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https://www.readbyqxmd.com/read/28424732/evidence-for-loss-in-identity-de-differentiation-and-trans-differentiation-of-islet-%C3%AE-cells-in-type-2-diabetes
#1
REVIEW
Chad S Hunter, Roland W Stein
The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28420418/adult-muscle-derived-stem-cells-engraft-and-differentiate-into-insulin-expressing-cells-in-pancreatic-islets-of-diabetic-mice
#2
Violeta Mitutsova, Wendy Wai Yeng Yeo, Romain Davaze, Celine Franckhauser, El-Habib Hani, Syahril Abdullah, Patrice Mollard, Marie Schaeffer, Anne Fernandez, Ned J C Lamb
BACKGROUND: Pancreatic beta cells are unique effectors in the control of glucose homeostasis and their deficiency results in impaired insulin production leading to severe diabetic diseases. Here, we investigated the potential of a population of nonadherent muscle-derived stem cells (MDSC) from adult mouse muscle to differentiate in vitro into beta cells when transplanted as undifferentiated stem cells in vivo to compensate for beta-cell deficiency. RESULTS: In vitro, cultured MDSC spontaneously differentiated into insulin-expressing islet-like cell clusters as revealed using MDSC from transgenic mice expressing GFP or mCherry under the control of an insulin promoter...
April 18, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28414315/the-emt-activator-zeb1-is-a-key-factor-for-cell-plasticity-and-promotes-metastasis-in-pancreatic-cancer
#3
Angela M Krebs, Julia Mitschke, María Lasierra Losada, Otto Schmalhofer, Melanie Boerries, Hauke Busch, Martin Boettcher, Dimitrios Mougiakakos, Wilfried Reichardt, Peter Bronsert, Valerie G Brunton, Christian Pilarsky, Thomas H Winkler, Simone Brabletz, Marc P Stemmler, Thomas Brabletz
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis...
April 17, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28409826/glycogen-phosphorylase-inhibition-improves-%C3%AE-cell-function
#4
Lilla Nagy, Judit Márton, András Vida, Gréta Kis, Éva Bokor, Sándor Kun, Mónika Gönczi, Tibor Docsa, Attila Tóth, Miklós Antal, Pál Gergely, Balázs Csóka, Pal Pacher, László Somsák, Péter Bai
BACKGROUND AND PURPOSE: Glycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi-s) are glucose lowering agents trapping glucose in the liver as glycogen. Glycogen metabolism has implications in β-cell function; glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in β-cells by GPi-s impacts β-cell function...
April 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28408354/therapeutic-effects-of-argyrin-f-in-pancreatic-adenocarcinoma
#5
Xi Chen, Khac Cuong Bui, Samarpita Barat, Mai Ly Thi Nguyen, Przemyslaw Bozko, Bence Sipos, Markus Kalesse, Nisar P Malek, Ruben R Plentz
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options. The proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. We hypothesize that his analogue Argyrin F (AF) may also prevent PDAC progression. We have used PDAC cells and engineered mice (Pdx1-Cre; LSL-KrasG12D; p53 (lox/+)) to assess AF anticancer activity. We analyzed the effect of AF on proliferation and epithelial plasticity using MTT-, wound healing-, invasion-, colony formation-, apoptosis-, cell cycle- and senescence assays...
April 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28407685/extra-pancreatic-invasion-induces-lipolytic-and-fibrotic-changes-in-the-adipose-microenvironment-with-released-fatty-acids-enhancing-the-invasiveness-of-pancreatic-cancer-cells
#6
Takashi Okumura, Kenoki Ohuchida, Masafumi Sada, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Chika Iwamoto, Daisuke Miura, Yusuke Mizuuchi, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Tatsuya Manabe, Takao Ohtsuka, Eishi Nagai, Kazuhiro Mizumoto, Yoshinao Oda, Makoto Hashizume, Masafumi Nakamura
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28397308/improvement-of-isolated-caprine-islet-survival-and-functionality-in-vitro-by-enhancing-of-pdx1-gene-expression
#7
Homayoun Hani, Zeenathul Nazariah Allaudin, Mohd-Azmi Mohd-Lila, Kazhal Sarsaifi, Mina Rasouli, Yew Joon Tam, Tengku-Azmi Tengku-Ibrahim, Abas Mazni Othman
BACKGROUND: Dead islets replaced with viable islets are a promising offer to restore normal insulin production to a person with diabetes. The main reason for establishing a new islet source for transplantation is the insufficiency of human donor pancreas while using xenogeneic islets perhaps assists this problem. The expression of PDX1 is essential for the pancreas expansion. In mature β-cells, PDX1 has several critical roles such as glucose sensing, insulin synthesis, and insulin secretion...
