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PubMed2005

Mouse models of PPAR-gamma deficiency: dissecting PPAR-gamma's role in metabolic homoeostasis.

The identification of humans with mutations in PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-gamma regulates metabolic processes. Ablation of PPAR-gamma in vivo is lethal and thus dissection of PPAR-gamma function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-gamma impairment and are useful to elucidate how PPAR-gamma regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-gamma in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-gamma regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-gamma increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-gamma, some murine models suggest PPAR-gamma expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-gamma that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-gamma have provided useful in vivo systems to dissect the function of PPAR-gamma, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-gamma in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.

Adipose Tissue↗
PubMed2005

Altered immunity accompanies disease progression in a mouse model of prostate dysplasia.

Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4(+)CD25(+) T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4(+)CD25(+) regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth.

Animals↗
PubMed2006

An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model.

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.

Animals↗
PubMed2004

Effects of SanOrg123781A, a synthetic hexadecasaccharide, in a mouse model of electrically induced carotid artery injury: synergism with the antiplatelet agent clopidogrel.

SanOrg123781A is a synthetic hexadecasaccharide that displays antithrombin-dependent inhibition of factor Xa and thrombin and potent antithrombotic effects. The antithrombotic activity of SanOrg123781A has been studied in a new mouse model of arterial thrombosis, where thrombus formation was induced by the application of an electrical current to the adventitial surface of a carotid artery. In this model, antiplatelet agents such as the ADP-receptor antagonist clopidogrel (30 mg/kg, p.o. 2 h before stimulation) and the GpIIb/IIIa antagonist SR121566A [3-(N-[4-(4-[amino(imino)methyl]phenyl)-1,3-thiazol-2-yl]-N-[1-(carboxymethyl)piperidin-4-yl]amino)propionic acid, trihydrochloride] (0.3 mg/kg, i.v. 5 min before stimulation) strongly prolonged the time to occlusion (TTO) (761 and 473% increases, respectively), whereas aspirin was devoid of antithrombotic activity. Standard heparin (2 mg/kg, i.v.), the low molecular weight heparin enoxaparin (20 mg/kg, i.v.), and the synthetic, antithrombin-dependent inhibitor of factor Xa fondaparinux (10 mg/kg, i.v.) were also active in this model (742, 707, and 602% TTO increases, respectively). Interestingly, SanOrg123781A was active at much lower doses than the other oligosaccharides (554% increase in TTO at 0.3 mg/kg, i.v. 5 min before stimulation). Low doses of SanOrg123781A administered in combination with low doses of clopidogrel led to a marked increase in TTO, which was statistically more important than the additive effects of the two compounds given alone. These results indicate that SanOrg123781A exerts a potent antithrombotic activity in a mouse model of arterial thrombosis when compared with reference compounds and show that the combination of SanOrg123781A with clopidogrel leads to a marked synergistic antithrombotic effect.

Animals↗
PubMed2007

Conditional mouse models for Friedreich ataxia, a neurodegenerative disorder associating cardiomyopathy.

Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Mouse models have been important tools in dissecting the steps of pathogenesis in FRDA. Furthermore, animal models that reproduce some of the key events in a pathology are essential for the development of effective therapies, both pharmacological and gene therapy approaches. This chapter presents an overview of the current mouse models that have been developed for FRDA.

Animals↗
PubMed1994

Myogenesis in thymic transplants in the severe combined immunodeficient mouse model of myasthenia gravis. Differentiation of thymic myoid cells into striated muscle cells.

Thymic myoid cells (TMCs) bearing acetylcholine receptors (AchR) on their surface have a central role in the concept of intrathymic autosensitization in the pathogenesis of myasthenia gravis. In a SCID mouse model of myasthenia gravis, solid pieces of thymuses with lymphofollicular hyperplasia were transplanted into SCID mice. The chimeric mice displayed long-term secretion of anti-AchR antibodies. Here, we traced the fate of TMCs contained in transplanted myasthenia gravis thymuses. Unexpectedly, the number of thymic TMCs in transplanted tissue was slightly higher than in untransplanted thymus. More strikingly, the transplanted TMCs were more highly differentiated than their nontransplanted counterparts. This was demonstrated by a more than 10-fold increase of AchR-main immunogenic region epitopes recognized by monoclonal antibody 198. Some TMCs had even differentiated into striated muscle cells. The abundance of AchRs in human thymic transplants in the SCID mouse model of myasthenia gravis may help to study the mechanisms of autosensitization against the AchR in vivo.

