JOURNAL OF CHEMICAL RESEARCH
·
2022
·
IF 1.097
Tiandi Ding,HaiJiao Chen,Yan Li,Ying Li,Ying Zhi,Zhiqiang Qu,Qiang Sun,Qingqiang Yao,Bo Liu
Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
研究领域:
药理学
·
癌症研究
·
药物发现
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生物化学
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分子生物学
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DOI
高影响因子
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
·
2023
·Vol. 26
·期 20
·e202300278
·
IF 2.8
Yonghang Mu,Zi Wang,Linhua Song,Kun Ma,Yao Chen,Peixun Li,Zifeng Yan
Graphical We report a gram-scale synthesis of sphingosines with different deuterated chains. The synthesis of highly stereoselective chain deuterated sphingosine was accomplished in five steps which started from hydrothermal platinum-catalyzed hydrogen/deuterium (H/D) exchange of protiated fatty acids. The subsequent synthesis of the deuterated-chain derivatives are also described. They were all characterized with deuterated content above 94 %. Sphingosine plays crucial roles in various cellular functions. Deuterated molecules are widely used as the important tools to explore the structure, property, and function of biochemical materials. We here report a gram-scale synthesis of sphingosines with different deuterated chains. The synthesis started from different protiated fatty acids, which underwent hydrothermal platinum-catalyzed hydrogen/deuterium (H/D) exchange to produce the deuterated chains with different length. The Horner–Wadsworth–Emmons (HWE) coupling of a chiral amino acid derivative with the deuterated chains generated the unsaturated ketone precursors. The following stereoselective reduction via cyclic Felkin–Anh transition led to the desired anti- amino alcohol geometry. This efficient protocol enabled the gram-scale synthesis of the chain-deuterated sphingosines. The subsequent synthesis of the chain-deuterated derivatives, i. e. ceramide, sphinganine and sphingosine-1-phosphate, is also described. Their deuterium content was simultaneously characterized by 1 H NMR and high-resolution mass spectrum (HRMS).
研究领域:
有机化学
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生物化学
·
药学
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DOI
高影响因子
ANALYTICA CHIMICA ACTA
·
2020
·
IF 5.977
Shi-En Chen,Shuyun Zhu,Jingwen Hu,Jing Sun,Zhenjia Zheng,Xian-En Zhao,Huwei Liu
Glucosylsphingosine (GlcS) in plasma is considered to be a reliable biomarker of Gaucher disease . The detection difficulty of GlcS is that it is difficult to achieve simultaneous separation and quantification with its isomer galactosylsphingosine (GalS), a biomarker of Krabbe disease . In this work, a multiplexed stable isotope labeling absolute quantization strategy coupled with magnetic dispersive solid phase extraction using new prepared dummy magnetic molecularly imprinted polymers (DMMIPs) has been developed for this purpose by ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). 8-Plex Amine-reactive Mass Difference Tags (M360/361/362/363/373/375/376/378-AMDTs), were designed, synthesized and used to label GalS and GlcS in different 8 plasma samples, respectively. Synchronously, M359-AMDTs was prepared and used to label mixed standards of GalS and GlcS, which served as internal standards in UHPLC-MS/MS quantitation. Then DMMIPs possessing dual recognition function were applied for specific enrichment and purification of all GlcS and GalS derivatives from a combined solution of labeled 8-plex plasma samples and mixed standards before UHPLC-MS/MS injection. The labeling efficiency, chromatographic retention and mass spectrometry responses of all the 9 AMDTs reagents were consistent for GlcS and GalS. The established and validated method enabled 8-plex plasma samples quantification in a single UHPLC-MS/MS run (<2.0 min). Good linearity of AMDTs-GlcS/GalS derivatives was obtained in the range of 0.02–800 nM. LODs of GlcS and GalS were both 0.005 nM. The recoveries were in the range of 96.1–107.2%. The method was successfully applied for multiplex quantitative analysis of GlcS and GalS in human plasma samples. The results indicated that this method was capable of better realizing the simultaneous separation and quantification of GalS and GlcS compared to reported methods.
研究领域:
医学检测
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生物化学
·
分析化学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
·
IF 3.1
Xiaomei Wu,Bin Pang,Jianwei You,Leiye Yu,Ruobing Ren,Hongyang Wang,Li Chen
Sphingosine-1-phosphate (S1P) is an active signaling metabolite synthesized by blood cells, exported into blood stream, and can trigger many downstream signaling pathways with disease implications. Understanding how S1P is transported is of great values for dissecting the function of S1P, but most existing methods for measuring S1P transporter activity use radioactive substrates or involve multiple workup steps, hindering their broader uses. In this study, we develop a workflow combining sensitive LC-MS measurement and a cell-based transporter protein system to measure the export activity of S1P transporter proteins. Our workflow demonstrated good applications in studying different S1P transporters SPNS2 and MFSD2B, WT and mutated protein, and different protein substrates. In summary, we provide a simple yet versatile workflow for measuring the export activity of S1P transporters, facilitating future studies of S1P transport mechanism and drug development.
