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1.
Biomolecules ; 14(6)2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38927130

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of 61 ALS patients and 30 age-matched HCs were enrolled in the study and the protein content of circulating EVs was analyzed by shotgun proteomics. The study was divided into a discovery phase (involving 12 ALS and 12 HC patients) and a validation one (involving 49 ALS and 20 HC patients). In the discovery phase, more than 300 proteins were identified, with 32 proteins showing differential regulation in ALS patients compared to HCs. In the validation phase, over 400 proteins were identified, with 20 demonstrating differential regulation in ALS patients compared to HCs. Notably, seven proteins were found to be common to both phases, all of which were significantly upregulated in EVs from ALS patients. Most of them have previously been linked to ALS since they have been detected in the serum or cerebrospinal fluid of ALS patients. Among them, proteoglycan (PRG)-4, also known as lubricin, was of particular interest since it was significantly increased in ALS patients with normal cognitive and motor functions. This study highlights the significance of EVs as a promising avenue for biomarker discovery in ALS. Moreover, it sheds light on the unexpected role of PRG-4 in relation to cognitive status in ALS patients.


Asunto(s)
Esclerosis Amiotrófica Lateral , Biomarcadores , Vesículas Extracelulares , Proteómica , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/sangre , Vesículas Extracelulares/metabolismo , Proteómica/métodos , Masculino , Persona de Mediana Edad , Femenino , Biomarcadores/sangre , Biomarcadores/metabolismo , Anciano , Proteoglicanos/metabolismo , Cognición , Estudios de Casos y Controles , Adulto
2.
Nutrients ; 16(11)2024 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-38892678

RESUMEN

The Mediterranean diet (MD) and Western diet (WD) are poles apart as dietary patterns. Despite the availability of epidemiological tools to estimate the adherence to MD, to date, there is a lack of combined scores. We developed MEDOC, a food frequency questionnaire (FFQ) designed to calculate a combined adherence score for both diets and validated it on 213 subjects. The test-retest reliability revealed all frequency questions falling within the acceptable range of 0.5 to 0.7 (Pearson correlation coefficient) in younger (<30 years old) subjects, while 1 question out of 39 fell below the range in older (>30 years old) participants. The reproducibility for portion size was less satisfying, with, respectively, 38.2% and 70.5% of questions falling below 0.5 (Cohen's Kappa index) for younger and older subjects. The good correlation (R = 0.63, p < 0.0001 for subjects younger than 30 years and R = 0.54, p < 0.0001 for subjects older than 30 years, Pearson's correlation coefficient) between the MEDOC score and the MediDietScore (MDS) confirmed the validity of the MEDOC score in identifying patients who adhere to the MD. Harnessing the capabilities of this innovative tool, we aim to broaden the existing perspective to study complex dietary patterns in nutritional epidemiology studies.


Asunto(s)
Encuestas sobre Dietas , Dieta Mediterránea , Dieta Occidental , Humanos , Adulto , Reproducibilidad de los Resultados , Femenino , Masculino , Persona de Mediana Edad , Encuestas sobre Dietas/métodos , Encuestas y Cuestionarios , Adulto Joven , Conducta Alimentaria , Cooperación del Paciente/estadística & datos numéricos , Anciano , Tamaño de la Porción
3.
Biomedicines ; 12(5)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38790944

RESUMEN

Osteopontin (OPN), a multifunctional protein, has emerged as a fascinating subject of study due to its diverse roles in various physiological and pathological processes [...].

4.
Int J Mol Sci ; 25(8)2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38674086

RESUMEN

Biomaterials are extensively used as replacements for damaged tissue with bioactive glasses standing out as bone substitutes for their intrinsic osteogenic properties. However, biomaterial implantation has the following risks: the development of implant-associated infections and adverse immune responses. Thus, incorporating metallic ions with known antimicrobial properties can prevent infection, but should also modulate the immune response. Therefore, we selected silver, copper and tellurium as doping for bioactive glasses and evaluated the immunophenotype and cytokine profile of human T-cells cultured on top of these discs. Results showed that silver significantly decreased cell viability, copper increased the T helper (Th)-1 cell percentage while decreasing that of Th17, while tellurium did not affect either cell viability or immune response, as evaluated via multiparametric flow cytometry. Multiplex cytokines assay showed that IL-5 levels were decreased in the copper-doped discs, compared with its undoped control, while IL-10 tended to be lower in the doped glass, compared with the control (plastic) while undoped condition showed lower expression of IL-13 and increased MCP-1 and MIP-1ß secretion. Overall, we hypothesized that the Th1/Th17 shift, and specific cytokine expression indicated that T-cells might cross-activate other cell types, potentially macrophages and eosinophils, in response to the scaffolds.


