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This review critically assessed the existence of presbygeusia, i.e., the impairment in taste perception occurring in the elderly, as a natural part of the aging process and its potential clinical implications. Several factors might contribute to age-related taste alterations (TAs), including structural changes in taste buds, alterations in saliva composition, central nervous system changes, and oral microbiota dysbiosis. A comprehensive literature review was conducted to disentangle the effects of age from those of the several age-related diseases or conditions promoting TAs. Most of the included studies reported TAs in healthy elderly people, suggesting that presbygeusia is a relatively frequent condition associated with age-related changes in the absence of pathological conditions. However, the impact of TAs on dietary preferences and food choices among the elderly seems to be less relevant when compared to other factors, such as cultural, psychological, and social influences. In conclusion, presbygeusia exists even in the absence of comorbidities or drug side effects, but its impact on dietary choices in the elderly is likely modest.
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Papilas Gustativas , Gusto , Humanos , Anciano , Gusto/fisiología , Percepción del Gusto/fisiología , Saliva/química , Saliva/fisiología , Papilas Gustativas/fisiología , Preferencias AlimentariasRESUMEN
Cancer cachexia is a complex multifactorial syndrome whose hallmarks are weight loss due to the wasting of muscle tissue with or without the loss of adipose tissue, anorexia, systemic inflammation, and multi-organ metabolic alterations, which negatively impact patients' response to anticancer treatments, quality of life, and overall survival. Despite its clinical relevance, cancer cachexia often remains an underestimated complication due to the lack of rigorous diagnostic and therapeutic pathways. A number of studies have shown alterations in gut microbiota diversity and composition in association with cancer cachexia markers and symptoms, thus supporting a central role for dysbiosis in the pathogenesis of this syndrome. Different tools of microbiota manipulation, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been investigated, demonstrating encouraging improvements in cachexia outcomes. Albeit pioneering, these studies pave the way for future research with the aim of exploring the role of gut microbiota in cancer cachexia more deeply and setting up effective microbiota-targeting interventions to be translated into clinical practice.
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Microbioma Gastrointestinal , Neoplasias , Probióticos , Humanos , Microbioma Gastrointestinal/fisiología , Caquexia/terapia , Caquexia/complicaciones , Calidad de Vida , Probióticos/uso terapéutico , Prebióticos , Neoplasias/complicaciones , Neoplasias/terapia , Trasplante de Microbiota Fecal , Disbiosis/complicaciones , Disbiosis/terapiaRESUMEN
Antibody-based anti-cancer therapy is considered a successful approach to impair tumour progression. This study aimed to investigate the clinical impact of targeting the IL-3 signalling in the microenvironment of solid tumours. We intended to investigate whether the IL-3Rα blockade on tumour-derived endothelial cells (TEC) can modulate PD-L1 expression in tumour cells and peripheral blood mononuclear cells (PBMC) to reshape the anti-tumour immune response. Extracellular vesicles released by TEC after IL-3Rα blockade (aTEV) were used as the ultimate effectors of the antibody-based approach, while naive TEC-derived extracellular vesicles (nTEV) served as control. Firstly, we demonstrated that, either directly or indirectly via nTEV, IL-3 controls the expression of its receptor on TEC and PBMC respectively. Moreover, we found that nTEV, moulded by the autocrine secretion of IL-3, increased PD-L1 expression in myeloid cells both in vitro and in vivo. In addition, we found that nTEV-primed PBMC favour tumour cell growth (TEC and MDA-MB-231 cells), whereas PBMC-primed with aTEV still retain their anti-tumour properties. Isolated T-cells pre-conditioned with nTEV or aTEV and co-cultured with TEC or MDA-MB-231 cells have no effects, thereby sustaining the key role of myeloid cells in tumour immune editing. In vivo nTEV, but not aTEV, increased the expression of PD-L1 in primary tumours, lung and liver metastases. Finally, we demonstrated that the enrichment of miR-214 in aTEV impacts on PD-L1 expression in vivo. Overall, these data indicate that an approach based on IL-3Rα blockade in TEC rearranges EV cargo and may reshape the anti-tumour immune response.
