Identification of Marker Genes That Discriminate between Different Myeloproliferative Disorders and Normal Individuals Including RUNX3 (AML2).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3522-3522
Author(s):  
Claudia I. Muller ◽  
Quang T. Luong ◽  
Letetia C. Jones ◽  
Julian C. Desmond ◽  
Norihiko Kawamata ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloproliferative Disorders ◽  
Differentially Expressed ◽  
Tnf Alpha ◽  
Cytokine Signaling ◽  
Marker Genes ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Myeloid Metaplasia ◽  
Expression Levels

Abstract Myeloproliferative disorders (MPD) are clonal stem cell diseases, which are defined by excessive production of cells in one or more hematopoietic lineages. The molecular mechanisms underlying the development of agnogenic myeloid metaplasia (AMM), polycythemia vera (PV), and essential thrombocythemia (ET) are currently poorly understood. We performed microarray analysis on 26 granulocyte samples from AMM (4), ET (5), PV (6) and normal (11) individuals in order to identify genes that: 1) distinguish MPD from normal samples and 2) distinguish between these diseases. Our data revealed a group of genes that were differentially expressed in MPD compared to normal or were differentially expressed between the three different diseases. Cytokine signaling has often been reported in development or progression of these diseases. Several of these aberrantly expressed genes included those involved in TGF-beta signaling. RUNX3 (AML2), a transcription factor that is involved in the signaling cascade mediated by TGF-beta, was markedly overexpressed in MPD (AMM 4.9-fold; PV 8.1-fold; ET 9.5-fold) compared to normal. TIEG1 (TGF-beta-inducible early growth response 1) was upregulated in AMM (6.4-fold), PV (9.5-fold), ET (16.7-fold) compared to normal. Moreover, TNFAIP3 (TNF alpha-induced protein 3) was overexpressed in MPD (AMM 13.8-fold; PV 11.6-fold; ET 9.3-fold) compared to normal, which might also suggest a potential role of TNF-alpha signaling in the pathogenesis of MPD. We also found several genes that could discriminate each disease from each other. For example, ZNF292 (zinc finger protein 292) was overexpressed in PV and ET (7.1-fold and 2.9-fold, respectively), but AMM had similar expression levels to normals. CCNL2 (cyclin L2) was overexpressed in ET (2.4-fold), unchanged in PV and downregulated by 5-fold in AMM compared to normal. Expression levels of all of these genes were confirmed by real-time PCR, and immunohistochemistry staining of normal and MPD samples for RUNX3 was comparable to our array data. We hypothesize that RUNX3 might play a role in myelopoiesis. RUNX3 mRNA levels in HL-60 cells cultured with ATRA (100 and 1000 nM) markedly (16 to 20-fold) and maximally increased by day 3. Levels subsided to control levels by day 7, suggesting that RUNX3 may be initially involved in HL-60 differentiation but returns to normal levels as these cells matured or underwent terminal differentiation. In MPD, the high levels of RUNX3 in the aberrant neutrophils might indicate that these cells are blocked at approximately the equivalent timepoint (day 3 for HL-60). Their differentiation program has been initiated, but they cannot undergo the final stages of terminal maturation as reflected by their high RUNX3 levels. In summary, this study identified genes, whose expression levels may serve as diagnostic markers in MPD.

scholarly journals Protective Effect of Psoralea corylifolia L. Seed Extract against Palmitate-Induced Neuronal Apoptosis in PC12 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yunkyoung Lee ◽  
Hee-Sook Jun ◽  
Yoon Sin Oh
Keyword(s):  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Marker Genes ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Protective Effects ◽  
Psoralea Corylifolia ◽  
Antioxidant Genes ◽  
Bax Protein

