21 results on '"Pappas EG"'
Search Results
2. Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.
- Author
-
Selck C, Jhala G, De George DJ, Kwong CJ, Christensen MK, Pappas EG, Liu X, Ge T, Trivedi P, Kallies A, Thomas HE, Kay TWH, and Krishnamurthy B
- Subjects
- Mice, Animals, Proteins metabolism, T-Cell Exhaustion, Glucose-6-Phosphatase genetics, Glucose-6-Phosphatase metabolism, Mice, Transgenic, Mice, Inbred NOD, CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 prevention & control, Islets of Langerhans metabolism
- Abstract
Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (T
PEX ) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
- Full Text
- View/download PDF
3. Insights into Cancer Immunotherapies: Recent Breakthroughs, Opportunities, and Challenges.
- Author
-
Pappas EG, Kershaw MH, and Slaney CY
- Abstract
This Special Issue reminds us that, although incredible developments have occurred in the field of cancer immunotherapy, there is still plenty of room for improvement [...].
- Published
- 2023
- Full Text
- View/download PDF
4. Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor.
- Author
-
Ge T, Phung AL, Jhala G, Trivedi P, Principe N, De George DJ, Pappas EG, Litwak S, Sanz-Villanueva L, Catterall T, Fynch S, Boon L, Kay TW, Chee J, Krishnamurthy B, and Thomas HE
- Abstract
Objectives: Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune-related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, can prevent diabetes secondary to PD-L1 blockade., Methods: Anti-PD-L1 antibody was injected into NOD mice to induce diabetes, and JAK1/JAK2 inhibitor LN3103801 was administered by oral gavage to prevent diabetes. Flow cytometry was used to study T cells and beta cells. Mesothelioma cells were inoculated into BALB/c mice to induce a transplantable tumour model., Results: Anti-PD-L1-induced diabetes was associated with increased immune cell infiltration in the islets and upregulated MHC class I on islet cells. Anti-PD-L1 administration significantly increased islet T cell proliferation and islet-specific CD8
+ T cell numbers in peripheral lymphoid organs. JAK1/JAK2 inhibitor treatment blocked IFNγ-mediated MHC class I upregulation on beta cells and T cell proliferation mediated by cytokines that use the common γ chain receptor. As a result, anti-PD-L1-induced diabetes was prevented by JAK1/JAK2 inhibitor administered before or after checkpoint inhibitor therapy. Diabetes was also reversed when the JAK1/JAK2 inhibitor was administered after the onset of anti-PD-L1-induced hyperglycaemia. Furthermore, JAK1/JAK2 inhibitor intervention after checkpoint inhibitors did not reverse or abrogate the antitumour effects in a transplantable tumour model., Conclusion: A JAK1/JAK2 inhibitor can prevent and reverse anti-PD-L1-induced diabetes by blocking IFNγ and γc cytokine activities. Our study provides preclinical validation of JAK1/JAK2 inhibitor use in checkpoint inhibitor-induced diabetes., Competing Interests: TWHK has an Investigator‐Initiated Clinical Trial agreement with Eli Lilly. However, Eli Lilly had no role in the current study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2022
