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Pathways of Acetyl-CoA Metabolism Involved in the Reversal of Palmitate-Induced Glucose Production by Metformin and Salicylate

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EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES 2016年第10期124卷 602-612页

作者： Hayward, B. Molero, J. C. Windmill, K. Sanigorski, A. Weir, J. McRae, N. L. Aston-Mourney, K. Osborne, B. Liao, B. Walder, K. R. Meikle, P. J. Konstantopoulos, N. Schmitz-Peiffer, C. Deakin Univ Sch Med Metab Res Unit Geelong Vic Australia RMIT Univ Hlth Innovat Res Inst Bundoora Vic Australia RMIT Univ Sch Hlth Sci Bundoora Vic Australia Baker IDI Heart & Diabet Inst Metabol Lab Melbourne Vic Australia UNSW Australia Sch Med Sci Kensington NSW Australia UNSW Australia Diabet & Metab Div Garvan Inst Med Res Sydney NSW Australia UNSW Australia St Vincents Clin Sch Sydney NSW Australia RMIT Univ Level 2110 Victoria St Melbourne Vic 3001 Australia Med Dev Global Hlth Level 1 18 Kavanagh St Southbank Vic 3006 Australia

The pathways through which fatty acids induce insulin resistance have been the subject of much research. We hypothesise that by focussing on the reversal of insulin resistance, novel insights can be made regarding the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered during the prevention of palmitate-induced glucose production in hepatocytes using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075 mM, 48 h) with or without metformin (0.25 mM) and sodium salicylate (2 mM) in the final 24 h of palmitate treatment, and effects on glucose production were determined. RNA microarray measurements followed by gene set enrichment analysis were performed to investigate pathway regulation. Lipidomic analysis and measurement of secreted bile acids and cholesterol were also performed. Reversal of palmitate-induced glucose production by metformin and sodium salicylate was characterised by co-ordinated down-regulated expression of pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. All 20 enzymes that regulate the conversion of acetyl-CoA to cholesterol were reduced following metformin and sodium salicylate. Selected findings were confirmed using primary mouse hepatocytes. Although total intracellular levels of diacylglycerol, triacylglycerol and cholesterol esters increased with palmitate, these were not, however, further altered by metformin and sodium salicylate. 6 individual diacylglycerol, triacylglycerol and cholesterol ester species containing 18: 0 and 18: 1 side-chains were reduced by metformin and sodium salicylate. These results implicate acetyl-CoA metabolism and C18 lipid species as modulators of hepatic glucose production that could be targeted to improve glucose homeostasis.

关键词： insulin resistance liver gene expression microarray lipidomics

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Tissue Remodeling and Nonendometrium-Like Menstrual Cycling Are Hallmarks of Peritoneal Endometriosis Lesions

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REPRODUCTIVE SCIENCES 2013年第1期20卷 85-102页

作者： Sohler, Florian Sommer, Anette Wachter, David L. Agaimy, Abbas Fischer, Oliver M. Renner, Stefan P. Burghaus, Stefanie Fasching, Peter A. Beckmann, Matthias W. Fuhrmann, Ulrike Strick, Reiner Strissel, Pamela L. Univ Clin Erlangen Dept Obstet & Gynaecol Mol Med Lab D-91054 Erlangen Germany Bayer Healthcare Pharmaceut Global Drug Discovery Target Discovery Berlin Germany Univ Clin Erlangen Inst Pathol D-91054 Erlangen Germany Bayer Healthcare Pharmaceut Therapeut Res Grp Womens Hlth Global Drug Discovery Berlin Germany

We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.

