Xiao Y

References (113)

Title : Resistance Mechanism of Plutella xylostella (L.) Associated with Amino Acid Substitutions in Acetylcholinesterase-1: Insights from Homology Modeling, Docking and Molecular Dynamic Simulation - Zolfaghari_2024_Insects_15_
Author(s) : Zolfaghari M , Xiao Y , Safiul Azam FM , Yin F , Peng ZK , Li ZY
Ref : Insects , 15 : , 2024
Abstract : Plutella xylostella, a destructive crucifer pest, can rapidly develop resistance to most classes of pesticides. This study investigated the molecular resistance mechanisms to chlorpyrifos, an organophosphate pesticide. Two P. xylostella genes, ace1 and ace2, were described. The nucleotide sequence results revealed no variation in ace2, while the resistant strain (Kar-R) had four amino acid alterations in ace1, two of which (A298S and G324A) were previously shown to confer organophosphate resistance in P. xylostella. In the present study, the 3D model structures of both the wild-type (Gu-S) and mutant (Kar-R) of P. xylostella ace1 strains were studied through molecular dynamics (MDs) simulations and molecular docking. Molecular dynamics simulations of RMSD revealed less structural deviation in the ace1 mutant than in its wild-type counterpart. Higher flexibility in the 425-440 amino acid region in the mutant active site (Glu422 and Acyl pocket) increased the active site's entropy, reducing the enzyme's affinity for the inhibitors. Gene expression analysis revealed that the relative transcription levels of ace1 were significantly different in the Kar-R strain compared with the Gu-S strain. This study enhances the understanding of the mechanisms governing ace1's resistance to insecticide and provides essential insights for new insecticides as well as valuable insights into environmentally conscious pest management techniques.
ESTHER : Zolfaghari_2024_Insects_15_
PubMedSearch : Zolfaghari_2024_Insects_15_
PubMedID: 38535339
Gene_locus related to this paper: pluxy-ACHE , pluxy-ACHE1

Title : Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity - Sun_2024_Bioorg.Chem_147_107377
Author(s) : Sun L , Wang XM , Tang Q , Xiao Y , Xu JB , Zhang TT , Liu YJ , Li X , Gao F
Ref : Bioorg Chem , 147 :107377 , 2024
Abstract : The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L(3) through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC(50) value of 7.1 microM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H(2)O(2)-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 microM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.
ESTHER : Sun_2024_Bioorg.Chem_147_107377
PubMedSearch : Sun_2024_Bioorg.Chem_147_107377
PubMedID: 38653150

Title : ZnO-rGO-based electrochemical biosensor for the detection of organophosphorus pesticides - Liu_2023_Bioelectrochemistry_156_108599
Author(s) : Liu Y , Xiao Y , Zhang Y , Gao X , Wang H , Niu B , Li W
Ref : Bioelectrochemistry , 156 :108599 , 2023
Abstract : The accurate determination of organophosphorus pesticide residues is of great importance for human disease monitoring and environmental safety. Numerous detection methods exist, among which sensitive monitoring of organophosphorus compounds using electrochemical sensors has gradually become a research hotspot. This paper used acetylcholinesterase (AChE) as an indicator anchored on a zinc oxide-reduced graphene oxide (ZnO-rGO) composite rich in active sites, in which green non-toxic zinc oxide (ZnO) nanomaterials were uniformly distributed on the reduced graphene for rapid detection of organophosphorus. The effects of different ratios of ZnO to reduced graphene on the performance of ZnO-rGO nanocomposites were investigated. The AChE/ZnO-rGO biosensor detects organophosphorus by electrochemical inhibition of acetylcholinesterase in the presence of organophosphorus. The developed electrochemical biosensor has high selectivity and good linearity, and the ZnO-rGO nanocomposite as a matrix for immobilization of acetylcholinesterase and detection of organophosphorus has the potential for highly sensitive pesticide detection.
ESTHER : Liu_2023_Bioelectrochemistry_156_108599
PubMedSearch : Liu_2023_Bioelectrochemistry_156_108599
PubMedID: 37988979

Title : Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues - Zhang_2023_J.Nat.Prod__
Author(s) : Zhang Y , Xu JB , Xiao Y , Ji WS , Shan LH , Wan LX , Zhou XL , Lei Y , Gao F
Ref : Journal of Natural Products , : , 2023
Abstract : A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC(50) = 0.19 microM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H(2)O(2)-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.
ESTHER : Zhang_2023_J.Nat.Prod__
PubMedSearch : Zhang_2023_J.Nat.Prod__
PubMedID: 36808969

Title : Co-exposure to sodium hypochlorite and cadmium induced locomotor behavior disorder by influencing neurotransmitter secretion and cardiac function in larval zebrafish - Ma_2023_Environ.Pollut_342_123070
Author(s) : Ma L , Yang H , Xiao X , Chen Q , Lv W , Xu T , Jin Y , Wang W , Xiao Y
Ref : Environ Pollut , 342 :123070 , 2023
Abstract : Sodium hypochlorite (NaClO) and cadmium (Cd) are widely co-occurring in natural aquatic environment; however, no study has been conducted on effects of their combined exposure on aquatic organisms. To assess effects of exposure to NaClO and Cd in zebrafish larvae, we designed six treatment groups, as follows: control group, NaClO group (300 microg/L), 1/100 Cd group (48 microg/L), 1/30 Cd group (160 microg/L), NaClO+1/100 Cd group, and NaClO+1/30 Cd group analyzed behavior, neurological function and cardiac function. Results revealed that exposure to 1/30 Cd and NaClO+1/30 Cd caused abnormal embryonic development in larvae by altering body morphology and physiological indicators. Combined exposure to NaClO and 1/30 Cd affected the free-swimming activity and behavior of larvae in response to light-dark transition stimuli. Moreover, exposure to 1/30 Cd or NaClO+1/30 Cd resulted in a significant increase in tyrosine hydroxylase and acetylcholinesterase activities, as well as significant changes of various neurotransmitters. Lastly, exposure to 1/30 Cd or NaClO+1/30 Cd influenced the transcription of cardiac myosin-related genes and disturbed the myocardial contractile function. Altogether, our results suggested that combined exposure to NaClO and Cd induced oxidative damage in larvae, resulting in detrimental effects on nervous system and cardiac function, thus altering their swimming behavior.
ESTHER : Ma_2023_Environ.Pollut_342_123070
PubMedSearch : Ma_2023_Environ.Pollut_342_123070
PubMedID: 38056588

Title : The GPIHBP1-LPL complex and its role in plasma triglyceride metabolism: Insights into chylomicronemia - Jiang_2023_Biomed.Pharmacother_169_115874
Author(s) : Jiang S , Ren Z , Yang Y , Liu Q , Zhou S , Xiao Y
Ref : Biomed Pharmacother , 169 :115874 , 2023
Abstract : GPIHBP1 is a protein found in the endothelial cells of capillaries that is anchored by glycosylphosphatidylinositol and binds to high-density lipoproteins. GPIHBP1 attaches to lipoprotein lipase (LPL), subsequently carrying the enzyme and anchoring it to the capillary lumen. Enabling lipid metabolism is essential for the marginalization of lipoproteins alongside capillaries. Studies underscore the significance of GPIHBP1 in transporting, stabilizing, and aiding in the marginalization of LPL. The intricate interplay between GPIHBP1 and LPL has provided novel insights into chylomicronemia in recent years. Mutations hindering the formation or reducing the efficiency of the GPIHBP1-LPL complex are central to the onset of chylomicronemia. This review delves into the structural nuances of the GPIHBP1-LPL interaction, the consequences of mutations in the complex leading to chylomicronemia, and cutting-edge advancements in chylomicronemia treatment.
ESTHER : Jiang_2023_Biomed.Pharmacother_169_115874
PubMedSearch : Jiang_2023_Biomed.Pharmacother_169_115874
PubMedID: 37951027

Title : Discovery of myrsinane-type Euphorbia diterpene derivatives through a skeleton conversion strategy from lathyrane diterpene for the treatment of Alzheimer's disease - Xiao_2023_Bioorg.Chem_138_106595
Author(s) : Xiao Y , Zhang Y , Ji WS , Jia XN , Shan LH , Li X , Liu YJ , Jiang T , Gao F
Ref : Bioorg Chem , 138 :106595 , 2023
Abstract : A series of novel myrsinane-type Euphorbia diterpene derivatives (1-37) were synthesized from the abundant natural lathyrane-type Euphorbia factor L(3), using a multi-step chemical process guided by a bioinspired skeleton conversion strategy, with the aim of discovering potential anti-Alzheimer's disease (AD) bioactive lead compounds. The synthesis process involved a concise reductive olefin coupling reaction through an intramolecular Michael addition with a free radical, followed by a visible-light-triggered regioselective cyclopropane ring-opening. The cholinesterase inhibitory and neuroprotective activities of the synthesized myrsinane derivatives were evaluated. Most of the compounds showed moderate to strong potency, highlighting the importance of ester groups in Euphorbia diterpene. In particular, derivative 37 displayed the most potent acetylcholinesterase (AChE) inhibition, with an IC(50) value of 8.3 microM, surpassing that of the positive control, tacrine. Additionally, 37 also showed excellent neuroprotective effect against H(2)O(2)-induced injury in SH-SY5Y cells, with a cell viability rate of 124.2% at 50 microM, which was significantly higher than that of the model group (viability rate 52.1%). Molecular docking, reactive oxygen species (ROS) analysis, immunofluorescence, and immunoblotting were performed to investigate the mechanism of action of myrsinane derivative 37. The results indicated that derivative 37 may be a promising myrsinane-type multi-functional lead compound for the treatment of Alzheimer's disease. Furthermore, a preliminary SAR analysis was performed to study the acetylcholinesterase inhibitory and neuroprotective activities of these diterpenes.
ESTHER : Xiao_2023_Bioorg.Chem_138_106595
PubMedSearch : Xiao_2023_Bioorg.Chem_138_106595
PubMedID: 37178652

Title : Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity - Huang_2022_Science_377_eabq3297
Author(s) : Huang S , Jia A , Song W , Hessler G , Meng Y , Sun Y , Xu L , Laessle H , Jirschitzka J , Ma S , Xiao Y , Yu D , Hou J , Liu R , Sun H , Liu X , Han Z , Chang J , Parker JE , Chai J
Ref : Science , 377 :eabq3297 , 2022
Abstract : Plant nucleotide-binding leucine-rich repeat-containing (NLR) receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain sense pathogen effectors to enable TIR-encoded NADase activity for immune signaling. TIR-NLR signaling requires helper NLRs N requirement gene 1 (NRG1) and Activated Disease Resistance 1 (ADR1), and Enhanced Disease Susceptibility 1 (EDS1) that forms a heterodimer with each of its paralogs Phytoalexin Deficient 4 (PAD4) and Senescence-Associated Gene101 (SAG101). Here, we show that TIR-containing proteins catalyze production of 2'-(5''-phosphoribosyl)-5'-adenosine mono-/di-phosphate (pRib-AMP/ADP) in vitro and in planta. Biochemical and structural data demonstrate that EDS1-PAD4 is a receptor complex for pRib-AMP/ADP, which allosterically promote EDS1-PAD4 interaction with ADR1-L1 but not NRG1A. Our study identifies TIR-catalyzed pRib-AMP/ADP as a missing link in TIR signaling via EDS1-PAD4 and as likely second messengers for plant immunity.
ESTHER : Huang_2022_Science_377_eabq3297
PubMedSearch : Huang_2022_Science_377_eabq3297
PubMedID: 35857645
Gene_locus related to this paper: arath-eds1 , arath-PAD4

Title : Biodegradation of highly crystallized poly(ethylene terephthalate) through cell surface codisplay of bacterial PETase and hydrophobin - Chen_2022_Nat.Commun_13_7138
Author(s) : Chen Z , Duan R , Xiao Y , Wei Y , Zhang H , Sun X , Wang S , Cheng Y , Wang X , Tong S , Yao Y , Zhu C , Yang H , Wang Y , Wang Z
Ref : Nat Commun , 13 :7138 , 2022
Abstract : The process of recycling poly(ethylene terephthalate) (PET) remains a major challenge due to the enzymatic degradation of high-crystallinity PET (hcPET). Recently, a bacterial PET-degrading enzyme, PETase, was found to have the ability to degrade the hcPET, but with low enzymatic activity. Here we present an engineered whole-cell biocatalyst to simulate both the adsorption and degradation steps in the enzymatic degradation process of PETase to achieve the efficient degradation of hcPET. Our data shows that the adhesive unit hydrophobin and degradation unit PETase are functionally displayed on the surface of yeast cells. The turnover rate of the whole-cell biocatalyst toward hcPET (crystallinity of 45%) dramatically increases approximately 328.8-fold compared with that of purified PETase at 30 degreesC. In addition, molecular dynamics simulations explain how the enhanced adhesion can promote the enzymatic degradation of PET. This study demonstrates engineering the whole-cell catalyst is an efficient strategy for biodegradation of PET.
ESTHER : Chen_2022_Nat.Commun_13_7138
PubMedSearch : Chen_2022_Nat.Commun_13_7138
PubMedID: 36414665
Gene_locus related to this paper: idesa-peth

Title : A Novel Paper-Based Electrochemical Biosensor Based on N,O-Rich Covalent Organic Frameworks for Carbaryl Detection - Xiao_2022_Biosensors.(Basel)_12_
Author(s) : Xiao Y , Wu N , Wang L , Chen L
Ref : Biosensors (Basel) , 12 : , 2022
Abstract : A new N,O-rich covalent organic framework (COF(DHNDA-BTH)) was synthesized by an amine-aldehyde condensation reaction between 2,6-dialdehyde-1,5-dihydroxynaphthalene (DHNDA) and 1,3,5-phenyltriformylhydrazine (BTH) for carbaryl detection. The free NH, OH, and C=O groups of COF(DHNDA-BTH) not only covalently couples with acetylcholinesterase (AChE) into the pores of COF(DHNDA-BTH), but also greatly improves the catalytic activity of AChE in the constrained environment of COF(DHNDA-BTH)'s pore. Under the catalysis of AChE, the acetylthiocholine (ATCl) was decomposed into positively charged thiocholine (TCl), which was captured on the COF(DHNDA-BTH) modified electrode. The positive charges of TCl can attract anionic probe [Fe(CN)(6)](3-/4-) on the COF(DHNDA-BTH)-modified electrode to show a good oxidation peak at 0.25 V (versus a saturated calomel electrode). The carbaryl detection can inhibit the activity of AChE, resulting in the decrease in the oxidation peak. Therefore, a turn-off electrochemical carbaryl biosensor based on a flexible carbon paper electrode loaded with COF(DHNDA-BTH) and AChE was constructed using the oxidation peak of an anionic probe [Fe(CN)(6)](3-/4-) as the detection signal. The detection limit was 0.16 microM (S/N = 3), and the linear range was 0.48~35.0 microM. The sensor has good selectivity, repeatability, and stability, and has a good application prospect in pesticide detection.
ESTHER : Xiao_2022_Biosensors.(Basel)_12_
PubMedSearch : Xiao_2022_Biosensors.(Basel)_12_
PubMedID: 36291036

Title : Serum cholinesterase may independently predict prognosis in non-small-cell lung cancer - Ran_2022_BMC.Cancer_22_93
Author(s) : Ran H , Ma J , Cai L , Zhou H , Yuan Z , Chen Y , Chang W , Huang Y , Xiao Y
Ref : BMC Cancer , 22 :93 , 2022
Abstract : BACKGROUND: Serum cholinesterase (ChE) was found to be involved in cancer initiation and progression. However, the survival association between serum ChE and non-small cell lung cancer (NSCLC) has not been extensively discussed. In the present study, we aim to elevate the role of ChE in overall survival (OS) of NSCLC patients. METHODS: A total of 961 histologically confirmed NSCLC patients diagnosed between 2013 and 2018 in a provincial cancer hospital in southwestern China were retrospectively selected. Relevant information, such as histological type, clinical stage, chemotherapy, smoking status, body mass index (BMI), important serum indicators (albumin, neutrophil-to-lymphocyte ratio, ChE), date of death of the patients was extracted from the computerized hospital information system. Univariate and multivariate Cox proportional hazards models were used to determine the association between baseline serum ChE measured at the diagnosis and the OS of NSCLC patients. RESULTS: The median of baseline ChE (7700 units/liter) was used as a cut-off to dichotomize NSCLC patients. After controlling for possible confounding factors, serum ChE at diagnosis was significantly associated with OS of NSCLC: patients with higher level of ChE were observed a better prognosis (hazard ratio, HR: 0.77, 95% CI: 0.67-0.93, p = 0.006). Subgroup analysis revealed significant ChE-OS association for NSCLC patients: with lower systemic inflammation level (baseline NLR < 2.95, HR: 0.71, 95% CI: 0.56-0.89, p = 0.003), of adenocarcinoma (HR: 0.66, 95% CI: 0.54-0.80, p < 0.001), in advanced stage (HR: 0.77, 95% CI: 0.66-0.92, p < 0.01), and received chemotherapy (HR: 0.75, 95% CI: 0.59-0.96, p < 0.02). CONCLUSION: Baseline ChE may have independent prognostic value for NSCLC patients. Longitudinal studies should be performed to corroborate this finding.
ESTHER : Ran_2022_BMC.Cancer_22_93
PubMedSearch : Ran_2022_BMC.Cancer_22_93
PubMedID: 35062903

Title : Hesperidin methyl chalcone ameliorates lipid metabolic disorders by activating lipase activity and increasing energy metabolism - Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
Author(s) : Liu S , Liu K , Wang Y , Wu C , Xiao Y , Yu J , Ma Z , Liang H , Li X , Li Y , Zhou L
Ref : Biochimica & Biophysica Acta Mol Basis Dis , :166620 , 2022
Abstract : Obesity has become an increasingly serious health issue with the continuous improvement in living standards. Its prevalence has become an economic burden on health care systems worldwide. Flavonoids have been shown to be beneficial in the prevention and treatment of obesity. Here, we evaluated the therapeutic potential of the flavonoid hesperidin methyl chalcone (HMC) on mice with high-fat diet (HFD)-induced hepatic steatosis in vivo and in vitro. Treatment with HMC reduced oleic and palmitic acid-induced increases in intracellular triglyceride accumulation in HepG2, AML12 and LMH cells. HMC also enhanced energy metabolism and lowered oxidative stress. We used Discovery studio to dock key proteins associated with lipid metabolism disorders to HMC, and found that HMC interacted with lipase. Furthermore, we demonstrated that HMC improved lipase activity and lipolysis. In addition, we found that HMC promoted glucose absorption, alleviated lipid metabolic disorders, improved HFD-induced liver injury, and regulated HFD-induced changes in energy metabolism. In conclusion, our study demonstrated that HMC ameliorated HFD-induced obesity and its complications by promoting lipase activity, and provides a novel approach for the prevention and treatment of obesity and related diseases.
ESTHER : Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
PubMedSearch : Liu_2022_Biochim.Biophys.Acta.Mol.Basis.Dis__166620
PubMedID: 36494040

Title : Isolation and acetylcholinesterase inhibitory activity of asterric acid derivatives produced by Talaromyces aurantiacus FL15, an endophytic fungus from Huperzia serrata - Xiao_2022_3.Biotech_12_60
Author(s) : Xiao Y , Liang W , Liu D , Zhang Z , Chang J , Zhu D
Ref : 3 Biotech , 12 :60 , 2022
Abstract : Alzheimer's disease (AD) is a neurodegenerative disease and the fourth leading cause of death after cardiovascular disease, tumors, and stroke. Acetylcholinesterase (AChE) inhibitors, which are based on cholinergic damage, remain the mainstream drugs to alleviate AD-related symptoms. This study aimed to explore novel AChE inhibitors produced by the endophytic fungus FL15 from Huperzia serrata. The fungus was identified as Talaromyces aurantiacus FL15 according to its morphological characteristics and ITS, 18S rDNA, and 28S rDNA sequence analysis. Subsequently, seven natural metabolites were isolated from strain FL15, and identified as asterric acid (1), methyl asterrate (2), ethyl asterrate (3), emodin (4), physcion (5), chrysophanol (6), and sulochrin (7). Compounds 1-3, which possess a diphenyl ether structure, exhibited highly selective and moderate AChE inhibitory activities with IC(50) values of 66.7, 23.3, and 20.1 microM, respectively. The molecular docking analysis showed that compounds 1-3 interacted with the active catalytic site and peripheral anionic site of AChE, and the esterification substitution groups at position 8 of asterric acid may contribute to its bioactivity. The asterric acid derivatives showed highly selective and moderate AChE inhibitory activities, probably via interaction with the peripheral anionic site and catalytic site of AChE. To the best of our knowledge, this study was the first report of the AChE inhibitory activity of asterric acid derivatives, which opens new perspectives for the design of more effective derivatives that could serve as a drug carrier for new chemotherapeutic agents to treat AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03125-2.
ESTHER : Xiao_2022_3.Biotech_12_60
PubMedSearch : Xiao_2022_3.Biotech_12_60
PubMedID: 35186657