April 11, 2017: Xenotransplantation
https://www.readbyqxmd.com/read/28386318/pax4-promotes-pdx1-induced-differentiation-of-mesenchymal-stem-cells-into-insulin-secreting-cells
#8
Lifa Xu, Congjing Xu, Shuping Zhou, Xueke Liu, Jian Wang, Xinkuang Liu, Suping Qian, Yingru Xin, Yi Gao, Yongqiang Zhu, Xiaolong Tang
A shortage of postmortem pancreatic tissue for islet isolation impedes the application of cell replacement therapy in patients with diabetes. As an alternative for islet cell transplantation, transcription factors, including PDX1, PAX4, and neurogenin-3, that aid in the formation of insulin-producing β cells during development have been investigated. The present study evaluated the effects of PAX4 and PDX1 on the differentiation of mesenchymal stem cells (MSCs) into insulin-producing β-like cells in vitro using recombinant adenoviruses carrying PDX1 or PDX1 plus PAX4...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28377501/the-transcription-factor-pax6-is-required-for-pancreatic-%C3%AE-cell-identity-glucose-regulated-atp-synthesis-and-ca2-dynamics-in-adult-mice
#9
Ryan K Mitchell, Marie-Sophie Nguyen-Tu, Pauline Chabosseau, Rebecca M Callingham, Timothy J Pullen, Rebecca Cheung, Isabelle Leclerc, David J Hodson, Guy A Rutter
Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia...
April 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28375156/%C3%AF-3-polyunsaturated-fatty-acids-ameliorate-type-1-diabetes-and-autoimmunity
#10
Xinyun Bi, Fanghong Li, Shanshan Liu, Yan Jin, Xin Zhang, Tao Yang, Yifan Dai, Xiaoxi Li, Allan Zijian Zhao
Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α...
April 4, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28374746/intracellular-hmgb1-as-a-novel-tumor-suppressor-of-pancreatic-cancer
#11
Rui Kang, Yangchun Xie, Qiuhong Zhang, Wen Hou, Qingping Jiang, Shan Zhu, Jinbao Liu, Dexing Zeng, Haichao Wang, David L Bartlett, Timothy R Billiar, Herbert J Zeh, Michael T Lotze, Daolin Tang
Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release...
April 4, 2017: Cell Research
https://www.readbyqxmd.com/read/28373667/bone-marrow-derived-mesenchymal-stem-cells-bmscs-repair-acute-necrotized-pancreatitis-by-secreting-microrna-9-to-target-the-nf-%C3%AE%C2%BAb1-p50-gene-in-rats
#12
Daohai Qian, Ge Wei, Chenglei Xu, Zhigang He, Jie Hua, Jian Li, Qili Hu, Shengping Lin, Jian Gong, Hongbo Meng, Bo Zhou, Hongfei Teng, Zhenshun Song
Acute pancreatitis (AP) is a common acute abdominal disease, 10-20% of which can evolve into severe AP (SAP) causing significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential of repairing SAP, but the detailed mechanism remains unknown. We demonstrate here that microRNA-9 (miR-9) modified BMSCs (pri-miR-9-BMSCs) can significantly reduce the pancreatic edema, infiltration, hemorrhage, necrosis, the release of amylase and lipase. Meanwhile, decreased local/systemic inflammatory response (TNF-α↓, IL-1β↓, IL-6↓, HMGB1↓, MPO↓, CD68↓, IL-4↑, IL-10↑, and TGF-β↑) and enhanced regeneration of damaged pancreas (Reg4↑, PTF1↑, and PDX1↑) are also promoted...
April 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28363269/establishing-a-large-animal-model-for-in-vivo-reprogramming-of-bile-duct-cells-into-insulin-secreting-cells-to-treat-diabetes
#13
Caitlin Marie Hill, Anannya Banga, Juan E Abrahante, Ce Yuan, Lucas A Mutch, Jody Janecek, Timothy O'Brien, Melanie L Graham, James Dutton
Type I diabetes manifests in autoimmune destruction of beta cells requiring metabolic management with an exogenous replacement source of insulin, either by repeated injection of recombinant insulin or by transplantation of allogenic islets from cadaveric donors. Both of these approaches have severe limitations. Repeated insulin injection requires intensive blood glucose monitoring, is expensive, and is associated with decreased quality of life measures. Islet transplant, while highly effective, is severely limited by shortage of donor organs...
March 31, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28362406/efficient-differentiation-of-pluripotent-stem-cells-to-nkx6-1-pancreatic-progenitors
#14
Emily C McGaugh, M Cristina Nostro
Pluripotent stem cells have the ability to self renew and differentiate to multiple lineages, making them an attractive source for the generation of pancreatic progenitor cells that can be used for the study of and future treatment of diabetes. This article outlines a four-stage differentiation protocol designed to generate pancreatic progenitor cells from human embryonic stem cells (hESCs). This protocol can be applied to a number of human pluripotent stem cell (hPSC) lines. The approach taken to generate pancreatic progenitor cells is to differentiate hESCs to accurately model key stages of pancreatic development...
