Mauro Maccarrone
@univaq.it
Professor and Chair, Department of Biotechnological and Applied Clinical Sciences
Università degli Studi dell'Aquila
Is Professor and Chair of Biochemistry at the Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila (Italy). He is also Head of the Lipid Neurochemistry Unit at the European Center for Brain Research – IRCCS Santa Lucia Foundation, Rome. For his research activity he has received the “4th Royan International Research Award for Reproductive Biomedicine” (2003), the “2007 IACM (International Association for Cannabis as Medicine) Award for Basic Research”, the “2016 Mechoulam Award”, the “2020 Tu Youyou Award”, and the “2020 International Space Station Research and Development Award” by the American Astronautical Society with NASA and CASIS. Chair of the 2015 Gordon Research Conference on “Cannabinoid Function in the CNS”. Visiting Professor at Leiden University (Leiden Institute of Chemistry, The Netherlands) in 2017, and at University of Cambridge (Department of Psychology, U.K.) in 2019.
EDUCATION
University of L’Aquila (I) M.S. in Biological Sciences (Biochemistry) - 1986
Universities of L’Aquila (I), of Chieti (I) and of Rome Tor Vergata (I) Ph.D. in Enzymology Applied to Medical Sciences - 1990
University of Utrecht (NL) Ph.D. in Bio-Organic Chemistry - 1992
RESEARCH INTERESTS
Bioactive lipids
Endocannabinoids
Proresolving lipid mediators
Signal transduction
Scopus Publications
Scopus Publications
Giulia Leanza, Francesca Cannata, Malak Faraj, Claudio Pedone, Viola Viola, Flavia Tramontana, Niccolò Pellegrini, Gianluca Vadalà, Alessandra Piccoli, Rocky Strollo,et al.
eLife Sciences Publications, Ltd
Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.
Giulia Carozza, Darin Zerti, Annamaria Tisi, Marco Ciancaglini, Mauro Maccarrone, and Rita Maccarone
Walter de Gruyter GmbH
Abstract Age-related macular degeneration (AMD) is a complex, multifactorial disease leading to progressive and irreversible retinal degeneration, whose pathogenesis has not been fully elucidated yet. Due to the complexity and to the multiple features of the disease, many efforts have been made to develop animal models which faithfully reproduce the overall AMD hallmarks or that are able to mimic the different AMD stages. In this context, light damage (LD) rodent models of AMD represent a suitable and reliable approach to mimic the different AMD forms (dry, wet and geographic atrophy) while maintaining the time-dependent progression of the disease. In this review, we comprehensively reported how the LD paradigms reproduce the main features of human AMD. We discuss the capability of these models to broaden the knowledge in AMD research, with a focus on the mechanisms and the molecular hallmarks underlying the pathogenesis of the disease. We also critically revise the remaining challenges and future directions for the use of LD models.
Fulvio Erba, Giampiero Mei, Velia Minicozzi, Annalaura Sabatucci, Almerinda Di Venere, and Mauro Maccarrone
MDPI AG
Lipoxygenases (LOXs) are a family of enzymes that includes different fatty acid oxygenases with a common tridimensional structure. The main functions of LOXs are the production of signaling compounds and the structural modifications of biological membranes. These features of LOXs, their widespread presence in all living organisms, and their involvement in human diseases have attracted the attention of the scientific community over the last decades, leading to several studies mainly focused on understanding their catalytic mechanism and designing effective inhibitors. The aim of this review is to discuss the state-of-the-art of a different, much less explored aspect of LOXs, that is, their interaction with lipid bilayers. To this end, the general architecture of six relevant LOXs (namely human 5-, 12-, and 15-LOX, rabbit 12/15-LOX, coral 8-LOX, and soybean 15-LOX), with different specificity towards the fatty acid substrates, is analyzed through the available crystallographic models. Then, their putative interface with a model membrane is examined in the frame of the conformational flexibility of LOXs, that is due to their peculiar tertiary structure. Finally, the possible future developments that emerge from the available data are discussed.
