Physicochemical 2D-Qsar and 3D Molecular Docking Studies on N-Chlorosulfonyl Isocyanate Analogs as Sterol O-Acyl-Transferase-1 “Soat-1” Inhibitors

A series of N-carbonyl-functionalized ureas, carbamates and thiocarbamates derivatives (or N-Chloro sulfonyl isocyanate “N-CSI”) were involved in linear and nonlinear physicochemical quantitative structure-activity relationship “QSAR” analysis to find out the structural keys to control the inhibition against Sterol O-Acyl-Transferase-1 “SOAT-1”. The results indicate the important effects of geometrical and chemical descriptors on the inhibitory activity of SOAT-1. The molecules were also screened for three-dimensional molecular docking on the crystal structure of ACAT-1 (1WL5 for ACAT-1, PDB). A comparison between 2D-QSAR and 3D molecular docking studies shows that the latter confirm the first results and represent a good prediction of the chemical and physical nature of interactions between our drug molecules and enzyme SOAT-1.

Comprehensive prognostic and immune analysis of sterol Oacyltransferase 1 in patients with hepatocellular carcinoma

BACKGROUND Sterol O-acyltransferase 1(SOAT1)is an important target in the diagnosis and treatment of liver cancer.However,the prognostic value of SOAT1 in patients with hepatocellular carcinoma(HCC)is still not clear.AIM To investigate the correlation of SOAT1 expression with HCC,using RNA-seq and gene expression data of The Cancer Genome Atlas(TCGA)-liver hepatocellular carcinoma(LIHC)and pan-cancer.METHODS The correlation between SOAT1 expression and HCC was analyzed.Cox hazard regression models were conducted to investigate the prognostic value of SOAT1 in HCC.Overall survival and disease-specific survival were explored based on TCGA-LIHC data.Biological processes and functional pathways mediated by SOAT1 were characterized by gene ontology(GO)analysis and the Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of differentially expressed genes.In addition,the protein-protein interaction network and co-expression analyses of SOAT1 in HCC were performed to better understand the regulatory mechanisms of SOAT1 in this malignancy.RESULTS SOAT1 and SOAT2 were highly expressed in unpaired samples,while only SOAT1 was highly expressed in paired samples.The area under the receiver operating characteristic curve of SOAT1 expression in tumor samples from LIHC patients compared with para-carcinoma tissues was 0.748,while the area under the curve of SOAT1 expression in tumor samples from LIHC patients compared with GTEx was 0.676.Patients with higher SOAT1 expression had lower survival rates.Results from GO/KEGG and gene set enrichment analyses suggested that the PI3K/AKT signaling pathway,the IL-18 signaling pathway,the calcium signaling pathway,secreted factors,the Wnt signaling pathway,the Jak/STAT signaling pathway,the MAPK family signaling pathway,and cell–cell communication were involved in such association.SOAT1 expression was positively associated with the abundance of macrophages,Th2 cells,T helper cells,CD56bright natural killer cells,and Th1 cells,and negatively linked to the abundance of Th17 cells,dendritic cells,and cytotoxic cells.CONCLUSION Our findings demonstrate that SOAT1 may serve as a novel target for HCC treatment,which is helpful for the development of new strategies for immunotherapy and metabolic therapy.

Sulfated Sterols Isolated from Starfish Asterias amurensis Lutken

Aim To study the chemical constituents of starfish Asterias amurensis. Methods The constituents were separated and purified by different chromatographic methods, and their structures were elucidated by MS and NMR. Results Six compounds were isolated from Asterias amurensis Lutken. Their structures were identified as 3β-O-sulfated-cholest-5-en sodium salt （1）, 3β-O-sulfated-6α-ol- pregn-9（ 11 ） -en-20-one sodium salt （ 2 ）, 3β-O-sulfated-6α-ol-cholest-9 （ 11 ） -en-23-one sodium salt （3）, 3β-O-sulfated-6α, 20β-diol-cholest-9 （ 11 ）-en-23-one sodium salt （ 4 ）, 3β-O-sulfated-6α-ol- cholesta-9 （ 11 ）, 20 （ 22 ） -dien-23-one sodium salt （ 5 ）, and 3β-O-sulfated-6ct-ol-ergost-9 （ 11 ） -en-23- one sodium salt （6）. Conclusion Compounds 1 - 6 were obtained from this species for the first time.

