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PubMed2005

Toll-like receptor-4 regulation of hepatic Cyp3a11 metabolism in a mouse model of LPS-induced CNS inflammation.

Central nervous system (CNS) infection and inflammation severely reduce the capacity of cytochrome P-450 metabolism in the liver. We developed a mouse model to examine the effects of CNS inflammation on hepatic cytochrome P-450 metabolism. FVB, C57BL/6, and C3H/HeouJ mice were given Escherichia coli LPS (2.5 microg) by intracerebroventricular (ICV) injection. The CNS inflammatory response was confirmed by the elevation of TNF-alpha and/or IL-1beta proteins in the brain. In all mouse strains, LPS produced a 60-70% loss in hepatic Cyp3a11 expression and activity compared with saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis. Endotoxin was detectable (1-10 ng/ml) in serum between 15 and 120 min after ICV dosing of 2.5 microg LPS. Peripheral administration of 2.5 microg LPS by intraperitoneal injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver. The loss of Cyp3a11 in response to centrally or peripherally administered LPS could not be evoked in Toll-like receptor-4 (TLR4)-mutant (C3H/HeJ) mice, indicating that TLR4 signaling pathways are directly involved in the enzyme loss. In summary, we conclude that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection or inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4-dependent mechanism in the periphery, evoking a reduction in Cyp3a11 expression and metabolism in the liver.

Animals↗
PubMed1998

Transgenic mouse models for tumor suppressor genes.

The identification and cloning of tumor suppressor genes has mostly relied on familial human cancer predisposition syndromes and reverse genetics. Recent advances in manipulating the mouse genome by gene targeting techniques in embryonic stem (ES) cells has led to the generation of mutant mouse models mimicking many human syndromes. Mice lacking one or both alleles of known tumor suppressor genes have been generated to evaluate the normal function of these genes in vivo. These mice have proven to be highly susceptible to tumor development, indicating that the mouse is a potent in vivo assay system for tumor suppressor genes. The initiation of gonadal tumor development in mice lacking both copies of the alpha-inhibin gene demonstrates that this assay is also useful for identifying new tumor suppressor genes. In the future, murine ES cell/gene targeting strategies will continue to be used to identify novel tumor suppressors and analyze their in vivo roles in growth control.

Animals↗
PubMed1999

Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development.

The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of colonic epithelial proliferation: It is mutated in the majority of colorectal tumors, and mutations occur at early stages of tumor development in mouse and man. These mutant proteins lack most of the seven 20-amino-acid repeats and all SAMP motifs that have been associated with down-regulation of intracellular beta-catenin levels. In addition, they lack the carboxy-terminal domains that bind to DLG, EB1, and microtubulin. APC also appears to be essential in development because homozygosity for mouse Apc mutations invariably results in early embryonic lethality. Here, we describe the generation of a mouse model carrying a targeted mutation at codon 1638 of the mouse Apc gene, Apc1638T, resulting in a truncated Apc protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing all of the carboxy-terminal domains thought to be associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T mutation is compatible with postnatal life. However, homozygous mutant animals are characterized by growth retardation, a reduced postnatal viability on the B6 genetic background, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly, Apc1638T/1638T animals that survive to adulthood are tumor free. Although the full complement of Apc1638T is sufficient for proper beta-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in beta-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this function as shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling beta-catenin/Tcf signaling. These results indicate that the association with DLG, EB1, and microtubulin is less critical for the maintenance of homeostasis by APC than has been suggested previously, and that proper beta-catenin regulation by APC appears to be required for normal embryonic development and tumor suppression.

Adenomatous Polyposis Coli Protein↗
PubMedDate not supplied

Roles of IL-1 in the development of rheumatoid arthritis: consideration from mouse models.

Expression of inflammatory cytokines is augmented in the joints of patients with rheumatoid arthritis (RA). We found that cytokine levels are also elevated in the joints of a mouse arthritis model, human T-cell leukemia virus type I (HTLV-I) transgenic (Tg) mouse. Depletion of IL-1 by gene targeting greatly reduced the incidence of the disease, indicating the importance of this cytokine in the development of arthritis. Furthermore, IL-1 receptor antagonist (IL-1Ra)-deficient mice develop autoimmunity and arthritis spontaneously. These observations suggest that excess IL-1 signaling the causes autoimmunity. We show that IL-1 activates the immune system non-specifically by inducing CD40L and OX40 co-signaling molecules on T cells. In this review, the roles of IL-1 in the development of autoimmunity and arthritis in mouse models will be discussed.

