Publications by authors named "Valeria Gasperi"

39 Publications

The Impact of Whole Grain Intake on Gastrointestinal Tumors: A Focus on Colorectal, Gastric, and Esophageal Cancers.

Nutrients 2020 Dec 29;13(1). Epub 2020 Dec 29.

Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.

Cereals are one of staple foods in human diet, mainly consumed as refined grains. Nonetheless, epidemiological data indicate that whole grain (WG) intake is inversely related to risk of type 2 diabetes, cardiovascular disease, and several cancer types, as well as to all-cause mortality. Particularly responsive to WG positive action is the gastrointestinal tract, daily exposed to bioactive food components. Herein, we shall provide an up-to-date overview on relationship between WG intake and prevention of gastrointestinal tumors, with a particular focus on colorectal, stomach, and esophagus cancers. Unlike refined counterparts, WG consumption is inversely associated with risk of these gastrointestinal cancers, most consistently with the risk of colorectal tumor. Some WG effects may be mediated by beneficial constituents (such as fiber and polyphenols) that are reduced/lost during milling process. Beside health-promoting action, WGs are still under-consumed in most countries; therefore, World Health Organization and other public/private stakeholders should cooperate to implement WG consumption in the whole population, in order to reach nutritionally effective intakes.
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http://dx.doi.org/10.3390/nu13010081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824588PMC
December 2020

Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions.

Cardiovasc Ther 2020 19;2020:2342837. Epub 2020 May 19.

Department of Experimental Medicine, Tor Vergata University of Rome, Rome 00133, Italy.

Cardiovascular diseases (CVD) represent one of the biggest causes of death globally, and their prevalence, aetiology, and outcome are related to genetic, metabolic, and environmental factors, among which sex- and age-dependent differences may play a key role. Among CVD risk factors, platelet hyperactivity deserves particular mention, as it is involved in the pathophysiology of main cardiovascular events (including stroke, myocardial infarction, and peripheral vascular injury) and is closely related to sex/age differences. Several determinants (, hormonal status and traditional cardiovascular risk factors), together with platelet-related factors (, plasma membrane composition, receptor signaling, and platelet-derived microparticles) can elucidate sex-related disparity in platelet functionality and CVD onset and outcome, especially in relation to efficacy of current primary and secondary interventional strategies. Here, we examined the state of the art concerning sex differences in platelet biology and their relationship with specific cardiovascular events and responses to common antiplatelet therapies. Moreover, as healthy nutrition is widely recognized to play a key role in CVD, we also focused our attention on specific dietary components (especially polyunsaturated fatty acids and flavonoids) and patterns (such as Mediterranean diet), which also emerged to impact platelet functions in a sex-dependent manner. These results highlight that full understanding of gender-related differences will be useful for designing personalized strategies, in order to prevent and/or treat platelet-mediated vascular damage.
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http://dx.doi.org/10.1155/2020/2342837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273457PMC
July 2020

Molecular Research on Platelet Activity in Health and Disease.

Int J Mol Sci 2020 May 27;21(11). Epub 2020 May 27.

Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.

This editorial summarizes and discusses the themes of eleven articles (five reviews and six original studies) published in the Special Issue "Molecular Research On Platelet Activity in Health and Disease". They give an international picture of the up-to-date understanding of i) platelet signalling under physiological and pathological conditions, ii) novel technologies for monitoring platelet functions and iii) clinical applications of platelet-based-therapy for management of pathological conditions, not directly related to haemostasis and thrombosis.
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http://dx.doi.org/10.3390/ijms21113804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312802PMC
May 2020

The "Janus Face" of Platelets in Cancer.

Int J Mol Sci 2020 Jan 25;21(3). Epub 2020 Jan 25.

Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.

Besides their vital role in hemostasis and thrombosis, platelets are also recognized to be involved in cancer, where they play an unexpected central role: They actively influence cancer cell behavior, but, on the other hand, platelet physiology and phenotype are impacted by tumor cells. The existence of this platelet-cancer loop is supported by a large number of experimental and human studies reporting an association between alterations in platelet number and functions and cancer, often in a way dependent on patient, cancer type and treatment. Herein, we shall report on an update on platelet-cancer relationships, with a particular emphasis on how platelets might exert either a protective or a deleterious action in all steps of cancer progression. To this end, we will describe the impact of (i) platelet count, (ii) bioactive molecules secreted upon platelet activation, and (iii) microvesicle-derived miRNAs on cancer behavior. Potential explanations of conflicting results are also reported: Both intrinsic (heterogeneity in platelet-derived bioactive molecules with either inhibitory or stimulatory properties; features of cancer cell types, such as aggressiveness and/or tumour stage) and extrinsic (heterogeneous characteristics of cancer patients, study design and sample preparation) factors, together with other confounding elements, contribute to "the Janus face" of platelets in cancer. Given the difficulty to establish the univocal role of platelets in a tumor, a better understanding of their exact contribution is warranted, in order to identify an efficient therapeutic strategy for cancer management, as well as for better prevention, screening and risk assessment protocols.
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http://dx.doi.org/10.3390/ijms21030788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037171PMC
January 2020

Polyunsaturated fatty acids modulate the delivery of platelet microvesicle-derived microRNAs into human breast cancer cell lines.

J Nutr Biochem 2019 12 27;74:108242. Epub 2019 Oct 27.

Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address:

Breast cancer is one of the most frequent and malignant types of cancer in women, with an increasing morbidity and mortality rate; in particular, treatment of triple negative breast cancer remains a challenge, since the efforts made with targeted therapies were ineffective. Among surrounding cells influencing the biology of cancer cells, platelets are recognizing as novel players. Activated platelets release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination; among factors contained in platelet-derived MVs, microRNAs are highly involved in cancer development. The growing interest in ω3 and ω6 polyunsaturated fatty acids (PUFAs) as adjuvants in anti-cancer therapy prompted us to investigate the ability of arachidonic acid (AA) and docosahexaenoic acid (DHA) to modulate MV biological functions. AA induced differential enhancement of platelet-specific microRNAs (miR-223 and miR-126), an effect further enhanced by the presence of DHA. MVs can be delivered to and microRNAs internalized by breast cancer cells, although with different efficiency; analysis of kinetics of MV delivery, indeed, suggested that tumor cells fine-tune the uptake of specific microRNA. Finally, we demonstrated that physiological delivery of platelet miR-223 and miR-126 induced cellular effects in breast cancer cells, including cell cycle arrest, inhibition of migration and sensitivity to cisplatin. These results have been confirmed by exogenous expression of miR-223 and miR-126 through transient transfection experiments. Our preliminary data suggest that ω6/ω3-PUFA supplementation, by modulating microRNA delivery, enhances platelet anti-tumor activities, thus opening new avenues for add-on therapies in cancer patients.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108242DOI Listing
December 2019

Nutrition and Breast Cancer: A Literature Review on Prevention, Treatment and Recurrence.

Nutrients 2019 Jul 3;11(7). Epub 2019 Jul 3.

Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.

Breast cancer (BC) is the second most common cancer worldwide and the most commonly occurring malignancy in women. There is growing evidence that lifestyle factors, including diet, body weight and physical activity, may be associated with higher BC risk. However, the effect of dietary factors on BC recurrence and mortality is not clearly understood. Here, we provide an overview of the current evidence obtained from the PubMed databases in the last decade, assessing dietary patterns, as well as the consumption of specific food-stuffs/food-nutrients, in relation to BC incidence, recurrence and survival. Data from the published literature suggest that a healthy dietary pattern characterized by high intake of unrefined cereals, vegetables, fruit, nuts and olive oil, and a moderate/low consumption of saturated fatty acids and red meat, might improve overall survival after diagnosis of BC. BC patients undergoing chemotherapy and/or radiotherapy experience a variety of symptoms that worsen patient quality of life. Studies investigating nutritional interventions during BC treatment have shown that nutritional counselling and supplementation with some dietary constituents, such as EPA and/or DHA, might be useful in limiting drug-induced side effects, as well as in enhancing therapeutic efficacy. Therefore, nutritional intervention in BC patients may be considered an integral part of the multimodal therapeutic approach. However, further research utilizing dietary interventions in large clinical trials is required to definitively establish effective interventions in these patients, to improve long-term survival and quality of life.
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http://dx.doi.org/10.3390/nu11071514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682953PMC
July 2019

Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications.

Int J Mol Sci 2019 Feb 23;20(4). Epub 2019 Feb 23.

Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.

Niacin (also known as "vitamin B₃" or "vitamin PP") includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B₃ has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer's, Parkinson's, and Huntington's diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders).
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http://dx.doi.org/10.3390/ijms20040974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412771PMC
February 2019

Essential Dietary Bioactive Lipids in Neuroinflammatory Diseases.

Antioxid Redox Signal 2018 07 24;29(1):37-60. Epub 2017 Jul 24.

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

Significance: Under physiological conditions, neurons and glia are in a healthy, redox-balanced environment; when injury perturbs this equilibrium, a neuroinflammatory state is established by activated microglia that triggers pro-inflammatory responses and alters the oxidant/antioxidant balance, thus leading to neuronal loss and neurodegeneration. In neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyothrophic lateral sclerosis, and multiple sclerosis), the brain is in a constitutively self-sustaining cycle of inflammation and oxidative stress that prompts and amplifies brain damage. Recent Advances: Recently, an increasing amount of scientific data highlight the ability of specific nutrients to cross the blood-brain barrier, and to modulate inflammatory and oxidative pathways. Therefore, nutritional approaches may contribute to restore the lost equilibrium among factors accounting for neurodegeneration.

