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PubMed1983

A therapeutic trial of gangliosides and thymosin in the Wobbler mouse model of motor neuron disease.

Mixed bovine gangliosides have been reported to enhance neuronal regeneration and sprouting. The Wobbler mouse model of motor neuron disease was used to test the clinical effects of long-term ganglioside administration on the course of the disease. Mixed gangliosides were injected subcutaneously into a group of 5 Wobbler mice and compared to a control group of 5 Wobbler mice which received saline. Because of several reports implicating involvement of the immune system in ALS, a 3rd group of 5 Wobbler mice received thymosin. All mice were 4 weeks old at commencement of injections. The 3 groups were examined weekly and graded with respect to front leg power, ability to climb a vertical grating, and walking posture. After 4 months of treatment, no significant difference between either experimental group and the controls was found.

Animals↗
PubMed2006

Proteomic analysis of brain tissue from an Alzheimer's disease mouse model by two-dimensional difference gel electrophoresis.

We used a beta-amyloid precursor protein (APP) transgenic (Tg) mouse model that displays some of the typical Alzheimer-associated pathological features to study the brain proteoma associated with amyloid plaque deposition. Two groups (male and female) of 14-month-old Tg mice were compared with their wild type littermates. We used differential 2D electrophoresis coupled with mass spectrometry to generate one of the first complete image of changes in brain protein expression occurring in this well-recognized model of Alzheimer's disease (AD). We identified 15 different proteins, which are significantly regulated in this pathology (p<0.05, > or =1.5-fold variation in expression comparing with the wild type samples). These comprise a number of proteins that were already known to be implicated in AD and neurodegeneration, as well as several proteins which relationship with AD had not been shown before. Identified proteins were grouped according to their biological key pathways. Results obtained are discussed in view of existing bibliographic data on human AD transcriptoma and proteoma.

Alzheimer Disease↗
PubMed2006

Inflammatory response in white adipose tissue in the non-obese hormone-sensitive lipase null mouse model.

In the present study, a local inflammatory response in white adipose tissue from the nonobese HSL-null mouse model is demonstrated. The protein levels of several well-known markers of inflammation, like TNFalpha and ferritin HC, were highly increased and accompanied by an activation of NFkappaB. A number of macrophage proteins, i.e., gal-3, Capg, and MCP-4, were expressed at increased levels and immunohistochemical analyses revealed an increased infiltration of F4/80+ cells.

Adipose Tissue↗
PubMed2003

Mouse models with modified p53 sequences to study cancer and ageing.

Experiments with p53 transgenic and p53 gene-targeted mouse strains have substantiated, and in some cases challenged, a number of hypotheses on the biology of the p53 protein. New questions have emerged regarding similarities and differences between murine and human genetic networks in various tissues. Mouse models with targeted p53 alleles are now applied not only to investigate tumour susceptibility, but also to address questions pertinent to molecular epidemiology, chemoprevention, development of anticancer p53-specific pharmaceuticals, and ageing.

Aging↗
PubMed2001

Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model.

Atherosclerosis is a complex disease resulting from the interaction of multiple genes. We have used the Ldlr knockout mouse model in an interspecific genetic cross to map atherosclerosis susceptibility loci. A total of 174 (MOLF/Ei x B6.129S7-Ldlr(tm1Her)) x C57BL/6J-Ldlr(tm1Her) backcross mice, homozygous for the Ldlr null allele, were fed a Western-type diet for 3 months and then killed for quantification of aortic lesions. A genome scan was carried out by using DNA pools and microsatellite markers spaced at approximately 18-centimorgan intervals. Quantitative trait locus analysis of individual backcross mice confirmed linkages to chromosomes 4 (Athsq1, logarithm of odds = 6.2) and 6 (Athsq2, logarithm of odds = 6.7). Athsq1 affected lesions in females only whereas Athsq2 affected both sexes. Among females, the loci accounted for approximately 50% of the total variance of lesion area. The susceptible allele at Athsq1 was derived from the MOLF/Ei genome whereas the susceptible allele at Athsq2 was derived from C57BL/6J. Inheritance of susceptible alleles at both loci conferred a 2-fold difference in lesion area, suggesting an additive effect of Athsq1 and Athsq2. No associations were observed between the quantitative trait loci and levels of plasma total cholesterol, high density lipoprotein cholesterol, non-high density lipoprotein cholesterol, insulin, or body weight. We provide strong evidence for complex inheritance of atherosclerosis in mice with elevated plasma low density lipoprotein cholesterol and show a major influence of nonlipoprotein-related factors on disease susceptibility. Athsq1 and Athsq2 represent candidate susceptibility loci for human atherosclerosis, most likely residing on chromosomes 1p36--32 and 12p13--12, respectively.

