25 results on '"Morelli, Martina"'
Search Results
2. The association between hypoalbuminemia and risk of death due to cancer and vascular disease in individuals aged 65 years and older: findings from the prospective Moli-sani cohort study
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Iacoviello, Licia, de Gaetano, Giovanni, Donati, Maria Benedetta, Cerletti, Chiara, Bonaccio, Marialaura, Bonanni, Americo, Costanzo, Simona, De Curtis, Amalia, Di Castelnuovo, Augusto, Gialluisi, Alessandro, Gianfagna, Francesco, Persichillo, Mariarosaria, Di Prospero, Teresa, Vermylen, Jos, Pegoraro, Renzo, Spagnolo, Antonio, Assanelli, Deodato, Rago, Livia, Olivieri, Marco, Orlandi, Sabatino, Panzera, Teresa, Esposito, Simona, Ghulam, Anwal, Parisi, Roberta, Pepe, Antonietta, Ruggiero, Emilia, Bracone, Francesca, Sharma, Sukshma, Civitillo, Concetta, Cretella, Alisia, Magnacca, Sara, Noro, Fabrizia, Di Costanzo, Giuseppe, Franciosa, Sabrina, Morelli, Martina, Pignatelli, Pasquale, Carnevale, Roberto, and Violi, Francesco
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- 2024
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3. Natural history and clinical burden of moderate aortic stenosis: a systematic review and explorative meta-analysis
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Morelli, Martina, Galasso, Michele, Esposito, Giuseppe, Soriano, Francesco Stefano, Nava, Stefano, Da Pozzo, Caterina, Bossi, Irene, Piccaluga, Emanuela, Bruschi, Giuseppe, Maloberti, Alessandro, Oliva, Fabrizio, Oreglia, Jacopo Andrea, Giannattasio, Cristina, and Montalto, Claudio
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- 2023
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4. Are Methylation Patterns in the KALRN Gene Associated with Cognitive and Depressive Symptoms? Findings from the Moli-sani Cohort.
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Quiccione, Miriam Shasa, Tirozzi, Alfonsina, Cassioli, Giulia, Morelli, Martina, Costanzo, Simona, Pepe, Antonietta, Bracone, Francesca, Magnacca, Sara, Cerletti, Chiara, Licastro, Danilo, Di Castelnuovo, Augusto, Donati, Maria Benedetta, de Gaetano, Giovanni, Iacoviello, Licia, and Gialluisi, Alessandro
- Abstract
The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826–124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms. [ABSTRACT FROM AUTHOR]
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- 2024
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5. SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation.
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Morelli, Martina, Madonna, Stefania, and Albanesi, Cristina
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SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3- derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Maintenance of Exercise Habit and Its Impact on Cardiovascular Risk Factors in Previously Sedentary People: A 7-Year Follow-Up.
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Masotti, Sabrina, Menegatti, Erica, Zerbini, Valentina, Raisi, Andrea, Piva, Tommaso, Morelli, Martina, Lordi, Rosario, Grazzi, Giovanni, Mazzoni, Gianni, and Mandini, Simona
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SEDENTARY lifestyles ,CARDIOVASCULAR diseases risk factors ,WALKING speed ,NON-communicable diseases ,BODY weight ,HABIT ,PHYSICAL activity ,HEALTH behavior ,EXERCISE ,WALKING ,DESCRIPTIVE statistics ,BODY mass index ,BEHAVIOR modification - Abstract
The aim of the study was to assess whether the level of physical activity in daily life in previously sedentary adults had been sustained 7 years beyond a 1-year supervised walking program. One hundred ten participants (63 females, 57.5 ± 8.4 years; 47 males, 66.4 ± 7.9 years) were recalled and assessed for physical activity in daily life, weight, body mass index, blood pressure, and walking speed. Fifty-nine percentage of the participants measured met and exceeded the World Health Organization physical activity guidelines (Group 1), while 41% did not (Group 2). In both groups, we observed a significant decrease of weight (72.0 ± 14.0 kg vs. 69.7 ± 14.0 kg in Group 1; 77.4 ± 19.5 kg vs. 75.4 ± 18.6 kg in Group 2) and body mass index (25.9 ± 3.7 vs. 25.1 ± 3.9 in Group 1; 27.9 ± 5.6 vs. 27.2 ± 5.4 in Group 2). Group 1 showed a significant increase in walking speed (5.8 ± 0.7 km/hr vs. 6.2 ± 0.8 km/hr), while systolic pressure did not change from the baseline. In Group 2, systolic pressure significantly increased (131.3 ± 13.5 mmHg vs. 138.0 ± 15.5 mmHg), while walking speed did not change. A guided walking program seems to have been effective in educating sedentary people to remain physically active over time. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Identification of immunological patterns characterizing immune-related psoriasis reactions in oncological patients in therapy with anti-PD-1 checkpoint inhibitors.
