Author: "Fernanda Ortis" - Searchworks@Jio Institute Digital Library Search Results

86 results on '"Fernanda Ortis"'

1. ARHGAP21 Acts as an Inhibitor of the Glucose-Stimulated Insulin Secretion Process

Author: Sandra M. Ferreira, José M. Costa-Júnior, Mirian A. Kurauti, Nayara C. Leite, Fernanda Ortis, Luiz F. Rezende, Helena C. Barbosa, Antonio C. Boschero, and Gustavo J. Santos
Subjects: ARHGAP21, insulin secretion, calcium influx, type 2 diabetes, Ob/Ob mice, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ARHGAP21 is a RhoGAP protein implicated in the modulation of insulin secretion and energy metabolism. ARHGAP21 transient-inhibition increase glucose-stimulated insulin secretion (GSIS) in neonatal islets; however, ARHGAP21 heterozygote mice have a reduced insulin secretion. These discrepancies are not totally understood, and it might be related to functional maturation of beta cells and peripheral sensitivity. Here, we investigated the real ARHGAP21 role in the insulin secretion process using an adult mouse model of acute ARHGAP21 inhibition, induced by antisense. After ARHGAP21 knockdown induction by antisense injection in 60-day old male mice, we investigated glucose and insulin tolerance test, glucose-induced insulin secretion, glucose-induced intracellular calcium dynamics, and gene expression. Our results showed that ARHGAP21 acts negatively in the GSIS of adult islet. This effect seems to be due to the modulation of important points of insulin secretion process, such as the energy metabolism (PGC1α), Ca2+ signalization (SYTVII), granule-extrusion (SNAP25), and cell-cell interaction (CX36). Therefore, based on these finds, ARHGAP21 may be an important target in Diabetes Mellitus (DM) treatment.
Published: 2020
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2. Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Author: Eloisa Aparecida Vilas-Boas, Davidson Correa Almeida, Leticia Prates Roma, Fernanda Ortis, and Angelo Rafael Carpinelli
Subjects: lipotoxicity, pancreatic β-cell, type 2 diabetes, NADPH oxidase, oxidative stress, ER stress, Cytology, QH573-671
Abstract: A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.
Published: 2021
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3. Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival

Author: Eloisa A. Vilas-Boas, Christopher Carlein, Lisa Nalbach, Davidson C. Almeida, Emmanuel Ampofo, Angelo R. Carpinelli, Leticia P. Roma, and Fernanda Ortis
Subjects: β-cell, ER stress, hydrogen peroxide, insulitis, NADPH oxidase, oxidative stress, Therapeutics. Pharmacology, RM1-950
Abstract: In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O2•− production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H2O2 sensor, we show, for the first time, a transient increase of cytosolic/nuclear H2O2 in islet cells between 4 and 5 h during cytokine exposure. The H2O2 increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca2+ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H2O2 production. As early NOX2-driven ROS production impacts β-cells’ function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset.
Published: 2021
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4. Augmented β-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

Author: André O. P. Protzek, José M. Costa-Júnior, Luiz F. Rezende, Gustavo J. Santos, Tiago Gomes Araújo, Jean F. Vettorazzi, Fernanda Ortis, Everardo M. Carneiro, Alex Rafacho, and Antonio C. Boschero
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.
Published: 2014
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5. Immunopurification of Polyclonal Antibodies to Recombinant Proteins of the Same Gene Family

Author: Celine Pompéia, Fernanda Ortis, and Mari Cleide Sogayar Armelin
Subjects: Biology (General), QH301-705.5
Published: 1996
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6. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.

Author: Décio L Eizirik, Michael Sammeth, Thomas Bouckenooghe, Guy Bottu, Giorgia Sisino, Mariana Igoillo-Esteve, Fernanda Ortis, Izortze Santin, Maikel L Colli, Jenny Barthson, Luc Bouwens, Linda Hughes, Lorna Gregory, Gerton Lunter, Lorella Marselli, Piero Marchetti, Mark I McCarthy, and Miriam Cnop
Subjects: Genetics, QH426-470
Abstract: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA-seq) to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ). Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the immune system and beta cell level.
Published: 2012
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7. JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells.

Author: Esteban N Gurzov, Fernanda Ortis, Latifa Bakiri, Erwin F Wagner, and Decio L Eizirik
Subjects: Medicine, Science
Abstract: Cytokines contribute to pancreatic beta-cell apoptosis in type 1 diabetes (T1D) by modulation of beta-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated beta-cell dysfunction and death. The cytokines IL-1beta+IFN-gamma induced an early and transitory upregulation of JunB by NF-kappaB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary beta-cells. JunB knockdown beta-cells and junB(-/-) fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected beta-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis.
Published: 2008
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8. Beneficial effects of physical exercise for β‐cell maintenance in a type 1 diabetes mellitus animal model

Author: Fernanda Ortis, Carolina Cavalcante de Paula, Sandra Mara Ferreira, Catharina de Barros Pimentel Villaça, Junia Carolina dos Santos-Silva, Caroline Cruz de Oliveira, Eloisa Aparecida Vilas-Boas, Fernando Abdulkader, and Sérgio Ferreira de Oliveira
Subjects: endocrine system, medicine.medical_specialty, endocrine system diseases, Physiology, medicine.medical_treatment, Physical exercise, 030204 cardiovascular system & hematology, Diabetes Mellitus, Experimental, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, Physiology (medical), Internal medicine, Diabetes mellitus, Animals, Insulin, Medicine, GLUCAGON, Type 1 diabetes, geography, Nutrition and Dietetics, geography.geographical_feature_category, business.industry, Transdifferentiation, General Medicine, Glucagon, medicine.disease, Streptozotocin, Islet, Diabetes Mellitus, Type 1, Endocrinology, PAX4, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: NEW FINDINGS What is the central question of this study? Type 1 diabetes mellitus (T1D) leads to hyperglycaemia owing to pancreatic β-cell destruction by the immune system. Physical exercise has been shown to have potentially beneficial protective roles against cytokine-induced pancreatic β-cell death, but its benefits are yet to be proved and should be understood better, especially in the islet environment. What is the main finding and its importance? Physical exercise protects against β-cell loss in a well-described animal model for T1D, induced by multiple low doses of streptozotocin. This seems to be related to reduced cytokine-induced β-cell death and increased islet cell proliferation. Contributions of islet neogenesis and/or transdifferentiation of pancreatic non-β-cells into β-cells cannot be excluded. ABSTRACT Physical exercise has beneficial effects on pancreatic β-cell function and survival in a pro-inflammatory environment. Although these effects have been linked to decreased islet inflammation and modulation of pro-apoptotic pathways, little is known about the islet microenvironment. Our aim was to evaluate the effects of physical exercise in islet histomorphology in a mouse model of type 1 diabetes mellitus induced by multiple low doses of streptozotocin. As expected, induction of type 1 diabetes mellitus led to β-cell loss and, consequently, decreased islet area. Interestingly, although the decrease in islet area was not prevented by physical exercise, this was not the case for the decrease in β-cell mass. This was probably related to induction of β-cell regeneration, because we observed increased proliferation and regeneration markers, such as Ki67 and Pcna, in islets of trained mice. These were found in the central and peripheral regions of the islets. An increase in the percentage of α- and δ-cells in these conditions, combined with an increase in proliferation and Pax4 labelling in peripheral regions, suggest that β-cell regeneration might also occur by transdifferentiation. This agrees with the presence of cells double stained for insulin and glucagon only in islets of diabetic trained mice. In addition, this group had more extra-islet insulin-positive cells and islets associated with ducts than diabetic mice. Physical exercise also decreased nuclear factor-κB activation in islet cells of diabetic trained compared with diabetic untrained mice, indicating a decrease in pro-inflammatory cytokine-induced β-cell death. Taken together, these findings indicate that preservation of β-cell mass induced by physical exercise involves an increase in β-cell replication and decrease in β-cell death, together with islet neogenesis and islet cell transdifferentiation.
Published: 2021
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9. Pre-treatment with IL-6 potentiates β-cell death induced by pro-inflammatory cytokines

Author: Viviane Rosa Oliveira, Carolina Cavalcante Paula, and Fernanda Ortis
Abstract: Background: Type I Diabetes mellitus (T1D) is characterized by a specific destruction of β-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for β-cells demise. Cytokine-induced iNOS activation, via NF-B, is implicated in induction of β-cells death, which includes ER stress activation. Physical exercise has been used as an adjunct for better glycemic control in patients with T1D, since it is able to increase glucose uptake independent of insulin. Recently, it was observed that the release of IL-6 by skeletal muscle, during physical exercise, could prevent β-cells death induced by pro-inflammatory cytokines. However, the molecular mechanisms involved in this beneficial effect on β-cells are not yet completely elucidated. Our aim was to evaluate the effect of IL-6 on β-cells exposed to pro-inflammatory cytokines. Results: Pre-treatment with IL-6 sensitized INS-1E cells to cytokine-induced cell death, increasing cytokine-induced iNOS and Caspase-3 expression. Under these conditions, however, there was a decrease in cytokines-induced, p-eIF2-α and p-IRE1expression, proteins related to ER stress. To address if this prevention of adequate UPR response is involved in the increase in β-cells death markers induced by IL-6 pre-treatment, we used a chemical chaperone (TUDCA), which improves ER folding capacity. Use of TUDCA increased cytokines-induced Caspase-3 expression in the presence of IL-6 pre-treatment. However, there is no modulation of p-eIF2-α expression by TUDCA in this condition. Conclusion: Treatment with IL-6 alone is not beneficial for β-cells, leading to increased cell death markers and impaired UPR activation. In addition, TUDCA has not been able to restore ER homeostasis or improve β-cells viability under this condition, suggesting that other mechanisms may be involved.
Published: 2022
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10. High-Resolution Optical Fluorescence Microscopy for Cell Biology Studies

Author: José Alberto Fracassi da Silva, Richard P. S. de Campos, Fernanda Ortis, and Fernando Abdulkader
Subjects: Materials science, Microscopy, Biophysics, High resolution, Optical fluorescence
Published: 2021
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11. Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Author: Angelo Rafael Carpinelli, Eloisa Aparecida Vilas-Boas, Fernanda Ortis, Leticia Prates Roma, and Davidson Correa Almeida
Subjects: medicine.medical_specialty, QH301-705.5, Type 2 diabetes, Review, medicine.disease_cause, Internal medicine, Insulin-Secreting Cells, medicine, Animals, Humans, Biology (General), chemistry.chemical_classification, pancreatic β-cell, Reactive oxygen species, NADPH oxidase, biology, Chemistry, Endoplasmic reticulum, NADPH Oxidases, General Medicine, lipotoxicity, medicine.disease, Endoplasmic Reticulum Stress, Lipids, Crosstalk (biology), Oxidative Stress, Endocrinology, Lipotoxicity, Diabetes Mellitus, Type 2, CÉLULAS MORTAS, biology.protein, Unfolded protein response, type 2 diabetes, ER stress, Oxidative stress
Abstract: A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.
Published: 2021