Asunto(s)
Citocinas , Vidrio , Humanos , Vidrio/química , Citocinas/metabolismo , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Metales/química , Cobre/química , Iones , Células Cultivadas , Células Th17/inmunología , Células TH1/inmunología , Células TH1/efectos de los fármacos
5.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38473756

RESUMEN

The inducible T cell co-stimulator ligand (ICOSL), expressed by antigen presenting cells, binds to the inducible T cell co-stimulator (ICOS) on activated T cells. Improper function of the ICOS/ICOSL pathway has been implicated in several autoimmune diseases, including multiple sclerosis (MS). Previous studies showed that ICOS-knockout (KO) mice exhibit severe experimental autoimmune encephalomyelitis (EAE), the animal model of MS, but data on ICOSL deficiency are not available. In our study, we explored the impact of both ICOS and ICOSL deficiencies on MOG35-55 -induced EAE and its associated immune cell dynamics by employing ICOSL-KO and ICOS-KO mice with a C57BL/6J background. During EAE resolution, MOG-driven cytokine levels and the immunophenotype of splenocytes were evaluated by ELISA and multiparametric flow cytometry, respectively. We found that both KO mice exhibited an overlapping and more severe EAE compared to C57BL/6J mice, corroborated by a reduction in memory/regulatory T cell subsets and interleukin (IL-)17 levels. It is noteworthy that an unsupervised analysis showed that ICOSL deficiency modifies the immune response in an original way, by affecting T central and effector memory (TCM, TEM), long-lived CD4+ TEM cells, and macrophages, compared to ICOS-KO and C57BL/6J mice, suggesting a role for other binding partners to ICOSL in EAE development, which deserves further study.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones , Animales , Ratones Noqueados , Citometría de Flujo , Encefalomielitis Autoinmune Experimental/metabolismo , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ligandos , Ratones Endogámicos C57BL , Linfocitos T , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo
6.
J Orthop ; 43: 121-124, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37583756

RESUMEN

Objective: The aim of this study was to assess the functional, radiological, and clinical outcomes of patellofemoral joint in patients who had total knee arthroplasty (TKA) without patellar resurfacing for end-stage osteoarthritis using inverse restricted kinematic alignment (irKA) compared to a control group using adjusted mechanical alignment (aMA), both executed with the same implant at the same Institution. The hypothesis was that patients undergoing TKA without patellar resurfacing for end-stage osteoarthritis using irKA would have superior outcomes related to the patellofemoral joint in comparison to a control group using aMA. Methods: A retrospective examination of registries' prospectively obtained from patients who underwent primary TKA at our Institution between 2016 and 2020 was performed. 40 consecutive patients who underwent TKA implant using irKA were compared to a control group of 80 who had undergone adjusted mechanically-aligned TKA. Groups were matched for age and body mass index. Clinical assessment included Visual Analog Scale (VAS), Knee Osteoarthritis Outcome Score (KOOS), Knee Society Score (KSS), and Kujala Knee Score. Standard weight-bearing anteroposterior and lateral view x-rays were used for radiographic evaluation. Patellar height was assessed using Caton-Deschamps (C-D) and Insall index on lateral view films. Results: In comparison to pre-operative status, both groups had postoperative improvements in VAS, KOOS, KSS, and Kujala ratings (p<0.001). Regarding Kujala score, there were no statistically significant differences between the groups (p = 0.68). Insall index and C-D index results were not statistically different across groups (p = 0.02 and 0.74 respectively). Conclusion: Improvements in post-operative clinical and functional outcomes following TKA were associated with either irKA or aMA. There were no discernible changes between the two groups in terms of postoperative patellofemoral discomfort or variations in patellar height.

7.
Int J Mol Sci ; 24(7)2023 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-37047229

RESUMEN

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.