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Morelli, Martina, Carbone, Maria Luigia, Scaglione, Giovanni Luca, Scarponi, Claudia, Di Francesco, Valentina, Pallotta, Sabatino, De Galitiis, Federica, Rahimi, Siavash, Madonna, Stefania, Failla, Cristina Maria, and Albanesi, Cristina
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IPILIMUMAB ,CANCER patients ,PSORIASIS ,GENETIC profile ,NATURAL immunity ,DISEASE susceptibility - Abstract
Introduction: Immunotherapy with biologics targeting programmed cell death protein-1 (PD-1) is highly effective in the treatment of various malignancies. Nevertheless, it is frequently responsible for unexpected cutaneous manifestations, including psoriasis-like dermatitis. The pathogenesis of anti-PD-1-induced psoriasis has yet to be clarified, even though it is plausible that some innate and adaptive immunity processes are in common with canonical psoriasis. The genetic predisposition to psoriasis of patients could also be a contributing factor. Here, we investigated the immunological and genetic profiles of two patients with metastatic melanoma and one patient affected by lung cancer, who developed severe psoriasis after receiving anti-PD-1 nivolumab therapy. Methods: The immune patterns of the three patients were compared with those detectable in classical, chronic plaque-type psoriasis or paradoxical psoriasis induced by anti-TNF-α therapy, mostly sustained by adaptive and innate immunity processes, respectively. Therefore, immunohistochemistry and mRNA analyses of innate and adaptive immunity molecules were conducted on skin biopsy of patients. Genetic analysis of polymorphisms predisposing to psoriasis was carried out by NGS technology. Results: We found that anti-PD-1-induced psoriasis showed immunological features similar to chronic psoriasis, characterized by the presence of cellular players of adaptive immunity, with abundant CD3
+ , CD8+ T cells and CD11c+ dendritic cells infiltrating skin lesions, and producing IL-23, IL-6, TNF-α, IFN-&#g947; and IL-17. On the contrary, a lower number of innate immunity cells (BDCA2+ plasmacytoid dendritic cells, CD15+ neutrophils, CD117+ mast cells) and reduced IFN-α/β, lymphotoxin (LT)-α/β, were observed in anti-PD-1-induced psoriasis lesions, as compared with anti-TNF-α-induced paradoxical psoriasis. Importantly, the disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) psoriasis autoantigen was significantly upregulated in psoriasis lesions of anti-PD-1-treated patients, at levels comparable with chronic plaque-type psoriasis. Finally, NGS analysis revealed that all patients carried several allelic variants in psoriasis susceptibility genes, such as HLA-C, ERAP1 and other genes of the major psoriasis susceptibility PSORS1 locus. Discussion: Our study showed that adaptive immunity predominates over innate immunity in anti-PD-1-induced psoriasis lesions, consistently with the local ADAMTSL5 overexpression. The presence of numerous SNPs in psoriasis susceptibility genes of the three patients also suggested their strong predisposition to the disease. [ABSTRACT FROM AUTHOR]- Published
- 2024
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8. Interleukin‐36 cytokines are overexpressed in the skin and sera of patients with bullous pemphigoid.
