Peptidyl prolyl isomerase Pin1-inhibitory activity of d-glutamic and d-aspartic acid derivatives bearing a cyclic aliphatic amine moiety

AbstractPin1 is a peptidyl prolyl isomerase that specifically catalyzes cis–trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity

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 β-hydroxybutyrate treatment on glycogen repletion and its related signaling cascades in epitrochlearis muscle during 120 min of postexercise recovery

We investigated the effects of β-hydroxybutyrate (β-HB), the most abundant type of ketone body in mammals, on postexercise glycogen recovery in skeletal muscle by using an in vitro experimental model. Male ICR mice swam for 60 min and then their epitrochlearis muscles were removed and incubated with either physiological levels of glucose (8 mmol/L) and insulin (60 μU/mL) or glucose and insulin plus 1, 2, or 4 mmol/L of sodium β-HB. Four millimoles per liter β-HB had a significant positive effect on glycogen repletion in epitrochlearis muscle at 120 min after exercise (p < 0.01), while 2 mmol/L of β-HB showed a tendency to increase the glycogen level (p < 0.09), and 1 mmol/L of β-HB had no significant effect. We further investigated the effect of 4 mmol/L β-HB treatment on the signaling cascade related to glycogen repletion in the epitrochlearis muscles throughout a 120-min recovery period. After incubating the muscles in 4 mmol/L of β-HB for 15 min postexercise, the Akt substrate of 160 kDa Thr642 (p < 0.05) and Akt Thr308 (p < 0.05) phosphorylations were significantly increased compared with the control treatment. At the same time point, 5′-AMP–activated protein kinase and acetyl-coenzyme A carboxylase phosphorylations were significantly lower (p < 0.05) in the epitrochlearis muscle incubated with 4 mmol/L of β-HB than in the control muscle. Our results demonstrate that postexercise 4 mmol/L β-HB administration enhanced glycogen repletion in epitrochlearis muscle. Four millimoles per liter β-HB treatment was associated with alternation of the phosphorylated status of several proteins involved in glucose uptake and metabolic/energy homeostasis at the early stage of postexercise.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Effects of combination of concentrated Kurozu supplementation and endurance training on mitochondrial enzyme activity and energy metabolism in mice

We examined the effects of endurance training with chronic pre-exercise concentrated Kurozu (black vinegar) supplementation on mitochondrial enzyme activity and energy metabolism in Institute of Cancer Research (ICR) mice. Mice were divided into a control group, an endurance training group, and an endurance training + concentrated Kurozu supplementation group. Mice were orally supplemented with water or concentrated Kurozu solution (500 mg/kg body weight/day) for 3 weeks. The mice in the training group were subjected to exercise on a treadmill (20–25 m/min × 30 min, five times/week) starting 30 min after the supplementation. The maximal activity of citrate synthase in the plantaris muscle in the endurance training + concentrated Kurozu supplementation group was significantly higher than that in the control group (p &lt; 0.01). The maximal activity of β-hydroxyacyl coenzyme dehydrogenase (β-HAD) in the soleus muscle in the endurance training + concentrated Kurozu supplementation group was significantly higher than that in the other two groups (p &lt; 0.05 for both). In the final week, significant negative correlation between blood lactate concentration after exercise and soleus β-HAD activity was observed. These findings suggest that endurance training with concentrated Kurozu supplementation increases mitochondrial enzyme activity and might enhance lipid metabolism during exercise