Animals↗
PubMed2006

Task-based imaging of colon cancer in the Apc(Min/+) mouse model.

Optical coherence tomography (OCT), laser-induced fluorescence (LIF), and laser-scanning confocal microscopy (LSCM) were used for the task of multimodal study of healthy and adenomatous mouse colon. The results from each modality were compared with histology, which served as the gold standard. The Apc(Min/+) genetic mouse model of colon cancer was compared with wild-type mice. In addition, a special diet was used for the task of studying the origins of a 680 nm autofluorescent signal that was previously observed in colon. The study found close agreement among each of the modalities and with histology. All four modalities were capable of identifying diseased tissue accurately. The OCT and LSCM images provided complementary structural information about the tissue, while the autofluorescence signal measured by LIF and LSCM provided biochemical information. OCT and LIF were performed in vivo and nondestructively, while the LSCM and histology required extraction of the tissue. The magnitude of the 680 nm signal correlates with chlorophyll content in the mouse diet, suggesting that the autofluorescent compound is a dietary metabolite.

Adenomatous Polyposis Coli Protein↗
PubMed2005

Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome.

Anatomical analyses of occipital and temporal cortex of patients with fragile X mental retardation syndrome (FXS) and in a mouse model of the syndrome (FraX mice) compared to controls have suggested that the fragile X mental retardation protein (FMRP) is important for normal spine structural maturation and pruning. However, a recent analysis of spine properties in somatosensory cortex of young FraX mice has suggested that this region may not exhibit spine abnormalities. While spine abnormalities were present 1 week after birth in somatosensory cortex, by 4 weeks almost all spine abnormalities had disappeared, suggesting that adult spine abnormalities observed in other cortical regions may not persist post-developmentally in somatosensory cortex. To resolve this discrepancy we examined spine properties in somatosensory cortex of young (day 25) and adult (day 73-76) FraX compared to wild-type (WT) mice. Spine properties in young FraX and WT mice did not consistently differ from each other, consistent with the recent analysis of developing somatosensory cortex. However, adult FraX mice exhibited increased spine density, longer spines, more spines with an immature-appearing structure, fewer shorter spines, and fewer spines with a mature structure, a pattern consistent with prior analyses from other adult cortical brain regions in humans and mice. These findings (1) support the previous report of the absence of major spine abnormalities in the fourth postnatal week, (2) demonstrate normal spine development in WT mice, (3) demonstrate abnormal spine development after the fourth postnatal week in FraX mice, and (4) demonstrate spine abnormalities in somatosensory cortex of adult FraX compared to adult WT mice. In doing so, these findings resolve a potential conflict in the literature and more thoroughly describe the role of FMRP in spine development.

Animals↗
PubMed2002

Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS.

The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating the disease. Cyclooxygenase-2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase-2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase-2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Bacterial protease treatment of natural rubber latex alters its primary immunogenicity in a mouse model of sensitization.

The purpose of the present investigation was to determine whether enzyme-treated (ET)-NRL is less immunogenic than untreated NRL in a BALB/c mouse model of primary in vivo sensitization following repeated subcutaneous injections with the aqueous phase of ammoniated NRL or ET-NRL. Mice immunized with NRL produced IgE against NRL and ET-NRL, indicating that protease treatment did not completely destroy IgE antibody epitopes. In contrast, ET-NRL-immunized mice did not produce IgE against either NRL or ET-NRL, suggesting that enzyme treatment reduced the number of antigenic polypeptides associated with NRL below the threshold for sensitization. Thelper-lymphocytes from NRL-immunized mice proliferated and produced IL-4 when stimulated in vitro with polypeptides from NRL, but not ET-NRL. In contrast, Thelper-lymphocytes from ET-NRL-immunized mice were nonresponsive to ET-NRL or NRL. We conclude that lack of IgE production by ET-NRL-immunized mice is likely related to a lack of T-cell help in the form of IL-4, rather than enzyme digestion of IgE antibody epitopes. These data indicate that there is an immunologic rationale for production of enzyme-treated NRL-containing medical devices.

