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https://www.readbyqxmd.com/read/28793244/rho-associated-kinases-and-non-muscle-myosin-iis-inhibit-the-differentiation-of-human-ipscs-to-pancreatic-endoderm
#1
Taro Toyoda, Azuma Kimura, Hiromi Tanaka, Tomonaga Ameku, Atsushi Mima, Yurie Hirose, Masahiro Nakamura, Akira Watanabe, Kenji Osafune
There has been increasing success with the generation of pancreatic cells from human induced pluripotent stem cells (hiPSCs); however, the molecular mechanisms of the differentiation remain elusive. The purpose of this study was to reveal novel molecular mechanisms for differentiation to PDX1(+)NKX6.1(+) pancreatic endoderm cells, which are pancreatic committed progenitor cells. PDX1(+) posterior foregut cells differentiated from hiPSCs failed to differentiate into pancreatic endoderm cells at low cell density, but Rho-associated kinase (ROCK) or non-muscle myosin II (NM II) inhibitors rescued the differentiation potential...
August 8, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28790184/adiponectin-protects-against-development-of-metabolic-disturbances-in-a-pcos-mouse-model
#2
Anna Benrick, Belén Chanclón, Peter Micallef, Yanling Wu, Laila Hadi, John M Shelton, Elisabet Stener-Victorin, Ingrid Wernstedt Asterholm
Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits...
August 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28774890/mir-338-controls-bpa-triggered-pancreatic-islets-insulin-secretory-dysfunction-from-compensation-to-decompensation-by-targeting-pdx-1
#3
Jie Wei, Dongxiao Ding, Tao Wang, Qiong Liu, Yi Lin
Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/day) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 (Pdx1) expression in mice...
August 3, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28765528/pdx1-cre-driven-conditional-gene-depletion-suggests-pak4-as-dispensable-for-mouse-pancreas-development
#4
Miao Zhao, Parisa Rabieifar, Tânia D F Costa, Ting Zhuang, Audrey Minden, Matthias Löhr, Rainer Heuchel, Staffan Strömblad
Constitutive depletion of p21-activated kinase 4 (PAK4) in the mouse causes embryonic lethality associated with heart and brain defects. Given that conventional gene depletion of PAK1 or PAK3 caused functional deficits in the mouse pancreas, while gene depletion of PAK5 or PAK6 did not, we asked if PAK4 might have a functional role in pancreas development. We therefore introduced conditional, Pdx1-Cre-mediated, pancreatic PAK4 gene depletion in the mouse, verified by loss of PAK4 protein expression in the pancreas...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28765173/a2a-adenosine-receptors-control-pancreatic-dysfunction-in-high-fat-diet-induced-obesity
#5
Balázs Csóka, Gábor Törő, Joana Vindeirinho, Zoltán V Varga, Balázs Koscsó, Zoltán H Németh, Endre Kókai, Luca Antonioli, Mara Suleiman, Piero Marchetti, Karolina Cseri, Ádám Deák, László Virág, Pál Pacher, Péter Bai, György Haskó
Adenosine, a key extracellular signaling mediator, regulates several aspects of metabolism by activating 4 G protein-coupled receptors, the A1, A2A, A2B, and A3 adenosine receptors (ARs). The role of A2AARs in regulating high-fat-diet (HFD)-induced metabolic derangements is unknown. To evaluate the role of A2AARs in regulating glucose and insulin homeostasis in obesity, we fed A2AAR knockout (KO) and control mice an HFD for 16 wk to initiate HFD-induced metabolic disorder. We found that genetic deletion of A2AARs caused impaired glucose tolerance in mice fed an HFD...
August 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28764929/inhibition-of-aurora-kinase-a-induces-necroptosis-in-pancreatic-carcinoma
#6
Yangchun Xie, Shan Zhu, Meizuo Zhong, Minghua Yang, Xiaofan Sun, Jinbao Liu, Guido Kroemer, Michael Lotze, Herbert J Zeh, Rui Kang, Daolin Tang
BACKGROUND & AIMS: Induction of non-apoptotic cell death could be an approach to eliminate apoptosis-resistant tumors. We investigated necroptosis-based therapies in mouse models of pancreatic ductal adenocarcinoma cancer (PDAC). METHODS: We screened 273 commercially available kinase inhibitors for cytotoxicity against a human PDAC cell line (PANC1). We evaluated the ability of the aurora kinase inhibitor CCT137690 to stimulate necroptosis in PDAC cell lines (PANC1, PANC2...