关键词： endometriosis gene expression microarray menstrual cycle tissue remodeling

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Genome-wide analysis of gene transcription in the hypothalamus

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PHYSIOLOGICAL GENOMICS 2005年第2期22卷 191-196页

作者： Bischof, JM Wevrick, R Univ Alberta Dept Med Genet Edmonton AB T6G 2H7 Canada

As the genomic regions containing loci predisposing to obesity-related traits are mapped in human population screens and mouse genetic studies, identification of susceptibility genes will increasingly be facilitated by bioinformatic methods. We hypothesized that candidate genes can be prioritized by their expression levels in tissues of central importance in obesity. Our objective was to develop a combined bioinformatics and molecular paradigm to identify novel genes as candidates for murine or human obesity genetic modifiers based on their differential expression patterns in the hypothalamus compared with other murine tissues. We used bioinformatics tools to search publicly available gene expression databases using criteria designed to identify novel genes differentially expressed in the hypothalamus. We used RNA methods to determine their expression sites and levels of expression in the hypothalamus of the murine brain. We identified the chromosomal location of the novel genes in mice and in humans and compared these locations with those of genetic loci predisposing to obesity-related traits. We developed a search strategy that correctly identified a set of genes known to be important in hypothalamic function as well as a candidate gene for Prader-Willi syndrome that was not previously identified as differentially expressed in the hypothalamus. Using this same strategy, we identified and characterized a set of 11 genes not previously known to be differentially expressed in the murine hypothalamus. Our results demonstrate the feasibility of combined bioinformatics and molecular approaches to the identification of genes that are candidates for obesity-related disorders in humans and mice.

关键词： hypothalamus candidate genes bioinformatics gene expression microarray

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Allergen challenge of peripheral blood mononuclear cells from patients with seasonal allergic rhinitis increases IL-17RB, which regulates basophil apoptosis and degranulation

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CLINICAL AND EXPERIMENTAL ALLERGY 2010年第8期40卷 1194-1202页

作者： Wang, H. Mobini, R. Fang, Y. Barrenas, F. Zhang, H. Xiang, Z. Benson, M. Univ Gothenburg Unit Clin Syst Biol S-40530 Gothenburg Sweden Univ Gothenburg Sahlgrenska Acad Mucosal Immunobiol & Vaccine Res Ctr Dept Microbiol & Immunol S-40530 Gothenburg Sweden Affiliated Hosp Guiyang Med Coll Dept Immunol Guiyang Peoples R China Nanjing Univ Sch Med Jiangsu Key Lab Mol Med Nanjing 210008 Peoples R China Queen Silvia Childrens Hosp Pediat Allergy Unit Gothenburg Sweden

P>Background Previously, expression profiling has been used to analyse allergen-challenged T-helper type 2 cells, nasal biopsies and nasal fluid cells from patients with seasonal allergic rhinitis (SAR). Allergen-challenged peripheral blood mononuclear cells (PBMCs) provide a human in vitro model of how antigen-presenting cells, CD4+ T cells and effector cells such as basophils interact in allergic inflammation. Objective To identify novel genes and pathways in allergen-challenged PBMCs from patients with SAR using gene expression profiling and functional studies. Methods PBMCs from 11 patients with SAR and 23 healthy controls were analysed with gene expression profiling. mRNA expression of IL17RB in basophils was evaluated using quantitative real-time PCR. Membrane protein expression and apoptosis of basophils were examined by flow cytometry. Degranulation of basophils was assessed by measuring beta-hexosaminidase release. Cytokine release was measured using ELISA. Results gene expression microarray analysis of allergen-challenged PBMCs showed that 209 out of 44 000 genes were differentially expressed in patients compared with controls. IL17RB was the gene whose expression increased most in patients (P < 0.0001). FACS analysis of PBMCs showed, for the first time, that basophils express IL-17RB. Following allergen challenge, IL-17RB protein increased significantly on basophils from patients compared with controls (P < 0.05). IL-3 significantly increased both mRNA and protein expressions of IL17RB. Activation of IL-17RB by its ligand, IL-25, inhibited apoptosis of basophils. Moreover, IgE-mediated degranulation was enhanced by IL-25. Conclusion Increased expression of IL-17RB on allergen-challenged basophil is regulated by IL-3, inhibits apoptosis and promotes IgE-mediated degranulation of basophils. Cite this as: H. Wang, R. Mobini, Y. Fang, F. Barrenas, H. Zhang, Z. Xiang and M. Benson, Clinical & Experimental Allergy, 2010 (40) 1194-1202.