The extract of Psoralea corylifolia seeds (PCE) has been widely used as a herbal medicine because of its beneficial effect on human health. In this study, we investigated the protective effects and molecular mechanisms of PCE on palmitate- (PA-) induced toxicity in PC12 cells, a neuron-like cell line. PCE significantly increased cell viability in PA-treated PC12 cells and showed antiapoptotic effects, as evidenced by decreased expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, and bax protein as well as increased expression of bcl-2 protein. In addition, PCE treatment reduced PA-induced reactive oxygen species production and upregulated mRNA levels of antioxidant genes such as nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase 1. Moreover, PCE treatment recovered the expression of autophagy marker genes such as beclin-1 and p62, which was decreased by PA treatment. Treatment with isopsoralen, one of the major components of PCE extract, also recovered the expression of autophagy marker genes and reduced PA-induced apoptosis. In conclusion, PCE exerts protective effects against lipotoxicity via its antioxidant function, and this effect is mediated by activation of autophagy. PCE might be a potential pharmacological agent to protect against neuronal cell injury caused by oxidative stress or lipotoxicity.

Enhanced HDAC (Histone Deacetylase) Enzyme Activities in Blood CD 34 + Cells in Patients with Myeloid Metaplasia Myelofibrosis (MMM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4657-4657 ◽  
Author(s):  
Jen-Chin Wang ◽  
Chi Chen ◽  
Theresa Dumlao ◽  
Thong Chang ◽  
Yng-Li Xiao ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Internal Control ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Normal Volunteer ◽  
Myeloproliferative Disorders ◽  
Mrna Levels ◽  
Myeloid Metaplasia ◽  
Mutation Status ◽  
Cd 34

Abstract We previously reported that histone deacetylase (HDAC) activity is elevated, but is not correlated to the JAK-2 mutation status, in patients with myelofibrosis myeloid metaplasia (MMM) (Blood 107:319b 2005). Now we have studied more patients: totally, 17 with MMM, 19 with other myeloproliferative disorders (MPD), and 16 normal volunteers as controls. Significantly elevated HDAC levels again was shown in patients with MMM compared with other MPD patients and normal volunteer controls (p<0.05). Sixteen patients with MMM were also studied for correlation between JAK-2 mutation status and HDAC levels; no significant correlation was found. We then studied which members of HDACs were elevated in patients with MMM. cDNA was prepared from total RNA obtained from blood CD 34+ cells; then QRT-PCR was performed using pre-made mixtures of primer and FAMTAMRA-labeled probes from ABI (www.appliedbiosystems.com). Primers and probe to GAPDH were used as internal controls. Cycle threshold (Ct) values were obtained graphically for target genes and internal control GAPDH gene products. Amplification efficiencies were calculated by plotting Ct s from serial diluted cDNAs for target genes and GAPDH and all with slopes below 0.1. Δ Ct values were obtained by subtracting GAPDH Ct from target gene Ct. Relative mRNA levels were determined by subtraction of normal control Δ Ct values from MMM Δ Ct values to give ΔΔ Ct values, which were converted to 2− ΔΔ Ct (Relative Quantitation of Gene Expression). The results showed elevated HDAC1 (2.80), HDAC2 (18.45), HDAC3 (2.10), HDAC 6 (2.03) HDAC 9 (2.71), SIRT3 (70.20), and SIRT6 (39.40) and depressed HDAC4 (0.01), HDAC5 (0.001), HDAC8 (0.001), SIRT2 (0.23), SIRT5 (0.005), and SIRT7 (0.88). () indicates relative mRNA values of MMM to controls. These results suggest that HDAC activities are elevated in patients with MMM and are elevated in many members of HDAC. This study may lay the basis for using HDAC inhibitors in clinical trials treating patients with MMM.

Aplidin Improves Megakaryocytopoiesis and Halts Neo-Angiogenesis in the Gata1low Murine Model of Myelofibrosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2787-2787
Author(s):  
Maria Verrucci ◽  
Alessandro Pancrazzi ◽  
Miguel Aracil ◽  
Fabrizio Martelli ◽  
Paola Guglielmelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Microvessel Density ◽  
Molecular Mechanisms ◽  
Primary Myelofibrosis ◽  
Bone Marrow Toxicity ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Inhibition Of Angiogenesis ◽  
Angiogenesis Process