12. Early cytokine-induced transient NOX2 activity is ER stress-dependent and impacts β-cell function and survival

Author: Christopher Carlein, Angelo Rafael Carpinelli, Fernanda Ortis, Emmanuel Ampofo, Davidson Correa Almeida, Leticia Prates Roma, Lisa Nalbach, and Eloisa A. Vilas-Boas
Subjects: Genetically modified mouse, endocrine system, Physiology, medicine.medical_treatment, Clinical Biochemistry, Context (language use), hydrogen peroxide, RM1-950, medicine.disease_cause, insulitis, Biochemistry, Article, Proinflammatory cytokine, medicine, oxidative stress, GLICOSE, Molecular Biology, geography, geography.geographical_feature_category, NADPH oxidase, Chemistry, Cell Biology, Islet, medicine.disease, β-cell, Cell biology, Cytokine, proinflammatory cytokines, Unfolded protein response, cardiovascular system, Therapeutics. Pharmacology, ER stress, Insulitis, Oxidative stress
Abstract: In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O2•− production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H2O2 sensor, we show, for the first time, a transient increase of cytosolic/nuclear H2O2 in islet cells between 4 and 5 h during cytokine exposure. The H2O2 increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca2+ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H2O2 production. As early NOX2-driven ROS production impacts β-cells’ function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset.
Published: 2021

13. Transient NADPH oxidase 2-dependent H2O2 production drives early palmitate-induced lipotoxicity in pancreatic islets

Author: Eloisa Aparecida Vilas-Boas, Fernanda Ortis, Leticia Prates Roma, Lisa Nalbach, Emmanuel Ampofo, Angelo Rafael Carpinelli, Léa Naudet, Bruce A. Morgan, and Camila Ferraz Lucena
Subjects: 0301 basic medicine, Genetically modified mouse, Calcium metabolism, medicine.medical_specialty, NADPH oxidase, biology, Chemistry, Pancreatic islets, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, Lipotoxicity, Physiology (medical), Internal medicine, biology.protein, medicine, Unfolded protein response, NAD+ kinase, HOMEOSTASE, 030217 neurology & neurosurgery, Oxidative stress
Abstract: Modern lifestyles, including lack of physical activity and poor nutritional habits, are driving the rapidly increasing prevalence of obesity and type 2 diabetes. Increased levels of free fatty acids (FFAs), particularly saturated FFAs, in obese individuals have been linked to pancreatic β-cell failure. This process, termed lipotoxicity, involves activation of several stress responses, including ER stress and oxidative stress. However, the molecular underpinnings and causal relationships between the disparate stress responses remain unclear. Here we employed transgenic mice, expressing a genetically-encoded cytosolic H2O2 sensor, roGFP2-Orp1, to monitor dynamic changes in H2O2 levels in pancreatic islets in response to chronic palmitate exposure. We identified a transient increase in H2O2 levels from 4 to 8 h after palmitate addition, which was mirrored by a concomitant decrease in cellular NAD(P)H levels. Intriguingly, islets isolated from NOX2 knock-out mice displayed no H2O2 transient upon chronic palmitate treatment. Furthermore, NOX2 knockout rescued palmitate-dependent impairment of insulin secretion, calcium homeostasis and viability. Chemical inhibition of NOX activity protected islets from palmitate-induced impairment in insulin secretion, however had no detectable impact upon the induction of ER stress. In summary, our results reveal that transient NOX2-dependent H2O2 production is a likely cause of early palmitate-dependent lipotoxic effects.
Published: 2021

14. Transient NADPH oxidase 2-dependent H

Author: Eloisa Aparecida, Vilas-Boas, Lisa, Nalbach, Emmanuel, Ampofo, Camila Ferraz, Lucena, Léa, Naudet, Fernanda, Ortis, Angelo Rafael, Carpinelli, Bruce, Morgan, and Leticia Prates, Roma
Subjects: Islets of Langerhans, Mice, Diabetes Mellitus, Type 2, Insulin-Secreting Cells, NADPH Oxidase 2, Palmitates, Animals, Insulin, Hydrogen Peroxide
Abstract: Modern lifestyles, including lack of physical activity and poor nutritional habits, are driving the rapidly increasing prevalence of obesity and type 2 diabetes. Increased levels of free fatty acids (FFAs), particularly saturated FFAs, in obese individuals have been linked to pancreatic β-cell failure. This process, termed lipotoxicity, involves activation of several stress responses, including ER stress and oxidative stress. However, the molecular underpinnings and causal relationships between the disparate stress responses remain unclear. Here we employed transgenic mice, expressing a genetically-encoded cytosolic H
Published: 2020

15. A role for NADPH oxidase in mediating lipotoxicity and inflammation in β-cells

Author: Eloisa Aparecida Vilas Boas, Fernanda Ortis, Leticia Prates Roma, and Angelo Rafael Carpinelli
Subjects: Physiology (medical), Biochemistry
Published: 2021
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16. ARHGAP21 acts as an inhibitor of the glucose-stimulated insulin secretion process

Author: Gustavo J. Santos, Sandra Mara Ferreira, Nayara C. Leite, Luiz F. Rezende, Mirian Ayumi Kurauti, Fernanda Ortis, José M. Costa-Júnior, Antonio C. Boschero, and Helena C. Barbosa
Subjects: Male, 0301 basic medicine, insulin secretion, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Calcium in biology, Mice, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, Ob/Ob mice, Hyperinsulinism, Insulin-Secreting Cells, Diabetes mellitus, Internal medicine, medicine, MODELOS ANIMAIS DE DOENÇAS, Animals, Homeostasis, Original Research, Mice, Knockout, Gene knockdown, geography, lcsh:RC648-665, geography.geographical_feature_category, Chemistry, GTPase-Activating Proteins, Insulin tolerance test, ARHGAP21, SNAP25, Heterozygote advantage, medicine.disease, Islet, Mice, Inbred C57BL, Glucose, 030104 developmental biology, Gene Expression Regulation, Sweetening Agents, type 2 diabetes, calcium influx
Abstract: ARHGAP21 is a RhoGAP protein implicated in the modulation of insulin secretion and energy metabolism. ARHGAP21 transient-inhibition increase glucose-stimulated insulin secretion (GSIS) in neonatal islets; however, ARHGAP21 heterozygote mice have a reduced insulin secretion. These discrepancies are not totally understood, and it might be related to functional maturation of beta cells and peripheral sensitivity. Here, we investigated the real ARHGAP21 role in the insulin secretion process using an adult mouse model of acute ARHGAP21 inhibition, induced by antisense. After ARHGAP21 knockdown induction by antisense injection in 60-day old male mice, we investigated glucose and insulin tolerance test, glucose-induced insulin secretion, glucose-induced intracellular calcium dynamics, and gene expression. Our results showed that ARHGAP21 acts negatively in the GSIS of adult islet. This effect seems to be due to the modulation of important points of insulin secretion process, such as the energy metabolism (PGC1α), Ca2+signalization (SYTVII), granule-extrusion (SNAP25), and cell-cell interaction (CX36). Therefore, based on these finds, ARHGAP21 may be an important target in Diabetes Mellitus (DM) treatment.
Published: 2020

17. SAT-162 Hepatocyte Nuclear Factor-4α (HNF44α) as a Target to Treat DM

Author: Angelo Di Stefano, Fernanda Ortis, Antonio C. Boschero, Severine Pechberty, Sandra Mara Ferreira, Gustavo J. Santos, Carolina Ruoso, and Alex Rafacho
Subjects: Hepatocyte nuclear factors, Novel Aspects of Diabetes and Metabolic Disease Across Tissues and Developmental Stages, Chemistry, Endocrinology, Diabetes and Metabolism, Cancer research, Diabetes Mellitus and Glucose Metabolism
Abstract: Diabetes Mellitus (DM) is a metabolic disorder with multiple etiology and characterized by chronic hyperglycemia. It results from total (Type 1) or partial (Type 2) depletion of β cells, associated or not with insulin resistance (IR). Any Processes that promote the functional β-cell mass regeneration may be a target for DM treatment. HNF4α is an important transcription factor for pancreatic β cells because, beyond the control of the insulin gene, it regulates the expression of genes related to glucose metabolism, it is crucial in increasing beta cell mass in response to stress, such as in pregnancy and it is important to β-cell fate. However, little is known of its involvement in pancreatic β-cell apoptosis and regeneration. Based on the fact that HNF4α (1) participates in cell death processes, (2) controls processes of compensatory increase of β-cell mass, and (3) acts directly in regenerative processes, we aimed to unravel possible mechanisms, dependent of HNF4α, which can be used to treat Diabetes Mellitus. First we analyzed, in vitro, the consequence of HNF4α knockdown in human β-cell line EndoC-βH1 in the gene expression of several markers to islet-cell fate and in the cytokine-induced apoptosis. We observed that the siRNA for HNF4α reduced the expression of genes important to β-cell fate (PDX-1, NKX2.2, MAF-A, UCN-3 and KIR) and increased the expression of genes not-related with β-cell (NGN3, SOX9 and GLUCAGON). In additional, HNF4α knockdown prevented the cytokine-induced Caspase-3 cleavage in human EndoC-βH1 and rat INS-1E cell line. Then, we addressed our focus to the HNF4α ability to promote β-cell expansion in response to a metabolic demand. Here we investigated the HNF4α role in the IR-induced β-cell proliferation. We used WildType (C) and Knockout (K) animals for HNF4-alpha (HNF4αloxP/loxP;Ins.Cre). After CRE-recombinase activation the induction of Knockout was confirmed by ipGTT. To induce an IR, animals C and K were treated (D) or not-treated (S) with 100 mg/kg of dexamethasone for 5 consecutive days. Then, we analyzed GSIS, pancreatic morphometry (IHC) and expression of genes involved in pancreatic islet cell proliferation/transdifferentiation. We observed that indeed Dexa induced an IR and a β-cell mass expansion in CD mice, which were not observed in KD mice. Moreover, Dexa induced, in CD mice, an increase in genes involved in islet-cell expansion (Glucagon, Somatostatin, PDX1, PAX4, HHEX, NGN3) and this increased were abolished in KD mice. So, we observed that HNF4α seems to be important in the β-cell fate since its knockdown induces a non-β-cell gene expression in a β-cell line. Moreover, HNF4α acts in the β-cell death process and is involved in the Dexa-induced β-cell mass expansion. Taking together, HNF4α may be a target to prevent β-cell apoptosis and to induce β-cell regeneration. Financial Support: FAPESC/CNPq/CAPES/FAPESP.
Published: 2019

