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At least 1,567 records · Page 87Linked to original sources
PubMed2003

Inhibition of the progression of type 2 diabetes in the C57BL/6J mouse model by an anti-diabetes herbal formula.

The effects of a specifically prepared anti-diabetic herbal formula (ADHF) on the course of established diet-induced type 2 diabetes in animal subjects has been studied. In a C57BL/6J mouse model for diet induced type 2 diabetes, intervention for 12 weeks using ADHF as a diet supplement resulted in a significant inhibition of diabetes related changes in major organs usually targeted by type 2 diabetes and a significant reduction in circulating levels of glucose and insulin. Young male mice were randomly assigned to receive ad libitum exposure to either a standard rodent chow diet or to a high fat, high simple sugar, low fibre diet (diabetes induction diet), respectively for 8 weeks. All mice fed the induction diet developed abnormally high blood glucose levels at 8 weeks. Animals with confirmed diet induced diabetic blood glucose levels were again randomly assigned into one of three groups (10 subjects per group), one group was thereafter fed only the diabetes induction diet and the other two groups were thereafter fed the diabetes induction diet into which ADHF had been mixed at 4% or at 8% fi nal concentrations. Normal mice were also randomized into two groups that were fed either a regular diet alone or 8% ADHF mixed in the regular diet. Blood glucose levels markedly increased over the 20 weeks of study in the diabetic mice fed the diabetes induction diet only. In contrast, diabetic mice fed induction diet into which 4% or 8% ADHF had been incorporated showed significantly decreased blood glucose and insulin levels over the time of the study. Additional parameters significantly reduced in diabetic mice fed ADHF included insulin resistance and histopathological changes in the pancreas and liver. This is the fi rst report to our knowledge to show in vivo evidence for significantly decreased circulating glucose and insulin levels and a significant reduction of progressive damage to major target organs by the addition of an herbal diet supplement to a diabetes induction diet proven to be capable of causing and maintaining type 2 diabetes.

Animals↗
PubMed2000

A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia.

Genetically modified mice serve as a powerful tool to determine the role of specific molecules in a wide variety of biological phenomena including vascular remodeling. Several models of arterial injury have been proposed to analyze transgenic/knock-out mice, but many questions have been raised about their reproducibility and physiological significance. Here, we report a new mouse model of vascular injury that resembles balloon-angioplasty. A straight spring wire was inserted into the femoral artery via arterioctomy in a small muscular branch. The wire was left in place for one minute to denude and dilate the artery. After the wire was removed, the muscular branch was tied off and the blood flow of the femoral artery was restored. The lumen was enlarged with rapid onset of medial cell apoptosis. While the circumference of the external elastic lamina remained enlarged, the lumen was gradually narrowed by neointimal hyperplasia composed of smooth muscle cells. At 4 weeks, a concentric and homogeneous neointimal lesion was formed reproducibly in the region where the wire had been inserted. Similar exuberant hyperplasia could be induced in all strains examined (C57BL/6J, C3H/HeJ, BALB/c, and 129/SVj). This model may be widely used to study the molecular mechanism of post-angioplasty restenosis at the genetic level.

Angioplasty, Balloon↗
PubMed1982

A mouse model of alcoholism.

A model of alcoholism should demonstrate self-administration of alcohol by the animal and a withdrawal syndrome when the animal no longer has access to the drug. A mouse model is described that meets these criteria and enables the induction of "alcoholism" in a large number of animals within a short period of time. Mice were injected daily with pyrazole, an inhibitor of alcohol dehydrogenase. The animals self-administered ethanol by inhaling vapour containing a relatively constant concentration of ethanol. Self-administration was voluntary: the mice could move to a chamber without ethanol vapour. During the first six days of each experiment, the animals were prompted to select the ethanol chamber by darkening that chamber. Most mice continued to self-administer ethanol without any prompting for at least 3 days; thereafter, preference for ethanol waned. Self-administration led to measurable levels of ethanol in blood and to the development of withdrawal when infusion of vapour was stopped.

Alcohol Withdrawal Delirium↗
PubMed2006

Mouse model of human infertility: transient and local inhibition of endometrial STAT-3 activation results in implantation failure.

Embryo implantation involves a series of biochemical reactions and its failure is an important therapeutic target of infertility treatment. We established an infertile mouse model using transient and local suppression of signal transducer and activator of transcription-3 (STAT-3) activity by STAT-3 decoy transfer into the uterine cavity during implantation, resulting in <30% implantation. This infertility is caused by suppression of decidualization, which is indispensable for implantation, and independent of progesterone. These conditions may mimic clinically unexplained infertility. Our results suggest that STAT-3 could be a useful target for diagnosis and therapy of human implantation failure.

