Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1.

Spontaneous adenocarcinoma with giant cell formation in the accessory sex glands in a male Sprague-Dawley rat.

In this study, we report the features of an adenocarcinoma with giant cell formation spontaneously occurring in the accessory sex glands of a male 10-month-old Sprague-Dawley rat. A milky white mass was found in the region corresponding to the left seminal vesicle and the left coagulating gland. Histologically, tumor cells exhibited diverse growth patterns, including glandular/trabecular, cystic, and sheet-like growth areas.

Skeletal muscle cells derived from mouse skin cultures.

We have established a novel, simple, and highly reproducible method to generate skeletal muscle cells from mouse skin. Small pieces of skin from the back of mice were cultured in extracellular material-coated dishes in typical culture medium for about 3 weeks. Myotubes formed after about a week, grew into twitching myotubes, and became twitching myotube clumps after 3 weeks.

Longitudinal analysis of motor symptoms and histopathology in woozy mice, a model of cerebellar ataxia.

Woozy (wz) mice develop ataxia and carry a mutation in the Sil1 gene. Homozygous wz mice have been characterized histopathologically, but no details of their motor function have been reported. In the present study, to comprehensively understand the relationship between symptomatic progression and pathological feature, we evaluated motor function and neurodegeneration with age from presymptomatic to terminal stages.

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice.

Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms.

Spontaneous cutaneous soft tissue sarcoma with differentiation into fibroblasts in a Sprague-Dawley rat.

A small mass with an ulcer was found in the skin of the dorsal cervix of a 7-month-old male Sprague-Dawley rat. Histologically, the central region of the tumor showed a high cellular density with oval-shaped tumor cells arranged in an alveolar pattern and thin collagen fiber bundles. The peripheral region of the tumor had a low cellular density with short spindle- or polygonal-shaped tumor cells surrounded by abundant collagen fiber bundles.

Spontaneous Subcutaneous Sarcoma in a 50-week-old Male Wistar Hannover GALAS Rat.

A subcutaneous mass was noted in the abdomen of a 50-week-old male Wistar Hannover GALAS rat. Histologically, the tumor was composed of vimentin-positive small round cells with scant cytoplasm arranged in a trabecular, sheet or pericytoma-like pattern and spindle cells arranged in a bundle pattern and vimentin-negative round cells proliferating in an island-shaped pattern. Argentophilic thin fibers were observed to wrap up the individual cells, and some of the tumor cells showed coexpression of vimentin and cytokeratin that formed juxtanuclear globes in the cytoplasm by double immunohistostaining.

KTO-7924, a Beta3-adrenergic receptor agonist, reduces hyperglycemia, and protects beta-cells in the islets of langerhans of db/db mice.

Introduction: The effect of beta3-adrenergic receptor agonists on beta cells in the islets of Langerhans is not yet clear. This study examined the beta3-adrenergic receptor agonist on beta cells in the islets of Langerhans.

Methods: Obese diabetic C57BL/KsJ-db/db mice were treated with KTO-7924, a newly-developed beta3-adrenergic receptor agonist for 28-day.

Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats.

In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7.

Renoprotective effect of the L/N-type calcium channel antagonist cilnidipine on puromycin aminonucleoside-induced nephrosis in rats.

The renoprotective effect of cilnidipine ((+/-)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 132203-70-4), a L/N-type calcium channel antagonist, on puromycin aminonucleoside (PAN)-induced nephrosis was investigated in rats. In the Experiment I, rats were given an intravenous injection of PAN (70 mg/kg). Cilnidipine (3 mg/kg/day) and enalapril (CAS 75847-73-3, 5 mg/kg/day) were administered orally from 6 days after treatment with PAN (day 6) to day 26, and urinary analysis was performed on days 9, 15, 20 and 27.

Embryonic mortality and intrauterine growth retardation (IUGR) associated with placental alterations in pregnant rats treated with methyl methanesulfonate (MMS) at the peri-implantation stage.