18. The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes

Author: Kira Meyerovich, Alessandra K Cardozo, and Fernanda Ortis
Subjects: 0301 basic medicine, ILHOTAS DE LANGERHANS, Population, Type 2 diabetes, Disease, Bioinformatics, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, Diabetes mellitus, Insulin-Secreting Cells, Medicine, Animals, Humans, education, Molecular Biology, Type 1 diabetes, education.field_of_study, business.industry, RELB, NF-kappa B, NF-κB, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, chemistry, Diabetes Mellitus, Type 2, Alternative complement pathway, business, Signal Transduction
Abstract: The prevalence of diabetes has reached 8.8% in worldwide population and is predicted to increase up to 10.4% by 2040. Thus, there is an urgent need for the development of means to treat or prevent this major disease. Due to its role in inflammatory responses, several studies demonstrated the importance of the transcription factor nuclear factor-κB (NF-κB) in both type 1 diabetes (T1D) and type 2 diabetes (T2D). The two major NF-κB pathways are the canonical and the non-canonical. The later pathway is activated by the NF-κB-inducing kinase (NIK) that triggers p100 processing into p52, which forms with RelB its main dimer. Cytokines mediating the activation of this pathway are present in the serum of T1D and T2D patients. Conversely, limited information is available regarding the role of the alternative pathway on diabetes development and β-cell fate. In the present review, we will briefly describe the involvement of NF-κB on diabetes pathology and discuss new studies indicating an important role for the non-canonical NF-κB activation in β-cell function and survival. The non-canonical NF-κB pathway is emerging as a novel potential target for the development of therapeutic strategies to treat or prevent diabetes.
Published: 2018

19. Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Author: Keli Cristina Benedicto, Alessandra K Cardozo, Flora Brozzi, Decio L. Eizirik, André Fujita, Antonio C. Boschero, Tarlliza R. Nardelli, Emerielle C. Vanzela, and Fernanda Ortis
Subjects: 0301 basic medicine, STAT3 Transcription Factor, medicine.medical_treatment, Blotting, Western, BIOINFORMÁTICA, 030209 endocrinology & metabolism, Apoptosis, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin-Secreting Cells, medicine, CXCL10, Animals, Interferon gamma, RNA, Small Interfering, Rats, Wistar, Promoter Regions, Genetic, Molecular Biology, Protein kinase B, Cells, Cultured, Chemistry, Reverse Transcriptase Polymerase Chain Reaction, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Prolactin, Rats, Transplantation, 030104 developmental biology, Cytokine, Cancer research, JNK cascade, Tumor necrosis factor alpha, Female, Beta cell, medicine.drug
Abstract: Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes IkBa, Fas, Mcp1, A20 and Cxcl10 and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.
Published: 2018

20. A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes

Author: Diane Delaroche, E C Vanzela, Fernanda Ortis, Henrik B. Mortensen, Lotte B Nielsen, Alessandra K Cardozo, Joachim Størling, Geert van Loo, Leen Catrysse, Makiko Fukaya, Rudi Beyaert, Flemming Pociot, Marie Louise Max M.L. Andersen, Caroline Brorsson, and Kira Meyerovich
Subjects: Male, 0301 basic medicine, Apoptosis, Biology, Polymorphism, Single Nucleotide, TNFAIP3, Mice, 03 medical and health sciences, Endocrinology, immune system diseases, Insulin-Secreting Cells, hemic and lymphatic diseases, Animals, Humans, Child, Protein kinase A, Molecular Biology, Protein kinase B, Transcription factor, Tumor Necrosis Factor alpha-Induced Protein 3, Original Research, Mice, Knockout, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, General Medicine, NFKB1, Rats, Antiapoptotic Agent, Cysteine Endopeptidases, Disease Models, Animal, Diabetes Mellitus, Type 1, 030104 developmental biology, Knockout mouse, Cancer research, Female, Mitogen-Activated Protein Kinases, Signal transduction, Signal Transduction
Abstract: Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to β-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-κB signaling and has strong antiapoptotic activities in β-cells. Although the role of A20 on NF-κB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the β-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in β-cells that are not restricted to inhibition of NF-κB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual β-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of β-cell survival and unveil novel mechanisms by which A20 controls β-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.
Published: 2016
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21. Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKIIa

Author: Fernanda Ortis, Ali Naji, Luiz F. Rezende, Sandra Mara Ferreira, Everardo M. Carneiro, Gustavo J. Santos, Chengyang Li, Antonio C. Boschero, and Klaus H. Kaestner
Subjects: INSULINA, medicine.medical_specialty, Period (gene), chemistry.chemical_element, Biology, Calcium, Brief Communication, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolic memory, Internal medicine, Ca2+/calmodulin-dependent protein kinase, medicine, Secretion, Neurotransmitter, Molecular Biology, 030304 developmental biology, 0303 health sciences, CaMKII, Pulse (signal processing), Transcription Factor MafA, Insulin secretion, Vesicle, Cell Biology, Endocrinology, chemistry, 030217 neurology & neurosurgery
Abstract: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of "metabolic memory", just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects. Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca(2+)-dependent vesicle secretion, and by elevated levels of the key ß-cell transcription factor MAFA. In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information.
Published: 2014
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22. JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

Author: Decio L. Eizirik, Daniel Andrade Da Cunha, Marco Bugliani, Fernanda Ortis, Esteban Nicolas Gurzov, Alessandra K Cardozo, Najib Naamane, Miriam Cnop, and Piero Marchetti
Subjects: Male, X-Box Binding Protein 1, XBP1, JUNB, Regulatory Factor X Transcription Factors, Biology, Insulin-Secreting Cells, hemic and lymphatic diseases, Animals, Humans, Phosphorylation, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Original Paper, Cell Biology, Middle Aged, Rats, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Lipotoxicity, Cancer research, Unfolded protein response, Female, Signal transduction, Proto-Oncogene Proteins c-akt, Signal Transduction, Transcription Factors
Abstract: Diets rich in saturated fats may contribute to the loss of pancreatic β-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes β-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated β-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to β-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient β-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPδ during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic β-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to β-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to β-cell apoptosis. In conclusion, JunB modulates the β-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic β-cell death. These findings elucidate novel β-cell-protective signal transduction in type 2 diabetes.
Published: 2014
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23. Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Author: Decio L. Eizirik, Florent Allagnat, Sigurd Lenzen, Alessandra K Cardozo, Pierre Pirot, Stephan Lortz, Fernanda Ortis, and Foteini Christulia
Subjects: Male, X-Box Binding Protein 1, Programmed cell death, Cell type, Indoles, XBP1, Cell Survival, Endocrinology, Diabetes and Metabolism, Blotting, Western, Fluorescent Antibody Technique, Apoptosis, Cell Count, Regulatory Factor X Transcription Factors, Biology, Endoplasmic Reticulum, Transfection, Interferon-gamma, Insulin-Secreting Cells, Insulin Secretion, Internal Medicine, Animals, Insulin, Secretion, RNA, Small Interfering, Rats, Wistar, Cells, Cultured, Homeodomain Proteins, Analysis of Variance, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-8, Rats, Cell biology, DNA-Binding Proteins, Trans-Activators, Unfolded protein response, Cancer research, Maf Transcription Factors, PDX1, RNA Interference, Beta cell, Transcription Factors
Abstract: Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)–C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis. Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated. Results Adenoviral-mediated overproduction of Xbp1s resulted in increased XBP1 activity and induction of several XBP1s target genes. Surprisingly, XBP1s overexpression impaired glucose-stimulated insulin secretion and increased beta cell apoptosis, whereas it protected fibroblasts against cell death induced by ER-stress. mRNA expression of Pdx1 and Mafa was inhibited in cells overproducing XBP1s, leading to decreased insulin expression. XBP1s knockdown partially restored cytokine/ER-stress-driven insulin and Pdx1 inhibition but had no effect on cytokine-induced ER-stress and apoptosis. Conclusions/interpretation XBP1 has a distinct inhibitory role in beta cell as compared with other cell types. Prolonged XBP1s production hampers beta cell function via inhibition of insulin, Pdx1 and Mafa expression, eventually leading to beta cell apoptosis.
Published: 2010
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24. Identification of New Pancreatic Beta Cell Targets for In Vivo Imaging by a Systems Biology Approach

Author: Decio L. Eizirik, Fernanda Ortis, Thomas Bouckenooghe, Serge Goldman, and Daisy Flamez
Subjects: Pharmacology, 0303 health sciences, Cell type, Systems Biology, Systems biology, 030209 endocrinology & metabolism, Computational biology, Biology, Bioinformatics, 3. Good health, Islets of Langerhans, 03 medical and health sciences, 0302 clinical medicine, Positron-Emission Tomography, Drug Discovery, Protein microarray, Humans, Biomarker (medicine), Identification (biology), Beta cell, Biomarkers, Preclinical imaging, Organism, 030304 developmental biology
Abstract: Systems biology is an emergent field that aims to understand biological systems at system-level. The increasing power of genome sequencing techniques and ranges of other molecular biology techniques is enabling the accumulation of in-depth knowledge of biological systems. This growing information, properly quantified, analysed and presented, will eventually allow the establishment of a system-based cartography of different cellular populations within the organism, and of their interactions at the tissue and organ levels. It will also allow the identification of specific markers of individual cell types. Systems biology approaches to discover diagnostic markers may have an important role in diabetes. There are presently no reliable ways to quantify beta cell mass (BCM) in vivo, which hampers the understanding of the pathogenesis and natural history of diabetes, and the development of novel therapies to preserve BCM. To solve this problem, novel and specific beta cell biomarkers must be identified to enable adequate in vivo imaging by methods such as Positron Emission Tomography (PET). The ideal biomarker should allow measurements by a minimally invasive technology enabling repeated examinations over time, should identify the early stages of decreased BCM, and should provide information on progression of beta cell loss and eventual responses to agents aiming to arrest or revert beta cell loss in diabetes. The present review briefly describes the "state-of-the-art" in the field, and then proposes a step-by-step systems biology approach for the identification and initial testing of novel candidates for beta cell imaging.
Published: 2010
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25. MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA

Author: Esteban Nicolas Gurzov, Maikel Luis Colli, Fernanda Ortis, Fabrice Moore, and Decio L. Eizirik
Subjects: Male, Small interfering RNA, Candidate gene, Apoptosis, Biology, DEAD-box RNA Helicases, Insulin-Secreting Cells, Genetics, Animals, Gene silencing, RNA, Small Interfering, Rats, Wistar, Promoter Regions, Genetic, Molecular Biology, Gene, Genetics (clinical), RNA, Double-Stranded, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Gene knockdown, JNK Mitogen-Activated Protein Kinases, NF-kappa B, RNA, MDA5, Interferon-beta, Articles, General Medicine, Molecular biology, Rats, Enzyme Activation, RNA silencing, Diabetes Mellitus, Type 1, Poly I-C, Viruses, Chemokines
Abstract: beta-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a 'dialog' between beta-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic beta-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic-polycitidilic acid-PIC). Real-time RT-PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate beta-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic beta-cell level.
Published: 2009
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26. Signaling by IL-1β+IFN-γ and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic β-cell apoptosis

Author: Daniel Andrade Da Cunha, Fernanda Ortis, Geoffrey Gosset, Alessandra K Cardozo, Esteban Nicolas Gurzov, Mengqing Li, and Decio L. Eizirik
Subjects: JUNB, Interleukin-1beta, Apoptosis, Inflammation, Endoplasmic Reticulum, Interferon-gamma, Downregulation and upregulation, Insulin-Secreting Cells, medicine, Animals, RNA, Small Interfering, Rats, Wistar, Molecular Biology, biology, Chemistry, Cytochrome c, Neuropeptides, JNK Mitogen-Activated Protein Kinases, Cytochromes c, Cell Biology, Rats, Up-Regulation, Cell biology, biology.protein, Unfolded protein response, Phosphorylation, Signal transduction, medicine.symptom, Apoptosis Regulatory Proteins, Signal Transduction
Abstract: Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic beta-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1beta+IFN-gamma and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in beta-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for beta-cell apoptosis after different stimuli, and that it can act up- and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1beta+IFN-gamma induce beta-cell death and the nature of the downstream signals by which ER stress 'convinces' beta-cells to trigger apoptosis.
Published: 2009
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27. Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