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Maglie, Roberto, Mercurio, Laura, Morelli, Martina, Madonna, Stefania, Salemme, Adele, Baffa, Maria E., Quintarelli, Lavinia, Di Zenzo, Giovanni M., Antiga, Emiliano, and Albanesi, Cristina
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BULLOUS pemphigoid ,POLYMERASE chain reaction ,CYTOKINES ,AUTOIMMUNE diseases ,DESMOGLEINS - Abstract
Bullous pemphigoid (BP) is an autoimmune bullous disease, characterized by autoantibodies targeting BP180 and BP230. The role of interleukin (IL)‐36, a potent chemoattractant for granulocytes, in BP remains elusive.The expression of IL‐36 cytokines (IL‐36α, β, γ) and their antagonists (IL‐36Ra and IL‐38) was analysed in the skin and serum samples of patients with BP (n = 31), psoriasis (n = 10) and healthy controls (HC) (n = 14) by quantitative polymerase chain reaction and enzyme linked immunosorbent assay, respectively. Skin and serum levels of all cytokines were correlated with the Bullous Pemphigoid Disease Area Index (BPDAI) score and with the serum concentration of pathogenic antibodies.IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra were significantly (p < 0.05) overexpressed in BP skin compared to HC, without remarkable differences relative to psoriasis skin. The expression of IL‐38 was significantly (p < 0.05) higher in BP compared to psoriasis skin.IL‐36α and γ, but not β, serum concentrations were significantly (p < 0.05) higher in BP compared to HC. IL‐36γ was significantly (p < 0.05) more expressed in the serum of psoriasis patients than BP. The serum concentration of IL‐36Ra and IL‐38 were similar between BP and HC, while IL‐38 serum levels were significantly (p < 0.05) higher in BP compared to psoriasis patients. Serum IL‐36α correlated significantly with BPDAI (r = 0.5 p = 0.001).IL‐36 agonists are increased in BP patients, both locally and systemically. Serum IL‐36α might represent a potential biomarker for BP. An inefficient balance between IL‐36 agonists and antagonists is likely to occur during BP inflammation. [ABSTRACT FROM AUTHOR]
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- 2023
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9. IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment
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Mercurio, Laura, Morelli, Martina, Scarponi, Claudia, Eisenmesser, Elan Z., Doti, Nunzianna, Pagnanelli, Gianluca, Gubinelli, Emanuela, Mazzanti, Cinzia, Cavani, Andrea, Ruvo, Menotti, Dinarello, Charles A., Albanesi, Cristina, and Madonna, Stefania
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- 2018
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10. CAROTID-FEMORAL PULSE WAVE VELOCITY PROGRESSION IN HYPERTENSIVE PATIENTS IS ASSOCIATED WITH SUBSEQUENT CV OUTCOMES.
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Maloberti, Alessandro, Rebora, Paola, Occhino, Giuseppe, Andreano, Anita, Intravaia, Rita Cristina My, Tognola, Chiara, Toscani, Giorgio, Morelli, Martina, Pezzoli, Stefano, D'Oro, Luca Cavalieri, Russo, Antonio, and Giannattasio, Cristina
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- 2024
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11. HYPERTRIGLYCERIDEMIA IN PATIENTS WITH ACUTE AND CHRONIC CORONARY SYNDROME: PREVALENCE AND THEIR ASSOCIATION WITH EXTREME CARDIOVASCULAR RISK AND LEFT VENTRICULAR FUNCTION.
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Maloberti, Alessandro, Rosa, Antonio La, Toscani, Giorgio, Caccia, Andrea, Gualini, Elena, Pezzoli, Stefano, Morelli, Martina, Busti, Andrea, Colombo, Valentina, Tognola, Chiara, Algeri, Michela, Intravaia, Rita Cristina My, Pirola, Roberto, Giannattasio, Cristina, and Garofani, Ilaria
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- 2024
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12. Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses.
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Mercurio, Laura, Failla, Cristina M., Capriotti, Lorena, Scarponi, Claudia, Facchiano, Francesco, Morelli, Martina, Rossi, Stefania, Pagnanelli, Gianluca, Albanesi, Cristina, Cavani, Andrea, and Madonna, Stefania
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KERATINOCYTES ,ENDOTHELIAL cells ,CROSSTALK ,VASCULAR endothelial growth factor antagonists ,SKIN ,PATHOLOGY ,VASCULAR cell adhesion molecule-1 ,CELL proliferation - Abstract
In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Paradoxical psoriasis induced by TNF‐α blockade shows immunological features typical of the early phase of psoriasis development.
