イソプレン ソクサ オ ユウスル ショクブツ セイブン ノ ex vivo ユウキ ゴウセイ ト ソノ セイリ カッセイ ノ ヒョウカ

Phytyl quinols, namely acyclic tocopherols, are key intermediates of tocopherol biosynthesis, but their biological activities remain unclear. We therefore investigated the structure-activity relationship of phytyl quinols to apply a chemical biosynthesis design for an antiatherosclerosis drug based on isoprenomics. We have achieved the biosynthesis-oriented synthesis of α- and β-phytyl quinol as an unnatural intermediate, other γ- and δ-phytyl quinol as a natural one. All four phytyl quinols showed almost the same moderate inhibitory activity against low-density lipoprotein oxidation instead of their different degree of C-methylation with character different from tocopherols. In vivo toxicities of phytyl quinols against chick embryo chorioallantoic membrane vasculature were hardly observed. We proposed phytyl quinols were possible antioxidants in plants and animals, like vitamin E

イソプレン ソクサ オ ユウスル ショクブツ セイブン ノ ex vivo ユウキ ゴウセイ ト ソノ セイリ カッセイ ノ ヒョウカ

Phytyl quinols, namely acyclic tocopherols, are key intermediates of tocopherol biosynthesis, but their biological activities remain unclear. We therefore investigated the structure-activity relationship of phytyl quinols to apply a chemical biosynthesis design for an antiatherosclerosis drug based on isoprenomics. We have achieved the biosynthesis-oriented synthesis of α- and β-phytyl quinol as an unnatural intermediate, other γ- and δ-phytyl quinol as a natural one. All four phytyl quinols showed almost the same moderate inhibitory activity against low-density lipoprotein oxidation instead of their different degree of C-methylation with character different from tocopherols. In vivo toxicities of phytyl quinols against chick embryo chorioallantoic membrane vasculature were hardly observed. We proposed phytyl quinols were possible antioxidants in plants and animals, like vitamin E

CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development

Lung cancer is one of the major causes of cancer death and clarification of its molecular pathology is highly prioritized. The physiological importance of mRNA degradation through the CCR4-NOT deadenylase has recently been highlighted. For example, mutation in CNOT3, a gene coding for CNOT3 subunit of the CCR4-NOT complex, is found to be associated with T-cell acute lymphoblastic leukemia, T-ALL, though its contribution to other cancers has not been reported. Here, we provide evidence suggesting that CNOT3 is required for the growth of non-small cell lung cancer. Depletion of CNOT3 suppresses proliferation of A549 human non-small cell lung cancer cells with enhanced mRNA stability and subsequent elevated expression of p21. In addition, we identified the mRNA for Kruppel-like factor 2 transcription factor, an inducer of p21, as a novel mRNA degradation target of CNOT3 in non-small cell lung cancer cells. Aberrant up-regulation of Kruppel-like factor 2 by CNOT3 depletion leads to impairment in the proliferation of A549 cells. Consistent with these findings, elevated mRNA expression of CNOT3 in non-small cell lung cancer in comparison with the paired normal lung epithelium was confirmed through scrutinization of the RNA-sequencing datasets from The Cancer Genome Atlas. Moreover, we found an inverse correlation between CNOT3 and CDKN1A (encoding p21) mRNA expression using the combined datasets of normal lung epithelium and non-small cell lung cancer. Thus, we propose that the up-regulation of CNOT3 facilitates the development of non-small cell lung cancer through down-regulation of Kruppel-like factor 2 and p21, contrary to tumor suppressive functions of CNOT3 in T-ALL

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats.

Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the renin-angiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH. In the choline-deficient L-amino acid-defined diet-induced rat NASH model, the effects of a clinically used selective Ald blocker (SAB) were elucidated in conjunction with the activated hepatic stellate cells (HSC) and neovascularization, which are both known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. Liver fibrosis development and the glutathione-S-transferase placental form-positive pre-neoplastic lesions were both markedly attenuated by SAB along with the suppression of the activated HSC and neovascularization. SAB inhibited the hepatic expression of transforming growth factor-β 1 and also that of the vascular endothelial growth factor. Our in vitro study showed that SAB also inhibited the Ald-induced HSC proliferation and in vitro angiogenesis in a dose-dependent manner. These results indicated that Ald plays a pivotal role in the progression of NASH. Considering that SAB is already widely used in clinical practice, this drug could represent a potential new strategy against NASH in the future

The vascular endothelial growth factor (VEGF) receptor-2 is a major regulator of VEGF-mediated salvage effect in murine acute hepatic failure

Although administration of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, could improve the overall survival of destroyed sinusoidal endothelial cells (SEC) in chemically induced murine acute hepatic failure (AHF), the mechanistic roles of the VEGF receptors have not been elucidated yet. The respective roles of VEGF receptors; namely, Flt-1 (VEGFR-1: R1) and KDR/Flk-1 (VEGFR-2: R2), in the D-galactosamine (Gal-N) and lipopolysaccharide (LPS)-induced AHF were elucidated with specific neutralizing monoclonal antibody against R1 and R2 (R1-mAb and R2-mAb, respectively). The serum ALT elevation, with a peak at 24 h after Gal-N+LPS intoxication, was markedly augmented by means of the R1-mAb and R2-mAb. The aggregative effect of R2-mAb was more potent than that of R1-mAb, and the survival rate was 70% in the R2-mAb-treated group and 100% in the other groups. The results of SEC destruction were almost parallel to those of the ALT changes. Our in-vitro study showed that R1-mAb and R2-mAb significantly worsened the Gal-N+LPS-induced cytotoxicity and apoptosis of SEC mediated by caspase-3, which were almost of similar magnitude to those in the in-vivo study. In conclusion, these results indicated that R2 is a major regulator of the salvage effect of VEGF on the maintenance of SEC architecture and the anti-apoptotic effects against chemically-induced murine AHF

Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat

<p>Abstract</p> <p>Background</p> <p>Apart from simple steatosis, the non-alcoholic steatohepatitis (NASH) can progress into liver fibrosis and cirrhosis. To date, however, no widely accepted therapeutic modalities have been established against NASH in the clinical practice. To find out promising new therapeutic agents, it is important to employ an appropriate experimental model of NASH, such as association with insulin resistance.</p> <p>Findings</p> <p>In the current study, we found that losartan, a clinically used angiotensin-II type 1 receptor blocker, significantly attenuated a choline-deficient L-amino acid-defined (CDAA) diet-induced steatohepatitis in obese diabetic- and insulin resistance-associated Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The transforming growth factor-beta, a well-known major fibrogenic cytokine, was also suppressed in a similar magnitude to that of the fibrosis area. Noteworthy was the finding that these inhibitory effects were achieved even at a clinically comparable low dose.</p> <p>Conclusion</p> <p>Since losartan is widely used without serious side effects in the clinical practice, this agent may be an effective new therapeutic strategy against NASH.</p

Light Scalar Top and Heavy Top Signature at CDF

We propose a mechanism which could explain a slight excess of top signal rate recently reported by CDF in the framework of the supersymmetric standard model. If the scalar partner of the top (stop) is sufficiently light, the gluino with an appropriate mass could decay into the stop plus the top with almost 100\% branching ratio and experimental signatures of the gluino pair production could be indistinguishable from those of the top production in the present integrated luminosity Tevatron running. In this case the standard top signal, $W$ $+$ multi-jets events, would be effectively enhanced by the additional gluino contribution. It is shown, moreover, that such a mechanism can actually work in the radiative SU(2)$\times$U(1) breaking model without the GUT relations between the gaugino mass parameters.Comment: 8 pages (LaTeX), 3 figures not included (available on request) ; ITP-SU-94/03, RUP-94-0

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