Alessandro Leuti, Marina Fava, Niccolò Pellegrini, Giulia Forte, Federico Fanti, Francesco Della Valle, Noemi De Dominicis, Manuel Sergi, and Mauro Maccarrone
MDPI AG
Space-related stressors such as microgravity are associated with cellular and molecular alterations of the immune and inflammatory homeostasis that have been linked to the disorders that astronauts suffer from during their missions. Most of the research of the past 30 years has consistently established that innate adaptive immune cells represent a target of microgravity, which leads to their defective or dysfunctional activation, as well as to an altered ability to produce soluble mediators—e.g., cytokines/chemokines and bioactive lipids—that altogether control tissue homeostasis. Bioactive lipids include a vast array of endogenous molecules of immune origin that control the induction, intensity and outcome of the inflammatory events. However, none of the papers published so far focus on a newly characterized class of lipid mediators called specialized pro-resolving mediators (SPMs), which orchestrate the “resolution of inflammation”—i.e., the active control and confinement of the inflammatory torrent mostly driven by eicosanoids. SPMs are emerging as crucial players in those processes that avoid acute inflammation to degenerate into a chronic event. Given that SPMs, along with their metabolism and signaling, are being increasingly linked to many inflammatory disorders, their study seems of the outmost importance in the research of pathological processes involved in space-related diseases, also with the perspective of developing therapeutic countermeasures. Here, we show that microgravity, simulated in the rotary cell culture system (RCCS) developed by NASA, rearranges SPM receptors both at the gene and protein level, in human monocytes but not in lymphocytes. Moreover, RCCS treatment reduces the biosynthesis of a prominent SPM like resolvin (Rv) D1. These findings strongly suggest that not only microgravity can impair the functioning of immune cells at the level of bioactive lipids directly involved in proper inflammation, but it does so in a cell-specific manner, possibly perturbing immune homeostasis with monocytes being primary targets.
Eleanna Kaffe, Annamaria Tisi, Christiana Magkrioti, Vassilis Aidinis, Wajahat Z. Mehal, Richard A. Flavell, and Mauro Maccarrone
Elsevier BV
Alessandro Leuti, Marina Fava, and Mauro Maccarrone
Elsevier BV
Emanuele Criscuolo, Maria Laura De Sciscio, Angela De Cristofaro, Catalin Nicoara, Mauro Maccarrone, and Filomena Fezza
MDPI AG
The cannabinoid receptor 1 (CB1R) plays a pivotal role in regulating various physiopathological processes, thus positioning itself as a promising and sought-after therapeutic target. However, the search for specific and effective CB1R ligands has been challenging, prompting the exploration of drug repurposing (DR) strategies. In this study, we present an innovative DR approach that combines computational screening and experimental validation to identify potential Food and Drug Administration (FDA)-approved compounds that can interact with the CB1R. Initially, a large-scale virtual screening was conducted using molecular docking simulations, where a library of FDA-approved drugs was screened against the CB1R’s three-dimensional structures. This in silico analysis allowed us to prioritize compounds based on their binding affinity through two different filters. Subsequently, the shortlisted compounds were subjected to in vitro assays using cellular and biochemical models to validate their interaction with the CB1R and determine their functional impact. Our results reveal FDA-approved compounds that exhibit promising interactions with the CB1R. These findings open up exciting opportunities for DR in various disorders where CB1R signaling is implicated. In conclusion, our integrated computational and experimental approach demonstrates the feasibility of DR for discovering CB1R modulators from existing FDA-approved compounds. By leveraging the wealth of existing pharmacological data, this strategy accelerates the identification of potential therapeutics while reducing development costs and timelines. The findings from this study hold the potential to advance novel treatments for a range of CB1R -associated diseases, presenting a significant step forward in drug discovery research.
Nicola Gambacorta, Valeria Gasperi, Tatiana Guzzo, Francesco Saverio Di Leva, Fulvio Ciriaco, Cristina Sánchez, Valentina Tullio, Diego Rozzi, Luciana Marinelli, Alessandra Topai,et al.
Elsevier BV
Annamaria Tisi, Sakthimala Palaniappan, and Mauro Maccarrone
MDPI AG
Advanced genomics, transcriptomics, and epigenomics techniques are providing unprecedented insights into the understanding of the molecular underpinnings of the central nervous system, including the neuro-sensory cochlea of the inner ear. Here, we report for the first time a comprehensive and updated overview of the most advanced omics techniques for the study of nucleic acids and their applications in cochlear research. We describe the available in vitro and in vivo models for hearing research and the principles of genomics, transcriptomics, and epigenomics, alongside their most advanced technologies (like single-cell omics and spatial omics), which allow for the investigation of the molecular events that occur at a single-cell resolution while retaining the spatial information.
