Chimeric mice with hepatocyte-humanized liver as an appropriate model to study human peroxisome proliferator-activated receptor-α.

Peroxisome proliferator (PP)-activated receptor-α (PPARα) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARα gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%.

Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice.

Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyper-filtration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated.

Gene expression in livers of BALB/C and C57BL/6J mice fed a high-fat diet.

We previously demonstrated that high-fat diet (HFD)-induced hepatic lipid accumulation is more severe in BALB/c mice than in C57BL/6J (B6) mice. To understand the changes in liver metabolism, we studied blood chemistry, gene expression, and histopathological changes of the liver in nine-week HFD-fed BALB/c and B6 mice and one- or four-week HFD-fed BALB/c mice. Serum total cholesterol and triglyceride levels were significantly increased in all HFD-fed groups, and one- and four-week HFD-fed BALB/c groups, respectively.

Spontaneous poorly differentiated carcinoma with cells positive for vimentin in a salivary gland of a young rat.

Spontaneous salivary gland tumors in rats are rare. The authors report a poorly differentiated carcinoma of a submandibular gland in a ten-week-old rat that was positive for vimentin. Microscopically, the neoplastic cells showed a diffuse growth pattern in most areas of the tumor mass and a nestlike structure in a part of the peripheral area.

Fenofibrate-induced muscular toxicity is associated with a metabolic shift limited to type-1 muscles in rats.

Morphological changes and mRNA expression levels in type-1 predominant soleus and type-2 predominant tensor fasciae latae muscles of rats treated with fenofibrate were investigated. After fenofibrate by oral gavage at 300 mg/kg/day for 28 days, degeneration/necrosis and regeneration of muscle fibers, cellular infiltration, and fibrosis were seen in soleus muscle. Additionally, expression of PDK4, CPT1-M, CPT2, and FACO mRNAs was increased.

Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more.

Evaluation of gene expression related to hepatic cell maturation and differentiation in a chemically induced mouse hepatoblastoma cell line.

The MHB-2 cell line, established from a mouse hepatoblastoma (HB), was subjected to the reverse transcriptase-polymerase chain reaction (RT-PCR) for evaluation of gene expression related to cell differentiation. RNAs for c-kit, CD34, thy-1, albumin, cytokeratin (CK) 8, 18 and 19 could be detected, but expression of alpha-fetoprotein, glucose-6-phosphatase, tyrosine aminotransferase and CK7 was not observed. MHB-2 cells were positive for CK8/18 but negative for c-kit, CD34, thy-1 and albumin on protein level.

Skeletal muscle susceptibility to clofibrate induction of lesions in rats.

Morphological changes induced by clofibrate in type-1 predominant soleus, type-2 predominant tensor fasciae latae, and type-1 and -2 mixed biceps femoris muscles and diaphragm in rats were investigated. Administration of the agent at 500 or 750 mg/kg/day by oral gavage for 14 or 28 days caused lesions in the soleus muscle and diaphragm, bur no changes in the tensor fasciae latae and biceps femoris muscles. In soleus muscle, vacuolation of muscle fibers was observed in all animals treated with clofibrate, and degeneration of muscle fibers and infiltration of leukocytes were noted at 750 mg/kg/day.

Histopathological characterization of the skeletal myopathy in rasH2 mice carrying human prototype c-Ha-ras gene.

A skeletal myopathy is found in approximately 100% of rasH2 mice. To confirm detailed features of the rasH2 skeletal myopathy, the biceps femoris, diaphragm, triceps brachii, gastrocnemial (types I and II fiber-mixed muscles) and soleus muscle (type I fiber-dominant muscle) obtained from male rasH2 and non-transgenic littermates aged 10-13 and 34 weeks were examined. Variations in the muscle fiber size, early-scattered degeneration/necrosis and regeneration of muscle fibers were detected in 10-13-week-old rasH2 mice.

One-step RT-PCR without initial RNA isolation sStep for laser-microdissected tissue sample.

One-step RT-PCR procedure without initial RNA extraction step is tested for laser microdissected tissue sample. Unfixed cryosections of liver and kidney tissue of male SD rats were cut using laser microdissection system and directly used as templates for RT-PCR study. To check the sensitivity, 5, 25, 125, and 625 hepatocytes were cut and put in PCR-tube.

Immunohistochemical localization of transforming growth factor alpha in regenerating rat liver.

Immunohistochemical localization of TGF-alpha and cell proliferation kinetics during liver regeneration after two-thirds partial hepatectomy (PH) were investigated. Twenty-four to 72 hr after PH, appreciable increase in the number of TGF-alpha-positive hepatocytes was observed in zones 1 and 2. At the peak at 36 hr, almost all positive cells were stained in their nuclei.

Skeletal myopathy in transgenic mice carrying human prototype c-Ha-ras gene.

Skeletal myopathy was found in almost all-transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mouse). Microscopically, variation of the muscle fiber size, centrally placed nuclei, regenerating fibers, and interstitial fibrosis were evident; hyalinization and necrosis were sometimes observed in the skeletal muscle (femoralis and pectoralis) of the rasH2 mice. Inflammatory changes in the skeletal muscle or abnormality of adjacent peripheral nerve were not observed.