Abstract Aplidin (plitidepsin) is a marine-derived depsipeptide currently in phase II clinical trials with evidence of activity in heavily pretreated multiple myeloma, T cell lymphoma, renal cell carcinoma and melanoma. Of importance, Aplidin lacks bone marrow toxicity. The molecular mechanisms of the anti-tumor activity of the drug have been mainly ascribed to induction of apoptosis of tumor cells through the extrinsic and intrinsic pathways, and inhibition of angiogenesis through an impact on the VEGF-VEGF-R loop. Primary myelofibrosis (MF) is a complex myeloproliferative disorder associated with abnormalities of megakaryocytic (MK) proliferation and maturation which result in increased release of several cytokines in the bone marrow microenvironment. VEGF and TGF-beta, in particular, are considered responsible for the profound abnormalities of the bone marrow stroma which include increased angiogenesis and fibrosis. Mice carrying the hypomorphic Gata1low mutation express MK abnormalities similar to those observed in MF patients and develop myelofibrosis with age, a syndrome that includes an increased angiogenesis process with striking similarities with that observed in human MF. While the molecular mechanism underlying MF in human and GATA1low mice are different, the cytokine-mediated events leading to the stromal changes are probably very similar. The aim of the present study was a pre-clinical assessment of the use of Aplidin as targeted therapeutic agent to halt development of myelofibrosis in Gata1low mice. Gata1low mice at an “early MF phase” (9-months age; n= 18) received Aplidin ip at 60 mg/kg/daily/9 days for two cycles 38 days a part; a second group of “late MF phase” mice (aged &gt;12 months; n= 18) received only one course of treatment. Equivalent numbers of age-matched Gata1low mice received saline only and were used as control. A significant increase of platelet count from 150±60 to 460±50×109/L (P&lt;.05) was observed in “early MF” Gata1low mice at day 16 after the first treatment. The increase was maintained after the second course. An increase in platelet count was also observed in “late MF” Gata1low mice. Moreover, an increase of hematocrit, although not statistically significant, was observed on day 16 (from 37% to 44%) and maintained a month later. There was a normalization of total femur cellularity, which is typically reduced in diseased mice, at the end of Aplidin treatment. It was particularly pronounced in the “early MF” mice: total cells/femur increased from a median of 6×106 in untreated Gata1low mice to 15×106 at 53 days after Aplidin, as compared to a median value of 16×106 (P&lt;0.01) in wild-type mice. Similar effects on platelet count and femur cellularity were observed in a third treatment where “early MF” mice (n=36) received Aplidin at 100 mg/kg/daily for 5 days 21 days apart for a total of four courses. In this case, there was a trend, though not statistically significant, towards less Mk number and reticulin fibers/mm2 of bone marrow area, while microvessel density, measured using immunostaining for CD34, was significantly reduced after the fourth cycle from 8±1.5 to 2.6±1.6 pixel arbitrary units (P&lt;.01). mRNA levels for both TGF-beta and VEGF, measured by quantitative PCR, were significantly reduced in the bone marrow of Aplid-intreated mice (P &lt;.01 for both). These data indicate that treatment with Aplidin ameliorated at least some of the traits of the myelofibrotic phenotype expressed by Gata1low mice. In particular, the observed inhibition of TGF-beta and VEGF expression, associated with reduced microvessel density, would suggest a possible activity of the drug in human MF where levels of these two cytokines are abnormally increased.

scholarly journals Identification of Key Genes and MicroRNAs in Gastric Cancer via miRNA-mRNA Regulatory Network

2020 ◽  
Author(s):  
Chao Huang ◽  
Xiaojian Zhu ◽  
Jiefeng Zhao ◽  
Fanqin Bu ◽  
Jun Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Molecular Markers ◽  
Expression Profiling ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Differentially Expressed ◽  
Expression Levels ◽  
Receptor Interactions