Author: Fernanda Ortis, Daisy Flamez, Decio L. Eizirik, and Fabrice Moore
Subjects: Programmed cell death, Cell Death, Systems Biology, Systems biology, Gene regulatory network, Biology, NFKB1, Biochemistry, Diabetes Mellitus, Type 1, Apoptosis, Immune System, Insulin-Secreting Cells, Immunology, STAT protein, Animals, Humans, Gene Regulatory Networks, Transcription factor, Neuroscience, NOD mice
Abstract: Accumulating evidence indicates that beta-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that beta-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-kappaB (nuclear factor kappaB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate beta-cell death and the 'dialogue' between beta-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a 'trial-and-error' approach to one that is really mechanistically driven.
Published: 2008
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28. Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Author: Fernanda Ortis, Alessandra K Cardozo, Florent Allagnat, and Kira Meyerovich
Subjects: 0301 basic medicine, endocrine system, medicine.medical_specialty, Inflammasomes, medicine.medical_treatment, Context (language use), Inflammation, Biology, 03 medical and health sciences, Islets of Langerhans, Endocrinology, Internal medicine, Insulin-Secreting Cells, medicine, Diabetes Mellitus, Animals, Humans, Molecular Targeted Therapy, Molecular Biology, Insulin, Endoplasmic reticulum, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Translation (biology), Endoplasmic Reticulum Stress, HISTOLOGIA, Cell biology, 030104 developmental biology, Unfolded protein response, Unfolded Protein Response, Cytokines, Disease Susceptibility, Signal transduction, medicine.symptom, Inflammation Mediators, Homeostasis, Molecular Chaperones, Signal Transduction
Abstract: Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.
Published: 2016

29. Cell-permeable peptides induce dose- and length-dependent cytotoxic effects

Author: Valérie Buchillier, Jianhua Chen, Laurence Ladrière, Christophe Bonny, Decio L. Eizirik, Fabienne Maurer, Alessandra K Cardozo, Stephan Kellenberger, Jacques S. Beckmann, Fernanda Ortis, Olivier Poirot, Marc Mathieu, and Nathalie Allaman-Pillet
Subjects: Cell Membrane Permeability, Cell Survival, Metabolic Clearance Rate, p38 mitogen-activated protein kinases, Cell, Biophysics, Apoptosis, Peptide, Biology, Cell-penetrating peptide, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, medicine, Animals, Cytotoxic T cell, Cytotoxicity, Pancreatic beta-cell, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Dose-Response Relationship, Drug, Kinase, Intracellular delivery, Cell Biology, Rats, Cell biology, Molecular Weight, medicine.anatomical_structure, chemistry, Tat, Peptides, HeLa cell, 030217 neurology & neurosurgery, Intracellular
Abstract: We have explored the threshold of tolerance of three unrelated cell types to treatments with potential cytoprotective peptides bound to Tat(48-57) and Antp(43-58) cell-permeable peptide carriers. Both Tat(48-57) and Antp(43-58) are well known for their good efficacy at crossing membranes of different cell types, their overall low toxicity, and their absence of leakage once internalised. Here, we show that concentrations of up to 100 microM of Tat(48-57) were essentially harmless in all cells tested, whereas Antp(43-58) was significantly more toxic. Moreover, all peptides bound to Tat(48-57) and Antp(43-58) triggered significant and length-dependent cytotoxicity when used at concentrations above 10 microM in all but one cell types (208F rat fibroblasts), irrespective of the sequence of the cargo. Absence of cytotoxicity in 208F fibroblasts correlated with poor intracellular peptide uptake, as monitored by confocal laser scanning fluorescence microscopy. Our data further suggest that the onset of cytotoxicity correlates with the activation of two intracellular stress signalling pathways, namely those involving JNK, and to a lesser extent p38 mitogen-activated protein kinases. These responses are of particular concern for cells that are especially sensitive to the activation of stress kinases. Collectively, these results indicate that in order to avoid unwanted and unspecific cytotoxicity, effector molecules bound to Tat(48-57) should be designed with the shortest possible sequence and the highest possible affinity for their binding partners or targets, so that concentrations below 10 microM can be successfully applied to cells without harm. Considering that cytotoxicity associated to Tat(48-57)- and Antp(43-58) bound peptide conjugates was not restricted to a particular type of cells, our data provide a general framework for the design of cell-penetrating peptides that may apply to broader uses of intracellular peptide and drug delivery.
Published: 2007
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30. Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells

Author: Alessandra K Cardozo, Yanjun Ma, Fernanda Ortis, Decio L. Eizirik, Miriam Cnop, Linda M. Hendershot, and Pierre Pirot
Subjects: Transcription, Genetic, Endocrinology, Diabetes and Metabolism, Restriction Mapping, Biology, CHOP, Endoplasmic Reticulum, Transfection, Polymerase Chain Reaction, Cell Line, chemistry.chemical_compound, Genes, Reporter, Transcription (biology), Insulin-Secreting Cells, Enhancer binding, Internal Medicine, Transcriptional regulation, Animals, Insulin, RNA, Messenger, Transcription factor, DNA Primers, Endoplasmic reticulum, ATF4, Rats, Cell biology, Gene Expression Regulation, chemistry, Biochemistry, Insulinoma, Cyclopiazonic acid, Transcription Factor CHOP
Abstract: Endoplasmic reticulum stress-mediated apoptosis may play an important role in the destruction of pancreatic beta-cells, thus contributing to the development of type 1 and type 2 diabetes. One of the regulators of endoplasmic reticulum stress-mediated cell death is the CCAAT/enhancer binding protein (C/EBP) homologous protein (Chop). We presently studied the molecular regulation of Chop expression in insulin-producing cells (INS-1E) in response to three pro-apoptotic and endoplasmic reticulum stress-inducing agents, namely the cytokines interleukin-1beta + interferon-gamma, the free fatty acid palmitate, and the sarcoendoplasmic reticulum pump Ca(2+) ATPase blocker cyclopiazonic acid (CPA). Detailed mutagenesis studies of the Chop promoter showed differential regulation of Chop transcription by CPA, cytokines, and palmitate. Whereas palmitate- and cytokine-induced Chop expression was mediated via a C/EBP-activating transcription factor (ATF) composite and AP-1 binding sites, CPA induction required the C/EBP-ATF site and the endoplasmic reticulum stress response element. Cytokines, palmitate, and CPA induced eIF2alpha phosphorylation in INS-1E cells leading to activation of the transcription factor ATF4. Chop transcription in response to cytokines and palmitate depends on the binding of ATF4 and AP-1 to the Chop promoter, but distinct AP-1 dimers were formed by cytokines and palmitate. These results suggest a differential response of beta-cells to diverse endoplasmic reticulum stress inducers, leading to a differential regulation of Chop transcription.
Published: 2007
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31. The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

Author: Letícia Ferreira Terra, Decio L. Eizirik, Makiko Fukaya, Kira Meyerovich, Fernanda Ortis, and Alessandra K Cardozo
Subjects: 0301 basic medicine, Male, Cell Survival, Endocrinology, Diabetes and Metabolism, Inflammation, Apoptosis, Biology, Nitric Oxide, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, Insulin-Secreting Cells, Internal Medicine, medicine, Animals, Humans, Immunoprecipitation, Rats, Wistar, Beta (finance), Transcription factor, Cell Death, NF-kappa B, NF-κB, NFKB1, HISTOLOGIA, Cell biology, Rats, 030104 developmental biology, Diabetes Mellitus, Type 1, chemistry, Cytokines, medicine.symptom, Beta cell, Signal transduction, Signal Transduction
Abstract: Activation of the transcription factor nuclear factor (NF)-κB by proinflammatory cytokines plays an important role in beta cell demise in type 1 diabetes. Two main signalling pathways are known to activate NF-κB, namely the canonical and the non-canonical pathways. Up to now, studies on the role of NF-κB activation in beta cells have focused on the canonical pathway. The aim of this study was to investigate whether cytokines activate the non-canonical pathway in beta cells, how this pathway is regulated and the consequences of its activation on beta cell fate. NF-κB signalling was analysed by immunoblotting, promoter reporter assays and real-time RT-PCR, after knockdown or overexpression of key genes/proteins. INS-1E cells, FACS-purified rat beta cells and the human beta cell line EndoC-βH1 exposed to cytokines were used as models. IL-1β plus IFN-γ induced stabilisation of NF-κB-inducing kinase and increased the expression and cleavage of p100 protein, culminating in the nuclear translocation of p52, the hallmark of the non-canonical signalling. This activation relied on different crosstalks between the canonical and non-canonical pathways, some of which were beta cell specific. Importantly, cytokine-mediated activation of the non-canonical pathway controlled the expression of ‘late’ NF-κB-dependent genes, regulating both pro-apoptotic and inflammatory responses, which are implicated in beta cell loss in early type 1 diabetes. The atypical activation of the non-canonical NF-κB pathway by proinflammatory cytokines constitutes a novel ‘feed-forward’ mechanism that contributes to the particularly pro-apoptotic effect of NF-κB in beta cells.
Published: 2015

32. Cytokine-Induced Proapoptotic Gene Expression in Insulin-Producing Cells Is Related to Rapid, Sustained, and Nonoscillatory Nuclear Factor-κB Activation

