMC
February 2018

Impact of Dietary Fats on Brain Functions.

Curr Neuropharmacol 2018 ;16(7):1059-1085

Department of Movement and Wellness Sciences, Parthenope University of Naples, Naples, Italy.

Background: Adequate dietary intake and nutritional status have important effects on brain functions and on brain health. Energy intake and specific nutrients excess or deficiency from diet differently affect cognitive processes, emotions, behaviour, neuroendocrine functions and synaptic plasticity with possible protective or detrimental effects on neuronal physiology. Lipids, in particular, play structural and functional roles in neurons. Here the importance of dietary fats and the need to understand the brain mechanisms activated by peripheral and central metabolic sensors. Thus, the manipulation of lifestyle factors such as dietary interventions may represent a successful therapeutic approach to maintain and preserve brain health along lifespan.

Methods: This review aims at summarizing the impact of dietary fats on brain functions.

Results: Starting from fat consumption, nutrient sensing and food-related reward, the impact of gut-brain communications will be discussed in brain health and disease. A specific focus will be on the impact of fats on the molecular pathways within the hypothalamus involved in the control of reproduction via the expression and the release of Gonadotropin-Releasing Hormone. Lastly, the effects of specific lipid classes such as polyunsaturated fatty acids and of the "fattest" of all diets, commonly known as "ketogenic diets", on brain functions will also be discussed.

Conclusion: Despite the knowledge of the molecular mechanisms is still a work in progress, the clinical relevance of the manipulation of dietary fats is well acknowledged and such manipulations are in fact currently in use for the treatment of brain diseases.
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http://dx.doi.org/10.2174/1570159X15666171017102547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120115PMC
October 2018

MicroRNAs, Cancer and Diet: Facts and New Exciting Perspectives.

Curr Mol Pharmacol 2018 ;11(2):90-96

Dipartimento di Scienze Motorie e del Benessere, Universita di Napoli Parthenope, Naples, Italy.

Background: MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at multiple levels. They are detected in tissues, blood, and other body fluids with high stability and have a recognized role in maintaining of tissue homeostasis. Aberrant expression profile of miRNAs has been observed in several diseases, primarily cancer. As a consequence, the analysis of miRNA signature has recognized diagnostic and prognostic role in human diseases, and the development of miRNA-based therapies is currently under investigation. Recently, emerging but controversial data have revealed the possibility that diet-derived miRNAs might be transferred from food in living organisms to regulate gene expression. Thus, exogenous dietderived miRNAs might substantially contribute to the pool of circulating miRNAs to preserve tissue homeostasis and health status in recipient's organisms, opening new perspectives for diet in heath and disease.

Objective: This brief review aims at summarizing data concerning the recognized role of miRNAs as biomarkers, drugs and therapeutic targets in cancer and the detection and the activity of diet-derived miRNAs in both physiological and pathological conditions.

Conclusion: MiRNAs have emerged as crucial molecules in anticancer therapies and diet-derived miRNAs might contribute to the pool of circulating miRNAs to preserve, maintain or restore health.
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http://dx.doi.org/10.2174/1874467210666171013123733DOI Listing
January 2019

Bisphenol A in Reproduction: Epigenetic Effects.

Curr Med Chem 2018 Feb;25(6):748-770

Dipartimento di Scienze Motorie e del Benessere, Universita di Napoli Parthenope, Napoli, Italy.

Background: Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively.

Objective: This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction.

Results: BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF).

Conclusion: The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring.
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http://dx.doi.org/10.2174/0929867324666171009121001DOI Listing
February 2018

Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian.

Reproduction 2017 10;154(4):403-414

Dipartimento di Scienze Motorie e del BenessereUniversità di Napoli Parthenope, Napoli, Italy