Title : In Situ Formation of o-Phenylenediamine Cascade Polymers Mediated by Metal-Organic Framework Nanozymes for Fluorescent and Photothermal Dual-Mode Assay of Acetylcholinesterase Activity - Li_2022_Anal.Chem__
Author(s) : Li S , Wei Z , Xiong L , Xu Q , Yu L , Xiao Y
Ref : Analytical Chemistry , : , 2022
Abstract : A fluorescent and photothermal dual-mode assay method was established for the detection of acetylcholinesterase (AChE) activity based on in situ formation of o-phenylenediamine (oPD) cascade polymers. First, copper metal-organic frameworks of benzenetricarboxylic acid (Cu-BTC) were screened out as nanozymes with excellent oxidase-like activity and confinement catalysis effect. Then, an ingenious oPD cascade polymerization strategy was proposed. That is, oPD was oxidized by Cu-BTC to oPD oligomers with strong yellow fluorescence, and oPD oligomers were further catalyzed to generate J-aggregation, which promotes the formation of oPD polymer nanoparticles with a high photothermal effect. By utilizing thiocholine (enzymolysis product of acetylthiocholine) to inhibit the Cu-BTC catalytic effect, AChE activity was detected through the fluorescence-photothermal dual-signal change of oPD oligomers and polymer nanoparticles. Both assay modes have low detection limitation (0.03 U L(-1) for fluorescence and 0.05 U L(-1) for photothermal) and can accurately detect the AChE activity of human serum (recovery 85.0-111.3%). The detection results of real serum samples by fluorescent and photothermal dual modes are consistent with each other (relative error >= 5.2%). It is worth emphasizing that this is the first time to report the high photothermal effect of oPD polymers and the fluorescence-photothermal dual-mode assay of enzyme activity.
ESTHER : Li_2022_Anal.Chem__
PubMedSearch : Li_2022_Anal.Chem__
PubMedID: 36463539

Title : Polyketide Derivatives from the Endophytic Fungus Phaeosphaeria sp. LF5 Isolated from Huperzia serrata and Their Acetylcholinesterase Inhibitory Activities - Xiao_2022_J.Fungi.(Basel)_8_
Author(s) : Xiao Y , Liang W , Zhang Z , Wang Y , Zhang S , Liu J , Chang J , Ji C , Zhu D
Ref : J Fungi (Basel) , 8 : , 2022
Abstract : The secondary metabolites of Phaeosphaeria sp. LF5, an endophytic fungus with acetylcholinesterase (AChE) inhibitory activity isolated from Huperzia serrata, were investigated. Their structures and absolute configurations were elucidated by means of extensive spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses, and calculations of electronic circular dichroism (ECD). A chemical study on the solid-cultured fungus LF5 resulted in 11 polyketide derivatives, which included three previously undescribed derivatives: aspilactonol I (4), 2-(1-hydroxyethyl)-6-methylisonicotinic acid (7), and 6,8-dihydroxy-3-(1'R, 2'R-dihydroxypropyl)-isocoumarin (9), and two new natural-source-derived aspilactonols (G, H) (2, 3). Moreover, the absolute configuration of de-O-methyldiaporthin (11) was identified for the first time. Compounds 4 and 11 exhibited inhibitory activity against AChE with half maximal inhibitory concentration (IC(50)) values of 6.26 and 21.18 microM, respectively. Aspilactonol I (4) is the first reported furanone AChE inhibitor (AChEI). The results indicated that Phaeosphaeria is a good source of polyketide derivatives. This study identified intriguing lead compounds for further research and development of new AChEIs.
ESTHER : Xiao_2022_J.Fungi.(Basel)_8_
PubMedSearch : Xiao_2022_J.Fungi.(Basel)_8_
PubMedID: 35330234

Title : Identification of Host Molecules Involved in the Proliferation of Nucleopolyhedrovirus in Bombyx mori - Xu_2022_J.Agric.Food.Chem__
Author(s) : Xu J , Xie X , Ma Q , Zhang L , Li Y , Chen Y , Li K , Xiao Y , Tettamanti G , Xu H , Tian L
Ref : Journal of Agricultural and Food Chemistry , : , 2022
Abstract : The Bombyx mori nucleopolyhedrovirus (BmNPV), a foodborne infectious virus, is the pathogen causing nuclear polyhedrosis and high lethality in the silkworm. In this study, we characterized the molecules involved in BmNPV-silkworm interaction by RNA sequencing of the fat body isolated from the virus-susceptible strain P50. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation showed that the upregulated differentially expressed genes (DEGs) were mainly involved in translation, signal transduction, folding, sorting, and degradation, as well as transport and catabolism, while the downregulated DEGs were predominantly enriched in the metabolism of carbohydrates, amino acids, and lipids at 72 h post BmNPV infection. Knockout of the upregulated somatomedin-B and thrombospondin type-1 domain-containing protein, probable allantoicase, trifunctional purine biosynthetic protein adenosine-3, and Psl and pyoverdine operon regulator inhibited the proliferation of BmNPV, while knockout of the downregulated clip domain serine protease 3 and carboxylesterase clade H, member 1 promoted it. The molecules herein identified provide a foundation for developing strategies and designing drugs against BmNPV.
ESTHER : Xu_2022_J.Agric.Food.Chem__
PubMedSearch : Xu_2022_J.Agric.Food.Chem__
PubMedID: 36321811

Title : Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response - Zhou_2021_Front.Immunol_12_670427
Author(s) : Zhou Q , Yan B , Sun W , Chen Q , Xiao Q , Xiao Y , Wang X , Shi D
Ref : Front Immunol , 12 :670427 , 2021
Abstract : Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E(2). Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.
ESTHER : Zhou_2021_Front.Immunol_12_670427
PubMedSearch : Zhou_2021_Front.Immunol_12_670427
PubMedID: 34079552
Gene_locus related to this paper: pig-PLE1 , pig-a0a1s6l967

Title : Celastrol Attenuates Learning and Memory Deficits in an Alzheimer's Disease Rat Model - Xiao_2021_Biomed.Res.Int_2021_5574207
Author(s) : Xiao Y , Wang X , Wang S , Li J , Xu X , Wang M , Li G , Shen W
Ref : Biomed Res Int , 2021 :5574207 , 2021
Abstract : Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder that is associated with learning, memory, and cognitive deficits. Neuroinflammation and synapse loss are involved in the pathology of AD. Diverse measures have been applied to treat AD, but currently, there is no effective treatment. Celastrol (CEL) is a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F that has been shown to enhance cell viability and inhibit amyloid-beta production induced by lipopolysaccharides in vitro. In the present study, the protective effect of CEL on Abeta (25-35)-induced rat model of AD was assessed. Our results showed that CEL administration at a dose of 2 mg/kg/day improved spatial memory in the Morris water maze. Further biochemical analysis showed that CEL treatment of intrahippocampal Abeta (25-35)-microinjected rats attenuated hippocampal NF-kappaB activity; inhibited proinflammatory markers, namely, IL-1beta, IL-6, and TNF-alpha; and upregulated anti-inflammatory factors, such as IL-4 and IL-10. Furthermore, CEL upregulated hippocampal neurexin-1beta, neuroligin-1, CA1, and PSD95 expression levels, which may improve synaptic function. Simultaneously, CEL also increased glucose metabolism in Abeta (25-35)-microinjected rats. In conclusion, CEL could exert protective effects against learning and memory decline induced by intrahippocampal Abeta (25-35) through anti-inflammation, promote synaptic development, and maintain hippocampal energy metabolism.
ESTHER : Xiao_2021_Biomed.Res.Int_2021_5574207
PubMedSearch : Xiao_2021_Biomed.Res.Int_2021_5574207
PubMedID: 34350293

Title : Yeast cell surface display of bacterial PET hydrolase as a sustainable biocatalyst for the degradation of polyethylene terephthalate - Chen_2021_Methods.Enzymol_648_457
Author(s) : Chen Z , Xiao Y , Weber G , Wei R , Wang Z
Ref : Methods Enzymol , 648 :457 , 2021
Abstract : Enzymatic hydrolysis of polyethylene terephthalate (PET) is considered to be an environmentally friendly method for the recycling of plastic waste. Recently, a bacterial enzyme named IsPETase was found in Ideonella sakaiensis with the ability to degrade amorphous PET at ambient temperature suggesting its possible use in recycling of PET. However, applying the purified IsPETase in large-scale PET recycling has limitations, i.e., a complicated production process, high cost of single-use, and instability of the enzyme. Yeast cell surface display has proven to be an effectual alternative for improving enzyme degradation efficiency and realizing industrial applications. This chapter deals with the construction and application of a whole-cell biocatalyst by displaying IsPETase on the surface of yeast (Pichia pastoris) cells.
ESTHER : Chen_2021_Methods.Enzymol_648_457
PubMedSearch : Chen_2021_Methods.Enzymol_648_457
PubMedID: 33579416
Gene_locus related to this paper: idesa-peth

Title : Influence of seasonal migration on evolution of insecticide resistance in Plutella xylostella - Wang_2021_Insect.Sci__
Author(s) : Wang M , Zhu B , Zhang L , Xiao Y , Liang P , Wu K
Ref : Insect Sci , : , 2021
Abstract : The diamondback moth, Plutella xylostella (L.), is one of the most destructive migratory pest species of cruciferous vegetables worldwide and has developed resistance to most of the insecticides used for its control. The migration regularity, migratory behavior, and relationship between flight and reproduction of P. xylostella have been widely reported. However, the effect of migration on insecticide resistance in this pest is still unclear. In this study, the effect of migration on P. xylostella resistance to seven insecticides was investigated using populations across the Bohai Sea that were collected in the early and late seasons during 2017-2019. The bioassay results showed that the early season populations of P. xylostella from South China possessed much higher resistance to insecticides because of intensive insecticide application; alternatively, the late season populations migrated from Northeast China, where the insecticides were only used occasionally, showed much lower insecticide resistance. The genome re-sequencing results revealed that, among the eight mutations involved in insecticide resistance, the frequencies of two acetylcholinesterase mutations (A298S and G324A) responsible for organophosphorus insecticide resistance were significantly decreased in the late season populations. The results indicated that P. xylostella migration between tropical and temperate regions significantly delayed the development of insecticide resistance. These findings illustrated the effect of regional migration on the evolution of insecticide resistance in P. xylostella, and provided foundational information for further research on the relationship between migration and insecticide resistance development in other insects. This article is protected by copyright. All rights reserved.
ESTHER : Wang_2021_Insect.Sci__
PubMedSearch : Wang_2021_Insect.Sci__
PubMedID: 34873833

Title : An uncharacterized protein from the metagenome with no obvious homology to known lipases shows excellent alkaline lipase properties and potential applications in the detergent industry - Xiao_2021_Biotechnol.Lett__
Author(s) : Xiao Y , Liu YD , Yuan G , Mao RQ , Li G
Ref : Biotechnol Lett , : , 2021
Abstract : A novel lipase, Lip486, which has no obvious homology with known lipases, was discovered using functional metagenomics technology. Phylogenetic tree analysis suggested that the enzyme belongs to a new subfamily called lipolytic enzyme family II. To explore the enzymatic properties, lip486 was expressed heterologously and efficiently in Escherichia coli. The recombinant enzyme displayed the highest activity on the substrate p-nitrophenyl caprate with a carbon chain length of 10, and its optimum temperature and pH were 53 degreesC and 8.0, respectively. The recombinant Lip486 showed good activity and stability in strong alkaline and medium-low-temperature environments. The results of compatibility and soaking tests showed that the enzyme had good compatibility with 4 kinds of commercial detergents, and an appropriate soaking time could further improve the enzyme activity. Oil stain removal test results for a cotton cloth indicated that the washing performance of commercial laundry detergent supplemented with Lip486 was further improved. In addition, as one of the smallest lipases found to date, Lip486 also has the advantages of high yield, good stability and easy molecular modification. These characteristics reflect the good application prospects for Lip486 in the detergent and other industries in the future.
ESTHER : Xiao_2021_Biotechnol.Lett__
PubMedSearch : Xiao_2021_Biotechnol.Lett__
PubMedID: 34698972

Title : Resolution of (R,S)-1-(4-methoxyphenyl)ethanol by lipase-catalyzed stereoselective transesterification and the process optimization - He_2021_Chirality__
Author(s) : He B , Tang F , Sun C , Su J , Wu B , Chen Y , Xiao Y , Zhang P , Tang K
Ref : Chirality , : , 2021
Abstract : An efficient lipase-catalyzed stereoselective transesterification reaction system was established for resolution of 1-(4-methoxyphenyl)ethanol (MOPE) enantiomers. A series of lipases were tested and compared. The immobilized lipase Novozym 40086 is selected as the best choice. The effects of organic solvent, acyl donor, time and temperature on substrate conversion (c), and optical purity of the remaining substrate (ee(S) ) were investigated. Response surface methodology and central composite design were employed to evaluate the effect of some important factors and to optimize the process. Under the optimized conditions including solvent of n-hexane, acyl donor of vinyl acetate, temperature of 35 degreesC, substrate molar ratio of 1:6, enzyme dosage of 20 mg, and reaction time of 2.5 h, ee(S) of 99.87% with c of 56.71% is achieved. The use of alkane solvent and immobilized enzyme, the mild reaction conditions, and the reduced reaction time make the system promising in industrial application.
ESTHER : He_2021_Chirality__
PubMedSearch : He_2021_Chirality__
PubMedID: 34904761

Title : Protective effects of chondroitin sulphate nano-selenium on a mouse model of Alzheimer's disease - Ji_2020_Int.J.Biol.Macromol__
Author(s) : Ji D , Wu X , Li D , Liu P , Zhang S , Gao D , Gao F , Zhang M , Xiao Y
Ref : Int J Biol Macromol , : , 2020
Abstract : In this study, the effect of chondroitin sulphate nano-selenium (CS@Se) on Alzheimer's disease (AD) in mice was investigated. CS@Se alleviated anxiety and improved the spatial learning and memory impairment in AD mice. CS@Se significantly reduced cell oedema and pyknosis, protected the mitochondria, and improved abnormal changes in the ultrastructure of hippocampal neuron synapses of AD mice. Moreover, CS@Se significantly increased the levels of superoxide dismutase(SOD), glutathione peroxidase (GSH-Px), Na(+)/K(+)-ATPase assay (Na(+)/K(+)-ATPase) and acetyltransferase (ChAT), and decreased the levels of malondialdehyde (MDA) and acetylcholinesterase (ChAE) in AD mice. Western blot results showed that CS@Se can attenuate excessive phosphorylation of tau (Ser396/Ser404) by regulating the expression of glycogen synthase kinase-3 beta (GSK-3beta). In addition, CS@Se can activate the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) signalling pathways to inhibit nuclear transcription factor kappa B (NF-kappaB) nuclear translocation, thereby regulating the expression of pro-inflammatory cytokines. In summary, CS@Se can reduce oxidative stress damage, inhibit excessive tau phosphorylation, reduce inflammation to delay AD development, and increase the learning and memory capacities of AD mice.
ESTHER : Ji_2020_Int.J.Biol.Macromol__
PubMedSearch : Ji_2020_Int.J.Biol.Macromol__
PubMedID: 32171837

Title : Cell Wall Polysaccharide-Mediated Cadmium Tolerance Between Two Arabidopsis thaliana Ecotypes - Xiao_2020_Front.Plant.Sci_11_473
Author(s) : Xiao Y , Wu X , Liu D , Yao J , Liang G , Song H , Ismail AM , Luo JS , Zhang Z
Ref : Front Plant Sci , 11 :473 , 2020
Abstract : Cadmium (Cd) is a toxic metal element and the mechanism(s) underlying Cd tolerance in plants are still unclear. Increasingly more studies have been conducted on Cd binding to plant cell walls (CW) but most of them have focused on Cd fixation by CW pectin, and few studies have examined Cd binding to cellulose and hemicellulose. Here we found that Cd binding to CW pectin, cellulose, and hemicellulose was significantly higher in Tor-1, a Cd tolerant A. thaliana ecotype, than in Ph2-23, a sensitive ecotype, as were the concentrations of pectin, cellulose, and hemicellulose. Transcriptome analysis revealed that the genes regulating CW pectin, cellulose, and hemicellulose polysaccharide concentrations in Tor-1 differed significantly from those in Ph2-23. The expressions of most genes such as pectin methyl esterase inhibitors (PMEIs), pectin lyases, xyloglucan endotransglucosylase/hydrolase, expansins (EXPAs), and cellulose hydrolase were higher in Ph2-23, while the expressions of cellulose synthase-like glycosyltransferase 3 (CSLG3) and pectin ethyl esterase 4 (PAE4) were higher in Tor-1. The candidate genes identified here seem to regulate CW Cd fixation by polysaccharides. In conclusion, an increase in pectin demethylation activity, the higher concentration of cellulose and hemicellulose, regulated by related genes, in Tor-1 than in Ph2-23 are likely involved in enhanced Cd CW retention and reduce Cd toxicity.
ESTHER : Xiao_2020_Front.Plant.Sci_11_473
PubMedSearch : Xiao_2020_Front.Plant.Sci_11_473
PubMedID: 32477379

Title : Relief of Cadmium-Induced Intestinal Motility Disorder in Mice by Lactobacillus plantarum CCFM8610 - Liu_2020_Front.Immunol_11_619574
Author(s) : Liu Y , Wu J , Xiao Y , Liu Q , Yu L , Tian F , Zhao J , Zhang H , Chen W , Zhai Q
Ref : Front Immunol , 11 :619574 , 2020
Abstract : Cadmium (Cd) is a toxic metal inducing a range of adverse effects on organs including liver and kidneys. However, the underlying molecular mechanisms of Cd-induced intestinal toxicity through dietary intake is poorly studied. This study evaluated the toxic effects of Cd on intestinal physiology and confirmed the effectiveness of the protective mechanism of the probiotic Lactobacillus plantarum CCFM8610 against chronic Cd toxicity. After treatment with Cd, the HT-29 cell line was subjected to iTRAQ analysis, which revealed that changes in the proteomic profiles after Cd exposure were related to pathways involved in the stress response and carbohydrate metabolism. The results of an animal trial also indicated that 10 weeks of Cd exposure decreased the fecal water content and contractile response of colonic muscle strips in mice, and delayed the excretion time of the first black feces. L. plantarum CCFM8610 treatment provided protective effects against these Cd-induced intestinal motility dysfunctions by recovering the levels of neurotransmitters, including substance P, acetyl cholinesterase, vasoactive intestinal peptide, 5-hydroxytryptamine, calcitonin gene-related peptide, and nitric oxide, and suppressing the cellular stress response in mice (e.g., the inhibition of mitogen-activated protein kinase pathways). The administration of this probiotic was also observed to reduce Cd levels in the tissues and blood of the mice. Our results suggest a newly identified protective mechanism of probiotics against Cd toxicity that involves the recovery of intestinal motility and increase in fecal cadmium excretion.
ESTHER : Liu_2020_Front.Immunol_11_619574
PubMedSearch : Liu_2020_Front.Immunol_11_619574
PubMedID: 33362802

Title : Synergistic Degradation of Pyrethroids by the Quorum Sensing-Regulated Carboxylesterase of Bacillus subtilis BSF01 - Xiao_2020_Front.Bioeng.Biotechnol_8_889
Author(s) : Xiao Y , Lu Q , Yi X , Zhong G , Liu J
Ref : Front Bioeng Biotechnol , 8 :889 , 2020
Abstract : The well-studied quorum sensing (QS) mechanism has established a complex knowledge system of how microorganisms behave collectively in natural ecosystems, which contributes to bridging the gap between the ecological functions of microbial communities and the molecular mechanisms of cell-to-cell communication. In particular, the ability of agrochemical degradation has been one most attractive potential of functional bacteria, but the interaction and mutual effects of intracellular degradation and intraspecific behavior remained unclear. In this study, we establish a connection between QS regulation and biodegradation by harnessing the previously isolated Bacillus subtilis BSF01 as a template which degrades various pyrethroids. First, we characterize the genetic and transcriptional basis of comA-involved QS system in B. subtilis BSF01 since the ComQXPA circuit coordinates group behaviors in B. subtilis isolates. Second, the genetic and transcriptional details of pyrethroid-degrading carboxylesterase CesB are defined, and its catalytic capacity is evaluated under different conditions. More importantly, we adopt DNA pull-down and yeast one-hybrid techniques to reveal that the enzymatic degradation of pyrethroids is initiated through QS signal regulator ComA binding to carboxylesterase gene cesB, highlighting the synergistic effect of QS regulation and pyrethroid degradation in B. subtilis BSF01. Taken together, the elucidated mechanism provides novel details on the intercellular response of functional bacteria against xenobiotic exposure, which opens up possibilities to facilitate the in-situ contaminant bioremediation via combining the QS-mediated strategies.
ESTHER : Xiao_2020_Front.Bioeng.Biotechnol_8_889
PubMedSearch : Xiao_2020_Front.Bioeng.Biotechnol_8_889
PubMedID: 32850741