Mauro Maccarrone, Vincenzo Di Marzo, Jürg Gertsch, Uwe Grether, Allyn C. Howlett, Tian Hua, Alexandros Makriyannis, Daniele Piomelli, Natsuo Ueda, and Mario van der Stelt
American Society for Pharmacology & Experimental Therapeutics (ASPET)
The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ9-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS)—made of receptors, metabolic enzymes, and transporters—that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of the ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here a critical review of our knowledge of the goods and bads of the ECS as a therapeutic target is presented to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. Significance Statement The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like cannabinoid receptors 1 and 2) and metabolic enzymes (like fatty acid amide hydrolase and monoacylglycerol lipase), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels, providing new opportunities to treat patients.
Michela Bossa, Ornella Argento, Chiara Piacentini, Nicola Manocchio, Lucia Scipioni, Sergio Oddi, Mauro Maccarrone, and Ugo Nocentini
MDPI AG
N-palmitoylethanolamine (PEA) plays a key role in preventing Aβ-mediated neuroinflammation and neurotoxicity in murine models. It has been demonstrated that PEA provides anti-neuroinflammatory, pain-relieving and neuroprotective actions even in humans. In this project, we aim to evaluate these anti-neuroinflammatory effects via the cognitive evaluation and biochemical analyses of a 12-month oral administration of PEA in subjects with mild cognitive impairment (MCI). Subjects with MCI will be randomized to placebo or PEA groups, and followed for another 6 months. Cognitive abilities and neurological inflammation will be examined at baseline and after treatment. The specific objectives of the project are to ascertain whether: (i) PEA influences the scores of the neuropsychological and behavioral evaluations after one-year treatment, comparing PEA-treated and placebo subjects in both MCI and control groups; (ii) PEA can change the inflammatory and neuronal damage markers of blood and urine in MCI subjects; and (iii) these changes correlate with the clinical scores of participating subjects.
Sergio Oddi, Maria Teresa Fiorenza, and Mauro Maccarrone
Elsevier BV
Federico Fanti, Flaminia Vincenti, Giulia Imparato, Camilla Montesano, Lucia Scipioni, Francesca Ciaramellano, Daniel Tortolani, Sergio Oddi, Mauro Maccarrone, Dario Compagnone,et al.
Elsevier BV
Sara Standoli, Cinzia Rapino, Camilla Di Meo, Agnes Rudowski, Nicole Kämpfer-Kolb, Luisa Michelle Volk, Dominique Thomas, Sandra Trautmann, Yannick Schreiber, Dagmar Meyer zu Heringdorf,et al.
MDPI AG
Microglia, the resident immune cells of the central nervous system, play important roles in brain homeostasis as well as in neuroinflammation, neurodegeneration, neurovascular diseases, and traumatic brain injury. In this context, components of the endocannabinoid (eCB) system have been shown to shift microglia towards an anti-inflammatory activation state. Instead, much less is known about the functional role of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) system in microglia biology. In the present study, we addressed potential crosstalk of the eCB and the S1P systems in BV2 mouse microglia cells challenged with lipopolysaccharide (LPS). We show that URB597, the selective inhibitor of fatty acid amide hydrolase (FAAH)—the main degradative enzyme of the eCB anandamide—prevented LPS-induced production of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), and caused the accumulation of anandamide itself and eCB-like molecules such as oleic acid and cis-vaccenic acid ethanolamide, palmitoylethanolamide, and docosahexaenoyl ethanolamide. Furthermore, treatment with JWH133, a selective agonist of the eCB-binding cannabinoid 2 (CB2) receptor, mimicked the anti-inflammatory effects of URB597. Interestingly, LPS induced transcription of both SphK1 and SphK2, and the selective inhibitors of SphK1 (SLP7111228) and SphK2 (SLM6031434) strongly reduced LPS-induced TNFα and IL-1β production. Thus, the two SphKs were pro-inflammatory in BV2 cells in a non-redundant manner. Most importantly, the inhibition of FAAH by URB597, as well as the activation of CB2 by JWH133, prevented LPS-stimulated transcription of SphK1 and SphK2. These results present SphK1 and SphK2 at the intersection of pro-inflammatory LPS and anti-inflammatory eCB signaling, and suggest the further development of inhibitors of FAAH or SphKs for the treatment of neuroinflammatory diseases.
