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1.
Aging Clin Exp Res ; 36(1): 84, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38558357

ABSTRACT

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.


Subject(s)
Taste Buds , Taste , Humans , Aged , Taste/physiology , Taste Perception/physiology , Saliva/chemistry , Saliva/physiology , Taste Buds/physiology , Food Preferences
2.
Nutrients ; 16(4)2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38398794

ABSTRACT

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.


Subject(s)
Non-alcoholic Fatty Liver Disease , Noncommunicable Diseases , Humans , Health Education , Choline O-Acetyltransferase , Health Facilities , Noncommunicable Diseases/prevention & control
3.
Int J Mol Sci ; 24(3)2023 Jan 17.
Article in English | MEDLINE | ID: mdl-36768173

ABSTRACT

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.


Subject(s)
Gastrointestinal Microbiome , Neoplasms , Probiotics , Humans , Gastrointestinal Microbiome/physiology , Cachexia/therapy , Cachexia/complications , Quality of Life , Probiotics/therapeutic use , Prebiotics , Neoplasms/complications , Neoplasms/therapy , Fecal Microbiota Transplantation , Dysbiosis/complications , Dysbiosis/therapy
4.
Pharmacol Res ; 179: 106206, 2022 05.
Article in English | MEDLINE | ID: mdl-35398240

ABSTRACT

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.


Subject(s)
Extracellular Vesicles , Liver Neoplasms , MicroRNAs , B7-H1 Antigen/metabolism , Endothelial Cells/metabolism , Extracellular Vesicles/metabolism , Humans , Immunity , Interleukin-3/metabolism , Leukocytes, Mononuclear/metabolism , Liver Neoplasms/metabolism , MicroRNAs/metabolism , Tumor Microenvironment
5.
Epidemiol Prev ; 45(6): 552-558, 2021.
Article in English | MEDLINE | ID: mdl-34711043

ABSTRACT

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.


Subject(s)
COVID-19 , Stress Disorders, Post-Traumatic , Communicable Disease Control , Cross-Sectional Studies , Female , Humans , Italy/epidemiology , Middle Aged , Pandemics , Prevalence , SARS-CoV-2 , Stress Disorders, Post-Traumatic/epidemiology
6.
JCI Insight ; 6(5)2021 03 08.
Article in English | MEDLINE | ID: mdl-33539327

ABSTRACT

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.


Subject(s)
Adipocytes , Adipose Tissue , Extracellular Vesicles/metabolism , Islets of Langerhans , Obesity/metabolism , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/metabolism , Adipose Tissue/metabolism , Adipose Tissue/pathology , Adult , Animals , Female , Humans , Islets of Langerhans/cytology , Islets of Langerhans/metabolism , Male , Mice
7.
Front Cell Dev Biol ; 8: 698, 2020.
Article in English | MEDLINE | ID: mdl-33015029

ABSTRACT

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.

8.
Am J Physiol Cell Physiol ; 317(2): C303-C313, 2019 08 01.
Article in English | MEDLINE | ID: mdl-31091143

ABSTRACT

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.


Subject(s)
Exosomes/metabolism , Stem Cell Niche , Stem Cells/metabolism , Animals , Exosomes/genetics , Exosomes/immunology , Exosomes/pathology , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Paracrine Communication , Signal Transduction , Stem Cells/immunology , Stem Cells/pathology , Tumor Microenvironment
9.
Cancer Lett ; 449: 252-262, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30790678

ABSTRACT

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.


Subject(s)
Acid Phosphatase/antagonists & inhibitors , Cell Proliferation/drug effects , Glycogen Synthase Kinase 3 beta/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neoplasms, Hormone-Dependent/enzymology , Omeprazole/toxicity , Phosphatidylinositol 3-Kinase/metabolism , Prostatic Neoplasms/enzymology , Proto-Oncogene Proteins c-akt/metabolism , Proton Pump Inhibitors/toxicity , Receptor, ErbB-2/metabolism , Acid Phosphatase/metabolism , Animals , Apoptosis/drug effects , Humans , Male , Mice, Inbred NOD , Mice, SCID , Neoplasms, Hormone-Dependent/pathology , PC-3 Cells , Phosphorylation , Prostatic Neoplasms/pathology , Signal Transduction
10.
Sci Rep ; 8(1): 17458, 2018 12 04.
Article in English | MEDLINE | ID: mdl-30514962

ABSTRACT

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.


