Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes

AIMS/HYPOTHESIS: Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival.METHODS: Islets (150) were co-transplanted, with or without human MAPCs (2.5 × 105) as separate or composite pellets, under the kidney capsule of syngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels were frequently monitored and IPGTTs were carried out. Grafts and serum were harvested at 2 and 5 weeks after transplantation to assess outcome.RESULTS: Human MAPCs produced high amounts of angiogenic growth factors, including vascular endothelial growth factor, in vitro and in vivo, as demonstrated by the induction of neo-angiogenesis in the chorioallantoic membrane assay. Islet-human MAPC co-transplantation as a composite pellet significantly improved the outcome of islet transplantation as measured by the initial glycaemic control, diabetes reversal rate, glucose tolerance and serum C-peptide concentration compared with the outcome following transplantation of islets alone. Histologically, a higher blood vessel area and density in addition to a higher vessel/islet ratio were detected in recipients of islet-human MAPC composites.CONCLUSIONS/INTERPRETATION: The present data suggest that co-transplantation of mouse pancreatic islets with human MAPCs, which secrete high amounts of angiogenic growth factors, enhance islet graft revascularisation and subsequently improve islet graft function

Tireotoxicose factícia causada pelo uso de suplementos alimentares e produtos naturais

Introduction: Overvaluation of the image leads to excessive consumption of dietary supplements and natural products such as multivitamins, herbs and substances used for weight loss. This consumption can lead to changes in the body, among them factitious Thyrotoxicosis. Objective: The goal is to describe what has been published in the scientific community concerning the effects of dietary supplements on the development of exogenous thyrotoxicosis, as well as the consequences for the organism. Methodology: Review of the literature non systematically based on databases Pubmed, Lilacs and Cochrane databases, where 136, 109 and 4 articles were respectively found. Among them 14 were selected according to the criteria of inclusion and exclusion. Development: Laboratory analysis concluded that many supplements contained excess of iodine or thyroid hormone. Most of the times, these substances were not included on product labels, making it difficult ANVISA and FDA inspections. The supplements that were analyzed contained extracts of gingko biloba, kelp, guggulu, xanthohumol and withamina somnifera related to increased thyroid function. The use of these products can lead to the development of factitious thyrotoxicosis that causes tachycardia, irritability, insomnia, cardiovascular disorders and hypertension. Drug interactions and nephrotoxic, hematologic and cardiac effects are also reported with the indiscriminate use of these substances. Conclusion: Literature shows that the use of supplements can cause damage in the body, such as factitious thyrotoxicosis and other systemic effects. However, further studies are needed comparing the relation of food supplementation and thyrotoxicosis as well as an efficient control

Vitamin D-modulated dendritic cells delay lethal graft-versus-host disease through induction of regulatory T cells

Graft-versus-host disease (GVHD) is the most lethal complication after allogeneic bone marrow transplantation (allo-BMT). Current approaches to prevent GVHD rely on donor lymphocyte/T cell depletion or general immunosuppression, leading to opportunistic infections and cancer relapse. Tolerogenic dendritic cells can induce regulatory T cells (Tregs) with the ability to suppress inflammation and prevent transplant rejection, making them an attractive cellular therapy to control GVHD. Active vitamin D (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) promotes the generation of tolerogenic dendritic cells (1,25D3-DCs). This study aimed to determine the ability of ex vivo generated 1,25D3-DCs to trigger the expansion of Tregs that are able to control lethal xenogeneic GVHD in humanized NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice. We demonstrate that 1,25D3-DCs express lower levels of HLA-DR and costimulatory molecules, such as CD80 and CD86, and produce higher levels of IL-10 and TNF-α and lower amounts of IL-12, compared to vehicle-treated DCs. Moreover, these cells express increased levels of various co-inhibitory molecules such as PD-L1 and ILT-3 and the glycoprotein CD52 that is known to suppress T cell activation. Consequently, 1,25D3-DCs are poor stimulators of alloantigen-primed T cells, but foster the generation of antigen-specific suppressive Tregs. When adoptively transferred in humanized NSG mice, these 1,25D3-DC-induced Tregs delayed GVHD caused by the co-transferred autologous human peripheral blood mononuclear cells (PBMCs). These results indicate that 1,25D3-DC-induced Tregs can inhibit xenogeneic GVHD and maintain their immunomodulatory function under conditions of inflammation.status: publishe