Gianna Rossi, Valentina Di Nisio, Alessandro Chiominto, Sandra Cecconi, and Mauro Maccarrone
MDPI AG
The endocannabinoid (eCB) system has gained ground as a key modulator of several female fertility-related processes, under physiological/pathological conditions. Nevertheless, its modulation during reproductive aging remains unclear. This study aimed to investigate the expression levels of the main receptors (cannabinoid receptor 1,CB1; cannabinoid receptor 2, CB2; G-protein coupled receptor, GPR55; and transient receptor potential vanilloid type 1 channel, TRPV1) and metabolic enzymes (N-acylphosphatidylethanolamine phospholipase D, NAPE-PLD; fatty acid amide hydrolase, FAAH; monoacylglycerol lipase, MAGL; and diacylglycerol lipase, DAGL-α and -β) of this system in the ovaries, oviducts, and uteri of mice at prepubertal, adult, late reproductive, and post-reproductive stages through quantitative ELISA and immunohistochemistry. The ELISA showed that among the receptors, TRPV1 had the highest expression and significantly increased during aging. Among the enzymes, NAPE-PLD, FAAH, and DAGL-β were the most expressed in these organs at all ages, and increased age-dependently. Immunohistochemistry revealed that, regardless of age, NAPE-PLD and FAAH were mainly found in the epithelial cells facing the lumen of the oviduct and uteri. Moreover, in ovaries, NAPE-PLD was predominant in the granulosa cells, while FAAH was sparse in the stromal compartment. Of note, the age-dependent increase in TRPV1 and DAGL-β could be indicative of increased inflammation, while that of NAPE-PLD and FAAH could suggest the need to tightly control the levels of the eCB anandamide at late reproductive age. These findings offer new insights into the role of the eCB system in female reproduction, with potential for therapeutic exploitation.
Giulia Leanza, Caterina Conte, Francesca Cannata, Camilla Isgrò, Alessandra Piccoli, Rocky Strollo, Carlo Cosimo Quattrocchi, Rocco Papalia, Vincenzo Denaro, Mauro Maccarrone,et al.
MDPI AG
Oxidative stress, a key mediator of cardiovascular disease, metabolic alterations, and cancer, is independently associated with menopause and obesity. Yet, among postmenopausal women, the correlation between obesity and oxidative stress is poorly examined. Thus, in this study, we compared oxidative stress states in postmenopausal women with or without obesity. Body composition was assessed via DXA, while lipid peroxidation and total hydroperoxides were measured in patient’s serum samples via thiobarbituric-acid-reactive substances (TBARS) and derivate-reactive oxygen metabolites (d-ROMs) assays, respectively. Accordingly, 31 postmenopausal women were enrolled: 12 with obesity and 19 of normal weight (mean (SD) age 71.0 (5.7) years). Doubled levels of serum markers of oxidative stress were observed in women with obesity in women with obesity compared to those of normal weight (H2O2: 32.35 (7.3) vs. 18.80 (3.4) mg H2O2/dL; malondialdehyde (MDA): 429.6 (138.1) vs. 155.9 (82.4) mM in women with or without obesity, respectively; p < 0.0001 for both). Correlation analysis showed that both markers of oxidative stress increased with an increasing body mass index (BMI), visceral fat mass, and trunk fat percentage, but not with fasting glucose levels. In conclusion, obesity and visceral fat are associated with a greater increase in oxidative stress in postmenopausal women, possibly increasing cardiometabolic and cancer risks.
Annamaria Tisi, Giulia Carozza, Alessandro Leuti, Rita Maccarone, and Mauro Maccarrone
MDPI AG
Resolvin E1 (RvE1) is an eicosapentaenoic acid-derived lipid mediator involved in the resolution of inflammation. Here, we investigated whether RvE1 alterations may occur in an animal model of age-related macular degeneration (AMD). To this end, Sprague Dawley albino rats underwent light damage (LD), and retinas and serum were analyzed immediately or seven days after treatment. Western blot of retinas showed that the RvE1 receptor ChemR23 and the RvE1 metabolic enzymes 5-LOX and COX-2 were unchanged immediately after LD, but they were significantly up-regulated seven days later. Instead, the RvE1 receptor BLT1 was not modulated by LD, and neither was the RvE1 degradative enzyme 15-PGDH. Moreover, ChemR23, 5-LOX, COX-2 and BLT1 were found to be more expressed in the inner retina under all experimental conditions, as observed through ImageJ plot profile analysis. Of note, amacrine cells highly expressed BLT1, while ChemR23 was highly expressed in the activated microglia of the outer retina. ELISA assays also showed that LD rats displayed significantly higher circulating levels and reduced retinal levels of RvE1 compared to controls. Altogether, our data indicate that RvE1 metabolism and signaling are modulated in the LD model, suggesting a potentially relevant role of this pathway in AMD.
