The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL)

Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d–l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain. Furthermore, selected compounds have been shown to achieve good brain penetration after oral administration in an animal study.     

A Dimeric Structural Scaffold for PRC2-PCL Targeting to CpG Island Chromatin

1. Download : Download high-res image (317KB)
2. Download : Download full-size image

     

Embelin impact on paraquat‐induced lung injury through suppressing oxidative stress,inflammatory cascade,and MAPK/NF‐κB signaling pathway

The current examination was intended to observe the defensive impacts of embelin against paraquat‐incited lung damage in relationship with its antioxidant and anti‐inflammatory action. Oxidative stress marker, like malondialdehyde (MDA), antioxidative enzymes, for example, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH Px), inflammatory cytokines, such as interleukin‐1β (IL‐1β), tumor necrosis factor‐α, and IL‐6, histological examination, and nuclear factor kappa B/mitogen‐activated protein kinase (NF‐κB/MAPK) gene expression were evaluated in lung tissue. Embelin treatment significantly decreased MDA and increased SOD, CAT, and GSH Px. Embelin significantly reduced levels of inflammatory cytokines in paraquat‐administered and paraquat‐intoxicated rats. In addition, embelin suggestively decreased relative protein expression of nuclear NF‐κB p65, p‐NF‐κBp65, p38 MAPK, and p‐p38 MAPKs in paraquat‐intoxicated rats. The outcomes show the impact of embelin inhibitory action on NF‐κB and MAPK and inflammatory cytokines release, and the decrease of lung tissue damage caused by paraquat.     

Fine-tuning of the Hsc70-based Human Protein Disaggregase Machinery by the Distinctive C-terminal Extension of Apg2

Apg2, one of the three cytosolic Hsp110 chaperones in humans, supports reactivation of unordered and ordered protein aggregates by Hsc70 (HspA8). Together with DnaJB1, Apg2 serves to nucleate Hsc70 molecules into sites where productive entropic pulling forces can be developed. During aggregate reactivation, Apg2 performs as a specialized nucleotide exchange factor, but the origin of its specialization is poorly defined. Here we report on the role of the distinctive C-terminal extension present in Apg2 and other metazoan homologs. We found that the first part of this Apg2 subdomain, with propensity to adopt α-helical structure, interacts with the nucleotide binding domain of Hsc70 in a nucleotide-dependent manner, contributing significantly to the stability of the Hsc70:Apg2 complex. Moreover, the second intrinsically disordered segment of Apg2 C-terminal extension plays an important role as a downregulator of nucleotide exchange. An NMR analysis showed that the interaction with Hsc70 nucleotide binding domain modifies the chemical environment of residues located in important functional sites such as the interface between lobe I and II and the nucleotide binding site. Our data indicate that Apg2 C-terminal extension is a fine-tuner of human Hsc70 activity that optimizes the substrate remodeling ability of the chaperone system.     

Drosophila female germline stem cells undergo mitosis without nuclear breakdown

1. Download : Download high-res image (189KB)
2. Download : Download full-size image

     

Microwave-And Ultrasound-Assisted Synthesis of Some Acyclonucleobases Based on a Uracil Moiety Using Dmap as Base

In this study, 1-(bromoalkanoyl)-1H-pyrimidine-2,4-diones, (2,4-dioxo-pyrimidin-1-yl)-oxo-alkanoic acids, and bis(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-alkanones were successfully prepared via electrophilic substitution of uracil and its derivatives. High yields and pure products were obtained when microwave and ultrasound methodologies were used for undertaking the reactions. Importantly, the use of 4-dimethylaminopyridine in the present investigation gave rise to higher conversions of the starting material and afforded facile access to regioselective N-1 products.     

TonB protein and energy transduction between membranes

TonB protein couples cytoplasmic membrane electrochemical potential to active transport of iron-siderophore complexes and vitamin B12 through high-affinity outer membrane receptors of Gram-negative bacteria. The mechanism of energy transduction remains to be determined, but important concepts have already begun to emerge. Consistent with its function, TonB is anchored in the cytoplasmic membrane by its uncleaved amino terminus while largely occupying the periplasm. Both the connection to the cytoplasmic membrane and the amino acid sequences of the anchor are essential for activity. TonB directly associates with a number of envelope proteins, among them the outer membrane receptors and cytoplasmic membrane protein ExbB. ExbB and TonB interact through their respective transmembrane domains. ExbB is proposed to recycle TonB to an active conformation following energy transduction to the outer membrane. TonB most likely associates with the outer membrane receptors through its carboxy terminus, which is required for function. In contrast, the novel prolinerich region of TonB can be deleted without affecting function. A model that incorporates this information, as well as tempered speculation, is presented.     

Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0–37.8] mg/dl) and slightly reduced in heterozygotes (218 [153–234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.     

H.pylori可塑区tfs3a分泌系统virB2基因功能

目的对virB2基因编码蛋白进行分析,为virB2基因及其编码蛋白功能提供实验依据。方法利用多种生物学软件以及网站对VirB2蛋白的结构和功能进行分析预测,VirB2蛋白序列通过基因推导获得并由生物公司合成,然后通过免疫动物实验制备鼠抗VirB2蛋白多克隆抗体,同时设计进行VirB2蛋白细胞毒试验(MTT法)。结果virB2基因编码蛋白属于疏水性蛋白,为鞭毛样结构,有较强的细胞毒作用。结论对VirB2蛋白的结构和功能进行了分析预测,证明VirB2蛋白在H.pylori相关的致病性特别是引起胃黏膜炎症方面起到一定的作用,能够为研究H.pylori致病机制提供帮助。