101 results on '"Gado F"'
Search Results
2. Achillea moschata Wulfen: From Ethnobotany to Phytochemistry, Morphology, and Biological Activity
- Author
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Bottoni, M., Baron, G., Gado, F., Milani, F., Santagostini, L., Lorenzo, C., Paola Sira Colombo, Caporali, E., Spada, A., Marco, B., Giuliani, C., Piero, B., Aldini, G., and Fico, G.
- Subjects
primary data ,traditional decoction ,flower heads ,aqueous and methanolic extracts ,mass spectrometry ,antioxidant activity ,anti-inflammatory activity ,glandular indumentum ,microscopy ,Settore BIO/15 - Biologia Farmaceutica ,Settore CHIM/08 - Chimica Farmaceutica - Published
- 2022
3. Proposal of outcome measures to be used on a 12-month open label drug trial in Juvenile Systemic Sclerosis. Results of the 3rd Consensus Meeting in Hamburg December 2018
- Author
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Foeldvari, I, Torok, K, Ambartsumyan, L, Anton, J, Beyer, C, Blakley, M, Constantin, T, Costa Reis, P, Curran, M, Cutolo, M, del Gado, F, Denton, CP, Fligelstone, K, Hinrichs, B, Höger, A, Ingegnoli, F, Kasapcopur, O, Li, S, Nemcova, D, Orteu, C, Pilkington, C, Smith, V, Stevens, A, Stevens, B, Zhen, A, Khanna, D, and Furst, D
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Background: Juvenile systemic sclerosis (jSSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed. To develop an open label drug trial for the treatment of jSSc patients, it is necessary to clearly define how to evaluate outcomes in this disease,[for full text, please go to the a.m. URL], 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)
- Published
- 2019
- Full Text
- View/download PDF
4. Clinical misleading: multiple bilateral nodules in an Ethiopian child
- Author
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Faina, P, Andreoli, GM, Cantisani, V, De Gado, F, Miller, DM, Grieco, T, and Cantisani, C
- Published
- 2009
- Full Text
- View/download PDF
5. Actinic keratosis: review of the literature and new patents
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Carmen, Cantisani, Federico De Gado, De Gado, F., Martina, Ulrich, Bottoni, Ugo, Francis, Iacobellis, Richetta, Antonio Giovanni, and Calvieri, Stefano
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Pathology ,medicine.medical_specialty ,Skin Neoplasms ,field cancerisation ,topical treatment ,non melanoma skin cancer ,immunomodulation ,actinic damage ,Treatment duration ,Administration, Cutaneous ,Patents as Topic ,Risk Factors ,Drug Discovery ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Basal cell ,business.industry ,Disease progression ,Actinic keratosis ,General Medicine ,Actinic keratoses ,medicine.disease ,Dermatology ,Keratosis, Actinic ,Increased risk ,Drug Design ,Carcinoma, Squamous Cell ,Disease Progression ,Field cancerization ,Dermatologic Agents ,business ,Normal skin - Abstract
Actinic Keratoses (AK) are considered a worldwide problem with continuously increasing incidence. They clinically present as rough or scaly plaques and are histologically characterized by a proliferation of atypical keratinocytes limited to the epidermis. AK are considered as an early step in the continuum of transformation from normal skin to invasive squamous cell carcinoma (SCC). These lesions develop on a background of field cancerization in which chronically UV- damaged-areas accumulate molecular changes, but remain clinically normal for prolonged periods. The presence of certain clinical features of AK, such as large size, ulceration, or bleeding, suggests an increased risk of disease progression. The risk is also increased by evidence of extensive solar damage, advanced age, and immune-suppression. Many treatment modalities are available, although recent developments have focused on the management of the whole actinically damaged field. In this regard, several topical drugs have been approved, differing in efficacy, side effects, application and cost. Research continuingly aims to develop the “ideal” treatment which combines high clearance rates with few side effects, short treatment duration and low costs. Herein, we aim to give an overview on current treatment modalities including their mechanism of action, application scheme and common side effects. Furthermore, recent patents in the field and future aspects are discussed in this review.
- Published
- 2012
6. Rinoplastica in pazienti con malformazioni della testa e del collo
- Author
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Alfano, Carmine, Campus, G. V., and De Gado, F.
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Rinoplastica - Published
- 2012
7. [Pregnancy in lupus patients: our experience]
- Author
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Antonella Giancotti, Spagnuolo A, D'ambrosio V, Pasquali G, Muto B, and De Gado F
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Adult ,Infant, Newborn ,Pregnancy Outcome ,Hypertension, Pregnancy-Induced ,Abortion, Spontaneous ,Pregnancy Complications ,Italy ,Pregnancy ,Risk Factors ,Humans ,Lupus Erythematosus, Systemic ,Premature Birth ,Female ,Infant, Premature ,Retrospective Studies - Abstract
Systematic lupus erythematosus (SLE) is the most common autoimmune disease associated with pregnancy. The aim of this study was to evaluate management and outcome of pregnancy complicated by SLE.Twenty pregnant women affected by SLE were admitted to Prenatal Diagnosis Centre of University "Sapienza" from January 2007 to July 2009. Pregnancy was monitored from diagnosis to delivery by at least a monthly consultation. At each visit general blood laboratory assessment were registered. An ultrasound examination was performed to evaluate fetal growth. From 26 weeks of gestation an estimation of fetal weight was calculated according to the standard of Lubchenco. At birth newborns weight was registered.Patient mean age was 32.9 years. There were 18 live births (90%), and 2 spontaneous abortions; 50% of pregnancy ended with a preterm delivery. 20% of the patient had signs of disease activity during pregnancy. Fifteen percent of women presented gestational hypertension. An high rate of small for gestational age was registered and 2 cases of intrauterine growth retardation (IUGR). Ultrasound evaluation at 28-30 weeks of gestation showed a normal weight (≥ 50th percentile) in 83% fetuses. Only 45% of the newborns presented ≥ 50th percentile. The mean weight of the newborns was 2700 grams.Pregnancy outcome could be improved by close obstetrical and ultrasound monitoring in a multidisciplinary setting.