Kisspeptin (Kp) system has a recognized role in the control of gonadotropic axis, at multiple levels. Recently, a major focus of research has been to assess any direct activity of this system on testis physiology. Using the amphibian anuran, , as animal model, we demonstrate - for the first time in non-mammalian vertebrate - that testis expresses both Kiss-1 and Gpr54 proteins during the annual sexual cycle and that 17B-estradiol (E, 10 M) increases both proteins over control group. Since the interstitium is the main site of localization of both ligand and receptor, its possible involvement in the regulation of steroidogenesis has been evaluated by treatment of testis pieces with increasing doses of Kp-10 (10-10 M). Treatments have been carried out in February - when a new wave of spermatogenesis occurs - and affect the expression of key enzymes of steroidogenesis inducing opposite effects on testosterone and estradiol intratesticular levels. Morphological analysis of Kp-treated testes reveals higher number of tubules with spermatozoa detached from Sertoli cells than control group and the expression of connexin 43, the main junctional protein in testis, is deeply affected by the treatment. In spite of the effects on spermatozoa observed , administration of Kp-10 has been unable to induce sperm release in cloacal fluid. In conclusion, we demonstrate Kp-10 effects on steroidogenesis with possible involvement in the balance between testosterone and estradiol levels, and report new Kp-10 activities on spermatozoa-Sertoli cell interaction.
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http://dx.doi.org/10.1530/REP-17-0030DOI Listing
October 2017

Kisspeptins, Estrogens and Male Fertility.

Curr Med Chem 2016 ;23(36):4070-4091

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy.

Background: The control of male fertility requires accurate endocrine, paracrine and autocrine communications along the hypothalamus-pituitary-gonad (HPG) axis. In this respect, the possible interplay between upcoming/classical modulators of reproductive functions deserves attention in that may be a successful tool for the future exploitation of new potential therapeutic targets in the treatment of fertility disorders.

Methods: In this review we will discuss upcoming data concerning the role of kisspeptins, the products of the Kiss1 gene, and estrogens - classically considered as female hormones - as well as their possible interplay in testis.

Results: Kisspeptins, via the activation of kisspeptin receptor Gpr54 represent the main gatekeeper of the hypothalamic Gonadotropin Releasing Hormone (GnRH) centrally modulating the onset and maintaining reproductive functions. As a consequence, the loss of kisspeptin signalling causes hypogonadotrophic hypogonadism in humans and animal models. In spite of the well recognized functions at hypothalamic levels, recent data strongly support direct production and activity of kisspeptin in testis and its involvement in the control of Leydig cells, germ cells progression and sperm functions. Similarly, estrogens exhibit high impact on proliferative/apoptotic/differentiative events in testis, thus resulting as local key modulators for the production - but also for the release, transport and maturation - of high quality spermatozoa.

Conclusion: This review summarizes the upcoming data from experimental models and humans concerning the testicular activity of kisspeptins and estrogens to preserve male fertility. Mutual enhancement of kisspeptin and estradiol signalling for the progression of spermatogenesis has also been discussed.
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http://dx.doi.org/10.2174/0929867323666160902155434DOI Listing
February 2017

Effects of Neuroendocrine CB1 Activity on Adult Leydig Cells.

Front Endocrinol (Lausanne) 2016 3;7:47. Epub 2016 Jun 3.

Dipartimento di Medicina Sperimentale, Seconda Università di Napoli , Napoli , Italy.

Endocannabinoids control male reproduction acting at central and local level via cannabinoid receptors. The cannabinoid receptor CB1 has been characterized in the testis, in somatic and germ cells of mammalian and non-mammalian animal models, and its activity related to Leydig cell differentiation, steroidogenesis, spermiogenesis, sperm quality, and maturation. In this short review, we provide a summary of the insights concerning neuroendocrine CB1 activity in male reproduction focusing on adult Leydig cell ontogenesis and steroid biosynthesis.
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http://dx.doi.org/10.3389/fendo.2016.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891325PMC
July 2016

Anandamide acts via kisspeptin in the regulation of testicular activity of the frog, Pelophylax esculentus.

Mol Cell Endocrinol 2016 Jan 14;420:75-84. Epub 2015 Nov 14.