Embryonic mortality and intrauterine growth retardation (IUGR) are induced by exposure of rodents to xenobiotic agents during the pregastrulation period of development. We examined the time course of the effects of methyl methanesulfonate (MMS), an alkylating agent, on conceptus development in order to clarify the relative roles of the embryo and the placenta in their induction. Pregnant rats were treated orally with a single dose of MMS (200 mg/kg) in the morning of gestation day (GD) 6 (peri-implantation stage).

Strain differences in hepatic cytochrome P450 1A and 3A expression between Sprague-Dawley and Wistar rats.

Expression of hepatic cytochrome P450 (CYP) isoforms was compared in Sprague-Dawley (SD) and Wistar (WI) rats, which are commonly used strains in preclinical studies. Basal CYP1A1, CYP1A2, and CYP3A2 mRNA levels were higher in WI rats than in SD rats (by 8-, 3- and 2-fold, respectively). Treatment with phenobarbital, a potent CYP inducer, increased the predominance of expression of these three mRNAs in WI rats (by 26-, 4-, and 2-fold, respectively) along with the predominance of increased microsomal total P450 contents and smooth-surface endoplasmic reticulum in the centrilobular hepatocytes.

[Toxicity profile of silodosin (KMD-3213)].

The toxicity profile of silodosin, a selective alpha(1A)-adrenoceptor antagonist, was evaluated. The lethal doses were 800 mg/kg in rats and 1500 mg/kg in dogs. Repeated-dose studies revealed fatty degeneration of hepatocytes and an induction of drug-metabolizing enzymes at 15 mg/kg/day or more in male rats, mammary gland hyperplasia at 60 mg/kg/day or more in female rats, and degeneration of the seminiferous tubular epithelium at 25 mg/kg/day or more only in young dogs.

[Effect of silodosin on intraurethral pressure increase induced by hypogastric nerve stimulation in dogs with benign prostatic hyperplasia].

We compared the urethral and cardiovascular effects of silodosin (selective alpha(1A)-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective alpha(1A)/alpha(1D)-adrenoceptor antagonist) and naftopidil (selective alpha(1D)-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP).

Evaluation of testicular toxicity and sperm morphology in rats treated with methyl methanesulphonate (MMS).

Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at 40 mg/kg. During the recovery period of up to 5 weeks, males were evaluated for testicular toxicity and sperm morphology. The 5-week recovery period were designated as follows: Day 1 (the day after final treatment); Week 1, Week 2, Week 3, Week 4 and Week 5 (1, 2, 3, 4 and 5 weeks after final treatment).

A time-course characterization of male reproductive toxicity in rats treated with methyl methanesulphonate (MMS).

Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at doses of 20, 30, and 40 mg/kg. During the recovery period of 5 weeks, males were evaluated for multiple endpoints such as organ weights, fertility, and sperm parameters. The 5-week recovery periods are designated as follows: Day 1 (1 day after final treatment); Week 1, Week 2, Week 3, Week 4, and Week 5 (first, second, third, fourth, and fifth week after final treatment).

Different inhibitory effects in the early and late phase of treatment with KAT-681, a liver-selective thyromimetic, on rat hepatocarcinogenesis induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.

We recently reported that short-term treatment with KAT-681 (KAT), a liver-selective thyromimetic, inhibits the development of preneoplastic lesions in rat livers and may be a candidate chemopreventive agent for hepatocarcinogenesis. In this study, time-course observations of hepatocellular proliferative lesions were carried out during short-term and long-term treatment with KAT to investigate its anti-hepatocarcinogenic effects. The hepatocellular proliferative lesions in male F344 rats were induced by the initiation treatment of diethylnitrosamine (DEN), followed by treatment with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH).

Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.

To examine the potential inhibitory effects of a novel liver-selective thyromimetic, KAT-681 (KAT), on the development of hepatocellular proliferative lesions, male F344 rats were given a single intraperitoneal injection of 150 mg/kg diethylnitrosamine (DEN), followed by gavage administration of 7.5 mg/kg per day of 2-acetylaminofluorene (2-AAF) twice daily from weeks 2 to 4 with partial hepatectomy (PH) at week 3. From 5 weeks after the completion of 2-AAF administration, the rats were orally dosed with 0.