Mechanism for p38α-mediated experimental autoimmune encephalomyelitis.

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.

Angiotensin type 1 receptor blockade prevents cardiac remodeling in mice with pregnancy-associated hypertension.

Pregnancy-induced hypertension (PIH) is a life-threatening disorder for both mother and fetus; cardiac dysfunction is the major complication and can result in further deterioration. Recently, it has been recognized that aberrant activation of angiotensin type 1 receptor (AT1) signaling contributes to the pathogenesis of PIH, but the details of the relationship between cardiac injury and enhanced AT1 signaling in PIH are still unclear. We previously generated a transgenic mouse model of pregnancy-associated hypertension (PAH) via overproduction of angiotensin II, an endogenous ligand of AT1, in the maternal circulation during late pregnancy. In the present study, we administered olmesartan, an AT1 blocker, to suppress redundant AT1 signaling in PAH mice and evaluated the efficacy of this treatment in cardiac remodeling. Olmesartan treatment significantly lowered the blood pressure of PAH mice, and hypertrophy as well as increased plasma levels of cardiac injury markers were also markedly reduced. Histological analyses revealed that morphological abnormalities and fibrosis in the hearts of PAH mice recovered to the levels of normal pregnant wild-type mice after the administration of olmesartan. Moreover, in fibrotic regions of PAH hearts, olmesartan treatment significantly decreased the extent of cardiac injury and apoptosis. These results indicate that the activation of AT1 signaling pathways during maternal hypertension plays a critical role in cardiac remodeling in PAH mice, and suggest that treatment with an AT1 blocker could effectively ameliorate cardiac dysfunction during pregnancy with hypertension in vivo.

Glycoconjugate histochemistry of the secretory epithelium lining the seminal vesicles of the miniature pig.

The present study thoroughly examined the localization and characterization of glycoconjugates in the secretory epithelium lining the seminal vesicles of the miniature pig, employing light and electron microscopic histochemical procedures, including lectin methods. The present results showed the epithelial cells and luminal secretions to contain glycoconjugates with abundant neutral saccharides and a small amount of acidic saccharides, containing varying types of terminal sugar residues. At ultrastructural levels, the free surface coat of the plasma membrane was rich in alpha-D-Man, alpha-D-Glc, beta-D-Gal, GlcNAc, and sialic acid. The flocculent contents of the secretory vesicles indicated the localization of alpha-D-Man, alpha-D-Glc, alpha-L-Fuc, beta-D-Gal, GlcNAc, and sialic acid; such sugar residues were also seen in the elements of the Golgi apparatus. The present results have characterized the seminal vesicles of the miniature pig as having a high secretory activity and copiously producing glycoconjugates with various sugar residues. Such glycoconjugates appear to be indispensable substances for porcine reproduction, possibly influencing the fertilizing capacity of spermatozoa within the female genital tract.