Abstract Background Gastric cancer (GC) is a malignant tumor with high mortality. MicroRNAs (miRNAs) participate in various biological processes and disease pathogenesis by targeting messenger RNA (mRNA). The purpose of this study was to identify potential prognostic molecular markers of GC and to characterize the molecular mechanisms of GC. Methods A gene expression profiling dataset (GSE54129) and miRNA expression profiling dataset (GSE113486) were downloaded from the Gene Expression Omnibus (GEO) database. A miRNA-mRNA interaction network was established. Functional and pathway enrichment analyses were performed for differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) using FunRich, the clusterProfiler package, and DIANA-mirPath. Survival analysis of key molecular markers was performed using the online tool Kaplan-Meier Plotter and the database OncomiR. Finally, experiments were carried out to verify the expression levels and biological functions of a key gene. Results A total of 390 DEMs and 341 DEGs were identified. Ultimately, 45 genes and 31 miRNAs were selected to establish a miRNA-mRNA regulatory network. Four hub genes (ZFPM2, FUT9, NEUROD1 and LIPH) and six miRNAs (hsa-let-7d-5p, hsa-miR-23b-3p, hsa-miR-23a-3p, hsa-miR-133b, hsa-miR-130a-3p and hsa-miR-124-3p) were identified in the network. DEGs and DEMs were associated with ECM-receptor interactions and metabolic pathways. Two genes (ZFPM2 and LIPH) and two miRNAs (hsa-miR-23a-3p and hsa-miR-130a-3p) were observed to be related to the prognosis of GC. ZFPM2 was highly expressed in GC tissues and various GC cell lines and could promote the proliferation, invasion and migration of GC cells. Conclusion The expression levels of ZFPM2, LIPH, hsa-miR-23a-3p and hsa-miR-130a-3p were closely related to the prognosis of GC. ZFPM2 may serve as a potential molecular marker and therapeutic target for GC. ECM receptor interactions and metabolic abnormalities play a critical role in the GC progression.

scholarly journals Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice.

1993 ◽  
Vol 4 (4) ◽  
pp. 1064-1072 ◽  
Author(s):  
T Nakamura ◽  
I Ebihara ◽  
M Fukui ◽  
S Osada ◽  
Y Tomino ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Proliferating Cell Nuclear Antigen ◽  
Transforming Growth Factor ◽  
Nuclear Antigen ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Receptor Mrna ◽  
Proliferating Cell

The renal mRNA levels of endothelin (ET)-1 and ET-3 and for ET receptors A and B were measured in the cystic kidneys of cpk/cpk mice at 1, 2, and 3 wk of age. At 1 wk of age, renal ET-1 mRNA was 3.2-fold greater in cystic mice than in controls and continued to increase with the progression of cyst formation to reach 10.4-fold more than controls at 3 wk. ET-3 mRNA levels did not differ between cystic and control mice. Renal ETA and ETB receptor mRNA increased gradually in cystic mice with the progression of their cysts, reaching 4.2- and 6.3-fold increases over controls, respectively, at 3 wk. Proliferating cell nuclear antigen mRNA expression was also examined, and proliferating cell nuclear antigen mRNA levels were found to be significantly increased in the kidneys of cystic mice compared with controls: 2. 1-fold at 1 wk, 4.5-fold at 2 wk, and 7.8-fold at 3 wk. The mRNA levels for transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha) in the kidneys of cystic mice were also examined and were found to be increased progressively with age (TGF-beta, 2.1-fold at 1 wk, 4.2-fold at 2 wk, and 6.2-fold at 3 wk; TNF-alpha, 2.2-fold at 1 wk, 3.8-fold at 2 wk, and 5.4-fold at 3 wk).(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular Progenitor Profiling in Human Myeloproliferative Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 118-118
Author(s):  
Catriona H.M. Jamieson ◽  
Jason Gotlib ◽  
Mark Chao ◽  
M Rajan Mariappan ◽  
Marla LayRaj ◽  
...  
Keyword(s):  
Myeloproliferative Disorders ◽  
Diagnostic Methods ◽  
Myelogenous Leukemia ◽  
Cytokine Signaling ◽  
Beta Catenin ◽  
Prognostic Information ◽  
Differentiation Potential ◽  
Myeloid Metaplasia ◽  
Molecular Abnormalities ◽  
V617f Mutation