Title : Copper(II) complex as a turn on fluorescent sensing platform for acetylcholinesterase activity with high sensitivity - Zhang_2020_Talanta_208_120406
Author(s) : Zhang P , Fu C , Xiao Y , Zhang Q , Ding C
Ref : Talanta , 208 :120406 , 2020
Abstract : Acetylcholinesterase (AChE) is an important enzyme associated with many nervous diseases, demonstrating the great need for smarter sensing platform with improved sensitivity, selectivity and simplified operation. A "turn on" fluorometric assay is described herein for AChE activity detection, according to the specific enzyme catalyzed reaction of acetylcholine (ATCh) by AChE, which generates thiocholine (TCh) as the product. The well-designed fluorescent probe HBTP possesses ESIPT (Excited State Intramolecular Proton Transfer) nature, leading to a larger Stokes shift, which could be quenched upon coordination with Cu(2+). The fluorescence-silent HBTP-Cu(2+) complex could be broken by TCh generated from reaction of ATCh with AChE, giving rise to HBTP release which originates from competitive coordination of TCh with Cu(2+). This complex probe HBTP-Cu(2+) offers a limit detection as low as 0.02 mUmL(-1), which is lower than most reported literatures. Furthermore, both HBTP-Cu(2+) and HBTP show little toxicity to live cells and is available in visualizing cellular AChE activity.
ESTHER : Zhang_2020_Talanta_208_120406
PubMedSearch : Zhang_2020_Talanta_208_120406
PubMedID: 31816742

Title : Pig liver esterases PLE1 and PLE6: heterologous expression, hydrolysis of common antibiotics and pharmacological consequences - Zhou_2019_Sci.Rep_9_15564
Author(s) : Zhou Q , Xiao Q , Zhang Y , Wang X , Xiao Y , Shi D
Ref : Sci Rep , 9 :15564 , 2019
Abstract : Carboxylesterases, historically referred as non-specific esterases, are ubiquitous hydrolases with high catalytic efficiency. Without exceptions, all mammalian species studied contain multiple forms of carboxylesterases. While having been widely studied in humans and experimental animals, these enzymes remain to be characterized in farm animals. In this study, we showed that pig liver esterase 1 (PLE1) and pig liver esterase 6 (PLE6) were highly active toward amoxicillin (AMO) and ampicillin (AMP), two major antibiotics that are widely used in food-supplements. Mass-spectrometric analysis established that the hydrolysis occurred at the beta-lactam amide bond and the hydrolysis drastically decreased or completely eliminated the antibacterial activity. Furthermore, hydrolytic activity and proteomic analysis suggested that trace PLEs existed in pig plasma and contributed little to the hydrolysis of AMO and AMP. These results suggested that carboxylesterases-based hydrolysis determines the therapeutic intensity of these and related antibiotics and the magnitude of the determination occurs in a species-dependent manner.
ESTHER : Zhou_2019_Sci.Rep_9_15564
PubMedSearch : Zhou_2019_Sci.Rep_9_15564
PubMedID: 31664043
Gene_locus related to this paper: pig-EST1 , pig-a0a1s6l967

Title : Selection of Reference Genes for Expression Analysis in Chinese Medicinal Herb Huperzia serrata - Yang_2019_Front.Pharmacol_10_44
Author(s) : Yang M , Wu S , You W , Jaisi A , Xiao Y
Ref : Front Pharmacol , 10 :44 , 2019
Abstract : Huperzine A (HupA) is a powerful and selective inhibitor of acetylcholinesterase. It has attracted widespread attention endangering the ultimate plant sources of Lycopodiaceae family. In this study, we used Huperzia serrata, extensively used in Traditional Chinese medicine (TCM), a slow growing vascular plant as the model plant of the Lycopodiaceae family to develop and validate the reference genes. We aim to use gene expression platform to understand the gene expression of different tissues and developmental stages of this medicinal herb. Eight candidate reference genes were selected based on RNA-seq data and evaluated with qRT-PCR. The expression of L/ODC and cytochrome P450s genes known for their involvement in lycopodium alkaloid biosynthesis, were also studied to validate the selected reference genes. The most stable genes were TBP, GAPDH, and their combination (TBP + GAPDH). We report for the first time the reference gene of H. serrata's different tissues which would provide important insights into understanding their biological functions comparing other Lycopodiaceae plants and facilitate a good biopharming approach.
ESTHER : Yang_2019_Front.Pharmacol_10_44
PubMedSearch : Yang_2019_Front.Pharmacol_10_44
PubMedID: 30774594

Title : Hydroquinone and terpene glucosides from Leontopodium leontopodioides and their lipase inhibitory activity - Gou_2018_Fitoterapia_130_89
Author(s) : Gou P , Xiao Y , Lv L , Xie H
Ref : Fitoterapia , 130 :89 , 2018
Abstract : Three new glucosides of hydroquinone, monoterpene, and megastigmane, benzyl 2,5-dihydroxybenzoate 5-O-beta-d-glucopyranoside (isotrichocarpin, 1), (2S,3R)-3,7-dimethyl-6-octene-1,2,3-triol 2-O-beta-d-glucopyranoside (leontopodioside D, 4), and (6R,7R,8R,9S)-6,9-epoxy-7,8-dihydroxymegastigman-4-en-3-one 8-O-beta-d-glucopyranoside (leontopodioside E, 7) were isolated from the whole herbs of Leontopodium leontopodioides (Willd.) Beauv. (Asteraceae), along with nebrodenside A (2), pungenin (3), betulalbuside A (5), geranyl O-beta-d-glucopyranoside (6), and 3beta-hydroxy-beta-ionone 3-O-beta-d-glucopyranoside (8). Their structure were determined by spectroscopic and chemical methods. All the known compounds were reported from this species for the first time. Compounds 2-6 showed potent in vitro pancreatic lipase inhibitory activity, suggesting their participation in the reductive effect of the herbs on triglyceride absorption.
ESTHER : Gou_2018_Fitoterapia_130_89
PubMedSearch : Gou_2018_Fitoterapia_130_89
PubMedID: 30145331

Title : Intestinal damage, neurotoxicity and biochemical responses caused by tris (2-chloroethyl) phosphate and tricresyl phosphate on earthworm - Yang_2018_Ecotoxicol.Environ.Saf_158_78
Author(s) : Yang Y , Xiao Y , Chang Y , Cui Y , Klobucar G , Li M
Ref : Ecotoxicology & Environmental Safety , 158 :78 , 2018
Abstract : Organophosphate esters (OPEs) draw growing concern about characterizing the potential risk on environmental health due to its wide usage and distribution. Two typical types of organophosphate esters (OPEs): tris (2-chloroethyl) phosphate (TCEP) and tricresyl phosphate (TCP) were selected to evaluate toxicity of OPEs to the soil organism like earthworm (Eisenia fetida). Histopathological examination (H&E), oxidative stress, DNA damage and RT-qPCR was used to identify the effects and potential mechanism of their toxicity. Hameatoxylin and eosin (H&E) demonstrated that intestinal cells suffered serious damage, and the observed up-regulation of chitinase and cathepsin L in mRNA levels confirmed it. Both TCEP and TCP significantly increased the DNA damage when the concentrations exceeded 1mg/kg (p<0.01), and a dose-response relationship was observed. In addition, TCEP and TCP also changed the acetylcholinesterase (AChE) activity and expression of genes associated with neurotoxic effects in earthworms even under exposure to low OPEs concentration (0.1mg/kg). Moreover, genes associated with nicotinic acetylcholine receptors (nAChR) and carrier protein further demonstrated that highest concentration of TCEP (10mg/kg) may have an overloading impact on the cholinergic system of E. fetida. Integrated Biological Response index (IBRv2) showed that TCEP exerted stronger toxicity than TCP under the same concentrations. We deduced that the observed intestinal damage, oxidative stress and neurotoxic effect might be the primary mechanisms of TCEP and TCP toxicity. This study provides insight into the toxicological effects of OPEs on earthworm model, and may be useful for risk assessment of OPEs on soil ecosystems.
ESTHER : Yang_2018_Ecotoxicol.Environ.Saf_158_78
PubMedSearch : Yang_2018_Ecotoxicol.Environ.Saf_158_78
PubMedID: 29660616

Title : Sublethal or not? Responses of multiple biomarkers in Daphnia magna to single and joint effects of BDE-47 and BDE-209 - Xiong_2018_Ecotoxicol.Environ.Saf_164_164
Author(s) : Xiong Q , Shi Y , Lu Y , Pan K , Dakhil MA , Zhang L , Xiao Y
Ref : Ecotoxicology & Environmental Safety , 164 :164 , 2018
Abstract : Polybrominated diphenyl ethers (PBDEs) are extremely incessant anthropogenic contaminants found in the environment, with dreadful risk to aquatic ecosystems. However, there is a limited amount of data concerning their impacts on freshwater organisms. 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are significant components of total PBDEs in water. The sublethal effects of BDE-47, BDE-209 and their binary mixtures on the aquatic organism Daphnia magna were investigated in acute and chronic exposure experiments. Immobilization and heartbeat were studied in daphnids after 48h of exposure. Mortality rate, breed number, Cholinesterase (ChE), Glutathione S-transferases (GST) and Catalase (CAT) activities were evaluated after 21 days of exposure. The results showed that at 100 and 200mug/L concentration of BDE-47, immobilization rate of daphnids were inhibited by 44.0+/-16.7% and 88.0+/-10.9%, respectively. The binary mixture of BDE-47 and BDE-209 had uncongenial effects on immobilization of D. magna under acute toxicity test. BDE-209 significantly increased the heartbeat rate of daphnids, which increased even further when combined with BDE-47. After 21 days of exposure, daphnids exposed to single BDE-47 were physiologically altered. The combination of BDE-47 with BDE-209 significantly decreased the mortality rate of daphnids. Irrespective of the concentration, higher numbers of offsprings were produced in the mixtures compared to BDE-47 treatment alone. ChE activities significantly (p<0.05) decreased at concentrations of 2 and 4mug/L in single BDE-47 treatment, while GST activity significantly (p<0.05) decreased at 0.5mug/L. CAT activities significantly increased with BDE-47 treatments in all the tested concentrations (p<0.05). The mixtures significantly affect ChE (p<0.05), GST (p<0.05) and CAT activities (p<0.05). The results illustrated that the toxicity of the mixture of PBDE congeners exposed to aquatic organisms may have antagonistic effects. The 21 days chronic test in this study suggests that acute toxicity tests, i.e. 48-h tests, using Daphnia may lead to underestimation of risks associated with PBDEs, especially, BDE-209. Hence, there is a necessity to re-examine PBDE congeners' environmental risk in aquatic organisms.
ESTHER : Xiong_2018_Ecotoxicol.Environ.Saf_164_164
PubMedSearch : Xiong_2018_Ecotoxicol.Environ.Saf_164_164
PubMedID: 30107326

Title : Characterization of the population structure, drug resistance mechanisms and plasmids of the community-associated Enterobacter cloacae complex in China - Zhou_2018_J.Antimicrob.Chemother_73_66
Author(s) : Zhou K , Yu W , Cao X , Shen P , Lu H , Luo Q , Rossen JWA , Xiao Y
Ref : J Antimicrob Chemother , 73 :66 , 2018
Abstract : OBJECTIVES: To investigate the population structure, drug resistance mechanisms and plasmids of community-associated Enterobacter cloacae complex (CA-ECC) isolates in China. METHODS: Sixty-two CA-ECC isolates collected from 31 hospitals across China were typed by hsp60 typing and MLST. ESBL and AmpC-overexpression phenotype was determined by double-disc synergy test. Replicon typing and conjugation were performed for plasmid analysis. All ESBL-positive isolates and representative conjugants were subjected to detailed characterization by WGS. RESULTS: Enterobacter hormaechei and Enterobacter kobei were predominant in our collections. MLST distinguished 46 STs with a polyclonal structure. ST591 was the most prevalent clone detected in northern China. Twenty-two isolates (35.5%) were ESBL positive and half of them were E. kobei. ESBL positivity was related to ESBL production (15/22) and to AmpC overexpression (18/22). Core-genome phylogenetic analysis identified intra- and inter-regional dissemination of ESBL-producing E. kobei clones. ESBL producers were exclusively classified as E. hormaechei and E. kobei, and blaCTX-M-3 was the most prevalent ESBL genotype (10/15) detected in four different environments. In the ESBL-positive population, the ESBL producers encoded more drug resistance genes (8-24 genes) by carrying more plasmids (1-3 plasmids) than the non-ESBL-producing isolates, resulting in an inter-group difference in drug susceptibilities. IncHI-type plasmids were prevalent in the ESBL producers (12/15). All IncHI2-type plasmids (n = 11) carried ESBL genes and shared a similar backbone to p09-036813-1A_261 recovered from Salmonella enterica in Canada. CONCLUSIONS: The species-specific distribution, species-dependent ESBL mechanism and endemic plasmids identified in our study highlight the necessity for tailored surveillance of CA-ECC in the future.
ESTHER : Zhou_2018_J.Antimicrob.Chemother_73_66
PubMedSearch : Zhou_2018_J.Antimicrob.Chemother_73_66
PubMedID: 29088362
Gene_locus related to this paper: 9entr-a0a2j0pr84

Title : Toxicological analysis of roast duck flavor components - Zhou_2018_Food.Chem.Toxicol_119_438
Author(s) : Zhou Y , Yan B , Zhao S , Zhou X , Xiao Y
Ref : Food & Chemical Toxicology , 119 :438 , 2018
Abstract : The aim of the study was to investigate toxicity of the synthesized roast duck flavor through animal experiment (mice feeding with the flavor for 35 days), and the major toxic compounds (acrylamide and 3,4-benzopyrene) were detected by high performance liquid chromatography. Compared with the control group, the blood biochemical indexes including protein content, bilirubin content, activity of alkaline phosphatase, activity of aspartate transaminase (AST) and alanine transaminase (ALT), cholesterol content, high density lipoprotein (HDL) and low density lipoprotein (LDL) content, triglycerides content, activity of creatine kinase (CK) and CK-MB, activity of cholinesterase (CHE) and lactate dehydrogenase (LDH), total bile acid (TBA) in high dose feeding group were significantly different. And body weight of mice fed by the flavor was decreased distinctly, and the heart weight was also decreased, while the liver weight was increased obviously. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver and heart were significantly decreased, while methane dicarboxylic aldehyde (MDA) contents were increased evidently. Acrylamide was detected by high performance liquid-mass spectrum (HPLC-MS), and the content was 5.21 mg/kg 3,4-benzoapryene was calculated by HPLC with fluorescence detector, and the content was 21.13 mug/kg. Thus, the roast duck flavor was considered to be potential toxicity to human being.
ESTHER : Zhou_2018_Food.Chem.Toxicol_119_438
PubMedSearch : Zhou_2018_Food.Chem.Toxicol_119_438
PubMedID: 29208505

Title : Chemo-Enzymatic Synthesis of Poly(4-piperidine lactone- b-w-pentadecalactone) Block Copolymers as Biomaterials with Antibacterial Properties - Xiao_2018_Biomacromolecules_19_2673
Author(s) : Xiao Y , Pan J , Wang D , Heise A , Lang M
Ref : Biomacromolecules , 19 :2673 , 2018
Abstract : With increasing troubles in bacterial contamination and antibiotic-resistance, new materials possessing both biocompatibility and antimicrobial efficacy are supposed to be developed for future biomedical application. Herein, we demonstrated a chemo-enzymatic ring opening polymerization (ROP) approach for block copolyester, that is, poly(4-benzyl formate piperidine lactone- b-omega-pentadecalactone) (PNPIL- b-PPDL), in a one-pot two-step process. Afterward, cationic poly(4-piperidine lactone- b-omega-pentadecalactone) (PPIL- b-PPDL) with pendent secondary amino groups was obtained via acidic hydrolysis of PNPIL- b-PPDL. The resulting cationic block copolyester exhibited high antibacterial activity against Gram negative E. coli and Gram positive S. aureus, while showed low toxicity toward NIH-3T3 cells. Moreover, the antibacterial property, cytotoxicity and degradation behavior could be tuned simply by variation of PPIL content. Therefore, we anticipate that such cationic block copolymers could potentially be applied as biomaterials for medicine or implants.
ESTHER : Xiao_2018_Biomacromolecules_19_2673
PubMedSearch : Xiao_2018_Biomacromolecules_19_2673
PubMedID: 29698599

Title : Breed Differences in Pig Liver Esterase (PLE) between Tongcheng (Chinese Local Breed) and Large White Pigs - Xiao_2018_Sci.Rep_8_16364
Author(s) : Xiao Q , Zhou Q , Yang L , Tian Z , Wang X , Xiao Y , Shi D
Ref : Sci Rep , 8 :16364 , 2018
Abstract : Human carboxylesterases has been proven to be age and race-related and a sound basis of clinical medication. PLE involve in signal transduction and highly catalyze hydrolysis. Therefore, the expression level of PLE most probably exist age and breed difference and lead to significant differences of pharmacology and physiology. Four age groups of Tongcheng (TC) and Large White (LW) pigs were selected to explore PLE breed and age differences, and it was found that PLE mRNA was most abundant in liver in both breeds. In liver, PLE levels and hydrolytic activities increased with age, and PLE levels (except for 3 month) and the hydrolytic activities were higher in LW than in TC across all age groups. Abundance of PLE isoenzymes was obvious different between breeds and among age groups. The most abundant PLE isoenzyme in LW and TC pigs was PLE-A1 (all age groups) and PLE-B9 (three early age groups) or PLE-G3 (adult groups), respectively. 103 new PLE isoenzymes were found, and 55 high-frequency PLE isoenzymes were accordingly classified into seven categories (A-G). The results of this research provide a necessary basis not only for clinical medication of pigs but also for pig breeding purposes.
ESTHER : Xiao_2018_Sci.Rep_8_16364
PubMedSearch : Xiao_2018_Sci.Rep_8_16364
PubMedID: 30397234
Gene_locus related to this paper: pig-a9gyw6 , pig-EST1 , pig-PLE1 , pig-a0a1s6l948 , pig-a0a1s6l959 , pig-a0a1s6l967

Title : Complex pectin metabolism by gut bacteria reveals novel catalytic functions - Ndeh_2017_Nature_544_65
Author(s) : Ndeh D , Rogowski A , Cartmell A , Luis AS , Basle A , Gray J , Venditto I , Briggs J , Zhang X , Labourel A , Terrapon N , Buffetto F , Nepogodiev S , Xiao Y , Field RA , Zhu Y , O'Neil MA , Urbanowicz BR , York WS , Davies GJ , Abbott DW , Ralet MC , Martens EC , Henrissat B , Gilbert HJ
Ref : Nature , 544 :65 , 2017
Abstract : The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiota. It is unclear, however, whether bacterial consortia or single organisms are required to depolymerize highly complex glycans. Here we show that the gut bacterium Bacteroides thetaiotaomicron uses the most structurally complex glycan known: the plant pectic polysaccharide rhamnogalacturonan-II, cleaving all but 1 of its 21 distinct glycosidic linkages. The deconstruction of rhamnogalacturonan-II side chains and backbone are coordinated to overcome steric constraints, and the degradation involves previously undiscovered enzyme families and catalytic activities. The degradation system informs revision of the current structural model of rhamnogalacturonan-II and highlights how individual gut bacteria orchestrate manifold enzymes to metabolize the most challenging glycan in the human diet.
ESTHER : Ndeh_2017_Nature_544_65
PubMedSearch : Ndeh_2017_Nature_544_65
PubMedID: 28329766