南海海绵Rhabdastrella属中新胆甾醇Rhabdasterol

人们已从海绵生物中发现了许多结构独特的有机化合物，如萜类、甾醇、苷类、生物碱、多肽和聚醚等，其中许多具有广谱抗菌、抗病毒、抗心血管病和抗肿瘤等生理活性．本文报道从我国南海海绵Ｒｈａｂｄａｓｔｒｅｌａｓｐ．中分离出一个具有新型侧链的胆甾醇：２５（２９）...

Nephthea属软珊瑚中19-羟基甾醇Nephalsterol A及B的结构测定

从南海软珊瑚Nephthea albida及N.tiexieral verseveldt中分离到2个含19-羟基的多羟基甾醇Nephalsterol A(1)及 B(2),通过波谱方法测定了1及2的结构依次为:24-亚甲基-胆甾-3β,5α,6β,19-四醇及24-亚甲基-胆甾-5-烯-3β,7β,19-三醇。

新甾醇Echifloristerol的结构测定

从中国南海采集的花刺柳珊瑚中分离到一种新的甾醇echifloristerol。通过波谱方法,确定其结构为22-ξ-甲基-Δ^(5(6)).23(24))-胆甾烷-3β-醇。

固醇敏感多肽区(Sterol-sensing dom ain)的分子进化

固醇敏感多肽区 (SSD)在胆固醇自我平衡调节、物质运输以及细胞信号转导中发挥重要的作用 .通过对三界系统中 ,不同门纲代表种 (2 2个种 )的 SSD序列分析发现 ,SSD在组成上有很大的偏向性 ,在三级结构上高度保守 .分子系统树的结果表明 SSD明显分为 PTC、NPC1、Ptr、SCAP、Disp、HMGCR和原核生物类 7大分枝 ,功能相关基因的 SSD并不聚集在一起 ,说明 SSD在进化中受到的选择压力是不同的 .推测是一种原始的拥有编码 SSD跨膜结构域序列通过交换转移和其他的编码序列组成新的基因 ,再逐步进化形成固定的功能 ,而 SSD保持了与运输有关的功能 .进一步证实了 Ref[13]提出的 Hh- PTC- Sm o信号系统作用模型 .

19-羟基甾醇Nephalsterol-B的结构研究

前文报道了从西沙群岛采集的软珊瑚Nephthea albida和南沙群岛采集的软珊瑚Nephthea tixiexae verseveldt分离到一种罕见的含19-羟基的四羟基甾醇Nephalsterol A（1）.本文报道从N.tixiexae verseveldt分离到的另一种19-羟基甾醇Nephalsterol-B的结构测定. Nephalstereol B（2）为无色针状结晶,m.p.159～161℃（乙酸乙酯）;160～162℃（丙酮）,[α]D27+25°（C 0.100,甲醇）,2的13C NMR及其DEPT谱表明分子中含有4个CH3。

Synthesis of 3 Nitrogen containing Function Substituted Lanosterol Derivatives Inhibitors of (S) Adenosyl L Me thionine:Δ 24(25) Sterol Methyltransferase

Syntheses of 3 ketolanosterol, 3 acetolanosterol, 3 oximolanosterol, 3α and 3β aminolanosterol were described The products have been fully characterized on the basis of their chromatographic (TLC R f, GLC RRTc) and spectral (IR, MS, 1 H NMR, 13 C NMR) properties

An Abietane Diterpene and a Sterol from Fungus Phellinus igniarius

A new abietane diterpene 12-hydroxy-7-oxo-5, 8, 11, 13-tetraene-18, 6-abietanolide, together with a new natural sterol stigmasta-7, 22-diene-3β, 5α 6α-triol have been isolated from the fruiting body of the fungus Phellinus igniarius. Their structures were elucidated by spectroscopic methods including 2D NMR techniques.

