scholarly journals In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 487 ◽  
Author(s):  
Youbao Zhong ◽  
Shanshan Li ◽  
Liling Chen ◽  
Zhiyong Liu ◽  
Xiaoquan Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Background ◽  
Mouse Strains ◽  
Male Mice ◽  
In Vivo Toxicity ◽  
Genes Expression ◽  
Family Gene ◽  
Ld50 Value ◽  
Different Strains

Solasonine was reported to inhibit tumour cell growth in several different models. The in vivo toxicity of solasonine, the effects of genetic background on its toxicity, and its possible roles in regulating the expression of cyp450 family genes were still unclear and required characterisation. Here, Horn’s assays were performed on male mice from four different strains, and the expression of cyp450 family genes in their livers was examined by RT-PCR and ELISA. Mice treated by intraperitoneal injection with high levels of solasonine showed immediate post-excitatory depression, intraperitoneal tissue adhesion, and dissolving of cells in the liver. Furthermore, these four mouse strains showed different toxicological sensitivity to solasonine. The strains, in decreasing order of LD50 value, rescuing speed of body weight, and more severe pathological symptoms, were KM, ICR, C57BL/6, and BALB/c. Interestingly, more cyp450 genes were downregulated at the mRNA and/or protein level in the livers of male mice from C57BL/6 or BALB/c strains than those from KM or ICR strains. These results suggest that (1) Solasonine has hepatic toxicity and downregulates cyp450 genes expression at transcriptional and/or post-transcriptional levels; (2) Genetic background is an important factor which can affect the in vivo toxicity; (3) Downregulation of cyp450 gene expression in the liver may be a clue to help understand whether or not a given strain is sensitive to solasonine; (4) Influences on the expression of cyp450 genes should be considered when using solasonine alone, or in combination with other drugs.

Abstract 268: Strain-specific Cardiac Fibroblast Response to Isoproterenol-induced Cardiac Fibrosis

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shuin Park ◽  
Sara Ranjbarvaziri ◽  
Fides Lay ◽  
Peng Zhao ◽  
Aldons J Lusis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Expression Profiles ◽  
Inbred Mouse ◽  
Gene Expression Profiles ◽  
Mouse Strains ◽  
Sequencing Analysis ◽  
Different Strains

Fibroblasts are a heterogeneous population of cells that function within the injury response mechanisms across various tissues. Despite their importance in pathophysiology, the effects of different genetic backgrounds on fibroblast contribution to the development of disease has yet to be addressed. It has previously been shown that mice in the Hybrid Mouse Diversity Panel, which consists of 110 inbred mouse strains, display a spectrum in severity of cardiac fibrosis in response to chronic treatment of isoproterenol (ISO). Here, we characterized cardiac fibroblasts (CFbs) from three different mouse strains (C57BL/6J, C3H/HeJ, and KK/HIJ) which exhibited varying degrees of fibrosis after ISO treatment. The select strains of mice underwent sham or ISO treatment via intraperitoneally-implanted osmotic pumps for 21 days. Masson’s Trichrome staining showed significant differences in fibrosis in response to ISO, with KK/HIJ mice demonstrating the highest levels, C3H/HeJ exhibiting milder levels, and C57BL/6J demonstrating little to no fibrosis. When CFbs were isolated and cultured from each strain, the cells demonstrated similar traits at the basal level but responded to ISO stimuli in a strain-specific manner. Likewise, CFbs demonstrated differential behavior and gene expression in vivo in response to ISO. ISO treatment caused CFbs to proliferate similarly across all strains, however, immunofluorescence staining showed differential levels of CFb activation. Additionally, RNA-sequencing analysis revealed unique gene expression profiles of all three strains upon ISO treatment. Our study depicts the phenotypic heterogeneity of CFbs across different strains of mice and our results suggest that ISO-induced cardiac fibrosis is a complex process that is independent of fibroblast proliferation and is mainly driven by the activation/inhibition of genes involved in pro-fibrotic pathways.

scholarly journals Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Rebekka Medert ◽  
Andy Pironet ◽  
Lucas Bacmeister ◽  
Sebastian Segin ◽  
Juan E. Camacho Londoño ◽  
...  
Keyword(s):  
Genetic Background ◽  
Transient Receptor Potential ◽  
Cardiac Contractility ◽  
Receptor Potential ◽  
Disease Status ◽  
Mouse Strains ◽  
Mouse Heart ◽  
Transient Receptor Potential Melastatin ◽  
Different Genetic Background