关键词： apoptosis basophils degranulation gene expression microarray IL-17RB seasonal allergic rhinitis

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Transcriptome profiling reveals distinctive traits of retinol metabolism and neonatal parallels in the MRL/MpJ mouse

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BMC GENOMICS 2015年第1期16卷 1-17页

作者： Podolak-Popinigis, Justyna Gornikiewicz, Bartosz Ronowicz, Anna Sachadyn, Pawel Gdansk Univ Technol Dept Mol Biotechnol & Microbiol Gdansk Poland Med Univ Gdansk Dept Biol & Pharmaceut Bot Gdansk Poland

Background: The MRL/MpJ mouse is a laboratory inbred strain known for regenerative abilities which are manifested by scarless closure of ear pinna punch holes. Enhanced healing responses have been reported in other organs. A remarkable feature of the strain is that the adult MRL/MpJ mouse retains several embryonic biochemical characteristics, including increased expression of stem cell markers. Results: We explored the transcriptome of the MRL/MpJ mouse in the heart, liver, spleen, bone marrow and ears. We used two reference strains, thus increasing the chances to discover the genes responsible for the exceptional properties of the regenerative strain. We revealed several distinctive characteristics of gene expression patterns in the MRL/MpJ mouse, including the repression of immune response genes, the up-regulation of those associated with retinol metabolism and PPAR signalling, as well as differences in expression of the genes engaged in wounding response. Another crucial finding is that the gene expression patterns in the adult MRL/MpJ mouse and murine neonates share a number of parallels, which are also related to immune and wounding response, PPAR pathway, and retinol metabolism. Conclusions: Our results indicate the significance of retinol signalling and neonatal transcriptomic relics as the distinguishing features of the MRL/MpJ mouse. The possibility that retinoids could act as key regulatory molecules in this regeneration model brings important implications for regenerative medicine.

关键词： Regeneration Retinol MRL/MpJ mouse Transcriptome profiling gene expression microarray Neonatal parallels Peroxisome proliferator-activated receptor

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The breast cancer molecular subtypes. Contributions of high throughput technologies

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ONCOLOGIE 2010年第7期12卷 396-402页

作者： Reyal, F. Bollet, M. -A. Roubaud, G. Vincent-Salomon, A. Salmon, R. -J. Inst Curie Dept Chirurg F-75005 Paris France Inst Curie CNRS UMR 144 F-75005 Paris France Inst Curie Dept Oncol Radiotherap F-75005 Paris France Inst Bergonie Dept Med Oncol F-33000 Bordeaux France Inst Curie Dept Biol Tumeurs F-75005 Paris France Inst Curie INSERM U830 F-75005 Paris France

For more than 10 years, continuous development of new high through-put technologies has given to scientists a wide range of diverse but complementary tools to study biology in general and cancers in particular. These tools can address simultaneous, genome-wide studies of DNA copy number alterations (amplification, gain or losses), loss of heterozygosity (LOH), gene-expression alterations, microRNA post-transcriptional control alterations and protein complex activations. We present here a summary of the discoveries generated by gene-expression studies of breast cancers that stresses their direct implications in the care of patients. Terabytes of biological data, gathered throughout the years by the scientist, are not the by-product of some technological whim but, on the contrary, seminal information for the modern characterisation of these tumours. To improve the prognosis of breast cancer patients requires the use of these technologies.

关键词： gene expression microarray Molecular subtypes Prognostic Treatment

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CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer

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geneS AND IMMUNITY 2011年第8期12卷 653-662页

