scholarly journals Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Erica M. Weekman ◽  
Tiffany L. Sudduth ◽  
Brittani R. Price ◽  
Abigail E. Woolums ◽  
Danielle Hawthorne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Time Course ◽  
Control Diet ◽  
Interleukin 1 ◽  
Amyloid Deposition ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Co Morbidity ◽  
In The Wild

Abstract Background Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice. Methods APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze. Results Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature. Conclusions The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.

scholarly journals Inducible Nitric Oxide Synthase Is Not Essential for Control of Trypanosoma cruzi Infection in Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 4081-4089 ◽  
Author(s):  
Kara L. Cummings ◽  
Rick L. Tarleton
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Trypanosoma Cruzi ◽  
Inducible Nitric Oxide Synthase ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Immune control of many intracellular pathogens, including Trypanosoma cruzi, is reported to be dependent on the production of nitric oxide. In this study, we show that mice deficient in inducible nitric oxide synthase (iNOS or NOS2) exhibit resistance to T. cruzi infection that is comparable to that of wild-type mice. This is the case for two iNOS-deficient mouse strains, Nos2tm1Lau and Nos2 N5, infected with the Brazil or Tulahuen strain of T. cruzi. In all cases, blood parasitemia, tissue parasite load, and survival rates are similar between wild-type and iNOS-deficient mice. In contrast, both wild-type and Nos2tm1Lau mice died within 32 days postinfection when treated with the nitric oxide synthase inhibitor aminoguanidine. Increased transcription of NOS1 or NOS3 is not found in iNOS-knockout (KO) mice, indicating that the absence of nitric oxide production through iNOS is not compensated for by increased production of other NOS isoforms. However, Nos2tm1Lau mice exhibit enhanced expression of tumor necrosis factor alpha, interleukin-1, and macrophage inflammatory protein 1α compared to that of wild-type mice, and these alterations may in part compensate for the lack of iNOS. These results clearly show that iNOS is not required for control of T. cruzi infection in mice.

scholarly journals Keratinocyte growth factor, tumor necrosis factor-alpha and interleukin-1 beta gene expression in cultured fibroblasts and keratinocytes from burned patients

2013 ◽  
Vol 28 (8) ◽  
pp. 551-558 ◽  
Author(s):  
Alfredo Gragnani ◽  
Bruno Rafael Müller ◽  
Ismael Dale Contrim Guerreiro da Silva ◽  
Samuel Marcos Ribeiro de Noronha ◽  
Lydia Masako Ferreira
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis ◽  
Keratinocyte Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Necrosis Factor Alpha ◽  
Cultured Fibroblasts ◽  
Factor Alpha ◽  
Beta Gene ◽  
Necrosis Factor

scholarly journals Role of Sigma Factors in Controlling Global Gene Expression in Light/Dark Transitions in the Cyanobacterium Synechocystis sp. Strain PCC 6803

2007 ◽  
Vol 189 (21) ◽  
pp. 7829-7840 ◽  
Author(s):  
Tina C. Summerfield ◽  
Louis A. Sherman
Keyword(s):  
Gene Expression ◽  
Global Gene Expression ◽  
Growth Conditions ◽  
Day Length ◽  
Regulation Of Transcription ◽  
Wild Type ◽  
Protein Levels ◽  
In The Wild ◽  
Altered Gene ◽  
Pcc 6803

ABSTRACT We report on differential gene expression in the cyanobacterium Synechocystis sp. strain PCC 6803 after light-dark transitions in wild-type, ΔsigB, and ΔsigD strains. We also studied the effect of day length in the presence of glucose on a ΔsigB ΔsigE mutant. Our results indicated that the absence of SigB or SigD predominately altered gene expression in the dark or in the light, respectively. In the light, approximately 350 genes displayed transcript levels in the ΔsigD strain that were different from those of the wild type, with over 200 of these up-regulated in the mutant. In the dark, removal of SigB altered more than 150 genes, and the levels of 136 of these were increased in the mutant compared to those in the wild type. The removal of both SigB and SigE had a major impact on gene expression under mixotrophic growth conditions and resulted in the inability of cells to grow in the presence of glucose with 8-h light and 16-h dark cycles. Our results indicated the importance of group II σ factors in the global regulation of transcription in this organism and are best explained by using the σ cycle paradigm with the stochastic release model described previously (R. A. Mooney, S. A. Darst, and R. Landick, Mol. Cell 20:335-345, 2005). We combined our results with the total protein levels of the σ factors in the light and dark as calculated previously (S. Imamura, S. Yoshihara, S. Nakano, N. Shiozaki, A. Yamada, K. Tanaka, H. Takahashi, M. Asayama, and M. Shirai, J. Mol. Biol. 325:857-872, 2003; S. Imamura, M. Asayama, H. Takahashi, K. Tanaka, H. Takahashi, and M. Shirai, FEBS Lett. 554:357-362, 2003). Thus, we concluded that the control of global transcription is based on the amount of the various σ factors present and able to bind RNA polymerase.

scholarly journals Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors.