Occurrence of Different Forms and Implications of Compound Specific Sterols in Continental Sediments of the Northeast South China Sea

The South China Sea(SCS) is one of the most productive and accumulative marginal shelves of organic carbon in the world. To expound the transformation and preservation of organic carbon in the Northeast SCS, where abundant oil and gas resources have been reported, compound specific sterols in free(FR), base hydrolytic(BH), and acid hydrolytic(AH) forms were analyzed in surface and columnar sediments in May, 2016. The results showed that the total contents of sterols detected ranged from 0.15 to 3.74 ppm dry weight in the surface sediments, and gradually decreased from 3.41 to0.17 ppm dry weight from surface to deep sediments, in which cholesterol(27^(△5)) was the most abundant component. Sterols mainly existed in the BH form(54.51%-74.20%), followed by the FR form(25.50%-45.49%) and then the AH form(0-3.77%) in turn, in the surface sediments. BH and FR sterols accounted for 0-49.08% and 50.92%-100% in the columnar sediments, while AH sterols were undetectable. The contents of specific sterols indicated that, the primary source of marine organic carbon was about 5 times as much as that from terrestrial input. More and more FR sterols transformed into BH sterols with increasing sedimentary depth, and BH sterols absolutely dominated in sediment depths under 25 cm. The forms of Sterols C27 were maintained at a relative consistence state, but Sterols C28 to C30 degraded gradually during the sedimentation process. It was suggested that the stability of sterols, based on the chemical structures, might be the primary factor controlling their degradation and preservation in deeper sediments. These results would help to understand the organic carbon(OC) transformation in a hydrate formation area in a marginal sea.

Cloning and expression of two sterol C-24 methyltransferase genes from upland cotton(Gossypium hirsuturm L.)

Brassinosteroids （BRs） are an important class of plant steroidal hormones that are essential in a wide variety of physiological processes. Two kinds of intermediates, sitosterol and campesterol, play a crucial role in cell elongation, cellulose biosynthesis, and accumulation. To illuminate the effects of sitosterol and campesterol on the development of cotton （Gossypiurn hirsuturm L.） fibers through screening cotton fiber EST database and contigging the candidate ESTs, two key genes GhSMT2-1 and GhSMT2-2 controlling the sitosterol biosynthesis were cloned from developing fibers of upland cotton cv. Xuzhou 142. The full length of GhSMT2-1 was 1,151 bp, including an 8 bp 5＇-untranslated region （UTR）, a 1,086 bp open reading frame （ORF）, and a 57 bp 3＇-UTR. GhSMT2-1 gene encoded a polypeptide of 361 amino acid residues with a predicted molecular mass of 40 kDa. The full length of GhSMT2-2 was 1,166 bp, including an 18 bp 5＇-UTR, a 1,086 bp ORF, and a 62 bp 3＇-UTR. GhSMT2-2 gene encoded a polypeptide of 361 amino acid residues with a predicted molecular mass of 40 kDa. The two deduced amino acid sequences had high homology with the SMT2 from Arabidopsis thaliana and Nicotiana tabacurn. Furthermore, the typical conserved structures characterized by the sterol C-24 methyltransferase, such as region I （LDVGCGVGGPMRAI）, region II （IEATCHAP）, and region III （YEWGWGQSFHF）, were present in both deduced proteins. Southern blotting analysis indicated that GhSMT2-1 or GhSMT2-2 was a single copy in upland cotton genome. Quantitative real-time RT-PCR analysis revealed that the highest expression levels of both genes were detected in 10 DPA （day post anthesis） fibers, while the lowest levels were observed in cotyledon and leaves. The expression level of GhSMT2-1 was 10 times higher than that of GhSMT2-2 in all the organs and tissues detected. These results indicate that the homologue of sterol C-24 methyltransferase gene was cloned from upland cotton and both GhSMT2 genes play a crucial role in fiber elongation. The role of GhSMT2-1 may be more important than that of GhSMT2-2.

Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins

The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.

Dynamics of hepatic and intestinal cholesterol and bile acid pathways: The impact of the animal model of estrogen deficiency and exercise training

Plasma cholesterol level is determined by a complex dynamics that involves transport lipoproteins which levels are tightly dependent on how the liver and the intestine regulate cholesterol and biliary acid metabolism. Regulation of cholesterol and biliary acids by the liver and the intestine is in turn coupled to a large array of enzymes and transporters that largely influence the inflow and the outflow of cholesterol and biliary acids through these organs. The activity of the key regulators of cholesterol and biliary acids may be influenced by several external factors such as pharmacological drugs and the nutritional status. In recent years, more information has been gathered about the impact of estrogens on regulation of cholesterol in the body. Exposure to high levels of estrogens has been reported to promote cholesterol gallstone formation and women are twice as likely as men to develop cholesterol gallstones. The impact of estrogen withdrawal, such as experienced by menopausal women, is therefore of importance and more information on how the absence of estrogens influence cholesterol regulation is started to come out, especially through the use of animal models. An interesting alternative to metabolic deterioration due to estrogen deficiency is exercise training. The present review is intended to summarize the present information that links key regulators of cholesterol and biliary acid pathways in liver and intestine to the absence of estrogens in an animal model and to discuss the potential role of exercise training as an alternative.

Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.

A New Cytotoxic Sterol Produced by an Endophytic Fungus from Castaniopsis fissa at the South China Sea Coast

A new sterol, ergosta-8(9),22-diene-3,5,6,7-tetraol(3β,5α,6β,7α,22E)(A) together with three known sterols: 3β, 5α,6β-trihydroxyergosta-7,22-diene (B), 3β-hydroxy-5α,8α- epidioxyer-gosta-6,22-diene (C) and ergosterol (D) were isolated from the mycelia of an unidentified endophytic fungus separated from Castaniopsis fissa (chestnut tree). Compound A exhibited potent selective cytotoxicity against Bel-7402, NCI4460 and L-02 cell lines with IC50 values 8.445, 5.03, 13.621 μg/mL, respectively.

Two New Sterols from Adenophora Stenanthina Subsp.Xifengensi

ＴｗｏＮｅｗＳｔｅｒｏｌｓｆｒｏｍＡｄｅｎｏｐｈｏｒａＳｔｅｎａｎｔｈｉｎａＳｕｂｓｐ．ＸｉｆｅｎｇｅｎｓｉｓＨＯＵＺｈｅｎ－ｆｕ，ＳＨＩＹａｎ－ｐｉｎｇ，ＭＥＩＳｈｕａｎｇ－ｘｉａｎｄＬＩＹｕ＊（ＩｎｓｔｉｔｕｔｅｏｆＯｒｇａｎｉｃＣｈｅｍｉｓｔｒ...

Dietary Calcium Decreases Plasma Cholesterol Level only in Female but not in Male Hamster Fed a High Cholesterol Diet

Objective To investigate the effect of dietary calcium on plasma lipoprotein profile in castrated and ovariectomized hamsters. Methods Male, castrated, female and ovariectomized hamsters （n=36 each group） were randomly divided into three sub-groups （n=12） and fed one of the three diets containing O, 2, and B g calcium per kg diet for a period of six weeks. Changes in plasma lipoprotein profile were monitored at the end of week O, 3 and 6. Results Plasma total cholesterol （TC）, non-high density lipoprotein cholesterol （non-HDL-C）, triacylglycerols （TG） and TC/HDL-C were decreased only in intact female and ovariectomized hamsters. In contrast, three levels of dietary calcium had no effect on lipoprotein profiles in both intact male and castrated hamsters. Conclusion Beneficial modification of lipoprotein profile by dietary calcium was gender-dependent at least in hamsters.

Crystallographic and NMR studies on sterols from green alga Chaetomorpha basiretorsa Setchell

Chemical investigation of the ethanol extract of the marine green alga Chaetomorpha basiretorsa Setchell led to the isolation of a new sterol stigmast-4,28-dien-3α,6β-diol 1 in addition to the five known sterols of β-lawsaritol 2, saringosterol 3, 24-hydroperoxy-24-vinyl - cholesterol 4, β-stigmasterol 5, 29-hydroxystigmasta-5, 24 （28） -dien-3β-ol 6. Compounds were isolated by normal phase silica gel and Sephadex LH - 20 gel colum chromatography, reverse phase HPLC and recrystalization. Their structures were elucidated by spectroscopic methods including MS, IR 1D/2D NMR and X-ray analysis. Cytotoxicity of compounds was screened by using the standard MTF method. All these compounds were isolated from the green alga Chaetomorpha basiretorsa Setchell for the first time and they were inactive （50% inhibitory concentration was greater than 10 μg/cm^3） against KB, Bel -7402, PC - 3M, Ketr 3 and MCF-7 cell lines.

The Identification of Two New Sterols from Marine Organism

Two new sterol have been isolated from the South China Sea marine organism. Compound 1 was isolated from the sponge Polymastia sobustia and compound 2 was obtained from the soft coral Sinularia inexplicata. Their structures were established as 3 beta-hydroxy-stigmast-5en-7-one and 24-methylene cholestan -3 beta, 6 beta, 9 alpha, 19-tetrol by variety of spectral analysis such as IR, EIMS, 1DNMR, H-1-H-1 COSY, HMQC, HMBC, NOESY.