AbstractTransient receptor potential melastatin 4 (TRPM4) cation channels act in cardiomyocytes as a negative modulator of the L-type Ca2+ current. Ubiquitous Trpm4 deletion in mice leads to an increased β-adrenergic inotropy in healthy mice as well as after myocardial infarction. In this study, we set out to investigate cardiac inotropy in mice with cardiomyocyte-specific Trpm4 deletion. The results guided us to investigate the relevance of TRPM4 for catecholamine-evoked Ca2+ signaling in cardiomyocytes and inotropy in vivo in TRPM4-deficient mouse models of different genetic background. Cardiac hemodynamics were investigated using pressure–volume analysis. Surprisingly, an increased β-adrenergic inotropy was observed in global TRPM4-deficient mice on a 129SvJ genetic background, but the inotropic response was unaltered in mice with global and cardiomyocyte-specific TRPM4 deletion on the C57Bl/6N background. We found that the expression of TRPM4 proteins is about 78 ± 10% higher in wild-type mice on the 129SvJ versus C57Bl/6N background. In accordance with contractility measurements, our analysis of the intracellular Ca2+ transients revealed an increase in ISO-evoked Ca2+ rise in Trpm4-deficient cardiomyocytes of the 129SvJ strain, but not of the C57Bl/6N strain. No significant differences were observed between the two mouse strains in the expression of other regulators of cardiomyocyte Ca2+ homeostasis. We conclude that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic endowment in different mouse strains as well as on the health/disease status. Therefore, the concept of inhibiting TRPM4 channels to improve cardiac contractility needs to be carefully explored in specific strains and species and prospectively in different genetically diverse populations of patients.

scholarly journals C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo

2019 ◽  
Vol 4 ◽  
pp. 124
Author(s):  
Barbara Clough ◽  
Ryan Finethy ◽  
Rabia T. Khan ◽  
Daniel Fisch ◽  
Sarah Jordan ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Genetic Background ◽  
Inbred Mouse ◽  
Shigella Flexneri ◽  
Protein Translation ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Immune Priming ◽  
Mrna Induction

Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

Abstract 328: Viral Anti-Atherogenic Proteins Alter Monocyte and Neutrophil Invasion in Mice and Bag3 Gene Expression

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Jennifer Davids ◽  
Sami Saikaly ◽  
Alexandra Lucas
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
Granzyme B ◽  
Nod Mice ◽  
Response To Treatment ◽  
Mouse Strains ◽  
Human Monocytes ◽  
Caspase 1 ◽  
Apoptotic Pathways

Aim Atherosclerosis is characterized by chronic inflammation and cell death (apoptosis). Serine protease inhibitors, or serpins, regulate inflammatory, thrombotic and apoptotic pathways. Poxviruses encode cross-class serpins that prevent host cell apoptosis. Serp-2, from Myxoma, reduces plaque, inflammation and apoptosis in animal models; CrmA, from Vaccinia, does not. Both serpins target Caspase 1 and Granzyme B, but the reasons for the differing effects in vivo are unknown. In prior research three Myxoma viral proteins, including Serp-2, reduced monocyte invasion, plaque growth, and aneurysm formation in ApoE-/- mice after angioplasty. These same proteins alter expression of a shared cohort of 48 apoptosis-related genes in human monocytes treated with camptothecin. This study assesses the effects of Serp-2 and CrmA on apoptotic gene expression in a mouse peritoneal inflammation model. Methods Mouse strains deficient for Granzyme B (GzmB, N=13) and Caspase 1 (Casp1, N=15) were compared to their respective background mice (C57Bl/6 and Nod, N=15 each) 18 hours after treatment with PMA and either Serp-2 or CrmA. RNA was isolated and analyzed by RT-PCR and normalized to GAPDH, then to the PMA-only treated control. Results Compared to human monocytes, mouse peritoneal exudates from knockout mice displayed differential alteration of BCL2-associated athanogene 3 (BAG3) in response to treatment with Serp-2 or CrmA. Serp-2 treatment reduced expression levels compared to CrmA treatment in GzmB (p=0.0267) and C57Bl/6 mice (p=0.0280). Casp1-/- mice treated with Serp-2 downregulate BAG3, expressing 9.7-fold less than Nod mice (p=0.0006), but CrmA had no significant effect in either strain. An associated differential migration of Ly6Chi and Ly6Ghi cells was also discovered in knockout mice with serpin treatments. Discussion One candidate gene found in human monocytes, BAG3, has reduced gene expression after Serp-2 treatment in mouse peritoneal exudates but increased by CrmA. BAG3 is known to alter cell migration and apoptosis, important to atherosclerotic progression. BAG3 is regulated by 3 myxomaviral proteins in human and mouse cells, underscoring a potential role as a lynchpin in viral protein anti-inflammatory and anti-apoptotic pathways.