Critical Issues: Herein, we critically examine how essential lipids (including fatty acids, liposoluble vitamins and phytosterols) might contribute to accelerate or prevent the onset and progression of such pathologies. In particular, we highlight that experimental and clinical findings, although promising, are still inadequate to draw definitive conclusions.

Future Directions: More research is warranted in order to establish the real impact of lipid intake on brain health, especially when redox balance and inflammatory responses have been already compromised. In the future, it would be hoped to gain a detailed knowledge of chemical modifications and dynamic properties of such nutrients, before planning to exploit them as potential therapeutics. Antioxid. Redox Signal. 29, 37-60.
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http://dx.doi.org/10.1089/ars.2016.6958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984567PMC
July 2018

Assay of CB1 Receptor Binding.

Methods Mol Biol 2016 ;1412:41-55

Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, via Montpellier 1, 00133, Rome, Italy.

Type-1 cannabinoid receptor (CB1), one of the main targets of endocannabinoids, plays a key role in several pathophysiological conditions that affect both central nervous system and peripheral tissues. Today, its biochemical identification and pharmacological characterization, as well as the screening of thousands of novel ligands that might be useful for developing CB1-based therapies, are the subject of intense research. Among available techniques that allow the analysis of CB1 binding activity, radioligand-based assays represent one of the best, fast, and reliable methods.Here, we describe radioligand binding methods standardized in our laboratory to assess CB1 binding in both tissues and cultured cells. We also report a high-throughput radioligand binding assay that allows to evaluate efficacy and potency of different compounds, which might represent the basis for the development of new drugs that target CB1 receptor-dependent human diseases.
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http://dx.doi.org/10.1007/978-1-4939-3539-0_5DOI Listing
December 2017

Downstream effects of endocannabinoid on blood cells: implications for health and disease.

Cell Mol Life Sci 2015 Sep 10;72(17):3235-52. Epub 2015 May 10.

Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133, Rome, Italy.

Endocannabinoids (eCBs), among which N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the most biologically active members, are polyunsaturated lipids able to bind cannabinoid, vanilloid and peroxisome proliferator-activated receptors. Depending on the target engaged, these bioactive mediators can regulate different signalling pathways, at both central and peripheral levels. The biological action of eCBs is tightly controlled by a plethora of metabolic enzymes which, together with the molecular targets of these substances, form the so-called "endocannabinoid system". The ability of eCBs to control manifold peripheral functions has received a great deal of attention, especially in the light of their widespread distribution in the body. In particular, eCBs are important regulators in blood, where they modulate haematopoiesis, platelet aggregation and apoptosis, as well as chemokine release and migration of immunocompetent cells. Here, we shall review the current knowledge on the pathophysiological roles of eCBs in blood. We shall also discuss the involvement of eCBs in those disorders affecting the haematological system, including cancer and inflammation. Knowledge gained to date underlines a fundamental role of the eCB system in blood, thus suggesting that it may represent a therapeutic promise for a broad range of diseases involving impaired hematopoietic cell functions.
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http://dx.doi.org/10.1007/s00018-015-1924-0DOI Listing
September 2015

Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors.

Life Sci 2015 Oct 15;138:41-51. Epub 2014 Oct 15.

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

Aims: Pro-inflammatory cytokines, growth and angiogenic factors released by leukocytes are involved in carcinogenesis and cancer progression, but they are also crucial for fighting tumour growth and spreading. We have previously demonstrated that endocannabinoids modulate cell-to-cell crosstalk during inflammation. Here, we investigated the inflammatory and tumourigenic properties of endocannabinoids in a human urinary bladder carcinoma cell line.

Main Methods: Endocannabinoid-treated ECV304 cells were checked for tumour necrosis factor (TNF)-α secretion (by ELISA assay) and surface exposure of selectins (by in situ ELISA and FACS analysis). ECV304/Jurkat T cell interaction was assessed by adhesion and live imaging experiments. Proliferation rate, cell death and cell cycle were determined by FACS analysis.

Key Findings: By binding to type-1 (CB1) and type-2 (CB2) cannabinoid receptors, the endocannabinoid 2-arachidonoylglycerol (2-AG) exacerbates the pro-inflammatory status surrounding bladder carcinoma ECV304 cells, by: (i) enhancing TNF-α release, (ii) increasing surface exposure of P- and E-selectins, and (iii) allowing Jurkat T lymphocytes to adhere to treated cancer cells. We also found that the CB1 inverse agonist AM281, unlike 2-AG, decreases cancer proliferation by delaying cell cycle progression.

Significance: Our data suggest that 2-AG modulates the inflammatory milieu of cancer cells in vitro, while AM281 plays a more specific role in proliferation. Collectively, these findings suggest that CB receptors may play distinct roles in cancer biology, depending on the specific ligand employed.

Conclusions: The in vivo assessment of the role of CB receptors in inflammation and cancer might be instrumental in broadening the understanding about bladder cancer biology.
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http://dx.doi.org/10.1016/j.lfs.2014.09.031DOI Listing
October 2015

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts.