Animals↗
PubMed1979

Ultrastructural observations on giardiasis in a mouse model. II. Endosymbiosis and organelle distribution in Giardia muris and Giardia lamblia.

Ultrastructural observations of Giardia muris in a mouse model revealed endosymbiotic microbes not previously reported in Giardia. Endosymbionts 240--360 nm wide, 600--1,400 nm long, and with an internal structure similar to that of bacilli were not seen entering Giardia but were found and appeared to divide within Giardia. No evidence was found of digestion of the endosymbionts by the giardia host in either the trophozoite or the cyst form. Endosymbionts were concentrated centrally around the nuclear area and were uncommon in peripheral feeding regions. The same cellular organelles seen in G. muris were found in Giardia lamblia from human jejunal biopsy material, but no endosymbionts were identified in G. lamblia trophozoites from the seven patients examined. Endosymbionts within Giardia may be found to alter trophozoite pathogenicity, metabolism, range of infectivity, antigenic surface characteristics, and host specificity, as they do in other protozoa.

Animals↗
PubMed1992

Activity and local delivery of azithromycin in a mouse model of Haemophilus influenzae lung infection.

We compared the activities of azithromycin and erythromycin against Haemophilus influenzae in a mouse model of nonparenchymatous lower respiratory tract infection. In vitro and in vivo efficacy data for both drugs were analyzed relative to their pharmacokinetics in lungs and in vivo uptake by phagocytes. Aged C57BL/6 mice (mean age, 15.1 +/- 1.9 months) were infected intratracheally with 10(8) CFU of H. influenzae serotype b. Oral drug administration was initiated 4 h after infection by various dosage regimens. In terms of bacterial killing in the lung, azithromycin was much more active than erythromycin (P less than 0.01). Its in vivo activity was also more durable after a single administration relative to the durability of three doses of erythromycin given at 6-h intervals. The MIC of azithromycin was eightfold lower than that of erythromycin, and better penetration and a longer half-life in lung tissue were achieved after a single oral administration. Phagocytes delivered increased amounts of both drugs to the infected lungs, particularly at the site of infection (bronchoalveolar airspaces), and detectable levels of azithromycin were maintained locally for long periods. The fact that the efficacy of azithromycin coincided with the arrival of large numbers of polymorphonuclear leukocytes within the airspaces suggests that active extracellular concentrations were provided by the release of azithromycin from these cells. This further supports the potential value of once-daily azithromycin regimens for the treatment of lower respiratory tract infections in humans, provided that inhibitory concentrations against common pathogens such as H. influenzae are maintained for adequate periods of time.

Administration, Oral↗
PubMed1983

Virulence of different Pseudomonas species in a burned mouse model: tissue colonization by Pseudomonas cepacia.

The virulence of Pseudomonas aeruginosa and other pseudomonads was examined in a burned mouse model. P. aeruginosa M-2 was highly virulent causing 100% mortality by 38 h with an injection of 10(2) CFU by either a subcutaneous or intraperitoneal route. Subcutaneous injection of 10(2) CFU revealed rapid multiplication of the bacteria at the burn wound with 10(8) CFU/g detectable in the burned skin by 28 h postinjection, 10(5) CFU/g of liver, and 10(3) CFU/ml of blood. Non-P. aeruginosa clinical isolates were markedly less virulent; an injection of greater than or equal to 10(7) CFU caused less than or equal to 60% lethality. P. cepacia SMH colonized the burned skin of thermally injured mice, persisting at levels of 10(7) to 10(8) CFU/g of burned skin after an initial injection of 10(5) CFU. P. cepacia persisted in the burn wound for at least 3 weeks. No organ invasion was detectable throughout this period. Studies with an additional clinical isolate of P. cepacia yielded similar results. An injection of a 10(2) CFU dose revealed that the level of persistence is dose dependent. Results suggest that the tenacious persistence of P. cepacia in the burn wound may provide a model for the study of persistent colonization and infection in a compromised host.

