Divergent roles of 25-hydroxyvitamin D and 1α,25-dihydroxyvitamin D in neural fate determination: A CYP27B1-dependent neuron formation and VDR-dependent astrocyte development.

Vitamin D plays a crucial role in neural differentiation, yet its precise mechanisms remain unclear. In this study, we investigated the effects of vitamin D metabolites, 25-hydroxyvitamin D (25D) and 1α,25-dihydroxyvitamin D (1α,25D), on neural differentiation using Cyp27b1 and Vdr knockout mice-derived neural stem cells. We found that 1α,25D promotes neuronal differentiation via vitamin D receptor (VDR), whereas some of its effects occur independently of VDR.

Gastric Epithelial Neoplasms in Patients with Pulmonary Arterial Hypertension Receiving Continuous Intravenous Prostacyclin Therapy.

: The association of intravenous prostacyclin therapy, essential for improving prognosis and survival in pulmonary arterial hypertension (PAH), with gastric epithelial neoplasms is uncertain. This study aimed to analyze the clinicopathologic features of gastric neoplasms in patients with PAH undergoing continuous intravenous prostacyclin therapy. : We screened the registry of patients with pulmonary hypertension who visited the NHO Okayama Medical Center.

Association between serum 25-hydroxyvitamin D concentrations and urinary vitamin D metabolite concentrations measured by the NLucVDR assay.

It is well known that vitamin D is essential for human health; however, many people suffer from vitamin D deficiency or insufficiency worldwide, including in Japan. Serum 25-hydroxyvitamin D (25(OH)D) concentrations are typically measured to evaluate vitamin D status. In a previous study, we demonstrated that the concentrations of vitamin D metabolites in urine, measured using the NLucVDR assay system composed of a split-type nanoluciferase and the ligand-binding domain (LBD) of the human vitamin D receptor, correlated with serum 25(OH)D concentrations measured using liquid chromatography-mass spectrometry (LC-MS) or electrochemiluminescence immunoassays (ECLIAs).

Ligand-Independent Vitamin D Receptor Actions Essential for Keratinocyte Homeostasis in the Skin.

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since -KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among -KO, -R270L/H301Q, and wild-type (WT) rats.

Structure-Function Analysis of CYP105A1 in the Metabolism of Nonsteroidal Anti-inflammatory Drugs.

CYP105A1 exhibits monooxygenase activity to a wide variety of structurally different substrates with regio- and stereospecificity, making its application range broad. Our previous studies have shown that CYP105A1 wild type and its variants metabolize 12 types of nonsteroidal anti-inflammatory drugs (NSAIDs). In particular, the R84A variant exhibited a high activity against many NSAIDs.

Discovery and Structural Analysis of Metabolites of Vitamin D Lactones.

25-Hydroxyvitamin D-23,26-lactone (1) and 1α,25-dihydroxyvitamin D-23,26-lactone (2) have long been considered as among the end metabolites of vitamin D. Recently, however, we found that these lactones exhibit biological activity related to the β-oxidation of fatty acids. We hypothesized that a metabolic pathway might exist to inactivate their physiological activity.

Tyrosine Kinase Inhibitor-induced Cerebrovascular Occlusion Presenting with Moyamoya Disease-like Stenosis of the Circle of Willis.

Vascular occlusive events are notable adverse effects of tyrosine kinase inhibitors (TKIs), which are promising treatments for chronic myeloid leukemia (CML). We herein report the case of a patient with CML who developed cerebrovascular occlusion of the circle of Willis during TKI treatment. Our patient did not meet the diagnostic criteria for moyamoya disease due to the insignificant development of moyamoya vessels.

Effect of long-term treatment with trivalent chromium on erythropoietin production in HepG2 cells.