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Vesículas Extracelulares , Neoplasias Hepáticas , MicroARNs , Antígeno B7-H1/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Inmunidad , Interleucina-3/metabolismo , Leucocitos Mononucleares/metabolismo , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Microambiente TumoralRESUMEN
OBJECTIVES: to assess the prevalence of post-traumatic stress disorder (PTSD) symptoms in a sample of Italian citizens during the first COVID-19 pandemic wave and its association with sociodemographic characteristics, housing conditions, and lifestyles modifications. DESIGN: cross-sectional survey. SETTING AND PARTICIPANTS: between 21st April and 7th June 2020, a self-administered online questionnaire aiming at investigating mental well-being and lifestyle habits during the lockdown period was disseminated online. Respondents were recruited through a snowball sampling. MAIN OUTCOME MEASURES: PTSD symptoms were assessed using a validated screening tool, the SPAN (Startle, Physiological arousal, Anger, Numbness) questionnaire. RESULTS: the study population is composed of 6,687 participants, of whom 71.5% were females. The mean age of the sample was 48.7 years. Globally, 43.8% of the participants reported symptoms of PTSD, especially females. PTSD prevalence showed a decreasing trend across age groups. The likelihood of PTSD symptoms was higher among those who increased alcohol consumption, decreased physical activity, and experienced restless sleep. CONCLUSIONS: a high prevalence of PTSD symptoms emerged from this survey, especially among women and younger subjects. Preventive strategies should be implemented to protect the mental health of the most vulnerable citizens in a period of emergency.
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COVID-19 , Trastornos por Estrés Postraumático , Control de Enfermedades Transmisibles , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Pandemias , Prevalencia , SARS-CoV-2 , Trastornos por Estrés Postraumático/epidemiologíaRESUMEN
The extracellular vesicles (EVs) are membrane vesicles carrying proteins, nucleic acids, and bioactive lipids of the cell of origin. These vesicles released within the extracellular space and entering into the circulation may transfer their cargo to neighboring or distant cells and induce phenotypical and functional changes that may be relevant in several physiopathological conditions. In an attempt to define the biological properties of EVs, several investigations have focused on their cargo and on the effects elicited in recipient cells. EVs have been involved in modulation of tumor microenvironment and behavior, as well as in the immune and inflammatory response. In the present review, we address the paracrine action of EVs released by stem cells and their potential involvement in the activation of regenerative programs in injured cells.
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Exosomas/metabolismo , Nicho de Células Madre , Células Madre/metabolismo , Animales , Exosomas/genética , Exosomas/inmunología , Exosomas/patología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Comunicación Paracrina , Transducción de Señal , Células Madre/inmunología , Células Madre/patología , Microambiente TumoralRESUMEN
AIMS/HYPOTHESIS: Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. METHODS: Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14(+) cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14(-) cell were co-cultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed. RESULTS: MSC- and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-ß, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3(+) regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.
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Diferenciación Celular , Células Dendríticas/fisiología , Diabetes Mellitus Tipo 1 , Vesículas Extracelulares/fisiología , Células Madre Mesenquimatosas/fisiología , Células Madre Mesenquimatosas/ultraestructura , Adulto , Diferenciación Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/patología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/fisiología , Células Th17/citología , Células Th17/fisiología , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes. METHODS: MVs were purified from heterologous human MSCs by differential centrifugation. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with type 1 diabetes at disease onset, and responses to GAD65 stimulation were assessed by IFN-γ enzyme-linked immunosorbent spot analysis. Levels of cytokines and prostaglandin E2 (PGE2) were measured in the supernatant fraction, and T helper 17 (Th17) and regulatory T cell analysis was performed. RESULTS: MVs were internalised by PBMCs, as assessed by confocal microscopy and flow cytometry analyses. MVs significantly decreased IFN-γ spots and levels in GAD65-stimulated PBMCs, and significantly increased transforming growth factor-ß (TGF-ß), IL-10, IL-6 and PGE2 levels. Furthermore, MVs decreased the number of Th17 cells and the levels of IL-17, and increased FoxP3(+) regulatory T cells in GAD65-stimulated PBMCs. CONCLUSIONS/INTERPRETATION: These results provide evidence that MSC-derived MVs can inhibit in vitro a proinflammatory response to an islet antigenic stimulus in type 1 diabetes. The action of MVs involves PGE2 and TGF-ß signalling pathways and IL-10 secretion, suggesting a switch to an anti-inflammatory response of T cells.
