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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
#1
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/28665920/lineage-conversion-of-mouse-fibroblasts-to-pancreatic-%C3%AE-cells
#2
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/28657902/induction-of-anti-aging-gene-klotho-with-a-small-chemical-compound-that-demethylates-cpg-islands
#3
Dongju Jung, Yuechi Xu, Zhongjie Sun
Klotho (KL) is described as an anti-aging gene because mutation of Kl gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how Kl expression could be induced. Here we discovered novel molecular mechanism for induction of Kl expression with a small molecule 'Compound H', N-(2-chlorophenyl)-1H-indole-3-caboxamide...
June 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28597969/the-role-of-epigenetic-regulation-and-pluripotency-related-micrornas-in-differentiation-of-pancreatic-stem-cells-to-beta-cells
#4
Ediz Coskun, Merve Ercin, Selda Gezginci-Oktayoglu
In this study, we aimed to research class-I HDACs and glucose on differentiation of pancreatic islet derived mesenchymal stem cells (PI-MSCs) to beta cells. Beta cell differentiation determined by flow cytometric analysis and gene expression levels of PDX1, PAX4, PAX6, NKX6.1, NGN3, INS2, and GLUT2. The valproic acid, is an inhibitor of class I HDACs, caused the highest beta cell differentiation in PI-MSCs. However, the cells in this group were at early stages of differentiation. Glucose co-administration to this group carried the differentiation to higher levels, but these newly formed beta cells were not functional...
June 9, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28386318/pax4-promotes-pdx1-induced-differentiation-of-mesenchymal-stem-cells-into-insulin-secreting-cells
#5
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/28375156/%C3%AF-3-polyunsaturated-fatty-acids-ameliorate-type-1-diabetes-and-autoimmunity
#6
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...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28282933/the-diabetes-linked-transcription-factor-pax4-from-gene-to-functional-consequences
#7
REVIEW
Petra I Lorenzo, Francisco Juárez-Vicente, Nadia Cobo-Vuilleumier, Mario García-Domínguez, Benoit R Gauthier
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis...
March 9, 2017: Genes
https://www.readbyqxmd.com/read/28268202/adverse-effects-of-parental-zinc-deficiency-on-metal-homeostasis-and-embryonic-development-in-a-zebrafish-model
#8
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...
May 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28253300/the-pax-gene-family-highlights-from-cephalopods
#9
Sandra Navet, Auxane Buresi, Sébastien Baratte, Aude Andouche, Laure Bonnaud-Ponticelli, Yann Bassaglia
Pax genes play important roles in Metazoan development. Their evolution has been extensively studied but Lophotrochozoa are usually omitted. We addressed the question of Pax paralog diversity in Lophotrochozoa by a thorough review of available databases. The existence of six Pax families (Pax1/9, Pax2/5/8, Pax3/7, Pax4/6, Paxβ, PoxNeuro) was confirmed and the lophotrochozoan Paxβ subfamily was further characterized. Contrary to the pattern reported in chordates, the Pax2/5/8 family is devoid of homeodomain in Lophotrochozoa...
2017: PloS One
https://www.readbyqxmd.com/read/28096335/myofibril-breakdown-during-atrophy-is-a-delayed-response-requiring-the-transcription-factor-pax4-and-desmin-depolymerization
#10
Alexandra Volodin, Idit Kosti, Alfred Lewis Goldberg, Shenhav Cohen
A hallmark of muscle atrophy is the excessive degradation of myofibrillar proteins primarily by the ubiquitin proteasome system. In mice, during the rapid muscle atrophy induced by fasting, the desmin cytoskeleton and the attached Z-band-bound thin filaments are degraded after ubiquitination by the ubiquitin ligase tripartite motif-containing protein 32 (Trim32). To study the order of events leading to myofibril destruction, we investigated the slower atrophy induced by denervation (disuse). We show that myofibril breakdown is a two-phase process involving the initial disassembly of desmin filaments by Trim32, which leads to the later myofibril breakdown by enzymes, whose expression is increased by the paired box 4 (PAX4) transcription factor...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28090703/differentiation-of-islet-progenitors-regulated-by-nicotinamide-into-transcriptome-verified-%C3%AE-cells-that-ameliorate-diabetes
#11
Fang-Xu Jiang, Kevin Li, Michael Archer, Munish Mehta, Emma Jamieson, Adrian Charles, Jan E Dickinson, Masahito Matsumoto, Grant Morahan
Developmental stage-specific differentiation of stem or progenitor cells into safe and functional cells is of fundamental importance in regenerative medicine, including β-cell replacement. However, the differentiation of islet progenitor cells (IPCs) into insulin-secreting β cells remains elusive. Here, we report that the multifunctional molecule nicotinamide (NIC) is a specific differentiation regulator of mouse IPCs. The differentiated cells regulated by NIC exhibited many characteristics of adult β cells, including ameliorating preclinical diabetes and a highly comparable transcriptome profile...
May 2017: Stem Cells
https://www.readbyqxmd.com/read/28059593/clinical-relevance-of-epigenetics-in-the-onset-and-management-of-type-2-diabetes-mellitus
#12
REVIEW
Linda Sommese, Alberto Zullo, Francesco Paolo Mancini, Rossella Fabbricini, Andrea Soricelli, Claudio Napoli
Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects...