Asunto(s)
COVID-19 , Proteínas Proto-Oncogénicas , Femenino , Humanos , Tirosina Quinasa c-Mer , COVID-19/complicaciones , Péptidos y Proteínas de Señalización Intercelular , Proteínas Tirosina Quinasas Receptoras
8.
Dis Markers ; 2022: 8074655, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35811660

RESUMEN

Platelet-derived extracellular vesicles (PLT-EVs), the most abundant circulating EVs, have been found to be increased in several human diseases, including viral infections. Recently, we documented that PLT-EV counts are higher in SARS-CoV-2+ patients, enrolled during the first two waves of COVID-19, occurred in Italy last year, and we suggested PLT-EVs as a biomarker of SARS-CoV-2 infection. The present study is aimed at testing the ability of PLT-EV levels, measured at hospital admission and within one week of hospitalization, to predict patient's outcome. We applied an easy, fast, and reliable method, based on flow cytometry, for the detection of PLT-EVs in unmanipulated blood samples. In a cohort of SARS-CoV-2 patients, enrolled during the third wave of COVID-19 in Italy, we confirmed that PLT-EV counts are higher in comparison to healthy controls. Moreover, their number is not affected by prehospitalization treatment neither with heparin nor with steroids that are recommended by WHO guidelines. Noteworthy, we identified two pattern of patients, those who increased their PTL-EV level during first week and those reducing it. The former group representented more compromised patients, with higher 4C score, and unfavorable outcome. In conclusion, our new findings would suggest that a worse evolution of the disease is linked with increasing PLT-EV levels in the week after hospital admission.


Asunto(s)
COVID-19 , Vesículas Extracelulares , Plaquetas , Humanos , Pronóstico , SARS-CoV-2
9.
Front Immunol ; 13: 1038227, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36601115

RESUMEN

Rationale: Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called "long COVID") are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. Methods: A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines. Results: In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1ß, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms. Conclusions: Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.


Asunto(s)
COVID-19 , Humanos , Adulto , Femenino , Estudios Prospectivos , SARS-CoV-2 , Síndrome Post Agudo de COVID-19 , Interleucina-12 , Citocinas , Progresión de la Enfermedad
11.
Nutrients ; 13(11)2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34836210

RESUMEN

Nutrition and immunity are closely related, and the immune system is composed of the most highly energy-consuming cells in the body. Much of the immune system is located within the GI tract, since it must deal with the huge antigenic load introduced with food. Moreover, the incidence of immune-mediated diseases is elevated in Westernized countries, where "transition nutrition" prevails, owing to the shift from traditional dietary patterns towards Westernized patterns. This ecological correlation has fostered increasing attempts to find evidence to support nutritional interventions aimed at managing and reducing the risk of immune-mediated diseases. Recent studies have described the impacts of single nutrients on markers of immune function, but the knowledge currently available is not sufficient to demonstrate the impact of specific dietary patterns on immune-mediated clinical disease endpoints. If nutritional scientists are to conduct quality research, one of many challenges facing them, in studying the complex interactions between the immune system and diet, is to develop improved tools for investigating eating habits in the context of immunomediated diseases.


Asunto(s)
Enfermedades Autoinmunes/etiología , Dieta , Enfermedades Autoinmunes/microbiología , Dieta Mediterránea , Dieta Occidental , Microbioma Gastrointestinal , Humanos , Cooperación del Paciente
12.
Sci Rep ; 11(1): 22666, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34811387

RESUMEN

Many coronavirus disease 2019 (Covid-19) survivors show symptoms months after acute illness. The aim of this work is to describe the clinical evolution of Covid-19, one year after discharge. We performed a prospective cohort study on 238 patients previously hospitalized for Covid-19 pneumonia in 2020 who already underwent clinical follow-up 4 months post-Covid-19. 200 consented to participate to a 12-months clinical assessment, including: pulmonary function tests with diffusing lung capacity for carbon monoxide (DLCO); post-traumatic stress (PTS) symptoms evaluation by the Impact of Event Scale (IES); motor function evaluation (by Short Physical Performance Battery and 2 min walking test); chest Computed Tomography (CT). After 366 [363-369] days, 79 patients (39.5%) reported at least one symptom. A DLCO < 80% was observed in 96 patients (49.0%). Severe DLCO impairment (< 60%) was reported in 20 patients (10.2%), related to extent of CT scan abnormalities. Some degree of motor impairment was observed in 25.8% of subjects. 37/200 patients (18.5%) showed moderate-to-severe PTS symptoms. In the time elapsed from 4 to 12 months after hospital discharge, motor function improves, while respiratory function does not, being accompanied by evidence of lung structural damage. Symptoms remain highly prevalent one year after acute illness.