Trivalent chromium (Cr(III)) is sometimes taken as a long-term supplement, but its effectiveness is unclear. Recently, Cr(III) reportedly modulates peroxisome proliferator-activated receptor gamma (PPARγ) expression. Our previous study reported that increased PPARγ after 24 h Cr(III) treatment promoted erythropoietin (EPO) production in HepG2 cells.

Characterization of Rickets Type II Model Rats to Reveal Functions of Vitamin D and Vitamin D Receptor.

Vitamin D has been known to exert a wide range of physiological effects, including calcemic, osteogenic, anticancer, and immune responses. We previously generated genetically modified (GM) rats and performed a comparative analysis of their physiological properties to elucidate the roles of vitamin D and vitamin D receptor (VDR). In this study, our primary goal was to investigate the manifestations of type II rickets in rats with the VDR(H301Q) mutation, analogous to the human VDR(H305Q).

Gene therapy for alopecia in type II rickets model rats using vitamin D receptor-expressing adenovirus vector.

Type II rickets is a hereditary disease caused by a mutation in the vitamin D receptor (VDR) gene. The main symptoms of this disease are bone dysplasia and alopecia. Bone dysplasia can be ameliorated by high calcium intake; however, there is no suitable treatment for alopecia.

Synthesis of (22)-, (22)-22-Fluoro-, and 22,22-Difluoro-25-hydroxyvitamin D and Effects of Side-Chain Fluorination on Biological Activity and CYP24A1-Dependent Metabolism.

Three novel analogues of C22-fluoro-25-hydroxyvitamin D (-) were synthesized and evaluated to investigate the effects of side-chain fluorination on biological activity and metabolism of vitamin D. These novel analogues were constructed by convergent synthesis applying the Wittig-Horner coupling reaction between CD-ring ketones (,,) and A-ring phosphine oxide (). The introduction of C22-fluoro units was achieved by stereoselective deoxy-fluorination for synthesizing and or two-step cationic fluorination for .

Analysis of vitamin D metabolites in biological samples using a nanoluc-based vitamin D receptor ligand sensing system: NLucVDR.

Many assays are currently being developed to measure the levels of vitamin D metabolites in various samples (such as blood, urine, and saliva). This study focused on the measurement of vitamin D metabolites in serum and urine using the NLucVDR assay system, which consists of a split-type nanoluciferase and ligand-binding domain (LBD) of the human vitamin D receptor. Blood and urine samples were collected from 23 participants to validate the NLucVDR assay.

Differential Metabolic Stability of 4α,25- and 4β,25-Dihydroxyvitamin D and Identification of Their Metabolites.

Vitamin D () is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D () and 4β,25-dihydroxyvitamin D () are both produced from 25-hydroxyvitamin D () by CYP3A4. However, is detectable in serum, whereas is not.

Increase in steryl glycoside levels and stimulation of lipid raft formation in azuki bean epicotyls under hypergravity conditions.

Sterols are the main components of the plasma membrane and are involved in various plant membrane functions. Azuki bean (Vigna angularis (Wild.) Ohwi et Ohashi) seedlings were cultivated under hypergravity conditions, and changes in the levels and composition of membrane sterols in their epicotyls were analyzed.

Synthesis of New 26,27-Difluoro- and 26,26,27,27-Tetrafluoro-25-hydroxyvitamin D: Effects of Terminal Fluorine Atoms on Biological Activity and Half-life.

As an extension of our research on providing a chemical library of side-chain fluorinated vitamin D analogues, we newly designed and synthesized 26,27-difluoro-25-hydroxyvitamin D (1) and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D (2) using a convergent method applying the Wittig-Horner coupling reaction between CD-ring ketones (13, 14) and A-ring phosphine oxide (5). The basic biological activities of analogues, 1, 2, and 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D [HF-25(OH)D] were examined. Although the tetrafluorinated new compound 2 exhibited higher binding affinity for vitamin D receptor (VDR) and resistance to CYP24A1-dependent metabolism compared with the difluorinated 1 and its non-fluorinated counterpart 25-hydroxyvitamin D [25(OH)D], HF-25(OH)D showed the highest activity among these compounds.