Animals↗
PubMed1994

Evaluation of temperature sensitivity of human papillomavirus type 11 by using the human xenograft severe combined immunodeficiency mouse model.

The temperature sensitivity of human papillomavirus type 11 was evaluated by using a human xenograft severe combined immunodeficiency mouse model. Incubation of the virus for 1 h at a temperature higher than 56 degrees C but lower than 72 degrees C was sufficient to inhibit the virally induced growth of infected human tissue. However, 100 degrees C was necessary to completely inactivate HPV type 11 genome expression.

Animals↗
PubMed2000

Antiallergic effect of apple polyphenols on the allergic model mouse.

We studied here the antiallergic effect of apple condensed tannins (ACT) administered orally to a type I allergy model mouse transplanted with an IgEL a2 hybridoma secreting anti-2,4,6-trinitrophenyl (TNP) immunoglobulin E (IgE). The oral administration of ACT significantly inhibited the ear swelling responses at 1 h after antigen-stimulation with picryl chloride. The response was dose dependent within 0.1 to 10 mg/mouse. The inhibition of the ear swelling response reached the maximal level (90% inhibition) when ACT was administered 2 h before the antigen challenge. These findings suggest that ACT has an antiallergic effect on type I allergic symptoms.

Animals↗
PubMed2002

NF-kappaB activation in light-induced retinal degeneration in a mouse model.

PURPOSE: To investigate the modulation of nuclear factor (NF)-kappaB in light-induced photoreceptor degeneration in a mouse model. METHODS: Mice were exposed to intense green light. Light-induced activation of NF-kappaB and its nuclear localization were studied by immunohistochemistry. The NF-kappaB DNA-binding activity in the retinas after exposure to light was measured by electrophoretic mobility shift assay (EMSA). Nuclear transactivation of NF-kappaB in the photoreceptor cells was determined by quantitative real-time (qRT)-PCR. The amount of NF-kappaB p65 in the photoreceptor cells after exposure to light was assessed by Western blot analysis. To obtain more photoreceptor-specific information, microdissected photoreceptor cells were used in some studies. RESULTS: By an immunohistochemical method, the perinuclear region of the photoreceptor cells was heavily labeled with an antibody to activated NF-kappaB after a 1-hour exposure to light. Nuclear localization of NF-kappaB in the photoreceptor nucleus was seen at 12 hours. In the experiments involving 3 hours of exposure to light followed by recovery in the dark, nuclear localization of NF-kappaB was also noted after 12 hours' recovery in the dark. During continuous exposure to light, the NF-kappaB DNA-binding activity gradually increased and reached its maximum at 12 hours. There was an increase of NF-kappaB p65 protein at 3 hours. The mRNA levels of IkappaBalpha were upregulated after 6 hours' exposure to light. CONCLUSIONS: Intense light activated NF-kappaB in the photoreceptor cells in vivo, increased the NF-kappaB DNA-binding activity, and increased the expression of mRNA of IkappaBalpha, a target gene of NF-kappaB.

Animals↗
PubMed2004

Establishment of transgenic mouse model carring the promoter of plunc sequence.

OBJECTIVE: To construct the vector using specific nasopharynx tissue promoter plunc to establish transgeneic mouse model. METHODS: Plunc-EGFP plasmid was digested with XhoI, the purified linearized DNA fragments were recovered by gel extraction and diluted to the final concentration of 4 microg/ml, before introduced into fertilized one-cell mouse eggs by pronuclear microinjection. RESULTS: Thirteen founder mice were obtained, 12 of which were positive for the integrated EGFP gene as detected by PCR, and 3 were positive shown by Southern blotting. CONCLUSION: Specific nasopharynx tissue promoter plunc can effectively induce exogenous gene integration into the mouse genome.

Animals↗
PubMed1994

Liver fatty acid composition correlates with body fat and sex in a multigenic mouse model of obesity.