Title : The genome draft of coconut (Cocos nucifera) - Xiao_2017_Gigascience_6_1
Author(s) : Xiao Y , Xu P , Fan H , Baudouin L , Xia W , Bocs S , Xu J , Li Q , Guo A , Zhou L , Li J , Wu Y , Ma Z , Armero A , Issali AE , Liu N , Peng M , Yang Y
Ref : Gigascience , 6 :1 , 2017
Abstract : Coconut palm (Cocos nucifera,2n = 32), a member of genus Cocos and family Arecaceae (Palmaceae), is an important tropical fruit and oil crop. Currently, coconut palm is cultivated in 93 countries, including Central and South America, East and West Africa, Southeast Asia and the Pacific Islands, with a total growth area of more than 12 million hectares [1]. Coconut palm is generally classified into 2 main categories: "Tall" (flowering 8-10 years after planting) and "Dwarf" (flowering 4-6 years after planting), based on morphological characteristics and breeding habits. This Palmae species has a long growth period before reproductive years, which hinders conventional breeding progress. In spite of initial successes, improvements made by conventional breeding have been very slow. In the present study, we obtained de novo sequences of the Cocos nucifera genome: a major genomic resource that could be used to facilitate molecular breeding in Cocos nucifera and accelerate the breeding process in this important crop. A total of 419.67 gigabases (Gb) of raw reads were generated by the Illumina HiSeq 2000 platform using a series of paired-end and mate-pair libraries, covering the predicted Cocos nucifera genome length (2.42 Gb, variety "Hainan Tall") to an estimated x173.32 read depth. A total scaffold length of 2.20 Gb was generated (N50 = 418 Kb), representing 90.91% of the genome. The coconut genome was predicted to harbor 28 039 protein-coding genes, which is less than in Phoenix dactylifera (PDK30: 28 889), Phoenix dactylifera (DPV01: 41 660), and Elaeis guineensis (EG5: 34 802). BUSCO evaluation demonstrated that the obtained scaffold sequences covered 90.8% of the coconut genome and that the genome annotation was 74.1% complete. Genome annotation results revealed that 72.75% of the coconut genome consisted of transposable elements, of which long-terminal repeat retrotransposons elements (LTRs) accounted for the largest proportion (92.23%). Comparative analysis of the antiporter gene family and ion channel gene families between C. nucifera and Arabidopsis thaliana indicated that significant gene expansion may have occurred in the coconut involving Na+/H+ antiporter, carnitine/acylcarnitine translocase, potassium-dependent sodium-calcium exchanger, and potassium channel genes. Despite its agronomic importance, C. nucifera is still under-studied. In this report, we present a draft genome of C. nucifera and provide genomic information that will facilitate future functional genomics and molecular-assisted breeding in this crop species.
ESTHER : Xiao_2017_Gigascience_6_1
PubMedSearch : Xiao_2017_Gigascience_6_1
PubMedID: 29048487
Gene_locus related to this paper: cocnu-a0a8k0hu18

Title : Third-Generation Sequencing and Analysis of Four Complete Pig Liver Esterase Gene Sequences in Clones Identified by Screening BAC Library - Zhou_2016_PLoS.One_11_e0163295
Author(s) : Zhou Q , Sun W , Liu X , Wang X , Xiao Y , Bi D , Yin J , Shi D
Ref : PLoS ONE , 11 :e0163295 , 2016
Abstract : AIM: Pig liver carboxylesterase (PLE) gene sequences in GenBank are incomplete, which has led to difficulties in studying the genetic structure and regulation mechanisms of gene expression of PLE family genes. The aim of this study was to obtain and analysis of complete gene sequences of PLE family by screening from a Rongchang pig BAC library and third-generation PacBio gene sequencing.
METHODS: After a number of existing incomplete PLE isoform gene sequences were analysed, primers were designed based on conserved regions in PLE exons, and the whole pig genome used as a template for Polymerase chain reaction (PCR) amplification. Specific primers were then selected based on the PCR amplification results. A three-step PCR screening method was used to identify PLE-positive clones by screening a Rongchang pig BAC library and PacBio third-generation sequencing was performed. BLAST comparisons and other bioinformatics methods were applied for sequence analysis.
RESULTS: Five PLE-positive BAC clones, designated BAC-10, BAC-70, BAC-75, BAC-119 and BAC-206, were identified. Sequence analysis yielded the complete sequences of four PLE genes, PLE1, PLE-B9, PLE-C4, and PLE-G2. Complete PLE gene sequences were defined as those containing regulatory sequences, exons, and introns. It was found that, not only did the PLE exon sequences of the four genes show a high degree of homology, but also that the intron sequences were highly similar. Additionally, the regulatory region of the genes contained two 720bps reverse complement sequences that may have an important function in the regulation of PLE gene expression. SIGNIFICANCE: This is the first report to confirm the complete sequences of four PLE genes. In addition, the study demonstrates that each PLE isoform is encoded by a single gene and that the various genes exhibit a high degree of sequence homology, suggesting that the PLE family evolved from a single ancestral gene. Obtaining the complete sequences of these PLE genes provides the necessary foundation for investigation of the genetic structure, function, and regulatory mechanisms of the PLE gene family.
ESTHER : Zhou_2016_PLoS.One_11_e0163295
PubMedSearch : Zhou_2016_PLoS.One_11_e0163295
PubMedID: 27695062
Gene_locus related to this paper: pig-EST1 , pig-PLE1 , pig-a0a1s6l948 , pig-a0a1s6l959 , pig-a0a1s6l967

Title : Genome and Transcriptome Sequences Reveal the Specific Parasitism of the Nematophagous Purpureocillium lilacinum 36-1 - Xie_2016_Front.Microbiol_7_1084
Author(s) : Xie J , Li S , Mo C , Xiao X , Peng D , Wang G , Xiao Y
Ref : Front Microbiol , 7 :1084 , 2016
Abstract : Purpureocillium lilacinum is a promising nematophagous ascomycete able to adapt diverse environments and it is also an opportunistic fungus that infects humans. A microbial inoculant of P. lilacinum has been registered to control plant parasitic nematodes. However, the molecular mechanism of the toxicological processes is still unclear because of the relatively few reports on the subject. In this study, using Illumina paired-end sequencing, the draft genome sequence and the transcriptome of P. lilacinum strain 36-1 infecting nematode-eggs were determined. Whole genome alignment indicated that P. lilacinum 36-1 possessed a more dynamic genome in comparison with P. lilacinum India strain. Moreover, a phylogenetic analysis showed that the P. lilacinum 36-1 had a closer relation to entomophagous fungi. The protein-coding genes in P. lilacinum 36-1 occurred much more frequently than they did in other fungi, which was a result of the depletion of repeat-induced point mutations (RIP). Comparative genome and transcriptome analyses revealed the genes that were involved in pathogenicity, particularly in the recognition, adhesion of nematode-eggs, downstream signal transduction pathways and hydrolase genes. By contrast, certain numbers of cellulose and xylan degradation genes and a lack of polysaccharide lyase genes showed the potential of P. lilacinum 36-1 as an endophyte. Notably, the expression of appressorium-formation and antioxidants-related genes exhibited similar infection patterns in P. lilacinum strain 36-1 to those of the model entomophagous fungi Metarhizium spp. These results uncovered the specific parasitism of P. lilacinum and presented the genes responsible for the infection of nematode-eggs.
ESTHER : Xie_2016_Front.Microbiol_7_1084
PubMedSearch : Xie_2016_Front.Microbiol_7_1084
PubMedID: 27486440
Gene_locus related to this paper: purli-a0a2u3dwt4 , purli-lcse

Title : AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat alpha3beta4 Nicotinic Cholinergic Receptors - Tuan_2015_Mol.Pharmacol_88_640
Author(s) : Tuan EW , Horti AG , Olson TT , Gao Y , Stockmeier CA , Al-Muhtasib N , Bowman Dalley C , Lewin AE , Wolfe BB , Sahibzada N , Xiao Y , Kellar KJ
Ref : Molecular Pharmacology , 88 :640 , 2015
Abstract : AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan-3-amine] is a high-affinity and highly selective ligand at alpha3beta4 nicotinic cholinergic receptors (nAChRs) that was reported to decrease nicotine self-administration in rats. It was initially reported to be an antagonist at rat alpha3beta4 nAChRs heterologously expressed in HEK293 cells. Here we compared AT-1001 actions at rat and human alpha3beta4 and alpha4beta2 nAChRs similarly expressed in HEK 293 cells. We found that, as originally reported, AT-1001 is highly selective for alpha3beta4 receptors over alpha4beta2 receptors, but its binding selectivity is much greater at human than at rat receptors, because of a higher affinity at human than at rat alpha3beta4 nAChRs. Binding studies in human and rat brain and pineal gland confirmed the selectivity of AT-1001 for alpha3beta4 nAChRs and its higher affinity for human compared with rat receptors. In patch-clamp electrophysiology studies, AT-1001 was a potent partial agonist with 65-70% efficacy at both human and rat alpha3beta4 nAChRs. It was also a less potent and weaker (18%) partial agonist at alpha4beta2 nAChRs. Both alpha3beta4 and alpha4beta2 nAChRs are upregulated by exposure of cells to AT-1001 for 3 days. Similarly, AT-1001 desensitized both receptor subtypes in a concentration-dependent manner, but it was 10 and 30 times more potent to desensitize human alpha3beta4 receptors than rat alpha3beta4 and human alpha4beta2 receptors, respectively. After exposure to AT-1001, the time to recovery from desensitization was longest for the human alpha3beta4 nAChR and shortest for the human alpha4beta2 receptor, suggesting that recovery from desensitization is primarily related to the dissociation of the ligand from the receptor.
ESTHER : Tuan_2015_Mol.Pharmacol_88_640
PubMedSearch : Tuan_2015_Mol.Pharmacol_88_640
PubMedID: 26162864

Title : Protective effects of low molecular weight chondroitin sulfate on amyloid beta (Abeta)-induced damage in vitro and in vivo - Zhang_2015_Neurosci_305_169
Author(s) : Zhang Q , Li J , Liu C , Song C , Li P , Yin F , Xiao Y , Jiang W , Zong A , Zhang X , Wang F
Ref : Neuroscience , 305 :169 , 2015
Abstract : In the present study, we investigated the effects of low molecular weight chondroitin sulfate (LMWCS) on amyloid beta (Abeta)-induced neurotoxicity in vitro and in vivo. The in vitro results showed that LMWCS blocked Abeta25-35-induced cell viability loss and apoptosis, decreased intracellular calcium concentration, reactive oxygen species (ROS) levels, the mitochondrial membrane potential (MMP) depolarization, and the protein expression of Caspase-3. During in vivo experiments, LMWCS improved the cognitive impairment induced by Abeta1-40, increased the level of choline acetyltransferase (ChAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased the level of malondialdehyde (MDA) and acetylcholinesterase (AChE) in the mouse brain. Moreover, LMWCS decreased the density of pyramidal cells of CA1 regions, and suppressed the protein expression of Bax/Bcl-2 and Caspase-3, -9 in the hippocampus of mice. In conclusion, LMWCS possessed neuroprotective properties against toxic effects induced by Abeta peptides both in vitro and in vivo, which might be related to anti-apoptotic activity. LMWCS might be a useful preventive and therapeutic compound for Alzheimer's disease.
ESTHER : Zhang_2015_Neurosci_305_169
PubMedSearch : Zhang_2015_Neurosci_305_169
PubMedID: 26254241

Title : Poster: Nicotinic treatments not only for tobacco, but also other addictions -
Author(s) : Levin ED , Rezvani AH , Xiao Y , Yenugonda VM , Brown ML , Kellar KJ
Ref : Biochemical Pharmacology , 97 :635 , 2015

Title : Structure-activity relationship studies of SEN12333 analogues: determination of the optimal requirements for binding affinities at alpha7 nAChRs through incorporation of known structural motifs - Beinat_2015_Eur.J.Med.Chem_95_277
Author(s) : Beinat C , Reekie T , Banister SD , O'Brien-Brown J , Xie T , Olson TT , Xiao Y , Harvey A , O'Connor S , Coles C , Grishin A , Kolesik P , Tsanaktsidis J , Kassiou M
Ref : Eur Journal of Medicinal Chemistry , 95 :277 , 2015
Abstract : Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described alpha7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the alpha7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).
ESTHER : Beinat_2015_Eur.J.Med.Chem_95_277
PubMedSearch : Beinat_2015_Eur.J.Med.Chem_95_277
PubMedID: 25827398

Title : Construction of an immobilised acetylcholinesterase column and its application in screening insecticidal constituents from Magnolia officinalis - Ye_2015_Pest.Manag.Sci_71_607
Author(s) : Ye YH , Li C , Yang J , Ma L , Xiao Y , Hu J , Rajput NA , Gao CF , Zhang YY , Wang MH
Ref : Pest Manag Sci , 71 :607 , 2015
Abstract : BACKGROUND: Application of a matrix-immobilised target enzyme for screening inhibitors is widely used in drug development, but there are few studies in insecticide discovery. In this paper, an economical and effective immobilised acetylcholinesterase (AChE) column was prepared using the sol-gel embedment method, which was further combined with high-performance liquid chromatography for screening the AChE inhibitors and insecticidal compounds from complex natural products.
RESULTS: AChE inhibitory constituents magnolol and honokiol were isolated from the ethanol extract of Magnolia officinalis, with IC50 values of 0.069 and 0.057 mM respectively. In an in vivo bioassay, magnolol and honokiol showed insecticidal activity against Nilaparvata lugens, with LC50 values of 0.324 and 0.137 mM, which are comparable with that of commonly used insecticide chlorpyrifos (0.233 mM). Moreover, molecular docking was carried out against a homology model of N. lugens AChE. The complexes showed that magnolol and honokiol placed themselves nicely into the active site of the enzyme and exhibited an interaction energy that was in accordance with our activity profile data. CONCLUSION: These results demonstrate that magnolol and honokiol have great applied potential to be developed as natural insecticides, and an immobilised AChE column is very useful as a rapid screening tool for target enzymes towards potent inhibitors. (c) 2014 Society of Chemical Industry.
ESTHER : Ye_2015_Pest.Manag.Sci_71_607
PubMedSearch : Ye_2015_Pest.Manag.Sci_71_607
PubMedID: 25228142

Title : Valeriana amurensis improves Amyloid-beta 1-42 induced cognitive deficit by enhancing cerebral cholinergic function and protecting the brain neurons from apoptosis in mice - Wang_2014_J.Ethnopharmacol_153_318
Author(s) : Wang Q , Wang C , Shu Z , Chan K , Huang S , Li Y , Xiao Y , Wu L , Kuang H , Sun X
Ref : J Ethnopharmacol , 153 :318 , 2014
Abstract : ETHNOPHAMACOLOGICAL RELEVANCE: Valeriana amurensis, a perennial medicinal herb, has been widely used as anxiolytic, antidepressant, antispasmodic, and sedative in traditional Chinese medicines (TCMs). Moreover, it has been used to treat dementia in Mongolia preparations. In our previous study, we reported that AD-effective fraction of Valeriana amurensis (AD-EFV) has protective effect on Abeta-induced toxicity in PC12 cells. Up to now, however, the therapeutic effect of Valeriana amurensis on Alzheimer disease (AD) has not been explored. This study was designed to determine whether the AD-EFV could improve the Amyloid-beta (Abeta)-induced cognitive deficit and to explore the mechanism of AD-EFV improves cognitive deficit in intact animals. MATERIALS AND
METHODS: The constituents of AD-EFV were isolated with silica gel, octadecyl silica gel (ODS) column chromatography (CC) and preparative HPLC. The structures of compounds were determined by detailed NMR and ESI-MS data analyses. AD mice model was established by injecting Abeta1-42 (1muL, 200mumol) into the bilateral ventricle. Cognitive performance was evaluated by the Morris water maze (MWM) test. The level of cerebral acetylcholine (ACh), the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were investigated using Enzyme-linked immunoassay (ELISA) kits. Brain sections were processed and neuronal apoptosis in hippocampus were evaluated by Hematoxylin and Eosin (HE), Nissl, and Tunel stainings. The analyses of p-ERK/ERK and Bcl-2/Bax protein expression by western blot assay were used to explore the anti-neuronal apoptosis mechanism of AD-EFV.
RESULTS: Seventeen compounds (15 lignans and two iridoids) were isolated from AD-EFV. A significant improvement in cognitive function was observed in administrated AD-EFV AD model mice. AD-EFV increased the ACh level by enhancing the ChAT activity but has no effect on AChE activity in the cerebral cortex and hippocampus in mice. Moreover, the histological injury in hippocampus CA1 induced by Abeta1-42 was inhibited following administration of the AD-EFV. As well as the expression ratios of Bcl-2 to Bax and p-ERK to ERK were increased significantly in the mice which were administrated AD-EFV. CONCLUSION: These findings suggest that AD-EFV could ameliorate Abeta induced cognitive dysfunction through two underlying mechanisms: AD-EFV enhances the cerebral cholinergic function by increasing the secretion of ACh and enhancing the ChAT activity, and AD-EFV protects the brain neurons from Abeta induced apoptosis via activating the p-ERK and Bcl-2 signaling and suppressing the Bax pathways. Besides, the main constituents of AD-EFV are lignans which might be responsible for the AD-activity of Valeriana amurensis.
ESTHER : Wang_2014_J.Ethnopharmacol_153_318
PubMedSearch : Wang_2014_J.Ethnopharmacol_153_318
PubMedID: 24269774

Title : Investigations of amide bond variation and biaryl modification in analogues of alpha7 nAChR agonist SEN12333 - Beinat_2014_Eur.J.Med.Chem_84C_200
Author(s) : Beinat C , Reekie T , Hibbs D , Xie T , Olson TT , Xiao Y , Harvey A , O'Connor S , Coles C , Tsanaktsidis J , Kassiou M
Ref : Eur Journal of Medicinal Chemistry , 84C :200 , 2014
Abstract : Several lines of experimental evidence support the involvement of the alpha7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the alpha7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel alpha7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at alpha7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.
ESTHER : Beinat_2014_Eur.J.Med.Chem_84C_200
PubMedSearch : Beinat_2014_Eur.J.Med.Chem_84C_200
PubMedID: 25019477

Title : Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain - Hussmann_2014_J.Neurochem_129_721
Author(s) : Hussmann GP , DeDominicis KE , Turner JR , Yasuda RP , Klehm J , Forcelli PA , Xiao Y , Richardson JR , Sahibzada N , Wolfe BB , Lindstrom JM , Blendy JA , Kellar KJ
Ref : Journal of Neurochemistry , 129 :721 , 2014
Abstract : Chronic nicotine administration increases the density of brain alpha4beta2* nicotinic acetylcholine receptors (nAChRs), which may contribute to nicotine addiction by exacerbating withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently, we found that sazetidine-A (saz-A), a potent partial agonist that desensitizes alpha4beta2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here, we investigated whether chronic saz-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the alpha4beta2 subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic saz-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, saz-A and varenicline each demonstrated anxiolytic effects in mice, but only saz-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, saz-A, or drugs like it, may be useful in achieving long-term abstinence from smoking.
ESTHER : Hussmann_2014_J.Neurochem_129_721
PubMedSearch : Hussmann_2014_J.Neurochem_129_721
PubMedID: 24422997

Title : A novel esterase from a marine metagenomic library exhibiting salt tolerance ability - Fang_2014_J.Microbiol.Biotechnol_24_771
Author(s) : Fang Z , Li J , Wang Q , Fang W , Peng H , Zhang X , Xiao Y
Ref : J Microbiol Biotechnol , 24 :771 , 2014
Abstract : A putative lipolytic enzyme gene, named as est9x, was obtained from a marine microbial metagenome of the South China Sea. Sequence analysis showed that Est9X shares lower than 27% sequence identities with the characterized lipolytic enzymes, but possesses a catalytic triad highly conserved in lipolytic enzymes of the alpha/beta hydrolase superfamily. By phylogenetic tree construction, Est9X was grouped into a new lipase/esterase family. To understand Est9X protein in depth, it was recombinantly expressed, purified, and biochemically characterized. Within potential hydrolytic activities, only lipase/esterase activity was detected for Est9X, confirming its identity as a lipolytic enzyme. When using p-nitrophenol esters with varying lengths of fatty acid as substrates, Est9X exhibited the highest activity to the C2 substrate, indicating it is an esterase. The optimal activity of Est9X occurred at a temperature of 65 degrees C, and Est9X was pretty stable below the optimum temperature. Distinguished from other salttolerant esterases, Est9X's activity was tolerant to and even promoted by as high as 4 M NaCl. Our results imply that Est9X is a unique esterase and could be a potential candidate for industrial application under extreme conditions.
ESTHER : Fang_2014_J.Microbiol.Biotechnol_24_771
PubMedSearch : Fang_2014_J.Microbiol.Biotechnol_24_771
PubMedID: 24633233
Gene_locus related to this paper: 9bact-j9vdv8