Cell Cycle 2014 ;13(24):3938-47

a Department of Experimental Medicine & Surgery ; University of Rome Tor Vergata ; Rome , Italy.

Platelets modulate vascular system integrity, and their loss is critical in haematological pathologies and after chemotherapy. Therefore, identification of molecules enhancing platelet production would be useful to counteract thrombocytopenia. We have previously shown that 2-arachidonoylglycerol (2-AG) acts as a true agonist of platelets, as well as it commits erythroid precursors toward the megakaryocytic lineage. Against this background, we sought to further interrogate the role of 2-AG in megakaryocyte/platelet physiology by investigating terminal differentiation, and subsequent thrombopoiesis. To this end, we used MEG-01 cells, a human megakaryoblastic cell line able to produce in vitro platelet-like particles. 2-AG increased the number of cells showing ruffled surface and enhanced surface expression of specific megakaryocyte/platelet surface antigens, typical hallmarks of terminal megakaryocytic differentiation and platelet production. Changes in cytoskeleton modeling also occurred in differentiated megakaryocytes and blebbing platelets. 2-AG acted by binding to CB1 and CB2 receptors, because specific antagonists reverted its effect. Platelets were split off from megakaryocytes and were functional: they contained the platelet-specific surface markers CD61 and CD49, whose levels increased following stimulation with a natural agonist like collagen. Given the importance of 2-AG for driving megakaryopoiesis and thrombopoiesis, not surprisingly we found that its hydrolytic enzymes were tightly controlled by classical inducers of megakaryocyte differentiation. In conclusion 2-AG, by triggering megakaryocyte maturation and platelet release, may have clinical efficacy to counteract thrombocytopenia-related diseases.
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http://dx.doi.org/10.4161/15384101.2014.982941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614031PMC
September 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

2-Arachidonoylglycerol modulates human endothelial cell/leukocyte interactions by controlling selectin expression through CB1 and CB2 receptors.

Int J Biochem Cell Biol 2014 Jun 8;51:79-88. Epub 2014 Apr 8.

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. Electronic address:

Accumulated evidence points to a key role for endocannabinoids in cell migration, and here we sought to characterize the role of these substances in early events that modulate communication between endothelial cells and leukocytes. We found that 2-arachidonoylglycerol (2-AG) was able to initiate and complete the leukocyte adhesion cascade, by modulating the expression of selectins. A short exposure of primary human umbilical vein endothelial cells (HUVECs) to 2-AG was sufficient to prime them towards an activated state: within 1h of treatment, endothelial cells showed time-dependent plasma membrane expression of P- and E-selectins, which both trigger the initial steps (i.e., capture and rolling) of leukocyte adhesion. The effect of 2-AG was mediated by CB1 and CB2 receptors and was long lasting, because endothelial cells incubated with 2-AG for 1h released the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) for up to 24h. Consistently, TNF-α-containing medium was able to promote leukocyte recruitment: human Jurkat T cells grown in conditioned medium derived from 2-AG-treated HUVECs showed enhanced L-selectin and P-selectin glycoprotein ligand-1 (PSGL1) expression, as well as increased efficiency of adhesion and trans-migration. In conclusion, our in vitro data indicate that 2-AG, by acting on endothelial cells, might indirectly promote leukocyte recruitment, thus representing a potential therapeutic target for treatment of diseases where impaired endothelium/leukocyte interactions take place.
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http://dx.doi.org/10.1016/j.biocel.2014.03.028DOI Listing
June 2014

Physical activity and the endocannabinoid system: an overview.

Cell Mol Life Sci 2014 Jul 14;71(14):2681-98. Epub 2014 Feb 14.

Department of Movement, Human and Health Sciences, Foro Italico University of Rome, Piazza Lauro de Bosis 6, 00135, Rome, Italy.

Recognized as a "disease modifier", physical activity (PA) is increasingly viewed as a more holistic, cost-saving method for prevention, treatment and management of human disease conditions. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. Moreover, it is now emerging that PA itself is able to modulate ECS in different ways. Against this background, in the present review we shall discuss evidence of the cross-talk between PA and the ECS, ranging from brain to peripheral districts and highlighting how ECS must be tightly regulated during PA, in order to maintain its beneficial effects on cognition, mood, and nociception, while avoiding impaired energy metabolism, oxidative stress, and inflammatory processes.
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http://dx.doi.org/10.1007/s00018-014-1575-6DOI Listing
July 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

Obesity-associated oxidative stress: strategies finalized to improve redox state.

Int J Mol Sci 2013 May 21;14(5):10497-538. Epub 2013 May 21.

Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

Obesity represents a major risk factor for a plethora of severe diseases, including diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and cancer. It is often accompanied by an increased risk of mortality and, in the case of non-fatal health problems, the quality of life is impaired because of associated conditions, including sleep apnea, respiratory problems, osteoarthritis, and infertility. Recent evidence suggests that oxidative stress may be the mechanistic link between obesity and related complications. In obese patients, antioxidant defenses are lower than normal weight counterparts and their levels inversely correlate with central adiposity; obesity is also characterized by enhanced levels of reactive oxygen or nitrogen species. Inadequacy of antioxidant defenses probably relies on different factors: obese individuals may have a lower intake of antioxidant- and phytochemical-rich foods, such as fruits, vegetables, and legumes; otherwise, consumption of antioxidant nutrients is normal, but obese individuals may have an increased utilization of these molecules, likewise to that reported in diabetic patients and smokers. Also inadequate physical activity may account for a decreased antioxidant state. In this review, we describe current concepts in the meaning of obesity as a state of chronic oxidative stress and the potential interventions to improve redox balance.
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http://dx.doi.org/10.3390/ijms140510497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676851PMC
May 2013

Acute reduction of anandamide-hydrolase (FAAH) activity is coupled with a reduction of nociceptive pathways facilitation in medication-overuse headache subjects after withdrawal treatment.

Headache 2012 Oct 1;52(9):1350-61. Epub 2012 Jun 1.

Headache Clinic, IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy.

Objectives: We investigated (1) a possible relationship between the functional activity of the endocannabinoid system and the facilitation of pain processing in migraineurs with medication-overuse headache, and (2) the effect of withdrawal treatment on both.

Background: The endocannabinoid system antinociception effect includes prevention of nociceptive pathways sensitization. The sensitization of the pain pathways has been demonstrated to be pivotal in the development and maintenance of chronic form of migraine, including medication-overuse headache.

Methods: We used the temporal summation threshold of the nociceptive withdrawal reflex to explore the spinal cord pain processing, and the platelet activity of the enzyme fatty acid amide hydrolase to detect the functional state of the endocannabinoid system in 27 medication-overuse headache subjects before and 10 and 60 days after a standard withdrawal treatment and compared results with those of 14 controls.

Results: A significantly reduced temporal summation threshold and increased related pain sensation was found in subjects before withdrawal treatment when compared with controls. A significant fatty acid amide hydrolase activity reduction coupled with a significant improvement (reduction) in facilitation of spinal cord pain processing (increase in temporal summation threshold and reduction in related pain sensation) was found in medication-overuse headache subjects at both 10 and 60 days after withdrawal treatment when compared with medication-overuse headache subjects before withdrawal treatment.

Conclusions: We demonstrated a marked facilitation in spinal cord pain processing in medication-overuse headache before withdrawal treatment when compared with controls. Furthermore, the acute reduction of the fatty acid amide hydrolase activity coupled with a reduction of the facilitation in pain processing immediately (10 days) after withdrawal treatment and its persistence 60 days after withdrawal treatment could represent the consequence of a mechanism devoted to acutely reduce the degradation of endocannabinoids and aimed to increase the activity of the endocannabinoid system that results in an antinociceptive effect.
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http://dx.doi.org/10.1111/j.1526-4610.2012.02170.xDOI Listing
October 2012

The endocannabinoid system and its relevance for nutrition.

Annu Rev Nutr 2010 Aug;30:423-40

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

Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed, as well as the possible exploitation of ECS components as novel drug targets for therapeutic intervention in eating disorders.
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http://dx.doi.org/10.1146/annurev.nutr.012809.104701DOI Listing
August 2010

Characterization of the endocannabinoid system in mouse embryonic stem cells.

Stem Cells Dev 2011 Jan 12;20(1):139-47. Epub 2010 Oct 12.

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

In this study, we have ascertained the presence and functionality in mouse embryonic stem cells (ESCs) of members of the endocannabinoid system that have been proposed as possible modulators of the survival and differentiation of various type of stem cells. We show that mouse ESCs, in addition to classical CB(1) and CB(2) cannabinoid receptors, express the transient receptor potential vanilloid receptor, at mRNA, protein, and binding levels. Remarkably, we demonstrate that ESCs have the mRNA, protein, and enzyme activity to synthesize and degrade the prominent endocannabinoids anandamide (through N-acyl-phosphatidylethanolamine-specific phospholipase D and fatty acid amide hydrolase) and 2-arachidonoylglycerol (through diacylglycerol lipase and monoacylglycerol lipase). In addition, both endocannabinoids were detected in ESCs that were also shown to constitutively release a fatty acid amide hydrolase-activating compound. Finally, we document that the stimulation of ESCs by methanandamide, a nonhydrolysable analog of anandamide, does not lead to overt alteration of the expression of Oct3/4, Nanog, and Cdx2, genes that are involved in early cell fate in the preimplantation embryo and stemness, or of the expression patterns of Brachyury and Hnf4, genes that are used as late markers of lineage differentiation capability of ESC-derived embryoid bodies. Similarly ineffective on the expression of the tested stemness genes was 2-arachidonoylglycerol. Taken together, these results confirm and extend the notion that ESCs express several functional members of the endocannabinoid system, but they leave open the question about their role in stem cells as modulators of stemness and differentiation potential.
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http://dx.doi.org/10.1089/scd.2009.0515DOI Listing
January 2011

The endocannabinoid system and migraine.