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Fania, Luca, Morelli, Martina, Scarponi, Claudia, Mercurio, Laura, Scopelliti, Fernanda, Cattani, Caterina, Scaglione, Giovanni Luca, Tonanzi, Tiziano, Pilla, Maria Antonietta, Pagnanelli, Gianluca, Mazzanti, Cinzia, Girolomoni, Giampiero, Cavani, Andrea, Madonna, Stefania, and Albanesi, Cristina
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HIDRADENITIS suppurativa ,PSORIASIS ,NATURAL immunity ,T cells ,MAST cells ,KERATINOCYTES ,MACROPHAGES ,MONOCYTES - Abstract
Immunomodulation with anti‐TNF‐α is highly effective in the treatment of various immune‐mediated inflammatory diseases, including hidradenitis suppurativa (HS). However, this may be responsible for unexpected paradoxical psoriasiform reactions. The pathogenic mechanisms underlying the induction of these events are not clear, even though the involvement of innate immune responses driven by plasmacytoid dendritic cells (pDC) has been described. In addition, the genetic predisposition to psoriasis of patients could be determinant. In this study, we investigated the immunological and genetic profiles of three HS patients without psoriasis who developed paradoxical psoriasiform reactions following anti‐TNF‐α therapy with adalimumab. We found that paradoxical psoriasiform skin reactions show immunological features common to the early phases of psoriasis development, characterized by cellular players of innate immunity, such as pDC, neutrophils, mast cells, macrophages, and monocytes. In addition, IFN‐β and IFN‐α2a, two type I IFNs typical of early psoriasis, were highly expressed in paradoxical skin reactions. Concomitantly, other innate immunity molecules, such as the catheledicin LL37 and lymphotoxin (LT)‐α and LT‐β were overproduced. Interestingly, these innate immunity molecules were abundantly expressed by keratinocytes, in addition to the inflammatory infiltrate. In contrast to classical psoriasis, psoriasiform lesions of HS patients showed a reduced number of IFN‐γ and TNF‐α‐releasing T lymphocytes. On the contrary, IL‐22 immunoreactivity was significantly augmented together with the IL‐36γ staining in leukocytes infiltrating the dermis. Finally, we found that all HS patients with paradoxical reactions carried allelic variants in genes predisposing to psoriasis. Among them, SNPs in ERAP1, NFKBIZ, and TNFAIP genes and in the HLA‐C genomic region were found. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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14. Synthesis of Functionalised Indoline and Isoquinoline Derivatives through a Silylcarbocyclisation/Desilylation Sequence.
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Albano, Gianluigi, Morelli, Martina, Lissia, Margherita, and Aronica, Laura A.
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INDOLINE , *SILYLATION , *CHEMICAL reactions - Abstract
A two steps sequence of silylcarbocyclisation‐TBAF promoted desilylation/aryl migration has been applied to the synthesis of indolines and tetrahydroisoquinolines derivatives starting from suitable tosylamides and aryldimethylsilanes. In both cases silylcarbocyclisation reactions determined the formation of the heterocyclic ring together with the insertion of a CO functionality. Under the experimental conditions the carbonyl moiety is reduced to OH quantitatively. Subsequent treatment of silylated indolinols with TBAF generates stereoselectively the corresponding arylmethyl‐tosylindolinols. In the case of tetrahydroisoquinolinols, during the desilylation step, migration of the aryl moiety is followed by spontaneous loss of water thus affording 3,4‐dihydroisoquinolines exclusively. The synthesis of indolines and tetrahydroisoquinolines derivatives has been achieved by a two steps sequence based on rhodium‐promoted silylcarbocyclisation‐desilylation/aryl migration reactions, starting from suitable tosylamides and aryldimethylsilanes [ABSTRACT FROM AUTHOR]
- Published
- 2019
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15. Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis.
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Morelli, Martina, Scarponi, Claudia, Mercurio, Laura, Facchiano, Francesco, Pallotta, Sabatino, Madonna, Stefania, Girolomoni, Giampiero, and Albanesi, Cristina
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IMMUNOREGULATION , *INFLAMMATION , *KERATINOCYTES , *JANUS kinases , *ENZYME inhibitors , *PSORIASIS - Abstract
IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes. [ABSTRACT FROM AUTHOR]
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- 2018
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16. EFFECTS OF PCSK-9 INHBITORS ON ARTERIAL STRUCTURE AND FUNCTION: PRELIMINARY RESULTS.
