Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening

Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration

Perceptions of the Health of People with Disabilities and Local Health Room ―Perspectives of the Employees of the Support Facilities for People with Disabilities―

障害者の効果的な健康支援を目指し，障害者支援施設の職員の視点から，障害者の健康に関する状況や「まちの保健室」についての認識を明らかにすることを目的に4 名にインタビューを行った．職員は，利用者に寄り添い支援をする中で，個別性をふまえた健康支援の難しさを認識し，専門的な知識に基づく支援を求めていた．障害者を対象とした「まちの保健室」は，方法や内容の工夫をすることで健康増進につながる効果への期待や職員も学べるものを望む一方で，具体的なイメージが持てない状況もみられた．departmental bulletin pape

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

Chiral and Molecular Recognition through Protonation between Aromatic Amino Acids and Tripeptides Probed by Collision-Activated Dissociation in the Gas Phase

Chiral and molecular recognition through protonation was investigated through the collision-activated dissociation (CAD) of protonated noncovalent complexes of aromatic amino acid enantiomers with l-alanine- and l-serine-containing tripeptides using a linear ion trap mass spectrometer. In the case of l-alanine-tripeptide (AAA), NH3 loss was observed in the CAD of heterochiral H+(d-Trp)AAA, while H2O loss was the main dissociation pathways for l-Trp, d-Phe, and l-Phe. The protonation site of heterochiral H+(d-Trp)AAA was the amino group of d-Trp, and the NH3 loss occurred from H+(d-Trp). The H2O loss indicated that the proton was attached to the l-alanine tripeptide in the noncovalent complexes. With the substitution of a central residue of l-alanine tripeptide to l-Ser, ASA recognized l-Phe by protonation to the amino group of l-Phe in homochiral H+(l-Phe)ASA. For the protonated noncovalent complexes of His enantiomers with tripeptides (AAA, SAA, ASA, and AAS), protonated His was observed in the spectra, except for those of heterochiral H+(d-His)SAA and H+(d-His)AAS, indicating that d-His did not accept protons from the SAA and AAS in the noncovalent complexes. The amino-acid sequences of the tripeptides required for the recognition of aromatic amino acids were determined by analyses of the CAD spectra

Combination of Octreotide and Oral Glucose Maintains the Blood Glucose Level and Improves Survival Rate in Rats after Monochloroacetic Acid Exposure

We report the combined therapeutic effect of subcutaneous injection of octreotide and oral glucose administration to monochloroacetic acid exposed rats. The control rats group was subcutaneously injected with 80 mg/kg sodium monochloroacetate and infused with 2 mL/hour 10% glucose solution for 10 hours 60 minutes after exposure. Group A was given 2 g/kg oral glucose after exposure, and then infused with glucose as control. Group B was given 2 g/kg oral glucose and a subcutaneous injection of 30 µg/kg octreotide after exposure, and then infused with glucose as control. The 14-day survival rate was 0.35 (control), 0.50 (group A) and 0.90 (group B). The blood glucose of group B increased to 188 mg/dl at the beginning of the glucose infusion, significantly higher than group A. Although there were significant differences in the lactate levels between the 3 groups, the levels were not abnormally high. In conclusion, our study suggests that it is important to elevate the blood glucose levels within 60 minutes after monochloroacetic acid exposure. In addition, a combination of subcutaneous octreotide and oral glucose is advantageous to maintain high blood glucose level at early stages after exposure and may be an effective therapy for monochloroacetic acid intoxication