- Published
- 2011
8. Multicentric study on a topical compound with lymph-draining action in the treatment of the phlebostatic ulcer of the inferior limbs
- Author
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Chiummariello, S, DE GADO, F, Monarca, C, Ruggiero, M, Carlesimo, B, Scuderi, N, and Alfano, C.
- Published
- 2009
9. Skin grafting: comparative evaluation of two dressing techniques in selected body areas
- Author
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Gado, F., Chiummariello, S., Monarca, C., Dessy, L. A., Maria Ida Rizzo, Alfano, C., and Scuderi, N.
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Adult ,Aged, 80 and over ,Male ,Wound Healing ,Adolescent ,Polyurethanes ,polyurethane sponge ,Skin Transplantation ,Middle Aged ,Bandages ,wound bed ,difficult body areas ,skin graft ,tie-over ,Treatment Outcome ,Humans ,Female ,Aged - Abstract
Skin grafting is a frequent surgical procedure used to reconstruct a soft-tissue deficit. Tie-over bolster dressing is the traditional technique made to fix the graft to the recipient area. This dressing does not always provide satisfactory results in some difficult body areas, with poor skin graft taking as an outcome. Here, we used a soft "polyurethane sponge" as a compressive tool.A therapeutic protocol was used to select patients, splitting them into 2 groups: tie-over bolster dressing versus polyurethane sponge. Data analysis and calculation of sample size were performed using the Statistical Package for the Social Sciences Windows version 13.0.Of the 106 patients treated by traditional compressive dressing, 11 had complications, thus achieving a success rate of 89.6%. Of the 106 patients treated by polyurethane sponge dressing, 3 had complications, providing a success rate of 97.1%.Compared with the conventional tie-over dressing, the sponge dressing technique was demonstrated to be more successful in graft taking in selected areas.
- Published
- 2008
10. Surgical correction of blepharoptosis using the levator aponeurosis-Müller's muscle complex readaptation technique: a 15-year experience
- Author
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Scuderi, N, Chiummariello, S, De Gado, F, Alfano, C, Scuderi, G, and Recupero, Sm.
- Subjects
blepharoptosis - Published
- 2008
11. La balbuzie:aspetti emotivo-relazionali e sociali
- Author
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Tomaiuoli, D, DEL GADO, F, and Ruoppolo, Giovanni
- Published
- 2008
12. Allergic contact dermatitis to synthetic rubber following breast augmentation
- Author
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Cantisani, C., Cigna, E., Grieco, Teresa, Miller, D. M., De Gado, F., Calvieri, Stefano, and Scuderi, Nicolo'
- Published
- 2007
13. Allergic contact dermatitis to synthetic rubber following breast augmentation
- Author
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Cantisani, C, Cigna, Emanuele, Grieco, T, Miller, Dm, De Gado, F, Calvieri, S, and Scuderi, N.
- Published
- 2007
14. Lateral canthoplasty- 10 year experience
- Author
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Alfano, Carmine, Chiummariello, S., de gado, F., Bistoni, G., and Scuderi, N.
- Published
- 2006
15. Johnson's baby oil, a new type of filler ?
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DE GADO, F, Mazzocchi, Marco, Chiummariello, S, Gagliardi, Dn, and Alfano, Carmine
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Paraffin oil ,Paraffinoma ,Self-injection ,Paraffin oil, Paraffinoma, Self-injection - Published
- 2006
16. Lateral canthoplasty--10-year experience. Acta Chir Plast
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Alfano, C, Chiummariello, S, DE GADO, F, Bistoni, G, and Scuderi, Nicolo'
- Published
- 2006
17. 'Becker 35:esperienza a 12 mesi nella ricostruzione mammaria'-54°Congresso Nazionale S.I.C.P.R.E
- Author
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De Gado, F., Mazzocchi, Marco, Chiummariello, S., Alfano, Carmine, and Scuderi, N.
- Subjects
ricostruzione mammaria ,becker 35 - Published
- 2005
18. DETERMINATION D'ESPECES VEGETALES UTILISABLES EN PHYTOREMEDIATION DANS LA VALLEE DE GOUNTI YENA DE NIAMEY.
- Author
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GADO, F. ABDOU, DAN-BADJO, A. TANKARI, and GUERO, Y.
- Abstract
Environmental problems have become very crucial for humanity. In fact, human activities bring important quantities of metal traces elements (MTE). This study has been made to remedy to these MTE by searching in the valley of Gounti Yena plants species able to be used in phytoremediation. At the end of this work, the floristic diversity of this valley is very remarkable. Indeed, 16 woody and 24 herbaceous have been inventoried; among them the Juliflora prosopis which is the dominant woody where as Eragrotis pilosa is the dominant herbaceous. The conformation with the bibliographic data has allowed holding back 10 herbaceous species and 4 woody species that could be hyper-accumulator. [ABSTRACT FROM AUTHOR]
- Published
- 2016
19. A Multidimensional, Integrated, Differentiated, Art‐Mediated Stuttering Programme
- Author
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Tomaiuoli, D., primary, Del Gado, F., additional, Lucchini, E., additional, and Spinetti, M. G., additional
- Published
- 2012
- Full Text
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20. Patch test reactions and breast implants
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Cantisani, C., primary, De Gado, F., additional, Grieco, T., additional, Faina, P., additional, Calvieri, S., additional, and Scuderi, N., additional
- Published
- 2008
- Full Text
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21. La gravidanza nelle pazienti con lupus: nostra esperienza.
- Author
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GIANCOTTI, A., SPAGNUOLO, A., D'AMBROSIO, V., PASQUALI, G., MUTO, B., and DE GADO, F.
- Published
- 2010
22. Studio multicentrico su un preparato topico ad azione linfodrenante nel trattamento dell'ulcera flebostatica degli arti inferiori.
- Author
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Chiummariello, S., De Gado, F., Monarca, C., Ruggiero, M., Carlesimo, B., Scuderi, N., and Alfano, C.
- Published
- 2009
23. Immune complexes in the sera and amniotic fluids of human pregnancy.
- Author
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Pachì, A., D'Amelio, R., Palmisano, L., Bilotta, P., Milano, C. F., De Gado, F., and Aiuti, F.