作者： Agesen, T. H. Berg, M. Clancy, T. Thiis-Evensen, E. Cekaite, L. Lind, G. E. Nesland, J. M. Bakka, A. Mala, T. Hauss, H. J. Fetveit, T. Vatn, M. H. Hovig, E. Nesbakken, A. Lothe, R. A. Skotheim, R. I. Oslo Univ Hosp Norwegian Radium Hosp Inst Canc Res Dept Canc Prevent NO-0424 Oslo Norway Univ Oslo Ctr Canc Biomed Oslo Norway Oslo Univ Hosp Norwegian Radium Hosp Inst Canc Res Dept Tumor Biol NO-0424 Oslo Norway Oslo Univ Hosp Rikshosp Dept Organ Transplantat Gastroenterol & Nephrol NO-0424 Oslo Norway Oslo Univ Hosp Norwegian Radium Hosp Div Pathol NO-0424 Oslo Norway Univ Oslo Fac Med Oslo Norway Akershus Univ Hosp Dept Digest Surg Lorenskog Norway Oslo Univ Hosp Dept Gastrointestinal Surg NO-0424 Oslo Norway Sorlandet Hosp Dept Gastrointestinal Surg Kristiansand Norway Sorlandet Hosp Dept Surg Arendal Norway Oslo Univ Hosp Norwegian Radium Hosp Inst Med Informat NO-0424 Oslo Norway Univ Oslo Dept Informat N-0316 Oslo Norway

Colorectal cancer (CRC) incidence increases with age, and early onset of the disease is an indication of genetic predisposition, estimated to cause up to 30% of all cases. To identify genes associated with early-onset CRC, we investigated gene expression levels within a series of young patients with CRCs who are not known to carry any hereditary syndromes (n=24;mean 43 years at diagnosis), and compared this with a series of CRCs from patients diagnosed at an older age (n=17;mean 79 years). Two individual genes were found to be differentially expressed between the two groups, with statistical significance;CLC was higher and IFNAR1 was less expressed in early-onset CRCs. Furthermore, genes located at chromosome band 19q13 were found to be enriched significantly among the genes with higher expression in the early-onset samples, including CLC. An elevated immune content within the early-onset group was observed from the differentially expressed genes. By application of outlier statistics, H3F3A was identified as a top candidate gene for a subset of the early-onset CRCs. In conclusion, CLC and IFNAR1 were identified to be overall differentially expressed between early-and late-onset CRC, and are important in the development of early-onset CRC. genes and Immunity (2011) 12, 653-662;doi:10.1038/gene.2011.43;published online 30 June 2011

关键词： colorectal neoplasm early onset of disease gene expression microarray genetic predisposition hereditary cancer

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Identification of candidate genes for rituximab response in rheumatoid arthritis patients by microarray expression profiling in blood cells

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PHARMACOGENOMICS 2009年第10期10卷 1697-1708页

作者： Julia, Antonio Barcelo, Mireia Erra, Alba Palacio, Carles Marsal, Sara Hosp Valle De Hebron Inst Recerca Grp Recerca Reumatol Barcelona Spain Hosp Univ Vall dHebron Barcelona Spain

Aims: Transient CD20(+) B-cell depletion with rituximab is an effective treatment for rheumatoid arthritis (RA). However, there is a subgroup of patients that do not show significant clinical response to rituximab and for these patients, other modes of treatment are preferred. Finding biomarkers for drug response in RA has immense potential for improving treatment and lowering healthcare costs for treating RA patients by facilitating the optimization of their pharmacotherapy. In the present study, we report on gene expression profiles of three different blood cell types in rituximab responders and nonresponder RA patients identifying new candidate genes associated with rituximab response. Materials & methods: Transcriptional profiles of whole-blood, CD4(+) T cells and B cells were analyzed from nine female patients (mean age 53 +/- 11 years) with active RA disease (DAS28 > 5.1), starting rituximab therapy using Illumina (CA, USA) gene-expression microarrays. Whole-blood RNA was extracted using the PAXgene (TM) system (PreAnalytix, Hombrechtikon, Switzerland) whilst the lymphocyte RNA was obtained following cell isolation using negative selection. Flow cytometry analysis was performed to determine whole blood subpopulations, as well as the lymphocyte isolation purity. A whole-genome expression profiling was performed on the RNA samples prepared from the three blood cell populations using the Illumina Human 6 Beadchip array system version 1 (Illumina). From the group of statistically significant genes showing differential expression in rituximab responders compared with nonresponder RA patients, we selected a group of candidate genes that were subsequently validated in the same RNA samples using TaqMan (R) real-time PCR assays. Results: Several genes were identified whose level of expression is associated significantly with the response to rituximab in all three blood cell types evaluated (multiple-test corrected p-value < 0.05). Real-time PCR-validated genes include