Asunto(s)
COVID-19/complicaciones , Hospitalización , Anciano , COVID-19/diagnóstico , COVID-19/diagnóstico por imagen , COVID-19/epidemiología , Monóxido de Carbono/metabolismo , Femenino , Humanos , Italia/epidemiología , Modelos Logísticos , Masculino , Salud Mental , Persona de Mediana Edad , Actividad Motora , Gravedad del Paciente , Alta del Paciente , Prevalencia , Estudios Prospectivos , Capacidad de Difusión Pulmonar , Pruebas de Función Respiratoria , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Sobrevivientes , Tomografía Computarizada por Rayos X , Prueba de Paso , Síndrome Post Agudo de COVID-19
13.
EMBO Mol Med ; 13(5): e14124, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33787012

RESUMEN

This study independently confirms increased levels of osteopontin in COVID-19 patients but also suggests that osteopontin cannot be used as a biomarker of SARS-CoV-2 infection, as elevated levels of circulating osteopontin are found in inflammatory lung disease regardless of SARS-CoV-2 infection.


Asunto(s)
COVID-19 , SARS-CoV-2 , Metabolismo Energético , Humanos , Mitocondrias , Monocitos , Osteopontina
14.
Front Mol Biosci ; 8: 632290, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33693030

RESUMEN

Knowledge of the host response to the novel coronavirus SARS-CoV-2 remains limited, hindering the understanding of COVID-19 pathogenesis and the development of therapeutic strategies. During the course of a viral infection, host cells release exosomes and other extracellular vesicles carrying viral and host components that can modulate the immune response. The present study used a shotgun proteomic approach to map the host circulating exosomes' response to SARS-CoV-2 infection. We investigated how SARS-CoV-2 infection modulates exosome content, exosomes' involvement in disease progression, and the potential use of plasma exosomes as biomarkers of disease severity. A proteomic analysis of patient-derived exosomes identified several molecules involved in the immune response, inflammation, and activation of the coagulation and complement pathways, which are the main mechanisms of COVID-19-associated tissue damage and multiple organ dysfunctions. In addition, several potential biomarkers-such as fibrinogen, fibronectin, complement C1r subcomponent and serum amyloid P-component-were shown to have a diagnostic feature presenting an area under the curve (AUC) of almost 1. Proteins correlating with disease severity were also detected. Moreover, for the first time, we identified the presence of SARS-CoV-2 RNA in the exosomal cargo, which suggests that the virus might use the endocytosis route to spread infection. Our findings indicate circulating exosomes' significant contribution to several processes-such as inflammation, coagulation, and immunomodulation-during SARS-CoV-2 infection. The study's data are available via ProteomeXchange with the identifier PXD021144.

15.
Cells ; 10(1)2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33430260

RESUMEN

Sars-Cov-2 infection causes fever and cough that may rapidly lead to acute respiratory distress syndrome (ARDS). Few biomarkers have been identified but, unfortunately, these are individually poorly specific, and novel biomarkers are needed to better predict patient outcome. The aim of this study was to evaluate the diagnostic performance of circulating platelets (PLT)-derived extracellular vesicles (EVs) as biomarkers for Sars-Cov-2 infection, by setting a rapid and reliable test on unmanipulated blood samples. PLT-EVs were quantified by flow cytometry on two independent cohorts of Sars-CoV-2+ (n = 69), Sars-Cov-2- (n = 62) hospitalized patients, and healthy controls. Diagnostic performance of PLT-EVs was evaluated by receiver operating characteristic (ROC) curve. PLT-EVs count were higher in Sars-Cov-2+ compared to Sars-Cov-2- patients or HC. ROC analysis of the combined cohorts showed an AUC = 0.79 and an optimal cut-off value of 1472 EVs/µL, with 75% sensitivity and 74% specificity. These data suggest that PLT-EVs might be an interesting biomarker deserving further investigations to test their predictive power.


Asunto(s)
Plaquetas/metabolismo , COVID-19/sangre , Vesículas Extracelulares/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Plaquetas/patología , COVID-19/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas
16.
Cells ; 11(1)2021 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-35011605

RESUMEN

Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.