- Published
- 1980
24. Short communications
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Pachi A, Bilotta P, Aiuti F, L. Palmisano, D'Amelio R, C. F. Milano, and De Gado F
- Subjects
Anamnesis ,Pregnancy ,medicine.medical_specialty ,Amniotic fluid ,Obstetrics ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Recurrent Abortions ,Immune system ,Diabetes mellitus ,Pediatrics, Perinatology and Child Health ,medicine ,Rheumatoid factor ,business - Abstract
The polyethylene-glicol (P.E.G.) precipitation assay was used to examine the sera of 91 pregnant women, 30 with normal pregnancies, 16 with EPH-Gestosis, 20 with pregnancy complicated by diabetes and 25 with case histories of recurrent abortions, in order to find evidence of eventual circulating immune complexes (C.I.C.). We also examined 30 amniotic fluids from normal pregnant women and 6 from pregnant women with diabetes. Several sera and all amniotic fluids were also examined by rheumatoid factor (RF) - inhibition test. C.I.C. were not discovered in the normal pregnant women neither in their sera nor in their amniotic fluids, while they were found in the following cases: in 8 patients with EPH-Gestosis (50%), in 8 with diabetes (40%) and in 3 with anamnesis positive for recurrent abortions (12%). The 6 amniotic fluid samples from women with diabetes were all negative. We were only able to examine 11 of the 19 positive cases from 4 days to 5 months after delivery and C.I.C. were absent in the sera of all the patients.
- Published
- 1980
25. Prenatal diagnosis of beta-thalassemia: the experience of the Center of Rome
- Author
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Tentori, L., Pachi, A., Bresadola, M., De Gado, F., Bilotta, P., Alvino, E., Paesano, R., Massa, A., Marinucci, M., Vignetti, Marco, Sposi, N. M., and Dallapiccola, B.
- Published
- 1982
26. Prenatal diagnosis of β-thalassemia: the experience of the center of Rome
- Author
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Tentori, L., Pachi, A., Bresadola, M., Gado, F., Bilotta, P., Alvino, E., ROSALBA PAESANO, Massa, A., Marinucci, M., Vignetti, M., Sposi, N. M., and Dallapiccola, B.
27. Influence of Pregnancy on Plasma Glucagon Levels in IDD Women
- Author
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Fallucca, F., primary, Russo, A., additional, Melilli, S., additional, De Gado, F., additional, Pedulla, C., additional, Scarciotta, O., additional, and Pachi, A., additional
- Published
- 1980
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28. Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate
- Author
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Bruno D'Agostino, Raffaele De Palma, Francesco Rossi, Francesco Del Galdo, Gianfranco De Dominicis, Fiorentina Roviezzo, Luca Parente, Edson Antunes, Gianfranco Abbate, Mariarosaria Bucci, Giuseppe Cirino, Roviezzo, Fiorentina, Del Galdo, F, Abbate, G, Bucci, Mariarosaria, D'Agostino, B, Antunes, E, De Dominicis, G, Parente, L, Rossi, F, Cirino, Giuseppe, De Palma, R., Roviezzo, F., DEL GADO, F., Abbate, G., Bucci, M., D'Agostino, Bruno, Antunes, E., DE DOMINICIS, G., Parente, L., Rossi, Francesco, Cirino, G., and DE PALMA, Raffaele
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Sphingosine-1-phosphate receptor ,Receptors, CCR3 ,CCR3 ,CCR3 Eosinophil migration Inflammation RANTES ,eosinophil migration ,Biology ,chemistry.chemical_compound ,Chemokine receptor ,RANTES ,immune system diseases ,Sphingosine ,Animals ,Edema ,Humans ,Sphingosine-1-phosphate ,Receptor ,Chemokine CCL5 ,Multidisciplinary ,organic chemicals ,Chemotaxis ,Biological Sciences ,Flow Cytometry ,Cell biology ,Rats ,Eosinophils ,Chemotaxis, Leukocyte ,chemistry ,Gene Expression Regulation ,inflammation ,Eosinophil chemotaxis ,lipids (amino acids, peptides, and proteins) ,Receptors, Chemokine ,Lysophospholipids - Abstract
Sphingosine 1-phosphate (S1P) is a sphingolipid mediator that is involved in diverse biological functions. Local administration of S1P causes inflammation coupled to a large eosinophil (EO) recruitment in the rat-paw tissue. The inflammatory response is accompanied by an increase in S1P receptors, namely S1P1, S1P2, S1P3, and by an enhanced expression of CCR3, which is the main chemokine receptor known to be involved in EO function. Human EOs constitutively express S1P1 and, at a lower extent, S1P2, S1P3 receptors. S1P in vitro causes cultured human EO migration and an increase in S1P receptor mRNA copies and strongly up-regulates CCR3 and RANTES (regulated on activation, normal T cell-expressed and secreted) message levels; in particular CCR3 is up-regulated 18,000-fold by S1P. A blocking anti-CCR3 Ab inhibits S1P-induced chemotaxis, implying that S1P acts as specific recruiting signal for EOs not only through its own receptors but also through CCR3. These results show that S1P is involved in EO chemotaxis and contribute to shed light on the complex mechanisms underlying EO recruitment in several diseases such as asthma and some malignancies. Sphingosine 1-phosphate (S1P) is a sphingolipid mediator that is involved in diverse biological functions. Local administration of S1P causes inflammation coupled to a large eosinophil (EO) recruitment in the rat-paw tissue. The inflammatory response is accompanied by an increase in S1P receptors, namely S1P1, S1P2, S1P3, and by an enhanced expression of CCR3, which is the main chemokine receptor known to be involved in EO function. Human EOs constitutively express S1P1 and, at a lower extent, S1P2, S1P3 receptors. S1P in vitro causes cultured human EO migration and an increase in S1P receptor mRNA copies and strongly up-regulates CCR3 and RANTES (regulated on activation, normal T cell-expressed and secreted) message levels; in particular CCR3 is up-regulated 18,000-fold by S1P. A blocking anti-CCR3 Ab inhibits S1P-induced chemotaxis, implying that S1P acts as specific recruiting signal for EOs not only through its own receptors but also through CCR3. These results show that S1P is involved in EO chemotaxis and contribute to shed light on the complex mechanisms underlying EO recruitment in several diseases such as asthma and some malignancies.