Abstract Myeloproliferative disorders (MPD) are clonal hematopoietic disorders characterized by a hypercellular marrow, an overabundance of distinct lineages of terminally differentiated progeny and a propensity to transform to acute myelogenous leukemia (AML). Recent reports revealed that a specific (V617F) mutation in JAK2 resulted in constitutive cytokine signaling and increased sensitivity to cytokines in a large proportion of patients with MPD. However, the stage of hematopoiesis at which this mutation occurs and whether additional mutations contribute to the evolution of MPD into AML has yet to be determined. We performed phenotypic and functional analyses of hematopoeitic stem cells (HSC), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythroid progenitors (MEP) in 63 MPD peripheral blood or bone marrow samples donated by patients with PV (n=15), essential thrombocythemia (ET; n=8), post-polycythemic myeloid metaplasia/myelofibrosis (PPMM/MF; n=5), chronic myelogenous leukemia (CML; n=7), atypical CML/myeloproliferative disease unspecified (aCML/UMPD; n=2), chronic eosinophilic leukemia (CEL; n=1), chronic myelomonocytic leukemia (CMML; n=13) and AML (n=12) in order to identify the stage of hematopoiesis at which mutations arose as well as to provide prognostic information on patients with a propensity to transform to AML. Of the MPD mononuclear cells sequenced, 12 of 15 PV, 2 of 5 ET, 3 of 3 post-polycythemic myeloid metaplasia, and 2 of 2 aCML samples were positive for the JAK2 V617F mutation. With regard to phenotypic changes in progenitor profiles, PV samples had an increase in CMP together with a distinctive IL-3Ra high population that distinguished it from all other MPD. Conversely, aCML, AML and proliferative CMML had a preponderance of GMP. Functional changes in progenitors were assessed using hematopoietic progenitor assays (Figure 1A and B). This methodology demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level in contrast to CMML, CML, aCML and AML HSC which produced a preponderance of myeloid colonies. In addition, the aberrant erythroid potential of PV HSC could be potently inhibited with a specific JAK2 inhibitor - AG490 suggesting that JAK2 plays a role in enhancing the erythroid differentiation potential of PV at the stem cell level. Finally, other molecular abnormalities were detected at the progenitor level in MPD including changes in GATA-1 and PU.1 expression, bcl-2 overexpression and beta-catenin activation that were associated with progression to AML. Thus, molecular progenitor profiling may provide prognostic information in a variety of MPD and could be a useful adjunct to current diagnostic methods. NBM versus MPD Colonies NBM versus MPD Colonies Normal BM vs PV Progenitor Colonies Normal BM vs PV Progenitor Colonies

Equivalence testing in microarray analysis: similarities in the transcriptome of human atherosclerotic and nonatherosclerotic macrophages

2010 ◽  
Vol 41 (3) ◽  
pp. 212-223 ◽  
Author(s):  
Wouter J. Eijgelaar ◽  
Anton J. G. Horrevoets ◽  
Ann-Pascale J. J. Bijnens ◽  
Mat J. A. P. Daemen ◽  
Wim F. J. Verhaegh
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
New Method ◽  
Expression Level ◽  
Marker Genes ◽  
Equivalence Testing ◽  
Expression Levels ◽  
Macrophage Populations

We focus on similarities in the transcriptome of human Kupffer cells and alveolar, splenic, and atherosclerotic plaque-residing macrophages. We hypothesized that these macrophages share a common expression signature. We performed microarray analysis on mRNA from these subsets (4 patients) and developed a novel statistical method to identify genes with significantly similar expression levels. Phenotypic and functional diversity between macrophage subpopulations reflects their plasticity to respond to microenvironmental signals. Apart from detecting differences in expression profiles, the comparison of the transcriptomes of different macrophage populations may also allow the definition of molecular similarities between these subsets. This new method calculates the maximum difference in gene expression level, based on the estimated confidence interval on that gene's expression variance. We listed the genes by equivalence ranking relative to expression level. FDR estimation was used to determine significance. We identified 500 genes with significantly equivalent expression levels in the macrophage subsets at 5.5% FDR using a confidence level of α = 0.05 for equivalence. Among these are the established macrophage marker CD68, IL1 receptor antagonist, and MHC-related CD1C. These 500 genes were submitted to IPA and GO clustering using DAVID. Additionally, hierarchical clustering of these genes in the Novartis human gene expression atlas revealed a subset of 200 genes specifically expressed in macrophages. Equivalently expressed genes, identified by this new method, may not only help to dissect common molecular mechanisms, but also to identify cell- or condition-specific sets of marker genes that can be used for drug targeting and molecular imaging.