研究领域:
生物化学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·Vol. 10
·期 25
·2300569
·
IF 15.1
Jing Hu,Effiong Kokoette,Caicai Xu,Shitao Huang,Tao Tang,Yiyi Zhang,Muyuan Liu,Yuzhou Huang,Shumiao Yu,Jie Zhu,Marianne Holmer,Xi Xiao
Harmful algal blooms (HABs), which are promoted by eutrophication and intensified by global warming, occur worldwide. Allelochemicals, which are natural chemicals derived from plants or microbes, are emerging weapons to eliminate these blooms. However, the cost and technical challenges have limited the discovery of novel antialgal allelochemicals. Herein, the decomposition of agricultural straws is manipulated by white-rot fungi and achieved elevated antialgal efficiency. The transcriptomic analysis reveals that nutrient limitation activated fungal decomposition. By using a comparative nontarget metabolomics approach, a new type of allelochemical sphingosines (including sphinganine, phytosphingosine, sphingosine, and N -acetylsphingosine) is identified. These novel natural algaecides exhibit superior antialgal capability, with as high as an order of magnitude lower effective concentration on blooming species than other prevalent allelochemicals. The co-expression relationship between transcriptomic and metabolomic results indicate that sphinganine is strongly correlated with the differentially expressed lignocellulose degradation unigenes. The algal growth suppression is triggered by the activation of programmed cell death, malfunction of algal photosystem and antioxidant system, the disruption on CO 2 assimilation and light absorption. The sphingosines reported here are a new category of allelochemicals in addition to the well-known antialgal natural chemicals, which are potential species-specific agents for HABs control identified by multi-omics methodology.
研究领域:
环境科学
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微生物学
·
植物化学
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产品关联
DOI
PubMed
高影响因子
Biochemistry and Cell Biology
·
2018
·Vol. 96
·期 6
·
IF 2.25
Xingcai Zhang,Yuli Cai,Wei Zhang,Xianhai Chen
Idiopathic pulmonary fibrosis is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I, and Collagen III. Similar results were observed in transforming growth factor (TGF)-β-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-β administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1, and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.
研究领域:
药理学
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肺病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2020
·
IF 2.014
Li YAO,Yu-Xia YANG,Hui CAO,Huan-Huan REN,Zheng NIU,Ling SHI
Osthole is observed to have the capacity to treat pulmonary arterial hypertension (PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro . These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1P via microRNA-21-PI3K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.
研究领域:
药理学
·
心血管疾病
·
代谢紊乱
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产品关联
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2014
·Vol. 172
·期 7
·3448-3460
·
IF 1.687
Zhang Jianfen,Chen Weiqing,Ke Wei,Chen Hong
The objective of this study was to screen glucoside 3-dehydrogenase (G3DH)-producing strain based on a high-throughput G3DH screening method. Optimization of culture conditions of the isolated strain was also applied in this study. This screening method employed electron transfer reaction in 96-well microtiter plates, α-methyl- d -glucoside, galactose, 2-deoxy- d -glucose, and 3- O -methyl- d -glucose were used as substrates. Using this screening method, one out of 78 strains isolated from different soil samples was obtained with high G3DH activity. The accuracy of the screening method was proved by alkaline treatment analysis of 3-keto sugars. The isolated strain was identified as Sphingobacterium faecium ZJF-D6 by phenotypic characterization and 16S rDNA sequence analysis. The culture conditions of S. faecium for G3DH production were optimized. Sucrose was found as the most suitable carbon source for the G3DH production. The highest G3DH production and cell growth were achieved using the medium at the initial pH of 7.0 at 25 °C for 36 h with activity of 8.03 × 10 −2 U/mL culture. This strain appears promising for potential application in the industry to produce 3-keto sugars. To our knowledge, this is the first report on S. faecium for G3DH production. The method described herein represents a useful tool for the high-throughput isolation of G3DH.