Title : 18F-ASEM, a radiolabeled antagonist for imaging the alpha7-nicotinic acetylcholine receptor with PET - Horti_2014_J.Nucl.Med_55_672
Author(s) : Horti AG , Gao Y , Kuwabara H , Wang Y , Abazyan S , Yasuda RP , Tran T , Xiao Y , Sahibzada N , Holt DP , Kellar KJ , Pletnikov MV , Pomper MG , Wong DF , Dannals RF
Ref : J Nucl Med , 55 :672 , 2014
Abstract : The alpha7-nicotinic cholinergic receptor (alpha7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for alpha7-nAChR are suitable for quantitative PET imaging, mostly because of insufficient specific binding. The goal of this study was to evaluate the potential of (18)F-ASEM ((18)F-JHU82132) as an alpha7-nAChR radioligand for PET.
METHODS: The inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of (18)F-ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET).
RESULTS: ASEM is an antagonist for the alpha7-nAChR with high binding affinity (Ki = 0.3 nM). (18)F-ASEM readily entered the baboon brain and specifically labeled alpha7-nAChR. The in vivo specific binding of (18)F-ASEM in the brain regions enriched with alpha7-nAChRs was 80%-90%. SSR180711, an alpha7-nAChR-selective partial agonist, blocked (18)F-ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of (18)F-ASEM was mediated by alpha7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for (18)F-ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus), and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of (18)F-ASEM and alpha7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous postmortem human data. CONCLUSION: (18)F-ASEM holds promise as a radiotracer with suitable imaging properties for quantification of alpha7-nAChR in the human brain.
ESTHER : Horti_2014_J.Nucl.Med_55_672
PubMedSearch : Horti_2014_J.Nucl.Med_55_672
PubMedID: 24556591

Title : Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A - Liu_2014_Bioorg.Med.Chem.Lett_24_2954
Author(s) : Liu Y , Paige M , Olson TT , Al-Muhtasib N , Xie T , Hou S , White MP , Cordova A , Guo JL , Kellar KJ , Xiao Y , Brown ML
Ref : Bioorganic & Medicinal Chemistry Lett , 24 :2954 , 2014
Abstract : The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its' bioisostere-the triazole via click chemistry, showed a high binding affinity to alpha4beta2 subtype (Ki=1.3 nM) and better selectivity to the alpha4beta2 subtype over alpha3beta4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a 'long tail' side chain for alpha4beta2 nAChR binding.
ESTHER : Liu_2014_Bioorg.Med.Chem.Lett_24_2954
PubMedSearch : Liu_2014_Bioorg.Med.Chem.Lett_24_2954
PubMedID: 24844195

Title : Design, synthesis and discovery of picomolar selective alpha4beta2 nicotinic acetylcholine receptor ligands - Yenugonda_2013_J.Med.Chem_56_8404
Author(s) : Yenugonda VM , Xiao Y , Levin ED , Rezvani AH , Tran T , Al-Muhtasib N , Sahibzada N , Xie T , Wells C , Slade S , Johnson JE , Dakshanamurthy S , Kong HS , Tomita Y , Liu Y , Paige M , Kellar KJ , Brown ML
Ref : Journal of Medicinal Chemistry , 56 :8404 , 2013
Abstract : Developing novel and selective compounds that desensitize alpha4beta2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for alpha4beta2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes alpha4beta2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs.
ESTHER : Yenugonda_2013_J.Med.Chem_56_8404
PubMedSearch : Yenugonda_2013_J.Med.Chem_56_8404
PubMedID: 24047231

Title : Caffeoyl shikimate esterase (CSE) is an enzyme in the lignin biosynthetic pathway in Arabidopsis - Vanholme_2013_Science_341_1103
Author(s) : Vanholme R , Cesarino I , Rataj K , Xiao Y , Sundin L , Goeminne G , Kim H , Cross J , Morreel K , Araujo P , Welsh L , Haustraete J , McClellan C , Vanholme B , Ralph J , Simpson GG , Halpin C , Boerjan W
Ref : Science , 341 :1103 , 2013
Abstract : Lignin is a major component of plant secondary cell walls. Here we describe caffeoyl shikimate esterase (CSE) as an enzyme central to the lignin biosynthetic pathway. Arabidopsis thaliana cse mutants deposit less lignin than do wild-type plants, and the remaining lignin is enriched in p-hydroxyphenyl units. Phenolic metabolite profiling identified accumulation of the lignin pathway intermediate caffeoyl shikimate in cse mutants as compared to caffeoyl shikimate levels in the wild type, suggesting caffeoyl shikimate as a substrate for CSE. Accordingly, recombinant CSE hydrolyzed caffeoyl shikimate into caffeate. Associated with the changes in lignin, the conversion of cellulose to glucose in cse mutants increased up to fourfold as compared to that in the wild type upon saccharification without pretreatment. Collectively, these data necessitate the revision of currently accepted models of the lignin biosynthetic pathway.
ESTHER : Vanholme_2013_Science_341_1103
PubMedSearch : Vanholme_2013_Science_341_1103
PubMedID: 23950498
Gene_locus related to this paper: arath-F14G24.3

Title : Derivatives of dibenzothiophene for positron emission tomography imaging of alpha7-nicotinic acetylcholine receptors - Gao_2013_J.Med.Chem_56_7574
Author(s) : Gao Y , Kellar KJ , Yasuda RP , Tran T , Xiao Y , Dannals RF , Horti AG
Ref : Journal of Medicinal Chemistry , 56 :7574 , 2013
Abstract : A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) (Ki = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of alpha7-nAChRs. Two radiolabeled members of the series [(18)F]7a (Ki = 0.4 nM) and [(18)F]7c (Ki = 1.3 nM) were synthesized. [(18)F]7a and [(18)F]7c readily entered the mouse brain and specifically labeled alpha7-nAChRs. The alpha7-nAChR selective ligand 1 (SSR180711) blocked the binding of [(18)F]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-alpha7-nAChR central nervous system drugs demonstrated that [(18)F]7a is highly alpha7-nAChR selective. In agreement with its binding affinity the binding potential of [(18)F]7a (BPND = 5.3-8.0) in control mice is superior to previous alpha7-nAChR PET radioligands. Thus, [(18)F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of alpha7-nAChR in non-human primates.
ESTHER : Gao_2013_J.Med.Chem_56_7574
PubMedSearch : Gao_2013_J.Med.Chem_56_7574
PubMedID: 24050653

Title : Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice - Meeusen_2013_Neurogastroenterol.Motil_25_84
Author(s) : Meeusen JW , Haselkorn KE , Fryer JP , Kryzer TJ , Gibbons SJ , Xiao Y , Lennon VA
Ref : Neurogastroenterol Motil , 25 :84 , 2013
Abstract : BACKGROUND: Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic-acetylcholine receptors containing alpha3 subunits [alpha3*- nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant alpha3-polypeptide produce alpha3*-nAChR autoantibodies, and profound AGID ensues. Human and rabbit alpha3*-nAChR-specific-IgGs induce transient hypomotility when injected into mice. Here, we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization.
METHODS: We repeatedly injected young adult mice of seven different strains susceptible to autoimmunity (spontaneous diabetes or neural antigen immunization-induced myasthenia gravis or encephalomyelitis) with: (i) alpha3-polypeptide, intradermally or (ii) live alpha3*-nAChR-expressing xenogeneic cells, intraperitoneally. We measured serum alpha3*-nAChR-IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal alpha3*-nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal-jejunal whole-mount preparations). KEY
RESULTS: Standard cutaneous inoculation with alpha3-polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally injected live cells were potently immunogenic. Self-reactive alpha3*-nAChR-IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric alpha3*-nAChR loss required high serum levels. Ganglionic neurons were not lost. CONCLUSIONS & INFERENCES: Autoimmune gastrointestinal dysmotility is inducible in mice by active immunization. Accompanying enteric alpha3*-nAChR reduction without neuronal death is consistent with an IgG-mediated rather than T cell-mediated pathogenesis, as is improvement of symptoms in patients receiving antibody-depleting therapies.
ESTHER : Meeusen_2013_Neurogastroenterol.Motil_25_84
PubMedSearch : Meeusen_2013_Neurogastroenterol.Motil_25_84
PubMedID: 23072523

Title : Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor beta2-\/- and alpha7-\/- mice - Levin_2013_Eur.J.Pharmacol_718_167
Author(s) : Levin ED , Sexton HG , Gordon K , Gordon CJ , Xiao Y , Kellar KJ , Yenugonda VM , Liu Y , White MP , Paige M , Brown ML , Rezvani AH
Ref : European Journal of Pharmacology , 718 :167 , 2013
Abstract : Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an alpha4beta2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to beta2 subunit-containing nicotinic receptors, we tested its efficacy in beta2 knockout (beta2(-/-)) mice. These effects were compared with wildtype (WT) and alpha7 knockout (alpha7(-/-)) mice. Confirming our earlier results, sazetidine-A elicited a pronounced and long-lasting hypothermia in WT mice. In comparison, sazetidine-A induced a much attenuated and shorter hypothermic response in beta2(-/-) mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on beta2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-beta2 receptors. Similar to WT mice, alpha7(-/-) mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on alpha7 nicotinic receptor subtype. Three other novel nicotinic receptor desensitizing agents derived from sazetidine-A, triazetidine-O, VMY-2-95 and YL-1-127 also produced hypothermia in WT and alpha7(-/-) mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL-1-127 did not show any hint of a hypothermic effect in beta2(-/-) mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the beta2(-/-) mice. These studies show that the hypothermic effects of sazetidine-A and the related compound VMY-2-95 are mainly mediated by nicotinic receptors containing beta2 subunit, but that a small component of the effect is apparently mediated by non-beta2 containing receptors.
ESTHER : Levin_2013_Eur.J.Pharmacol_718_167
PubMedSearch : Levin_2013_Eur.J.Pharmacol_718_167
PubMedID: 24036108

Title : Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective alpha4beta2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats - Liu_2013_J.Med.Chem_56_3000
Author(s) : Liu Y , Richardson J , Tran T , Al-Muhtasib N , Xie T , Yenugonda VM , Sexton HG , Rezvani AH , Levin ED , Sahibzada N , Kellar KJ , Brown ML , Xiao Y , Paige M
Ref : Journal of Medicinal Chemistry , 56 :3000 , 2013
Abstract : Neuronal acetylcholine receptors mediate the addictive effects of nicotine and may also be involved in alcohol addiction. Varenicline, an approved smoking cessation medication, showed clear efficacy in reducing alcohol consumption in heavy-drinking smokers. More recently, sazetidine-A, which selectively desensitizes alpha4beta2 nicotinic receptors, was shown to significantly reduce alcohol intake in a rat model. To develop novel therapeutics for treating alcohol use disorder, we designed and synthesized novel sazetidine-A analogues containing a methyl group at the 2-position of the pyridine ring. In vitro pharmacological studies revealed that some of the novel compounds showed overall pharmacological property profiles similar to that of sazetidine-A but exhibited reduced agonist activity across all nicotinic receptor subtypes tested. In rat studies, compound (S)-9 significantly reduced alcohol uptake. More importantly, preliminary results from studies in a ferret model indicate that these novel nAChR ligands have an improved adverse side-effect profile in comparison with that of varenicline.
ESTHER : Liu_2013_J.Med.Chem_56_3000
PubMedSearch : Liu_2013_J.Med.Chem_56_3000
PubMedID: 23540678

Title : Effects of chronic sazetidine-A, a selective alpha4beta2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats - Rezvani_2013_Psychopharmacology.(Berl)_226_35
Author(s) : Rezvani AH , Cauley M , Xiao Y , Kellar KJ , Levin ED
Ref : Psychopharmacology (Berl) , 226 :35 , 2013
Abstract : RATIONALE: Nicotine and nicotinic agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all nicotinic agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of nicotinic agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at alpha4beta2 nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine.
METHODS: In the current study, we tested the effects of chronic subcutaneous infusion of sazetidine-A (0, 2, or 6 mg/kg/day) on attention in Sprague-Dawley rats. Furthermore, we investigated the effects of chronic sazetidine-A treatment on attentional impairment induced by an acute administration of 0.02 mg/kg scopolamine.
RESULTS: During the first week period, the 6-mg/kg/day sazetidine-A dose significantly reversed the attentional impairment induced by scopolamine. During weeks 3 and 4, the scopolamine-induced impairment was no longer seen, but sazetidine-A (6 mg/kg/day) significantly improved attentional performance on its own. Chronic sazetidine-A also reduced response latency and response omissions.
CONCLUSIONS: This study demonstrated that similar to its acute effects, chronic infusions of sazetidine-A improve attentional performance. The results indicate that the desensitization of alpha4beta2 nicotinic receptors with some activation of these receptors may play an important role in improving effects of sazetidine-A on attention.
ESTHER : Rezvani_2013_Psychopharmacology.(Berl)_226_35
PubMedSearch : Rezvani_2013_Psychopharmacology.(Berl)_226_35
PubMedID: 23100170

Title : Lhx8 promote differentiation of hippocampal neural stem\/progenitor cells into cholinergic neurons in vitro - Shi_2012_In.Vitro.Cell.Dev.Biol.Anim_48_603
Author(s) : Shi J , Li H , Jin G , Zhu P , Tian M , Qin J , Tan X , Zhao S , Wang F , Hua Y , Xiao Y
Ref : In Vitro Cell Developmental Biology Anim , 48 :603 , 2012
Abstract : Lhx8, also named L3, is a recently identified member of the LIM homeobox gene family. Previously, we found acetylcholinesterase (AChE)-positive cells in fimbria-fornix (FF) transected rat hippocampal subgranular zone (SGZ). In the present study, we detected choline acetyltransferase (ChAT)-positive cholinergic cells in hippocampal SGZ after FF transaction, and these ChAT-positive cells were double labeled by Lhx8. Then we overexpressed Lhx8 during neural differentiation of hippocampal neural stem/progenitor cells on adherent conditions using lentivirus Lenti6.3-Lhx8. The result indicated that overexpression of Lhx8 did not affect the proportion of MAP2-positive neurons, but increased the proportion of ChAT-positive cells in vitro. These results suggested that FF-transected hippocampal niche promoted the ChAT/Lhx8-positive cholinergic neurons generation in rodent hippocampus, and Lhx8 was not associated with the MAP2-positive neurons differentiation on adherent conditions, but played a role in the specification of cholinergic neurons derived from hippocampal neural stem/progenitor cells in vitro.
ESTHER : Shi_2012_In.Vitro.Cell.Dev.Biol.Anim_48_603
PubMedSearch : Shi_2012_In.Vitro.Cell.Dev.Biol.Anim_48_603
PubMedID: 23150137

Title : Imidacloprid affects Pardosa pseudoannulata adults and their unexposed offspring - Chen_2012_Bull.Environ.Contam.Toxicol_88_654
Author(s) : Chen XQ , Xiao Y , Wu LB , Chen Y , Peng Y
Ref : Bulletin of Environmental Contamination & Toxicology , 88 :654 , 2012
Abstract : Imidacloprid is a nicotine-based, systemic, widely used insecticide. In order to investigate the effects of imidacloprid on the spider Pardosa pseudoannulata (Araneae: Lycosidae), specimens were exposed to different concentrations of imidacloprid (12.5, 25, 50, 100, 200 mg/L) by the dipping method. Surviving spiders were used to determine the fecundity, development time of unexposed offspring, predation, and the activities of detoxification enzymes. Significant reductions were observed in survival rate and fecundity of spiders exposed to imidacloprid. The development times of unexposed offspring (F(1)) were prolonged significantly with increased concentrations of imidacloprid. Spiders exposed to concentrations of imidacloprid above 25 mg/L showed significantly weaker predation on Drosophila melanogaster than the control group, but a low dose of imidacloprid (12.5 mg/L) increased predation ability. The activities of carboxyl esterase, acetyl cholinesterase, and the mixed-function oxidase were significantly inhibited by imidacloprid. With increasing concentrations of imidacloprid, the activities of all three kinds of enzymes were decreased significantly. These results suggest that imidacloprid can stimulate the performance of spiders (in low concentration) and has chronic toxicity to the spiders.
ESTHER : Chen_2012_Bull.Environ.Contam.Toxicol_88_654
PubMedSearch : Chen_2012_Bull.Environ.Contam.Toxicol_88_654
PubMedID: 22395200

Title : Correlations between cholinesterase activity and cognitive scores in post-ischemic rats and patients with vascular dementia - Xiao_2012_Cell.Mol.Neurobiol_32_399
Author(s) : Xiao Y , Guan ZZ , Wu CX , Li Y , Kuang SX , Pei JJ
Ref : Cellular Molecular Neurobiology , 32 :399 , 2012
Abstract : The biochemical changes such as the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were investigated in rats with global cerebral ischemia and in vascular dementia (VaD) subjects in this study. The AChE activity showed a significant decrease in plasma and a significant increase in the hippocampus but not in the cerebral cortices in the post-ischemic rats as compared to the controls. The learning abilities and spatial memory were impaired in the post-ischemic rats as compared to controls. Furthermore, the AChE activity in plasma was significantly reduced in VaD subjects as compared to normal control subjects. The BuChE activity did not show any change in both post-ischemic rats and VaD patients. Interestingly, the decreased AChE activity in plasma from the post-ischemic rats and the VaD subjects showed a significant correlation with the declined learning and memory ability, and the Mini-Mental State Examination score, respectively. These data suggest that the AChE activity is involved in the cognitive recovery after ischemia, and the plasma level of AChE might be a reliable supplementary peripheral biomarker to evaluate the cognitive recovery degree of VaD patients.
ESTHER : Xiao_2012_Cell.Mol.Neurobiol_32_399
PubMedSearch : Xiao_2012_Cell.Mol.Neurobiol_32_399
PubMedID: 22090160

Title : Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain - Hussmann_2012_J.Pharmacol.Exp.Ther_343_441
Author(s) : Hussmann GP , Turner JR , Lomazzo E , Venkatesh R , Cousins V , Xiao Y , Yasuda RP , Wolfe BB , Perry DC , Rezvani AH , Levin ED , Blendy JA , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 343 :441 , 2012
Abstract : Chronic nicotine administration increases alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This up-regulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at alpha4beta2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were approximately 150 times its affinity for alpha4beta2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not up-regulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all alpha4beta2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.
ESTHER : Hussmann_2012_J.Pharmacol.Exp.Ther_343_441
PubMedSearch : Hussmann_2012_J.Pharmacol.Exp.Ther_343_441
PubMedID: 22899752

Title : Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats - Johnson_2012_Psychopharmacology.(Berl)_222_269
Author(s) : Johnson JE , Slade S , Wells C , Petro A , Sexton H , Rezvani AH , Brown ML , Paige MA , McDowell BE , Xiao Y , Kellar KJ , Levin ED
Ref : Psychopharmacology (Berl) , 222 :269 , 2012
Abstract : RATIONALE: Sazetidine-A is a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined. OBJECTIVES: This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4 weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.
METHODS: Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for 4 weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2 weeks of infusion followed by 1 week of forced abstinence from nicotine and 1 week of resumed nicotine access.
RESULTS: The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p < 0.001) and female (p < 0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p < 0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the 4-week treatment. In the vehicle control group, male rats self-administered significantly (p < 0.001) more nicotine than females.
CONCLUSIONS: The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.
ESTHER : Johnson_2012_Psychopharmacology.(Berl)_222_269
PubMedSearch : Johnson_2012_Psychopharmacology.(Berl)_222_269
PubMedID: 22297831

Title : Effects of sazetidine-A, a selective alpha4beta2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats - Rezvani_2012_Eur.J.Pharmacol_682_110
Author(s) : Rezvani AH , Timofeeva O , Sexton HG , DeCuir D , Xiao Y , Gordon CJ , Kellar KJ , Levin ED
Ref : European Journal of Pharmacology , 682 :110 , 2012
Abstract : Nicotine-induced hypothermia is well established, but the nicotinic receptor actions underlying this effect are not clear. Nicotine causes activation and desensitization at a variety of nicotinic receptor subtypes. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2* nicotinic receptors. The main goal of this study was to investigate the effects of sazetidine-A, on core body temperature (Tc) in mice and rats. Sazetidine-A effects on Tc and the interactions of sazetidine-A with nicotine and selective nicotinic antagonists were investigated to determine the receptor actions underlying nicotine-induced hypothermia. Adult male mice were injected with different dose of nicotine (0.2, 0.4 and 0.8 mg/kg), sazetidine-A (0.3, 1, and 3mg/kg), a mixture of nicotine (0.4 or 0.8 mg/kg) and sazetidine-A (0.3 or 0.6 mg/kg) or saline and Tc was monitored telemetrically. In another set of experiments, the interaction between sazetidine-A and dihydro-beta-erythroidine (DHbetaE), an alpha4beta2* nicotinic receptors antagonist, and methyllycaconitine (MLA), an alpha7 antagonist, was investigated. Tc of mice was monitored following DHbetaE (1, 3 and 6 mg/kg), a combination of DHbetaE (3mg/kg) and sazetidine-A (0.6 mg/kg), MLA (1.5, 3 or 6 mg/kg) or combination of MLA (6 mg/kg) and sazetidine (0.6 mg/kg) or saline. The acute effect of sazetidine-A (1, 3, and 6 mg/kg) on rats Tc was also studied. Acute sazetidine-A caused a pronounced and long-lasting hypothermia in mice; Tc decreased to about 28 degrees C at 100 min and recovered within 230 min. The hypothermic effect of sazetidine in rats was much less in magnitude (about 3 degrees C) and shorter in duration compared with that in mice. Nicotine co-administration with low doses of sazetidine potentiated the magnitude and duration of hypothermia in mice. The alpha4beta2* nicotinic receptors antagonist DHbetaE significantly prolonged sazetidine-A-induced hypothermia but did not increase its depth. The alpha7 antagonist MLA caused a modest degree of hypothermia with relatively short duration in mice. MLA failed to counteract the sazetidine-A-induced hypothermia. Overall, our results show that pharmacological modulation of alpha4beta2* nicotinic receptors elicits changes in body temperature that may involve desensitization of these receptors.
ESTHER : Rezvani_2012_Eur.J.Pharmacol_682_110
PubMedSearch : Rezvani_2012_Eur.J.Pharmacol_682_110
PubMedID: 22387853