Animals↗
PubMed2003

Behavioural and anatomical effects of systemically administered leukemia inhibitory factor in the SOD1(G93A G1H) mouse model of familial amyotrophic lateral sclerosis.

We investigated the anatomical and behavioural effects of daily intraperitoneal injection of 25 microg/kg of LIF in the SOD1(G93A G1H) mouse model of familial ALS. We found some subtle beneficial behavioural changes in LIF treated mice. These included later onset of clinical disease in females as determined by clinical scoring; better grip strength in males; and delayed development of motor impairment in males as determined by the rotarod test. However, we found no significant rescue of motoneurons or prolongation of survival as a result of this systemic dose of LIF in these mice.

Aging↗
PubMed2002

Metabolic profiles of dystrophin and utrophin expression in mouse models of Duchenne muscular dystrophy.

Metabolic profiles from (1)H nuclear magnetic resonance spectroscopy have been used to describe both one and two protein systems in four mouse models related to Duchenne muscular dystrophy using the pattern recognition technique partial least squares. Robust statistical models were built for extracts and intact cardiac tissue, distinguishing mice according to expression of dystrophin. Using metabolic profiles of diaphragm, models were built describing dystrophin and utrophin, a dystrophin related protein, expression. Increased utrophin expression counteracted some of the deficits associated with dystrophic tissue. This suggests the method may be ideal for following treatment regimes such as gene therapy.

Animals↗
PubMed2003

Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease.

Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals. The goal of the present work was to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9]. We show here that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. These results suggest new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.

Animals↗
PubMed2005

Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury.

STUDY DESIGN: Experimental laboratory investigation of the role and pathways of reactive oxygen species (ROS)-mediated motor neuron cell death in a mouse model of compression spinal cord injury. OBJECTIVES: To analyze ROS-mediated oxidative stress propagation and signal transduction leading to motor neuron apoptosis induced by compression spinal cord injury. SETTING: University of Louisville Health Science Center. METHODS: Adult C57BL/6J mice and transgenic mice overexpressing SOD1 were severely lesioned at the lumbar region by compression spinal cord injury approach. Fluorescent oxidation, oxidative response gene expression and oxidative stress damage markers were used to assay spinal cord injury-mediated ROS generation and oxidative stress propagation. Biochemical and immunohistochemical analyses were applied to define the ROS-mediated motor neuron apoptosis resulted from compression spinal cord injury. RESULTS: ROS production was shown to be elevated in the lesioned spinal cord as detected by fluorescent oxidation assays. The early oxidative stress response markers, NF-kappaB transcriptional activation and c-Fos gene expression, were significantly increased after spinal cord injury. Lipid peroxidation and nucleic acid oxidation were also elevated in the lesioned spinal cord and motor neurons. Cytochrome c release, caspase-3 activation and apoptotic cell death were increased in the spinal cord motor neuron cells after spinal cord injury. On the other hand, transgenic mice overexpressing SOD1 showed lower levels of steady-state ROS production and reduction of motor neuron apoptosis compared to that of control mice after spinal cord injury. CONCLUSION: These data together provide direct evidence to demonstrate that the increased production of ROS is an early and likely causal event that contributes to the spinal cord motor neuron death following spinal cord injury. Thus, antioxidants/antioxidant enzyme intervention combined with other therapy may provide an effective approach to alleviate spinal cord injury-induced motor neuron damage and motor dysfunction.

Animals↗
PubMed2005

Genistein inhibited retinal neovascularization and expression of vascular endothelial growth factor and hypoxia inducible factor 1alpha in a mouse model of oxygen-induced retinopathy.