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Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/inmunología , Células Madre Mesenquimatosas/metabolismo , Linfocitos T/inmunología , Adulto , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Dinoprostona/metabolismo , Femenino , Humanos , Masculino , Linfocitos T/metabolismo , Adulto JovenRESUMEN
The chatbot Chat Generative Pretrained Transformer (ChatGPT) is becoming increasingly popular among patients for searching health-related information. Prior studies have raised concerns regarding accuracy in offering nutritional advice. We investigated in November 2023 ChatGPT's potential as a tool for providing nutritional guidance in relation to different non-communicable diseases (NCDs). First, the dietary advice given by ChatGPT (version 3.5) for various NCDs was compared with guidelines; then, the chatbot's capacity to manage a complex case with several diseases was investigated. A panel of nutrition experts assessed ChatGPT's responses. Overall, ChatGPT offered clear advice, with appropriateness of responses ranging from 55.5% (sarcopenia) to 73.3% (NAFLD). Only two recommendations (one for obesity, one for non-alcoholic-fatty-liver disease) contradicted guidelines. A single suggestion for T2DM was found to be "unsupported", while many recommendations for various NCDs were deemed to be "not fully matched" to the guidelines despite not directly contradicting them. However, when the chatbot handled overlapping conditions, limitations emerged, resulting in some contradictory or inappropriate advice. In conclusion, although ChatGPT exhibited a reasonable accuracy in providing general dietary advice for NCDs, its efficacy decreased in complex situations necessitating customized strategies; therefore, the chatbot is currently unable to replace a healthcare professional's consultation.
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Enfermedad del Hígado Graso no Alcohólico , Enfermedades no Transmisibles , Humanos , Educación en Salud , Colina O-Acetiltransferasa , Instituciones de Salud , Enfermedades no Transmisibles/prevención & controlRESUMEN
Obestatin is a 23 amino acid amidated peptide, member of the preproghrelin gene-derived peptides. Initially, obestatin was reported to exert opposite effects to those of ghrelin on food intake and body weight gain, through interaction with GPR39; however, these findings are still strongly debated and obestatin biological role remains largely unknown. Interestingly, binding of obestatin to the glucagon-like peptide 1 receptor has been recently suggested. Despite being a controversial peptide, recent findings have clearly indicated that obestatin is indeed a multifunctional peptide, exerting a variety of effects, such as stimulation of cell proliferation, survival and differentiation, influence on glucose and lipid metabolism, as well as anti-inflammatory and cardioprotective actions. Its positive effects on glucose and lipid metabolism candidate this peptide as a potential therapeutic tool in pathological conditions such as insulin resistance and diabetes.
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Tejido Adiposo Blanco/metabolismo , Ghrelina/fisiología , Páncreas/metabolismo , Animales , Apoptosis , Péptido 1 Similar al Glucagón/fisiología , Humanos , Insulina/fisiología , Metabolismo de los Lípidos , Transducción de SeñalRESUMEN
Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic ß cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic ß cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E ß cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused ß cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-ßH3 ß cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of ß cell genes, adipokines, and cytokines in recipient ß cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence ß cell fate and function.