关键词： biological agents biomarkers gene expression microarray response to therapy rheumatoid arthritis rituximab

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Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain

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PAIN 2008年第1期137卷 182-201页

作者： Levin, Margaret E. Jin, Jason G. Ji, Rui-Ru Tong, Jeifei Pomonis, James D. Lavery, Daniel J. Miller, Scott W. Chiang, Lillian W. Aestus Tehrapeut Inc No Brunswick NJ USA Galenea Cambridge MA 02139 USA MaxBio Corp N Brunswick NJ 08902 USA Bristol Myers Squibb Co Pennington NJ 08534 USA Hosp Sick Children Program Mol Struct & Funct Toronto ON M5G 1L7 Canada Chronocell Corp N Brunswick NJ USA Wyeth Ayerst Res Monmouth Jct NJ 08852 USA

Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. gene-expression micro array-analysis performed on the rat spinal nerve ligation (SNL) model of neuropathic pain revealed that multiple complement components including the Cl inhibitor, C1q alpha, beta, and gamma, C1r, C1s, C2, C3, C4, C7, and factors B, D, H, and P, were up-regulated while DAF was down-regulated. Regulation of C3 and DAF was confirmed by real-time RT-PCR and in situ hybridization. To test the hypothesis that complement plays a role in neuropathic pain, SNL rats were treated with cobra venom factor (CVF) to deplete plasma of complement component C3. Pain behavior was significantly attenuated in SNL rats treated with CVF as was complement activity at the ipsilateral dorsal root ganglia. Our results suggest the complement pathway might be a novel target for the development of neuropathic pain therapeutics. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

关键词： neuropathic pain neurogenic pain peripheral dorsal root ganglia complement activation hyperalgesia gene expression microarray neuroinflammation immune system

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Upregulation of eIF-5A1 in the paralyzed muscle after spinal cord transection associates with spontaneous hindlimb locomotor recovery in rats by upregulation of the ErbB, MAPK and neurotrophin signal pathways

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JOURNAL OF PROTEOMICS 2013年 91卷 188-199页

作者： Shang, Fei-Fei Zhao, Wei Zhao, Qi Liu, Jia Li, Da-Wei Zhang, Hua Zhou, Xin-Fu Li, Cheng-Yun Wang, Ting-Hua Sichuan Univ West China Hosp Inst Neurol Dis State Key LabBiotherapy & Translat Neurosci Ctr Chengdu 610041 Peoples R China Kunming Med Univ Inst Neurosci Kunming 650031 Peoples R China Yunnan Agr Univ Educ Minist China Key Lab Agrobiodivers & Pest Management Kunming 650000 Yunnan Peoples R China Univ S Australia Sansom Inst Sch Pharm & Med Sci Adelaide SA 5001 Australia

It is well known that trauma is frequently accompanied by spontaneous functional recovery after spinal cord injury (SCI), but the underlying mechanisms remain elusive. In this study, BBB scores showed a gradual return of locomotor functions after SCT. Proteomics analysis revealed 16 differential protein spots in the gastrocnemius muscle between SCT and normal rats. Of these differential proteins, eukawotic translation initiation factor 5A1 (elf-5A1), a highly conserved molecule throughout eukaryotes, exhibited marked upregulation in the gastrocnemius muscle after SCT. To study the role of eIF-5A1 in the restoration of hindlimb locomotor functions following SCT, we used siRNA to downregulate the mRNA level of eIF-5A1. Compared with untreated SCT control rats, those subjected to eIF-5A1 knockdown exhibited impaired functional recovery. Moreover, gene expression microarrays and bioinformatic analysis showed high correlation between three main signal pathways (ErbB, MAPK and neurotrophin signal pathways) and eIF-5A1. These signal pathways regulate cell proliferation, differentiation and neurocyte growth. Consequently, eIF-5A1 played a pivotal role via these signal pathways in hindlimb locomotor functional recovery after SCT, which could pave the way for the development of a new strategy for the treatment of spinal cord injury in clinical trials. (C) 2012 Published by Elsevier B.V.

关键词： Spinal cord transection Skeletal muscle eIF-5A1 Proteomics RNAi gene expression microarray

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