A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents.

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE-052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE-052 inhibited the Th1-, Th2- and Th17-type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE-052 inhibited skin inflammation in hapten-induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)-4 production in skin, and enhanced IgE production in serum. Oral administration of JTE-052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL-23. The maximal efficacy of JTE-052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE-052 ointment ameliorated hapten-induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE-052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE-052 is a promising candidate as an anti-inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.

Pathophysiological analyses of skeletal muscle in obese type 2 diabetes SDT fatty rats.

Sarcopenia is the age-related decrease of muscle mass and function. Diabetes and obesity are known to be risk factors that exacerbate sarcopenia, but the underlying mechanism of diabetes-related sarcopenia is still unknown. Obese type 2 diabetes SDT fatty rats show early onset of severe diabetes and there have been no reports on the characteristics of their skeletal muscle. Therefore, pathophysiological analyses were performed for the skeletal muscle in these rats. Diabetic male SDT fatty rats were sacrificed at 8, 16, 24, 32 and 40 weeks of age. Age-matched Sprague Dawley (SD) rats were used as the normal control. In addition to biological blood parameters, the soleus and the extensor digitorum longus muscles were examined for muscle weight, histopathology, and protein synthesis and degradation. Muscle grip strength was also examined. These results revealed that the muscle weights of the SDT fatty rats were significantly decreased from 16 weeks of age. The mean cross-sectional area of muscle fibers in the SDT fatty rats decreased from 24 weeks of age. Increased intramyocellular lipid accumulation, identified by immunohistochemistry for adipophilin and TEM, was observed in the SDT fatty rats from 8 weeks of age. Plasma insulin-like growth factor (IGF)-1 levels and muscle strength in the SDT fatty rats decreased at 24 weeks of age and thereafter. These pathophysiological findings have been reported both in sarcopenia in aged humans and in patients with diabetes. In conclusion, the SDT fatty rat was considered to be a useful model for analysis of diabetes-related sarcopenia.

Hepatocellular adenoma with severe fatty change in a male Spontaneously Diabetic Torii rat.

The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, and hepatocellular adenomas have not been reported in this model. We report a hepatocellular adenoma with severe fatty change in a male 42-week-old SDT rat fed a high-fat diet. At necropsy, the animal had a whitish nodular mass of approximately 2 cm in diameter in the right medial lobe. Histologically, the mass was well demarcated from the surrounding tissues, slightly compressing the adjacent hepatic parenchyma and widely compartmented by fibrous connective tissues. The mass consisted of vacuolated tumor cells resembling hepatocytes with a solid and occasionally trabecular growth pattern. Abundant neutral lipids, which were positive for fat with Oil Red O stain and which ultrastructurally had moderately dense material, were contained within the vacuoles of the tumor cells. Immunohistochemically, the tumor cells showed an increase in immunoreactivity or number for Cytokeratin 8/18 and proliferating cell nuclear antigen but were negative for mesenchymal markers. From these findings, the mass could be distinguished from hepatocellular hyperplasia and was diagnosed as hepatocellular adenoma. In rats, hepatocellular adenoma accompanied by severe fatty change is rare, and this is the first report of a hepatocellular tumor with severe fatty change in a SDT rat.