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Maloberti, Alessandro, Vatta, Alessandro, Grasso, Alice, Garofani, Ilaria, Morelli, Martina, Giani, Valentina, Fortuna, Matteo, Gualini, Elena, and Giannattasio, Cristina
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- 2023
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17. POLYVASCULAR ATHEROSCLEROSIS INVOLVEMENT AND CARDIAC REHABILITATION: FUNCTIONAL IMPROVEMENT AND RISK RECLASSIFICATION.
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Pezzoli, Stefano, Maloberti, Alessandro, Ghidini, Simone, Colombo, Valentina, Daus, Francesca, Censi, Lorenzo De, Morelli, Martina, Alloni, Marta, and Giannattasio, Cristina
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- 2023
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18. Synthesis of Functionalised 3-Isochromanones by Silylcarbocyclisation/Desilylation Reactions.
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Albano, Gianluigi, Morelli, Martina, and Aronica, Laura Antonella
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CHROMANONES , *RING formation (Chemistry) , *SILYLATION , *CHEMICAL synthesis , *BENZYL alcohol - Abstract
A new protocol for the synthesis of 3-isochromanone derivatives based on rhodium-promoted silylcarbocyclisation reactions of ethynylbenzyl alcohol with different arylsilanes is described. The structure of the isochromanone depends upon the reaction conditions used: when the reaction is carried out without base, ( Z)-4-[(aryldimethylsilyl)methylene]isochroman-3-ones are obtained as major products. These compounds can be submitted to a desilylation/aryl migration reaction to give 4-(arylmethyl)isochroman-3-ones in high yields. In contrast, in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), hydrogenation of methyleneisochroman-3-ones takes place, and the corresponding β-(silylmethyl)-3-isochromanones are formed. Moreover, when internal alkynes are treated with hydrosilanes under silylcarbocyclisation reaction conditions, alcoholysis of the hydrosilanes occurs exclusively. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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19. PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis.
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Mercurio, Laura, Morelli, Martina, Scarponi, Claudia, Scaglione, Giovanni Luca, Pallotta, Sabatino, Albanesi, Cristina, and Madonna, Stefania
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KERATINOCYTES , *PHOSPHATIDYLINOSITOL 3-kinases , *PSORIASIS , *CELLULAR signal transduction , *LABORATORY mice ,KERATINOCYTE differentiation - Abstract
The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits.
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Mercurio, Laura, Morelli, Martina, Scarponi, Claudia, Scaglione, Giovanni Luca, Pallotta, Sabatino, Avitabile, Daniele, Albanesi, Cristina, and Madonna, Stefania
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PATHOGENESIS , *PSORIASIS , *EPITHELIAL cells , *ENDOTHELIAL cells , *FIBROBLASTS , *NEUTROPHILS - Abstract
Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. Allelic Variants of HLA-C Upstream Region, PSORS1C3 , MICA , TNFA and Genes Involved in Epidermal Homeostasis and Barrier Function Influence the Clinical Response to Anti-IL-12/IL-23 Treatment of Patients with Psoriasis.
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Morelli M, Galluzzo M, Scarponi C, Madonna S, Scaglione GL, Girolomoni G, Talamonti M, Bianchi L, and Albanesi C
- Abstract
Several biologic therapies have been developed to treat moderate-to-severe psoriasis, with patients exhibiting different clinical benefits, possibly due to the heterogeneity of pathogenic processes underlying their conditions. Ustekinumab targets the IL-12/IL-23-p40 subunit and inhibits type-1 and type-17 T-cell responses. Although ustekinumab is effective as both short- and long-term treatment, therapeutic response varies considerably among patients. Ustekinumab biosimilars will be commercialized in the very next future, likely broadening the use of this drug in the treatment of psoriasis patients. Our pharmacogenomic study evaluated the influence of 417 single-nucleotide polymorphisms (SNPs) in psoriasis-risk alleles on the clinical response to ustekinumab in a cohort of 152 patients affected by moderate-to-severe plaque-type psoriasis. Differences in SNP pattern characterizing HLA-Cw6
+ or HLA-Cw6- patients, showing high or low responses to ustekinumab, were also analysed. We identified twelve SNPs in HLA-C upstream region (rs12189871, rs4406273, rs9348862 and rs9368670), PSORS1C3 (rs1265181), MICA (rs2523497), LCE3A-B intergenic region (rs12030223, rs6701730), CDSN (rs1042127, rs4713436), CCHCR1 (rs2073719) and in TNFA (rs1800610) genes associated with excellent response to ustekinumab. We also found that HLA-Cw6+ and HLA-Cw6- patients carried out distinct patterns of SNPs associated with different clinical responses. The assessment of HLA-C alleles, together with other genetic variants, could be helpful for defining patients who better benefit from anti-IL-12/IL-23 therapy.- Published
- 2022
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22. HLA-Cw6 and other HLA-C alleles, as well as MICB-DT, DDX58, and TYK2 genetic variants associate with optimal response to anti-IL-17A treatment in patients with psoriasis.