Animals↗
PubMed2006

Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment.

BACKGROUND: The primary cause of early death in untreated Marfan syndrome (MFS) patients is aortic dilatation and dissection. METHODS AND RESULTS: We investigated whether ascending aortic samples from the fibrillin-1-underexpressing mgR mouse model for MFS or a recombinant fibrillin-1 fragment containing an elastin-binding protein (EBP) recognition sequence can act as chemotactic stimuli for macrophages. Both the aortic extracts from the mgR/mgR mice and the fibrillin-1 fragment significantly increased macrophage chemotaxis compared with extracts from wild-type mice or buffer controls. The chemotactic response was significantly diminished by pretreatment of macrophages with lactose or with the elastin-derived peptide VGVAPG and by pretreatment of samples with a monoclonal antibody directed against an EBP recognition sequence. Mutation of the EBP recognition sequence in the fibrillin-1 fragment also abolished the chemotactic response. These results indicate the involvement of EBP in mediating the effects. Additionally, investigation of macrophages in aortic specimens of MFS patients demonstrated macrophage infiltration in the tunica media. CONCLUSIONS: Our findings demonstrate that aortic extracts from mgR/mgR mice can stimulate macrophage chemotaxis by interaction with EBP and show that a fibrillin-1 fragment possesses chemotactic stimulatory activity similar to that of elastin degradation peptides. They provide a plausible molecular mechanism for the inflammatory infiltrates observed in the mgR mouse model and suggest that inflammation may represent a component of the complex pathogenesis of MFS.

Animals↗
PubMed2003

Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease.

An expanded CAG repeat is the underlying genetic defect in Huntington disease, a disorder characterized by motor, psychiatric and cognitive deficits and striatal atrophy associated with neuronal loss. An accurate animal model of this disease is crucial for elucidation of the underlying natural history of the illness and also for testing experimental therapeutics. We established a new yeast artificial chromosome (YAC) mouse model of HD with the entire human HD gene containing 128 CAG repeats (YAC128) which develops motor abnormalities and age-dependent brain atrophy including cortical and striatal atrophy associated with striatal neuronal loss. YAC128 mice exhibit initial hyperactivity, followed by the onset of a motor deficit and finally hypokinesis. The motor deficit in the YAC128 mice is highly correlated with striatal neuronal loss, providing a structural correlate for the behavioral changes. The natural history of HD-related changes in the YAC128 mice has been defined, demonstrating the presence of huntingtin inclusions after the onset of behavior and neuropathological changes. The HD-related phenotypes of the YAC128 mice show phenotypic uniformity with low inter-animal variability present, which together with the age-dependent striatal neurodegeneration make it an ideal mouse model for the assessment of neuroprotective and other therapeutic interventions.

Age Factors↗
PubMed2006

Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis.

Mosquito-borne alphaviruses are a significant cause of both encephalitic and arthritic disease in humans worldwide. In contrast to the encephalitic alphaviruses, the pathogenesis of alphavirus-induced arthritic disease is not well understood. Utilizing a mouse model of Ross River virus (RRV) disease, we found that the primary targets of RRV infection are bone, joint, and skeletal muscle tissues of the hind limbs in both outbred CD-1 mice and adult C57BL/6J mice. Moreover, histological analyses demonstrated that RRV infection resulted in severe inflammation of these tissues. Characterization of the inflammatory infiltrate within the skeletal muscle tissue identified inflammatory macrophages, NK cells, and CD4+ and CD8+ T lymphocytes. To determine the contribution of the adaptive immune system, the outcome of RRV-induced disease was examined in C57BL/6J RAG-1(-/-) mice, which lack functional T and B lymphocytes. RAG-1(-/-) and wild-type mice developed similar disease signs, infiltration of inflammatory macrophages and NK cells, and muscle pathology, suggesting that the adaptive immune response does not play a critical role in the development of disease. These results establish the mouse model of RRV disease as a useful system for the identification of viral and host factors that contribute to alphavirus-induced arthritis and myositis.

Alphavirus Infections↗
PubMed2003

Gastric transitional zones, areas where Helicobacter treatment fails: results of a treatment trial using the Sydney strain mouse model.