To determine whether there is altered liver lipid-fraction fatty acid distribution in a multigenic obese mouse model, we examined livers from eight lean (0.2-4.2% carcass fat), seven intermediate (5.7-13.8%), and five obese (20.2-48.7%) backcross progeny [(C57BL/6J x Mus spretus) x C57BL/6J] aged 2-3 mo. Thirteen males and seven females were fed a nonpurified stock diet. Liver lipid fractions were separated and fatty acids quantitated by thin-layer and gas chromatography. There was a significant effect of obesity on 18:2 omega 6 in liver phospholipids (PL), cholesteryl esters, and triglycerides. PL 18:2 omega 6 was negatively correlated with carcass fat (r = -0.74, P < 0.001); 20:3 omega 6 was elevated in PL with increased obesity (P < 0.0001), and was correlated with carcass fat (r = 0.92, P < 0.0001); and 20:4 omega 6 in PL did not differ with obesity status. PL 20:3 omega 6 and 20:4 omega 6 were lower in males (P < 0.01 and 0.02, respectively) than in females. We conclude that obesity and sex affect distribution of omega 6 essential fatty acids in mouse liver lipid fractions.

Animals↗
PubMed2003

OSI-211, a novel liposomal topoisomerase I inhibitor, is active in SCID mouse models of human AML and ALL.

OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1mg/kg, d1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6-8) or late treatment (LT, days 15-19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2 x 10(7) (KBM-3B) or 1 x 10(7) (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1mg/kg qd1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6 mg/kg d1, 8 schedule. As a result, the activity of the 6 mg/kg d1, 8 schedule is detailed for each model. ET significantly (P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human beta-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly (P<0.005) improved average life span in the KBM-3B model, with an average ILS=196+/-11% and one LTS. Treatment of HL-60 leukemia animals significantly (P<0.005) increased life span, with an ILS=213+/-9% and two LTS for ET, and with an ILS=219+/-4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly (P<0.005) increased life span, with an average ILS=181+/-3% and no LTS for ET and an average ILS=172+/-1% with no LTS for LT. In the CEM model, ET resulted in a significantly (P<0.005) improved ILS=244+/-24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.

Animals↗
PubMed2002

Monitoring the correction of glycogen storage disease type 1a in a mouse model using [(18)F]FDG and a dedicated animal scanner.

Monitoring gene therapy of glycogen storage disease type 1a in a mouse model was achieved using [(18)F]FDG and a dedicated animal scanner. The G6Pase knockout (KO) mice were compared to the same mice after infusion with a recombinant adenovirus containing the murine G6Pase gene (Ad-mG6Pase). Serial images of the same mouse before and after therapy were obtained and compared with wild-type (WT) mice of the same strain to determine the uptake and retention of [(18)F]FDG in the liver. Image data were acquired from heart, blood pool and liver for twenty minutes after injection of [(18)F]FDG. The retention of [(18)F]FDG was lower for the WT mice compared to the KO mice. The mice treated with adenovirus-mediated gene therapy had retention similar to that found in age-matched WT mice. These studies show that FDG can be used to monitor the G6Pase concentration in liver of WT mice as compared to G6Pase KO mice. In these mice, gene therapy returned the liver function to that found in age matched WT controls as measured by the FDG kinetics in the liver compared to that found in age matched wild type controls.

Animals↗
PubMed2002

Characterization of a renal cell carcinoma cell line derived from a human bone metastasis and establishment of an experimental nude mouse model.

PURPOSE: We provide the necessary tools to study the biology of bone metastasis using renal cell carcinoma as a model. A relevant renal cell carcinoma cell line developed from a human bone metastasis is described and an experimental model in the nude mouse was established. MATERIALS AND METHODS: The novel cell line RBM1 was developed from bone metastasis from a patient with renal cell carcinoma. In vitro methods used to study the cell line included karyotype analysis, reverse-transcriptase polymerase chain reaction, ribonuclease protection assay and Western blot analysis. An intratibial injection model in the nude mouse resulted in bone lesions similar to those in human patients. RESULTS: Chromosomal analysis of this cell line revealed characteristic cytogenetic abnormalities common in renal cell carcinoma. RBM1 cells expressed parathyroid hormone parathyroid hormone related peptide, interleukin-6 and macrophage colony-stimulating factor, which are cytokines involved in osteoclast activation and subsequent bone resorption. Western blot analysis revealed the presence of high levels of epidermal growth factor receptor and c-MET. Reproducible osteolytic lesions developed in the nude mouse after injecting 1 x 106 cells into the tibia. CONCLUSIONS: This cell line and animal model may allow further study of the biology and mechanism of renal cell carcinoma bone metastasis.