- Full Text
- View/download PDF
5. Interferons limit autoantigen-specific CD8 + T-cell expansion in the non-obese diabetic mouse.
- Author
-
Jhala G, Krishnamurthy B, Brodnicki TC, Ge T, Akazawa S, Selck C, Trivedi PM, Pappas EG, Mackin L, Principe N, Brémaud E, De George DJ, Boon L, Smyth I, Chee J, Kay TWH, and Thomas HE
- Subjects
- Animals, Autoantigens, CD8-Positive T-Lymphocytes, Cytokines metabolism, Interferon-gamma metabolism, Interferons metabolism, Mice, Mice, Inbred NOD, Suppressor of Cytokine Signaling 1 Protein genetics, Suppressor of Cytokine Signaling 1 Protein metabolism, Suppressor of Cytokine Signaling Proteins metabolism, Diabetes Mellitus, Interleukin-2 metabolism
- Abstract
Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNγ is ineffective in reducing disease. We characterize islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes is minimally affected, but at 125 days of age, antigen-specific CD8
+ T cells, quantified using major histocompatibility complex class I tetramers, are present in 10-fold greater numbers in Ifngr-mutant NOD mice. T cells from Ifngr-mutant mice have increased proliferative responses to interleukin-2 (IL-2). They also have reduced phosphorylated STAT1 and its target gene, suppressor of cytokine signaling 1 (SOCS-1). IFNγ controls the expansion of antigen-specific CD8+ T cells by mechanisms which include increased SOCS-1 expression that regulates IL-2 signaling. The expanded CD8+ T cells are likely to contribute to normal diabetes progression despite reduced inflammation in Ifngr-mutant mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
6. Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes.
- Author
-
Yang CH, Ann-Onda D, Lin X, Fynch S, Nadarajah S, Pappas EG, Liu X, Scott JW, Oakhill JS, Galic S, Shi Y, Moreno-Asso A, Smith C, Loudovaris T, Levinger I, Eizirik DL, Laybutt DR, Herzog H, Thomas HE, and Loh K
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Diabetes Mellitus, Type 2 metabolism, Glucose metabolism, Glycemic Control methods, Insulin metabolism, Male, Mice, Mice, Inbred C57BL, Neuropeptide Y metabolism, Obesity metabolism, Receptors, Neuropeptide Y antagonists & inhibitors, Receptors, Neuropeptide Y genetics, Insulin-Secreting Cells physiology, Receptors, Neuropeptide Y metabolism
- Abstract
Objectives: Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D., Methods: The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed., Results: In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice., Conclusions: Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
7. Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice.
- Author
-
Akazawa S, Mackin L, Jhala G, Fynch S, Catterall T, Selck C, Graham KL, Krishnamurthy B, Pappas EG, Kwong CJ, Sutherland APR, Kay TWH, Brodnicki TC, and Thomas HE
- Subjects
- Adoptive Transfer, Animals, Autoimmunity, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes transplantation, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Disease Models, Animal, Female, Gene Expression Regulation, Islets of Langerhans immunology, Male, Membrane Proteins genetics, Mice, Inbred NOD, Mice, Knockout, Signal Transduction, Mice, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Diabetes Mellitus, Type 1 metabolism, Islets of Langerhans metabolism, Lymphocyte Activation, Membrane Proteins metabolism
- Abstract
Aims/hypothesis: Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway. Recent studies suggest that STING also has antiproliferative and proapoptotic functions in T cells that are independent of IFN. To investigate whether STING is involved in autoimmune diabetes, we examined the impact of genetic deletion of STING in NOD mice., Methods: CRISPR/Cas9 gene editing was used to generate STING-deficient NOD mice. Quantitative real-time PCR was used to assess the level of type I IFN-regulated genes in islets from wild-type and STING-deficient NOD mice. The number of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)
206-214 -specific CD8+ T cells was determined by magnetic bead-based MHC tetramer enrichment and flow cytometry. The incidence of spontaneous diabetes and diabetes after adoptive transfer of T cells was determined., Results: STING deficiency partially attenuated the type I IFN gene signature in islets but did not suppress insulitis. STING-deficient NOD mice accumulated an increased number of IGRP206-214 -specific CD8+ T cells (2878 ± 642 cells in NOD.STING-/- mice and 728.8 ± 196 cells in wild-type NOD mice) in peripheral lymphoid tissue, associated with a higher incidence of spontaneous diabetes (95.5% in NOD.STING-/- mice and 86.2% in wild-type NOD mice). Splenocytes from STING-deficient mice rapidly induced diabetes after adoptive transfer into irradiated NOD recipients (median survival 75 days for NOD recipients of NOD.STING-/- mouse splenocytes and 121 days for NOD recipients of NOD mouse splenocytes)., Conclusions/interpretation: Data suggest that sensing of endogenous nucleic acids through the STING pathway may be partially responsible for the type I IFN gene signature but not autoimmunity in NOD mice. Our results show that the STING pathway may play an unexpected intrinsic role in suppressing the number of diabetogenic T cells.- Published
