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Cytokines and pancreatic beta cell damage

Pengfei Xu, Yingjie Zhang, Xinghao Jiang, Junyan Li, Liying Song, Mir Hasson Khoso, Yunye Liu, Qiang Wu, Guiping Ren, Deshan Li
Diabetes mellitus is a common endocrinopathy in dog. Fibroblast growth factor 21 (FGF-21) is a secreted protein, which is involved in glucose homeostasis. We speculate that the recombinant canine FGF-21 (cFGF-21) has the potential to become a powerful therapeutics to treat canine diabetes. The cFGF-21 gene was cloned and expressed in E. coli Rosetta (DE3). After purification, a cFGF-21 protein with the purity exceeding 95% was obtained. Mouse 3T3-L1 adipocytes and type 1 diabetic mice/dogs induced by STZ were used to examine the biological activity of cFGF-21 in vitro and in vivo, respectively...
2016: PloS One
Flora Brozzi, Tarlliza R Nardelli, Miguel Lopes, Isabelle Millard, Jenny Barthson, Mariana Igoillo-Esteve, Fabio A Grieco, Olatz Villate, Joana M Oliveira, Marina Casimir, Marco Bugliani, Feyza Engin, Gökhan S Hotamisligil, Piero Marchetti, Decio L Eizirik
AIMS/HYPOTHESIS: Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokine-induced ER stress involves NO production and consequent inhibition of the ER Ca(2+) transporting ATPase sarco/endoplasmic reticulum Ca(2+) pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field...
October 2015: Diabetologia
Bryndon J Oleson, Jennifer A McGraw, Katarzyna A Broniowska, Mani Annamalai, Jing Chen, Justin R Bushkofsky, Dawn B Davis, John A Corbett, Clayton E Mathews
While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets...
September 2015: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
L Yu, J F Chen, X Shuai, Y Xu, Y Ding, J Zhang, W Yang, X Liang, D Su, C Yan
AIM: Artesunate (ART) has been known as the most effective and safe reagents to treat malaria for many years. In this study, we explored whether ART could protect pancreatic beta-cell against cytokine-induced damage. MATERIALS AND METHODS: The production of nitrite (NO) was detected with the Griess Assay Kit. SIRT1 and inducible nitric oxide synthase (iNOS) expression were determined with Western blot. The transcriptional activity of NF-κB was evaluated by luciferase reporter assay...
January 2016: Journal of Endocrinological Investigation
S Hubackova, A Kucerova, G Michlits, L Kyjacova, M Reinis, O Korolov, J Bartek, Z Hodny
Cellular senescence provides a biological barrier against tumor progression, often associated with oncogene-induced replication and/or oxidative stress, cytokine production and DNA damage response (DDR), leading to persistent cell-cycle arrest. While cytokines such as tumor necrosis factor-alpha (TNFα) and interferon gamma (IFNγ) are important components of senescence-associated secretome and induce senescence in, for example, mouse pancreatic β-cancer cell model, their downstream signaling pathway(s) and links with oxidative stress and DDR are mechanistically unclear...
March 10, 2016: Oncogene
Ying Ding, Yuemei Xu, Xuanyu Shuai, Xuhui Shi, Xiang Chen, Wenbin Huang, Yun Liu, Xiubin Liang, Zhihong Zhang, Dongming Su
The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure that may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3 alpha (Reg3α) is a pancreatic secretory protein, which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice...
December 17, 2014: Molecular Medicine
David A Taylor-Fishwick, Jessica Weaver, Lindsey Glenn, Norine Kuhn, Ganesha Rai, Ajit Jadhav, Anton Simeonov, Angela Dudda, Dieter Schmoll, Theodore R Holman, David J Maloney, Jerry L Nadler
AIMS/HYPOTHESIS: Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. METHODS: Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors...