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3

The nuclear vitamin D receptor (VDR) is generally recognized as a ligand-dependent transcription factor that mediates the actions of its natural ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on multiple target genes involved in mineral homeostasis, bone development, as well as immune reactivity. As the VDR is widely distributed in nearly all cells of the body, it implies that the vitamin D endocrine system may regulate many cell types and functions. Experiments in VDR null mice established that the VDR has intrinsically critical roles in skin and keratinocyte biology but not in immune responses. Oppositely, absence of the VDR ligand is linked to susceptibility to autoimmunity, illustrating a potential role for the unliganded VDR in the immune system. This discrepancy stimulated us to further investigate the impact of the VDR on the phenotype and function of myeloid dendritic cells (DCs) generated ex vivo from bone marrow precursors of VDR null (with a truncated VDR) and VDR ΔAF2 mice (with a mutated C-terminal activation factor 2 domain thus rendering ligand-induced gene transcription impossible). Absent or unliganded VDR did not affect bone marrow-derived myeloid DC generation. DCs obtained from VDR null and VDR ΔAF2 bone marrow cells had comparable MHC-II, and costimulatory molecule CD86, CD80 and CD40 expression than DCs from wild-type bone marrow cells. Additionally, an unliganded VDR did not affect the cytokine production nor the antigen-specific T cell stimulatory capacity of bone marrow-derived DCs. In conclusion, we showed that although clear effects of 1α,25-dihydroxyvitamin D3 are described on DC generation, absence of VDR or presence of an unliganded VDR does not affect the profile and function of ex vivo generated bone marrow-derived DCs.publisher: Elsevier articletitle: The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3 journaltitle: The Journal of Steroid Biochemistry and Molecular Biology articlelink: http://dx.doi.org/10.1016/j.jsbmb.2015.08.010 content_type: article copyright: © 2015 Elsevier Ltd. All rights reserved.status: publishe

Differential Proteomic Analysis of Hepatocellular Carcinomas from Knockout Mice and Normal (Knockout) Livers.

BACKGROUND: Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Mice lacking the tumor-suppressive protein phosphatase 2A subunit B56δ (Ppp2r5d) spontaneously develop HCC, correlating with increased c-MYC oncogenicity. MATERIALS AND METHODS: We used two-dimensional difference gel electrophoresis-coupled matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to identify differential proteomes of livers from wild-type, non-cancerous and HCC-affected B56δ knockout mice. RESULTS: A total of 23 proteins were differentially expressed/regulated in liver between wild-type and non-cancerous knockout mice, and 119 between non-cancerous and HCC knockout mice ('cancer proteins'). Overlap with our reported differential transcriptome data was poor. Overall, 56% of cancer proteins were reported before in HCC proteomics studies; 44% were novel. Gene Ontology analysis revealed cancer proteins mainly associated with liver metabolism (18%) and mitochondria (15%). Ingenuity Pathway Analysis identified 'cancer' and 'gastrointestinal disease' as top hits. CONCLUSION: We identified several proteins for further exploration as novel potential HCC biomarkers, and independently underscored the relevance of Ppp2r5d knockout mice as a valuable hepatocarcinogenesis model

Differential proteomic analysis of hepatocellular carcinomas from Ppp2r5d knockout mice and normal (knockout) livers

BACKGROUND: Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Mice lacking the tumor-suppressive protein phosphatase 2A subunit B56δ (Ppp2r5d) spontaneously develop HCC, correlating with increased c-MYC oncogenicity. MATERIALS AND METHODS: We used two-dimensional difference gel electrophoresis-coupled matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to identify differential proteomes of livers from wild-type, non-cancerous and HCC-affected B56δ knockout mice. RESULTS: A total of 23 proteins were differentially expressed/regulated in liver between wild-type and non-cancerous knockout mice, and 119 between non-cancerous and HCC knockout mice ('cancer proteins'). Overlap with our reported differential transcriptome data was poor. Overall, 56% of cancer proteins were reported before in HCC proteomics studies; 44% were novel. Gene Ontology analysis revealed cancer proteins mainly associated with liver metabolism (18%) and mitochondria (15%). Ingenuity Pathway Analysis identified 'cancer' and 'gastrointestinal disease' as top hits. CONCLUSION: We identified several proteins for further exploration as novel potential HCC biomarkers, and independently underscored the relevance of Ppp2r5d knockout mice as a valuable hepatocarcinogenesis model.status: publishe