- 2021
- Full Text
- View/download PDF
8. Tolerance to Proinsulin-1 Reduces Autoimmune Diabetes in NOD Mice.
- Author
-
Jhala G, Selck C, Chee J, Kwong CJ, Pappas EG, Thomas HE, Kay TWH, and Krishnamurthy B
- Subjects
- Animals, Autoantibodies analysis, Glucose-6-Phosphatase physiology, Insulin immunology, Mice, Mice, Inbred NOD, Proinsulin genetics, Proinsulin immunology, Diabetes Mellitus, Type 1 prevention & control, Immune Tolerance, Proinsulin physiology
- Abstract
T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jhala, Selck, Chee, Kwong, Pappas, Thomas, Kay and Krishnamurthy.)
- Published
- 2021
- Full Text
- View/download PDF
9. The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.
- Author
-
Ge T, Jhala G, Fynch S, Akazawa S, Litwak S, Pappas EG, Catterall T, Vakil I, Long AJ, Olson LM, Krishnamurthy B, Kay TW, and Thomas HE
- Subjects
- Animals, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells immunology, Janus Kinase Inhibitors pharmacokinetics, Male, Mice, Inbred C57BL, Mice, Inbred NOD, Signal Transduction drug effects, Spleen immunology, Diabetes Mellitus, Type 1 immunology, Interferon-gamma immunology, Interleukin Receptor Common gamma Subunit immunology, Janus Kinase 1 antagonists & inhibitors, Janus Kinase Inhibitors pharmacology
- Abstract
Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8
+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8+ T cell proliferation as well as the number of KLRG+ effector and CD44hi CD62Llo effector memory CD8+ T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes., Competing Interests: At the time of the study, AL and LO were both employees of Abbvie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ge, Jhala, Fynch, Akazawa, Litwak, Pappas, Catterall, Vakil, Long, Olson, Krishnamurthy, Kay and Thomas.)- Published
- 2020
- Full Text
- View/download PDF
10. Metallothionein 1 negatively regulates glucose-stimulated insulin secretion and is differentially expressed in conditions of beta cell compensation and failure in mice and humans.
- Author
-
Bensellam M, Shi YC, Chan JY, Laybutt DR, Chae H, Abou-Samra M, Pappas EG, Thomas HE, Gilon P, and Jonas JC
- Subjects
- Acrylates, Animals, Cell Line, Diabetes Mellitus, Type 2 genetics, Diet, High-Fat, Female, Gene Expression, Glucose Tolerance Test, Humans, Insulin blood, Insulin Secretion drug effects, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Metallothionein genetics, Mice, Obesity genetics, Obesity metabolism, Phenyl Ethers, Prediabetic State genetics, Prediabetic State metabolism, Blood Glucose metabolism, Diabetes Mellitus, Type 2 metabolism, Glucose pharmacology, Insulin Secretion physiology, Insulin-Secreting Cells metabolism, Metallothionein metabolism
- Abstract