Title : Genome sequence of duck pathogen Mycoplasma anatis strain 1340 - Guo_2011_J.Bacteriol_193_5883
Author(s) : Guo Z , Chen P , Ren P , Kuang S , Zhou Z , Li Z , Liu M , Shi D , Xiao Y , Wang X , Zhou R , Jin H , Bi D
Ref : Journal of Bacteriology , 193 :5883 , 2011
Abstract : Mycoplasma anatis, a member of the class Mollicutes, is the causative agent of a contagious infectious disease of domestic ducklings, wild birds, and eggs. Increasing reports show that coinfection of M. anatis with Escherichia coli results in substantial economic impacts on the duck farms in China. Here, we announce the first genome sequence of M. anatis.
ESTHER : Guo_2011_J.Bacteriol_193_5883
PubMedSearch : Guo_2011_J.Bacteriol_193_5883
PubMedID: 21952548

Title : Endogenously expressed muscarinic receptors in HEK293 cells augment up-regulation of stably expressed alpha4beta2 nicotinic receptors - Hussmann_2011_J.Biol.Chem_286_39726
Author(s) : Hussmann GP , Yasuda RP , Xiao Y , Wolfe BB , Kellar KJ
Ref : Journal of Biological Chemistry , 286 :39726 , 2011
Abstract : Nicotine-induced up-regulation of neuronal nicotinic receptors (nAChRs) has been known and studied for more than 25 years. Other nAChR ligands can also up-regulate nAChRs, but it is not known if these ligands induce up-regulation by mechanisms similar to that of nicotine. In this study, we compared up-regulation by three different nicotinic agonists and a competitive antagonist of several different nAChR subtypes expressed in HEK293 cells. Nicotine markedly increased alpha4beta2 nAChR binding site density and beta2 subunit protein. Carbachol, a known nAChR and muscarinic receptor agonist, up-regulated both alpha4beta2 nAChR binding sites and subunit protein 2-fold more than did nicotine. This increased up-regulation was shown pharmacologically to involve endogenously expressed muscarinic receptors, and stimulation of these muscarinic receptors also correlated with a 2-fold increase in alpha4 and beta2 mRNA. Muscarinic receptor activation in these cells appears to affect CMV promoter activity only minimally ( approximately 1.2 fold), suggesting that the increase in alpha4 and beta2 nAChR mRNA may not be dependent on enhanced transcription. Instead, other mechanisms may contribute to the increase in mRNA and a consequent increase in receptor subunits and binding site density. These studies demonstrate the possibility of augmenting nAChR expression in a cell model through mechanisms and targets other than the nAChR receptor itself.
ESTHER : Hussmann_2011_J.Biol.Chem_286_39726
PubMedSearch : Hussmann_2011_J.Biol.Chem_286_39726
PubMedID: 21940627

Title : Poster: Pharmacological properties of sazetidine A, a selective ligand of alpha4\/beta2 nicotinic acetylcholine receptors -
Author(s) : Xiao Y , Tuan E , Yasuda RP , Sahibzada N , Wolfe BB , Horton L , Tran T , Al-Muhtasib N , Iwueze AF , Dipietro JR , Xie T , Paige M , Brown ML , Kellar KJ
Ref : Biochemical Pharmacology , 82 :1029 , 2011

Title : Genome sequence of poultry pathogen Riemerella anatipestifer strain RA-YM - Zhou_2011_J.Bacteriol_193_1284
Author(s) : Zhou Z , Peng X , Xiao Y , Wang X , Guo Z , Zhu L , Liu M , Jin H , Bi D , Li Z , Sun M
Ref : Journal of Bacteriology , 193 :1284 , 2011
Abstract : Riemerella anatipestifer is a Gram-negative, rod-shaped bacterium associated with epizootic infections in poultry. R. anatipestifer strain RA-YM, belonging to the serotype 1 prevalent in China, is a clinically isolated strain with high-level virulence. Here, we report the first genome sequence of this species.
ESTHER : Zhou_2011_J.Bacteriol_193_1284
PubMedSearch : Zhou_2011_J.Bacteriol_193_1284
PubMedID: 21183670
Gene_locus related to this paper: riean-e6jgw6 , riean-e6jh69 , riean-e6jim0

Title : Sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats - Rezvani_2011_Psychopharmacology.(Berl)_215_621
Author(s) : Rezvani AH , Cauley M , Sexton H , Xiao Y , Brown ML , Paige MA , McDowell BE , Kellar KJ , Levin ED
Ref : Psychopharmacology (Berl) , 215 :621 , 2011
Abstract : BACKGROUND: Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of alpha4beta2 nicotinic receptors in sustained attention using a novel selective alpha4beta2 nicotinic receptor ligand, sazetidine-A.
METHODS: Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination.
RESULTS: Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration.
CONCLUSIONS: These studies imply an important role for alpha4beta2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.
ESTHER : Rezvani_2011_Psychopharmacology.(Berl)_215_621
PubMedSearch : Rezvani_2011_Psychopharmacology.(Berl)_215_621
PubMedID: 21274704

Title : Cholinesterase activity and mRNA level of nicotinic acetylcholine receptors (alpha4 and beta2 Subunits) in blood of elderly Chinese diagnosed as Alzheimer's disease - Zhang_2010_J.Alzheimers.Dis_19_849
Author(s) : Zhang LJ , Xiao Y , Qi XL , Shan KR , Pei JJ , Kuang SX , Liu F , Guan ZZ
Ref : J Alzheimers Dis , 19 :849 , 2010
Abstract : The aim of the study is to investigate the cholinergic deficit in Alzheimer's disease (AD) and identify candidate blood biomarkers for the diagnosis of the disease. Twenty-nine elderly Chinese diagnosed with AD and 33 age-matched controls were selected. The activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in plasma were detected by a spectrophotometric method, and the mRNA levels of alpha4 and beta2 nicotinic acetylcholine receptor (nAChR) subunits in blood leukocytes were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that AChE activity in plasma was significantly lower in the AD group than in normal controls, while BuChE activity did not show any differences between AD and controls; mRNA levels of both alpha4 and beta2 nAChR subunits in blood leukocytes were significantly lower in the AD group than in controls. The AChE activity and the mRNA levels of alpha4 and beta2 nAChR subunits in the AD patients were also significantly correlated with cognitive test scores. No differences of AChE in plasma or alpha4 and beta2 nAChR subunits in blood leukocytes were detected between smoking and non-smoking subjects. The results indicated that the decreases in the activity of AChE and in the mRNA levels of nAChR alpha4 and beta2 subunits from the peripheral blood of patients with AD might serve as supplementary indicators for the clinical diagnosis of AD.
ESTHER : Zhang_2010_J.Alzheimers.Dis_19_849
PubMedSearch : Zhang_2010_J.Alzheimers.Dis_19_849
PubMedID: 20157241

Title : Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats - Levin_2010_J.Pharmacol.Exp.Ther_332_933
Author(s) : Levin ED , Rezvani AH , Xiao Y , Slade S , Cauley M , Wells C , Hampton D , Petro A , Rose JE , Brown ML , Paige MA , McDowell BE , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 332 :933 , 2010
Abstract : Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha4beta2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha4beta2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.
ESTHER : Levin_2010_J.Pharmacol.Exp.Ther_332_933
PubMedSearch : Levin_2010_J.Pharmacol.Exp.Ther_332_933
PubMedID: 20007754

Title : Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats - Rezvani_2010_Psychopharmacology.(Berl)_211_161
Author(s) : Rezvani AH , Slade S , Wells C , Petro A , Lumeng L , Li TK , Xiao Y , Brown ML , Paige MA , McDowell BE , Rose JE , Kellar KJ , Levin ED
Ref : Psychopharmacology (Berl) , 211 :161 , 2010
Abstract : RATIONALE: Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation. OBJECTIVES: The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.
METHODS: P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed.
RESULTS: Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.
CONCLUSIONS: Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.
ESTHER : Rezvani_2010_Psychopharmacology.(Berl)_211_161
PubMedSearch : Rezvani_2010_Psychopharmacology.(Berl)_211_161
PubMedID: 20535453

Title : [18F]ZW-104, a new radioligand for imaging alpha2-alpha3-alpha4\/beta2 central nicotinic acetylcholine receptors: Evaluation in mutant mice -
Author(s) : Saba W , Valette H , Granon S , Xiao Y , Kellar KJ , Dolle F , Bottlaender M
Ref : Synapse , 64 :570 , 2010
PubMedID: 20222155

Title : 18F-ZW-104: a new radioligand for imaging neuronal nicotinic acetylcholine receptors--in vitro binding properties and PET studies in baboons - Valette_2009_J.Nucl.Med_50_1349
Author(s) : Valette H , Xiao Y , Peyronneau MA , Damont A , Kozikowski AP , Wei ZL , Kassiou M , Kellar KJ , Dolle F , Bottlaender M
Ref : J Nucl Med , 50 :1349 , 2009
Abstract : An extensive series of radioligands has been developed for imaging central nicotinic acetylcholine receptors (nAChRs) with PET. Two halogeno-derivatives of A-85380 are being used in humans. Nevertheless, these derivatives still display too-slow brain kinetics and low signal-to-noise ratio.
METHODS: A novel nAChR radioligand, 5-(6-fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy]pyridine (ZW-104), was characterized in vitro using competition binding assays (nAChR subtypes heterologously expressed in HEK 293 cells and in native alpha4beta2 nAChRs from rat brain). (18)F-ZW-104 was prepared as follows: no-carrier-added nucleophilic aliphatic radiofluorination of the corresponding N-Boc-protected tosyloxy derivative 5-(6-tosyloxyhexyn-1-yl)-3-[2(S)-(N-(tert-butoxycarbonyl))-2-azetidinylmethoxy] pyridine) with the activated 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]hexacosane (K-(18)F-F-Kryptofix 222 [K(222)] complex), followed by quantitative trifluoroacetic acid-induced removal of the N-Boc protective group. (18)F-ZW-104 was then studied in baboons using PET.
RESULTS: ZW-104 showed high binding affinities for rat alpha4beta2 nAChRs (K(i), 0.2 nM) and other subtypes containing the beta2 subunit but much lower affinities for rat alpha3beta4 nAChRs (K(i), 5,500 nM) and other subtypes containing the beta4 subunit. The regional radioactivity distribution in the baboon brain matched that of the alpha4beta2 nAChR, which was similar to that of 2-(18)F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-(18)F-A-85380), a radioligand used in humans. Comparison between (18)F-ZW-104 and 2-(18)F-A-85380 demonstrated better in vivo binding properties of the new radioligand: a substantially greater amount of radioactivity accumulated in the brain, and the occurrence of peak uptake in the thalamus was earlier than that of 2-(18)F-A-85380 and was followed by washout. Distribution volume values in different brain regions were 2-fold higher for (18)F-ZW-104 than for 2-(18)F-A-85380. Displacement by nicotine or unlabeled ZW-104 demonstrated a lower nonspecific binding than that of 2-F-A-85380. CONCLUSION: These results suggest that (18)F-ZW-104 is a promising PET radioligand for studying nAChRs containing the beta2 subunits in humans.
ESTHER : Valette_2009_J.Nucl.Med_50_1349
PubMedSearch : Valette_2009_J.Nucl.Med_50_1349
PubMedID: 19652217

Title : Cumulated advantages of enzymatic and carbene chemistry for the non-organometallic synthesis of (co)polyesters - Xiao_2009_Chem.Commun.(Camb)__2472
Author(s) : Xiao Y , Coulembier O , Koning CE , Heise A , Dubois P
Ref : Chem Commun (Camb) , :2472 , 2009
Abstract : Enzymatic and carbene catalysed ring opening polymerisation can be combined in a one-pot reaction for the metal-free synthesis of degradable block copolymers.
ESTHER : Xiao_2009_Chem.Commun.(Camb)__2472
PubMedSearch : Xiao_2009_Chem.Commun.(Camb)__2472
PubMedID: 19532860

Title : Rat neuronal nicotinic acetylcholine receptors containing alpha7 subunit: pharmacological properties of ligand binding and function - Xiao_2009_Acta.Pharmacol.Sin_30_842
Author(s) : Xiao Y , Abdrakhmanova GR , Baydyuk M , Hernandez S , Kellar KJ
Ref : Acta Pharmacol Sin , 30 :842 , 2009
Abstract : AIM: To compare pharmacological properties of heterologously expressed homomeric alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) with those of native nAChRs containing alpha7 subunit (alpha7* nAChRs) in rat hippocampus and cerebral cortex.
METHODS: We established a stably transfected HEK-293 cell line that expresses homomeric rat alpha7 nAChRs. We studies ligand binding profiles and functional properties of nAChRs expressed in this cell line and native rat alpha7* nAChRs in rat hippocampus and cerebral cortex. We used [(125)I]-alpha-bungarotoxin to compare ligand binding profiles in these cells with those in rat hippocampus and cerebral cortex. The functional properties of the alpha7 nAChRs expressed in this cell line were studied using whole-cell current recording.
RESULTS: The newly established cell line, KXalpha7R1, expresses homomeric alpha7 nAChRs that bind [(125)I]-alpha-bungarotoxin with a K(d) value of 0.38+/-0.06 nmol/L, similar to K(d) values of native rat alpha7* nAChRs from hippocampus (K(d)=0.28+/-0.03 nmol/L) and cerebral cortex (K(d)=0.33+/-0.05 nmol/L). Using whole-cell current recording, the homomeric alpha7 nAChRs expressed in the cells were activated by acetylcholine and (-)-nicotine with EC(50) values of 280+/-19 micromol/L and 180+/-40 micromol/L, respectively. The acetylcholine activated currents were potently blocked by two selective antagonists of alpha7 nAChRs, alpha-bungarotoxin (IC(50)=19+/-2 nmol/L) and methyllycaconitine (IC(50)=100+/-10 pmol/L). A comparative study of ligand binding profiles, using 13 nicotinic ligands, showed many similarities between the homomeric alpha7 nAChRs and native alpha7* receptors in rat brain, but it also revealed several notable differences. CONCLUSION: This newly established stable cell line should be very useful for studying the properties of homomeric alpha7 nAChRs and comparing these properties to native alpha7* nAChRs.
ESTHER : Xiao_2009_Acta.Pharmacol.Sin_30_842
PubMedSearch : Xiao_2009_Acta.Pharmacol.Sin_30_842
PubMedID: 19448648

Title : Systematic comparison of HEA and HEMA as initiators in enzymatic ring-opening polymerizations - Xiao_2009_Macromol.Biosci_9_713
Author(s) : Xiao Y , Takwa M , Hult K , Koning CE , Heise A , Martinelle M
Ref : Macromol Biosci , 9 :713 , 2009
Abstract : Two initiators containing a cleavable ester bond were compared in the lipase-catalyzed ROP of CL and PDL. The results show that transesterification reactions are present at high rates throughout the enzymatic ROP and start at low conversion. HEA and HEMA displayed similar reaction efficiencies as initiators (acyl acceptors) in the enzymatic ROP. However, transacylation reactions on the HEA-initiated polyesters were found to be 15 times faster. While in both cases the amount of HEA- and HEMA-initiated polymers could be maximized by short reaction times, a well-defined (meth)acrylation by this approach was not possible. Our results show that transesterification reactions have to be considered when performing an enzyme-catalyzed ROP.
ESTHER : Xiao_2009_Macromol.Biosci_9_713
PubMedSearch : Xiao_2009_Macromol.Biosci_9_713
PubMedID: 19242919
Gene_locus related to this paper: canar-LipB

Title : A novel fluorescent alpha-conotoxin for the study of alpha7 nicotinic acetylcholine receptors - Hone_2009_J.Neurochem_111_80
Author(s) : Hone AJ , Whiteaker P , Christensen S , Xiao Y , Meyer EL , McIntosh JM
Ref : Journal of Neurochemistry , 111 :80 , 2009
Abstract : Homomeric alpha7 nicotinic acetylcholine receptors are a well-established, pharmacologically distinct subtype. The more recently identified alpha9 subunit can also form functional homopentamers as well as alpha9alpha10 heteropentamers. Current fluorescent probes for alpha7 nicotinic ACh receptors are derived from alpha-bungarotoxin (alpha-BgTx). However, alpha-BgTx also binds to alpha9* and alpha1* receptors which are coexpressed with alpha7 in multiple tissues. We used an analog of alpha-conotoxin ArIB to develop a highly selective fluorescent probe for alpha7 receptors. This fluorescent alpha-conotoxin, Cy3-ArIB[V11L;V16A], blocked ACh-evoked alpha7 currents in Xenopus laevis oocytes with an IC(50) value of 2.0 nM. Observed rates of blockade were minute-scale with recovery from blockade even slower. Unlike FITC-conjugated alpha-BgTx, Cy3-ArIB[V11L;V16A] did not block alpha9alpha10 or alpha1beta1deltaepsilon receptors. In competition binding assays, Cy3-ArIB[V11L;V16A] potently displaced [(125)I]-alpha-BgTx binding to mouse hippocampal membranes with a K(i) value of 21 nM. Application of Cy3-ArIB[V11L;V16A] resulted in specific punctate labeling of KXalpha7R1 cells but not KXalpha3beta2R4, KXalpha3beta4R2, or KXalpha4beta2R2 cells. This labeling could be abolished by pre-treatment with alpha-cobratoxin. Thus, Cy3-ArIB[V11L;V16A] is a novel and selective fluorescent probe for alpha7 receptors.
ESTHER : Hone_2009_J.Neurochem_111_80
PubMedSearch : Hone_2009_J.Neurochem_111_80
PubMedID: 19650873

Title : Toxicological analysis of low-nicotine and nicotine-free cigarettes - Chen_2008_Toxicology_249_194
Author(s) : Chen J , Higby R , Tian D , Tan D , Johnson MD , Xiao Y , Kellar KJ , Feng S , Shields PG
Ref : Toxicology , 249 :194 , 2008
Abstract : Low-nicotine and nicotine-free cigarettes are commercially available under the brand-name Quest. Some consumers may believe that these are safer cigarettes, and they may smoke more cigarettes or inhale more smoke to compensate for low nicotine yields. Thus, we have studied the toxicological effects of these two cigarettes and compared them with the Kentucky reference cigarette 2R4F. Also, the availability of nicotine-free cigarettes allows for the assessing the role of nicotine in cigarette smoke. In addition to nicotine, some tobacco-specific nitrosamines, aldehydes, and volatile organic compounds were also reduced in the Quest cigarettes compared to the 2R4F. However, aromatic amines were higher in the nicotine-free compared with low nicotine cigarettes. The Ames test revealed that cigarette smoke condensates from the nicotine-free (CSC-F), low nicotine (CSC-L) and 2R4F (CSC-R) cigarettes had a similar mutagenic potency. Exposure to any CSC caused a similar dose-dependent LDH leakage from normal human bronchial epithelial cells. However, CSC-F had more inhibitory effects on the cell growth than CSC-L and CSC-R. Adding nicotine to the CSC-F attenuated this inhibition. Both Quest CSCs decreased gap junction intercellular communication and caused cell cycle arrest. CSC exposure increased cytoplasmic nucleosomes, sub-G1/G0 population and apoptotic comet tails. Proapoptotic protein Bax increased independent of p53 induction after exposure to CSC-F. In conclusion, these studies are not consistent with a perception that low-nicotine or nicotine-free cigarettes may have less toxicity in human cells. Nicotine, as it exists in CSC, attenuates cytotoxicity possibly in part through inhibition of apoptotic pathways.
ESTHER : Chen_2008_Toxicology_249_194
PubMedSearch : Chen_2008_Toxicology_249_194
PubMedID: 18599178