Animals↗
PubMed2006

Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease.

Previously, uridine pro-drug 2',3',5'-tri-O-acetyluridine (PN401) was shown to be protective in the mitochondrial complex II inhibitor 3-nitropropionic acid model of Huntington's disease (HD). In this study, PN401 increased survival and improved motor function on the rotarod in both R6/2 and N171-82Q polyglutamine repeat mouse models of HD. PN401 significantly decreased neurodegeneration in both the piriform cortex and striatum although PN401 decreased huntingtin protein aggregates only in the striatum. Cortical and striatal brain-derived neurotrophic factor (BDNF) protein levels were reduced in the +/- compared to the -/- N171-82Q mice and PN401 treatment significantly increased cortical BDNF in both +/- and -/- mice, but PN401 did not affect striatal BDNF. These results suggest that PN401 may have beneficial effects in the treatment of neurodegenerative diseases such as HD.

Acetates↗
PubMed2004

Abbreviated action potential kinetics in a mouse model of potassium channel overexpression during hippocampal development.

Loss or "gain" of function mutations in voltage-gated ion channels often results in an adverse neurological phenotype. We have examined the electrical characteristics of hippocampal pyramidal cells in a transgenic mouse model to determine how overexpression of a Shaker-type potassium channel subunit during early postnatal development might alter excitability properties of developing neurons. We found that in CA3 neurons potassium channel overexpression led to a transient shortening in duration of single action potentials during the first two postnatal weeks. There was an increase in maximal repolarization rate, without significant effect on the rate of rise. Transgenic CA3 neurons also showed a decrease of firing frequency in response to sustained depolarizing current injection. In contrast, repolarization of action potentials in CA1 neurons was not significantly altered by trangene expression. Western Blot Analysis of membrane-associated transgene protein indicated that transgene protein levels decreased during development, in agreement with functional measures of spike width. Our data indicate that the functional consequences of potassium channel transgene expression are dependent on cellular environment and developmental stage. A transient period of hypoexcitability during a critical period of development for CA3 neurons may contribute to the hyperexcitable phenotype observed in adult animals.

Action Potentials↗
PubMed1999

Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model.

Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.

Adenocarcinoma↗
PubMed2003

The role of activity-dependent neuroprotective protein in a mouse model of fetal alcohol syndrome.

OBJECTIVE: Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation. Peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL), related to activity-dependent neuroprotective protein (ADNP), prevent alcohol-induced damage in a mouse model of FAS. Our objective was to characterize ADNP in this model to relate this protein to the mechanisms of damage and peptide neuroprotection. STUDY DESIGN: Timed, pregnant C57Bl6/J mice were treated on day 8. Groups were control, alcohol, peptide pretreatment, or peptide alone. Embryo and decidua were harvested at 6 and 24 hours and 10 days. To evaluate ADNP expression, real-time polymerase chain reaction was performed with results presented as the ratio of ADNP-to-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) concentration. Analysis of variance was performed for overall comparisons with P<.05 considered significant. RESULTS: At 6 hours, there was no difference in ADNP between alcohol-exposed embryos compared with control embryos. At 24 hours, there was an increase in ADNP in alcohol-exposed embryos compared with controls (P<.001); these findings persisted at 10 days (P<.001). In the decidua at 6 hours, there was no difference between alcohol and control. At 24 hours, there was greater ADNP in alcohol-exposed decidua compared with controls (P<.001), which did not persist at 10 days (P=.97). Peptide pretreatment did not prevent the alcohol-induced increase in ADNP in embryo or decidua. CONCLUSION: Alcohol increased embryonic and decidual ADNP expression at 24 hours and it persisted in the embryo for 10 days. Because ADNP is a known neuroprotectant, these findings suggest that it may be released as a protective mechanism in FAS. Changes in the embryo were persistent suggesting that the embryo is more vulnerable to alcohol-induced damage than the mother.

Animals↗
PubMed2004

Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase.

Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate the essential role of AIPL1 in retina, we generated a mouse model of LCA by inactivating the Aipl1 gene. In Aipl1(-/-) retinas, the outer nuclear layer develops normally, but rods and cones then quickly degenerate. Aipl1(-/-) mice have highly disorganized, short, fragmented photoreceptor outer segments and lack both rod and cone electroretinogram responses. Recent biochemical evidence indicates that AIPL1 can enhance protein farnesylation. Our study reveals that rod cGMP phosphodiesterase, a farnesylated protein, is absent and cGMP levels are elevated in AIPL1(-/-) retinas before the onset of degeneration. Our findings demonstrate that AIPL1 enhances the stability of phosphodiesterase and is essential for photoreceptor viability.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy.