March 2015: Diabetologia
Apolline Salama, Nolwenn Fichou, Marie Allard, Laurence Dubreil, Laurence De Beaurepaire, Alexis Viel, Dominique Jégou, Steffi Bösch, Jean-Marie Bach
In addition to important regulatory roles in gene expression through RNA interference, it has recently been shown that microRNAs display immune stimulatory effects through direct interaction with receptors of innate immunity of the Toll-like receptor family, aggravating neuronal damage and tumour growth. Yet no evidence exists on consequences of microRNA immune stimulatory actions in the context of an autoimmune disease. Using microRNA analogues, we here show that pancreatic beta cell-derived microRNA sequences induce pro-inflammatory (TNFa, IFNa, IL-12, IL-6) or suppressive (IL-10) cytokine secretion by primary mouse dendritic cells in a sequence-dependent manner...
2014: PloS One
Mattias S Dahllöf, Dan P Christensen, Mette Harving, Bridget K Wagner, Thomas Mandrup-Poulsen, Morten Lundh
Histone deacetylase (HDAC) inhibition protects pancreatic beta-cells against apoptosis induced by the combination of the proinflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ. Decreased expression of cell damage-related genes is observed on the transcriptional level upon HDAC inhibition using either IL-1β or IFN-γ alone. Whereas HDAC inhibition has been shown to regulate NFκB-activity, related primarily to IL-1β signaling, it is unknown whether the inhibition of HDACs affect IFN-γ signaling in beta-cells...
January 2015: Journal of Interferon & Cytokine Research
Mazhar A Kanak, Morihito Takita, Faisal Kunnathodi, Michael C Lawrence, Marlon F Levy, Bashoo Naziruddin
Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation...
2014: International Journal of Endocrinology
S S Kim, H J Jang, M Y Oh, D W Eom, K S Kang, Y J Kim, J H Lee, J Y Ham, S Y Choi, Y M Wee, Y H Kim, D J Han
BACKGROUND: The transplantation of isolated islets is thought to be an attractive approach for curative treatment of diabetes mellitus. Panax ginseng has been used in oriental countries for its pharmacologic effects, such as antidiabetic and antiinflammatory activities. 20(S)-ginsenoside Rg3 (Rg3), an active ingredient of ginseng saponins, has been reported to enhance insulin secretion-stimulating and antiapoptotic activities in pancreatic beta cells. We performed this study to examine the hypothesis that preoperative Rg3 administration can enhance islet cell function and antiapoptosis before islet transplantation...
May 2014: Transplantation Proceedings
Dong-Sung Lee, Gil-Saeng Jeong
Cudratricusxanthone A (CTXA) has an isoprenylated xanthone skeleton that is known to exert a variety of biological activities, including anti-inflammatory, neuroprotective, hepatoprotective, anti-proliferative, and mono-amine oxidase inhibitory effects. In this study, we investigated the effect of CTXA on IL-1β (5 ng/ml) and IFN-γ (100 U/ml)-induced β-cell damage. Pre-treatment with CTXA increased the viability and reactive oxygen species (ROS) inhibition of cytokine-treated RINm5F cells at concentrations of 1-10 μM...
July 2014: International Immunopharmacology
Sophie Calderari, Jean-Claude Irminger, Marie-Hélène Giroix, Jan A Ehses, Marie-Noëlle Gangnerau, Josiane Coulaud, Katharina Rickenbach, Dominique Gauguier, Philippe Halban, Patricia Serradas, Françoise Homo-Delarche
Regenerating (REG) proteins are associated with islet development, β-cell damage, diabetes and pancreatitis. Particularly, REG-1 and REG-3-beta are involved in cell growth/survival and/or inflammation and the Reg1 promoter contains interleukin-6 (IL-6)-responsive elements. We showed by transcriptome analysis that islets of Goto-Kakizaki (GK) rats, a model of spontaneous type 2 diabetes, overexpress Reg1, 3α, 3β and 3γ, vs Wistar islets. Goto-Kakizaki rat islets also exhibit increased cytokine/chemokine expression/release, particularly IL-6...
2014: PloS One
Srividya Vasu, Neville H McClenaghan, Jane T McCluskey, Peter R Flatt
BACKGROUND: Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line, 1.1B4, after exposure to proinflammatory cytokines - IL-1β, IFN-γ, TNF-α. METHODS: MTT assay, insulin radioimmunoassay, glucokinase assay, real time reverse transcription PCR, western blotting, nitrite assay, caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity. RESULTS: Viability of 1.1B4 cells decreased after 18h cytokine exposure...
