Effects of estradiol on very low density lipoprotein receptor mRNA levels in rabbit heart

AbstractThe VLDL receptor, a newly identified lipoprotein receptor, has a domain structure homologous with the LDL receptor but has one additional cysteine rich repeat in the ligand binding domain. To study the regulation of the VLDL receptor in vivo, we administered 17 α-ethinyl estradiol to rabbits and examined its effects on VLDL receptor mRNA levels in the heart, one of the organs with highly expressed VLDL receptors, by RNA blotting. The ventricular level of VLDL receptor mRNA increased dramatically after estradiol administration. We could not detect VLDL receptor mRNA in the liver even after estradiol administration. We have confirmed the enhanced expression of liver LDL receptor mRNA by estradiol, however, only weak expression of the LDL receptor was detected in the ventricle of the rabbit heart. These results suggest that estradiol exerts its effect on the VLDL receptor gene expression in the heart

Impact of Vonoprazan Triple-Drug Blister Packs on H. pylori Eradication Rates in Japan: Interrupted Time Series Analysis

INTRODUCTION: Helicobacter pylori eradication therapy requires a complex prescribing schedule combining clarithromycin, amoxicillin, and a proton-pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB, vonoprazan). To reduce the burden of complex prescribing and increase adherence, a vonoprazan triple-drug blister pack comprising all three medications was launched in June 2016. This study aimed to assess the impact of the combination blister pack on eradication success rate in Japan immediately after launch. METHODS: We performed an interrupted time series analysis using a large administrative claims database of 7, 300, 000 insured individuals. We identified 36, 570 patients who received first-line clarithromycin triple therapy from June 2015 to May 2016 (prelaunch) and 35, 721 who received the same therapy from July 2016 to June 2017 (post-launch). The primary outcome was the success rate of clarithromycin triple therapy and the secondary outcomes were proportion of vonoprazan use and proportion of combination blister pack use. RESULTS: The success rate of clarithromycin triple therapy increased by 2.44% (95% confidence interval [CI] 1.36-3.52; P < 0.0001) after the launch of the vonoprazan triple-drug blister pack. The proportion of vonoprazan use and proportion of combination blister pack use increased by 12.7% (95% CI 10.0-15.3; P < 0.0001) and 29.2% (95% CI 25.4-32.9; P < 0.0001), respectively. CONCLUSIONS: Launch of the vonoprazan triple-drug blister pack had a significant impact on the success rate of clarithromycin triple therapy, with greater proportions of vonoprazan and combination blister pack use. Introducing an easy-to-use formulation may be effective in changing prescribing practice and subsequent patient outcomes

Efficacy of Mucosal Cutting Biopsy for the Histopathological Diagnosis of Gastric Submucosal Tumors

Background: Gastrointestinal stromal tumors occur frequently. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is performed commonly for diagnosis. However, the success rate of histological diagnosis is insufficient when the submucosal tumor (SMT) is small. Recently, another technique, mucosal cutting biopsy (MCB) has been reported. The aim of this study is to evaluate the efficacy and safety of MCB. Method: Between January 2012 and August 2018, MCB and EUS-FNA were performed 16 and 31 times for diagnosing gastric SMT. The diagnostic rate, the rate of successful immunohistochemistry, and the safety were reviewed. Difficult locations for EUS-FNA were also evaluated. Results: The mean SMT sizes measured on MCB and EUS-FNA were 21.2 and 36.2 mm. The diagnostic rates of MCB and EUS-FNA were almost the same (88 vs. 81%), but successful immunohistochemistry was significantly higher in the MCB group (93 vs. 59%, p = 0.03). In the subgroup of SMTs &#x3c; 20 mm, the successful histological diagnosis rate from EUS-FNA was relatively low. There were no complications. Failures of EUS-FNA were more frequent in the middle third of the stomach. Conclusions: MCB was an effective procedure for diagnosing gastric SMT, especially in the case of small SMTs located at the middle third of the stomach

PDZRN3 Negatively Regulates BMP-2–induced Osteoblast Differentiation through Inhibition of Wnt Signaling

PDZRN3, a member of the PDZ domain–containing RING finger family of proteins plays an important role in negative feedback control of BMP-2–induced osteoblast differentiation in C2C12 mouse mesenchymal progenitor cells through inhibition of Wnt–β-catenin signaling

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

Effects of Long-Term Administration of Gardeniae Fructus on Intra-Abdominal Organs of Rats

Many recent reports have suggested a possible association between Japanese traditional (Kampo) medicines containing Gardeniae Fructus (GF, the fruit of Gardenia jasminoides J. Ellis) and the mesenteric phlebosclerosis (MP). MP is a chronic orphan disease characterized by venous calcification extending from the colonic wall to the mesentery, usually developing in the proximal colon. In the present study, we administered GF to Wistar/ST female rats as 1% and 2% feed in the diet for 11 months to evaluate any calcification and/or fibrosis of veins in the colonic wall and mesentery. The reversibility of GF’s effects was examined by feeding a normal diet for an additional 3 months. A significant decrease in body weight gain and food consumption occurred in the 2% GF group. Pigmentation of the liver, kidney, and spleen in macroscopic or histopathological examination was observed after 11-month administration, which disappeared after the 3-month recovery period. Histopathological findings such as fibrous thickening and calcification of vein walls, characteristic of human MP, were not observed. Fibrosis in the colonic lamina propria was observed in the 2% GF group but not in the 1% GF group during the treatment period, but the incidence as well as grade of this type of fibrosis decreased in the recovery period, suggesting that the effects of GF were reversible. In the present study, chronic GF administration did not result in any venous pathological changes but induced pigmentation in the liver, kidneys, and spleen and moderate fibrosis in the colonic lamina propria, all of which being reversible. Further studies are required to determine the association between GF and MP