Validation of pairs of antagonist teeth for the evaluation of shortened dental arch in epidemiological studies

Abstract The aim of this study was to evaluate the accuracy of pairs of antagonist teeth (epidemiological criterion) for defining pairs of teeth in occlusal contact (clinical criterion) and to estimate the agreement between the prevalence of “shortened dental arch” (SDA) and “functional dentition” (FD) when occlusal units (OUs) or posterior occluding pairs (POPs) are defined by the epidemiological or clinical criterion. Data were collected in an epidemiological oral health survey conducted in a municipality in Minas Gerais, Brazil. OUs and POPs were defined by the epidemiological criterion (dental crown status) or clinical criterion “gold standard” (carbon paper record of occlusal contacts during habitual maximum intercuspation). SDA corresponded to the presence of an intact anterior region and three to five OUs. FD was based on the concomitant presence of ≥ 1 tooth in each arch, 10 teeth in each arch, 12 anterior teeth, ≥ 3 premolar POPs, and ≥ 1 molar POP bilaterally. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the epidemiological criterion were calculated. The study included 197 adults. Sensitivity, specificity, PPV, and NPV were 88.5, 87.9, 92.5, and 81.9%, respectively, and accuracy was 88.3%. The epidemiological criterion proved to be valid and could be used in epidemiological studies to calculate the prevalence of reduced dental configurations that consider POPs. The assessment of oral functionality is an aspect that should be included in the diagnosis of the clinical condition of patients, contributing to a more effective individual and collective oral health care plan

Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes

Post-translational modifications of self-proteins play a substantial role in the initiation or propagation of the autoimmune attack in several autoimmune diseases, but their contribution to type 1 diabetes is only recently emerging. In the present study we demonstrate that inflammatory stress, induced by the cytokines IL-1β and IFNγ, leads to citrullination of GRP78 in beta-cells. This is coupled with translocation of this endoplasmic reticulum chaperone to the beta-cell plasma membrane and subsequent secretion. Importantly, expression and activity of peptidylarginine deiminase 2, one of the 5 enzymes responsible for citrullination and a candidate gene for type 1 diabetes in mice, is increased in islets from diabetes-prone NOD mice. Finally, (pre-)diabetic NOD mice have autoantibodies and effector T-cells that react against citrullinated GRP78, indicating that inflammation-induced citrullination of GRP78 in beta-cells generates a novel autoantigen in type 1 diabetes, opening new avenues for biomarker development and therapeutic intervention.status: publishe

Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes

Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival.status: publishe

Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes

Posttranslational modifications of self-proteins play a substantial role in the initiation or propagation of the autoimmune attack in several autoimmune diseases, but their contribution to type 1 diabetes is only recently emerging. In the current study, we demonstrate that inflammatory stress, induced by the cytokines interleukin-1β and interferon-γ, leads to citrullination of GRP78 in β-cells. This is coupled with translocation of this endoplasmic reticulum chaperone to the β-cell plasma membrane and subsequent secretion. Importantly, expression and activity of peptidylarginine deiminase 2, one of the five enzymes responsible for citrullination and a candidate gene for type 1 diabetes in mice, is increased in islets from diabetes-prone nonobese diabetic (NOD) mice. Finally, (pre)diabetic NOD mice have autoantibodies and effector T cells that react against citrullinated GRP78, indicating that inflammation-induced citrullination of GRP78 in β-cells generates a novel autoantigen in type 1 diabetes, opening new avenues for biomarker development and therapeutic intervention.SCOPUS: ar.jinfo:eu-repo/semantics/publishe