Subject(s)
Extracellular Vesicles/metabolism , Hindlimb/blood supply , Hindlimb/metabolism , Ischemia/etiology , Ischemia/metabolism , Mesenchymal Stem Cells/metabolism , Platelet-Derived Growth Factor/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Biomarkers , Extracellular Vesicles/ultrastructure , Immunophenotyping , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/ultrastructure , Peptides/pharmacology
11.
Diabetologia ; 59(2): 325-33, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26592240

ABSTRACT

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.


Subject(s)
Cell Differentiation , Dendritic Cells/physiology , Diabetes Mellitus, Type 1 , Extracellular Vesicles/physiology , Mesenchymal Stem Cells/physiology , Mesenchymal Stem Cells/ultrastructure , Adult , Cell Differentiation/physiology , Cells, Cultured , Coculture Techniques , Dendritic Cells/pathology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Female , Humans , Male , Middle Aged , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/physiology , Th17 Cells/cytology , Th17 Cells/physiology , Young Adult
12.
Diabetologia ; 57(8): 1664-73, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24838680

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Glutamate Decarboxylase/immunology , Mesenchymal Stem Cells/metabolism , T-Lymphocytes/immunology , Adult , Cytokines/metabolism , Diabetes Mellitus, Type 1/metabolism , Dinoprostone/metabolism , Female , Humans , Male , T-Lymphocytes/metabolism , Young Adult
13.
Diabetes Care ; 37(4): 1108-15, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24550215

ABSTRACT

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.


Subject(s)
Autoimmunity , Autonomic Nervous System/immunology , Diabetes Mellitus, Type 1/immunology , Diabetic Neuropathies/immunology , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/complications , Diabetic Neuropathies/physiopathology , Disease Progression , Female , Humans , Male , Prospective Studies , Quality of Life
14.
IUBMB Life ; 65(12): 976-82, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24217898

ABSTRACT

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.


Subject(s)
Adipose Tissue, White/metabolism , Ghrelin/physiology , Pancreas/metabolism , Animals , Apoptosis , Glucagon-Like Peptide 1/physiology , Humans , Insulin/physiology , Lipid Metabolism , Signal Transduction
15.
J Clin Endocrinol Metab ; 95(8): 3788-97, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20466784

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Glutamate Decarboxylase/pharmacology , Immunity, Cellular/immunology , Mesenchymal Stem Cells/immunology , T-Lymphocytes/immunology , Cells, Cultured , Coculture Techniques , Diabetes Mellitus, Type 1/metabolism , Dinoprostone/immunology , Dinoprostone/metabolism , Enzyme-Linked Immunosorbent Assay , Glutamate Decarboxylase/immunology , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-4/immunology , Interleukin-4/metabolism , Islets of Langerhans/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mesenchymal Stem Cells/cytology , Statistics, Nonparametric , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
16.
Transpl Int ; 23(3): 333-7, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-19906032

ABSTRACT

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.


Subject(s)
Autoantigens , Autoimmunity , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/immunology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/surgery , Islets of Langerhans/immunology , Pancreas Transplantation/immunology , Adult , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/physiopathology , Female , Humans , Immunity, Cellular , Immunity, Humoral , Pancreas Transplantation/adverse effects , Pancreas Transplantation/pathology , Pancreas Transplantation/physiology , Recurrence
17.
Am J Pathol ; 173(2): 442-50, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18599614

ABSTRACT

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.


Subject(s)
Apoptosis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hyperglycemia/metabolism , Islets of Langerhans/blood supply , Phosphatidylinositol 3-Kinases/physiology , Pravastatin/pharmacology , Proto-Oncogene Proteins c-akt/physiology , Caspase 3/metabolism , Cell Survival/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/physiology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Glucose/physiology , Humans , Interleukin-1beta/metabolism , Membrane Proteins/metabolism , Microcirculation , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Phosphorylation , Signal Transduction
18.
Curr Diabetes Rev ; 4(1): 1-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18220689

ABSTRACT

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.