Exp Neurol 2010 Jul 29;224(1):85-91. Epub 2010 Mar 29.

Headache Science Centre, IRCCS Neurological Institute C. Mondino Foundation, Pavia, Italy.

The recently discovered endocannabinoid system (ECS), which includes endocannabinoids and the proteins that metabolize and bind them, has been implicated in multiple regulatory functions both in health and disease. Several studies have suggested that ECS is centrally and peripherally involved in the processing of pain signals. This finding is corroborated by the evidence that endocannabinoids inhibit, through a cannabinoid type-1 receptor (CB1R)-dependent retrograde mechanism, the release of neurotransmitters controlling nociceptive inputs and that the levels of these lipids are high in those regions (such as sensory terminals, skin, dorsal root ganglia) known to be involved in transmission and modulation of pain signals. In this review we shall describe experimental and clinical data that, intriguingly, demonstrate the link between endocannabinoids and migraine, a neurovascular disorder characterized by recurrent episodic headaches and caused by abnormal processing of sensory information due to peripheral and/or central sensitization. Although the exact ECS-dependent mechanisms underlying migraine are not fully understood, the available results strongly suggest that activation of ECS could represent a promising therapeutical tool for reducing both the physiological and inflammatory components of pain that are likely involved in migraine attacks.
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http://dx.doi.org/10.1016/j.expneurol.2010.03.029DOI Listing
July 2010

Anandamide extends platelets survival through CB(1)-dependent Akt signaling.

Cell Mol Life Sci 2010 Feb 20;67(4):601-10. Epub 2009 Nov 20.

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.

Platelets are stored at 22 degrees C, since incubation at 37 degrees C results in loss of viability. Nonetheless, in our body (37 degrees C), platelets survive for 8-10 days. This discrepancy has been explained in terms of deprivation of viability factors or accumulation of apoptotic factors during storage. We report that the endocannabinoid anandamide (AEA) may be one of the agents allowing platelet survival. In fact, at 37 degrees C, human platelets enhance the expression of pro-apoptotic proteins (caspases, Bax, Bak) and decrease the expression of Bcl-xL, thus changing the Bcl-xL/Bak ratio, a key platelet biological clock. AEA or its non-hydrolyzable analogue, methanandamide, extend platelet life span, without reversing the changes in Bcl-xL/Bak ratio induced by heat stress. Instead, AEA binding to type-1 cannabinoid receptor activates Akt, which regulates, through phosphorylation of Bad, the interactions among different Bcl-2 family members. These findings could have implications for platelet collection and, potentially, for their clinical use.
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http://dx.doi.org/10.1007/s00018-009-0198-9DOI Listing
February 2010

Lipid rafts regulate 2-arachidonoylglycerol metabolism and physiological activity in the striatum.

J Neurochem 2009 Apr 2;109(2):371-81. Epub 2009 Feb 2.

Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Italy.

Several G protein-associated receptors and synaptic proteins function within lipid rafts, which are subdomains of the plasma membranes that contain high concentrations of cholesterol. In this study we addressed the possible role of lipid rafts in the control of endocannabinoid system in striatal slices. Disruption of lipid rafts following cholesterol depletion with methyl-beta-cyclodestrin (MCD) failed to affect synthesis and degradation of anandamide, while it caused a marked increase in the synthesis and concentration of 2-arachidonoylglycerol (2-AG), as well as in the binding activity of cannabinoid CB1 receptors. Surprisingly, endogenous 2-AG-mediated control of GABA transmission was not potentiated by MCD treatment and, in contrast, neither basal nor 3,5-Dihydroxyphenylglycine-stimulated 2-AG altered GABA synapses in cholesterol-depleted slices. Synaptic response to the cannabinoid CB1 receptor agonist HU210 was however intact in MCD-treated slices, indicating that reduced sensitivity of cannabinoid CB1 receptors does not explain why endogenous 2-AG is ineffective in inhibiting striatal GABA transmission after cholesterol depletion. Confocal microscopy analysis suggested that disruption of raft integrity by MCD might uncouple metabotropic glutamate 5-CB1 receptor interaction by altering the correct localization of both receptors in striatal neuron elements. In conclusion, our data indicate that disruption of raft integrity causes a complex alteration of the endocannabinoid signalling in the striatum.
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http://dx.doi.org/10.1111/j.1471-4159.2009.05948.xDOI Listing
April 2009

Expression of the endocannabinoid system in the bi-potential HEL cell line: commitment to the megakaryoblastic lineage by 2-arachidonoylglycerol.

