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Dahae Lee, Young-Mi Kim, Kiwon Jung, Young-Won Chin, Ki Sung Kang
Alpha (α)-mangostin, a yellow crystalline powder with a xanthone core structure, is isolated from mangosteen ( Garcinia mangostana ), which is a tropical fruit of great nutritional value. The aim of the present study was to investigate the anti-diabetic effects of α-mangostin and to elucidate the molecular mechanisms underlying its effect on pancreatic beta (β)-cell dysfunction. To assess the effects of α-mangostin on insulin production, rat pancreatic INS-1 cells were treated with non-toxic doses of α-mangostin (1⁻10 μM) and its impact on insulin signaling was examined by Western blotting...
May 16, 2018: International Journal of Molecular Sciences
Murugesan Chandrasekaran, Se Chul Chun
Vitamin B6 (VitB6) is an essential cofactor for >140 biochemical reactions. Also, VitB6 is a potent antioxidant and helps plants cope with both biotic and abiotic stress conditions. However, the role of VitB6 in plant disease resistance has yet to be confirmed using molecular biology approaches. Here, we analyzed the expression patterns of VitB6 biosynthetic genes, including the de novo (PDX1 [PDX1.2 and 1.3] and PDX2) and the salvage (SOS4) pathways during the response to Erwinia carotovora subsp. carotovora...
May 5, 2018: International Journal of Biological Macromolecules
Lizhen Wang, Hailing Fan, Ludan Zhou, Yanjun Wu, Hongping Lu, Jing Luo
PURPOSE: To investigate the effect of gestational diabetes mellitus (GDM) on the expression and methylation of PGC-1α and PDX1 in placenta and their effects on fetal glucose metabolism. METHODS: 20 cases of full-term placenta without pregnancy complications and umbilical cord abnormalities and 20 cases of GDM group were collected. DNA and RNA were isolated from samples of tissue collected from the fetal side of the placenta immediately after delivery. DNA methylation was quantified at 7 CpG sites within the PGC-1α and PDX1 genes using PCR amplification of bisulfite treated DNA and subsequent DNA sequencing...
May 7, 2018: Biochemical and Biophysical Research Communications
Stephanie Robyn Johnson, Paul Leo, Louise Sonia Conwell, Mark Harris, Matthew Arthur Brown, Emma Letitia Duncan
Maturity-onset diabetes of the young (MODY) is the commonest form of monogenic diabetes, resulting from dominant mutations in one of fourteen genes that regulate beta-cell function (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8,KCNJ11 and APPL1 1,2 ). MODY accounts for 2-2.5% of childhood diabetes 3 , yet MODY genetic screening is uncommon, even in highly suggestive families, and when performed often limited to the commonest genes (e.g.HNF1A and GCK) 4 .
May 4, 2018: Journal of Diabetes
Eri Ikeguchi, Norio Harada, Yoshinori Kanemaru, Akiko Sankoda, Shunsuke Yamane, Kanako Iwasaki, Masamichi Imajo, Yuki Murata, Kazuyo Suzuki, Erina Joo, Nobuya Inagaki
Fat accumulation with aging is a serious problem; glucose-dependent insulinotropic polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor-knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, age-related changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter (GIP-GFP knock-in heterozygous; GIPgfp/+ ) mice...
May 3, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Chia-Chi Chen, Li-Li Chen, Chung-Pin Li, Yu-Ting Hsu, Shih-Sheng Jiang, Chi-Shuan Fan, Kee Voon Chua, Sheng-Xiang Huang, Yi-Ming Shyr, Li-Tzong Chen, Tze-Sing Huang
We detected a significant elevation of serum HSP90α levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90α levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90α levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90α levels were detected before PDAC formation and an extracellular HSP90α (eHSP90α) inhibitor effectively prevented PDAC development...
2018: Oncoimmunology
Kiyohiko Takahashi, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Naoyuki Kitao, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
To examine the effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment...
May 1, 2018: Scientific Reports
Navid Nobakht-Haghighi, Mahban Rahimifard, Maryam Baeeri, Mohammad Amin Rezvanfar, Shermineh Moini Nodeh, Hamed Haghi-Aminjan, Emre Hamurtekin, Mohammad Abdollahi
Oxidative stress has been involved in the aging process and the pathogenesis of type-2 diabetes, which is a serious health problem worldwide. This study investigates the anti-aging, anti-apoptotic, and antioxidant properties of alpha-lipoic acid (ALA), aiming to improve aged rat pancreatic cells. In this regard, half maximal effective concentration (EC50 ) of ALA based on the survival of aged pancreatic islet cells was determined as 100 µM. Following this, p38 and p53 genes expression as key factors in aging, oxidative stress biomarkers, insulin secretion, and Pdx1 protein expression were evaluated using real-time PCR, ELISA reader, and fluorescence microscope...