- Author
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Morelli M, Galluzzo M, Madonna S, Scarponi C, Scaglione GL, Galluccio T, Andreani M, Pallotta S, Girolomoni G, Bianchi L, Talamonti M, and Albanesi C
- Subjects
- Alleles, Cohort Studies, DEAD Box Protein 58, Humans, Receptors, Immunologic, TYK2 Kinase, Treatment Outcome, HLA-C Antigens genetics, Psoriasis drug therapy, Psoriasis genetics
- Abstract
Objective : Our pharmacogenomic study evaluated the influence of the presence/absence of genetic variants of psoriasis-risk loci on the clinical response to secukinumab. Differences in the single-nucleotide polymorphism (SNP) pattern characterizing HLA-Cw6
+ or HLA-Cw6- patient subpopulations, showing high or low responses to secukinumab, were also analyzed. Methods : 417 SNPs were analyzed by Next-Generation Sequencing technology, in a cohort of 62 psoriatic patients and undergone secukinumab treatment. Univariate regression analysis was employed to examine the association between SNP and clinical response to secukinumab. Multivariate analysis was also performed to assess multivariate differences in SNP pattern of HLA-Cw6+ or HLA-Cw6- patients showing high or low responses to secukinumab. Results : Eight SNPs in HLA-C and upstream region (rs13207315, rs6900444, rs12189871, rs12191877, rs4406273, and rs10484554), including HLA-Cw6 classical allele (rs1131118), and three in MICB-DT (rs9267325), DDX58 (rs34085293) and TYK2 (rs2304255) genes, associating with excellent response to secukinumab were identified. Importantly, rs34085293 or r s2304255 SNP status defined a subgroup of super-responder patients. We also found that HLA-Cw6+ and HLA-Cw6- patients carried out specific patterns of SNPs associating with different responses to secukinumab. Conclusion : Assessment of HLA-Cw6 , together with other allelic variants of genes, could be helpful to define patients which better benefit from anti-IL-17 therapy. Abbreviations: PASI: Psoriasis Area and Severity Index; SNP: Single-Nucleotide Polymorphism Rs: Reference SNP; PASI75: 75% reduction in Psoriasis Area and Severity Index; PASI90: 90% reduction in Psoriasis Area and Severity Index; PASI100: 100% reduction in Psoriasis Area and Severity Index; NGS: Next-Generation Sequencing; OR: Odds Ratio; CAP: Canonical Analysis of Principal coordinates; BMI: Body Mass Index; LD: Linkage Disequilibrium.- Published
- 2021
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23. Experimental Methods for the Immunological Characterization of Paradoxical Psoriasis Reactions Induced by TNF-α Biologics.
- Author
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Morelli M, Scarponi C, Madonna S, and Albanesi C
- Subjects
- Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Humans, Immunity, Innate drug effects, Psoriasis pathology, Biological Products adverse effects, Immunologic Factors adverse effects, Psoriasis etiology, Psoriasis metabolism, Tumor Necrosis Factor-alpha adverse effects
- Abstract
Immunomodulation with anti-TNFα biologics is highly effective in the treatment of various immune-mediated inflammatory diseases, even though 2-5% of patients treated can develop paradoxical psoriasiform skin lesions. We recently analyzed three patients affected by severe hidradenite suppurativa (HS), and who developed paradoxical psoriasiform reactions following treatment with the TNF-α blockers. Psoriasiform skin reactions showed immunological and immunohistochemical features common to acute psoriasis, characterized by cellular players of innate immunity, such as plasmacytoid dendritic cells (pDC), neutrophils, mast cells, macrophages, and monocytes. In addition, IFN-β and IFN-α2a, two type I IFNs typical of early psoriasis, were highly expressed in paradoxical skin reactions. Concomitantly, the lymphotoxin (LT)-α and LT-β were overproduced. Detection of innate immunity cells was carried out on skin sections from HS patients, by immunohistochemistry (IHC) by using antibodies (Abs) against markers identifying specific leukocyte subpopulations. Anti-BDCA2, anti-CD15, anti-CD117, anti-CD68, anti-CD11c, and anti-CD3 Abs were employed to detect pDC, neutrophils, mast cells, macrophages, monocytes/dendritic cells, and T lymphocytes, respectively. In parallel, skin expression of the innate immunity soluble mediators IL-36γ, IFN-β, IFN-κ, LT-α and LT-β was also evaluated by IHC by using specific Abs. In this chapter, we describe the methods and protocols to detect the in situ expression and localization of innate immunity molecules and leukocyte subpopulations in skin lesions where inflammatory and psoriasiform reactions are evoked by anti-TNF- α biological therapy.