- Published
- 2004
29. Watermelon: setup and validation of an in silico fragment-based approach.
- Author
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Di Stefano M, Galati S, Piazza L, Gado F, Granchi C, Macchia M, Giordano A, Tuccinardi T, and Poli G
- Subjects
- Molecular Structure, Monoacylglycerol Lipases antagonists & inhibitors, Monoacylglycerol Lipases metabolism, Monoacylglycerol Lipases chemistry, Ligands, Structure-Activity Relationship, Molecular Dynamics Simulation, Dose-Response Relationship, Drug, Molecular Docking Simulation, Citrullus chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis
- Abstract
We present a new computational approach, named Watermelon , designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach.
- Published
- 2024
- Full Text
- View/download PDF
30. A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells.
- Author
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Polini B, Zallocco L, Gado F, Ferrisi R, Ricardi C, Zuccarini M, Carnicelli V, Manera C, Ronci M, Lucacchini A, Zucchi R, Giusti L, and Chiellini G
- Subjects
- Humans, Ligands, Neuroglia drug effects, Neuroglia metabolism, Cell Line, Tumor, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides toxicity, Proteomics methods, Receptor, Cannabinoid, CB2 metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Autophagy drug effects
- Abstract
Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer's disease (AD). We recently developed the first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed the ability to induce neuroprotection with fewer side effects. To explore the potential of FD22a as a multitarget drug for the treatment of NDDs, we investigated here its ability to prevent the toxic effect of β-amyloid (Aβ
25-35 peptide) on human cellular models of neurodegeneration, such as microglia (HMC3) and glioblastoma (U87-MG) cell lines. Our results displayed that FD22a efficiently prevented Aβ25-35 cytotoxic and proinflammatory effects in both cell lines and counteracted β-amyloid-induced depression of autophagy in U87-MG cells. Notably, a quantitative proteomic analysis of U87-MG cells revealed that FD22a was able to potently stimulate the autophagy-lysosomal pathway (ALP) by activating its master transcriptional regulator TFEB, ultimately increasing the potential of this novel CB2R bitopic/dualsteric ligand as a multitarget drug for the treatment of NDDs.- Published
- 2024
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31. Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.
- Author
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Di Stefano M, Masoni S, Bononi G, Poli G, Galati S, Gado F, Manzi S, Vagaggini C, Brai A, Caligiuri I, Asif K, Rizzolio F, Macchia M, Chicca A, Sodi A, Di Bussolo V, Minutolo F, Meier P, Gertsch J, Granchi C, Dreassi E, and Tuccinardi T
- Subjects
- Mice, Animals, Enzyme Inhibitors chemistry, Endocannabinoids, Models, Molecular, Monoacylglycerol Lipases metabolism, Monoglycerides
- Abstract
The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
32. Identification of New GSK3β Inhibitors through a Consensus Machine Learning-Based Virtual Screening.
- Author
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Galati S, Di Stefano M, Bertini S, Granchi C, Giordano A, Gado F, Macchia M, Tuccinardi T, and Poli G
- Subjects
- Molecular Docking Simulation, Consensus, Glycogen Synthase Kinase 3 beta, Reproducibility of Results, Wnt Signaling Pathway
- Abstract
Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays key roles in glycogen metabolism, Wnt/β-catenin signaling cascade, synaptic modulation, and multiple autophagy-related signaling pathways. GSK3β is an attractive target for drug discovery since its aberrant activity is involved in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the present study, multiple machine learning models aimed at identifying novel GSK3β inhibitors were developed and evaluated for their predictive reliability. The most powerful models were combined in a consensus approach, which was used to screen about 2 million commercial compounds. Our consensus machine learning-based virtual screening led to the identification of compounds G1 and G4 , which showed inhibitory activity against GSK3β in the low-micromolar and sub-micromolar range, respectively. These results demonstrated the reliability of our virtual screening approach. Moreover, docking and molecular dynamics simulation studies were employed for predicting reliable binding modes for G1 and G4 , which represent two valuable starting points for future hit-to-lead and lead optimization studies.
- Published
- 2023
- Full Text
- View/download PDF
33. The Interplay between Cannabinoid Receptors and Microglia in the Pathophysiology of Alzheimer's Disease.
- Author
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Ferrisi R, Gado F, Ricardi C, Polini B, Manera C, and Chiellini G
- Abstract
Alzheimer's disease (AD) is characterized by massive neuronal death, brain atrophy, and loss of neurons and synapses, which all lead to a progressive cognitive decline. Neuroinflammation has been recently identified as one of the main causes of AD progression, and microglia cells are considered to have a central role in this process. Growing evidence suggests that cannabinoids may be used as preventive treatment for AD. An altered expression of the endocannabinoids (eCBs) and their receptors (CBRs) is reported in several neurodegenerative disorders, including AD. Moreover, the modulation of CBRs demonstrated neuroprotective effects in reducing aggregated protein deposition, suggesting the therapeutic potential of natural and synthetic CBR ligands in the treatment of neurodegenerative proteinopathies. Here, we review the current knowledge regarding the involvement of CBRs in the modulation of microglia activation phenotypes, highlighting the role of neuroinflammation in the pathogenesis of neurodegenerative diseases, like AD. We also provide an overview of recently developed candidate drugs targeting CBRs that may afford a new innovative strategy for the treatment and management of AD.