April 25, 2018: Molecular and Cellular Biochemistry
Komariah Komariah, Wasmen Manalu, Bambang Kiranadi, Adi Winarto, Ekowati Handharyani, M Orliando Roeslan
Valproic acid (VPA) plays a role in histone modifications that eventually inhibit the activity of histone deacetylase (HDAC), and will affect the expressions of genes Pdx1, Nkx6.1, and Ngn3 during pancreatic organogenesis. This experiment was designed to study the effect of VPA exposure in pregnant rats on the activity of HDAC that controls the expression of genes regulating the development of beta cells in the pancreas to synthesize and secrete insulin. This study used 30 pregnant Sprague-Dawley rats, divided into 4 groups, as follows: (1) a control group of pregnant rats without VPA administration, (2) pregnant rats administered with 250 mg VPA on day 10 of pregnancy, (3) pregnant rats administered with 250 mg VPA on day 13 of pregnancy, and (4) pregnant rats administered with 250 mg VPA on day 16 of pregnancy...
April 2018: Toxicological Research
Nicola Rath, June Munro, Marie Fa Cutiongco, Alicja Jagiełło, Nikolaj Gadegaard, Lynn McGarry, Mathieu Unbekandt, Evdokia Michalopoulou, Jurre J Kamphorst, David Sumpton, Gillian Mackay, Claire Vennin, Marina Pajic, Paul Timpson, Michael F Olson
The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation...
April 18, 2018: Cancer Research
Xiao-Yan Cao, Xiao-Xin Zhang, Min-Wei Yang, Li-Peng Hu, Shu-Heng Jiang, Guang-Ang Tian, Li-Li Zhu, Qing Li, Yong-Wei Sun, Zhi-Gang Zhang
Pancreatic Ductal Adenocarcinoma (PADC) metastasis is the leading cause of morality of this severe malignant tumor. Proteases are key players in the degradation of extracellular matrix which promotes the cascade of tumor metastasis. As a kind of serine proteases, the kallikrein family performs vital function on the cancer proteolysis scene, which have been proved in diverse malignant tumors. However, the specific member of kallikrein family and its function in PDAC remain unexplored. In this study, by data mining of GEO datasets, we have identified KLK10 is upregulated gene in PDAC...
April 2, 2018: Biochemical and Biophysical Research Communications
Idil I Aigha, Bushra Memon, Ahmed K Elsayed, Essam M Abdelalim
BACKGROUND: The expression of a specific combination of transcription factors (TFs) in the multipotent progenitor cells (MPCs) is critical for determining pancreatic cell fate. NKX6.1 expression in PDX1+ MPCs is required for functional β cell generation. We have recently demonstrated the generation of a novel population of human pluripotent stem cell (hPSC)-derived MPCs that exclusively express NKX6.1, independently of PDX1 (PDX1- /NKX6.1+ ). Therefore, the aim of this study was to characterize this novel population to elucidate its role in pancreatic development...
April 3, 2018: Stem Cell Research & Therapy
Jian Gao, Yue Yuan, Yuqing Chen
In this study, we observed the differentiation potential of human ADMSCs (hADMSCs) into functional islet-like cells and the therapeutic effect of hADMSCs transplantation in diabetic rats. Firstly, the PDX1 gene was transfected into hADMSCs by an adenovirus. Cell differentiation and insulin secretion were identified and detected by dithizone staining and ELISA, respectively. Twenty male Sprague-Dawley rats were randomly divided into control group (n=4), diabetes group (n=8) and transplantation group (n=8). Rats in the latter two groups were subjected to making diabetic models by 65 mg/kg streptozotocin injection...
April 2, 2018: Die Pharmazie
Takuro Matsuzawa, Takeo Yoshikawa, Tomomitsu Iida, Anikó Kárpáti, Haruna Kitano, Ryuichi Harada, Tadaho Nakamura, Akira Sugawara, Yu Yamaguchi, Kazuhiko Yanai
Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic β-cells and may be involved in β-cell functions. However, the importance of HS for β-cell function remains unknown. Here, we generated mice with β-cell-specific deletion of Ext1 (βExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in β-cell function. βExt1CKO mice decreased body weights compared with control mice, despite increased food intake...
