Utility of rekkotoken （Rhododendron anthopogonoides Maxim), Tibetan herbal medicine, as cosmetics

研究ノート (Note

胃部分切除一症例でのイトラコナゾール固形製剤と内用液剤投与後の血中濃度比較

In this paper, we report that in pulmonary aspergillosis patient who had history of resection of the stomach, the blood concentrations of itraconazole（ITCZ）and its active metabolite, hydroxy-ITCZ（OHITCZ） after taking oral solid formulation of ITCZ were remarkably low, whereas their blood concentrations significantly increased after switching from the solid formulation to the solution formulation.During administration of the ITCZ tablets（200 mg/day）, trough blood concentration of ITCZ and OH-ITCZ were 15 ng/mL and 18 ng/mL, respectively. On the other hand, when it was switched from the tablet to the oral solution（200 mg/day as ITCZ）, blood concentrations of ITCZ and OH-ITCZ increased to 1056 ng/mL and 1492 ng/mL, respectively. It was considered that the absorption of ITCZ tablets declined because the gastric acid secretion ability of the patients was decreased by gastrectomy.研究ノー

肺アスペルギルス症患者におけるイトラコナゾールおよび

A patient was given generic itraconazole (ITCZ) tablet, brand-name-ITCZ capsule, ITCZ oral solution and ITCZ injection to treat pulmonary aspergillosis. We monitored concentrations of ITCZ and its active metabolite hydroxy-ITCZ (OH-ITCZ) in plasma and lung tissues. During administration of the generic product (400 mg/day), trough plasma concentrations of ITCZ and OH-ITCZ were 76 ng/mL and 126 ng/mL, respectively. After administration of the brand-name product (200 mg/day), they increased to 229 ng/mL and 540 ng/mL, respectively. ITCZ and OH-ITCZ concentrations/dosage ratios were 6.1 and 8.4 times higher by switching to the brand-name product, respectively. It was suggested that there may be a difference in pharmacokinetics between the brand-name ITCZ and the generic. Also, we determined ITCZ and OH-ITCZ concentrations infected and uninfected tissues of resected lung simultaneously. The ITCZ concentration in the infected lesion of the lung was approximately 2.3 times higher than that in plasma and 1.6 times higher than in uninfected lung tissue. The OH-ITCZ concentration in the infected lesion was higher than ITCZ in the same region. It was considered that the high concentrations of ITCZ and its metabolite at infected lesion were due to their high affinities with ergosterol in fungal membrane.研究ノー

カルパペネム系抗菌薬・メロペネムの血液試料中での安定性に関する研究

Meropenem is a relatively unstable compound when dissolved; therefore, in studying pharmacokinetics (PK), accurate PK analysis may be interrupted depending on the handling of collected blood samples because it also rapidly degrades during processing and preserving of the blood samples. Thus, prior to PK studies, we determined the stability of meropenem in plasma with and without the same volume of 1 M 3-(N-morpholino)-propane-sulfonic acid (MOPS) buffer as a stabilizer were preserved under the conditions of -80℃, -20℃, 4℃ and 25℃, and the remaining meropenem level upon high-performance liquid chromatography at 1, 3, 7, 14, 30, 60, 120 and 180 days following preservation was measured to calculate the meropenem residual rate. The residual rate of plasma samples preserved at -80℃ was 95% or higher for 180 days. On the other hand, under the preservation condition over -20℃, the residual rate at 1 day following preservation was less than 95%. The stability of plasma sample was improved by adding MOPS buffer, and the residual rate was 95% or higher for 7 days at -20℃. Therefore, plasma samples for PK study of meropenem should be added MOPS buffer and preserved in a frozen state.研究ノー

血中濃度解析に基づくイトラコナゾール内用液剤の至適服用タイミングの検討

In this study, we examined the optimal time for taking itraconazole（ITCZ）oral solution based on the analysis of its blood concentration. The trough blood concentrations of both itraconazole and its active metabolite hydroxy-ITCZ were about twice higher under taking ITCZ oral solution between meals than under taking it before meals. The results of this study show that the absorption of ITCZ oral solution was affected not only by the meal before taking but also by the meal after taking it. Our findings suggest that the timing for taking ITCZ oral solution was better between meals than before meals.論

Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions

Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions. Loss-of-function Enpp1 ttw/ttw mice under phosphate overload conditions exhibited phenotypes resembling human aging and Klotho mutants, such as short life span, arteriosclerosis and osteoporosis, with elevated serum 1,25(OH)2D3 levels. Enpp1ttw/ttw mice also exhibited significantly reduced renal Klotho expression under phosphate overload conditions, and aging phenotypes in these mice were rescued by Klotho overexpression, a low vitamin D diet or vitamin D receptor knockout. These findings indicate that Enpp1 plays a crucial role in regulating aging via Klotho expression under phosphate overload conditions

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead