[Show abstract][Hide abstract] ABSTRACT: The Japan Aerospace Exploration Agency developed the mouse Habitat Cage Unit (HCU) for installation in the Cell Biology Experiment Facility (CBEF) onboard the Japanese Experimental Module (“Kibo”) on the International Space Station. The CBEF provides “space-based controls” by generating artificial gravity in the HCU through a centrifuge, enabling a comparison of the biological consequences of microgravity and artificial gravity of 1 g on mice housed in space. Therefore, prior to the space experiment, a ground-based study to validate the habitability of the HCU is necessary to conduct space experiments using the HCU in the CBEF. Here, we investigated the ground-based effect of a 32-day housing period in the HCU breadboard model on male mice in comparison with the control cage mice. Morphology of skeletal muscle, the thymus, heart, and kidney, and the sperm function showed no critical abnormalities between the control mice and HCU mice. Slight but significant changes caused by the HCU itself were observed, including decreased body weight, increased weights of the thymus and gastrocnemius, reduced thickness of cortical bone of the femur, and several gene expressions from 11 tissues. Results suggest that the HCU provides acceptable conditions for mouse phenotypic analysis using CBEF in space, as long as its characteristic features are considered. Thus, the HCU is a feasible device for future space experiments.
Preview · Article · Jan 2016 · Experimental Animals
[Show abstract][Hide abstract] ABSTRACT: Protein arginine methyltransferase 1 (PRMT1) is involved in cell proliferation, DNA damage response, and transcriptional regulation.
While PRMT1 is extensively expressed in the central nervous system (CNS) at embryonic and perinatal stages, the physiological
role of PRMT1 was poorly understood. Here, to investigate the primary function of PRMT1 in the CNS, we generated CNS-specific
PRMT1 knockout mice by Cre-loxP system. These mice exhibited post-natal growth retardation with tremors and most of them died
in two weeks after birth. Brain histological analyses revealed the prominent cell reduction in the white matter tracts of
the mutant mice. Furthermore, ultrastructural analysis demonstrated that myelin sheath was almost completely ablated in the
CNS of these animals. In agreement with hypomyelination, we also observed that most major myelin proteins including MBP, CNPase,
and MAG were dramatically decreased, although neuronal and astrocytic markers were preserved in the brain of CNS-specific
PRMT1 knockout mice. These animals had reduced number of OLIG2+ oligodendrocyte lineage cells in the white matter. We found
that expressions of transcription factors essential for oligodendrocyte specification and further maturation were significantly
suppressed in the brain of the mutant mice. Our findings provide evidence that PRMT1 is required for CNS development, especially
for oligodendrocyte maturation processes.
Preview · Article · Dec 2015 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Abstract Context: There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown. Objective: We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD. Methods: Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model. Results: LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice. Conclusion: In a new experimental COPD mouse model, p38 accelerates the development of emphysema.
No preview · Article · Mar 2014 · Journal of Receptor and Signal Transduction Research
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is a serious complication during pregnancy, and recent epidemiological studies indicate the association between preeclampsia and cardiac morbidity and mortality during the postpartum period. Although the risk of cardiovascular diseases in the postpartum period is affected by lactation, its role in maternal heart with a history of preeclampsia remains unclear. In this study, we investigated postpartum change in cardiac remodeling and function of pregnancy-associated hypertensive (PAH) mice with and without lactation. The systolic blood pressure was increased in PAH mice at day 19 of gestation (E19) and was reduced to normal levels in both lactating and nonlactating (NL) groups in the postpartum period. Histological analyses revealed that cardiac hypertrophy and macrophage infiltration in PAH mice at E19 were improved in both lactating and NL groups at 4 weeks postpartum (4W-PP), while marked fibrosis remained. Increased mRNA expression of profibrotic genes and proinflammatory cytokines in PAH mice at E19 was significantly reduced in both lactating and NL groups at 4W-PP. Echocardiographic analysis found no significant differences in fractional shortening between PAH mice and C57BL/6J mice at E19. On the other hand, at 4W-PP, NL PAH mice showed normal fractional shortening, but lactating PAH mice exhibited significant decreases in cardiac contractility compared with NL PAH mice. These results show that cardiac remodeling induced by hypertension during pregnancy are improved in the postpartum period except fibrosis, whereas lactation induces cardiac contractile dysfunction in mice with a history of pregnancy-associated hypertension.
[Show abstract][Hide abstract] ABSTRACT: One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses.
In this study, we analyzed the roles of p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis
(EAE). p38α+/− mice (p38α−/− showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC)
from sensitized WT mice with MOG(35–55) to naive WT-induced EAE was much more severe compared with the case using LNC from
sensitized p38α+/− mice. Comprehensive analysis of cytokines from MOG(35–55)-challenged LNC by Western blot array revealed that production of
IL-17 was significantly reduced by a single copy disruption of the p38α gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization
of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription
of the Il17 gene. Furthermore, oral administration of a highly specific p38α inhibitor (UR-5269) to WT mice at the onset of EAE markedly
suppressed the progression of EAE compared with a vehicle group. These results suggest that p38α participates in the pathogenesis
of EAE through IL-17 induction.
Preview · Article · May 2012 · Journal of Biological Chemistry