Subject(s)
Endothelial Cells/physiology , Endothelium, Vascular/physiology , Insulin-Secreting Cells/physiology , Islets of Langerhans/physiology , Animals , Cell Communication , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 1/surgery , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/physiopathology , Endothelial Cells/cytology , Endothelium, Vascular/cytology , Humans , Insulin-Secreting Cells/cytology , Islets of Langerhans/blood supply , Islets of Langerhans/cytology , Islets of Langerhans Transplantation , Microcirculation/physiology , Neovascularization, Physiologic , Oxygen Consumption , Vascular Endothelial Growth Factor A/physiology
19.
FASEB J ; 21(12): 3308-17, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17494992

ABSTRACT

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.


Subject(s)
Coxsackievirus Infections/metabolism , Endothelial Cells/metabolism , Enterovirus B, Human/metabolism , Islets of Langerhans/cytology , Receptors, Virus/metabolism , Animals , Aorta/cytology , CD55 Antigens/genetics , CD55 Antigens/metabolism , Cell Adhesion , Cells, Cultured , Chemokines/metabolism , Coxsackie and Adenovirus Receptor-Like Membrane Protein , Cytokines/metabolism , Endothelial Cells/cytology , Endothelial Cells/virology , Humans , Immunophenotyping , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Microcirculation , Oligonucleotide Array Sequence Analysis , Receptors, Virus/genetics
20.
J Immunol ; 171(1): 438-46, 2003 Jul 01.
Article in English | MEDLINE | ID: mdl-12817028

ABSTRACT

Numerous studies indicate that enteroviruses, such as the Coxsackievirus (CV) group, are linked to autoimmune diseases. Virus tropism and tissue access are modulated by vascular endothelial cells (ECs), mainly at the level of the microvasculature. Data on the permissiveness of ECs to CV are, however, scanty and derived from studies on large vessel ECs. To examine the susceptibility of microvascular ECs to infection of group B CV (CVB), human dermal microvascular ECs (HMEC-1) were infected with three CVB strains, and the immunological phenotype of the infected cells was analyzed. All CVB persistently infected the EC cultures without producing overt cytopathic effects. Infected ECs retained endothelial characteristics. Release of infectious particles in cell supernatants persisted for up to 3 mo of culture. Infection up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1, with the highest values detected during the first 30 days of infection (p < 0.05 vs uninfected HMEC-1). CVB infection increased production of the proinflammatory cytokines, IL-6, IL-8, and TNF-alpha, which may account for the enhanced expression of adhesion molecules. Parallel infection of macrovascular HUVEC had less evident effects on induction of ICAM-1 and did not significantly increase expression of VCAM-1. Moreover, mononuclear cell adhesion to CVB-infected HMEC-1 monolayers was increased, compared with uninfected monolayers. These results provide evidence that small vessel ECs can harbor a persistent viral infection, resulting in quantitative modification of adhesion molecule expression, which may contribute to the selective recruitment of subsets of leukocytes during inflammatory immune responses. Furthermore, our data confirm that the behavior against a viral challenge of ECs in large vessels and microvessels may differ.


Subject(s)
Cell Adhesion Molecules/biosynthesis , Endothelium, Vascular/immunology , Endothelium, Vascular/virology , Enterovirus B, Human/immunology , Enterovirus B, Human/pathogenicity , Up-Regulation/immunology , Cell Adhesion/immunology , Cell Line , Cell Line, Transformed , Cytokines/biosynthesis , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Enterovirus B, Human/physiology , Humans , Immunophenotyping , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Microcirculation/immunology , Microcirculation/metabolism , Microcirculation/pathology , Microcirculation/virology , Monocytes/pathology , Monocytes/virology , T-Lymphocytes/pathology , T-Lymphocytes/virology , Tumor Cells, Cultured , Virus Replication/immunology
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