[Practical Pharmaceutical Researches Utilizing Clock Genes]

The biological clock system regulates gene transcription in approximately 24 h cycles, creating circadian rhythms with respect to drug pharmacokinetics and pharmacological efficacy. My research focuses on clinical applications of clock systems and the elucidation of pathophysiological mechanisms involving clock genes. In the present study, I aimed to identify the optimal timing of methylprednisolone (mPSL) administration to pediatric patients undergoing liver transplantation. A randomized clinical trial of 60 such patients demonstrated that evening administration (20:00) was associated with significantly fewer episodes of acute rejection and lower histological damage scores than morning administration (08:00). Notably, in patients who were not undergoing pretreatment with rituximab, mPSL administration in the evening completely prevented acute rejection within 14 d of transplantation. Pathophysiological studies revealed low clock gene expression rhythms in the adipose tissue of obese diabetic (ob/ob) mice, mediated through low histone H3K9 acetylation of the Dbp gene. Pharmacological correction of the abnormal histone acetylation increased the circulating adiponectin concentration and insulin sensitivity through peroxisome proliferator-activated receptor (PPAR)-γ mediated adipocyte differentiation. Importantly, low Dbp and PPAR-γ expression was also identified in human omental adipose tissue samples from patients with diabetes. I also discovered that diabetic microvascular complications can result from circadian clock dysfunction, with low zonula occludens-1 expression causing greater vascular permeability in the liver. Currently, I am evaluating the utility of microRNAs in extracellular vesicles as non-invasive biomarkers of intracellular clock gene expression. These findings should contribute to the optimization of chronotherapy and the identification of novel therapeutic targets.