J Mol Med (Berl) 2009 Jan 27;87(1):65-74. Epub 2008 Sep 27.

Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.

The role of the endocannabinoid system in haematopoietic cells is not completely understood. We investigated whether human erythroleukemia (HEL) cells were able to bind, metabolise and transport the main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). We also investigated whether AEA or 2-AG could modulate HEL differentiation. Although able to internalise both endocannabinoids, HEL cells had the machinery to metabolise 2-AG only, since they were devoid of the enzymes needed to synthesise and degrade AEA. Nonetheless, the intracellular transport of exogenous AEA might be required to activate the vanilloid receptors, with yet unknown implications for vascular biology. On the contrary, 2-AG appeared to play a role in lineage determination. Indeed, 2-AG itself drove HEL cells towards megakaryocytic differentiation, as it enhanced expression of beta3 integrin subunit, a megakaryocyte/platelet surface antigen, and glycoprotein VI, a late marker of megakaryocytes; in parallel, it reduced the amount of messenger RNA encoding for glycophorin A, a marker of erythroid phenotype. All these effects were mediated by activation of CB(2) cannabinoid receptors that triggered an extracellular signal-regulated kinase-dependent signalling cascade. In addition, classical inducers of megakaryocyte differentiation reduced 2-AG synthesis (although they did not affect the binding efficiency of CB(2) receptors), suggesting that levels of this endocannabinoid may be critical for committing HEL cells towards the megakaryocytic lineage.
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http://dx.doi.org/10.1007/s00109-008-0406-3DOI Listing
January 2009

Effect of RNAlater on lipoxygenase activity and expression, and immune cell apoptosis: opening the gate to the "ROALD" experiment aboard the space shuttle.

J Gravit Physiol 2007 Jul;14(1):P131-2

Department of Biomedical Sciences, University of Teramo, Piazz A. Moro 45, 64100 Teramo, Italy.

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July 2007

Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum.

Nat Neurosci 2008 Feb 20;11(2):152-9. Epub 2008 Jan 20.

Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Piazza Aldo Moro 45, 64100 Teramo, Italy.

Of the endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have received the most study. A functional interaction between these molecules has never been described. Using mouse brain slices, we found that stimulation of metabotropic glutamate 5 receptors by 3,5-dihydroxyphenylglycine (DHPG) depressed inhibitory transmission in the striatum through selective involvement of 2-AG metabolism and stimulation of presynaptic CB1 receptors. Elevation of AEA concentrations by pharmacological or genetic inhibition of AEA degradation reduced the levels, metabolism and physiological effects of 2-AG. Exogenous AEA and the stable AEA analog methanandamide inhibited basal and DHPG-stimulated 2-AG production, confirming that AEA is responsible for the downregulation of the other eCB. AEA is an endovanilloid substance, and the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels mimicked the effects of endogenous AEA on 2-AG metabolism through a previously unknown glutathione-dependent pathway. Consistently, the interaction between AEA and 2-AG was lost after pharmacological and genetic inactivation of TRPV1 channels.
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http://dx.doi.org/10.1038/nn2042DOI Listing
February 2008

Type-1 cannabinoid receptors colocalize with caveolin-1 in neuronal cells.

Neuropharmacology 2008 Jan 20;54(1):45-50. Epub 2007 Jul 20.

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.

Type-1 (CB1) and type-2 (CB2) cannabinoid receptors belong to the rhodopsin family of G protein-coupled receptors, and are activated by endogenous lipids termed "endocannabinoids". Recent reports have demonstrated that CB1R, unlike CB2R and other receptors and metabolic enzymes of endocannabinoids, functions in the context of lipid rafts, i.e. plasma membrane microdomains which may be important in modulating signal transduction. Here, we present novel data based on cell subfractionation, immunoprecipitation and confocal microscopy studies, that show that in C6 cells CB1R co-localizes almost entirely with caveolin-1. We also show that trafficking of CB1R in response to the raft disruptor methyl-beta-cyclodextrin (MCD) is superimposable on that of caveolin-1, and that MCD treatment increases the accessibility of CB1R to its specific antibodies. These findings may be relevant for the manifold CB1R-dependent activities of endocannabinoids, like the regulation of apoptosis and of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neuropharm.2007.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706320PMC
January 2008

Involvement of the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats.

Invest Ophthalmol Vis Sci 2007 Jul;48(7):2997-3004

Physiopathological Optics, Department of Biopathology and Diagnostic Imaging, University of Rome Tor Vergata, Rome, Italy.

Purpose: To evaluate whether high intraocular pressure (IOP)-induced ischemia is associated with modifications in the retinal endocannabinoid metabolism and to ascertain whether drugs that interfere with the endocannabinoid system may prevent retinal damage due to ischemic insult.