1995 ◽  
Vol 15 (2) ◽  
pp. 943-953 ◽  
Author(s):  
R I Scheinman ◽  
A Gualberto ◽  
C M Jewell ◽  
J A Cidlowski ◽  
A S Baldwin
Keyword(s):  
Gene Expression ◽  
Hela Cells ◽  
Transcriptional Activation ◽  
Glucocorticoid Receptors ◽  
Interleukin 1 ◽  
Direct Interaction ◽  
Significant Loss ◽  
Nf Kappa B ◽  
Necrosis Factor Alpha ◽  
Important Regulator

Glucocorticoids are potent immunosuppressants which work in part by inhibiting cytokine gene transcription. We show here that NF-kappa B, an important regulator of numerous cytokine genes, is functionally inhibited by the synthetic glucocorticoid dexamethasone (DEX). In transfection experiments, DEX treatment in the presence of cotransfected glucocorticoid receptor (GR) inhibits NF-kappa B p65-mediated gene expression and p65 inhibits GR activation of a glucocorticoid response element. Evidence is presented for a direct interaction between GR and the NF-kappa B subunits p65 and p50. In addition, we demonstrate that the ability of p65, p50, and c-rel subunits to bind DNA is inhibited by DEX and GR. In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-kappa B at the levels of both DNA binding and transcriptional activation. DEX treatment of HeLa cells also results in a significant loss of nuclear p65 and a slight increase in cytoplasmic p65. These data reveal a second mechanism by which NF-kappa B activity may be regulated by DEX. We also report that RU486 treatment of wild-type GR and DEX treatment of a transactivation mutant of GR each can significantly inhibit p65 activity. In addition, we found that the zinc finger domain of GR is necessary for the inhibition of p65. This domain is also required for GR repression of AP-1. Surprisingly, while both AP-1 and NF-kappa B can be inhibited by activated GR, synergistic NF-kappa B/AP-1 activity is largely unaffected. These data suggest that NF-kappa B, AP-1, and GR interact in a complex regulatory network to modulate gene expression and that cross-coupling of NF-kappa B and GR plays an important role in glucocorticoid-mediated repression of cytokine transcription.

Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines

1990 ◽  
Vol 10 (2) ◽  
pp. 561-568
Author(s):  
H Shimizu ◽  
K Mitomo ◽  
T Watanabe ◽  
S Okamoto ◽  
K Yamamoto
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Interleukin 6 ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Necrosis Factor Alpha ◽  
Mediators Of Inflammation

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-alpha despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-kappa B transcription factor-binding motifs and binds an IL-1-TNF-alpha-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-kappa B. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-alpha in vivo. These results indicate that a nuclear factor indistinguishable from NF-kappa B is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-alpha.

Effect of 5-azacytidine on gene expression in marrow stromal cells

1989 ◽  
Vol 9 (6) ◽  
pp. 2748-2751
Author(s):  
D F Andrews ◽  
J Nemunaitis ◽  
C Tompkins ◽  
J W Singer
Keyword(s):  
Stromal Cells ◽  
Time Course ◽  
Matrix Protein ◽  
Interleukin 1 ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Marrow Stromal Cells ◽  
Necrosis Factor Alpha ◽  
Factor Alpha

When exposed to 5-azacytidine, marrow stromal cells from active long-term marrow cultures and cell lines derived from simian virus 40-transformed stromal cells rapidly upregulated c-abl and interleukin-6 transcripts while downregulating the expression of collagen I, a major matrix protein. Similar effects occurred with interleukin-1 alpha and tumor necrosis factor alpha, although the time course was considerably prolonged.

scholarly journals Time course and progression of wild type α-Synuclein accumulation in a transgenic mouse model

2013 ◽  
Vol 14 (1) ◽  
pp. 6 ◽  
Author(s):  
David Amschl ◽  
Jörg Neddens ◽  
Daniel Havas ◽  
Stefanie Flunkert ◽  
Roland Rabl ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Time Course ◽  
Transgenic Mouse Model ◽  
Wild Type

scholarly journals Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide.

1993 ◽  
Vol 178 (4) ◽  
pp. 1435-1440 ◽  
Author(s):  
R Kamijo ◽  
J Le ◽  
D Shapiro ◽  
E A Havell ◽  
S Huang ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Receptor Gene ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Bacillus Calmette Guerin ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Lps Challenge ◽  
Gamma Receptor

Mice with a targeted disruption of the interferon gamma receptor gene (IFN-gamma R0/0 mice) and control wild-type mice were inoculated with the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis. BCG infection was not lethal for wild-type mice whereas all IFN-gamma R0/0 mice died approximately 7-9 wk after inoculation. Histological examination at 2 and 6 wk after BCG inoculation showed that livers of IFN-gamma R0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, especially at 6 wk. In parallel, the livers of IFN-gamma R0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk after inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for wild-type mice. Reduced lethality of LPS correlated with a drastically reduced production of tumor necrosis factor alpha (TNF-alpha) in the IFN-gamma R0/0 mice. Interleukin 1 alpha (IL-1 alpha) and IL-6 levels in the serum were also significantly reduced in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-gamma receptor is essential for the recovery of mice from BCG infection, and that IFN-gamma is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin.