March 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28343707/fibrin-scaffold-enhances-function-of-insulin-producing-cells-differentiated-from-human-umbilical-cord-matrix-derived-stem-cells
#15
Fatemeh Seyedi, Alireza Farsinejad, Seyed Noureddin Nematollahi-Mahani
Tissue engineering is a new strategy which proposed to treat numerous human diseases nowadays. Three dimensional (3D) scaffolds fill the gap between two dimensional cell culture (2D) and animal tissues through mimicking the environmental behaviors surrounding the cells. In this study, hUCMs into insulin producing cells in fibrin scaffold were differentiated compare to conventional culture condition. Differentiation rate was estimated by real time PCR, immunocytochemistry (ICC) and the chemiluminesence (CLIA) and enzyme immunoassay (EIA)...
April 2017: Tissue & Cell
https://www.readbyqxmd.com/read/28315323/increased-serotonin-signaling-contributes-to-the-warburg-effect-in-pancreatic-tumor-cells-under-metabolic-stress-and-promotes-growth-of-pancreatic-tumors-in-mice
#16
Shu-Heng Jiang, Jun Li, Fang-Yuan Dong, Jian-Yu Yang, De-Jun Liu, Xiao-Mei Yang, Ya-Hui Wang, Min-Wei Yang, Xue-Liang Fu, Xiao-Xin Zhang, Qing Li, Xiu-Feng Pang, Yan-Miao Huo, Jiao Li, Jun-Feng Zhang, Ho-Young Lee, Su-Jae Lee, Wen-Xin Qin, Jian-Ren Gu, Yong-Wei Sun, Zhi-Gang Zhang
BACKGROUND & AIMS: The desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. METHODS: We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras(G12D/+); Trp53(R172H/+); Pdx1-Cre; (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples...
March 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28303247/effect-of-wnt-signaling-on-the-differentiation-of-islet-%C3%AE-cells-from-adipose-derived-stem-cells
#17
Hefei Wang, Yu Ren, Xiao Hu, Min Ma, Xiao Wang, Hao Liang, Dongjun Liu
The Wnt signaling is critical for pancreatic development and islet function; however, its precise effects on the development and function of the β-cells remain controversial. Here we examined mRNA and protein expression of components of the Wnt signaling throughout the differentiation of islet β-cells from adipose-derived stem cells (ADSCs). After induction, ADSCs expressed markers of β-cells, including the insulin, PDX1, and glucagon genes, and the PDX1, CK19, nestin, insulin, and C-peptide proteins, indicating their successful differentiation...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28288081/conditional-tissue-specific-foxa2-ablation-in-mouse-pancreas-causes-hyperinsulinemic-hypoglycemia-retracted
#18
Zengbin Wu, Aihua Fei, Yingbin Liu, Shuming Pan
The forkhead/winged helix transcription factor Foxa2 is a major upstream regulator of Pdx1, a transcription factor necessary for pancreatic development. In the present study, we conditionally knocked out Foxa2 in Pdx1-expressing domain and further analyzed the contribution of Foxa2 to α- and β-cell development and the effect of Foxa2 deletion on plasma insulin, glucagon, and glucose levels. Homozygous pdx1 Foxa2 mice and heterozygous pdx1 Foxa2 mice were generated by homologous recombination using a Foxa2 gene-targeting vector...
March 2017: American Journal of Therapeutics
https://www.readbyqxmd.com/read/28270834/metabolic-stress-and-compromised-identity-of-pancreatic-beta-cells
#19
REVIEW
Avital Swisa, Benjamin Glaser, Yuval Dor
Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28268202/adverse-effects-of-parental-zinc-deficiency-on-metal-homeostasis-and-embryonic-development-in-a-zebrafish-model
#20
Laura M Beaver, Yasmeen M Nkrumah-Elie, Lisa Truong, Carrie L Barton, Andrea L Knecht, Greg D Gonnerman, Carmen P Wong, Robert L Tanguay, Emily Ho
The high prevalence of zinc deficiency is a global public health concern, and suboptimal maternal zinc consumption has been associated with adverse effects ranging from impaired glucose tolerance to low birthweights. The mechanisms that contribute to altered development and poor health in zinc deficient offspring are not completely understood. To address this gap, we utilized the Danio rerio model and investigated the impact of dietary zinc deficiency on adults and their developing progeny. Zinc deficient adult fish were significantly smaller in size, and had decreases in learning and fitness...
February 20, 2017: Journal of Nutritional Biochemistry
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