Methods: Anandamide (AEA) synthesis, transport, hydrolysis, and AEA endogenous levels were assessed by means of high-performance liquid chromatography in the retinas of rats undergoing 45 minutes of ischemia followed by 12 hours of reperfusion. Under these experimental conditions, binding to cannabinoid (CB1R) and vanilloid (TRPV1) receptor was assessed with rapid-filtration assays. AEA-hydrolase (FAAH, fatty acid amide hydrolase), CB1R and TRPV1 protein content was determined by enzyme-linked immunosorbent assay. Finally, to characterize the neuroprotective profile of drugs that interfere with the endocannabinoid system, cell counting in the retinal ganglion cell (RGC) layer and real-time polymerase chain reactions for Thy-1 mRNA expression were used.

Results: In rat retina, ischemic insult followed by reperfusion resulted in enhanced FAAH activity and protein expression paralleled by a significant decrease in the endogenous AEA tone, whereas the AEA-membrane transporter or the AEA-synthase NAPE-PLD (N-acyl-phosphatidylethanolamine-hydrolyzing-phospholipase-d) were not affected. Retinal ischemia-reperfusion decreased the expression of cannabinoid (CB1) and vanilloid (TRPV1) receptors. Systemic administration of a specific FAAH inhibitor (e.g., URB597) reduced enzyme activity and minimized the retinal damage observed in ischemic-reperfused samples. Similarly, intravitreal injection of the AEA stable analogue, R(+)-methanandamide, reduced cell loss in the RGC layer, and this was prevented by systemic administration of a CB1 or TRPV1 selective antagonist (e.g., SR141716 and capsazepine, respectively).

Conclusions: The original observation that retinal ischemia-reperfusion reduces endogenous AEA via enhanced expression of FAAH supports the deduction that this is implicated in retinal cell loss caused by high IOP in the RGC layer.
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http://dx.doi.org/10.1167/iovs.06-1355DOI Listing
July 2007

Endocannabinoids limit metabotropic glutamate 5 receptor-mediated synaptic inhibition of striatal principal neurons.

Mol Cell Neurosci 2007 Jun 15;35(2):302-10. Epub 2007 Mar 15.

Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy.

Synaptic transmission in the striatum is regulated by metabotropic glutamate (mGlu) receptors through pre- and postsynaptic mechanisms. We investigated the involvement of mGlu 1 and 5 receptors in the control of both excitatory and inhibitory transmission in the striatum. The mGlu 1 and 5 receptor agonist 3,5-DHPG failed to affect glutamate transmission, while it caused a biphasic effect on GABA transmission, characterized by early increase and late decrease in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from striatal principal neurons. Both mGlu 1 and 5 receptors were involved in the early response to 3,5-DHPG, through membrane depolarization of striatal GABAergic interneurons and action potential generation. The 3,5-DHPG-mediated late depression of inhibitory inputs to striatal principal neurons was conversely secondary to mGlu 5 receptor activation and subsequent endocannabinoid release. In conclusion, we have identified an mGlu-dependent mechanism of GABA transmission regulation of potential relevance for physiological neuronal activity.
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http://dx.doi.org/10.1016/j.mcn.2007.03.005DOI Listing
June 2007

Closing the gate to the active site: effect of the inhibitor methoxyarachidonyl fluorophosphonate on the conformation and membrane binding of fatty acid amide hydrolase.

J Biol Chem 2007 Feb 7;282(6):3829-36. Epub 2006 Dec 7.

INFM and Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.

Fatty acid amide hydrolase (FAAH) is a dimeric, membranebound enzyme that degrades neuromodulatory fatty acid amides and esters and is expressed in mammalian brain and peripheral tissues. The cleavage of approximately 30 amino acids from each subunit creates an FAAH variant that is soluble and homogeneous in detergent-containing buffers, opening the avenue to the in vitro mechanistic and structural studies. Here we have studied the stability of FAAH as a function of guanidinium hydrochloride concentration and of hydrostatic pressure. The unfolding transition was observed to be complex and required a fitting procedure based on a three-state process with a monomeric intermediate. The first transition was characterized by dimer dissociation, with a free energy change of approximately 11 kcal/mol that accounted for approximately 80% of the total stabilization energy. This process was also paralleled by a large change in the solvent-accessible surface area, because of the hydration occurring both at the dimeric interface and within the monomers. As a consequence, the isolated subunits were found to be much less stable (DeltaG approximately 3 kcal/mol). The addition of methoxyarachidonyl fluorophosphonate, an irreversible inhibitor of FAAH activity, enhanced the stability of the dimer by approximately 2 kcal/mol, toward denaturant- and pressure-induced unfolding. FAAH inhibition by methoxyarachidonyl fluorophosphonate also reduced the ability of the protein to bind to the membranes. These findings suggest that local conformational changes at the level of the active site might induce a tighter interaction between the subunits of FAAH, affecting the enzymatic activity and the interaction with membranes.
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http://dx.doi.org/10.1074/jbc.M605653200DOI Listing
February 2007