Author: Alessandra K Cardozo, Joachim Størling, Daisy Crispim, Fernanda Ortis, Decio L. Eizirik, and Thomas Mandrup-Poulsen
Subjects: Gene isoform, Protein Denaturation, Cell type, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Nitric Oxide Synthase Type II, Apoptosis, Biology, Response Elements, Endocrinology, Insulin-Secreting Cells, Internal medicine, Gene expression, medicine, Animals, Insulin, Protein Isoforms, Extracellular Signal-Regulated MAP Kinases, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Cells, Cultured, CD40, Gene Expression Profiling, NF-kappa B, General Medicine, Rats, Cell biology, Nitric oxide synthase, Kinetics, Cytokine, Gene Expression Regulation, biology.protein, Cytokines, I-kappa B Proteins
Abstract: Cytokines, such as IL-1beta and TNF-alpha, contribute to pancreatic beta-cell death in type 1 diabetes mellitus. The transcription factor nuclear factor-kappaB (NF-kappaB) mediates cytokine-induced beta-cell apoptosis. Paradoxically, NF-kappaB has mostly antiapoptotic effects in other cell types. The cellular actions of NF-kappaB depend on the cell type, the nature and duration of the stimulus, the periodicity, and the degree of activity of the particular dimers involved. To clarify the reasons behind the proapoptotic effects of NF-kappaB in pancreatic beta-cells, we compared the pattern of cytokine-induced NF-kappaB activation between rat insulin-producing cells (INS-1E cells) and fibroblasts (208F cells). NF-kappaB activation was induced in INS-1E cells and in 208F cells after exposure to cytokines, but apoptosis was induced only in INS-1E cells, with a more pronounced proapoptotic effect of IL-1beta than of TNF-alpha. NF-kappaB activation in IL-1beta-exposed INS-1E cells was earlier and more marked as compared with TNF-alpha-exposed INS-1E cells or IL-1beta-exposed 208F cells. Both cytokines induced a prolonged (up to 48 h) and stable NF-kappaB activation in INS-1E cells, whereas IL-1beta induced an oscillatory NF-kappaB activation in 208F cells. p65/p65 and p65/p50 were the predominant NF-kappaB dimers in IL-1beta-exposed INS-1E cells and 208F cells, respectively. IL-1beta induced a differential usage of cis-elements in the inducible nitric oxide synthase promoter region in the two cell-lines and an increase in ERK1/2 activity in INS-1E cells but not in 208F cells. Cytokine-induced expression of IkappaB isoforms and other NF-kappaB target genes (Fas, MCP-1, and inducible nitric oxide synthase) was severalfold higher in INS-1E cells than in 208F cells. These results suggest that cytokine-induced NF-kappaB activation in insulin-producing cells is more rapid, marked, and sustained than in fibroblasts, which correlates with a more pronounced activation of downstream genes and a proapoptotic outcome.
Published: 2006
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33. Cytokines Downregulate the Sarcoendoplasmic Reticulum Pump Ca2+ ATPase 2b and Deplete Endoplasmic Reticulum Ca2+, Leading to Induction of Endoplasmic Reticulum Stress in Pancreatic β-Cells

Author: Joanne Rasschaert, André Herchuelz, Morten Tonnesen, Alessandra K Cardozo, Thomas Mandrup-Poulsen, Françoise Van Eylen, Ying-Mei Feng, Joachim Størling, Decio L. Eizirik, and Fernanda Ortis
Subjects: medicine.medical_specialty, Thapsigargin, SERCA, Endocrinology, Diabetes and Metabolism, Calcium-Transporting ATPases, Biology, Endoplasmic Reticulum, Gene Expression Regulation, Enzymologic, Islets of Langerhans, chemistry.chemical_compound, Internal medicine, Internal Medicine, medicine, Animals, ASK1, Rats, Wistar, Protein kinase A, DNA Primers, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, ATF6, Endoplasmic reticulum, STIM1, Rats, Cell biology, Oxidative Stress, Sarcoplasmic Reticulum, Endocrinology, chemistry, Unfolded protein response, Cytokines, Calcium
Abstract: Cytokines and free radicals are mediators of beta-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1beta (IL-1beta) + gamma-interferon (IFN-gamma) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic beta-cells. We have previously shown, by microarray analysis of primary beta-cells, that IL-1beta + IFN-gamma decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump Ca(2+) ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress-related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). In the present study we show that cytokine-induced apoptosis and necrosis in primary rat beta-cells and INS-1E cells largely depends on NO production. IL-1beta + IFN-gamma, via NO synthesis, markedly decreased SERCA2b protein expression and depleted ER Ca(2+) stores. Of note, beta-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER Ca(2+) depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol-requiring ER-to-nucleus signal kinase 1alpha (IRE1alpha) and PRK (RNA-dependent protein kinase)-like ER kinase (PERK)/activating transcription factor 4 (ATF4), but not ATF6. In contrast, the ER stress-inducing agent thapsigargin triggered these four pathways in parallel. In conclusion, our results suggest that the IL-1beta + IFN-gamma-induced decrease in SERCA2b expression, with subsequent depletion of ER Ca(2+) and activation of the ER stress pathway, is a potential contributory mechanism to beta-cell death.
Published: 2005
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34. Interactions between Cationic Vesicles and Cultured Mammalian Cells

Author: R. I. Schumacher, Ana Maria Carmona-Ribeiro, Fernanda Ortis, and M. C. S. Armelin
Subjects: Liposome, medicine.diagnostic_test, Chemistry, Vesicle, Synthetic membrane, Surfaces and Interfaces, Adhesion, Condensed Matter Physics, Flow cytometry, Microelectrophoresis, Biochemistry, Electrochemistry, Biophysics, medicine, General Materials Science, Viability assay, Turbidimetry, Spectroscopy
Abstract: The interaction of small cationic vesicles composed of dioctadecyldimethylammonium bromide (DODAB) with normal versus transformed mouse fibroblasts is described using cell microelectrophoresis, turbidimetry, and cell viability assays over a wide range of DODAB concentrations (10-7−10-3 M). Normal and transformed cells (104 cells/mL) attain a point of zero charge at, respectively, 18.0 and 1.6 μM DODAB. Further increasing DODAB concentration (C) generates positively charged cells. At 105 cells/mL and C ≥ 50 μM, DODAB induces cell−cell adhesion. For transformed and normal cells, peak adhesion occurs at 100 and 1000 μM DODAB, respectively. Upon 0.5 h interaction time with 100 μM DODAB, at 104 cells/mL, 20% of cell death is obtained for normal cells whereas transformed cells remain unaffected. Transformed cells have a higher affinity for DODAB vesicles than their normal counterparts but are more resistant to DODAB-induced cell death. The results indicate that DODAB vesicles interact with cells with very high ...
Published: 1997
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35. Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

Author: Shigetaka Kitajima, Decio L. Eizirik, Piero Marchetti, Chantal Mathieu, Mariana Igoillo-Esteve, Fernanda Ortis, Esteban Nicolas Gurzov, Ihsane Marhfour, Najib Naamane, Latifa Bakiri, Conny Gysemans, Torben F. Ørntoft, Erwin F. Wagner, and Jenny Barthson
Subjects: Genetically modified mouse, Cancer Research, JUNB, Proto-Oncogene Proteins c-jun, Inflammation, Mice, Transgenic, Biology, Mice, Downregulation and upregulation, Mice, Inbred NOD, Insulin-Secreting Cells, hemic and lymphatic diseases, Genetics, medicine, Animals, Humans, Molecular Biology, Transcription factor, ATF3, Activating Transcription Factor 3, Activator (genetics), Tumor Necrosis Factor-alpha, Diabetes Mellitus, Type 1, Gene Knockdown Techniques, Cancer research, Tumor necrosis factor alpha, medicine.symptom, Signal Transduction
Abstract: Destruction of insulin-producing pancreatic β-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ induce JunB expression as a protective mechanism against apoptosis in both human and rodent β-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified β-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for β-cell survival after TNF-α+IFN-γ treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary β-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of β-cells under inflammatory stress. Destruction of insulin-producing pancreatic β-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ induce JunB expression as a protective mechanism against apoptosis in both human and rodent β-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified β-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for β-cell survival after TNF-α+IFN-γ treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary β-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of β-cells under inflammatory stress.Oncogene advance online publication, 15 August 2011; doi:10.1038/onc.2011.353.
Published: 2012
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36. Differential usage of NF-κB activating signals by IL-1β and TNF-α in pancreatic beta cells

Author: Daniel Andrade Da Cunha, Florent Allagnat, Alain Chariot, Esteban Nicolas Gurzov, Fernanda Ortis, Michela Miani, Maikel Luis Colli, and Decio L. Eizirik
Subjects: Proteasome Endopeptidase Complex, medicine.medical_treatment, Interleukin-1beta, Biophysics, Inflammation, IκB kinase, Biochemistry, NF-κB, Cell Line, chemistry.chemical_compound, Mice, Structural Biology, Insulin-Secreting Cells, Genetics, medicine, Animals, Humans, Protease Inhibitors, IKK complex, Gene Silencing, Molecular Targeted Therapy, Rats, Wistar, Pancreatic β-cell, Cytokine, Molecular Biology, Protein Kinase Inhibitors, Cells, Cultured, Tumor Necrosis Factor-alpha, NF-kappa B, Interleukin, Cell Biology, NFKB1, Interleukin-1β, Recombinant Proteins, I-kappa B Kinase, Rats, Protein Subunits, Diabetes Mellitus, Type 1, chemistry, Proteasome, Immunology, Proteolysis, Cancer research, Tumor necrosis factor alpha, medicine.symptom, Proteasome Inhibitors, Signal Transduction
Abstract: The cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α induce β-cell death in type 1 diabetes via NF-κB activation. IL-1β induces a more marked NF-κB activation than TNF-α, with higher expression of genes involved in β-cell dysfunction and death. We show here a differential usage of the IKK complex by IL-1β and TNF-α in β-cells. While TNF-α uses IKK complexes containing both IKKα and IKKβ, IL-1β induces complexes with IKKα only; this effect is achieved by induction of IKKβ degradation via the proteasome. Both IKKγ and activation of the TRAF6-TAK1-JNK pathway are involved in IL-1β-induced IKKβ degradation.
Published: 2011

37. Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and β-cell apoptosis

Author: Zenia M Størling, Claus Heiner Bang-Berthelsen, Regine Bergholdt, Caroline Brorsson, Søren Brunak, Decio L. Eizirik, Kasper Lage, Joachim Størling, Fernanda Ortis, Lukas Adrian Berchtold, Jacob Hald, and Flemming Pociot
Subjects: Adult, Male, Candidate gene, Adolescent, Cell Survival, In silico, Interleukin-1beta, Apoptosis, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proinflammatory cytokine, Mice, Young Adult, SDG 3 - Good Health and Well-being, RNA interference, Insulin-Secreting Cells, Insulin Secretion, Animals, Humans, Insulin, Genetic Predisposition to Disease, HUNTINGTIN-INTERACTING PROTEIN 14, Child, Gene, Genetics, Gene knockdown, Binding Sites, Multidisciplinary, biology, NF-kappa B, Middle Aged, NFKB1, Rats, Cell biology, Diabetes Mellitus, Type 1, Glucose, PNAS Plus, Cytokines, Female, biology.gene, Protein Binding, Transcription Factors
Abstract: Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting β-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico “phenome–interactome analysis” on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17 . Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for β-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1β and IFN-γ) that mediate β-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1β–induced NF-κB activity and protection against IL-1β–mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches.
Published: 2011
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38. STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation

Author: Najib Naamane, Thomas Thykjaer, Esteban Nicolas Gurzov, Torben F. Ørntoft, Chantal Mathieu, Mariana Igoillo-Esteve, Fernanda Ortis, Fabrice Moore, Decio L. Eizirik, Thomas Bouckenooghe, Gianluca Bontempi, and Maikel Luis Colli
Subjects: Male, Chemokine, Transcription, Genetic, Interleukin-1beta, 030209 endocrinology & metabolism, Inflammation, Apoptosis, Biochemistry, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Insulin-Secreting Cells, medicine, Animals, Gene Regulation, STAT1, RNA, Small Interfering, Rats, Wistar, Molecular Biology, Transcription factor, Cells, Cultured, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, geography, geography.geographical_feature_category, biology, Microarray analysis techniques, Neuropeptides, Cell Differentiation, Cell Biology, Islet, Rats, STAT1 Transcription Factor, Pancreatitis, Gene Knockdown Techniques, Cancer research, biology.protein, PDX1, medicine.symptom, Signal transduction, Apoptosis Regulatory Proteins, Interferon Regulatory Factor-1
Abstract: Cytokines produced by islet-infiltrating immune cells induce β-cell apoptosis in type 1 diabetes. The IFN-γ-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on β-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in β-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1β and IFN-γ. Relevant microarray findings were further studied in INS-1E cells and primary rat β-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated β-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-γ/STAT1/IRF-1 axis controls β-cell function/differentiation, demise, and islet inflammation.
Published: 2010
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39. p53 Up-regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic β-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum Stress*