Current combination therapies cure Helicobacter pylori infection in 75 to 85% of cases. However, many treatment failures are not explained by antibiotic resistance. Our goal was to explore treatment failures under in vivo conditions by using the H. pylori Sydney strain (SS1) mouse model. Mice infected with H. pylori (SS1) were treated with monotherapies or combination therapies used in human trials. Bacterial levels and distribution of organisms within the stomach were assessed 24 h after treatment to determine clearance and location of treatment failures and 29 days after treatment to determine cure rates. Except for treatment with metronidazole, mono- and dual therapies did not cure infection but resulted in decreases in bacterial levels and differences in distribution within the stomach. In cases of treatment failure when clarithromycin was used, omeprazole and dual therapy with omeprazole and amoxicillin resulted in organisms being cleared from the antrum, but organisms remained in the antrum-body transitional zone. The triple therapies of OMC and bismuth subcitrate, metronidazole, and tetracycline were successful in eradicating infection. Except for metronidazole monotherapy and triple therapy with OAC, there was good correlation between the Sydney strain mouse model and humans with respect to the success of antimicrobial therapy. The antrum-body transitional zone was identified as a sanctuary site in treatment failure. This could result from antimicrobial agents not functioning effectively at this site or bacteria in this location expressing products that protect them against antimicrobial agents. This is the first demonstration of a possible sanctuary site as a reason for failure of therapy.

Amoxicillin↗
PubMed2004

Duration of action of antispasmodic agents: novel use of a mouse model as an in vivo pharmacological assay.

OBJECTIVE: Radial arteries are increasingly used as conduits for coronary artery bypass grafts, but perioperative graft vasospasm remains a concern. In vitro testing has demonstrated the efficacy of phenoxybenzamine and verapamil/nitroglycerin as topical antispasmodic agents, but their duration of action in vivo is unknown. Using an in vivo mouse model, we measured their duration of action in functioning vascular grafts, and compared this to their in vitro duration of action in ungrafted vascular segments. METHODS: Two millimetre mouse aortic segments (C57/BL6) were incubated with phenoxybenzamine, verapamil/nitroglycerin, or buffer (controls) for 15 min in organ chambers. Isometric tension responses to phenylephrine and prostaglandin F2alpha were measured at 0, 2, 6 and 12 h post-incubation. In parallel, 36 murine infrarenal aortic interposition grafts (2 mm) were performed. Twelve grafts were pre-treated (15 min) with phenoxybenzamine, 12 with verapamil/nitroglycerin and 12 remained untreated (controls). Isometric tension responses to the same agonists were measured in grafts harvested 2, 6, 13 and 23 h after surgery. RESULTS: Phenoxybenzamine prevented alpha-adrenergic vasoconstriction for up to 16 h in vivo (grafts), and 12h in vitro (ungrafted segments). Verapamil/nitroglycerin was effective for at least 2 h in vitro, but did not prevent vasoconstriction after 2 h in vivo. CONCLUSIONS: The mouse model appears to be a useful technique for assessing the pharmacological properties of antispasmodic agents in vivo. Phenoxybenzamine has an extended action in arterial grafts in vivo. Verapamil/nitroglycerin is short-lived in vivo but lasts longer in vitro. Measurements of antispasmodic duration of action in vitro should be interpreted with caution.

Animals↗
PubMed2004

Elevation of lung surfactant phosphatidylcholine in mouse models of Sandhoff and of Niemann-Pick A disease.

Sandhoff disease is caused by the defective activity of the lysosomal enzyme beta-hexosaminidase, resulting in accumulation of the glycolipids, GA2 and GM2. Niemann-Pick A/B disease is caused by the defective activity of lysosomal acid sphingomyelinase resulting in sphingomyelin accumulation. Pulmonary complications have been observed in both diseases. We now demonstrate changes in phospholipid levels in pulmonary surfactant in mouse models of these diseases. In the Hexb mouse, a model of Sandhoff disease, lipid phosphate levels were elevated in surfactant from 3- and 4-month-old mice, which was mainly due to elevated levels of phosphatidylcholine. In the ASM mouse, a model of Niemann-Pick A disease, levels of the primary storage material, sphingomyelin, were elevated as expected, and levels of phosphatidylcholine and two other phospholipids were also significantly elevated in pulmonary surfactant and in lung tissue from 5-, 6- and 7-month-old mice. These results suggest that changes in phospholipid levels and composition in lung surfactant might be a general feature of sphingolipid storage diseases, which may be in part responsible for the increased susceptibility of these patients to respiratory infections and lung pathology, often the main reason for the death of these patients.

Animals↗
PubMed2006

Mouse models of triplet repeat diseases.