June 3, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27810688/clinical-whole-exome-sequencing-in-early-onset-diabetes-patients
#13
Soo Heon Kwak, Chan-Hyeon Jung, Chang Ho Ahn, Jungsun Park, Jeesoo Chae, Hye Seung Jung, Young Min Cho, Dae Ho Lee, Jong-Il Kim, Kyong Soo Park
AIMS: There could be an overlap of monogenic diabetes and early onset type 2 diabetes in those who are diagnosed before age of 30years. Genetic diagnosis in these patients might improve the quality of care. A limited number of studies have used whole exome sequencing (WES) in Asian patients with early onset diabetes, and the clinical utility of WES is largely unknown. METHODS: We performed whole exome capture and massive parallel sequencing in 28 patients with early onset diabetes...
December 2016: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/27744525/exome-chip-association-analysis-reveals-an-asian-specific-missense-variant-in-pax4-associated-with-type-2-diabetes-in-chinese-individuals
#14
Chloe Y Y Cheung, Clara S Tang, Aimin Xu, Chi-Ho Lee, Ka-Wing Au, Lin Xu, Carol H Y Fong, Kelvin H M Kwok, Wing-Sun Chow, Yu-Cho Woo, Michele M A Yuen, JoJo S H Hai, Ya-Li Jin, Bernard M Y Cheung, Kathryn C B Tan, Stacey S Cherny, Feng Zhu, Tong Zhu, G Neil Thomas, Kar-Keung Cheng, Chao-Qiang Jiang, Tai-Hing Lam, Hung-Fat Tse, Pak-Chung Sham, Karen S L Lam
AIMS/HYPOTHESIS: Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population. METHODS: An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip...
January 2017: Diabetologia
https://www.readbyqxmd.com/read/27500257/mtor-inhibition-reduced-insulin-secretion-and-sensitivity-in-a-rat-model-of-metabolic-syndrome
#15
Jordi Rovira, María Jose Ramírez-Bajo, Elisenda Banon-Maneus, Daniel Moya-Rull, Pedro Ventura-Aguiar, Natalia Hierro-Garcia, Marta Lazo-Rodriguez, Ignacio Revuelta, Armando Torres, Federico Oppenheimer, Josep M Campistol, Fritz Diekmann
BACKGROUND: Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β -cell toxicity. METHODS: Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days...
February 2016: Transplantation Direct
https://www.readbyqxmd.com/read/27420379/a-preliminary-study-to-evaluate-the-strategy-of-combining-clinical-criteria-and-next-generation-sequencing-ngs-for-the-identification-of-monogenic-diabetes-among-multi-ethnic-asians
#16
Su Fen Ang, Su Chi Lim, Clara Sh Tan, Jessie Cw Fong, Winston Yc Kon, Joyce X Lian, Tavintharan Subramanium, Chee Fang Sum
AIMS: Diabetes is increasing globally and Asia is the epicenter. Among those with young-onset diabetes (<45years), the prevalence of monogenic diabetes is estimated to be non-trivial (∼5%). An accurate diagnosis of monogenic diabetes is important to inform treatment, prognosis and genetic counseling. Therefore, a robust clinical algorithm to identify probands for testing is needed. Our aims are (1) to select probands for genetic testing and variant identification based on their clinical phenotype and (2) to evaluate the MODY probability calculator in our multi-ethnic Asian population...
September 2016: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/27371613/differing-expression-profiles-of-notch-enterocyte-and-wnt-secretory-lineage-signallings-are-associated-with-morphological-diversity-of-appendiceal-tumours
#17
Xianyong Gui, Ziran Meng, Yarrow J McConnell, Shuhong Liu, Vincent G Falck, Lloyd A Mack, Walley J Temple
BACKGROUND: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells)...
January 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27334367/pax4-r192h-and-p321h-polymorphisms-in-type-2-diabetes-and-their-functional-defects
#18
Jatuporn Sujjitjoon, Suwattanee Kooptiwut, Nalinee Chongjaroen, Namoiy Semprasert, Wanthanee Hanchang, Kanjana Chanprasert, Watip Tangjittipokin, Pa-Thai Yenchitsomanus, Nattachet Plengvidhya
We have previously identified PAX4 mutations causing MODY9 and a recent genome-wide association study reported a susceptibility locus of type 2 diabetes (T2D) near PAX4. In this study, we aim to investigate the association between PAX4 polymorphisms and T2D in Thai patients and examine functions of PAX4 variant proteins. PAX4 rs2233580 (R192H) and rs712701 (P321H) were genotyped in 746 patients with T2D and 562 healthy normal control subjects by PCR and restriction-fragment length polymorphism method. PAX4 variant proteins were investigated for repressor function on human insulin and glucagon promoters and for cell viability and apoptosis upon high glucose exposure...
November 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27243814/generation-of-functional-beta-like-cells-from-human-exocrine-pancreas
#19
Maria J Lima, Kenneth R Muir, Hilary M Docherty, Neil W A McGowan, Shareen Forbes, Yves Heremans, Harry Heimberg, John Casey, Kevin Docherty
Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells...
2016: PloS One
https://www.readbyqxmd.com/read/27240324/enhanced-differentiation-of-human-amniotic-fluid-derived-stem-cells-into-insulin-producing-cells-in-vitro
#20
Xu-Peng Mu, Li-Qun Ren, Hao-Wei Yan, Xin-Min Zhang, Tian-Min Xu, An-Hui Wei, Jin-Lan Jiang
AIMS/INTRODUCTION: To investigate the ability of human amniotic fluid stem cells (hAFSCs) to differentiate into insulin-producing cells. MATERIALS AND METHODS: hAFSCs were induced to differentiate into pancreatic cells by a multistep protocol. The expressions of pancreas-related genes and proteins, including pancreatic and duodenal homeobox-1, insulin, and glucose transporter 2, were detected by polymerase chain reaction and immunofluorescence. Insulin secreted from differentiated cells was tested by enzyme-linked immunosorbent assay...
January 2017: Journal of Diabetes Investigation
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