The effects of genistein on neovascularization, vascular endothelial growth factor (VEGF), and hypoxia inducible factor 1alpha (HIF1alpha) protein expression in a mouse model of oxygen-induced retinopathy were studied. The model of oxygen-induced retinal neovascularization was induced in newborn C57BL/6 mice by exposing 7-day-old mice to 75% oxygen for 5 days and then housing them in room air (relative hypoxia). Retinopathy was assessed by quantitation of vascular cell nuclei anterior to inner limiting membrane. Judged by relative fluorescence using a confocal scanning laser microscope coupled to a computer, VEGF and HIF1alpha protein expression were investigated. Genistein markedly inhibited the numbers of nuclei protruding above the inner limiting membrane under relative hypoxia conditions. The levels of nuclei numbers were suppressed by 50, 100, and 200 mg/kg body weight /day genistein to 87.4%, 72.0%, and 59.4%, respectively, compared to that untreated with genistein. VEGF protein was constitutively expressed in the preretinal area under normoxia conditions. Genistein markedly inhibited relative-hypoxia-elicited VEGF expression elevation in a dose-dependent manner. HIF1alpha expression was also observed in normoxia conditions. There was a 2.4-fold induction in preretinal HIF1alpha expression in oxygen-reared animals when compared to room-air-reared animals. Genistein dose-dependently suppressed HIF1alpha protein expression. These results indicated that the inhibition of VEGF and HIF1alpha protein expression by genistein may partly account for its effect on retinal neovascularization in vivo, and genistein could be an effective agent in the prevention and treatment of ocular neovascularization.

Angiogenesis Inhibitors↗
PubMed2025

Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San in a chronic unpredictable mild stress mouse model of depression.

OBJECTIVE: To reveal the antidepressant mechanisms of Jiawei DanZhiXiaoYaoSan (,JD) in chronic unpredictable mild stress (CUMS)-induced depression in mice. METHODS: Using the CUMS mouse model of depression, the antidepressant effects of JD were assessed using the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Tandem mass tag (TMT)-based quantitative proteomic analysis of the brain was performed following JD treatment. Hierarchical clustering, Gene Ontology function annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interactions (PPIs) were used to analyze differentially expressed proteins (DEPs), which were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: Behavioral tests confirmed the anti-depressant effects of JD, and bioinformatics analysis revealed 59 DEPs, including 33 up-regulated and 26 down-regulated proteins, between the CUMS and JD-M groups. KEGG and PPI analyses revealed that neuro-filament proteins and the Ras signaling pathway may be key targets of JD in the treatment of depression. qRT-PCR and Western blotting results demonstrated that CUMS reduced the protein expression of neurofilament light (NEFL) and medium (NEFM) and inhibited the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2), whereas JD promoted the phosphorylation of ERK1/2 and up-regulated the protein expression of NEFL and NEFM. CONCLUSIONS: The antidepressant mechanism of JD may be related to the up-regulation of p-ERK1/2 and neurofilament proteins.

Animals↗
PubMed2005

MRI of fat distribution in a mouse model of lysosomal acid lipase deficiency.

OBJECTIVE: We assessed the use of MRI in the evaluation of abdominal fat distribution in a lysosomal acid lipase (LAL)-deficient mouse model. MATERIALS AND METHODS: LAL-deficient mice are born with a normal fat distribution but over time deplete the fat stores in the subcutaneous and retroperitoneal tissues and accumulate fat in the liver, spleen, and bowel. Four MRI studies of LAL-deficient mice and control mice were obtained with 3-T T1-weighted spin-echo images and volume segmentation processing to create parameters for the study of fat distribution: intraabdominal adipose tissue-subcutaneous adipose tissue (IAT/SAT) ratio, liver volume, reproductive fat, and retroperitoneal fat. MRI adiposity parameters in LAL-deficient mice were compared with those in control mice. Adiposity volumes calculated on MRI were compared with those calculated at autopsy. RESULTS: Statistically significant differences were found between LAL-deficient and control mice for IAT/SAT ratio (p=0.0336), liver volume (p=0.0336), and reproductive fat (p=0.0336), and a statistically significant trend was found for retroperitoneal fat (p=0.0514). No statistically significant difference was found between adiposity volumes calculated on MRI and adiposity volumes found at autopsy (all p >0.2). CONCLUSION: Use of an in vivo model showed MRI techniques to be accurate in predicting visceral adiposity. LAL-deficient mice provided a unique model showing a pattern of adipose distribution that is markedly different from that in control mice, and MRI may provide a means of evaluating therapeutic interventions sequentially.