The relationship between frailty and social participation: focus on subjective health.

Objective: Active participation of the older adults in the society is crucial; however, frailty prevents social participation. Meanwhile, many older adults participate daily in social activities, even with frailty. This study aims to examine whether older adults with frailty have lower social participation than those without frailty in Japan.

Phosphorylation of nuclear receptors: Novelty and therapeutic implications.

Nuclear receptors (NR) collectively regulate several biological functions in various organs. While NRs can be characterized by activation of the transcription of their signature genes, they also have other diverse roles. Although most NRs are directly activated by ligand binding, which induces cascades of events leading to gene transcription, some NRs are also phosphorylated.

Expression of Rat Cyp27b1 in HepG2 Cells Using Adenovirus Vector and Its Application to Evaluation of Self-Made and Commercially Available Anti-Cyp27b1 Antibodies.

Rat Cyp27b1 was successfully expressed in HepG2 cells using an adenovirus vector. High vitamin D 1α-hydroxylation activity was detected in them, whereas no activity was observed in non-infected cells. Similarly, vitamin D 1α-hydroxylation activity was also observed in HepG2 cells expressing Cyp27b1-Flag, which is tagged with a Flag at the C-terminus of Cyp27b1.

Functional analysis of vitamin D receptor (VDR) using adenovirus vector.

Recently, we generated type II rickets model rats, including Vdr(R270L), Vdr(H301Q), Vdr(R270L/H301Q), and Vdr-knockout (KO), by genome editing. All generated animals showed symptoms of rickets, including growth retardation and abnormal bone formation. Among these, only Vdr-KO rats exhibited abnormal skin formation and alopecia.

Do media events still unite the host nation's citizens? The case of the Tokyo 2020 Olympic Games.

The Olympic Games are a typical media event and are seen as a festive occasion that monopolizes people's attention through the mass media. The Games and their media coverage have a predetermined schedule that enhances the nation's sense of unity by placing a temporary truce on political conflicts. Governments, especially those of Olympic host countries, tend to take advantage of this effect to garner support for their own policies.

Development of nanoluciferase-based sensing system that can specifically detect 1α,25-dihydroxyvitamin D in living cells.

Previously, we reported a FLucN-LXXLL+LBD-FLucC system that detects VDR ligands using split firefly luciferase techniques, ligand binding domain (LBD) of VDR, and LXXLL sequences that interact with LBD after VDR ligand binding. In vivo, 25-hydroxyvitamin D (25(OH)D) and 1α,25-dihydroxyvitamin D (1α,25(OH)D) act as VDR ligands that bind to VDR, and regulate bone-related gene expression. Therefore, the amount of 25(OH)D and 1α,25(OH)D are indicators of bone-related diseases such as rickets and osteoporosis.

Glasgow-Blatchford score combined with nasogastric aspirate as a new diagnostic algorithm for patients with nonvariceal upper gastrointestinal bleeding.

Objectives: The Glasgow-Blatchford score (GBS) is a widely used risk assessment tool for patients with upper gastrointestinal bleeding. However, it only identifies a relatively low proportion of patients at low risk for adverse events and poor outcomes. We developed a simple diagnostic algorithm combining the GBS and nasogastric aspirate and evaluated its diagnostic performance.

Negative attitudes of healthy older adults toward unhealthy older adults: Focus on the subjective health.

Negative attitudes toward older adults, especially those with declining physical function and/or advanced dementia (i.e., unhealthy older adults), are serious.

The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities.

In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D () and its 24-hydroxylated analogues (,), which are candidates for the CYP24A1 main metabolites of . The key fragments, 23,23-difluoro-CD-ring precursors (-), were synthesized starting from Inhoffen-Lythgoe diol (), and introduction of the C23 difluoro unit to α-ketoester () was achieved using ,-diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F-25(OH)D () showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D ().