Title : Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug - Cucchiaro_2008_Anesthesiology_109_512
Author(s) : Cucchiaro G , Xiao Y , Gonzalez-Sulser A , Kellar KJ
Ref : Anesthesiology , 109 :512 , 2008
Abstract : BACKGROUND: The use of nicotinic agonists for analgesia is limited by their unacceptable side effects. Sazetidine-A is a new partial agonist nicotinic ligand that has very high selectivity for beta2-containing nicotinic acetylcholine receptors. It potently and selectively desensitizes alpha4beta2 nicotinic acetylcholine receptors without measurable effects on alpha3beta4 receptors. The authors investigated the analgesic effects of Sazetidine-A using the formalin model of chronic inflammatory pain.
METHODS: The formalin test was conducted after rats received intraperitoneal saline, Sazetidine-A (0.125, 0.25, 0.5, 1, 2 mg/kg), or subcutaneous epibatidine (2.5-5-10 mug/kg). In other experiments, Sazetidine-A was preceded by naloxone (0.5 mg/kg) or mecamylamine (10 mg). Effects of Sazetidine-A and epibatidine on locomotor were tested in an open field, and seizure activity was measured using the Racine scale. Locus coeruleus neuron extracellular single-unit spontaneous discharge was recorded in anesthetized animals after Sazetidine-A and epibatidine.
RESULTS: Higher doses of Sazetidine-A (0.5, 1, or 2 mg/kg) induced analgesia, with pain scores significantly lower than those seen after saline, lower doses of Sazetidine-A, and epibatidine (P < 0.001). Naloxone did not antagonize the effects of Sazetidine-A, and mecamylamine had partial, dose-dependent antagonistic effects. Epibatidine excited locus coeruleus neurons, whereas Sazetidine-A had no effect on these neurons. Epibatidine and Sazetidine-A affected animals' locomotor activity for the initial 20 min. While analgesic doses of epibatidine caused seizures, no seizure activity or other neurologic complications were seen in animals that received as much as four times the minimum analgesic dose of Sazetidine-A.
CONCLUSIONS: Sazetidine-A seems to be a potent analgesic without causing neurologic side effects.
ESTHER : Cucchiaro_2008_Anesthesiology_109_512
PubMedSearch : Cucchiaro_2008_Anesthesiology_109_512
PubMedID: 18719450

Title : Discovery of (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2 .1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties - Gao_2008_J.Med.Chem_51_4751
Author(s) : Gao Y , Kuwabara H , Spivak CE , Xiao Y , Kellar K , Ravert HT , Kumar A , Alexander M , Hilton J , Wong DF , Dannals RF , Horti AG
Ref : Journal of Medicinal Chemistry , 51 :4751 , 2008
Abstract : Several isomers of 7-methyl-2-exo-([(18)F]fluoropyridinyl-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are beta-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D7.4= 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2- exo-[3'-(6-[(18)F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D 7.4 = 0.99) exhibited optimal brain kinetics. [(18)F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an alpha4beta2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)- 6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans.
ESTHER : Gao_2008_J.Med.Chem_51_4751
PubMedSearch : Gao_2008_J.Med.Chem_51_4751
PubMedID: 18605717

Title : Lipase catalyzed HEMA initiated ring-opening polymerization: in situ formation of mixed polyester methacrylates by transesterification - Takwa_2008_Biomacromolecules_9_704
Author(s) : Takwa M , Xiao Y , Simpson N , Malmstrom E , Hult K , Koning CE , Heise A , Martinelle M
Ref : Biomacromolecules , 9 :704 , 2008
Abstract : 2-Hydroxyethyl methacrylate (HEMA) was used as initiator for the enzymatic ring-opening polymerization (ROP) of omega-pentadecalactone (PDL) and epsilon-caprolactone (CL). The lipase B from Candida antarctica was found to catalyze the cleavage of the ester bond in the HEMA end group of the formed polyesters, resulting in two major transesterification processes, methacrylate transfer and polyester transfer. This resulted in a number of different polyester methacrylate structures, such as polymers without, with one, and with two methacrylate end groups. Furthermore, the 1,2-ethanediol moiety (from HEMA) was found in the polyester products as an integral part of HEMA, as an end group (with one hydroxyl group) and incorporated within the polyester (polyester chains acylated on both hydroxyl groups). After 72 h, as a result of the methacrylate transfer, 79% (48%) of the initial amount of the methacrylate moiety (from HEMA) was situated (acylated) on the end hydroxyl group of the PPDL (PCL) polyester. In order to prepare materials for polymer networks, fully dimethacrylated polymers were synthesized in a one-pot procedure by combining HEMA-initiated ROP with end-capping using vinyl methacrylate. The novel PPDL dimethacrylate (>95% incorporated methacrylate end groups) is currently in use for polymer network formation. Our results show that initiators with cleavable ester groups are of limited use to obtain well-defined monomethacrylated macromonomers due to the enzyme-based transesterification processes. On the other hand, when combined with end-capping, well-defined dimethacrylated polymers (PPDL, PCL) were prepared.
ESTHER : Takwa_2008_Biomacromolecules_9_704
PubMedSearch : Takwa_2008_Biomacromolecules_9_704
PubMedID: 18198845
Gene_locus related to this paper: canar-LipB

Title : Initial synthesis and characterization of an alpha7 nicotinic receptor cellular membrane affinity chromatography column: effect of receptor subtype and cell type - Moaddel_2008_Anal.Chem_80_48
Author(s) : Moaddel R , Oliveira RV , Kimura T , Hyppolite P , Juhaszova M , Xiao Y , Kellar KJ , Bernier M , Wainer IW
Ref : Analytical Chemistry , 80 :48 , 2008
Abstract : In this study, cellular membrane fragments from SH-EP1-pCEP4-halpha7 and alpha7 HEK-293 cell lines were used to synthesize cellular membrane affinity chromatography (CMAC) columns containing functional alpha7 nicotinic acetylcholine receptors, CMAC(alpha7 nAChR) columns. The synthesis of stable columns required the addition of cholesterol to the 2% cholate solubilization/immobilization (s/i) buffer and to the mobile phase. In addition, when membranes from the SH-EP1 cell line were used, l-alpha-phosphatidylserine and l-alpha-phosphatidylethanolamine also had to be added to the s/i buffer. A CMAC(alpha4beta2 nAChR) column was prepared using membrane fragments from a SH-EP1-pCEP4-halpha4beta2 cell line, and this process required the addition of l-alpha-phosphatidylserine and l-alpha-phosphatidylethanolamine to the s/i buffer, but not cholesterol. The s/i buffers from the three columns were compared with the s/i buffer utilized in the preparation of a CMAC(alpha4beta2 nAChR) column prepared using an alpha4beta2 HEK-293 cell line, which required no additions to the 2% cholate s/i buffer. The data demonstrate that both cell type and receptor type affect the protocol required to produce a stable CMAC column and that, at the current time, the development of an optimum immobilization protocol is an empirical process. The results are also consistent with the observation that the alpha7 nAChR is localized in lipid rafts in both of these cell lines and that the cholate detergent removed cholesterol from these microdomains.
ESTHER : Moaddel_2008_Anal.Chem_80_48
PubMedSearch : Moaddel_2008_Anal.Chem_80_48
PubMedID: 18062706

Title : Effects of statins on alpha7 nicotinic receptor, cholinesterase and alpha-form of secreted amyloid precursor peptide in SH-SY5Y cells - Roensch_2007_Neurochem.Int_50_800
Author(s) : Roensch J , Crisby M , Nordberg A , Xiao Y , Zhang LJ , Guan ZZ
Ref : Neurochem Int , 50 :800 , 2007
Abstract : In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.
ESTHER : Roensch_2007_Neurochem.Int_50_800
PubMedSearch : Roensch_2007_Neurochem.Int_50_800
PubMedID: 17412455

Title : Acetylenic pyridines for use in PET imaging of nicotinic receptors -
Author(s) : Kozikowski AP , Chellappan SK , Henderson D , Fulton R , Giboureau N , Xiao Y , Wei ZL , Guilloteau D , Emond P , Dolle F , Kellar KJ , Kassiou M
Ref : ChemMedChem , 2 :54 , 2007
PubMedID: 17096450

Title : Chemical medicine: novel 10-substituted cytisine derivatives with increased selectivity for alpha4beta2 nicotinic acetylcholine receptors -
Author(s) : Kozikowski AP , Chellappan SK , Xiao Y , Bajjuri KM , Yuan H , Kellar KJ , Petukhov PA
Ref : ChemMedChem , 2 :1157 , 2007
PubMedID: 17530728

Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity - Chellappan_2006_J.Med.Chem_49_2673
Author(s) : Chellappan SK , Xiao Y , Tueckmantel W , Kellar KJ , Kozikowski AP
Ref : Journal of Medicinal Chemistry , 49 :2673 , 2006
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
ESTHER : Chellappan_2006_J.Med.Chem_49_2673
PubMedSearch : Chellappan_2006_J.Med.Chem_49_2673
PubMedID: 16640326

Title : Mouse beta-TC6 insulinoma cells: high expression of functional alpha3beta4 nicotinic receptors mediating membrane potential, intracellular calcium, and insulin release - Ohtani_2006_Mol.Pharmacol_69_899
Author(s) : Ohtani M , Oka T , Badyuk M , Xiao Y , Kellar KJ , Daly JW
Ref : Molecular Pharmacology , 69 :899 , 2006
Abstract : Nicotine elicited membrane depolarization, elevation of intracellular calcium, rubidium efflux, and release of insulin from mouse beta-TC6 insulinoma cells. Such responses were blocked by the nicotinic antagonist mecamylamine but not by the muscarinic antagonist atropine. Neither the selective alpha4beta2 antagonist dihydro-beta-erythroidine nor the selective alpha7 antagonist methyllycaconitine significantly blocked the nicotine-elicited depolarization or the calcium response. The elevation of intracellular calcium did not occur in calcium-free media, indicating that the increase in intracellular calcium was due to the influx of calcium. The rank order of potency for nicotinic agonists was as follows: epibatidine > nicotine = 3-(azetidinylmethoxy)pyridine (A-85380), cytisine, dimethylphenylpiperazinium (DMPP). Cytisine and DMPP seemed to be partial agonists. The density of nicotinic receptors measured by [3H]epibatidine binding was 7-fold higher in membranes from beta-TC6 cells than in rat brain membranes. No binding of 125I-A-85380 was detected, indicating the absence of beta2-containing receptors. Reverse transcription-polymerase chain reaction analyses indicated the presence of mRNA for alpha3 and alpha4 subunits and beta2 and beta4 subunits in beta-TC6 cells. The binding and functional data suggest that the major nicotinic receptor is composed of alpha3 and beta4 subunits. The beta-TC6 cells thus provide a model system for pharmacological study of such nicotinic receptors.
ESTHER : Ohtani_2006_Mol.Pharmacol_69_899
PubMedSearch : Ohtani_2006_Mol.Pharmacol_69_899
PubMedID: 16332988

Title : Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them - Xiao_2006_Mol.Pharmacol_70_1454
Author(s) : Xiao Y , Fan H , Musachio JL , Wei ZL , Chellappan SK , Kozikowski AP , Kellar KJ
Ref : Molecular Pharmacology , 70 :1454 , 2006
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the central and peripheral nervous systems. They are crucial to normal physiology and have been clearly implicated in nicotine addiction. In addition, they are possible therapeutic targets in a wide range of pathological conditions, including cognitive disorders, Parkinson's disease, and neuropathic pain. Nicotinic ligands are usually classified as agonists (or partial agonists), competitive antagonists, or noncompetitive antagonists. Sazetidine-A is a new nicotinic ligand that shows a different pharmacological profile from any of these known classes of ligands. Sazetidine-A competes with very high binding affinity (Ki approximately 0.5 nM) and selectivity for the alpha4beta2 nAChR subtype (Ki ratio alpha3beta4/alpha4beta2 approximately 24,000). Despite its high affinity, sazetidine-A neither activates nAChR channel function nor prevents channel activation when it is applied simultaneously with nicotine. However, when it is pre-incubated for 10 min with the receptors, it potently blocks nicotine-stimulated alpha4beta2 nAChR function (IC50 approximately 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the alpha4beta2 nAChRs, and its very high affinity for the desensitized state of the receptor. We propose that sazetidine-A is a "silent desensitizer" of nAChRs, meaning that it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at alpha4beta2 nAChRs suggests that the predominant effects of nicotine and other nicotinic agonists are related to desensitization of the receptors and that sazetidine-A potently mimics these effects.
ESTHER : Xiao_2006_Mol.Pharmacol_70_1454
PubMedSearch : Xiao_2006_Mol.Pharmacol_70_1454
PubMedID: 16857741

Title : Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits - Wei_2005_J.Med.Chem_48_1721
Author(s) : Wei ZL , Xiao Y , Yuan H , Baydyuk M , Petukhov PA , Musachio JL , Kellar KJ , Kozikowski AP
Ref : Journal of Medicinal Chemistry , 48 :1721 , 2005
Abstract : Introduction of a hydrophobic or hydrogen-bonding alkynyl group into the C5 position of the pyridyl ring of epibatidine and A-84543 significantly increased the selectivity for neuronal nicotinic acetylcholine receptors (nAChRs) containing beta2 subunits over nAChRs containing beta4 subunits (K(i) ratio up to 92000-fold). Our data indicate that the extracellular domains of the nAChRs are sufficiently different to allow for the design of novel ligands with high affinity and selectivity for the nAChR subtypes.
ESTHER : Wei_2005_J.Med.Chem_48_1721
PubMedSearch : Wei_2005_J.Med.Chem_48_1721
PubMedID: 15771418

Title : Nicotinic cholinergic receptors in the rat retina: simple and mixed heteromeric subtypes - Marritt_2005_Mol.Pharmacol_68_1656
Author(s) : Marritt AM , Cox BC , Yasuda RP , McIntosh JM , Xiao Y , Wolfe BB , Kellar KJ
Ref : Molecular Pharmacology , 68 :1656 , 2005
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) were measured in the rat retina to determine the heteromeric subtypes. We detected seven nicotinic receptor subunit mRNA transcripts, alpha2-alpha4, alpha6, and beta2-beta4, with RNase protection assays. The density of heteromeric nAChR binding sites is approximately 3 times higher in the retina than in the cerebral cortex. Moreover, the density of the sites in the retina measured with [3H]epibatidine ([3H]EB) is approximately 30% higher than with 125I-3-(2(S)-azetidinylmethoxy)pyridine (A-85380) and more than twice that measured with [3H]cytisine or [3H](-)nicotine. These data suggest that the retina expresses multiple subtypes of nAChRs, including a large fraction of receptors containing the beta2 subunit and a smaller fraction containing the beta4 subunit. Consistent with this, in binding competition studies, nicotinic ligands fit a model for two affinity classes of binding sites, with the higher affinity sites representing 70 to 80% of the nAChRs in the retina. To determine the specific subtypes of nAChRs in the rat retina, we used subunit-specific antibodies in immunoprecipitation assays. Immunoprecipitation of [3H]EB-labeled nAChRs with antibodies specific to the beta2 and beta4 subunits indicated that approximately 80% of the receptors contained beta2 subunits and approximately 25% contained beta4 receptors, consistent with the binding pharmacology results. Sequential immunoprecipitation assays indicated that the rat retina contains multiple subtypes of nAChRs. The majority of the receptors measured seemed to be simple heteromeric subtypes, composed of a single type of alpha and a single type of beta subunit; but a significant fraction are mixed heteromeric subtypes, composed of two or more alpha and/or beta subunits.
ESTHER : Marritt_2005_Mol.Pharmacol_68_1656
PubMedSearch : Marritt_2005_Mol.Pharmacol_68_1656
PubMedID: 16129735

Title : The Genomes of Oryza sativa: a history of duplications - Yu_2005_PLoS.Biol_3_e38
Author(s) : Yu J , Wang J , Lin W , Li S , Li H , Zhou J , Ni P , Dong W , Hu S , Zeng C , Zhang J , Zhang Y , Li R , Xu Z , Li X , Zheng H , Cong L , Lin L , Yin J , Geng J , Li G , Shi J , Liu J , Lv H , Li J , Deng Y , Ran L , Shi X , Wang X , Wu Q , Li C , Ren X , Li D , Liu D , Zhang X , Ji Z , Zhao W , Sun Y , Zhang Z , Bao J , Han Y , Dong L , Ji J , Chen P , Wu S , Xiao Y , Bu D , Tan J , Yang L , Ye C , Xu J , Zhou Y , Yu Y , Zhang B , Zhuang S , Wei H , Liu B , Lei M , Yu H , Li Y , Xu H , Wei S , He X , Fang L , Huang X , Su Z , Tong W , Tong Z , Ye J , Wang L , Lei T , Chen C , Chen H , Huang H , Zhang F , Li N , Zhao C , Huang Y , Li L , Xi Y , Qi Q , Li W , Hu W , Tian X , Jiao Y , Liang X , Jin J , Gao L , Zheng W , Hao B , Liu S , Wang W , Yuan L , Cao M , McDermott J , Samudrala R , Wong GK , Yang H
Ref : PLoS Biol , 3 :e38 , 2005
Abstract : We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
ESTHER : Yu_2005_PLoS.Biol_3_e38
PubMedSearch : Yu_2005_PLoS.Biol_3_e38
PubMedID: 15685292
Gene_locus related to this paper: orysa-Q7XTC5 , orysa-Q852M6 , orysa-Q8GSE8 , orysa-Q9S7P1 , orysa-Q9FYP7 , orysa-Q5ZBH3 , orysa-Q5ZA26 , orysa-Q5JLP6 , orysa-Q8H5P9 , orysa-Q8H5P5 , orysa-Q7F1Y5 , orysa-Q949C9 , orysa-cbp1 , orysa-cbp3 , orysa-cbpx , orysa-Q33B71 , orysa-Q8GSJ3 , orysa-LPL1 , orysa-Q6YSZ8 , orysa-Q8S5X5 , orysa-Q8LIG3 , orysa-Q6K7F5 , orysa-Q7F1B1 , orysa-Q8H4S9 , orysa-Q69UB1 , orysa-Q9FW17 , orysa-Q337C3 , orysa-Q7F959 , orysa-Q84QZ6 , orysa-Q84QY7 , orysa-Q851E3 , orysa-Q6YTH5 , orysa-Q0JK71 , orysa-Q8S1D9 , orysa-Q5N8V4 , orysa-Q0JCY4 , orysa-Q8GTK2 , orysa-B9EWJ8 , orysa-Q8H3K6 , orysa-Q6ZDG8 , orysa-Q6ZDG6 , orysa-Q6ZDG5 , orysa-Q6ZDG4 , orysa-Q5NAI4 , orysa-Q658B2 , orysa-Q5JMQ8 , orysa-Q5QMD9 , orysa-Q5N7L1 , orysa-Q8RYV9 , orysa-Q8H3R3 , orysa-Q5SNH3 , orysa-Q8W0F0 , orysa-pir7a , orysa-pir7b , orysa-q2qlm4 , orysa-q2qm78 , orysa-q2qm82 , orysa-q2qn31 , orysa-q2qnj4 , orysa-q2qnt9 , orysa-q2qur1 , orysa-q2qx94 , orysa-q2qyi1 , orysa-q2qyj1 , orysa-q2r051 , orysa-q2r077 , orysa-q2ram0 , orysa-q2rat1 , orysa-q2rbb3 , orysa-Q4VWY7 , orysa-q5na00 , orysa-q5nbu1 , orysa-Q5QLC0 , orysa-q5smv5 , orysa-Q5VP27 , orysa-q5vrt2 , orysa-q5w6c5 , orysa-q5z5a3 , orysa-q5z9i2 , orysa-q5z417 , orysa-q5z901 , orysa-Q5ZAM8 , orysa-Q5ZBI5 , orysa-Q5ZCR3 , orysa-q6atz0 , orysa-q6ave2 , orysa-q6f358 , orysa-q6h6s1 , orysa-q6h7i6 , orysa-q6i5q3 , orysa-q6i5u7 , orysa-q6j657 , orysa-q6k3d9 , orysa-q6k4q2 , orysa-q6k880 , orysa-q6l5b6 , orysa-Q6L5F5 , orysa-q6l556 , orysj-q6yse8 , orysa-q6yy42 , orysa-q6yzk1 , orysa-q6z8b1 , orysa-q6z995 , orysa-q6zc62 , orysa-q6zia4 , orysa-q6zjq6 , orysa-q7x7y5 , orysa-Q7XC50 , orysa-q7xej4 , orysa-q7xem8 , orysa-q7xkj9 , orysa-q7xr62 , orysa-q7xr63 , orysa-q7xr64 , orysa-q7xsg1 , orysa-q7xsq2 , orysa-q7xts6 , orysa-q7xv53 , orysa-Q7XVB5 , orysa-Q8L562 , orysa-Q8LQS5 , orysa-Q8RZ40 , orysa-Q8RZ79 , orysa-Q8S0U8 , orysa-Q8S0V0 , orysa-Q8S125 , orysa-Q8SAY7 , orysa-Q8SAY9 , orysa-Q8W3C6 , orysa-Q8W3F2 , orysa-Q8W3F4 , orysa-Q8W3F6 , orysa-Q9LHX5 , orysa-q33aq0 , orysa-q53lh1 , orysa-q53m20 , orysa-q53nd8 , orysa-q60e79 , orysa-q60ew8 , orysa-q67iz2 , orysa-q67iz3 , orysa-q67iz7 , orysa-q67iz8 , orysa-q67j02 , orysa-q67j05 , orysa-q67j07 , orysa-q67j09 , orysa-q67j10 , orysa-q67tr6 , orysa-q67tv0 , orysa-q67uz1 , orysa-q67v34 , orysa-q67wz5 , orysa-q69j38 , orysa-q69k08 , orysa-q69md7 , orysa-q69me0 , orysa-q69pf3 , orysa-q69ti3 , orysa-q69xr2 , orysa-q69y12 , orysa-q69y21 , orysa-q75hy2 , orysa-q75i01 , orysa-Q94JD7 , orysa-Q0J0A4 , orysa-q651a8 , orysa-q651z3 , orysa-q652g4 , orysa-q688m0 , orysa-q688m8 , orysa-q688m9 , orysa-Q6H8G1 , orysi-a2wn01 , orysi-a2xc83 , orysi-a2yh83 , orysi-a2z179 , orysi-a2zef2 , orysi-b8a7e6 , orysi-b8a7e7 , orysi-b8bfe5 , orysi-b8bhp9 , orysj-a3b9l8 , orysj-b9eub8 , orysj-b9eya5 , orysj-b9fi05 , orysj-b9fkb0 , orysj-b9fn42 , orysj-b9gbb7 , orysj-cgep , orysj-PLA7 , orysj-q0d4u5 , orysj-q0djj0 , orysj-q0jaf0 , orysj-q5jl22 , orysj-q5jlw7 , orysj-q5z419 , orysj-q6h7q9 , orysj-q6yvk6 , orysj-q6z6i1 , orysj-q7f8x1 , orysj-q7xcx3 , orysj-q9fwm6 , orysj-q10j20 , orysj-q10ss2 , orysj-q69uw6 , orysj-q94d71 , orysj-q338c0 , orysi-b8bly4 , orysj-b9gbs4 , orysi-a2zb88 , orysj-b9gbs1 , orysi-b8b698 , orysj-pla4 , orysj-pla1

