Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells.

Vitamin D (VD) exerts a wide variety of biological functions including calcemic activity. VD nutritional status is closely associated with the onset and development of chronic diseases. To develop a VD analog with the desired VD activity but without calcemic activity, we screened synthetic VDR antagonists. We identified 1α,25-dihydroxyvitamin D3-26-23-lactams (DLAM)-2a-d (DLAM-2s) as nuclear vitamin D receptor (VDR) ligands in a competitive VDR binding assay for 1α,25(OH)2 vitamin D3 (1α,25(OH)2D3), and DLAM-2s showed an antagonistic effect on 1α,25(OH)2 D3-induced cell differentiation in HL60 cells. In a luciferase reporter assay in which human VDR was exogenously expressed in cultured COS-1 cells, DLAM-2s acted as transcriptional antagonists. Consistently, DLAM-2s had an antagonistic effect on the 1α,25(OH)2D3-induced expression of a known VD target gene [Cytochrome P450 24A1 (CYP24A1)], and VDR bound DLAM-2s was recruited to an endogenous VD response element in chromatin in human keratinocytes (HaCaT cells) endogenously expressing VDR. In an ATAC-seq assay, the effects of 1α,25(OH)2 D3 and DLAM-2b on chromatin reorganization were undetectable in HaCaT cells, while the effect of an androgen receptor (AR) antagonist (bicalutamide) was confirmed in prostate cancer cells (LNCaP) expressing endogenous AR. However, whole genome analysis using RNA-seq and ATAC (Assay for Transposase Accessible Chromatin)-seq revealed differential gene expression profiles regulated by DLAM-2b versus 1α,25(OH)2D3. The upregulated and downregulated genes only partially overlapped between cells treated with 1α,25(OH)2D3 and those treated with DLAM-2b. Thus, the present findings illustrate a novel VDR ligand with gene regulatory activity differing from that of 1α,25(OH)2D3.

Advances in the Administration of Vitamin D Analogues to Support Bone Health and Treat Chronic Diseases.

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.

[The actual activity of the Fukuoka Medical Network for the Seriously Intractable Neurological Diseases].

The Fukuoka Prefectural Medical Health Care Network for Seriously Intractable Neurological Diseases was initiated in 1998 to improve the care of patients for seriously intractable neurological diseases. The network, now, consists of 15 basic cooperative hospitals, and 105 general cooperative hospitals. Two medical care coordinators manage the transfer of network patients based on information of the patient's condition and the capacity of cooperative hospitals using information about the number of available beds in cooperative hospitals. A total number of patients with seriously intractable neurological diseases who were referred to the network for the last eight years was 277, 163 of whom were amyotrophic lateral sclerosis (ALS) patients and of which 75 of them were under mechanical ventilation. Of these 277 patients, 253 were successfully transferred to chronic care hospitals or referred to regional visiting physicians through the network. Cooperative and non-cooperative hospitals accepted 157 and 49 patients, respectively, while 38 were referred to visiting physicians. A number of medical care consultations has increased year by year, and reached 17,652 in the eighth year. The main issues for these consultations were to make hospital arrangements for a patient. Comprehensive long-term care is necessary for Japanese ALS patients because one-third is under mechanical ventilation. Despite this, it is still difficult to secure available beds for such patients who require long-term care. In the future, it will be necessary to improve the support for an environment for home care and to make the system in which cooperative hospitals support patients during the home care.