January 2014: Biochimica et Biophysica Acta
Rong Zhou, Xingang Yao, Xing Xu, Gaihong Wang, Zhiyuan Zhu, Jing Chen, Lili Chen, Xu Shen
The progesterone receptor (PR), a member of nuclear receptor superfamily, is closely associated with gestational, type 1 and type 2 diabetes. However, the underlying mechanisms remain obscure. Here we found that PR activation increased the pro-inflammatory cytokines (PIC)-induced injury in Min6 cells, and PR blockage with siRNA interference protected the cells from damage. Moreover, the new discovered PR antagonist SC51089 effectively improved cell survival by reducing the PIC-stimulated cell apoptosis in Min6 cells...
October 2013: Steroids
K Goosse, T Bouckenooghe, G Sisino, S Aurientis, C Remacle, B Reusens
BACKGROUND: Epidemiological studies related poor maternal nutrition and subsequent growth retardation in the progeny to the development of diabetes later in life. Low-protein diet during gestation altered the beta-cell development of the rat progeny by decreasing beta-cell proliferation and increasing their sensitivity to nitric oxide and cytokines in the foetus. This disturbed maternal environment had long-lasting consequences because the higher beta-cell vulnerability was maintained at adulthood...
January 2014: Acta Physiologica
Meghan M Delmastro-Greenwood, Hubert M Tse, Jon D Piganelli
SIGNIFICANCE: High levels of reactive oxygen species can facilitate DNA and protein damage beyond the control of endogenous antioxidants, resulting in oxidative stress. Oxidative stress then triggers inflammation, which can lead to pathological conditions. In genetically susceptible individuals, the conglomeration of oxidative stress and inflammation can enhance autoreactive immune cell activation, causing beta-cell destruction in autoimmune type 1 diabetes. As a means of shielding pancreatic islets, manganese porphyrin (MnP) oxidoreductant treatment has been tested in a number of reported studies...
May 20, 2014: Antioxidants & Redox Signaling
Ilaria Capua, Alessia Mercalli, Matteo S Pizzuto, Aurora Romero-Tejeda, Samantha Kasloff, Cristian De Battisti, Francesco Bonfante, Livia V Patrono, Elisa Vicenzi, Valentina Zappulli, Vito Lampasona, Annalisa Stefani, Claudio Doglioni, Calogero Terregino, Giovanni Cattoli, Lorenzo Piemonti
Influenza A viruses commonly cause pancreatitis in naturally and experimentally infected animals. In this study, we report the results of in vivo investigations carried out to establish whether influenza virus infection could cause metabolic disorders linked to pancreatic infection. In addition, in vitro tests in human pancreatic islets and in human pancreatic cell lines were performed to evaluate viral growth and cell damage. Infection of an avian model with two low-pathogenicity avian influenza isolates caused pancreatic damage resulting in hyperlipasemia in over 50% of subjects, which evolved into hyperglycemia and subsequently diabetes...
January 2013: Journal of Virology
Gitta M Seleznik, Theresia Reding, Franziska Romrig, Yasuyuki Saito, Alexander Mildner, Stephan Segerer, Li-Kang Sun, Stephan Regenass, Maciej Lech, Hans-Joachim Anders, Donal McHugh, Teru Kumagi, Yoichi Hiasa, Carolin Lackner, Johannes Haybaeck, Eliane Angst, Aurel Perren, Maria Luisa Balmer, Emma Slack, Andrew MacPherson, Markus G Manz, Achim Weber, Jeffrey L Browning, Melek Canan Arkan, Thomas Rülicke, Adriano Aguzzi, Marco Prinz, Rolf Graf, Mathias Heikenwalder
BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. METHODS: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP...
November 2012: Gastroenterology
M Lundh, D P Christensen, M Damgaard Nielsen, S J Richardson, M S Dahllöf, T Skovgaard, J Berthelsen, C A Dinarello, A Stevenazzi, P Mascagni, L G Grunnet, N G Morgan, T Mandrup-Poulsen
AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi...
September 2012: Diabetologia
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