Triplet repeat expansions were first discovered in 1991 and since then have been found to be the mutation underlying a range of neurodegenerative, neuromuscular, and cognitive disorders including fragile X syndrome, myotonic dystrophy, Friedreich's ataxia, and the polyglutamine disorders that include Huntington's disease. The repeats exert their detrimental effects through different molecular mechanisms dependent on whether they are located in coding or noncoding regions of the gene in question. During the past 10 yr, a wide range of strategies have been used to successfully establish mouse models for all of these disorders. This review presents an overview of these mouse models, discusses the insights into the molecular pathogenesis of these disorders that have been gained from their analysis and the strategies that are being used to uncover novel therapeutic options.

Animals↗
PubMed2002

An extract of Stachybotrys chartarum causes allergic asthma-like responses in a BALB/c mouse model.

Environmental exposure to Stachybotrys chartarum has been associated with multiple adverse health effects in humans. The goal of this study was to assess soluble components of this fungus for their ability to cause an asthma-like response in a BALB/c mouse model. Five isolates of S. chartarum were combined and extracted to form a crude antigen preparation (S. chartarum extract 1 [SCE-1]). Female BALB/c mice were sensitized by involuntary aspiration of SCE-1 and subsequently reexposed at 2, 3, and 4 weeks. To distinguish immune from nonspecific inflammatory effects, mice were exposed to 3 doses of Hanks' balanced salt solution (HBSS) and a final dose of SCE-1; or to 4 doses of bovine serum albumin (BSA) as a negative control protein. Serum and bronchoalveolar lavage fluid (BALF) were collected before the fourth aspiration (Day 0), and at Days 1, 3, and 7 following the final exposure, and lungs were fixed for histopathological examination. SCE-1-exposed mice displayed increased BALF total protein on Days 0, 1, and 3 and increased lactate dehydrogenase (LDH) at Days 1 and 3 only, compared to HBSS controls. BALF total cell numbers were elevated on each day, and differential counts of BALF cells showed neutrophilia on Day 1, marked eosinophilia on all days, and increased numbers of lymphocytes at Days 1, 3, and 7. Serum and BALF total IgE levels were elevated at all days, and BALF IL-5 levels were greatly increased (7-fold) on Day 1. Mice exposed to a single dose of SCE-1 exhibited inflammatory responses but not allergic responses, while BSA-treated mice showed neither inflammatory nor allergic responses. Histopathology confirmed the biochemical findings. Barometric whole-body plethysmography was performed 10 min prior to (baseline) and one h following each aspiration exposure in a second group of mice, to assess immediate respiratory responses. Airway hyperresponsiveness to increasing concentrations of nebulized methacholine (MCh) was assessed on Days 1 and 3 following the fourth aspiration exposure. Exposure to HBSS or BSA did not alter baseline enhanced pause (PenH) values or PenH following the aspiration exposures, nor did it cause an increase in airway responsiveness to MCh. Exposure to SCE-1 resulted in a 4.7-fold increase in PenH over baseline after the third exposure, increasing to 5.6-fold after the final exposure, and increased responsiveness to a 32 mg/ml MCh aerosol challenge. We conclude that multiple respiratory exposures to SCE-1 cause responses typical of allergic airway disease in this mouse model. However, BSA was nonallergenic and did not generate respiratory physiological responses when administered by aspiration.

Administration, Inhalation↗
PubMed2001

Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease.

Mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Huntington's disease (HD). We examined concentrations of 8-hydroxy-2-deoxyguanosine (OH(8)dG), a well-established marker of oxidative damage to DNA, in a transgenic mouse model of HD (R6/2). Increased concentrations of OH(8)dG were found in the urine, plasma and striatal microdialysates of the HD mice. Increased concentrations were also observed in isolated brain DNA at 12 and 14 weeks of age. Immunocytochemistry showed increased OH(8)dG staining in late stages of the illness. These results suggest that oxidative damage may play a role in the pathogenesis of neuronal degeneration in the R6/2 transgenic mouse model of HD.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Comparative immunohistochemical study of M-CSF and G-CSF in feto-maternal interface in a multiparity mouse model.

