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Abstract: Background: Our genomewide association study documented an association between cold medicine‐related Stevens‐Johnson syndrome/toxic epidermal necrolysis (CM‐SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. Methods: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5‐Ikzf1‐EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. Results: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. Conclusion: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation. [ABSTRACT FROM AUTHOR]

Background Recent reports support the notion that patients with Crohn's disease have a dysregulated innate immune response to endogenous flora. Aim To reveal the distinct gene expression clusters of a lipopolysaccharide-stimulated pathway in the peripheral blood monocytes of Japanese patients with Crohn's disease. Materials and methods Total RNA was extracted from peripheral blood monocytes of four patients in the remission stage of Crohn's disease as well as four controls, and gene expression profiles before and after lipopolysaccharide stimulation were investigated using a high-density oligonucleotide probe array. To focus on innate immunity, the expression of genes to be studied was narrowed down to 118 probe sets which were selected using the following keywords: lipopolysaccharide, toll, myd and tir along with a software of NetAffx Analysis Center. Results Using hierarchical clustering analysis, we picked up to 44 and 36 probe sets for which expression had decreased before and after lipopolysaccharide stimulation, respectively, in patients with Crohn's disease compared with healthy volunteers. The expression of TLR5, 7, MyD88, SIGIRR, and Tollip was decreased both before and after lipopolysaccharide stimulation in patients with Crohn's disease. Conclusion We found several interesting clusters in monocytes before and after stimulation with lipopolysaccharide. These genes may have been responsible for the immunological differences between the Crohn's disease and control patients. [ABSTRACT FROM AUTHOR]

Background Ischemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. MURC (muscle-restricted coiled-coil protein)/Cavin-4 (caveolae-associated protein 4), which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown. Methods and Results The systems network genomic analysis based on PC-corr network inference on microarray data between wild-type and MURC knockout mouse hearts predicted a network of discriminating genes associated with reactive oxygen species. To demonstrate the prediction, we analyzed I/R-injured mouse hearts. MURC deletion decreased infarct size and preserved heart contraction with reactive oxygen species-related molecule EGR1 (early growth response protein 1) and DDIT4 (DNA-damage-inducible transcript 4) suppression in I/R-injured hearts. Because PC-corr network inference integrated with a protein-protein interaction network prediction also showed that MURC is involved in the apoptotic pathway, we confirmed the upregulation of STAT3 (signal transducer and activator of transcription 3) and BCL2 (B-cell lymphoma 2) and the inactivation of caspase 3 in I/R-injured hearts of MURC knockout mice compared with those of wild-type mice. STAT3 inhibitor canceled the cardioprotective effect of MURC deletion in I/R-injured hearts. In cardiomyocytes exposed to hydrogen peroxide, MURC overexpression promoted apoptosis and MURC knockdown inhibited apoptosis. STAT3 inhibitor canceled the antiapoptotic effect of MURC knockdown in cardiomyocytes. Conclusions Our findings, obtained by prediction from systems network genomic analysis followed by experimental validation, suggested that MURC modulates cardiac I/R injury through the regulation of reactive oxygen species-induced cell death and STAT3-meditated antiapoptosis. Functional inhibition of MURC may be effective in reducing cardiac I/R injury.

New Findings: What is the central question of this study? Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice. What is the main finding and its importance? The combination of a DPP-4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36., Abstract: The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP-4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP-4 inhibitor, enhances the preventive effect of exercise-induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high-fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K-A, KK/Ta mice with alogliptin (0.01%); K-Ex, KK/Ta mice with exercise training (3 days week -1 , 15-20 m min -1 for 30 min); and K-Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K-Ex+A group than in the K group. The liver expression level of PPAR-γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K-Ex+A and B groups than in the K group. Thus, combined therapy of a DPP-4 inhibitor with exercise training was effective against high-fat diet-induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP-4 inhibitor., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)