- Published
- 2023
- Full Text
- View/download PDF
34. Acoustic analysis in stuttering: a machine-learning study.
- Author
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Asci F, Marsili L, Suppa A, Saggio G, Michetti E, Di Leo P, Patera M, Longo L, Ruoppolo G, Del Gado F, Tomaiuoli D, and Costantini G
- Abstract
Background: Stuttering is a childhood-onset neurodevelopmental disorder affecting speech fluency. The diagnosis and clinical management of stuttering is currently based on perceptual examination and clinical scales. Standardized techniques for acoustic analysis have prompted promising results for the objective assessment of dysfluency in people with stuttering (PWS)., Objective: We assessed objectively and automatically voice in stuttering, through artificial intelligence (i.e., the support vector machine - SVM classifier). We also investigated the age-related changes affecting voice in stutterers, and verified the relevance of specific speech tasks for the objective and automatic assessment of stuttering., Methods: Fifty-three PWS (20 children, 33 younger adults) and 71 age-/gender-matched controls (31 children, 40 younger adults) were recruited. Clinical data were assessed through clinical scales. The voluntary and sustained emission of a vowel and two sentences were recorded through smartphones. Audio samples were analyzed using a dedicated machine-learning algorithm, the SVM to compare PWS and controls, both children and younger adults. The receiver operating characteristic (ROC) curves were calculated for a description of the accuracy, for all comparisons. The likelihood ratio (LR), was calculated for each PWS during all speech tasks, for clinical-instrumental correlations, by using an artificial neural network (ANN)., Results: Acoustic analysis based on machine-learning algorithm objectively and automatically discriminated between the overall cohort of PWS and controls with high accuracy (88%). Also, physiologic ageing crucially influenced stuttering as demonstrated by the high accuracy (92%) of machine-learning analysis when classifying children and younger adults PWS. The diagnostic accuracies achieved by machine-learning analysis were comparable for each speech task. The significant clinical-instrumental correlations between LRs and clinical scales supported the biological plausibility of our findings., Conclusion: Acoustic analysis based on artificial intelligence (SVM) represents a reliable tool for the objective and automatic recognition of stuttering and its relationship with physiologic ageing. The accuracy of the automatic classification is high and independent of the speech task. Machine-learning analysis would help clinicians in the objective diagnosis and clinical management of stuttering. The digital collection of audio samples here achieved through smartphones would promote the future application of the technique in a telemedicine context (home environment)., Competing Interests: LM has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support and a grant contribution from the International Parkinson Disease Movement Disorders Society for the Unified Tremor Rating Scale Validation Program. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FM declared a past collaboration with the authors LM at the time of the review., (Copyright © 2023 Asci, Marsili, Suppa, Saggio, Michetti, Di Leo, Patera, Longo, Ruoppolo, Del Gado, Tomaiuoli and Costantini.)
- Published
- 2023
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35. Chemical, Nutritional and Biological Evaluation of a Sustainable and Scalable Complex of Phytochemicals from Bergamot By-Products.
- Author
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Della Vedova L, Gado F, Vieira TA, Grandini NA, Palácio TLN, Siqueira JS, Carini M, Bombardelli E, Correa CR, Aldini G, and Baron G
- Subjects
- Animals, Rats, Polyphenols pharmacology, Polyphenols chemistry, Phytochemicals pharmacology, Mass Spectrometry, Anti-Inflammatory Agents pharmacology, Oils, Volatile pharmacology, Citrus chemistry
- Abstract
The present paper reports a sustainable raw material obtained from the by-products derived from the industrial production of bergamot ( Citrus × Bergamia Risso & Poiteau) essential oils. The procedure to obtain the raw material is designed to maintain as much of the bioactive components as possible and to avoid expensive chemical purification. It consists of spray-drying the fruit juice obtained by squeezing the fruits, which is mixed with the aqueous extract of the pulp, i.e., the solid residue remained after fruit pressing. The resulting powder bergamot juice (PBJ) contains multiple bioactive components, in particular, among others, soluble fibers, polyphenols and amino-acid betaines, such as stachydrine and betonicine. LC-MS analysis identified 86 compounds, with hesperetin, naringenin, apigenin and eridictyol glucosides being the main components. In the second part of the paper, dose-dependent anti-inflammatory activity of PBJ and of stachydrine was found, but neither of the compounds were effective in activating Nrf2. PBJ was then found to be effective in an in vivo model of a metabolic syndrome induced by a high-sugar, high-fat (HSF) diet and evidenced by a significant increase of the values related to a set of parameters: blood glucose, triglycerides, insulin resistance, systolic blood pressure, visceral adipose tissue and adiposity index. PBJ, when given to control rats, did not significantly change these values; in contrast, they were found to be greatly affected in rats receiving an HSF diet. The in vivo effect of PBJ can be ascribed not only to bergamot polyphenols with well-known anti-inflammatory, antioxidant and lipid-regulating effects, but also to the dietary fibers and to the non-phenolic constituents, such as stachydrine. Moreover, since PBJ was found to affect energy homeostasis and to regulate food intake, a mechanism on the regulation of energy homeostasis through leptin networking should also be considered and deserves further investigation.
- Published
- 2023
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36. Targeting Nrf2 and NF-κB Signaling Pathways in Cancer Prevention: The Role of Apple Phytochemicals.
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Gado F, Ferrario G, Della Vedova L, Zoanni B, Altomare A, Carini M, Aldini G, D'Amato A, and Baron G
- Subjects
- Humans, NF-kappa B metabolism, NF-E2-Related Factor 2 metabolism, Signal Transduction, Phytochemicals pharmacology, Phytochemicals therapeutic use, Malus metabolism, Neoplasms prevention & control, Neoplasms metabolism
- Abstract
Plant secondary metabolites, known as phytochemicals, have recently gained much attention in light of the "circular economy", to reutilize waste products deriving from agriculture and food industry. Phytochemicals are known for their onco-preventive and chemoprotective effects, among several other beneficial properties. Apple phytochemicals have been extensively studied for their effectiveness in a wide range of diseases, cancer included. This review aims to provide a thorough overview of the main studies reported in the literature concerning apple phytochemicals, mostly polyphenols, in cancer prevention. Although there are many different mechanisms targeted by phytochemicals, the Nrf2 and NF-κB signaling pathways are the ones this review will be focused on, highlighting also the existing crosstalk between these two systems.