- Published
- 2021
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24. Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21.
- Author
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Mercurio L, Lulli D, Mascia F, Dellambra E, Scarponi C, Morelli M, Valente C, Carbone ML, Pallotta S, Girolomoni G, Albanesi C, Pastore S, and Madonna S
- Subjects
- Adult, Aged, Apoptosis, Biopsy, CDC2 Protein Kinase genetics, Cell Proliferation, Cells, Cultured, Cellular Senescence, Cyclin A1 genetics, Cytoplasm metabolism, Gene Expression, Humans, Middle Aged, Phosphorylation, Psoriasis metabolism, Psoriasis pathology, RNA, Messenger metabolism, Skin metabolism, Up-Regulation, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Insulin-Like Growth Factor Binding Protein 2 genetics, Insulin-Like Growth Factor Binding Protein 2 metabolism, Keratinocytes physiology, Psoriasis genetics, Skin pathology
- Abstract
Psoriasis is a chronic Th1/Th17 lymphocytes-mediated inflammatory skin disease, in which epidermal keratinocytes exhibit a peculiar senescent state, resistance to apoptosis and the acquisition of senescence-associated secretory phenotype (SASP). SASP consists of the release of soluble factors, including IGFBPs, that exert extracellular and intracellular functions in IGF-dependent or independent manner.In this report, we investigated the expression and function of IGFBP2 in senescent keratinocytes isolated from the skin of patients with plaque psoriasis. We found that IGFBP2 is aberrantly expressed and released by these cells in vivo , as well as in vitro in keratinocyte cultures undergoing progressive senescence, and it associates with the cyclin-dependent kinase inhibitors p21 and p16 expression. For the first time, we provide evidence for a dual action of IGFBP2 in psoriatic keratinocytes during growth and senescence processes. While extracellular IGFBP2 counter-regulates IGF-induced keratinocyte hyper-proliferation, intracellular IGFBP2 inhibits apoptosis by interacting with p21 and protecting it from ubiquitin-dependent degradation. Indeed, we found that cytoplasmic p21 sustains anti-apoptotic processes, by inhibiting pro-caspase 3 cleavage and JNK phosphorylation in senescent psoriatic keratinocytes. As a consequence, abrogation of p21, as well as that of IGFBP2, found to stabilize cytoplasmic p21 levels, lead to the restoration of apoptosis mechanisms in psoriatic keratinocytes, commonly observed in healthy cells.
- Published
- 2020
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25. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes.
- Author
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Madonna S, Scarponi C, Morelli M, Sestito R, Scognamiglio PL, Marasco D, and Albanesi C
- Subjects
- Animals, Biomimetic Materials pharmacology, Gene Knockdown Techniques, Heterografts, Humans, Interleukins metabolism, Keratinocytes pathology, Lymphocytes, Tumor-Infiltrating metabolism, Male, Mice, Mice, Nude, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Suppressor of Cytokine Signaling 1 Protein biosynthesis, Suppressor of Cytokine Signaling 1 Protein genetics, Suppressor of Cytokine Signaling 1 Protein metabolism, Suppressor of Cytokine Signaling 3 Protein biosynthesis, Suppressor of Cytokine Signaling 3 Protein metabolism, Transfection, Interleukin-22, Interleukins antagonists & inhibitors, Keratinocytes metabolism, Skin Neoplasms genetics, Suppressor of Cytokine Signaling 3 Protein genetics
- Abstract
Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.
- Published
- 2017
- Full Text
- View/download PDF
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