scholarly journals Activation of alternative NF-κB signaling during recovery of disuse-induced loss of muscle oxidative phenotype

2014 ◽  
Vol 306 (6) ◽  
pp. E615-E626 ◽  
Author(s):  
A. H. V. Remels ◽  
N. A. Pansters ◽  
H. R. Gosker ◽  
A. M. W. J. Schols ◽  
R. C. J. Langen
Keyword(s):  
Molecular Mechanisms ◽  
Myosin Heavy Chain Isoforms ◽  
Sirtuin 1 ◽  
Hindlimb Suspension ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Levels ◽  
Protein Levels ◽  
Oxidative Phenotype

Physical inactivity-induced loss of skeletal muscle oxidative phenotype (OXPHEN), often observed in chronic disease, adversely affects physical functioning and quality of life. Potential therapeutic targets remain to be identified, since the molecular mechanisms involved in reloading-induced recovery of muscle OXPHEN remain incompletely understood. We hypothesized a role for alternative NF-κB, as a recently identified positive regulator of muscle OXPHEN, in reloading-induced alterations in muscle OXPHEN. Markers and regulators (including alternative NF-κB signaling) of muscle OXPHEN were investigated in gastrocnemius muscle of mice subjected to a hindlimb suspension/reloading (HLS/RL) protocol. Expression levels of oxidative phosphorylation subunits and slow myosin heavy chain isoforms I and IIA increased rapidly upon RL. After an initial decrease upon HLS, mRNA levels of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC) molecules PGC-1α and PGC-1β and mRNA levels of mitochondrial transcription factor A (Tfam) and estrogen-related receptor α increased upon RL. PPAR-δ, nuclear respiratory factor 1 (NRF-1), NRF-2α, and sirtuin 1 mRNA levels increased during RL although expression levels were unaltered upon HLS. In addition, both Tfam and NRF-1 protein levels increased significantly during the RL period. Moreover, upon RL, IKK-α mRNA and protein levels increased, and phosphorylation of P100 and subsequent processing to P52 were elevated, reflecting alternative NF-κB activation. We conclude that RL-induced recovery of muscle OXPHEN is associated with activation of alternative NF-κB signaling.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

scholarly journals Gene expression studies in Depression development and treatment: an overview of the underlying molecular mechanisms and biological processes to identify biomarkers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicole Mariani ◽  
Nadia Cattane ◽  
Carmine Pariante ◽  
Annamaria Cattaneo
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Antidepressant Medication ◽  
Postmortem Brain ◽  
Mrna Levels ◽  
Biological Processes ◽  
Brain Disorder ◽  
Expression Levels ◽  
Postmortem Brain Tissue ◽  
The Right

AbstractA combination of different risk factors, such as genetic, environmental and psychological factors, together with immune system, stress response, brain neuroplasticity and the regulation of neurotransmitters, is thought to lead to the development of major depressive disorder (MDD). A growing number of studies have tried to investigate the underlying mechanisms of MDD by analysing the expression levels of genes involved in such biological processes. These studies have shown that MDD is not just a brain disorder, but also a body disorder, and this is mainly due to the interplay between the periphery and the Central Nervous System (CNS). To this purpose, most of the studies conducted so far have mainly dedicated to the analysis of the gene expression levels using postmortem brain tissue as well as peripheral blood samples of MDD patients. In this paper, we reviewed the current literature on candidate gene expression alterations and the few existing transcriptomics studies in MDD focusing on inflammation, neuroplasticity, neurotransmitters and stress-related genes. Moreover, we focused our attention on studies, which have investigated mRNA levels as biomarkers to predict therapy outcomes. This is important as many patients do not respond to antidepressant medication or could experience adverse side effects, leading to the interruption of treatment. Unfortunately, the right choice of antidepressant for each individual still remains largely a matter of taking an educated guess.

Sign in / Sign up

Export Citation Format

Share Document