Aims/hypothesis: The mechanisms responsible for beta cell compensation in obesity and for beta cell failure in type 2 diabetes are poorly defined. The mRNA levels of several metallothionein (MT) genes are upregulated in islets from individuals with type 2 diabetes, but their role in beta cells is not clear. Here we examined: (1) the temporal changes of islet Mt1 and Mt2 gene expression in mouse models of beta cell compensation and failure; and (2) the role of Mt1 and Mt2 in beta cell function and glucose homeostasis in mice., Methods: Mt1 and Mt2 expression was assessed in islets from: (1) control lean (chow diet-fed) and diet-induced obese (high-fat diet-fed for 6 weeks) mice; (2) mouse models of diabetes (db/db mice) at 6 weeks old (prediabetes) and 16 weeks old (after diabetes onset) and age-matched db/+ (control) mice; and (3) obese non-diabetic ob/ob mice (16-week-old) and age-matched ob/+ (control) mice. MT1E, MT1X and MT2A expression was assessed in islets from humans with and without type 2 diabetes. Mt1-Mt2 double-knockout (KO) mice, transgenic mice overexpressing Mt1 under the control of its natural promoter (Tg-Mt1) and corresponding control mice were also studied. In MIN6 cells, MT1 and MT2 were inhibited by small interfering RNAs. mRNA levels were assessed by real-time RT-PCR, plasma insulin and islet MT levels by ELISA, glucose tolerance by i.p. glucose tolerance tests and overnight fasting-1 h refeeding tests, insulin tolerance by i.p. insulin tolerance tests, insulin secretion by RIA, cytosolic free Ca
2+ concentration with Fura-2 leakage resistant (Fura-2 LR), cytosolic free Zn2+ concentration with Fluozin-3, and NAD(P)H by autofluorescence., Results: Mt1 and Mt2 mRNA levels were reduced in islets of murine models of beta cell compensation, whereas they were increased in diabetic db/db mice. In humans, MT1X mRNA levels were significantly upregulated in islets from individuals with type 2 diabetes in comparison with non-diabetic donors, while MT1E and MT2A mRNA levels were unchanged. Ex vivo, islet Mt1 and Mt2 mRNA and MT1 and MT2 protein levels were downregulated after culture with glucose at 10-30 mmol/l vs 2-5 mmol/l, in association with increased insulin secretion. In human islets, mRNA levels of MT1E, MT1X and MT2A were downregulated by stimulation with physiological and supraphysiological levels of glucose. In comparison with wild-type (WT) mice, Mt1-Mt2 double-KO mice displayed improved glucose tolerance in association with increased insulin levels and enhanced insulin release from isolated islets. In contrast, isolated islets from Tg-Mt1 mice displayed impaired glucose-stimulated insulin secretion (GSIS). In both Mt1-Mt2 double-KO and Tg-Mt1 models, the changes in GSIS occurred despite similar islet insulin content, rises in cytosolic free Ca2+ concentration and NAD(P)H levels, or intracellular Zn2+ concentration vs WT mice. In MIN6 cells, knockdown of MT1 but not MT2 potentiated GSIS, suggesting that Mt1 rather than Mt2 affects beta cell function., Conclusions/interpretation: These findings implicate Mt1 as a negative regulator of insulin secretion. The downregulation of Mt1 is associated with beta cell compensation in obesity, whereas increased Mt1 accompanies beta cell failure and type 2 diabetes.- Published
- 2019
- Full Text
- View/download PDF
11. Loss of BIM increases mitochondrial oxygen consumption and lipid oxidation, reduces adiposity and improves insulin sensitivity in mice.