July 29, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28753672/an-increase-in-immature-%C3%AE-cells-lacking-glut2-precedes-the-expansion-of-%C3%AE-cell-mass-in-the-pregnant-mouse
#7
Christine A Beamish, Linhao Zhang, Sandra K Szlapinski, Brenda J Strutt, David J Hill
A compensatory increase in β-cell mass occurs during pregnancy to counter the associated insulin resistance, and a failure in adaptation is thought to contribute to gestational diabetes. Insulin-expressing but glucose-transporter-2-low (Ins+Glut2LO) progenitor cells are present in mouse and human pancreas, being predominantly located in extra-islet β-cell clusters, and contribute to the regeneration of the endocrine pancreas following induced ablation. We therefore sought to investigate the contribution of Ins+Glut2LO cells to β-cell mass expansion during pregnancy...
2017: PloS One
https://www.readbyqxmd.com/read/28739109/generation-of-glucose-sensitive-insulin-secreting-beta-like-cells-from-human-embryonic-stem-cells-by-incorporating-a-synthetic-lineage-control-network
#8
Pratik Saxena, Daniel Bojar, Henryk Zulewski, Martin Fussenegger
We previously reported novel technology to differentiate induced pluripotent stem cells (IPSCs) into glucose-sensitive insulin-secreting beta-like cells by engineering a synthetic lineage-control network regulated by the licensed food additive vanillic acid. This genetic network was able to program intricate expression dynamics of the key transcription factors Ngn3 (neurogenin 3, OFF-ON-OFF), Pdx1 (pancreatic and duodenal homeobox 1, ON-OFF-ON) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A, OFF-ON) to guide the differentiation of IPSC-derived pancreatic progenitor cells to beta-like cells...
July 21, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/28738823/metformin-suppresses-cancer-initiation-and-progression-in-genetic-mouse-models-of-pancreatic-cancer
#9
Ke Chen, Weikun Qian, Zhengdong Jiang, Liang Cheng, Jie Li, Liankang Sun, Cancan Zhou, Luping Gao, Meng Lei, Bin Yan, Junyu Cao, Wanxing Duan, Qingyong Ma
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer...
July 24, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28738518/teucrium-polium-extract-reverses-symptoms-of-streptozotocin-induced-diabetes-in-rats-via-rebalancing-the-pdx1-and-foxo1-expressions
#10
Parvaneh Sadat Tabatabaie, Razieh Yazdanparast
BACKGROUND AND OBJECTIVE: Teucrium polium Lamiaceae. an antidiabetic traditional medicine was observed to stimulate insulin secretion and β-cell mass restoration in pancreatic of diabetic rats. Bioactive compounds in T. polium such as terpenoids and flavonoids have a wide range of antioxidant properties. Given this background, our research was aimed at probing the effective molecular mechanism of T. polium which in turn protects the pancreatic β-cells of diabetic rats through attenuation of streptozotocin-induced oxidative stress...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28727822/dna-methylation-of-candidate-genes-in-peripheral-blood-from-patients-with-type-2-diabetes-or-the-metabolic-syndrome
#11
Sanne D van Otterdijk, Alexandra M Binder, Katarzyna Szarc Vel Szic, Julia Schwald, Karin B Michels
INTRODUCTION: The prevalence of type 2 diabetes (T2D) and the metabolic syndrome (MetS) is increasing and several studies suggested an involvement of DNA methylation in the development of these metabolic diseases. This study was designed to investigate if differential DNA methylation in blood can function as a biomarker for T2D and/or MetS. METHODS: Pyrosequencing analyses were performed for the candidate genes KCNJ11, PPARγ, PDK4, KCNQ1, SCD1, PDX1, FTO and PEG3 in peripheral blood leukocytes (PBLs) from 25 patients diagnosed with only T2D, 9 patients diagnosed with T2D and MetS and 11 control subjects without any metabolic disorders...