BCL-2 Inhibition with ABT-737 Prolongs Survival in an NRAS/BCL2-Mediated MOUSE MODEL of Myelodyspastic Syndrome (MDS) Progressing to ACUTE Myelogenous Leukemia (AML) by Targeting Leukemia Initiating CELLS

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 678-678
Author(s):  
Petra Gorombei ◽  
Beurlet Stephanie ◽  
Nader Omidvar ◽  
Krief Patricia ◽  
Le Pogam Carole ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Mouse Model ◽  
Transgenic Mouse Model ◽  
Wild Type ◽  
Double Transgenic Mouse ◽  
Apoptotic Genes

Abstract Abstract 678 Background and aims: BCL-2 activation plays a role in the progression of MDS to AML and BCL 2 inhibition may represent a therapeutic target in such patients. Using our double transgenic mouse model MRP8[NRASD12/BCL2], in which the transgenes induce MDS progressing to AML with dysplasia (Omidvar Cancer Res, 2007), we assessed the effect of ABT-737, a small molecule and mimetic inhibitor binding the BH3 domain of the BCL-2 family of proteins, on survival and leukemia initiating cells (LIC) in this mouse model. Methods: In this MRP8[NRASD12/hBCL2] double transgenic mouse model 2-week old mice have MDS with a mean of 6% bone marrow (BM) blasts (compared with 3% in the normal wild type littermates), while adult mice have AML, with a mean of 60% marrow blasts. In the present study, double transgenic mice were treated just after weaning and genotyping at 3 weeks of age with 75 mg/kg dose of ABT-737 (MDA & Abbott) 3 times weekly for 30 days. A cohort of mice (60 untreated and 35 treated) was followed for survival. Mice were sacrificed and BM harvested after treatment and Giemsa stained for BM analysis by microscopy (n=6 in each group), for LICs characterized as part of the lineage negative (Lin-)/Sca1+/cKit+ (LSK) population by flow cytometry (in 8 treated and 12 untreated mice), and for progenitor assays (n=4 in each group). Hematoxylin and eosin stained liver sections were examined and apoptosis assessed by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assays of liver sections (n=4 per group). RNA was extracted from Sca+ enriched spleen cells from untreated and treated mice (n=3 from each group) and assayed for gene expression profiling using exon specific arrays (Affymetrix). Results: Survival from birth of 35 treated mice was significantly longer than for 60 untreated mice (p<0.0001) underscoring drug efficacy and tolerance (Fig. 1). This correlated with a reduction of bone marrow blasts (19%±7% in treated versus 60%±6% in untreated mice, p<0.0001). After ABT-737 treatment, the proportion of BM LSK cell population decreased to nearly normal levels (normal wild type littermates mean of 3%, n=4) (12.9±1.4 in untreated versus 6.4±1.1 in treated, p<0.005)) with a complete restoration of colony growth to normal range (40±10 in wild type normal mice, 79.6±7.0 in untreated versus 48.6±13.5 in treated, p<0.01). Decreased invasion of the liver and spleen was observed due to increased apoptosis (3±2 in untreated to 50±12% in treated, p<0.001). Exon specific gene expression arrays with Sca1+ enriched splenocytes showed that 997 genes were differentially expressed between the treated and the untreated mice; 764 and 233 genes were upregulated and downregulated respectively amongst which were upregulated genes important for stem cell development, maintenance and differentiation such as TCF712 (or TCF4), PIWII2, BRMPR1a and Spp1. This may reflect the partial restoration of normal stem cell function, which is consistent with the reduced LSK and progenitor numbers. Downregulation of anti-apoptotic genes such as BCL-2a1b or upregulation of pro-apoptotic genes such as PARP4, CALPAIN2, TNFR, and CARD was observed, consistent with the TUNEL data. Restoration of normal hematopoiesis was confirmed by the upregulation of myeloid differentiation genes (CD14, CSF1, RARalpha) and down regulation of genes implicated in cell cycle (Hsp60, MYC and E2F1). Conclusions: ABT-737 extends lifespan in NRASD12/BCL2 transgenic mice, a preclinical model of high risk MDS/AML. ABT-737 targets the leukemia initiating cell, and regulates, amongst several, cell cycle (proliferation), differentiation and apoptosis pathways. These data suggest that clinical trials in high risk MDS and AML patients are warranted. Disclosures: Grange: Genosplice Technology: Employment.

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