Abdomen↗
PubMed2000

Electrochemotherapy with bleomycin against colorectal carcinoma in a mouse model: evaluations of the dose and administration route of the drug and the electric field intensity.

Effectiveness of electrochemotherapy against colorectal carcinoma (CRC) was evaluated in a mouse model. When mice with a subcutaneously established CRC tumor were administered intratumorally, intravenously or intraperitoneally with bleomycin (BLM) ranging from 1/50 to 1/2 of the 50% lethal dose, significant suppression of tumor development and even some cures were observed. When various electric field intensities ranging from 500 to 2,000 V/cm were applied for electrochemotherapy with BLM, all treatment protocols were similarly effective. Furthermore, when electrochemotherapy with the lowest dose of BLM and the lowest electric field intensity was repeated, complete cures of CRC were achieved in all animals.

Animals↗
PubMed1985

Hormonal therapy of human endometrial adenocarcinoma in a nude mouse model.

The hypothesis that 17 beta-estradiol or tamoxifen (TAM) can potentiate clinical response of endometrial cancer treated with progestin was tested in an ovariectomized nude mouse system, using a sex steroid receptor-positive and a receptor-negative human endometrial carcinoma. Animals were divided into three groups: control; 17 beta-estradiol-treated; and TAM-treated. When tumors of a group reached about 1 cm in diameter, subgroups were given either 0.9% NaCl solution (saline) or medroxyprogesterone acetate (MPA). The receptor-negative tumor grew rapidly in all three groups, and several animals were dead before or during progestin treatment. The growth rate of receptor-containing carcinoma was significantly increased in TAM-treated mice compared to controls (p less than 0.02) but significantly less than that in 17 beta-estradiol-treated animals (p less than 0.01). Endometrial carcinoma in 17 beta-estradiol-saline-treated animals continued to grow rapidly, and all animals were dead by 11 weeks. The growth of tumors in the 17 beta-estradiol-progestin group was suppressed at 11 weeks, and some of these animals lived 20 weeks. Administration of progestin to TAM-exposed animals resulted in a remarkable regression of the tumor compared to TAM-saline-treated group. The growth rate of tumors in control animals (no implants) was unaffected by progestin treatment. We conclude that, in this nude mouse model, treatment with TAM and MPA is superior to MPA alone, or 17 beta-estradiol plus MPA for sex steroid receptor-positive endometrial carcinoma.

Adenocarcinoma↗
PubMed2005

Distal Chr 4 harbors a genetic locus (Gct1) fundamental for spontaneous ovarian granulosa cell tumorigenesis in a mouse model.

The spontaneous development of juvenile-onset ovarian granulosa cell tumors in mice of the SWXJ-9 recombinant inbred strain is a model for juvenile-type granulosa cell tumors that appear in very young girls. To expedite gene discovery in this mouse model of childhood cancer, we did a gene mapping study with the SWXJ-9 recombinant inbred strain and the evolutionarily divergent Mus musculus castaneus (CAST/Ei) strain as a mapping partner. Our mapping strategy focused on autosomal determinants of susceptibility with a backcross scheme that exploited a paternal, parent-of-origin effect for a X-linked gene (Gct4) that strongly supports granulosa cell tumor development. Of 1,968 backcross females examined, we detected 81 granulosa cell tumor-bearing animals and compared their allelic inheritance patterns to non-tumor-bearing siblings in a case-control analysis. The results of our study have confirmed an important locus on mouse chromosome (Chr) 4 (Gct1) and have revealed new loci for granulosa cell tumor susceptibility (Gct7-Gct9) on Chrs 1, 2, and 13 with susceptibility alleles contributed by the SWXJ-9 progenitor. Two novel gene-gene interactions supportive for granulosa cell tumor development were also observed between loci on Chrs 17 and 18 and loci on Chrs 2 and 10. Our data substantiate the evidence that Gct1 on Chr 4 is a fundamental oncogene for granulosa cell tumorigenesis in mice and has identified additional interacting autosomal loci that support tumor development.

Animals↗