- Author
-
Wali JA, Galic S, Tan CY, Gurzov EN, Frazier AE, Connor T, Ge J, Pappas EG, Stroud D, Varanasi LC, Selck C, Ryan MT, Thorburn DR, Kemp BE, Krishnamurthy B, Kay TW, McGee SL, and Thomas HE
- Subjects
- Animals, Bcl-2-Like Protein 11 genetics, Electron Transport Complex IV metabolism, Energy Metabolism, Glucose metabolism, Hepatocytes metabolism, Insulin Resistance, Liver metabolism, Membrane Potential, Mitochondrial, Mice, Oxidation-Reduction, Oxygen Consumption, Weight Loss, Adiposity, Bcl-2-Like Protein 11 physiology, Lipid Metabolism, Mitochondria metabolism
- Abstract
BCL-2 proteins are known to engage each other to determine the fate of a cell after a death stimulus. However, their evolutionary conservation and the many other reported binding partners suggest an additional function not directly linked to apoptosis regulation. To identify such a function, we studied mice lacking the BH3-only protein BIM. BIM
-/- cells had a higher mitochondrial oxygen consumption rate that was associated with higher mitochondrial complex IV activity. The consequences of increased oxygen consumption in BIM-/- mice were significantly lower body weights, reduced adiposity and lower hepatic lipid content. Consistent with reduced adiposity, BIM-/- mice had lower fasting blood glucose, improved insulin sensitivity and hepatic insulin signalling. Lipid oxidation was increased in BIM-/- mice, suggesting a mechanism for their metabolic phenotype. Our data suggest a role for BIM in regulating mitochondrial bioenergetics and metabolism and support the idea that regulation of metabolism and cell death are connected.- Published
- 2018
- Full Text
- View/download PDF
12. Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon-Dependent Pathway.
- Author
-
Mollah ZUA, Quah HS, Graham KL, Jhala G, Krishnamurthy B, Dharma JFM, Chee J, Trivedi PM, Pappas EG, Mackin L, Chu EPF, Akazawa S, Fynch S, Hodson C, Deans AJ, Trapani JA, Chong MMW, Bird PI, Brodnicki TC, Thomas HE, and Kay TWH
- Subjects
- Animals, DNA, Single-Stranded metabolism, Female, Granzymes deficiency, Islets of Langerhans metabolism, Mice, Mice, Inbred C57BL, Signal Transduction, Diabetes Mellitus, Type 1 etiology, Granzymes physiology, Immune Tolerance, Interferon Type I physiology
- Abstract
Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance., (© 2017 by the American Diabetes Association.)
- Published
- 2017
- Full Text
- View/download PDF
13. The JAK/STAT pathway in obesity and diabetes.
- Author
-
Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, and Gough DJ
- Subjects
- Adipose Tissue enzymology, Adipose Tissue metabolism, Animals, Brain enzymology, Brain metabolism, Diabetes Mellitus enzymology, Diabetes Mellitus therapy, Fatty Liver metabolism, Humans, Insulin-Secreting Cells enzymology, Insulin-Secreting Cells metabolism, Janus Kinases antagonists & inhibitors, Mice, Muscle, Skeletal enzymology, Muscle, Skeletal metabolism, Obesity enzymology, Obesity therapy, STAT Transcription Factors antagonists & inhibitors, Signal Transduction, Diabetes Mellitus metabolism, Janus Kinases metabolism, Obesity metabolism, STAT Transcription Factors metabolism
- Abstract
Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes., (© 2016 Federation of European Biochemical Societies.)
- Published
- 2016
- Full Text
- View/download PDF
14. p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity.
- Author
-
Litwak SA, Loh K, Stanley WJ, Pappas EG, Wali JA, Selck C, Strasser A, Thomas HE, and Gurzov EN
- Subjects
- Adipose Tissue pathology, Animals, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins physiology, Diet, High-Fat adverse effects, Glucose Tolerance Test, Homeostasis physiology, Insulin pharmacology, Insulin Resistance, Leptin blood, Liver pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity pathology, Recombinant Proteins pharmacology, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins physiology, Apoptosis Regulatory Proteins deficiency, Body Weight physiology, Eating physiology, Glucose metabolism, Obesity physiopathology, Tumor Suppressor Proteins deficiency
- Abstract
BCL-2 proteins have been implicated in the control of glucose homeostasis and metabolism in different cell types. Thus, the aim of this study was to determine the role of the pro-apoptotic BH3-only protein, p53-upregulated-modulator-of-apoptosis (PUMA), in metabolic changes mediated by diet-induced obesity, using PUMA deficient mice. At 10 weeks of age, knockout and wild type mice either continued consuming a low fat chow diet (6% fat), or were fed with a high fat diet (23% fat) for 14-17 weeks. We measured body composition, glucose and insulin tolerance, insulin response in peripheral tissues, energy expenditure, oxygen consumption, and respiratory exchange ratio in vivo. All these parameters were indistinguishable between wild type and knockout mice on chow diet and were modified equally by diet-induced obesity. Interestingly, we observed decreased food intake and ambulatory capacity of PUMA knockout mice on high fat diet. This was associated with increased adipocyte size and fasted leptin concentration in the blood. Our findings suggest that although PUMA is dispensable for glucose homeostasis in lean and obese mice, it can affect leptin levels and food intake during obesity.