Author: Lin Zhang, Esteban Nicolas Gurzov, Decio L. Eizirik, Daniel Andrade Da Cunha, Fernanda Ortis, Piero Marchetti, Jean-Marie Vanderwinden, and Carla Maria Ramos C.M. Germano
Subjects: Biochimie, Blotting, Western, Interleukin-1beta, bcl-X Protein, Gene Expression, Apoptosis, Mitochondrion, Endoplasmic Reticulum, Biochemistry, Piperazines, Proinflammatory cytokine, Nitrophenols, Interferon-gamma, Downregulation and upregulation, Puma, Cell Line, Tumor, Insulin-Secreting Cells, Proto-Oncogene Proteins, Animals, Humans, Rats, Wistar, Molecular Biology, Cells, Cultured, Sulfonamides, Binding Sites, biology, Activator (genetics), Reverse Transcriptase Polymerase Chain Reaction, Cytochrome c, Endoplasmic reticulum, Biphenyl Compounds, NF-kappa B, Biologie moléculaire, Molecular Bases of Disease, Cell Biology, biology.organism_classification, Rats, Mutation, Cancer research, biology.protein, Cytokines, Biologie cellulaire, RNA Interference, biological phenomena, cell phenomena, and immunity, Apoptosis Regulatory Proteins
Abstract: Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic β-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1β, combined with interferon-γ, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in β-cells. Transcriptional activation of PUMAis regulated by nuclear factor-κB and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in β-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the β-cells and antagonizesPUMAaction, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed β-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA dependent β-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of β-cell apoptosis in the context of inflammation and type 1 diabetes. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2010

40. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

Author: Kasper Thorsen, Laurence Ladrière, Fernanda Ortis, Daniel Andrade Da Cunha, Maikel Luis Colli, Decio L. Eizirik, Daisy Flamez, Najib Naamane, Thomas Thykjaer, Fabrice Moore, and Torben F. Ørntoft
Subjects: Transcription, Genetic, Cell Survival, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Citric Acid Cycle, Interleukin-1beta, Gene Expression, Biology, Incretins, Exon, Interferon-gamma, Insulin-Secreting Cells, Commentaries, Gene expression, Internal Medicine, medicine, Humans, Animals, RNA, Small Interfering, Gene, Differential gene expression, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Homeodomain Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Gene Expression Profiling, Alternative splicing, Diabetes, Interleukin, Genetic Variation, Exons, Sciences bio-médicales et agricoles, Flow Cytometry, Cell biology, Rats, Alternative Splicing, Cytokine, Diabetes Mellitus, Type 1, Phenotype, Gene Expression Regulation, Immunology, RNA splicing, Trans-Activators, Citrulline, Cytokines, Original Article, Signal Transduction
Abstract: OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis. RESULTS Nearly 16,000 transcripts were detected as present in beta-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also shows that cytokines modify alternative splicing in beta-cells, opening a new avenue of research for the field., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
Published: 2010

41. Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB

Author: Daniel Andrade Da Cunha, Piero Marchetti, Mariana Igoillo-Esteve, Fernanda Ortis, Roberto Lupi, Laurence Ladrière, Esteban Nicolas Gurzov, Decio L. Eizirik, and Miriam Cnop
Subjects: Male, Proto-Oncogene Proteins c-jun, Endocrinology, Diabetes and Metabolism, Biologie générale, Apoptosis, Endoplasmic Reticulum, Polymerase Chain Reaction, Salubrinal, chemistry.chemical_compound, Glucagon-Like Peptide 1, Insulin-Secreting Cells, Receptors, Glucagon, Venoms -- pharmacology, Heat-Shock Proteins, Transcription Factors -- metabolism, Forskolin, Endoplasmic Reticulum -- metabolism, Sciences bio-médicales et agricoles, Cell biology, Up-Regulation, DNA-Binding Proteins, Receptors, Glucagon -- metabolism, Original Article, RNA Interference, Signal transduction, Biologie, DNA-Binding Proteins -- metabolism, Antigens, Differentiation -- metabolism, endocrine system, medicine.medical_specialty, JUNB, Cell Survival, Hypoglycemic Agents -- pharmacology, Blotting, Western, Regulatory Factor X Transcription Factors, Diabetes Mellitus, Type 2 -- metabolism -- prevention & control, Peptides -- pharmacology, Biology, Inhibitor of apoptosis, Glucagon-Like Peptide-1 Receptor, Proto-Oncogene Proteins c-jun -- genetics -- metabolism, Downregulation and upregulation, Proto-Oncogene Proteins, Internal medicine, Internal Medicine, medicine, Hypoglycemic Agents, Animals, Heat-Shock Proteins -- genetics -- metabolism, Colforsin -- pharmacology, Rats, Wistar, Diabétologie, Venoms, Endoplasmic reticulum, Colforsin, Glucagon-Like Peptide 1 -- agonists -- metabolism, Biologie moléculaire, Lipid Metabolism -- drug effects, Enseignement des sciences, Lipid Metabolism, Antigens, Differentiation, Rats, Proto-Oncogene Proteins -- metabolism, Endocrinology, Diabetes Mellitus, Type 2, Islet Studies, chemistry, Insulin-Secreting Cells -- metabolism, Unfolded protein response, Exenatide, Biologie cellulaire, Peptides, Transcription Factors
Abstract: Chronic exposure of pancreatic beta-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis and may contribute to beta-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved in the protection of beta-cells from lipotoxic ER stress by glucagon-like peptide (GLP)-1 agonists utilized in the treatment of type 2 diabetes., info:eu-repo/semantics/published
Published: 2009

42. Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes

Author: Laurence Ladrière, Fernanda Ortis, Gordon C. Weir, Piero Marchetti, Mariana Igoillo-Esteve, Fabio Arturo Grieco, Francesco Dotta, Lorella Marselli, Daniel Andrade Da Cunha, Miriam Cnop, and Decio L. Eizirik
Subjects: Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Chemokine CXCL1, Palmitates, Fluorescent Antibody Technique, Type 2 diabetes, Polymerase Chain Reaction, Pathogenesis, Insulin-Secreting Cells, NF-kappa B -- metabolism, Chemokine CCL2, Oligonucleotide Array Sequence Analysis, geography.geographical_feature_category, Diabetes Mellitus, Type 2 -- metabolism, NF-kappa B, Sciences bio-médicales et agricoles, Middle Aged, Islet, Cytokine, medicine.anatomical_structure, Interleukin-6 -- metabolism, Female, Beta cell, medicine.symptom, medicine.medical_specialty, Radioimmunoassay, Inflammation, Enzyme-Linked Immunosorbent Assay, Biology, In Vitro Techniques, Cell Line, Islets of Langerhans, Chemokine CCL2 -- metabolism, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Aged, geography, Palmitates -- pharmacology, Interleukin-6, Tumor Necrosis Factor-alpha, Pancreatic islets, Interleukin-8, medicine.disease, Islets of Langerhans -- drug effects -- metabolism, Endocrinology, Diabetes Mellitus, Type 2, Insulin-Secreting Cells -- metabolism, Interleukin-8 -- metabolism, Tumor Necrosis Factor-alpha -- metabolism
Abstract: Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate., In Vitro, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
Published: 2009

43. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes

Author: Decio L. Eizirik, Fernanda Ortis, and Maikel Luis Colli
Subjects: Autoimmune disease, Inflammation, Type 1 diabetes, Chemokine, Innate immune system, biology, business.industry, Endocrinology, Diabetes and Metabolism, medicine.disease, Islets of Langerhans, Endocrinology, Immune system, Diabetes Mellitus, Type 1, Insulin-Secreting Cells, Immunology, medicine, biology.protein, Animals, Humans, Beta cell, medicine.symptom, business, Insulitis
Abstract: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease with a strong inflammatory component. The latest studies indicate that innate immunity and inflammatory mediators have a much broader role in T1DM than initially assumed. Inflammation might contribute to early induction and amplification of the immune assault against pancreatic beta cells and, at later stages, to the stabilization and maintenance of insulitis. Inflammatory mediators probably contribute to the suppression of beta-cell function and subsequent apoptosis; they may also inhibit or stimulate beta-cell regeneration and might cause peripheral insulin resistance. The different effects of inflammation take place in different phases of the course of T1DM, and should be considered in the context of a 'dialog' between invading immune cells and the target beta cells. This dialog is mediated both by cytokines and chemokines that are released by beta cells and immune cells, and by putative, immunogenic signals that are delivered by dying beta cells. In this Review, we divided the role of inflammation in T1DM into three arbitrary stages: induction, amplification and maintenance or resolution of insulitis. These stages, and their progression or resolution, might depend on a patient's genetic background, which contributes to disease heterogeneity.
Published: 2009

44. JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells

Author: Latifa Bakiri, Erwin F. Wagner, Fernanda Ortis, Esteban Nicolas Gurzov, and Decio L. Eizirik
Subjects: Programmed cell death, Small interfering RNA, JUNB, Proto-Oncogene Proteins c-jun, medicine.medical_treatment, Genetic Vectors, lcsh:Medicine, Endoplasmic Reticulum -- physiology, Apoptosis, Biology, Endoplasmic Reticulum, Nitric Oxide, Adenoviridae, Mice, Proto-Oncogene Proteins c-jun -- genetics, Downregulation and upregulation, hemic and lymphatic diseases, Insulin-Secreting Cells, medicine, Animals, Fibroblasts -- physiology, Proto-Oncogene Proteins c-jun -- physiology, Rats, Wistar, lcsh:Science, Molecular Biology, Cells, Cultured, Insulin-Secreting Cells -- cytology, Gene knockdown, Multidisciplinary, Insulin-Secreting Cells -- physiology, Cell Death, lcsh:R, Cell Biology/Cellular Death and Stress Responses, 3T3 Cells, Sciences bio-médicales et agricoles, Fibroblasts, Proto-Oncogene Proteins c-jun -- deficiency, Rats, Cytokine, Unfolded protein response, Cancer research, lcsh:Q, Fibroblasts -- cytology, Diabetes and Endocrinology/Type 1 Diabetes, Gene Deletion, Nitric Oxide -- physiology, Research Article
Abstract: Cytokines contribute to pancreatic beta-cell apoptosis in type 1 diabetes (T1D) by modulation of beta-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated beta-cell dysfunction and death. The cytokines IL-1beta+IFN-gamma induced an early and transitory upregulation of JunB by NF-kappaB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary beta-cells. JunB knockdown beta-cells and junB(-/-) fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected beta-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis., Journal Article, info:eu-repo/semantics/published
Published: 2008

45. Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Author: Joanne Rasschaert, Lutgart Overbergh, Elisa A. Bellomo, Fernanda Ortis, Guy A. Rutter, Marion C. Wakeham, Roberto Lupi, Miriam Cnop, Alessandra K Cardozo, Piero Marchetti, Chantal Mathieu, Daniel Andrade Da Cunha, Paul Hekerman, Fabrice Moore, André Herchuelz, Laurence Ladrière, Tsonwin Hai, Angie Bazarra-Castro, and Decio L. Eizirik
Subjects: Male, medicine.medical_specialty, Apoptosis, Biology, Fatty Acids, Nonesterified, Protein Serine-Threonine Kinases, Endoplasmic Reticulum, Article, Mice, eIF-2 Kinase, Internal medicine, Insulin-Secreting Cells, medicine, Animals, Humans, Rats, Wistar, Transcription Factor CHOP, EIF-2 kinase, Activating Transcription Factor 3, ATF6, Endoplasmic reticulum, JNK Mitogen-Activated Protein Kinases, Membrane Proteins, Cell Biology, Middle Aged, Activating Transcription Factor 6, Rats, Endocrinology, Glucose, Lipotoxicity, biology.protein, Unfolded protein response, Calcium, Signal transduction, Signal Transduction
Abstract: Free fatty acids (FFA) cause apoptosis of pancreatic beta-cells and might contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. We studied here the molecular mechanisms implicated in FFA-induced ER stress initiation and apoptosis in INS-1E cells, FACS-purified primary beta-cells and human islets exposed to oleate and/or palmitate. Treatment with saturated and/or unsaturated FFA led to differential ER stress signaling. Palmitate induced more apoptosis and markedly activated the IRE1, PERK and ATF6 pathways, owing to a sustained depletion of ER Ca(2+) stores, whereas the unsaturated FFA oleate led to milder PERK and IRE1 activation and comparable ATF6 signaling. Non-metabolizable methyl-FFA analogs induced neither ER stress nor beta-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary beta-cells is primarily lipotoxic, and not glucolipotoxic. Palmitate, but not oleate, activated JNK. JNK inhibitors reduced palmitate-mediated AP-1 activation and apoptosis. Blocking the transcription factor CHOP delayed palmitate-induced beta-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP.
Published: 2008

46. Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells

Author: Decio L. Eizirik, Najib Naamane, Pierre Pirot, Catherine Verhaeghe, Fernanda Ortis, A Y Kreins, Torben F. Ørntoft, Alain Chariot, Joanne Rasschaert, Francis D. Moore, E Théâtre, and Nils E. Magnusson
Subjects: medicine.medical_specialty, Programmed cell death, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Interleukin-1beta, Apoptosis, IκB kinase, Biology, Insulin-Secreting Cells, Internal medicine, Internal Medicine, medicine, Animals, Rats, Wistar, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Cell Nucleus, Tumor Necrosis Factor-alpha, Gene Expression Profiling, NF-kappa B, NFKB1, I-kappa B Kinase, Rats, XIAP, Cell biology, Apoptosis - Diabetes mellitus - IL-1β - NF-κB - Pancreatic beta cells - TNF-α, Diabetes Mellitus, Type 1, Cytokine, Endocrinology, Gene Expression Regulation, Hepatocyte nuclear factor 4, Tumor necrosis factor alpha, Beta cell, Signal Transduction
Abstract: Udgivelsesdato: July AIMS/HYPOTHESIS: IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN-gamma-induced beta cell apoptosis. The aim of the present study was to compare the effects of IL-1beta and TNF-alpha on cell death and the pattern of NF-kappaB activation and global gene expression in beta cells. METHODS: Cell viability was measured after exposure to IL-1beta or to TNF-alpha alone or in combination with IFN-gamma, and blockade of NF-kappaB activation or protein synthesis. INS-1E cells exposed to IL-1beta or TNF-alpha in time course experiments were used for IkappaB kinase (IKK) activation assay, detection of p65 NF-kappaB by immunocytochemistry, real-time RT-PCR and microarray analysis. RESULTS: Blocking NF-kappaB activation protected beta cells against IL-1beta + IFNgamma- or TNFalpha + IFNgamma-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-alpha- or IL-1beta-induced beta cell death, in line with the observations that cytokines induced the expression of the anti-apoptotic genes A20, Iap-2 and Xiap to a similar extent. Microarray analysis of INS-1E cells treated with IL-1beta or TNF-alpha showed similar patterns of gene expression. IL-1beta, however, induced a higher rate of expression of NF-kappaB target genes putatively involved in beta cell dysfunction and death and a stronger activation of the IKK complex, leading to an earlier translocation of NF-kappaB to the nucleus. CONCLUSIONS/INTERPRETATION: NF-kappaB activation in beta cells has a pro-apoptotic role following exposure not only to IL-1beta but also to TNF-alpha. The more marked beta cell death induced by IL-1beta is explained at least in part by higher intensity NF-kappaB activation, leading to increased transcription of key target genes.
Published: 2008
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47. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis

Author: Zeynep Dogusan, Alessandra K Cardozo, Daisy Flamez, Paul Hekerman, Fernanda Ortis, Miriam Cnop, Laurence Ladrière, Michael Boyce, Junying Yuan, and Decio L. Eizirik
Subjects: Male, Eukaryotic Initiation Factor-2, Apoptosis, Biology, Fatty Acids, Nonesterified, Endoplasmic Reticulum, Biochemistry, Dephosphorylation, Salubrinal, chemistry.chemical_compound, Insulin-Secreting Cells, Protein biosynthesis, Initiation factor, Animals, Phosphorylation, Rats, Wistar, Molecular Biology, Cells, Cultured, Transcription Factor CHOP, Endoplasmic reticulum, Thiourea, Cell Biology, Cell biology, Rats, Oxidative Stress, chemistry, Cinnamates, Unfolded protein response
Abstract: Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2alpha phosphorylation trigger beta-cell failure and diabetes. Salubrinal selectively inhibits eIF2alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.
Published: 2006

48. Loss of PPAR gamma in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue

Author: Fernanda Ortis, Umesh D. Wankhade, Gerardo Ferrer, Raquel Hontecillas, Hongwei Si, Oriol Casagran, Amir J. Guri, Alexis M Noble, Josep Bassaganya-Riera, Miriam Cnop, Dongmin Liu, and Decio L. Eizirik
Subjects: Blood Glucose, medicine.medical_specialty, CCR2, Endocrinology, Diabetes and Metabolism, Adipose tissue macrophages, medicine.medical_treatment, Adipose Tissue, White, Clinical Biochemistry, Adipose tissue, Inflammation, Mice, Inbred Strains, White adipose tissue, Biology, Biochemistry, Mice, Insulin resistance, Internal medicine, medicine, Animals, Obesity, Molecular Biology, Chemokine CCL2, Triglycerides, Nutrition and Dietetics, Monocyte, Insulin, Macrophages, Body Weight, food and beverages, medicine.disease, PPAR gamma, medicine.anatomical_structure, Endocrinology, Phenotype, Liver, medicine.symptom, Insulin Resistance, Abscisic Acid
Abstract: Abscisic acid (ABA) is a natural phytohormone and peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that significantly improves insulin sensitivity in db/db mice. Although it has become clear that obesity is associated with macrophage infiltration into white adipose tissue (WAT), the phenotype of adipose tissue macrophages (ATMs) and the mechanisms by which insulin-sensitizing compounds modulate their infiltration remain unknown. We used a loss-of-function approach to investigate whether ABA ameliorates insulin resistance through a mechanism dependent on immune cell PPARgamma. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80(hi) ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80(lo) ATMs. ABA significantly decreased CCR2(+) F4/80(hi) infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARgamma in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80(hi) ATMs into WAT, to repress WAT MCP-1 expression and to improve glucose tolerance. We provide molecular evidence in vivo demonstrating that ABA improves insulin sensitivity and obesity-related inflammation by inhibiting MCP-1 expression and F4/80(hi) ATM infiltration through a PPARgamma-dependent mechanism.
Published: 2006

49. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author: S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. Obrosova, J Fruchart, M Ilic, Björn Eliasson, Gilles Chatellier, M A Martín, D M Kendall, Holger Luthman, V F Varillas, D Maccubbin, Jang S-A., Amalia Gastaldelli, E Salzsieder, P. de Mol, A Yoshida, H D Lindner, D Gostiljac, M Just, Pan C-Y., J M Fujitaki, G Eiermann, K Bergenheim, A D Frick, A Agacdiken, K Varytimiadis, K Cseh, D A Jackson, S Calderari, Dena G. Hernandez, H M Liebich, K Min, F. de Zegher, Bernd Kulzer, K Han, Ulrich A. Müller, D Marrero, H Hatakeyama, René Koopman, Doo H-K., Petr Wohl, P. Sharp, P Forder, Thor Aspelund, N Meneveau, R M Schmülling, R Aubert, Thom Sam., H Youshikawa, M Ankelo, D Bowden, I Kelly, Frédéric Fumeron, M Sartini, Robert S. Sherwin, L Varadhan, A Criscimanna, John Betteridge, V Jelic, M Bartnik, N Lemke, B Ursø, A Bertoldo, A M Owona, H Okochi, L Pérez-Tamajó, S L Monfre, Daniel Brandhorst, K T Legg, Andries J. Smit, Veronica Sancho, Masashi Hirai, C Klein, Paul J. Thornalley, A Chaidaroglou, K Miura, B Zinman, O M Dvoynishnikova, J Plank, Jan Bolinder, C Lush, B Rubi, R Pozzilli, M Bashir, S A Shtandel, F Mosca, A Naskalska, Josef Vcelak, U Sausbier, P Cavaiani, T U Baehring, Michele Solimena, P Formisano, M Rastaldi, Bernard Thorens, J Ruzzin, E Arbit, M. Hori, Torkel B. Brismar, E Soltes Rak, A Filo, P Heinke, Matthew P. Coghlan, M Masotti, I Perevozskaya, K Ahn, I Moules, K Van Dyck, I Goldstein, Z Mathe, G Z Zhao, S Fajardo, J Taylor, S Chrul, J C Pareja, D Hadjidakis, A J Scheen, N Siddiqua, D C Cavan, R Grella, Krabbe S, H J Rochlitz, A E Hinkkanen, W Wilpshaar, Richard Stevens, M Dreyer, S Hara, X Wang, Melania Manco, D Gillen, Magalie A. Ravier, Olli Simell, John C. Lawrence, Kohnert K-D., Agardh C-D., A Berghold, L Kristensen, Grant Sfa., N Gursoy, Leif Groop, N Freemantle, Anja Schweizer, L Pala, Legros J-J., C. Di Pietro, N. Yamamoto, J Magyar, B Nikolovski, H Ikeda, D Lee, Bruce A. 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Lyu, G Rizzo, V V Bogomolov, N Krasova, G M McGuire, Tina Parkner, A Timi, Johann Bauersachs, S Foussas, S A Schreiber, T Monauni, Schwarz Peh., Allenberg, J D Lee, S Dewan, Y G Zheng, D Carroll, E Sarti, C Wollheim, Anna Kaminski, C Menneila, P Bucher, Xu Jyu., Vincent Rigalleau, A Schöpfer, Hans Jörnvall, A Ben Drief, X Jeunemaitre, E Schuster, Chan Slf., S Bilgic, J Coverly, K Szafraniec, Stalenhoef Afh., H Bergert, David I. W. Phillips, J Maksimovic Pavlovic, Sergio E. Starkstein, E Chaim, T Lehmann-Lintz, P Salacone, Tim Armstrong, Ingrid Klöting, C M Frampton, Franco Cavalot, A.K.Azad Khan, H Rose, Marta Letizia Hribal, Jette Kolding Kristensen, H Gröbe, M Nishi, A Vanderplas, Howlett Hsc., L E Bowen, R Malik, A Wu, Charles C. Richardson, Y Li, P G McNally, Yoon K-H., A Baleydier, M J Murphy, P. M. Nilsson, U Lindblad, Sten Madsbad, T Bíró, Riitta Veijola, Charlotte Glümer, Assunta Pandolfi, Lydia Aguilar-Bryan, M Namba, C Franzen, S Lopatriello, David Russel Jones, S. 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Jeffcoate, J Pariès, K Huoponen, Anne Jörns, G Shanmugam, A Tsiavou, S Yoshida, Kim M-J., Annapaula Giulietti, S Paillasson, K Tsuchiya, Divyen K Shah, P Saar, S S Juarez, Stefanie Maxion-Bergemann, J Briody, V Schmitz, C M Pena, J Fernádez-Real, S Naruse, M Kalis, A P Klimenko, X H Chen, H.H. Lervang, G Bock, Mirja Tiikkainen, J Potockova, N Pekcanli, George Dragicevic, Timothy M. Rose, David C. Goff, H Komori, V Vasseur-Delannoy, S Hanley, P Hajos, C W Ahn, Matsuoka T-A., J Burns, Petar M. Seferovic, Yuki Kita, K Lyons, K Kohri, Eleftheria Zeggini, Y Ding, G Belcher, Steven V. Edelman, N Dinççaǧ, Christopher J. Rhodes, Manders Rjf., S Giveon, Dario Iafusco, L Li, M C Ribaudo, Kang S-K., Laurie J. Goodyear, L Martinez, C Vermigli, H Dabire, R Raymond, J de Haan, Christopher J. Groves, Å Norberg, H Jahr, M Gloster, Christopher D. 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Leon, Alberti Gkm., A Opel, S Kokkoris, S B Hong, Philippe Courtois, L Haque, Maria Sörhede Winzell, M C Beauvois, A Szypowska, D Yu, M Gutniak, D Petzinna, B Isomaa, K S Prickett, Maria Felice Brizzi, Pavel Hamet, P J Hammond, K. F. Michelmore, Yumie Takeshita, N Hariharan, Corrado M. Cilio, G Pogatsa, W G Jerome, E Bartley, K Schlembacher, G Blohmó, Guy A. Rutter, Kyung Mook Choi, S. C Tamer, Felix K. Assah, K A Jandeleit-Dahm, M Chan, H Darius, Jørgen F. P. Wojtaszewski, A Papazisi, M Amaya, A Knopff, M Tadayyon, I J Kim, W Russ, T Myrnäs, M. Tryon, S Poonsatha, Noel Cameron, Kim M-H., Alejandra Tomas, F Homo-Dekarche, G. Di Cianni, M Stotzka, C Solimine, Mikhail Borisovich Antsiferov, H Naserke, M Bianchi-Biscay, J I Lara, Moon C-K., Alain Ktorza, Alison N. Jeffery, V Lilla, Eun Seok Kang, Hanley Ajg., J Widder, R Ratner, C Goretti, P J Weston, J Perkins, V Rasmussen, M Evans, T M Gibson, A Jaffe, S I Chisalita, C Owman, L Hiltunen, E Kakishita, C M Mack, H C Potter, M Femerling, M Desai, M Soinio, K Yang, Patricia L. Brubaker, M Meyer, V Dy, J Berden, R Komers, Milos Adamec, R Petzoldt, Alan G. Robinson, R Stevens, A Doi, A Leunda, Eduard Montanya, Alessandra K Cardozo, N Kraenkel, Claudio Cobelli, U A Mueller, S Yamashiro, B R Gedulin, G Francisco, J Dennenmoser, Lesch K-P., Martin G. Bischof, M Ichita, C Fernandes, Jochen Hampe, S Kern, D Kelly, E Zeender, P Perna, J D Best, A C Calkin, Vivian Fonseca, J Prestle, D G Parkes, Satish K. Garg, T Burrell, B M Fischer, D Kruger, J S Skinner, Lin T-M., Jozef Ukropec, Maria Jeziorska, K Arii, David D. D’Alessio, M B Gomes, L Quandt, I Fragaki, M C Brindisi, A Gladkih, E Kitsou, S Di Cola, T Iwasaki, Peter Diem, T Lakka, V V Popova, G Lee, Hannah J. 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Cavanagh, Allen Taylor, M Balabolkin, G Schreier, E Stern, J Lips, V Serban, G Sparacino, Roser Casamitjana, Aine McKillop, I Groza, E Bernal, Kathleen M Gillespie, T Ledet, A Garzaniti, F Hawkins, K M Tushaus, C Renaudin, Christina Maier, A Dormi, A Ubertalli, Inge Tetens, M Ostojic, E Pierre-Justin, A Bhushan, E Ur, L I Jeltova, Tilo Moede, E Tibiriça, Zoran Gucev, Knoch K-P., G Pizzolanti, A M Şengül, T P Degenhardt, Cristina Lencioni, M Fitchet, E Santini, E Devangelio, C Panaite, Y I Karachentsev, S B Solerte, Christos Manes, M Lipka, C H Teng, P Mrak, G Fegan, R C Milton, M Negrean, Astrid Plamboeck, L Patti, M Houk, Ritva Kauppinen-Mäkelin, Christoph F Ebenbichler, O Sysoyeva, Frantisek Saudek, H Wysocki, Robert A. Rizza, J Altirriba, Bjørn Richelsen, L. Lam, Rémy Burcelin, A Antsaklis, G Galimberti, R. de Vries, A Lewin, Marcia A. 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Vingrys, S Habu, Mariella Trovati, H Sobajima, Pierre Lecomte, Kim T-H., D Virsaladze, M Oprean, F Pullen, A Rußmann, G J Bruining, Martina Düfer, Wen Xu, Min Y-K., Norman E Cameron, Gianfranco Pagano, K Harley, M Su, J P Le Berre, Sian Ellard, S Howard, D Russell-Jones, Z Li, S Carpenter, E L Thomas, W Tang, Lee M-S., N Ubrich, M. M. McMahon, G Vassilikos, N Brossa, M S Joergensen, S Smith, A Vania, Y Laurent, S Basir, A Freudenthaler, Sally M. Marshall, D Niedermayer, V I Pankiv, J Mentel, S Pruna, J M Pou Torelló, Y Ito, G Chrysos, Werner Kramer, Hironori Yamasaki, L Bowman, F Palumbo, P Ruth, G Lankas, Z H Liao, D Park, W Otter, C Montrone, Sevasti Zervou, Jennifer L. Wilkinson-Berka, Bo Feldt-Rasmussen, I Banu, Paolo Sbraccia, Bani Mukhopadhyay, Mark E. Cooper, M Kidron, Pål R. Njølstad, A M Jonsdottir, M R Burge, G Valpiani, Yutaka Oiso, David J. 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Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, EASD, Endocrinology, Diabetes and Metabolism, Human physiology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Family medicine, Internal Medicine, Medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2004

50. Role of the global transcriptional regulators, BRG1 and Brm, in the glucocorticoid induced -phenotypic reversion of ST1 cells

Author: Mari Cleide Sogayar, Fernanda Ortis, Mari Cleide Sogayar, Roger Chammas, José Franco da Silveira Filho, Eugenia Costanzi Strauss, and Luísa Lina Villa
Abstract: Os hormônios glicocorticóides (GCs) têm sido amplamente empregados como agentes antiinflamatórios e anti-tumorais. Sua ação ocorre via receptores nucleares (GR) sendo dependente da remodelação da estrutura da cromatina. As proteínas Brm e BRG1, componentes essenciais de um complexo regulador global da transcrição (SWI/SNF), por remodelamento da cromatina, exercem um papel-chave na ação de GR. Para estudar o mecanismo de ação de GCs, foram utilizadas as linhagens celulares ST1 e P7, derivadas da linhagem celular C6, de glioma de rato. P7 é insensível ao tratamento com GC, enquanto ST1 apresenta reversão fenotípica tumoral→normal, gerando um bloqueio específico na fase G1. Um anti-soro policlonal específico para Brm e BRG1, foi gerado através da inoculaçâo de coelha com a proteína hBRG1 recombinante. Este antisoro foi utilizado para análisar os níveis destas proteínas nas duas linhagens celulares, sob ação de GC. Enquanto em ST1, Brm é induzida por GC, em células P7, o nível basal de Brm é relativamente alto, mantendo-se inalterado na presença de GC. A possíbilidade de existirem mutações no gene brm de células P7, foi investigada através de amplificação do DNA, por PCR, e seqüenciamento. A superexpressão de brm e BRG1 em células P7 mostrou que clones isolados apresentavam, de um modo geral, achatamento celular, diminuição da taxa de crescimento e da eficiência de plaqueamento em substrato sólido e semi-sólido. Alguns destes clones passaram a responder ao tratamento com GC, porém não tão drasticamente como as células ST1. Co-imunonoprecipitação mostrou algumas diferenças entre os complexos SWI/SNF de células ST1 e P7. Glucocorticoid hormones (GCs) have been used as anti-inflammatory and anti-tumor agents, acting via nuclear receptors (GR) and being dependent on remodeling of the chromatin structure. As components of the global chromatin remodeling transcription complex (SWI/SNF), Brm and BRG-1 proteins play a key role in the action of GR. In order to study the mechanisms of action of GCs, we have been using the ST1 and P7 cell lines, derived from the C6, a rat glioma cell line. P7 is insensitive to the GC treatment, while ST1 displays a complete phenotypic reversion from tumoral to normal, including a G1-specific block in the cell cycle. A Brm and BRG1-specific polyclonal antiserum was generated, in rabbit, using recombinant hBRG1 protein as antigen. This antiserum was used to analyze the levels of Brm and BRG1 in these two cell lines, under GC treatment. While Brm is induced by GC, in ST1 cells, the basal level of Brm, in P7 cells, is relatively high, remaining unchanged under GC treatment. The possibility of brm mutations occurring in the P7 cells, was analyzed by DNA sequencing. Overexpression of brm and BRG1 in P7 cells led to morphological alterations (cell flattening) and decreased colony formation in agarose suspension and in solid substrate. Some of these clones became partially responsive to GC, when compared to the ST1 cell line. Co-immunoprecipitation assays revealed some differences in the SWI/SNF complex between ST1 and P7 cells.
Published: 2002

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