Dipartimento di Medicina Sperimentale sez "F. Bottazzi", Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy. Electronic address:

In the frog Pelophylax esculentus, the endocannabinoid anandamide (AEA) modulates Gonadotropin Releasing Hormone (GnRH) system in vitro and down-regulates steroidogenic enzymes in vivo. Thus, male frogs were injected with AEA ± SR141716A, a cannabinoid receptor 1 (CB1) antagonist, to evaluate possible effects on GnRH and Kiss1/Gpr54 systems, gonadotropin receptors and steroid levels. In frog diencephalons, AEA negatively affected both GnRH and Kiss1/Gpr54 systems. In testis, AEA induced the expression of gonadotropin receptors, cb1, gnrh2 and gnrhr3 meanwhile reducing gnrhr2 mRNA and Kiss1/Gpr54 proteins. Furthermore, aromatase (Cyp19) expression increased in parallel to testosterone decrease and estradiol increase. In vitro treatment of testis with AEA revealed direct effects on Cyp19 and induced the expression of the AEA-degrading enzyme Faah. Lastly, AEA effects on Faah were counteracted by the antiestrogen ICI182780, indicating estradiol mediated effect. In conclusion, for the first time we show in a vertebrate that AEA regulates testicular activity through kisspeptin system.
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http://dx.doi.org/10.1016/j.mce.2015.11.011DOI Listing
January 2016

Expression analysis of gnrh1 and gnrhr1 in spermatogenic cells of rat.

Int J Endocrinol 2015 12;2015:982726. Epub 2015 Mar 12.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy.

Hypothalamic Gonadotropin Releasing Hormone (GnRH), via GnRH receptor (GnRHR), is the main actor in the control of reproduction, in that it induces the biosynthesis and the release of pituitary gonadotropins, which in turn promote steroidogenesis and gametogenesis in both sexes. Extrabrain functions of GnRH have been extensively described in the past decades and, in males, local GnRH activity promotes the progression of spermatogenesis and sperm functions at several levels. The canonical localization of Gnrh1 and Gnrhr1 mRNA is Sertoli and Leydig cells, respectively, but ligand and receptor are also expressed in germ cells. Here, we analysed the expression rate of Gnrh1 and Gnrhr1 in rat testis (180 days old) by quantitative real-time PCR (qPCR) and by in situ hybridization we localized Gnrh1 and Gnrhr1 mRNA in different spermatogenic cells of adult animals. Our data confirm the testicular expression of Gnrh1 and of Gnrhr1 in somatic cells and provide evidence that their expression in the germinal compartment is restricted to haploid cells. In addition, not only Sertoli cells connected to spermatids in the last steps of maturation but also Leydig and peritubular myoid cells express Gnrh1.
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http://dx.doi.org/10.1155/2015/982726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377535PMC
April 2015

Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes.

Gen Comp Endocrinol 2015 Jan 18;211:81-91. Epub 2014 Nov 18.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy. Electronic address:

Kisspeptin, via Gpr54 receptor, regulates puberty onset in most vertebrates. Thus, the direct involvement of kisspeptin activity in testis physiology was investigated in the anuran amphibian, Pelophylax esculentus. In this vertebrate gpr54 mRNA has been localized in both interstitial compartment and spermatogonia (SPG), whereas SPG proliferation requires the cooperation between estradiol and testicular Gonadotropin releasing hormone (Gnrh). In the pre-reproductive period, dose response curve to assess the effects of Kisspeptin-10 (Kp-10) was carried out in vitro (dose range: 10(-9)-10(-6)M; incubation times: 1 and 4h); proliferative activity and germ cell progression were evaluated by expression analysis of proliferating cell nuclear antigen (pcna), estrogen receptor beta (erβ), Gnrh system (gnrh1, gnrh2, gnrhr1, r2, r3) and by the count of empty, mitotic and meiotic tubules. All selected markers were up regulated at 4h Kp-10 incubation. Histological analysis also proved the increase of mitotic activity and the progression of spermatogenesis. Besides Kp-10 modulation of testicular Gnrh system, in vitro treatment with 17β-estradiol (10(-6)M) ± the antagonist ICI182-780 (10(-5)M) revealed gnrh2 and gnrhr3 estrogen dependent expression. In the reproductive period, testes were incubated for 1 and 4h with Kp-10 (10(-7)M) or Kp-10 (10(-7)M)+kisspeptin antagonist [Kp-234 (10(-6)M)]. Results obtained in the pre-reproductive period were confirmed and Kp-234 completely counteracted Kp-10 effects. In conclusion, Kp-10 modulated the expression of pcna, erβ, gnrhs and gnrhrs, inducing the progression of the spermatogenesis.
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http://dx.doi.org/10.1016/j.ygcen.2014.11.008DOI Listing
January 2015

Modulators of hypothalamic-pituitary-gonadal axis for the control of spermatogenesis and sperm quality in vertebrates.