- Published
- 2023
- Full Text
- View/download PDF
37. New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2.
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Ferrisi R, Polini B, Ricardi C, Gado F, Mohamed KA, Baron G, Faiella S, Poli G, Rapposelli S, Saccomanni G, Aldini G, Chiellini G, Laprairie RB, Manera C, and Ortore G
- Subjects
- Humans, Ligands, Receptors, Cannabinoid, Allosteric Regulation, Allosteric Site
- Abstract
Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a , with that of the CB2R selective orthosteric agonist LV62 , both synthesized in our laboratories. The functional examination enabled us to identify JR14a , JR22a , and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a . Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.
- Published
- 2023
- Full Text
- View/download PDF
38. Achillea moschata Wulfen: From Ethnobotany to Phytochemistry, Morphology, and Biological Activity.
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Bottoni M, Baron G, Gado F, Milani F, Santagostini L, Colombo L, Colombo PS, Caporali E, Spada A, Biagi M, Giuliani C, Bruschi P, Aldini G, and Fico G
- Subjects
- Chromatography, Liquid, Plant Extracts pharmacology, Plant Extracts chemistry, Tandem Mass Spectrometry, Antioxidants pharmacology, Antioxidants chemistry, Anti-Inflammatory Agents pharmacology, Phytochemicals pharmacology, Achillea chemistry
- Abstract
A multidisciplinary investigation on Achillea moschata Wulfen (Asteraceae) is outlined herein. This work, part of the European Interreg Italy-Switzerland B-ICE project, originated from an ethnobotanical survey performed in Chiesa in Valmalenco (Sondrio, Lombardy, Northern Italy) in 2019-2021 which highlighted this species' relevance of use in folk medicine to treat gastrointestinal diseases. In addition, this contribution included analyses of the: (a) phytochemical profile of the aqueous and methanolic extracts of the dried flower heads using LC-MS/MS; (b) morpho-anatomy and histochemistry of the vegetative and reproductive organs through Light, Fluorescence, and Scanning Electron Microscopy; (c) biological activity of the aqueous extract concerning the antioxidant and anti-inflammatory potential through cell-based in vitro models. A total of 31 compounds (5 phenolic acids, 13 flavonols, and 13 flavones) were detected, 28 of which included in both extracts. Covering and secreting trichomes were observed: the biseriate 10-celled glandular trichomes prevailing on the inflorescences represented the main sites of synthesis of the polyphenols and flavonoids detected in the extracts, along with volatile terpenoids. Finally, significant antioxidant and anti-inflammatory activities of the aqueous extract were documented, even at very low concentrations; for the first time, the in vitro tests allowed us to formulate hypotheses about the mechanism of action. This work brings an element of novelty due to the faithful reproduction of the traditional aqueous preparation and the combination of phytochemical and micromorphological research approaches.
- Published
- 2022
- Full Text
- View/download PDF
39. Bergamot leaf extract treats cardiorenal metabolic syndrome and associated pathophysiological factors in rats fed with a high sugar fat diet.
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Siqueira JS, Vieira TA, Nakandakare-Maia ET, Palacio TLN, Sarzi F, Garcia JL, de Paula BH, Bazan SGZ, Baron G, Tucci L, Janda E, Altomare A, Gado F, Ferron AJT, Aldini G, Francisqueti-Ferron FV, and Correa CR
- Subjects
- Animals, Diet, High-Fat adverse effects, Plant Extracts chemistry, Plant Extracts pharmacology, Plant Extracts therapeutic use, Rats, Sugars therapeutic use, Citrus chemistry, Insulin Resistance, Metabolic Syndrome complications, Metabolic Syndrome drug therapy, Oils, Volatile
- Abstract
Bergamot citrus (Citrus bergamia Risso et Poiteau), have been used as a strategy to prevent or treat comorbidities associated with metabolic syndrome parameters, such as cardiorenal metabolic syndrome (CRMS). The aim was to test the effect of bergamot leaf extract on CRMS and associated pathophysiological factors in rats fed with a high sugar-fat diet. Animals were divided into two experimental groups with control diet (Control, n = 30) and high sugar-fat diet (HSF, n = 30) for 20 weeks. Once CRMS was detected, animals were redivided to begin the treatment with Bergamot Leaf Extract (BLE) by gavage (50 mg/kg) for 10 weeks: control diet + placebo (Control, n = 09), control diet + BLE (Control + BLE, n = 09), HSF diet + placebo (HSF, n = 09), HSF + BLE (n = 09). Evaluation included nutritional, metabolic and hormonal analysis; and renal and cardiac parameters. HSF groups presented obesity, dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, insulin resistance. BLE showed protection against effects on hypertriglyceridemia, insulin resistance, renal damage, and structural and functional alterations of the heart. Conclusion: Bergamot leaf extract shows potential as a therapeutic to treat CRMS in animals fed with a high sugar-fat diet., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
40. Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB 2 R).
- Author
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Ferrisi R, Gado F, Polini B, Ricardi C, Mohamed KA, Stevenson LA, Ortore G, Rapposelli S, Saccomanni G, Pertwee RG, Laprairie RB, Manera C, and Chiellini G
- Abstract
It is well known that G protein-coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several advantages over monovalent targeting strategies, including an increased affinity or selectivity, a bias in signaling pathway activation, reduced off-target activity and therapeutic resistance. Our study focused on the cannabinoid receptor type 2 (CB
2 R), considered a clinically promising target for the control of brain damage in neurodegenerative disorders. Indeed, CB2 R was found highly expressed in microglial cells, astrocytes, and even in some neuron subpopulations. Here, we describe the design, synthesis, and biological evaluation of two new classes of potential dualsteric (bitopic) CB2 R ligands. The new compounds were obtained by connecting, through different linkers, the pharmacophoric portion of the CB2 R positive allosteric modulator (PAM), EC21a , with that of the CB2 R selective orthosteric agonist LV62 , both developed in our laboratories. A preliminary screening enabled us to identify compound JR64a as the most promising of the series. Indeed, functional examination highlighted a signaling 'bias' in favor of G protein activation over βarrestin2 recruitment, combined with high affinity for CB2 R and the ability to efficiently prevent inflammation in human microglial cells (HMC3) exposed to LPS/TNFα stimulation, thus demonstrating great promise for the treatment of neurodegenerative diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ferrisi, Gado, Polini, Ricardi, Mohamed, Stevenson, Ortore, Rapposelli, Saccomanni, Pertwee, Laprairie, Manera and Chiellini.)- Published
- 2022
- Full Text
- View/download PDF
41. Polyphenols from Thinned Young Apples: HPLC-HRMS Profile and Evaluation of Their Anti-Oxidant and Anti-Inflammatory Activities by Proteomic Studies.