2017: PloS One
https://www.readbyqxmd.com/read/28705881/defining-a-novel-role-for-the-pdx1-transcription-factor-in-islet-%C3%AE-cell-maturation-and-proliferation-during-weaning
#12
Jason M Spaeth, Manisha Gupte, Mark Perelis, Yu-Ping Yang, Holly Cyphert, Shuangli Guo, Jin-Hua Liu, Min Guo, Joseph Bass, Mark A Magnuson, Christopher Wright, Roland Stein
The transcription factor encoded by the Pancreas Duodenum Homeobox-1 (Pdx1) gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β cell development, and adult islet β cell function. Transgenic- and cell line-based experiments have identified 5'-flanking conserved sequences that control pancreatic and β cell-type-specific transcription, which are found within Area I (base pairs (bp) -2694 to -2561), II (bp -2139 to -1958), III (bp -1879 to -1799), and IV (bp -6200 to -5670)...
July 13, 2017: Diabetes
https://www.readbyqxmd.com/read/28702321/a-high-content-small-molecule-screen-identifies-novel-inducers-of-definitive-endoderm
#13
Alexander Korostylev, Pallavi U Mahaddalkar, Oliver Keminer, Kamyar Hadian, Kenji Schorpp, Philip Gribbon, Heiko Lickert
OBJECTIVES: Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can generate any given cell type in the human body. One challenge for cell-replacement therapy is the efficient differentiation and expansion of large quantities of progenitor cells from pluripotent stem cells produced under good manufacturing practice (GMP). FOXA2 and SOX17 double positive definitive endoderm (DE) progenitor cells can give rise to all endoderm-derived cell types in the thymus, thyroid, lung, pancreas, liver, and gastrointestinal tract...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28701182/do-we-really-need-to-differentiate-mesenchymal-stem-cells-into-insulin-producing-cells-for-attenuation-of-the-autoimmune-responses-in-type-1-diabetes-immunoprophylactic-effects-of-precursors-to-insulin-producing-cells
#14
Anshu Sharma, Rajni Rani
BACKGROUND: Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where pancreatic beta cells are lost before the clinical manifestations of the disease. Administration of mesenchymal stem cells (MSCs) or MSCs differentiated into insulin-producing cells (IPCs) have yielded limited success when used therapeutically. We have evaluated the immunoprophylactic potentials of precursors to insulin-producing cells (pIPCs) and IPCs in nonobese diabetic (NOD) mice to ask a basic question: do we need to differentiate MSCs into IPCs or will pIPCs suffice to attenuate autoimmune responses in T1D? METHODS: Bone marrow-derived MSCs from Balb/c mice were characterized following the International Society for Cellular Therapy (ISCT) guidelines...
July 12, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28697136/circulating-epithelial-cells-in-intraductal-papillary-mucinous-neoplasms-and-cystic-pancreatic-lesions
#15
Katherine E Poruk, Vicente Valero, Jin He, Nita Ahuja, John L Cameron, Matthew J Weiss, Anne Marie Lennon, Michael Goggins, Laura D Wood, Christopher L Wolfgang
OBJECTIVES: Circulating epithelial cells (CECs) are identified in the blood of patients with intraductal papillary mucinous neoplasms (IPMNs) despite the absence of malignancy. We assessed the blood of patients undergoing resection for IPMN or other benign pancreatic lesions for CECs. METHODS: Peripheral blood was collected from 26 patients prior to pancreatic resection and filtered by the ISET (Isolation by Size of Epithelial Tumor Cells) method. Circulating epithelial cells were identified with antibodies to cytokeratin and Pdx1 (pancreas and duodenal homeobox protein 1), a pancreas marker...