- Published
- 2016
- Full Text
- View/download PDF
15. Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System.
- Author
-
Litwak SA, Wali JA, Pappas EG, Saadi H, Stanley WJ, Varanasi LC, Kay TW, Thomas HE, and Gurzov EN
- Subjects
- Animals, Cell Line, Cell Survival drug effects, Endoplasmic Reticulum Stress drug effects, Humans, Insulin-Secreting Cells drug effects, Leupeptins pharmacology, Mice, Ubiquitination drug effects, Apoptosis drug effects, Insulin-Secreting Cells metabolism, Palmitic Acid pharmacology, Proteasome Endopeptidase Complex metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Ubiquitin metabolism
- Abstract
Pancreatic β-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism of β-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress in β-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protected β-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to prevent β-cell demise in type 2 diabetes.
- Published
- 2015
- Full Text
- View/download PDF
16. Peanut allergy.
- Author
-
Wilkin JK, Pappas EG, and DeCamp WH
- Subjects
- Heating, Humans, Ointments adverse effects, Peanut Oil, Plant Oils adverse effects, Plant Proteins adverse effects, United States, United States Food and Drug Administration, Arachis adverse effects, Ointments standards, Peanut Hypersensitivity etiology, Plant Oils standards
- Published
- 2003
17. Congenital aortic stenosis, coarctation of the aorta and patent ductus arteriosus: report of two cases.
- Author
-
PAPPAS EG, LAZARIDES DP, and DOWNING DF
- Subjects
- Constriction, Pathologic, Humans, Aorta, Aortic Arch Syndromes, Aortic Coarctation, Aortic Valve, Aortic Valve Stenosis, Ductus Arteriosus, Ductus Arteriosus, Patent complications, Vascular Malformations
- Published
- 1958
- Full Text
- View/download PDF
18. Bacterial endocarditis following cardiac surgery.
- Author
-
DENTON C, PAPPAS EG, URICCHIO JF, GOLDBERG H, and LIKOFF W
- Subjects
- Humans, Cardiac Surgical Procedures, Endocarditis, Endocarditis, Bacterial etiology, Thoracic Surgery
- Published
- 1957
- Full Text
- View/download PDF
19. Ventricular septal defect and aortic insufficiency; report of three cases.
- Author
-
DENTON C and PAPPAS EG
- Subjects
- Bicuspid Aortic Valve Disease, Humans, Aortic Valve, Aortic Valve Insufficiency, Disease, Heart Defects, Congenital, Heart Septal Defects, Heart Septal Defects, Ventricular, Heart Septum abnormalities, Heart Valve Diseases
- Published
- 1958
- Full Text
- View/download PDF
20. High output failure following arterialization of the coronary sinus.
- Author
-
PAPPAS EG and LIKOFF W
- Subjects
- Humans, Coronary Sinus, Coronary Vessels physiology, Heart Failure etiology, Neovascularization, Pathologic
- Published
- 1957
- Full Text
- View/download PDF
21. Marfan's syndrome: a report of three patients with aneurysm of the aorta.
- Author
-
PAPPAS EG, MASON D, and DENTON C
- Subjects
- Humans, Aneurysm, Aorta, Aortic Aneurysm complications, Arachnodactyly, Marfan Syndrome complications
- Published
- 1957
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.