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Adipocitos , Tejido Adiposo , Vesículas Extracelulares/metabolismo , Islotes Pancreáticos , Obesidad/metabolismo , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adulto , Animales , Femenino , Humanos , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Masculino , RatonesRESUMEN
Association of type 1 diabetes and cytomegalovirus (CMV) is suspected and CMV infections have also been linked to increased risk of new onset post-transplantation diabetes. We monitored response to islet autoantigens, pancreatic endocrine function, and CMV infections in one type 1 diabetic patient receiving pancreas allograft. Time course analyses of levels of islet autoantibodies (Abs), IFN-gamma ELISPOT response, analysis of T cell function, levels of C peptide together with CMV pp65 antigenaemia and viraemia and graft biopsy histopathology were performed in comparison with a cohort of diabetic recipients. Evidence of autoimmune activation to GAD and IA2, modification of CD4(+) CD25hi T cells, loss of pancreatic function, concomitantly with multiple CMV infections and allograft rejection with peri-insulitis is provided. The parallel between metabolic outcome, initiation and progression of autoreactivity to islet autoantigens and early CMV infections after transplantation, suggests that persistent CMV infections may be relevant to the pathogenesis of type 1 diabetes.
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Autoantígenos , Autoinmunidad , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/cirugía , Islotes Pancreáticos/inmunología , Trasplante de Páncreas/inmunología , Adulto , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Inmunidad Celular , Inmunidad Humoral , Trasplante de Páncreas/efectos adversos , Trasplante de Páncreas/patología , Trasplante de Páncreas/fisiología , RecurrenciaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) has a high recurrence and metastatic rate with an unknown mechanism of cancer spread. Tumor inflammation is the most critical processes of cancer onset, growth, and metastasis. We hypothesize that the release of extracellular vesicles (EVs) by tumor endothelial cells (TECs) induce reprogramming of immune cells as well as stromal cells to create an immunosuppressive microenvironment that favor tumor spread. We call this mechanism as non-metastatic contagious carcinogenesis. Extracellular vesicles were collected from primary HNSCC-derived endothelial cells (TEC-EV) and were used for stimulation of peripheral blood mononuclear cells (PBMCs) and primary adipose mesenchymal stem cells (ASCs). Regulation of ASC gene expression was investigated by RNA sequencing and protein array. PBMC, stimulated with TEC-EV, were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. We validated in vitro the effects of TEC-EV on ASCs or PBMC by measuring invasion, adhesion, and proliferation. We found and confirmed that TEC-EV were able to change ASC inflammatory gene expression signature within 24-48 h. TEC-EV were also able to enhance the secretion of TGF-ß1 and IL-10 by PBMC and to increase T regulatory cell (Treg) expansion. TEC-EV carry specific proteins and RNAs that are responsible for Treg differentiation and immune suppression. ASCs and PBMC, treated with TEC-EV, enhanced proliferation, adhesion of tumor cells, and their invasion. These data indicate that TEC-EV exhibit a mechanism of non-metastatic contagious carcinogenesis that regulates tumor microenvironment and reprograms immune cells to sustain tumor growth and progression.
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Pancreatic islet microendothelium and beta cells exhibit an interdependent physical and functional relationship. In this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1beta, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to high-glucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. Intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 mumol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1beta and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to beta cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet function.
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Apoptosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hiperglucemia/metabolismo , Islotes Pancreáticos/irrigación sanguínea , Fosfatidilinositol 3-Quinasas/fisiología , Pravastatina/farmacología , Proteínas Proto-Oncogénicas c-akt/fisiología , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Glucosa/fisiología , Humanos , Interleucina-1beta/metabolismo , Proteínas de la Membrana/metabolismo , Microcirculación , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Transducción de SeñalRESUMEN
Prostate cancer (PCa) is one of the most common cancer in men. Although hormone-sensitive PCa responds to androgen-deprivation, there are no effective therapies for castration-resistant PCa. It has been recently suggested that proton pump inhibitors (PPIs) may increase the risk of certain cancers; however, association with PCa remains elusive. Here, we evaluated the tumorigenic activities of PPIs in vitro, in PCa cell lines and epithelial cells from benign prostatic hyperplasia (BPH) and in vivo, in PCa mice xenografts. PPIs increased survival and proliferation, and inhibited apoptosis in LNCaP cells. These effects were attenuated or absent in androgen-insensitive DU-145 and PC3 cells, respectively. Specifically, omeprazole (OME) promoted cell cycle progression, increased c-Myc expression, ErbB2 activity and PSA secretion. Furthermore, OME induced the phosphorylation of MAPK-ERK1/2, PI3K/Akt and GSK-3ß, and blunted the expression and activity of cellular prostatic acid phosphatase. OME also increased survival, proliferation and PSA levels in BPH cells. In vivo, OME promoted tumor growth in mice bearing LNCaP xenografts. Our results indicate that PPIs display tumorigenic activities in PCa cells, suggesting that their long-term administration in patients should be carefully monitored.