The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomal-dominant fashion. Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas. Using laser capture microdissection, we show that induced blisters healed by migration of surrounding nonphenotypic stem cells into the wound bed. This observation provides an explanation for the lack of mosaic forms of EBS-DM. In addition, we show that decreased mutant keratin 14 expression resulted in normal morphology and functions of the skin. Our results have important implications for gene therapy of EBS and other dominantly inherited diseases.

Animals↗
PubMed2002

Age-related progressive neuronal DNA damage associated with cerebral degeneration in a mouse model of accelerated senescence.

The DNA of cerebral neurons in subjects with Alzheimer's disease is extensively damaged, although the morphological features of apoptosis are absent. We investigated whether DNA is damaged in the brains of the SAMP10 strain of mouse, in which accelerated senescence is characterized by age-related cerebral atrophy and cognitive impairment. We performed quantitative terminal deoxynucleotidyl transferase-mediated digoxigenin-labeled dUTP nick end labeling (TUNEL), using paraffin sections. TUNEL positive cells increased in number in the cerebral neurons of SAMP10 mice with aging. TUNEL positive cells were widely distributed in mice at age 13-14 months, and obvious in the olfactory tubercle, anterior cingulate cortex, insular cortex, and amygdala. These TUNEL positive cells did not have the morphological features of apoptosis. Therefore, the DNA became damaged with advancing age through a mechanism other than apoptosis. SAMP10 is a useful mouse model of brain aging that mimics the progressive neuronal DNA damage associated with human neurodegenerative disorders.

Aging↗
PubMed2000

Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy.

Deletion of the murine survival of motor neuron gene (SMN) exon 7, the most frequent mutation found in spinal muscular atrophy (SMA) patients, directed to neurons but not to skeletal muscle, enabled generation of a mouse model of SMA providing evidence that motor neurons are the primary target of the gene defect. Moreover, the mutated SMN protein (SMNDeltaC15) is dramatically reduced in the motor neuron nuclei and causes a lack of gems associated with large aggregates of coilin, a coiled-body-specific protein. These results identify the lack of the nuclear targeting of SMN as the biochemical defect in SMA.

Animals↗
PubMedDate not supplied

Effect of duration of dosing on onset of ovarian failure in a chemical-induced mouse model of perimenopause.

OBJECTIVE: Repeated daily dosing with 4-vinylcyclohexene diepoxide (VCD) causes gradual ovarian failure in mice. As a result, the animal undergoes ovarian failure, but retains residual ovarian tissue. The purpose of this study was to use a mouse model to regulate the induction of a period analogous to perimenopause in women. DESIGN: Female B6C3F1 mice (28 days old; n = 8) were dosed daily for 10 or 20 days with VCD (160 mg/kg/d) or sesame oil. The animals were evaluated for reproductive function on days 10, 20, 35 after the onset of dosing, and on the day of follicle depletion. Each animal was killed at the specified time points, and ovaries, uteri, and plasma were collected. RESULTS: VCD reduced (P < 0.05) the number of primordial (by 93.2%) and primary (by 85.1%) follicles after 10 days of dosing, whereas essentially all primordial and primary follicles were lost (P < 0.05) after 20 days of dosing. The average time to ovarian failure was on day 135 for 10-day-dosed mice and on day 52 for 20-day-dosed mice. Follicle-depleted mice in both groups had decreased (P < 0.05) ovarian and uterine weights. Circulating follicle-stimulating hormone levels were increased (P < 0.05) on day 44 after the onset of dosing in 10-day-dosed mice and on day 35 in 20-day-dosed mice. CONCLUSION: These results demonstrate that ovarian failure can be caused by VCD more rapidly if repeated daily dosing occurs for a longer period. Thus, the length of time leading up to ovarian failure (model for perimenopause) can be adjusted by varying the length of exposure.

Animals↗
PubMedDate not supplied

Successful reversal of diabetes by single donor isologous islet transplantation in a mouse model.

A method for isolating mouse islets which consistently gives a high yield with good purity is described. Using a bovine serum albumin gradient, the mean yield of islets per pancreas is 425 (SEM +/- 15) with a consistent purity of over 90%. Single donor to single recipient of islets transplanted under the renal capsule restores normoglycemia in the diabetic recipients within 2 to 5 days of transplantation.

Animals↗
PubMed2002

Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31(hi)Ly-6C(neg) bone marrow precursors in a mouse model of asthma.