PROBLEM: Multiparity status has been found to bring beneficial effects both to the maintenance of pregnancy and to the offspring; however, these effects have not been fully explained. We have previously reported that placentae obtained from multiparous females belonging to a syngeneic mouse crossbreeding showed an important increase in the number of placental macrophages, suggesting that they might constitute a protective subpopulation. Taking into account that macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF) have proved to modulate macrophage activity and that both factors and/or their receptors have been found at feto-maternal interface, in this paper we analyzed the presence of M-CSF and G-CSF in placental tissue employing the same multiparity mouse model in order to investigate the influence of parity status on local immunoregulation factors of macrophage activity. METHOD OF STUDY: Three groups of mice (CBA/J x CBA/J) were analyzed: Primiparous Young, 3.0 +/- 0.5 months old (PY); Primiparous Old, 8.5 +/- 0.5 months old (PO) and Multiparous Old, 8.5 +/- 0.5 months old, with three to four previous pregnancies (MO). The presence of M-CSF and G-CSF in placental tissue was analyzed by immunohistochemistry. Cytokeratin (CK) and vimentin (VIM) expression and PAS staining were also studied. RESULTS: The three groups showed a similar immunostaining pattern for M-CSF in the whole placental trophoblast, while the expression of G-CSF was significantly higher only in the spongy zone in the MO group. Furthermore, all the MO placentae showed 5-11 layers of cells adjacent to the decidua, where G-CSF and M-CSF were highly detected. Conversely, they constituted a thin layer in PY and PO placentae. These cells were proved to be CK(+) and VIM(-) thus demonstrating their trophoblast origin. In addition, the layers closer to the decidua were also PAS+ suggesting that they could be interstitial cells, a type of invading trophoblast. CONCLUSIONS: In our mouse model, we observed an increase in the expression of G-CSF in placental spongiotrophoblast cells in multiparous females, which have been previously proposed as progenitors of the interstitial cells. Furthermore, this is the first report that indicates that parity status increases trophoblast invasion inducing a proliferative effect of the invading cells on the maternal tissue. We suggest that M-CSF and G-CSF secreted by these invading cells could favor the recruitment of macrophages to the trophoblast and might modulate their activity inducing a switch to a protective, non-inflammatory population.

Animals↗
PubMed1997

Sequestration of coenzyme A by the industrial surfactant, Toximul MP8. A possible role in the inhibition of fatty-acid beta-oxidation in a surfactant/influenza B virus mouse model for acute hepatic encephalopathy.

We have investigated the mechanistic basis of our recent observation that exposing young mice to an industrial surfactant potentiates the inhibition of fatty-acid beta-oxidation that occurs with subsequent virus infection (Murphy et al., Biochim. Biophys. Acta 1315, 208-216, 1996). In our mouse model for acute hepatic encephalopathy (AHE), neonatal mice were painted on their abdomens from birth to postnatal day 12 with nontoxic amounts of the industrial surfactant, Toximul MP8 (Tox), and then infected with a sublethal dose (LD30) of mouse-adapted human Influenza B (Lee) virus (FluB). Mortality in mice treated with Tox + FluB was significantly higher than that in mice treated with FluB alone. In vitro assays of hepatic beta-oxidation of [1-(14)C]palmitic and [1-(14)C]octanoic acids in the presence or absence of exogenous coenzyme A (CoA) indicated that Tox-mediated inhibition of oxidation was masked when CoA was added to the assays. FluB also inhibited beta-oxidation by 20-30%, however this effect was independent of exogenous CoA which suggested that it involved a different mechanism. Tox-mediated potentiation of the inhibitory effect was most obvious (> 80% inhibition) when assays were done without added CoA. Analysis of hepatic CoA and its esters indicated that levels of both free CoA and acetyl-CoA were significantly lower in mice that were painted with Tox for 12 days. Tox-dependent reductions of acetyl-CoA were transient and returned to normal values after cessation of painting, whereas those of CoA persisted. FluB infection alone significantly reduced hepatic acetyl-CoA and the magnitude of this reduction (> 30%) was not affected by pre-exposing the mice to Tox. Relative to control mice, levels of acid insoluble acyl-CoA esters were elevated significantly in FluB and Tox + FluB treated mice. Activation of both [1-(14)C]palmitic and [1-(14)C]octanoic acids was reduced in Tox-exposed mice at experimental day 12, but only when exogenous CoA was not included in the assay media; this effect appeared to persist after cessation of painting. Collectively, these data support the concept that Tox and FluB have independent effects on hepatic CoA metabolism that are associated with abnormalities in fatty-acid beta-oxidation. However, these do not fully explain the synergistic effect of the virus and chemical on beta-oxidation inhibition, which is a candidate co-mechanism for potentiation of mortality in this mouse model of AHE.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis.

Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1beta, were significantly reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice compared with that of caspase-11+/-; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.

Amyotrophic Lateral Sclerosis↗