August 2017: Pancreas
https://www.readbyqxmd.com/read/28674003/genome-sequence-of-a-diabetes-prone-rodent-reveals-a-mutation-hotspot-around-the-parahox-gene-cluster
#16
Adam D Hargreaves, Long Zhou, Josef Christensen, Ferdinand Marlétaz, Shiping Liu, Fang Li, Peter Gildsig Jansen, Enrico Spiga, Matilde Thye Hansen, Signe Vendelbo Horn Pedersen, Shameek Biswas, Kyle Serikawa, Brian A Fox, William R Taylor, John Frederick Mulley, Guojie Zhang, R Scott Heller, Peter W H Holland
The sand rat Psammomys obesus is a gerbil species native to deserts of North Africa and the Middle East, and is constrained in its ecology because high carbohydrate diets induce obesity and type II diabetes that, in extreme cases, can lead to pancreatic failure and death. We report the sequencing of the sand rat genome and discovery of an unusual, extensive, and mutationally biased GC-rich genomic domain. This highly divergent genomic region encompasses several functionally essential genes, and spans the ParaHox cluster which includes the insulin-regulating homeobox gene Pdx1...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28665920/lineage-conversion-of-mouse-fibroblasts-to-pancreatic-%C3%AE-cells
#17
Tianjin Liu, Liangliang Sun, Beige Jiang, Limei Li, Jin Cen, Xiaotao Chen, Zhaoyun Zhang, Qinghua Wang, Xin Cheng, Yongquan Shi, Lijian Hui
α-cells, which synthesize glucagon, also support β-cell survival and have the capacity to transdifferentiate into β-cells. However, the role of α-cells in pathological conditions and their putative clinical applications remain elusive due in large part to the lack of mature α-cells. Here, we present a new technique to generate functional α-like cells. α-like cells (iAlpha cells) were generated from mouse fibroblasts by transduction of transcription factors, including Hhex, Foxa3, Gata4, Pdx1 and Pax4, which induce α-cell-specific gene expression and glucagon secretion in response to KCl and Arg stimulation...
June 30, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28657136/reprogramming-mouse-embryo-fibroblasts-to-functional-islets-without-genetic-manipulation
#18
Bhawna Chandravanshi, Ramesh Bhonde
The constant quest for generation of large number of islets aimed us to explore the differentiation potential of mouse embryo fibroblast cells. Mouse embryo fibroblast cells isolated from 12-14 day old pregnant mice were characterized for their surface markers and tri-lineage differentiation potential. They were subjected to serum free media containing a cocktail of islet differentiating reagents and analysed for the expression of pancreatic lineage transcripts .The islet like cell aggregates (ICAs) was confirmed for their pancreatic properties via immunofluorecence for C-peptide, glucagon and somatostain...
June 28, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28647274/sonic-hedgehog-pathway-suppression-and-reactivation-accelerates-differentiation-of-rat-adipose-derived-mesenchymal-stromal-cells-toward-insulin-producing-cells
#19
Dian Dayer, Mahmoud Hashemi Tabar, Eskandar Moghimipour, Mohammad Reza Tabandeh, Ata A Ghadiri, Elham Allah Bakhshi, Mahmoud Orazizadeh, Mohammad Ali Ghafari
BACKGROUND AIMS: Sonic hedgehog (Shh) is an intercellular signaling molecule that regulates pancreas development in mammals. Manipulation of Shh signaling pathway can be used as reliable approach to improve the generation of functional insulin-producing cells (IPCs) from mesenchymal stromal cells (MSCs). METHODS: In the present study, a novel differentiation protocol was used to produce IPCs from adipose tissue-derived MSCs (ATDMSCs) based on sequential inhibition and reactivation of Shh pathway...
June 21, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28642969/diverse-metabolic-effects-of-o-glcnacylation-in-the-pancreas-but-limited-effects-in-insulin-sensitive-organs-in-mice
#20
Shogo Ida, Katsutaro Morino, Osamu Sekine, Natsuko Ohashi, Shinji Kume, Tokuhiro Chano, Kanako Iwasaki, Norio Harada, Nobuya Inagaki, Satoshi Ugi, Hiroshi Maegawa
AIMS/HYPOTHESIS: O-GlcNAcylation is characterised by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O-GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O-GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions...
June 22, 2017: Diabetologia
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