Front Endocrinol (Lausanne) 2014 18;5:135. Epub 2014 Aug 18.

Department of Experimental Medicine, Second University of Naples , Naples , Italy.

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http://dx.doi.org/10.3389/fendo.2014.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135230PMC
September 2014

Molecular chaperones, cochaperones, and ubiquitination/deubiquitination system: involvement in the production of high quality spermatozoa.

Biomed Res Int 2014 19;2014:561426. Epub 2014 Jun 19.

Dipartimento di Medicina Sperimentale, Sezione "F. Bottazzi", Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.

Spermatogenesis is a complex process in which mitosis, meiosis, and cell differentiation events coexist. The need to guarantee the production of qualitatively functional spermatozoa has evolved into several control systems that check spermatogenesis progression/sperm maturation and tag aberrant gametes for degradation. In this review, we will focus on the importance of the evolutionarily conserved molecular pathways involving molecular chaperones belonging to the superfamily of heat shock proteins (HSPs), their cochaperones, and ubiquitination/deubiquitination system all over the spermatogenetic process. In this respect, we will discuss the conserved role played by the DNAJ protein Msj-1 (mouse sperm cell-specific DNAJ first homologue) and the deubiquitinating enzyme Ubpy (ubiquitin-specific processing protease-y) during the spermiogenesis in both mammals and nonmammalian vertebrates.
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http://dx.doi.org/10.1155/2014/561426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089148PMC
March 2015

Intra-testicular signals regulate germ cell progression and production of qualitatively mature spermatozoa in vertebrates.

Front Endocrinol (Lausanne) 2014 8;5:69. Epub 2014 May 8.

Dipartimento di Medicina Sperimentale sez "F. Bottazzi", Seconda Università degli Studi di Napoli , Naples , Italy.

Spermatogenesis, a highly conserved process in vertebrates, is mainly under the hypothalamic-pituitary control, being regulated by the secretion of pituitary gonadotropins, follicle stimulating hormone, and luteinizing hormone, in response to stimulation exerted by gonadotropin releasing hormone from hypothalamic neurons. At testicular level, gonadotropins bind specific receptors located on the somatic cells regulating the production of steroids and factors necessary to ensure a correct spermatogenesis. Indeed, besides the endocrine route, a complex network of cell-to-cell communications regulates germ cell progression, and a combination of endocrine and intra-gonadal signals sustains the production of high quality mature spermatozoa. In this review, we focus on the recent advances in the area of the intra-gonadal signals supporting sperm development.
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http://dx.doi.org/10.3389/fendo.2014.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021137PMC
June 2014

Endocannabinoids are Involved in Male Vertebrate Reproduction: Regulatory Mechanisms at Central and Gonadal Level.

Front Endocrinol (Lausanne) 2014 15;5:54. Epub 2014 Apr 15.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope , Naples , Italy.

Endocannabinoids (eCBs) are natural lipids regulating a large array of physiological functions and behaviors in vertebrates. The eCB system is highly conserved in evolution and comprises several specific receptors (type-1 and type-2 cannabinoid receptors), their endogenous ligands (e.g., anandamide and 2-arachidonoylglycerol), and a number of biosynthetic and degradative enzymes. In the last few years, eCBs have been described as critical signals in the control of male and female reproduction at multiple levels: centrally, by targeting hypothalamic gonadotropin-releasing-hormone-secreting neurons and pituitary, and locally, with direct effects on the gonads. These functions are supported by the extensive localization of cannabinoid receptors and eCB metabolic enzymes at different levels of the hypothalamic-pituitary-gonadal axis in mammals, as well as bonyfish and amphibians. In vivo and in vitro studies indicate that eCBs centrally regulate gonadal functions by modulating the gonadotropin-releasing hormone-gonadotropin-steroid network through direct and indirect mechanisms. Several proofs of local eCB regulation have been found in the testis and male genital tracts, since eCBs control Sertoli and Leydig cells activity, germ cell progression, as well as the acquisition of sperm functions. A comparative approach usually is a key step in the study of physiological events leading to the building of a general model. Thus, in this review, we summarize the action of eCBs at different levels of the male reproductive axis, with special emphasis, where appropriate, on data from non-mammalian vertebrates.
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http://dx.doi.org/10.3389/fendo.2014.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995072PMC
June 2014