Animals↗
PubMed1997

Staphylococcal enterotoxin B mutants (N23K and F44S): biological effects and vaccine potential in a mouse model.

Superantigens produced by Staphylococcus aureus can cause food poisoning and toxic shock syndrome. The biological activities and vaccine potential of mutant staphylococcal enterotoxin B (SEB) proteins, N23K and F44S, were studied in a lipopolysaccharide-potentiated mouse model. Although 10 micrograms of SEB per mouse is equivalent to 30 LD50, the same intraperitoneal dose of either mutant protein was nonlethal and did not elevate serum levels of tumor necrosis factors (TNF). N23K, F44S, and SEB were serologically identical in an enzyme-linked immunosorbent assay with polyclonal anti-SEB. Immunization with alum containing N23K, F44S, or SEB elicited an anti-SEB response that protected 80-87% of the mice against a 10 micrograms SEB challenge. Controls lacking an anti-SEB titer did not survive. Pooled sera from immunized mice effectively blocked SEB-induced T-cell proliferation in vitro. Naive mice survived a lethal SEB challenge when given pooled antisera 1, 2, or 4 h later, whereas the antisera failed to protect animals when administered 6 or 8 h after the toxin. Lethality at the later times was consistent with increased serum levels of TNF observed 6 h after SEB injection. These studies suggest that the N23K and F44S mutant proteins of SEB are less biologically active than the wild-type toxin, yet retain epitopes useful for eliciting a protective antibody response.

Animals↗
PubMed2002

The G gamma / T-15 transgenic mouse model of androgen-independent prostate cancer: target cells of carcinogenesis and the effect of the vitamin D analogue EB 1089.

Transgenic mouse models of prostate cancer provide unique opportunities to understand the molecular events in prostate carcinogenesis and for the preclinical testing of new therapies. We studied the G gamma T-15 transgenic mouse line, which contains the human fetal globin promoter linked to SV40 T antigen (Tag) and which develops androgen-independent prostate cancer. Using the immunohistochemistry of normal mouse prostates before tumor formation, we showed that the target cells of carcinogenesis in G gamma T-15 mice are located in the basal epithelial layer. We tested the efficacy of the 1,25(OH)(2)D(3) analogue, EB 1089, to chemoprevent prostate cancer in these transgenic mice. Compared with treatment with placebo, treatment with EB 1089 at three different time points before the onset of prostate tumors in mice did not prevent or delay tumor onset. However, EB 1089 significantly inhibited prostate tumor growth. At the highest dose, EB 1089 inhibited prostate tumor growth by 60% (P = 0.0003) and the growth in the number of metastases, although this dose also caused significant hypercalcemia and weight loss. We conducted several in vitro experiments to explore why EB 1089 did not prevent the occurrence of the primary tumors. EB 1089 significantly inhibited the growth of a Tag-expressing human prostate epithelial cell line, BPH-1, and an androgen-insensitive subline of LNCaP cells [which was not inhibited by 1,25(OH)(2)D(3)]. Thus, neither Tag expression nor androgen insensitivity explain the absence of chemopreventive effect. Conversely, neither 1,25(OH)(2)D(3) nor EB 1089 inhibited the growth of the normal rat prostate basal epithelial cell line NRP-152. It is likely that EB 1089 was not effective in delaying the growth of the primary tumor in G gamma T-15 transgenic mice because the target cells of carcinogenesis in these mice are located in the basal epithelial layer. We conclude that G gamma T-15 transgenic mice are a useful model for testing vitamin D-based therapies in androgen-insensitive prostate cancer but are not suitable for studies of vitamin D-based chemoprevention. The superiority of EB 1089 over 1,25(OH)(2)D(3) in the growth suppression of androgen-insensitive prostate cancer cells supports the use of EB 1089 in androgen-insensitive prostate cancer.

Androgens↗