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Fosfatasa Ácida/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neoplasias Hormono-Dependientes/enzimología , Omeprazol/toxicidad , Fosfatidilinositol 3-Quinasa/metabolismo , Neoplasias de la Próstata/enzimología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inhibidores de la Bomba de Protones/toxicidad , Receptor ErbB-2/metabolismo , Fosfatasa Ácida/metabolismo , Animales , Apoptosis/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Hormono-Dependientes/patología , Células PC-3 , Fosforilación , Neoplasias de la Próstata/patología , Transducción de SeñalRESUMEN
Enteroviruses, such as the coxsackievirus (CV) group, have been linked to the induction of inflammatory and autoimmune diseases. Virus tropism and tissue access are modulated by endothelial cells. To examine the susceptibility of microvascular endothelial cells (MECs) derived from pancreatic islets to infection with CV group B (CVB), purified cultured human islet MECs were infected with CVB-4 strain, and the immunological phenotype of the infected cells was analyzed. CVB-4 persistently infected the islet MECs, which expressed the CV receptors human coxsackievirus and adenovirus receptor (HCAR) and decay accelerating factor (DAF) and maintained EC characteristics, without overt cytopathic effects. CVB-4 infection transiently up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1 and increased production of the proinflammatory cytokines IL-1beta and IL-6, and chemokines IL-8 and lymphotactin, as well as IFN-alpha. Mononuclear cell adhesion to CVB infected monolayers was increased, compared to uninfected monolayers. Moreover, infection up-regulated the viral receptors HCAR and DAF and coreceptor alpha(v)beta3 integrin on islet MECs, while down-regulating expression of HCAR on human aortic endothelial cells, indicating potential tissue-specific influence on the pathological outcome of infection. These results provide evidence that islet MECs are natural targets and reservoirs for persistent CVB infection resulting in acute endothelial cell activation by virus, which may contribute to selective recruitment of subsets of leukocytes during inflammatory immune responses, such as insulitis in type 1 diabetes.
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Infecciones por Coxsackievirus/metabolismo , Células Endoteliales/metabolismo , Enterovirus Humano B/metabolismo , Islotes Pancreáticos/citología , Receptores Virales/metabolismo , Animales , Aorta/citología , Antígenos CD55/genética , Antígenos CD55/metabolismo , Adhesión Celular , Células Cultivadas , Quimiocinas/metabolismo , Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus , Citocinas/metabolismo , Células Endoteliales/citología , Células Endoteliales/virología , Humanos , Inmunofenotipificación , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Microcirculación , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores Virales/genéticaRESUMEN
We previously have shown that platelet-derived growth factor (PDGF) modulates the biological activity of extracellular vesicles released by adipose-derived mesenchymal stem cells (ASC-EVs). ASC-EVs may interact with blood and vessel cells by transferring proteins and nucleic acids and regulate their functions. In this study, we investigated immunomodulatory activity and protection from acute hindlimb ischemia of EVs released by PDGF-stimulated ASC (PDGF-EVs). PDGF treatment of ASC changed protein and RNA composition of released EVs by enhancing the expression of anti-inflammatory and immunomodulatory factors. In vitro, control EVs (cEVs) derived from non-stimulated ASC increased the secretion of both the IL-1b, IL-17, IFNγ, TNFα pro-inflammatory factors and the IL-10 anti-inflammatory factor, and enhanced the in vitro peripheral blood mononuclear cell (PBMC) adhesion on endothelium. In contrast, PDGF-EVs enhanced IL-10 secretion and induced TGF-ß1 secretion by PBMC. Moreover, PDGF-EVs stimulated the formation of T regulatory cells. In vivo, PDGF-EVs protected muscle tissue from acute ischemia, reduced infiltration of inflammatory cells and increased T regulatory cell infiltration in respect to cEVs. Our results suggest that PDGF-EVs are enriched in anti-inflammatory and immunomodulatory factors and induced in PBMC an enhanced production of IL-10 and TGF-ß1 resulting in protection of muscle from acute ischemia in vivo.