Lucia Scipioni, Daniel Tortolani, Francesca Ciaramellano, Federico Fanti, Thais Gazzi, Manuel Sergi, Marc Nazaré, Sergio Oddi, and Mauro Maccarrone
MDPI AG
Dysfunctional phenotype of microglia, the primary brain immune cells, may aggravate Alzheimer’s disease (AD) pathogenesis by releasing proinflammatory factors, such as nitric oxide (NO). The endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids increasingly recognised for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. To investigate the possible impact of chronic exposure to β-amyloid peptides (Aβ) on the microglial endocannabinoid signalling, we characterised the functional expression of the endocannabinoid system on neonatal microglia isolated from wild-type and Tg2576 mice, an AD-like model, which overexpresses Aβ peptides in the developing brain. We found that Aβ-exposed microglia produced 2-fold more 2-AG than normal microglia. Accordingly, the expression levels of diacylglycerol lipase-α (DAGLα) and monoacylglycerol lipase (MAGL), the main enzymes responsible for synthesising and hydrolysing 2-AG, respectively, were consistently modified in Tg2576 microglia. Furthermore, compared to wild-type cells, transgenic microglia basally showed increased expression of the cannabinoid 2 receptor, typically upregulated in an activated proinflammatory phenotype. Indeed, following inflammatory stimulus, Aβ-exposed microglia displayed an enhanced production of NO, which was abolished by pharmacological inhibition of DAGLα. These findings suggested that exposure to Aβ polarises microglial cells towards a pro-AD phenotype, possibly by enhancing 2-AG signalling.
Mauro Maccarrone
MDPI AG
Lipids are usually viewed as metabolic fuel and structural membrane components. Yet, in recent years, different families of lipids able to act as authentic messengers between cells and/or intracellularly have been discovered. Such lipid signals have been shown to exert their biological activity via specific receptors that, by triggering distinct signal transduction pathways, regulate manifold pathophysiological processes in our body. Here, endogenous bioactive lipids produced from arachidonic acid (AA) and other poly-unsaturated fatty acids will be presented, in order to put into better perspective the relevance of their mutual interactions for health and disease conditions. To this end, metabolism and signal transduction pathways of classical eicosanoids, endocannabinoids and specialized pro-resolving mediators will be described, and the intersections and commonalities of their metabolic enzymes and binding receptors will be discussed. Moreover, the interactions of AA-derived signals with other bioactive lipids such as shingosine-1-phosphate and steroid hormones will be addressed.
Daniel Tortolani, Camilla Di Meo, Sara Standoli, Francesca Ciaramellano, Salam Kadhim, Eric Hsu, Cinzia Rapino, and Mauro Maccarrone
MDPI AG
Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array. Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH. Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.
Patrizia Morciano, Valentina Dini, Francesco Berardinelli, Giorgio Baiocco, Valeria Conte, Ion Udroiu, Federica Barbato, Jessica Marinaccio, Pasqualino Anello, Antonio Antoccia,et al.
Frontiers Media SA
One of the most intriguing and still pending questions in radiobiology is to understand whether and how natural environmental background radiation has shaped Life over millions of years of evolution on Earth. Deep Underground Laboratories (DULs) represent the ideal below-background exposure facilities where to address such a question. Among the few worldwide DULs, INFN-Laboratorio Nazionale del Gran Sasso (LNGS) is one of the largest in terms of size and infrastructure. Designed and built to host neutrino and dark matter experiments, since the 1990 s the LNGS has been one of the first DULs to systematically host radiobiology experiments. Here we present the DISCOVER22 (DNA Damage and Immune System Cooperation in VEry low Radiation environment 2022) experiment recently started at LNGS. DISCOVER22 aims at investigating how the low radiation background modulates the Immune System (IS) response in in vitro and in vivo models. Underground radiobiology experiments are particularly complex and tricky to design and perform. In these studies, the accurate characterization of exposure scenarios is mandatory, but a challenging aspect is to understand how the very few ionizing tracks in the ultra-Low Radiation Environment (LRE) interact with the living matter in space and time in order to trigger different biological responses. In this Perspective, we describe these challenges and how we address them through a microdosimetric and a radiobiological approaches. We aim at linking physical microdosimetric measurements and the corresponding biological radiation responses by using radiation biophysical models that could shed light on many as yet unresolved questions.