- Author
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Ferrario G, Baron G, Gado F, Della Vedova L, Bombardelli E, Carini M, D'Amato A, Aldini G, and Altomare A
- Abstract
The qualitative profile of thinned apple polyphenols (TAP) fraction (≈24% of polyphenols) obtained by purification through absorbent resin was fully investigated by LC-HRMS in positive and negative ion mode and using ESI source. A total of 68 polyphenols were identified belonging to six different classes: flavanols, flavonols, dihydrochalchones, flavanones, flavones and organic and phenolic acids. The antioxidant and anti-inflammatory activities were then investigated in cell models with gene reporter for NRF2 and NF-κB and by quantitative proteomic (label-free and SILAC) approaches. TAP dose-dependently activated NRF2 and in the same concentration range (10-250 µg/mL) inhibited NF-κB nuclear translocation induced by TNF-α and IL-1α as pro-inflammatory promoters. Proteomic studies elucidated the molecular pathways evoked by TAP treatment: activation of the NRF2 signaling pathway, which in turn up-regulates protective oxidoreductases and their nucleophilic substrates such as GSH and NADPH, the latter resulting from the up-regulation of the pentose phosphate pathway. The increase in the enzymatic antioxidant cellular activity together with the up-regulation of the heme-oxygenase would explain the anti-inflammatory effect of TAP. The results suggest that thinned apples can be considered as a valuable source of apple polyphenols to be used in health care products to prevent/treat oxidative and inflammatory chronic conditions.
- Published
- 2022
- Full Text
- View/download PDF
42. Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands.
- Author
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Gado F, Ferrisi R, Polini B, Mohamed KA, Ricardi C, Lucarini E, Carpi S, Domenichini F, Stevenson LA, Rapposelli S, Saccomanni G, Nieri P, Ortore G, Pertwee RG, Ghelardini C, Di Cesare Mannelli L, Chiellini G, Laprairie RB, and Manera C
- Subjects
- Allosteric Regulation, Allosteric Site, Animals, Binding Sites, Humans, Ligands, Mice, Receptor, Cannabinoid, CB2, Receptors, G-Protein-Coupled metabolism
- Abstract
The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature.
- Published
- 2022
- Full Text
- View/download PDF
43. Liquid Chromatography-High-Resolution Mass Spectrometry (LC-HRMS) Profiling of Commercial Enocianina and Evaluation of Their Antioxidant and Anti-Inflammatory Activity.
- Author
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Della Vedova L, Ferrario G, Gado F, Altomare A, Carini M, Morazzoni P, Aldini G, and Baron G
- Abstract
Enocianina is an anthocyanin-rich extract obtained from grape pomace. It is widely used as a colorant in the food industry and, in addition to anthocyanins, it also contains a variety of polyphenols. To understand whether enocianina, besides its coloring effect, may offer potential health benefit applications, we aimed to fully characterize the profile of four commercial enocianinas and assess their radical scavenging, enzymatic, antioxidant, and anti-inflammatory activities. LC-ESI-MS/MS analysis identified 90 phytochemicals. The relative content of each anthocyanin was assessed by a semi-quantitative analysis, with malvidin derivatives being the most abundant. UV-VIS spectroscopy detected total amounts of polyphenols and anthocyanins of 23% and 3.24%, respectively, indicating that anthocyanins represent a minor fraction of total polyphenols. Multiple linear regression analysis indicated that the radical scavenging activity is related to the total polyphenol content and not to anthocyanins. All four enocianinas dose-dependently activate Nrf2, and such activity was correlated with catechol-containing polyphenol content. Finally, all enocianinas showed dose-dependent anti-inflammatory activity, which at the highest concentrations tested was closely related to the total polyphenol content and was explained by radical scavenging, Nrf2 activation, and other mechanisms related to the polyphenolic components.
- Published
- 2022
- Full Text
- View/download PDF
44. Photodynamic Therapy with 5-Aminolevulinic Acid Patch for the Treatment of Actinic Keratosis.
- Author
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Kiss N, Farkas K, Tosti G, De Gado F, Bergler-Czop B, Fazia G, Tammaro A, and Cantisani C
- Abstract
Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an emerging treatment option in the care of actinic keratosis (AK). A self-adhesive 5-ALA patch was recently developed that allows a precise PDT procedure. Here, we review the current literature and report the findings of our case series that observed the outcomes and safety of 5-ALA patch PDT. Ten patients with a total of 40 AKs were treated with a single session of conventional or daylight PDT using 5-ALA patch at the Department of Dermatology and Venereology, Sapienza University of Rome or at the European Institute of Oncology, Milan, Italy. Complete response was observed in three patients, while partial response was seen in seven patients. Overall tolerability was good or excellent, with local adverse events observed in four patients. This is the first case series reported where the 5-ALA patch was applied using daylight PDT, and its efficacy and tolerability in the treatment of AK were demonstrated. In conclusion, the self-adhesive 5-ALA patch is a convenient application of PDT that provides a well-tolerated and effective treatment option with satisfactory cosmetic outcomes.
- Published
- 2022
- Full Text
- View/download PDF
45. Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells.
- Author
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Gado F, Ferrisi R, Di Somma S, Napolitano F, Mohamed KA, Stevenson LA, Rapposelli S, Saccomanni G, Portella G, Pertwee RG, Laprairie RB, Malfitano AM, and Manera C
- Subjects
- Cannabinoid Receptor Agonists chemistry, Cell Survival, Humans, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Cannabinoids, Neuroblastoma drug therapy
- Abstract
1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1 H )-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC
50 of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a , was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.- Published
- 2022
- Full Text
- View/download PDF
46. CB1 receptor binding sites for NAM and PAM: A first approach for studying, new n‑butyl‑diphenylcarboxamides as allosteric modulators.