Airway dendritic cells (DCs) are held responsible for inducing sensitization to inhaled antigen, leading to eosinophilic airway inflammation, typical of asthma. However, less information is available about the role of these cells in ongoing inflammation. In a mouse model of asthma, sensitization to ovalbumin (OVA) was induced by intratracheal injection of myeloid OVA-pulsed DCs. Upon OVA aerosol challenge and induction of eosinophilic airway inflammation in sensitized mice, there was a time-dependent and almost 100-fold increase in the number of MHCII(+) CD11b(+) CD11c(+) endogenous airway DCs as well as CD11b(+) blood DCs. The mechanism of this increase was studied. Adoptive transfer experiments demonstrated that accumulation of airway DCs was not due to reduced migration to the mediastinal lymph nodes. Rather, the massive increase in airway and lymph node DCs was supported by an almost 3-fold expansion of myeloid CD31(hi)Ly-6C(neg) hematopoietic precursor cells in the bone marrow (BM). There was no change in any of the other 5 populations revealed by CD31/Ly-6C staining. When these CD31(hi)Ly-6C(neg) BM precursors were sorted and grown in granulocyte macrophage-colony-stimulating factor, they differentiated into MHCII(+) CD11c(+) DCs. The same CD31(hi)Ly-6C(neg) precursors also expressed the eotaxin receptor CCR3 and differentiated into eosinophils when grown in interleukin 5. Serum levels of eotaxin were doubled in mice with inflammation. These findings in an animal model of asthma suggest that the BM increases its output of myeloid precursors to meet the enhanced demand for DCs and eosinophils in inflamed airways.

Allergens↗
PubMed2003

Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization.

Macrophages are important participants in neovascularization. This study was designed to examine the role of the monocyte/macrophage chemotactic proteins, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha) in a mouse model of oxygen-induced ischemic retinopathy and to determine whether the morphology and distribution of macrophages/microglia are concomitantly altered. The MCP-1, MIP-1alpha mRNA levels increased at 3 h after ischemia. MCP-1, MIP-1alpha, and vascular endothelial growth factor protein levels were also increased markedly and were maximal on days 1, 0.5, and 1, respectively, after ischemia. In situ hybridization showed that MCP-1 and MIP-1alpha were localized in the hypoxic inner retina. Immunostaining demonstrated that the macrophages/microglia in the retina had morphological changes with enlarged processes, and some were closely associated with neovascular tufts at postnatal day 17. Coadministration of the neutralizing antibodies against MCP-1 and MIP-1alpha inhibited retinal neovascularization by 30%. Our data suggest that MCP-1 and MIP-1alpha are involved in the induction of retinal neovascularization and play a role in the inflammation induced by the ischemic retinopathy, possibly by modulating or attracting macrophages/microglia.

Animals↗
PubMed2006

A novel mouse model for preeclampsia by transferring activated th1 cells into normal pregnant mice.

Immunological imbalances have been hypothesized as a cause for the onset of preeclampsia, which is a very severe, pregnancy-related disease. We recently described a novel preeclampsia mouse model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation. This cell transfer provoked preeclampsia symptoms (increased blood pressure and glomerulonephritis accompanied by proteinuria). Interestingly, preeclampsia-like symptoms could not be detected in nonpregnant animals receiving activated Th1-like cells. Adoptive cell transfer further affected pregnancy outcome by increasing fetal rejection through an inflammatory profile of uterine immune cells. This chapter describes the methods employed to develop the model as well as additional experiments developed to analyze cellular and molecular mechanisms involved.

Animals↗
PubMed2005

Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta-cell differentiation and secretory function in the db/db mouse model of diabetes.

The beta-cell is a highly specialized cell with a unique differentiation that optimizes glucose-induced insulin secretion (GIIS). Here, we evaluated changes in gene expression that accompany beta-cell dysfunction in the db/db mouse model of type 2 diabetes. In db/db islets, mRNA levels of many genes implicated in beta-cell glucose sensing were progressively reduced with time, as were several transcription factors important for the maintenance of beta-cell differentiation. Conversely, genes normally suppressed in beta-cells, such as a variety of stress response mediators and inhibitor of differentiation/DNA binding 1, a gene capable of inhibiting differentiation, were markedly increased. We assessed whether this global alteration in the pattern of beta-cell gene expression was related more to chronic hyperglycemia or hyperlipidemia; db/db mice were treated with phlorizin, which selectively lowered plasma glucose, or bezafibrate, which selectively lowered plasma lipids. GIIS as well as the majority of the changes in gene expression were completely normalized by lowering glucose but were unaffected by lowering lipids. However, the restoration of GIIS was not accompanied by normalized uncoupling protein 2 or peroxisome proliferator-activated receptor gamma mRNA levels, which were upregulated in db/db islets. These studies demonstrate that hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta-cell differentiation and secretory function in db/db mice.

Aging↗