F. Fezza, E. Criscuolo, M.L. De Sciscio, and M. Maccarrone
Elsevier
Luca Navarini, Marta Vomero, Damiano Currado, Onorina Berardicurti, Alice Biaggi, Annalisa Marino, Pietro Bearzi, Erika Corberi, Amelia Rigon, Luisa Arcarese,et al.
Frontiers Media SA
IntroductionCOVID-19 and autoinflammatory diseases, such as Adult-onset Still’s Disease (AOSD), are characterized by hyperinflammation, in which it is observed massive production and uncontrolled secretion of pro-inflammatory cytokines. The specialized pro-resolving lipid mediators (SPMs) family is one the most important processes counteracting hyperinflammation inducing tissue repair and homeostasis restoration. Among SPMs, Protectin D1 (PD1) is able to exert antiviral features, at least in animal models. The aim of this study was to compare the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with AOSD and COVID-19 and to evaluate the role of PD1 on those diseases, especially in modulating macrophages polarization.MethodsThis study enrolled patients with AOSD, COVID-19, and healthy donors HDs, undergoing clinical assessment and blood sample collection. Next-generation deep sequencing was performed to identify differences in PBMCs transcripts profiles. Plasma levels of PD1 were assessed by commercial ELISA kits. Monocyte-derived macrophages were polarized into M1 and M2 phenotypes. We analyzed the effect of PD1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays.ResultsIn the transcriptomes from AOSD patients and COVID-19 patients, genes involved in inflammation, lipid catabolism, and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Patients affected by COVID-19, hospitalized in intensive care unit (ICU), showed higher levels of PD1 when compared to not-ICU hospitalized patients and HDs (ICU COVID-19 vs not-ICU COVID-19, p= 0.02; HDs vs ICU COVID-19, p= 0.0006). PD1 levels were increased in AOSD patients with SS ≥1 compared to patients with SS=0 (p=0.028) and HDs (p=0.048). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p&lt;0.05). Furthermore, a significant release of IL-10 and MIP-1β from M2 macrophages was observed when compared to controls (p&lt;0.05).DiscussionPD1 is able to induce pro-resolutory programs in both AOSD and COVID-19 increasing M2 polarization and inducing their activity. In particular, PD1-treated M2 macrophages from AOSD and COVID-19 patients increased the production of IL-10 and enhanced homeostatic restoration through MIP-1β production.
Valeria Gasperi, Tatiana Guzzo, Alessandra Topai, Nicola Gambacorta, Fulvio Ciriaco, Orazio Nicolotti, and Mauro Maccarrone
Bentham Science Publishers Ltd.
Abstract: In the last decade, selective modulators of type-2 cannabinoid receptor (CB2) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our body, CB2 actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB2 modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB2 agonists in the last five years. Against this background, here we discuss the most recent evidence of the protective effects of CB2 against pathological conditions, emphasizing central nervous system disorders, bone and synovial diseases, and cancer. We also summarize the most recent advances in the development of CB2 agonists, focusing on the correlation between different chemical classes and diverse therapeutic applications. Data mining includes a review of the CB2 ligands disclosed in patents also released in the last five years. Finally, we discuss how the recent elucidation of CB2 tertiary structure has provided new details for the rational design of novel and more selective CB2 agonists, thus supporting innovative strategies to develop effective therapeutics. Our overview of the current knowledge on CB2 agonists provides pivotal information on the structure and function of different classes of molecules and opens possible avenues for future research.