- Author
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Gado F, Ceni C, Ferrisi R, Sbrana G, Stevenson LA, Macchia M, Pertwee RG, Bertini S, Manera C, and Ortore G
- Subjects
- Allosteric Regulation, Binding Sites, Humans, Ligands, Niacinamide, Receptor, Cannabinoid, CB1
- Abstract
The development of cannabinoid receptor type-1 (CB1R) modulators has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others, even if their central psychiatric side effects such as depression, anxiety, and suicidal tendencies, have limited their clinical use. Thus, the identification of ligands which selectively act on peripheral CB1Rs, is becoming more interesting. A recent study reported a class of peripheral CB1R selective antagonists, characterized by a 5-aryl substituted nicotinamide core. These derivatives have structural similarities with the biphenyl compounds, endowed with CB2R antagonist activity, previously synthesized by our research group. In this work we combined the pharmacophoric portion of both classes, in order to obtain novel CBR antagonists. Among the synthesized compounds rather unexpectedly two compounds of this series, C7 and C10, did not show the radioligand ([
3 H]CP55940) displacement on CB1R but increased binding (∼ 150%), suggesting a possible allosteric behavior. Computational studies were performed to investigate the role of these compounds in CB1R modulation. The analysis of their binding poses in two different binding cavities of the CB1R surface, revealed a preferred interaction with the experimental binding site for negative allosteric modulators., (Copyright © 2021. Published by Elsevier B.V.)- Published
- 2022
- Full Text
- View/download PDF
47. Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells.
- Author
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Capozzi A, Caissutti D, Mattei V, Gado F, Martellucci S, Longo A, Recalchi S, Manganelli V, Riitano G, Garofalo T, Sorice M, Manera C, and Misasi R
- Subjects
- Animals, Anti-Inflammatory Agents chemistry, Apoptosis drug effects, Cannabinoid Receptor Agonists chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Cytokines metabolism, Humans, Inflammation Mediators metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Molecular Structure, Phosphorylation drug effects, Signal Transduction drug effects, Anti-Inflammatory Agents pharmacology, Cannabinoid Receptor Agonists pharmacology, Receptor, Cannabinoid, CB2 agonists, Receptor, Cannabinoid, CB2 metabolism
- Abstract
The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.
- Published
- 2021
- Full Text
- View/download PDF
48. Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile.
- Author
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Sestito S, Bacci A, Chiarugi S, Runfola M, Gado F, Margheritis E, Gul S, Riveiro ME, Vazquez R, Huguet S, Manera C, Rezai K, Garau G, and Rapposelli S
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Aurora Kinase A metabolism, Cell Proliferation drug effects, Cells, Cultured, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Molecular Structure, Oxindoles chemical synthesis, Oxindoles chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyruvate Dehydrogenase Acetyl-Transferring Kinase metabolism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Aurora Kinase A antagonists & inhibitors, Drug Development, Oxindoles pharmacology, Protein Kinase Inhibitors pharmacology, Pyruvate Dehydrogenase Acetyl-Transferring Kinase antagonists & inhibitors
- Abstract
We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
49. Contemporary issues with stuttering: The Fourth Croatia Stuttering Symposium.
- Author
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Lowe R, Jelčić Jakšić S, Onslow M, O'Brian S, Vanryckeghem M, Millard S, Kelman E, Block S, Franken MC, Van Eerdenbrugh S, Menzies R, Shenker R, Byrd C, Bosshardt HG, Del Gado F, and Lim V
- Subjects
- Anxiety Disorders, Child, Croatia, Humans, Cognitive Behavioral Therapy, Speech-Language Pathology, Stuttering therapy
- Abstract
Purpose: During the 2019 Fourth Croatia Clinical Symposium, speech-language pathologists (SLPs), scholars, and researchers from 29 countries discussed speech-language pathology and psychological practices for the management of early and persistent stuttering. This paper documents what those at the Symposium considered to be the key contemporary clinical issues for early and persistent stuttering., Methods: The authors prepared a written record of the discussion of Symposium topics, taking care to ensure that the content of the Symposium was faithfully reproduced in written form., Results: Seven contemporary issues for our field emerged from the Symposium., Conclusion: Effective early intervention is fundamental to proper health care for the disorder. However, as yet, there is no consensus about the timing of early intervention and how it should be managed. Currently, clinical translation is a barrier to evidence-based practice with early stuttering, and proactive strategies were suggested for junior SLPs. Apprehension emerged among some discussants that treatment of early stuttering may cause anxiety. For persistent stuttering, assessment procedures were recommended, as were strategies for dealing with childhood bullying. There was agreement that SLPs are the ideal professionals to provide basic cognitive-behavior therapy for clients with persistent stuttering. Questions were raised about our discipline standards for basic professional preparation programs for stuttering management., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
50. The Role of Cannabinoids in Bone Metabolism: A New Perspective for Bone Disorders.
- Author
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Saponaro F, Ferrisi R, Gado F, Polini B, Saba A, Manera C, and Chiellini G
- Subjects
- Antineoplastic Agents therapeutic use, Bone Density Conservation Agents therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Bone Neoplasms pathology, Bone Remodeling physiology, Bone Resorption genetics, Bone Resorption pathology, Bone Resorption prevention & control, Bone and Bones drug effects, Bone and Bones metabolism, Bone and Bones pathology, Gene Expression Regulation, Hematopoiesis drug effects, Hematopoiesis genetics, Humans, Neoplasm Metastasis, Osteoblasts pathology, Osteoclasts pathology, Osteoporosis drug therapy, Osteoporosis genetics, Osteoporosis pathology, RANK Ligand genetics, RANK Ligand metabolism, Receptor Activator of Nuclear Factor-kappa B genetics, Receptor Activator of Nuclear Factor-kappa B metabolism, Receptors, Cannabinoid genetics, Receptors, Cannabinoid metabolism, Signal Transduction, Bone Neoplasms metabolism, Bone Resorption metabolism, Endocannabinoids metabolism, Osteoblasts metabolism, Osteoclasts metabolism, Osteoporosis metabolism
- Abstract
Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.
- Published
- 2021
- Full Text
- View/download PDF
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