scholarly journals Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss

2014 ◽  
Vol 369 (1637) ◽  
pp. 20120471 ◽  
Author(s):  
Federico Tinarelli ◽  
Celina Garcia-Garcia ◽  
Francesco Nicassio ◽  
Valter Tucci
Keyword(s):  
Gene Expression ◽  
Sleep Deprivation ◽  
Neuronal Plasticity ◽  
Genetic Background ◽  
Rebound Effect ◽  
Sleep Loss ◽  
Mouse Strains ◽  
Specific Gene ◽  
Expression Of Genes ◽  
Parent Of Origin

Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico , specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects.

scholarly journals Acquired Immunity to Chlamydia pneumoniae Is Dependent on Gamma Interferon in Two Mouse Strains That Initially Differ in This Respect after Primary Challenge

2000 ◽  
Vol 68 (2) ◽  
pp. 960-964 ◽  
Author(s):  
Jenni M. Vuola ◽  
Vuokko Puurula ◽  
Marjukka Anttila ◽  
P. Helena Mäkelä ◽  
Nina Rautonen
Keyword(s):  
Genetic Background ◽  
Primary Infection ◽  
Chlamydia Pneumoniae ◽  
Inbred Mouse ◽  
Gamma Interferon ◽  
Mouse Strains ◽  
Acquired Immunity ◽  
Ifn Γ

ABSTRACT The role of gamma interferon (IFN-γ) in a Chlamydia pneumoniae mouse model was studied by in vivo neutralization in two inbred mouse strains. During primary C. pneumoniaeinfection, neutralization of IFN-γ increased both the numbers of bacteria and the pneumonia score in the lungs of C57BL/6 mice but not BALB/c mice. During reinfection, the bacterial counts in the lungs were increased by IFN-γ neutralization in both mouse strains. Thus, the effect of IFN-γ neutralization was dependent on the genetic background in primary infection. However, IFN-γ appeared to be equally important in both mouse strains during reinfection.

scholarly journals Memo1 gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones

2020 ◽  
Author(s):  
Matthias B. Moor ◽  
Olivier Bonny
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Phenotypic Traits ◽  
Dietary Interventions ◽  
Calciotropic Hormones ◽  
Genes Expression ◽  
17Β Estradiol ◽  
And Control

AbstractMediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, and Memo1-deficient mice share some phenotypic traits with Fgf23- or Klotho-deficient mouse models. Here, we tested whether Memo1 gene expression is regulated by calciotropic hormones or by changing the dietary mineral load.MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17β-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression of Memo1 and control genes was assessed by qPCR.1,25(OH)2-vitamin D3 caused an acute decrease in Memo1 transcript levels in vitro, but not in vivo. None of the hormones tested had an influence on Memo1 transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affect Memo1 transcripts but altered the chosen control genes’ expression.We observed that Memo1 was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles of Klotho, Fgf23 and Memo1.

scholarly journals Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

2019 ◽  
Vol 108 (4) ◽  
pp. 291-307 ◽  
Author(s):  
Nancy M. Lainez ◽  
Djurdjica Coss
Keyword(s):  
Gene Expression ◽  
Leukemia Inhibitory Factor ◽  
Mapk Pathway ◽  
Reproductive Function ◽  
Inhibitory Factor ◽  
Spine Density ◽  
Male Mice ◽  
Subsequent Decrease ◽  
Gnrh Neurons

Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

scholarly journals Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo.

1993 ◽  
Vol 177 (3) ◽  
pp. 775-781 ◽  
Author(s):  
H L Wong ◽  
G L Costa ◽  
M T Lotze ◽  
S M Wahl
Keyword(s):  
Gene Expression ◽  
Serum Levels ◽  
Blood Monocytes ◽  
Normal Individuals ◽  
Family Gene ◽  
Activated Monocytes ◽  
Rna Stabilization ◽  
Vitro Analysis

Interleukin (IL) 4 is a multifunctional T cell-derived cytokine that inhibits cytokine production and certain effector functions in human monocytes, while enhancing others. We show that IL-4 may contribute to the downregulation and resolution of an inflammatory response by selectively promoting expression of the IL-1 receptor antagonist (IL-1ra) that blocks the action of IL-1. IL-1ra specifically binds to the IL-1 receptor without initiating signal transduction. Peripheral blood monocytes obtained from cancer patients, before and immediately after a regimen of IL-4 immunotherapy, were examined for IL-1ra gene expression. After IL-4 therapy, monocytes from the patients showed a marked increase in IL-1ra mRNA. This selective induction of IL-1ra mRNA in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (p < 0.01) during IL-4 therapy, which declined after IL-4 treatment. In vitro analysis of IL-4 regulation of monocytes from normal individuals revealed a dose-dependent induction of IL-1ra mRNA within 2-4 h after stimulation without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we demonstrate both in vitro and in vivo, suggests that IL-4 may prove clinically useful as a systemic antiinflammatory agent.

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