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Vesículas Extracelulares/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Isquemia/etiología , Isquemia/metabolismo , Células Madre Mesenquimatosas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Antiinflamatorios/farmacología , Biomarcadores , Vesículas Extracelulares/ultraestructura , Inmunofenotipificación , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/ultraestructura , Péptidos/farmacologíaRESUMEN
Recent studies have linked autoimmunity to nervous tissue structures and diabetic autonomic neuropathy. To evaluate prospectively the early stage of type 1 diabetes and the natural history of this association, we monitored the autonomic function and the presence of autoantibodies (Ab) to sympathetic and parasympathetic nervous structures in a cohort of 92 diabetic adolescent patients, recruited and followed-up after 40+/-3 months. The presence of circulating Ab and their ability to activate complement was also assessed using a human adrenergic neuroblastoma cell line, and the effect of patients' sera on these cells was evaluated by different methods assessing cytotoxic effects and apoptosis. Thirty-nine percent of the Ab-positive patients had one abnormal test (p=0.07 vs. Ab-negative patients). Serum from four patients positive for anti-cervical ganglia Ab showed positive staining of neuroblastoma cells and displayed ability to activate complement. Serum from two adolescent patients with anti-cervical ganglia and anti-neuroblastoma cells Ab, induced cytotoxic effects and damaged the plasma membrane of the neuroblastoma cells. Moreover, sera from two adult patients with overt autonomic neuropathy, used as positive controls, induced apoptosis of these cells, assessed by TUNEL. Our data indicate that symptomatic autonomic neuropathy is not characteristic of young diabetic patients, but that autoantibodies to autonomic structures are present and persist in the first 20 years of disease, possibly associated with subtle autonomic dysfunction and cytotoxic effect on sympathetic cells.
Asunto(s)
Sistema Nervioso Autónomo/inmunología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/inmunología , Neuropatías Diabéticas/inmunología , Polirradiculoneuropatía/inmunología , Adolescente , Adulto , Formación de Anticuerpos/inmunología , Autoanticuerpos/sangre , Sistema Nervioso Autónomo/patología , Sistema Nervioso Autónomo/fisiopatología , Membrana Celular/efectos de los fármacos , Membrana Celular/inmunología , Estudios de Cohortes , Diabetes Mellitus Tipo 1/fisiopatología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/fisiopatología , Femenino , Estudios de Seguimiento , Ganglios Simpáticos/inmunología , Ganglios Simpáticos/patología , Ganglios Simpáticos/fisiopatología , Humanos , Masculino , Polirradiculoneuropatía/sangre , Polirradiculoneuropatía/fisiopatología , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/inmunología , Nervio Vago/inmunología , Nervio Vago/patología , Nervio Vago/fisiopatologíaRESUMEN
OBJECTIVE We prospectively evaluated the association between autoimmunity to autonomic nervous structures and autonomic neuropathy in type 1 diabetes in relation to clinical variables. RESEARCH DESIGN AND METHODS A cohort of 112 patients with type 1 diabetes was prospectively followed from adolescence (T0) to approximately 4 (T4) and 16 (T16) years later. Standard cardiovascular (CV) tests and neurological examination were performed and related to the presence of circulating antibodies (Ab) to autonomic nervous structures detected at T0 and T4. Quality of life was assessed by a diabetes-specific questionnaire. RESULTS Sixty-six patients (59% of the cohort) were reexamined at T16 (age 31.4 ± 2 years; disease duration 23.4 ± 3.7 years). Nineteen had circulating Ab to autonomic structures. Prevalence of abnormal tests and autonomic symptoms were higher in Ab-positive (68 and 26%, respectively) than Ab-negative (32 and 4%) patients (P < 0.05). Among Ab-positive patients, the relative risk (RR) of having at least one altered CV test was 5.77 (95% CI 1.56-21.33), and an altered deep breathing (DB) test (<15 bpm) was 14.65 (2.48-86.46). Previous glycemic control was the only other predictor (RR 1.06 [1.002-1.13]/mmol/mol HbA1c increase). Presence of Ab carried over a 68% probability of developing an altered CV test; absence of Ab carried a 91% probability of not having an altered DB test and an 89% probability of not having an altered Valsalva ratio. Autonomic neuropathy was independently associated with worse quality of life. CONCLUSIONS Circulating Ab to autonomic structures are associated with the development of autonomic dysfunction in young diabetic patients independent of glycemic control.