Asunto(s)
Vesículas Extracelulares/metabolismo , Enfermedades Musculoesqueléticas/fisiopatología , Enfermedades Musculoesqueléticas/terapia , Sistema Musculoesquelético/metabolismo , Regeneración/fisiología , Materiales Biocompatibles/farmacología , Vesículas Extracelulares/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Sistema Musculoesquelético/efectos de los fármacos , Regeneración/efectos de los fármacos
17.
Biomedicines ; 10(1)2021 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-35052731

RESUMEN

Recently, we demonstrated that inducible T-cell costimulator (ICOS) shares its unique ligand (ICOSL) with osteopontin (OPN), and OPN/ICOSL binding promotes tumor metastasis and angiogenesis in the 4T1 breast cancer model. Literature showed that OPN promotes melanoma metastasis by suppressing T-cell activation and recruiting myeloid suppressor cells (MDSC). On the opposite, ICOS/ICOSL interaction usually sustains an antitumor response. Here, we engineered murine B16F10 melanoma cells, by transfecting or silencing ICOSL. In vitro data showed that loss of ICOSL favors anchorage-independent growth and induces more metastases in vivo, compared to ICOSL expressing cells. To dissect individual roles of the three molecules, we compared data from C57BL/6 with those from OPN-KO, ICOS-KO, and ICOSL-KO mice, missing one partner at a time. We found that OPN produced by the tumor microenvironment (TME) favors the metastasis by interacting with stromal ICOSL. This activity is dominantly inhibited by ICOS expressed on TME by promoting Treg expansion. Importantly, we also show that OPN and ICOSL highly interact in human melanoma metastases compared to primary tumors. Interfering with this binding may be explored in immunotherapy either for nonresponding or patients resistant to conventional therapies.

18.
Neural Regen Res ; 16(6): 1131-1137, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33269761

RESUMEN

Osteopontin is a broadly expressed pleiotropic protein, and is attracting increased attention because of its role in the pathophysiology of several inflammatory, degenerative, autoimmune, and oncologic diseases. In fact, in the last decade, several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion, but also increasing their survival. The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions (i.e., multiple sclerosis, Parkinson's, and Alzheimer's diseases). Intriguingly, recent findings show that osteopontin is involved not only in promoting tissue damage (the Yin), but also in repair/regenerative mechanisms (the Yang), mostly triggered by the inflammatory response. These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule, which are exposed after thrombin or metalloproteases cleavages. Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions. This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases. Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.

19.
Int J Mol Sci ; 21(22)2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-33207699

RESUMEN

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.


Asunto(s)
Infecciones por Coronavirus/metabolismo , Metaboloma , Neumonía Viral/metabolismo , Anciano , Anciano de 80 o más Años , Aminoácidos/sangre , Ácido Araquidónico/sangre , Biomarcadores/sangre , COVID-19 , Ciclo del Ácido Cítrico , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Femenino , Gluconeogénesis , Humanos , Masculino , Persona de Mediana Edad , Ácido Oléico/sangre , Pandemias , Fosfatidilcolinas/sangre , Fosfatidiletanolaminas/sangre , Fosfolipasas A2/sangre , Neumonía Viral/sangre , Neumonía Viral/patología , Triglicéridos/sangre
20.
Commun Biol ; 3(1): 615, 2020 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-33106594

RESUMEN

ICOSL/ICOS are costimulatory molecules pertaining to immune checkpoints; their binding transduces signals having anti-tumor activity. Osteopontin (OPN) is here identified as a ligand for ICOSL. OPN binds a different domain from that used by ICOS, and the binding induces a conformational change in OPN, exposing domains that are relevant for its functions. Here we show that in vitro, ICOSL triggering by OPN induces cell migration, while inhibiting anchorage-independent cell growth. The mouse 4T1 breast cancer model confirms these data. In vivo, OPN-triggering of ICOSL increases angiogenesis and tumor metastatization. The findings shed new light on ICOSL function and indicate that another partner beside ICOS may be involved; they also provide a rationale for developing alternative therapeutic approaches targeting this molecular trio.


Asunto(s)
Movimiento Celular/fisiología , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Osteopontina/metabolismo , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Células CHO , Línea Celular Tumoral , Cricetulus , Femenino , Silenciador del Gen , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ratones , Metástasis de la Neoplasia/prevención & control , Neoplasias Experimentales
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