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Klotho : a fundamental regulator of aging
Nabeshima, Yo-ichi 한림대학교 환경·생명과학연구소 2002 [일송 국제심포지엄] 노화와 만성퇴행성 신경질환 Vol.- No.4
To escape aging and aging-related disorders has been one of mankind's biggest dreams from the beginning of history. However, our knowledge regarding the molecular mechanisms of aging has been limited. We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as koltho. The most characteristic phenotypes seem to be caused by abnormalities in calcium metabolism. Furthermore, the klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus in the brain, and the main cells of the parathyroid gland. Klotho plays a critical role for the regulation of calcium and phosphorus homeostasis by negatively regulation the synthesis of active Vitamin D. The deficiency of the klotho gene results in degradation of cells by the activation of calcium-dependent proteolysis in kidney, lung, heart and other tissues. Importantly, the increased activation of calcium-dependent proteolysis occurs in the tissues of old mice together with the down regulation of klotho gene expression. What is Klotho protein required for and how does it act? In this review, I will discuss our working hypotheses on the biological roles and molecular functions of Klotho protein.
Involvement of Genetic and Environmental Factors in the Onset of Depression
Toshitaka Nabeshima,김형춘 한국뇌신경과학회 2013 Experimental Neurobiology Vol.22 No.4
First, this article provides a brief overview of the previous hypotheses regarding depression and then focuses on involvement ofgenetic and environmental factors in development of depression. According to epidemiological research, 30~40% of occurrences ofbipolar disorder involve a genetic factor. Therefore, environmental factors play a more important role in development of depression. Resilience and resistance to stress are common; therefore, although a certain extent of stress might be received during the embryonicor perinatal period, having a genetic predisposition to mental disorders does not imply that a mental disorder will develop. However,having a genetic predisposition to disorders does weaken resistance to stresses received during puberty, and without the ability torecover, a mental disorder is triggered. The importance of epigenetics in maintaining normal development and biology is reflected bythe observation that development of many diseases occurs when the wrong type of epigenetic marks are introduced or are added atthe wrong time or in the wrong place. Involvement of genetic and environmental factors in the onset of depression was investigatedin relation to epigenetics. When mice with the disrupted in schizophrenia 1 (DISC1) abnormal gene received isolated rearing stress,depression-like abnormal behaviors and decreased gene expression of tyrosine hydroxylase in the frontal cortex by epigeneticalsuppression via DNA methylation were observed. Decrease of dopamine in the frontal cortex triggers behavioral disorders. Administration of a glucocorticoid receptor antagonist resulted in full recovery from neurological and behavioral disorders. Theseresults suggest a new therapeutic approach to depression.
Structural-mechanical stabilized slopes/walls with vegetation and planting works
Yasuyuki Nabeshima,Seung-Kyong You 한국토목섬유학회 2007 한국토목섬유학회지 Vol.6 No.4
Many slopes and walls with vegetation and/or planting works are constructed today in Japan from viewpoints of landscape and environmental requests. Structural and mechanical stabilizations are usually necessary for these slopes and walls because they are very sever geographical, geological and geotechnical conditions. The vegetation and planting works on these slopes and walls are difficult. Brief reviews of structural-mechanical stabilized slopes and walls with vegetation and planting works are summarized in this paper. And some field application examples were demonstrated.
Park, Seok-Joo,Shin, Eun-Joo,Min, Sun Seek,An, Jihua,Li, Zhengyi,Hee Chung, Yoon,Hoon Jeong, Ji,Bach, Jae-Hyung,Nah, Seung-Yeol,Kim, Won-Ki,Jang, Choon-Gon,Kim, Yong-Sun,Nabeshima, Yo-ichi,Nabeshima, American College of Neuropsychopharmacology 2013 Neuropsychopharmacology Vol.38 No.8
We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.