研究领域:
微生物学
·
生物化学
·
工业生物技术
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产品关联
DOI
PubMed
高影响因子
Probiotics and Antimicrobial Proteins
·
2022
·Vol. 15
·期 4
·941-954
·
IF 5.265
He Xi,Zhou Meiling,Chen Xuemei,Wang Jing,Zhao Xiaoli,Zhu Yanxia,Liu Tao
Overcoming the bacterial infection and promoting angiogenesis are challenge and imperious demands in wound healing and skin regeneration. Hereby, we developed a multifunctional AMP/S1P@PLA/gelatin wound dressing fabricated by electrospinning poly ( l -lactic acid) (PLA)/gelatin with antimicrobial polypeptides (AMPs) and sphingosine-1-phosphate (S1P) in order to inhibit the bacteria growth and induce angiogenesis. In our work, AMP/S1P@PLA/gelatin wound dressing was obtained by two-step method of electrospinning and dopamine adsorption. Our results showed that incorporating AMP into PLA/gelatin nanofibrous membranes significantly improved antibacterial properties against both Escherichia coli and Staphylococcus aureus . S1P releasing from AMP/S1P@PLA/gelatin nanofibrous membranes could significantly enhance tube formation. Simultaneously, we found that the AMP/S1P@PLA/gelatin nanofibrous membranes facilitated the adhesion, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) and murine fibroblast (L929). AMP/S1P@PLA/gelatin membranes could also accelerate infected wound healing and skin regeneration by antibacterial and pro-angiogenesis effects. In summary, our developed AMP/S1P@PLA/gelatin nanofibrous membranes could be multifunctional dressing for infected wound healing and skin regeneration. Graphical Abstract Schematic figure to describe the characterizations and preparation of AMP/S1P@PLA/gelatin nanofibrous membranes.
研究领域:
生物材料学
·
医学
·
组织工程学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Host & Microbe
·
2024
·
IF 20.6
Xuemei Wang,Shuang Zhou,Xiaomin Hu,Chuan Ye,Qixing Nie,Kai Wang,Sen Yan,Jun Lin,Feng Xu,Meng Li,Qing Wu,Lulu Sun,Bo Liu,Yi Zhang,Chuyu Yun,Xian Wang,Huiying Liu,Wen-Bing Yin,Dongyu Zhao,Jing Hang,Shuyang Zhang,Changtao Jiang,Yanli Pang
The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans ( C. albicans ), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C. albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C. albicans . Mechanistically, formyl-methionine, a metabolite of C. albicans , activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment.
研究领域:
微生物学
·
心血管疾病
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2016
·Vol. 23
·期 12
·12019-12029
·
IF 2.76
Bai Naling,Wang Sheng,Abuduaini Rexiding,Zhu Xufen,Zhao Yuhua
Nonylphenol polyethoxylates (NPEOs), although banned for decades, are still widely used in manufactories and thus affect human lives. In this study, a highly efficient NPEO-degrading bacterium, Sphingomonas sp. Y2, was isolated from sewage sludge by enrichment culture. Strain Y2 ensured the complete removal of NPEO in 48 h and degraded 99.2 % NPEO (1,000 mg L −1 ) within 30 h at a specific growth rate of 0.73 h −1 in minimum salt medium. To date, this degradation efficiency is the highest reported for NPEO metabolism by a pure bacterium under this condition. Furthermore, the application of this bacterium to wastewater treatment demonstrated that it metabolized 98.5 % NPEO (1,000 mg L −1 ) within 5 days with a specific growth rate of 2.03 day −1 . The degradation intermediates, identified as nonylphenol, short-chain NPEOs and short-chain nonylphenol polyethoxycarboxylates by high-performance liquid chromatography and gas chromatography-mass spectrometry, indicated the sequential exo-cleavage of the EO chain. Additionally, the enzymes involved in the biodegradation were inducible rather than constitutive. Considering that strain Y2 exhibits prominent biodegradation advantages in industrial wastewater treatment, it might serve as a promising potential candidate for in situ bioremediation of contamination by NPEOs and other structurally similar compounds.
研究领域:
环境微生物学
·
废物管理
·
生物技术
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Guiping Liu,Songmeng Liu,Jie Yang,Xiaoyang Zhang,Lianghua Lu,Hongxia Xu,Shujun Ye,Jichun Wu,Jiandong Jiang,Wenjing Qiao
Tetrabromobisphenol A (TBBPA), a common brominated flame retardant and a notorious pollutant in anaerobic environments, resists aerobic degradation but can undergo reductive dehalogenation to produce bisphenol A (BPA), an endocrine disruptor . Conversely, BPA is resistant to anaerobic biodegradation but susceptible to aerobic degradation. Microbial degradation of TBBPA via anoxic/oxic processes is scarcely documented. We established an anaerobic microcosm for TBBPA dehalogenation to BPA facilitated by humin. Dehalobacter species increased with a growth yield of 1.5 × 10 8 cells per μmol Br - released, suggesting their role in TBBPA dehalogenation. We innovatively achieved complete and sustainable biodegradation of TBBPA in sand/soil columns columns, synergizing TBBPA reductive dehalogenation by anaerobic functional microbiota and BPA aerobic oxidation by Sphingomonas sp. strain TTNP3. Over 42 days, 95.11 % of the injected TBBPA in three batches was debrominated to BPA. Following injection of strain TTNP3 cells, 85.57 % of BPA was aerobically degraded. Aerobic BPA degradation column experiments also indicated that aeration and cell colonization significantly increased degradation rates. This treatment strategy provides valuable technical insights for complete TBBPA biodegradation and analogous contaminants.
研究领域:
环境科学
·
微生物学
·
生物修复
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）