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Cytokines and pancreatic beta cell damage

Joselyn Rojas, Valmore Bermudez, Jim Palmar, María Sofía Martínez, Luis Carlos Olivar, Manuel Nava, Daniel Tomey, Milagros Rojas, Juan Salazar, Carlos Garicano, Manuel Velasco
Purpose of Review: Describing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. Recent Findings: Beta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus...
2018: Journal of Diabetes Research
Eiji Yamato
OBJECTIVE: Histone deacytylase inhibitors (HDACis) inhibit the deacetylation of the lysine residue of proteins, including histones, and regulate the transcription of a variety of genes. Recently, HDACis have been used clinically as anti-cancer drugs and possible anti-diabetic drugs. Even though HDACis have been proven to protect the cytokine-induced damage of pancreatic beta cells, evidence also shows that high doses of HDACis are cytotoxic. In the present study, we, therefore, investigated the eff ect of HDACis on insulin secretion in a pancreatic beta cell line...
January 1, 2018: Endocrine Regulations
L Alberto Llacua, Marijke M Faas, Paul de Vos
Extracellular matrix (ECM) molecules are responsible for structural and biochemical support, as well as for regulation of molecular signalling and tissue repair in many organ structures, including the pancreas. In pancreatic islets, collagen type IV and VI, and laminins are the most abundant molecules, but other ECM molecules are also present. The ECM interacts with specific combinations of integrin α/β heterodimers on islet cells and guides many cellular processes. More specifically, some ECM molecules are involved in beta cell survival, function and insulin production, while others can fine tune the susceptibility of islet cells to cytokines...
January 6, 2018: Diabetologia
Kathleen Waugh, Janet Snell-Bergeon, Aaron Michels, Fran Dong, Andrea K Steck, Brigitte I Frohnert, Jill M Norris, Marian Rewers
BACKGROUND: Type 1 diabetes (TID) is characterized by a loss of pancreatic islet beta cell function resulting in loss of insulin production. Genetic and environmental factors may trigger immune responses targeting beta cells thus generating islet antibodies (IA). Immune response pathways involve a cascade of events, initiated by cytokines and chemokines, producing inflammation which can result in tissue damage. METHODS: A nested case-control study was performed to identify temporal changes in cytokine levels in 75 DAISY subjects: 25 diagnosed T1D, 25 persistent IA, and 25 controls...
2017: PloS One
Dornadula Sireesh, Munuswamy-Ramanujam Ganesh, Umapathy Dhamodharan, Murugesan Sakthivadivel, Srinivasan Sivasubramanian, Palani Gunasekaran, Kunka Mohanram Ramkumar
Nrf2 (nuclear factor erythroid 2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress response and also suppress inflammation. Nrf2 signaling is associated with an increased susceptibility to various kinds of stress. Nrf2 has been shown as a promising therapeutic target in various human diseases including diabetes. Our earlier studies showed Pterostilbene (PTS) as a potent Nrf2 activator, and it protects the pancreatic β-cells against oxidative stress. In this study, we investigated PTS confer protection against cytokine-induced β-cell apoptosis and its role on insulin secretion in streptozotocin (STZ)-induced diabetic mice...
June 2017: Journal of Nutritional Biochemistry
Sridhar M Reddy, Pooja M Reddy, Nitin Amdare, Vishal Khatri, Aaditya Tarnekar, Kalyan Goswami, Maryada Venkata Rami Reddy
Type 1 diabetes (T1D) that accounts for about 5-10 % of all diabetes cases results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. It is characterized by severe inflammatory reaction mediated by pronounced T helper type-1 response. Parasitic infections having the ability to skew the host immune responses towards type-2 type as a part of their defense mechanism are able to induce protection against autoimmune diseases like T1D. Hence, the present study is undertaken to explore a recombinant abundant larval transcript protein of the human lymphatic filarial parasite Brugia malayi ( rBm ALT-2), a known anti-inflammatory molecule for its therapeutic effect on streptozotocin (STZ)-induced T1D in mice...
March 2017: Indian Journal of Clinical Biochemistry: IJCB
Craig S Nunemaker
Proinflammatory cytokines have been implicated in the pathophysiology of both type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D is an autoimmune disease involving the adaptive immune system responding to pancreatic beta-cells as antigen-presenting cells. This attracts immune cells that surround pancreatic islets (insulitis) and secrete cytokines, such as IL-1beta, IFN-gamma, and TNF-alpha, in close proximity to pancreatic beta-cells. In contrast, there is little evidence for such a focused autoimmune response in T2D...
2016: Journal of Diabetes Research
Steffi Bosch, Laurence de Beaurepaire, Marie Allard, Mathilde Mosser, Claire Heichette, Denis Chrétien, Dominique Jegou, Jean-Marie Bach
Exosomes are important mediators in intercellular communication. Released by many cell types, they transport proteins, lipids, and nucleic acids to distant recipient cells and contribute to important physiopathological processes. Standard current exosome isolation methods based on differential centrifugation protocols tend to induce aggregation of particles in highly concentrated suspensions and freezing of exosomes can induce damage and inconsistent biological activity. Trehalose is a natural, non-toxic sugar widely used as a protein stabilizer and cryoprotectant by the food and drug industry...
November 8, 2016: Scientific Reports
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
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