Asunto(s)
Autoinmunidad , Sistema Nervioso Autónomo/inmunología , Diabetes Mellitus Tipo 1/inmunología , Neuropatías Diabéticas/inmunología , Adulto , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Neuropatías Diabéticas/fisiopatología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Estudios Prospectivos , Calidad de VidaRESUMEN
CONTEXT: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking. OBJECTIVE: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes. DESIGN: Human MSCs were isolated and characterized. Peripheral blood mononuclear cells (PBMCs) were obtained from nine type 1 diabetic patients at disease onset and 13 healthy control subjects. IFN-gamma, IL-10, and IL-4 enzyme-linked immunospot responses of lymphocytes incubated with glutamic acid decarboxylase 65 (GAD65) were investigated in PBMC cultures and PBMC/MSC cocultures. Levels of prostaglandin E2 (PGE2), IFN-gamma, IL-4, and IL-10 in supernatants were measured by ELISA. PGE2 inhibition experiments with NS-398 and indomethacin were also performed. RESULTS: Five diabetic patients were identified with a positive PBMC IFN-gamma response to GAD65 and negative IL-10 and IL-4 response. PBMC/MSC cocultures resulted in a significant decrease in the number of spots and in detection of IL-4-secreting cells. PGE2 inhibitors abrogated the immune-suppressive effect, indicating an involvement of PGE2 production, and the constitutive production of PGE2 by MSCs was enhanced in PBMC/MSC coculture. Moreover, in GAD-responder patients, GAD-stimulated PBMC/MSC cocultures significantly decreased secretion of IFN-gamma and IL-10 and increased secretion of IL-4. CONCLUSIONS: These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/farmacología , Inmunidad Celular/inmunología , Células Madre Mesenquimatosas/inmunología , Linfocitos T/inmunología , Células Cultivadas , Técnicas de Cocultivo , Diabetes Mellitus Tipo 1/metabolismo , Dinoprostona/inmunología , Dinoprostona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Glutamato Descarboxilasa/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Islotes Pancreáticos/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Células Madre Mesenquimatosas/citología , Estadísticas no Paramétricas , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The microvasculature is a key interface between blood and tissues and participates in numerous pathophysiological processes. The heterogeneity of microvascular endothelial cells derived from different organs, suggests that these cells have specialised functions at different anatomical sites. Pancreatic islet microcirculation exhibits distinctive features, with an islet capillary network showing five times higher density than the capillary network of the exocrine counterpart and high permeability. Moreover, the islet microvascular endothelial cells show about 10 times more fenestrations than those of the exocrine tissue. In an interdependent physical and functional relationship with beta cells, islet endothelial cells are involved not only in the delivery of oxygen and nutrients to endocrine cells, but induce insulin gene expression during islet development, affect adult beta cell function, promote beta cell proliferation, and produce a number of vasoactive, angiogenic substances and growth factors. Specific markers of islet microvasculature are alpha-1 proteinase inhibitor and nephrin, a highly specific barrier protein with adhesion and signalling function. The islet microendothelium also appears to have a role in fine-tuning blood glucose sensing and regulation, and to behave as an active "gatekeeper" in the control of leukocyte recruitment into the islets, adopting an activated phenotype during autoimmune insulitis in type 1 diabetes. This dense vasculature is therefore likely to play a role in the physiology as well as in the disease of the pancreatic islets. In this review we will describe the phenotypic and functional characteristics of islet microendothelium and its possible involvement in type 1 and 2 diabetes, and islet revascularisation in transplantation settings.