ligand

摘要： There are numerous evaluations of natural products,of which majority are food bioactives,performed up to date for their various health beneficial activities via targeting specific proteins.However,the direct identification of a targeted protein remains unexplored for natural occurring compounds.Proteolysis targeting chimera(PROTAC)is a type of bifunctional chimeric molecules that can directly degrade the binding proteins targeted by bioactive molecules in an ubiquitin-proteasome pathway.As the agents in protein degradation dependent on ubiquitin ligase,the bifunctional molecule connects the target protein ligand and E3 ligase ligand together via an appropriate linker.It is highly selective and efficient to induce the ubiquitin-mediated degradation of targeted binding proteins.Therefore,it has been demonstrated that the PROTAC technology has broad application in the modulation of the target protein level.In this review,we outlined the advances in PROTAC combined molecule compounds,summarized its quantitative structure-activity relationship,and finally reviewed the methods applied in identifying the target proteins of natural products.We hope it will provide an insightful application of PROTAC techniques in the target protein identification of natural products including food bioactive molecules.

摘要： Studies have found that a large number of inflammatory cells,P-selectin,and mature dendritic cells(DCs)are expressed in the damaged and shoulder parts of atherosclerotic plaque,which demonstrates that P-selectin and mature DCs participate in the immune inflammatory response leading to the development of atherosclerosis.However,it is unclear how the above factors interact in this setting.In this study,we investigated the role of P-selectin and its receptor,P-selectin glycoprotein ligand(PSGL)-1 in atherosclerosis,with the finding that DC surface marker expression was consistently high in the P-selectin group while consistently low in the PGSL-1+DCs group,with CD40 and CD86 expressed by 3.84%and 2.05%for the latter.The highest expression of CD80,CD83,and MHC II was discovered in the DC group,at 7.49%,3.68%,and 8.98%,respectively.Results of this study are similar to those obtained previously by Ye et al.(2017),which showed larger atherosclerotic lesions in mice that received exogenous DCs,compared with those treated with PBS.In this study,the greatest level of atherosclerosis,fibrosis,and lipid deposition was also seen in mice that received exogenous DCs.

摘要： Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R;OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among?the GPCRs, CX3CR1 is focused as target of PET during inflammation of brain and spinal cord.

摘要： BACKGROUND Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1(PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas(G-NECs) remains unknown.AIM To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.METHODS We investigated the expression of PD-L1 on tumor cells and PD-1^+, CD8^+, and FOXP3^+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.RESULTS Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43G-NECs, 21(48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival(OS). The high expression of PD-L1 was correlated with abundant PD-1^+ tumor infiltrating lymphocytes(TILs) instead of CD8^+ TILs and FOXP3^+ regulatory T cells(Tregs).Our analysis also suggested that the infiltration of CD8^+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance(P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.CONCLUSION Our data demonstrated for the first time that high expression of PD-L1 in GNECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in GNECs.

摘要： Four easily available ferrocenyl chiral ligands have been screened firstly for ruthenium (II)-catalyzed asymmetric transfer hydrogenation of acetophenone with HCOOH/Et3N azeotrope as the hydrogen source. A moderate chemical yield of 1-phenylethanol with 83% ee was obtained when (RC, SFc)-1-(Diphe-nylphosphino)-2-[1-N-(3-methylpyridin-2-ylmethyl) ethyl] ferrocene (L1) was used. Particularly, both ruthenium and iridium could coordinate with L1 to accomplish the asymmetric reduction of series of aromatic ketones separately. The desired products were achieved with up to 86% ee.

摘要： Syntheses of (1R,2S,3R,4S)-1,7,7-trimethyl-2-pyridin-2-ylmethylbicyclo[2.2.1]-heptane-2,3-diol (7), (1R,2S,3R,4S)-1,7,7-trimethyl-2-[(6-methyl)-pyridin-2-ylmethyl-bicyclo-[2.2.1]heptane-2,3-diol (13), and (1R,2S,2’R,4R)-1,7,7-trimethyl-2-piperidin-2-ylmethyl-bicyclo[2.2.1]heptan-2-ol (19b) from commercially available (d)-camphor (1) are described. Key steps of the syntheses involved substrate-controlled diastereoselective alkylation and platinum oxide-catalyzed hydrogenation reactions. These compounds, and other intermediate amino alcohols in their syntheses, were successfully utilized as ligands in enantioselective diethyl zinc (Et2Zn) addition to benzaldehyde with moderate enantioselectivity.

摘要： Schiff base ligand (L) derived from glyoxal and 4-aminoantipyrine was synthesized. The ligand (L) has been characterized by IR, NMR, electronic spectral studies and electrochemical studies. Cu(II) complexes of a Schiff base ligand (L) from 4-aminoantpyrine and glyoxal having the composition [CuL1]X2 where X = Clˉ?or NO3ˉ? have been prepared and characterized by elemental analysis, electrical conductivity in non-aqueous solvent, infrared and electronic, as well as cyclic voltammetric studies. L acts as a neutral tetradentate ligand coordinating through both the carbonyl oxygen and azomethine nitrogen. On both the complexes both the anions are not coordinated. A square planar geometry is assigned for complexes. The electrochemical studies of ligand show a typical cyclic voltammogram for an irreversible process. While copper(II) complexes show the typical cyclic voltammograms for quasi reversible process.

摘要： Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

摘要： Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.

摘要： AIM To investigate the role of Delta-like ligand 4(DLL4) on tumour growth in hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC) in vivo.METHODS We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively.RESULTS Eighteen days after implantation, tumour volume in mice implanted with sh DLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15(P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group(P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours.CONCLUSION This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.

摘要： 本发明属于快速估算电离辐射剂量生物指标。具体涉及Flt-3Ligand作为快速估算电离辐射剂量生物指标的应用。由于辐照后，血清或血浆中Flt-3L表达量与照后时间、辐照剂量存在时间-剂量-效应关系，可经过统计分析拟合各参数(Flt-3L表达量、照后时间与辐照剂量)响应曲面及换算公式，并可通过响应曲面及换算公式，在已知Flt-3L表达量和照后时间的情况下，估算辐照剂量。此外Flt-3L表达量检测可以通过ELISA、蛋白芯片等简便易行的方法进行快速检测，检测需要的样本量少，采样、保存方便，耗时短，结果客观。因此Flt-3Ligand可作为快速估算电离辐射剂量的生物指标。