March 29, 2018: Biochemical and Biophysical Research Communications
Yu Zhang, Michelle Zoltan, Erick Riquelme, Hanwen Xu, Ismet Sahin, Susana Castro-Pando, Maria Fernanda Montiel, Kyle Chang, Zhengyu Jiang, Jianhua Ling, Sonal Gupta, William Horne, Melissa Pruski, Huamin Wang, Shao-Cong Sun, Guillermina Lozano, Paul Chiao, Anirban Maitra, Steven D Leach, Jay K Kolls, Eduardo Vilar Sanchez, Timothy C Wang, Jennifer M Bailey, Florencia McAllister
BACKGROUND & AIMS: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17 A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to PanIN initiation and progression. We investigated the effects of IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena. METHODS: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KCiMist ;G) and Kras(G12D); Trp53(R172H); Pdx1-Cre (KPC) mice (which upon tamoxifen induction spontaneously develop pancreatic intraepithelial neoplasias, PanINs) and control littermates...
March 28, 2018: Gastroenterology
Jie Wang, Wenyi Gu, Chen Chen
Type 2 diabetes (T2D) is a metabolic disorder characterized by beta cell dysfunction and insulin resistance in fat, muscle and liver cells. Recent studies have shown that the development of insulin resistance in pancreatic beta cell lines may contribute to beta cell dysfunction in T2D. However, there still is a lack of detailed investigations regarding the mechanisms by which insulin deficiency may contribute in diabetes. In this study, we firstly established a stable insulin receptor knockdown cell line in pancreatic beta cells INS-1 (InsRβKD cells) using anti InsRβ small hairpin RNA (InsRβ-shRNA) encoded by lentiviral vectors...
March 26, 2018: International Journal of Molecular Sciences
Mark P Keller, Daniel M Gatti, Kathryn L Schueler, Mary E Rabaglia, Donnie S Stapleton, Petr Simecek, Matthew Vincent, Sadie Allen, Aimee Teo Broman, Rhonda Bacher, Christina Kendziorski, Karl W Broman, Brian S Yandell, Gary A Churchill, Alan D Attie
The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts...
March 22, 2018: Genetics
Yuhan Wang, Craig Dorrell, Willscott E Naugler, Michael Heskett, Paul Spellman, Bin Li, Feorillo Galivo, Annelise Haft, Leslie Wakefield, Markus Grompe
Direct lineage reprogramming can convert readily available cells in the body into desired cell types for cell replacement therapy. This is usually achieved through forced activation or repression of lineage-defining factors or pathways. In particular, reprogramming toward the pancreatic β cell fate has been of great interest in the search for new diabetes therapies. It has been suggested that cells from various endodermal lineages can be converted to β-like cells. However, it is unclear how closely induced cells resemble endogenous pancreatic β cells and whether different cell types have the same reprogramming potential...
February 21, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Abraham Neelankal John, Ramesh Ram, Fang-Xu Jiang
Type 2 diabetes (T2D) is a global health issue and dedifferentiation plays underlying causes in the pathophysiology of T2D; however, there is a lack of understanding in the mechanism. Dedifferentiation results from the loss of function of pancreatic β-cells alongside a reduction in essential transcription factors under various physiological stressors. Our study aimed to establish db/db as an animal model for dedifferentiation by using RNA sequencing to compare the gene expression profile in islets isolated from wild-type, db/+ and db/db mice, and qPCR was performed to validate those significant genes...
March 14, 2018: Endocrine Pathology
Cindy J M Loomans, Nerys Williams Giuliani, Jeetindra Balak, Femke Ringnalda, Léon van Gurp, Meritxell Huch, Sylvia F Boj, Toshiro Sato, Lennart Kester, Susana M Chuva de Sousa Lopes, Matthias S Roost, Susan Bonner-Weir, Marten A Engelse, Ton J Rabelink, Harry Heimberg, Robert G J Vries, Alexander van Oudenaarden, Françoise Carlotti, Hans Clevers, Eelco J P de Koning
Generating an unlimited source of human insulin-producing cells is a prerequisite to advance β cell replacement therapy for diabetes. Here, we describe a 3D culture system that supports the expansion of adult human pancreatic tissue and the generation of a cell subpopulation with progenitor characteristics. These cells display high aldehyde dehydrogenase activity (ALDHhi ), express pancreatic progenitors markers (PDX1, PTF1A, CPA1, and MYC), and can form new organoids in contrast to ALDHlo cells. Interestingly, gene expression profiling revealed that ALDHhi cells are closer to human fetal pancreatic tissue compared with adult pancreatic tissue...
March 13, 2018: Stem Cell Reports
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