Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity.

Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mutations in the protein-coding sequences of clock genes. Here, we report generation of mutant mice carrying a mutation only at the E'-box cis-element in the promoter region of the core clock gene Per2. The Per2 E'-box mutation abolishes sustainable molecular clock oscillations and renders circadian locomotor activity and body temperature rhythms unstable. Without the E'-box, Per2 messenger RNA and protein expression remain at mid-to-high levels. Our work delineates the Per2 E'-box as a critical nodal element for keeping sustainable cell-autonomous circadian oscillation and reveals the extent of the impact of the non-coding cis-element in daily maintenance of animal locomotor activity and body temperature rhythmicity.

Herbal Medicine Ninjin'yoeito in the Treatment of Sarcopenia and Frailty.

Frailty and sarcopenia have recently gained considerable attention in terms of preventive care in Japan, which has an ever-increasing aging population. Sarcopenia is defined as atrophy of skeletal muscles caused by the age-related decrease in growth hormone/insulin-like growth factor and sex hormones. The Japanese Ministry of Health, Labor and Welfare reports that frailty can lead to impairment of both mental and physical functioning. Chronic diseases such as diabetes and dementia may underlie frailty. It is important to prevent progression of frailty and extend the healthy lifespan. In herbal medicine practice, including Japanese Kampo medicine, "Mibyo," a presymptomatic state, has long been recognized and may be applicable to frailty. Kampo medicines may include several medicinal plants and are thought to have the potential to improve symptoms of frailty, such as loss of appetite and body weight, fatigue, and sarcopenia, as well as anxiety, depression, and cognitive decline. Ninjin'yoeito (Ren Shen Yang Ying Tang) is the most powerful Kampo medicine and has been widely applied to palliative care of cancer patients. This review includes recent anti-aging studies and describes the effects and mechanisms of Ninjin'yoeito (Ren Shen Yang Ying Tang) when used for frailty or to extend a healthy life expectancy.

Transportin 1 in the mouse brain: appearance in regions of neurogenesis, cerebrospinal fluid production/sensing, and circadian clock.

Transportin1 (Tnpo1) is a carrier protein belonging to the importin-ß family, which transports substrates between the cytoplasm and the nucleus. To gain insight into the role of Tnpo1 gene in the brain, we investigated the localization of Tnpo1-, Tnpo2-, and Tnpo3-expressing cells by in situ hybridization histochemistry. Tnpo1 mRNA-positive cells were distributed throughout the brain from the olfactory bulb to the medulla oblongata. The cells in the subventricular zone of the lateral ventricle, where neurogenesis occurs even in the adult, and its progeny neurons in the granular cells of the olfactory bulb and the islands of Calleja were strongly labeled. It is also noteworthy that cerebrospinal fluid (CSF)-generating epithelial cells in the choroid plexus and CSF-contacting and -sensing circumventricular organs, including organum vasculosum lamina terminalis, subfornical organ, and subcommissural organ, expressed high amounts of Tnpo1. The strongest signals were found in the suprachiasmatic nucleus (SCN), where the biological clock resides, which prompted us to examine the circadian characteristics of Tnpo1. Under constant-dark conditions, the circadian expression profiles of Tnpo1 mRNA in the SCN showed a peak in the subjective night and a trough in the subjective day. Tnpo2 and Tnpo3 showed similar patterns of expression, except in the choroids plexus, the subventricular zone, and the SCN, where the expression was notably weaker. These findings suggest that Tnpo1 is involved in a variety of functions in the adult brain, including neurogenesis, CSF production and sensing, and circadian rhythms.