Publications
Published more than 520 full papers, of which 65 with I.F. ≥ 9, 15 with I.F. ≥ 15, 65 with 100 - 475 citations (total I.F. > 2700; citations = 20795, h-index = 76 according to Scopus), including more than 45 review articles and more than 60 invited papers in international refereed journals, be-sides more than 100 mini-papers and more than 330 Congress communications. Among others, he published 14 papers in J. Biol. Chem., 10 in J. Neurosci., 9 in Cell. Mol. Life Sci., 8 in Cell Death Differ., 6 in Trends Pharmacol. Sci., 4 in Blood, Neuropsychopharmacol. and FASEB J., 3 in Prog. Lipid Res., Biol. Psych. and J. Immunol., 2 in Prog. Neurobiol., Nature Commun., PNAS, Ann. Neurol. and Brain, 1 in NEJM, Nature Rev. Neurosci., Science, Science Trans. Med., Lancet, Lancet Neurol., JAMA, Endocr. Rev., Nature Neurosci., Trends Biochem. Sci., Annu. Rev. Nutr., and Gastroenterology.
Due to his scientific activity and impact, is included by Stanford University in the “2021 World Top 2% Scientists' List”, where he holds the 179th position among 4955 Italian researchers. He is also listed among the “Top Italian Scientists”.
GRANT DETAILS
a. MoMa Project of the Italian Space Agency (ASI-ESA-NASA) 2006 – The endocannabinoid system in the induction of T cell apoptosis un-der microgravity conditions. Local PI. DCMC Project of the Italian Space Agency (ASI-ESA-NASA) 2006 – The endocannabinoid system in the control of neuronal cell death under microgravity conditions. Local PI.
b. Research Project HIGH Q FOUNDATION Inc. (New Jersey, U.S.A.) 2007 – Endocannabinoid system as potential biomarker and therapeu-tic target in HD. PI.
c. Research Project NATIONAL INSTITUTES OF HEALTH (NIH) 2007 – Characterization of anandamide transport in brain (subaward No. 2007-1917 under NIH prime award No. DA012413). Local PI.
d. Research Project of National Interest (PRIN) 2008 - Interaction of anandamide hydrolase (FAAH) with membranes: how to get hydropho-bic substrates and release hydrophilic products. PI.
e. Medical Research Council (MRC)-funded research 2009-2011 –The endocannabinoid, anandamide as a biomarker of outcome in preg-nancies complicated by threatened miscarriage. Local PI.
f. L’Oreal (Paris) 2009-2012 - Endocannabinoid system in melanocytes: A target for novel cosmetic drugs. PI.
g. SIGMA TAU Industries (Rome) 2009-2010 – Study of potential reversible inhibitors of FAAH. PI.
h. GW Pharmaceuticals PLC (London) 2010-2011 - Regulation of gene expression through DNA methylation by cannabidiol and other phy-tocannabinoids. PI.
i. Fondazione Italiana Sclerosi Multipla 2010-2011 - Role of the endocannabinoid system in the n
RESEARCH OUTPUTS (PATENTS, SOFTWARE, PUBLICATIONS, PRODUCTS)
Holder of the following granted patents: 1) Enol carbamate derivatives as modulators of fatty acid amide hydrolase (TW200948805, AR072346). 2) Oxime carbamoyl derivatives as modulators of fatty acid amide hydrolase (WO2009138416, AR071800). 3) Compounds of 2,3-dihydro-4H-1,3-benzoxazine-4-one, method for preparing them and pharmaceutical form comprising them (WO2013IB61106, ITMI20122221). 4) Use of canna-binoid compounds for stimulating melanogenesis (FR2978659, 2014). 5) Use of a cb1 receptor antagonist as a whitening and/or anti-browning agent for keratin material (FR2978660, 2013). 6) Design and synthesis of biotinylated probes for n-acyl-ethanolamines (US7955816, 2011). 7) Method and kit for the early diagnosis of miscarriage in human beings (EP1272659, 2007). 8) Funzionalizzazione innovativa su sensori in fase liquida per la rilevazione di lipidi bioattivi (IT20180008035). 9) Metodo per la diagnosi della malattia di Huntington (IT0001378173).
CONSULTANCY
Consultant for different pharmaceutical companies, at the national (Dompè, Sigma-Tau, Vetagro, Angelini) and international level (Takeda Phar-maceutical Company, Reddy U.S. Therapeutics, GW Pharmaceuticals, Hoffmann-La Roche, Almirall, Phytecs, InMed Pharmaceuticals).