Title : Inhibition of the acetycholine esterase-stimulated growth of Au nanoparticles: nanotechnology-based sensing of nerve gases - Pavlov_2005_Nano.Lett_5_649
Author(s) : Pavlov V , Xiao Y , Willner I
Ref : Nano Lett , 5 :649 , 2005
Abstract : The acetylcholine esterase, AChE, mediated hydrolysis of acetylthiocholine (1) yields a reducing agent thiocholine (2) that stimulates the catalytic enlargement of Au NP seeds in the presence of AuCl(4)(-). The reductive enlargement of the Au NPs is controlled by the concentration of the substrate (1) and by the activity of the enzyme. The catalytic growth of the Au NPs is inhibited by 1,5-bis(4-allyldimethylammoniumphenyl)pentane-3-one dibromide (3) or by diethyl p-nitrophenyl phosphate (paraoxon; 4), thus enabling a colorimetric test for AChE inhibitors. The colorimetric assay was also developed on glass supports.
ESTHER : Pavlov_2005_Nano.Lett_5_649
PubMedSearch : Pavlov_2005_Nano.Lett_5_649
PubMedID: 15826103

Title : The nicotinic receptor in the rat pineal gland is an alpha3beta4 subtype - Hernandez_2004_Mol.Pharmacol_66_978
Author(s) : Hernandez SC , Vicini S , Xiao Y , Davila-Garcia MI , Yasuda RP , Wolfe BB , Kellar KJ
Ref : Molecular Pharmacology , 66 :978 , 2004
Abstract : The rat pineal gland contains a high density of neuronal nicotinic acetylcholine receptors (nAChRs). We characterized the pharmacology of the binding sites and function of these receptors, measured the nAChR subunit mRNA, and used subunit-specific antibodies to establish the receptor subtype as defined by subunit composition. In ligand binding studies, [3H]epibatidine ([3H]EB) binds with an affinity of approximately 100 pM to nAChRs in the pineal gland, and the density of these sites is approximately 5 times that in rat cerebral cortex. The affinities of nicotinic drugs for binding sites in the pineal gland are similar to those at alpha3beta4 nAChRs heterologously expressed in human embryonic kidney 293 cells. In functional studies, the potencies and efficacies of nicotinic drugs to activate or block whole-cell currents in dissociated pinealocytes match closely their potencies and efficacies to activate or block 86Rb+ efflux in the cells expressing heterologous alpha3beta4 nAChRs. Measurements of mRNA indicated the presence of transcripts for alpha3, beta2, and beta4 nAChR subunits but not those for alpha2, alpha4, alpha5, alpha6, alpha7, or beta3 subunits. Immunoprecipitation with subunit-specific antibodies showed that virtually all [3H]EB-labeled nAChRs contained alpha3 and beta4 subunits associated in one complex. The beta2 subunit was not associated with this complex. Taken together, these results indicate that virtually all of the nAChRs in the rat pineal gland are the alpha3beta4 nAChR subtype and that the pineal gland can therefore serve as an excellent and convenient model in which to study the pharmacology and function of these receptors in a native tissue.
ESTHER : Hernandez_2004_Mol.Pharmacol_66_978
PubMedSearch : Hernandez_2004_Mol.Pharmacol_66_978
PubMedID: 15247319

Title : Synthesis and pharmacological characterization of bivalent ligands of epibatidine at neuronal nicotinic acetylcholine receptors - Wei_2004_Bioorg.Med.Chem.Lett_14_1855
Author(s) : Wei ZL , Xiao Y , Kellar KJ , Kozikowski AP
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1855 , 2004
Abstract : A series of bivalent ligands 6a-d of epibatidine were synthesized. All four ligands showed nanomolar binding affinities at six neuronal nicotinic acetylcholine receptor (nAChR) subtypes in competition binding assays. In contrast to epibatidine, these bivalent ligands are weak partial agonists at the alpha3beta4 nAChR as shown by functional assays.
ESTHER : Wei_2004_Bioorg.Med.Chem.Lett_14_1855
PubMedSearch : Wei_2004_Bioorg.Med.Chem.Lett_14_1855
PubMedID: 15050615

Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells - Xiao_2004_Bioorg.Med.Chem.Lett_14_1845
Author(s) : Xiao Y , Baydyuk M , Wang HP , Davis HE , Kellar KJ
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1845 , 2004
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
ESTHER : Xiao_2004_Bioorg.Med.Chem.Lett_14_1845
PubMedSearch : Xiao_2004_Bioorg.Med.Chem.Lett_14_1845
PubMedID: 15050613

Title : The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells - Xiao_2004_J.Pharmacol.Exp.Ther_310_98
Author(s) : Xiao Y , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 310 :98 , 2004
Abstract : We stably transfected human embryonic kidney cells (HEK 293 cells) with genes encoding rat neuronal nicotinic receptor alpha2, alpha3, or alpha4 subunits in combination with the beta2 or beta4 subunit to generate six cell lines that express defined subunit combinations that represent potential subtypes of rat neuronal nicotinic acetylcholine receptors (nAChRs). These cell lines were designated KXalpha2beta2, KXalpha2beta4, KXalpha3beta2, KXalpha3beta4, KXalpha4beta2, and KXalpha4beta4. The Kd values of [3H](+/-)epibatidine ([3H]EB) binding to membranes from these six cell lines ranged from approximately 0.02 to 0.3 nM. The pharmacological profiles of the agonist binding sites of these putative nAChR subtypes were examined in competition studies in which unlabeled nicotinic ligands, including 10 agonists and two antagonists, competed against [3H]EB. Most nicotinic ligands examined had higher affinity for the receptor subtypes containing the beta2 subunit compared with those containing the beta4 subunit. An excellent correlation (r > 0.99) of the binding affinities of the 10 agonists was observed between receptors from KXalpha4beta2 cells and from rat forebrain tissue, in which [3H]EB binding represents predominantly alpha4beta2 nAChRs. More important, the affinities (Ki values) for the two tissues were nearly identical. The densities of the binding sites of all six cell lines were increased after a 5-day exposure to (-)-nicotine or the quaternary amine agonist carbachol. These data indicate that these cell lines expressing nAChR subunit combinations should be useful models for investigating pharmacological properties and regulation of the binding sites of potential nAChR subtypes, as well as for studying the properties of nicotinic compounds.
ESTHER : Xiao_2004_J.Pharmacol.Exp.Ther_310_98
PubMedSearch : Xiao_2004_J.Pharmacol.Exp.Ther_310_98
PubMedID: 15016836

Title : Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues - Wei_2003_J.Med.Chem_46_921
Author(s) : Wei ZL , Petukhov PA , Xiao Y , Tuckmantel W , George C , Kellar KJ , Kozikowski AP
Ref : Journal of Medicinal Chemistry , 46 :921 , 2003
Abstract : Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized using a radical cyclization as the key step. Radioligand displacement assays to six defined rat nicotinic acetylcholine receptor (nAChR) subtypes showed that 20a,b bind with moderate affinities, while 23a,b have low affinities. 20a exhibits higher affinity for the beta2 containing subtype than for the beta4 containing counterpart, while 20b possesses reversed selectivity. Modeling studies suggest that the spatial distribution of the ligand's atoms around the pharmacophore elements may control their nAChR subtype selectivity.
ESTHER : Wei_2003_J.Med.Chem_46_921
PubMedSearch : Wei_2003_J.Med.Chem_46_921
PubMedID: 12620069

Title : Functionalization of the alicyclic skeleton of epibatidine: synthesis and nicotinic acetylcholine receptor binding affinities of epibatidine analogues - Wei_2003_Org.Biomol.Chem_1_3878
Author(s) : Wei ZL , Xiao Y , George C , Kellar KJ , Kozikowski AP
Ref : Org Biomol Chem , 1 :3878 , 2003
Abstract : A novel method for the epimerization of endo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptan-3-one (12) on silica gel was developed and used as the key step to synthesize functionalized analogues of epibatidine which were evaluated for their nicotine receptor subtype selectivity in binding studies.
ESTHER : Wei_2003_Org.Biomol.Chem_1_3878
PubMedSearch : Wei_2003_Org.Biomol.Chem_1_3878
PubMedID: 14664377

Title : Differential regulation of nicotinic acetylcholine receptors in PC12 cells by nicotine and nerve growth factor - Avila_2003_Mol.Pharmacol_64_974
Author(s) : Avila AM , Davila-Garcia MI , Ascarrunz VS , Xiao Y , Kellar KJ
Ref : Molecular Pharmacology , 64 :974 , 2003
Abstract : Neuronal nicotinic receptors in PC12 cells were measured by binding with [3H]epibatidine and in functional studies with agonist-stimulated 86Rb+ efflux and [3H]norepinephrine release assays. Two subtypes of receptors labeled by [3H]epibatidine were found: one that was increased about 4-fold in cells grown for 2 to 4 days in the presence of nicotine and one that was increased 5-fold in cells grown for 2 to 4 days in the presence of nerve growth factor (NGF). The actions of the two treatments were superadditive, resulting in approximately a 13-fold increase in binding sites in cells grown in the combination of the two treatments. The pharmacology of the binding sites in the nicotine- and NGF-treated cells was compared with the pharmacology of defined alpha3beta2 and alpha3beta4 nicotinic acetylcholine receptor (nAChR) subtypes heterologously expressed in human embryonic kidney 293 cells. Nicotine treatment predominantly increased a receptor with characteristics of an alpha3beta2 subtype, whereas the NGF treatment exclusively increased a receptor with characteristics of an alpha3beta4 subtype. Nicotinic receptor-mediated function measured with the 86Rb+ efflux assay was evident only in the NGF-treated cells, and it had a pharmacological profile that was, again, nearly identical to that of the heterologously expressed alpha3beta4 receptor subtype. Receptor function measured with the [3H]norepinephrine release assay was measurable in both nicotine-treated and NGF-treated cells; however, cytisine-stimulated [3H]norepinephrine release indicated that nicotine treatment increased an nAChR containing beta2 subunits, whereas NGF increased a receptor containing beta4 subunits. NGF treatment increased mRNA only for beta4 subunits in these cells, whereas nicotine treatment did not affect mRNA for any of the subunits measured. After withdrawal of the treatments, the receptors increased by nicotine were much less stable than those increased by NGF.
ESTHER : Avila_2003_Mol.Pharmacol_64_974
PubMedSearch : Avila_2003_Mol.Pharmacol_64_974
PubMedID: 14500754

Title : Membrane potential fluorescence: a rapid and highly sensitive assay for nicotinic receptor channel function - Fitch_2003_Proc.Natl.Acad.Sci.U.S.A_100_4909
Author(s) : Fitch RW , Xiao Y , Kellar KJ , Daly JW
Ref : Proc Natl Acad Sci U S A , 100 :4909 , 2003
Abstract : Seven cell lines expressing native and transfected nicotinic receptor subtypes were evaluated functionally by using fluorescent assays based on membrane potential and calcium dynamics with "no-wash" dye systems. Both assays provided the same rank orders of potency for (+/-)-epibatidine, 2S-(-)-nicotine, 7R,9S-(-)-cytisine, and 1,1-dimethyl-4-phenylpiperazinium in a cell line expressing rat alpha 3 beta 4 receptors. Nicotinic antagonists mecamylamine and dihydro-beta-erythroidine inhibited responses in both assays. Both agonist and antagonist activity were assessed within the same experiment. Agonists seemed more potent in the membrane potential assay than in the calcium assay, whereas the converse was true for antagonists. The membrane potential assay afforded robust responses in K-177 cells expressing human alpha 4 beta 2 receptors, in IMR-32 and SH-SY5Y cells expressing human ganglionic receptors, and in TE-671 cells expressing human neuromuscular receptors. These lines gave weak to modest calcium responses. Moreover, membrane potential responses were obtained in cell lines expressing rat alpha 4 beta 2 and alpha 4 beta 4 receptors, which were devoid of calcium responses. Thus, membrane potential serves as a sensitive measure of nicotinic activity, and the resulting depolarization may be as important as calcium in cell signaling.
ESTHER : Fitch_2003_Proc.Natl.Acad.Sci.U.S.A_100_4909
PubMedSearch : Fitch_2003_Proc.Natl.Acad.Sci.U.S.A_100_4909
PubMedID: 12657731

Title : Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography - Perry_2002_J.Neurochem_82_468
Author(s) : Perry DC , Xiao Y , Nguyen HN , Musachio JL , Davila-Garcia MI , Kellar KJ
Ref : Journal of Neurochemistry , 82 :468 , 2002
Abstract : Comparison of [125I]epibatidine and 5-[125I]iodo-3-(2-azetidinylmethoxy)pyridine ([125I]A-85380) autoradiography showed evidence for nicotinic receptor heterogeneity. To identify the receptor subtypes, we performed [125I]epibatidine autoradiography in the presence of cytisine or A-85380. By comparing these results with binding data from human embryonic kidney (HEK) 293 cells stably transfected with different combinations of rat nicotinic receptor subunits, we were able to quantify three distinct populations of [125I]epibatidine binding sites with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 receptors. Although the predominant subtype in rat brain was alpha4beta2, non-alpha4beta2 binding sites were prominent in many regions. In the habenulo-peduncular system, cerebellum, substantia gelatinosa, and many medullary nuclei, alpha3beta4-like binding accounted for more than 40% of [125I]epibatidine binding, and nearly all binding in superior cervical ganglion and pineal gland. Other regions enriched in alpha3beta4-like binding included locus ceruleus, dorsal tegmentum, subiculum and anteroventral thalamic nucleus. Regions enriched in alpha3beta2-like binding included the habenulo-peduncular system, many visual system structures, certain geniculate nuclei, and dopaminergic regions. The combination of autoradiography using a broad spectrum radioligand in the presence of selective competitors, and data from binding to defined receptor subtypes in expression systems, allowed us to quantify the relative populations of these three subtypes.
ESTHER : Perry_2002_J.Neurochem_82_468
PubMedSearch : Perry_2002_J.Neurochem_82_468
PubMedID: 12153472

Title : Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs - Xiao_2001_J.Pharmacol.Exp.Ther_299_366
Author(s) : Xiao Y , Smith RD , Caruso FS , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 299 :366 , 2001
Abstract : The opioid agonist properties of (+/-)-methadone are ascribed almost entirely to the (-)-methadone enantiomer. To extend our knowledge of the pharmacological actions of methadone at ligand-gated ion channels, we investigated the effects of the two enantiomers of methadone and its metabolites R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate (EDDP) and R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride (EMDP), as well as structural analogs of methadone, including (-)-alpha-acetylmethadol hydrochloride (LAAM) and (+)-alpha-propoxyphene, on rat alpha3beta4 neuronal nicotinic acetylcholine receptors (nAChRs) stably expressed in a human embryonic kidney 293 cell line, designated KXalpha3beta4R2. (+/-)-methadone inhibited nicotine-stimulated 86Rb+ efflux from the cells in a concentration-dependent manner with an IC50 value of 1.9 +/- 0.2 microM, indicating that it is a potent nAChR antagonist. The (-)- and (+)-enantiomers of methadone have similar inhibitory potencies on nicotine-stimulated 86Rb+ efflux, with IC50 values of approximately 2 microM. EDDP, the major metabolite of methadone, is even more potent, with an IC50 value of approximately 0.5 microM, making it one of the most potent nicotinic receptor blockers reported. In the presence of (+/-)-methadone, EDDP, or LAAM, the maximum nicotine-stimulated 86Rb+ efflux was markedly decreased, but the EC50 value for nicotine stimulation was altered only slightly, if at all, indicating that these compounds block alpha3beta4 nicotinic receptor function by a noncompetitive mechanism. Consistent with a noncompetitive mechanism, (+/-)-methadone, its metabolites, and structural analogs have very low affinity for nicotinic receptor agonist binding sites in membrane homogenates from KXalpha3beta4R2 cells. We conclude that both enantiomers of methadone and its metabolites as well as LAAM and (+)-alpha-propoxyphene are potent noncompetitive antagonists of alpha3beta4 nAChRs.
ESTHER : Xiao_2001_J.Pharmacol.Exp.Ther_299_366
PubMedSearch : Xiao_2001_J.Pharmacol.Exp.Ther_299_366
PubMedID: 11561100

Title : Agonist regulation of rat alpha 3 beta 4 nicotinic acetylcholine receptors stably expressed in human embryonic kidney 293 cells - Meyer_2001_Mol.Pharmacol_60_568
Author(s) : Meyer EL , Xiao Y , Kellar KJ
Ref : Molecular Pharmacology , 60 :568 , 2001
Abstract : Effects of agonists on rat alpha 3 beta 4 nicotinic acetylcholine receptors expressed in KX alpha 3 beta 4R2 cells [human embryonic kidney 293-derived cells] were studied. The potencies of seven agonists varied over a 7000-fold range, with a rank order of epibatidine >> A85380 > cytisine approximately 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) approximately nicotine > acetylcholine > carbachol. The efficacies of all of the agonists studied here were similar except for DMPP, which seemed to be a partial agonist compared with nicotine and acetylcholine. Nicotine and carbachol desensitized the receptors in a time- and concentration-dependent manner. The EC(50) values for nicotine and carbachol to desensitize the receptors during a 60-min exposure were 3 and 51 microM, respectively, indicating that these agonists are more potent at desensitizing the receptors than at activating them. The function of the receptors recovered from agonist-induced desensitization rapidly and almost completely. The half-time for recovery of function from desensitization after a 60-min treatment with nicotine increased with the concentration of nicotine used to desensitize the receptors. In contrast, no such concentration dependence for time to recovery of function was found when carbachol was used to desensitize the receptors. We propose that this difference may be due to the cell permeability of nicotine, allowing it to enter and be sequestered inside of cells and then slowly diffuse out to maintain receptor desensitization. After a 5-day exposure to 100 microM nicotine, the receptors were completely desensitized, but receptor function recovered to 83% of control values with a half-time of about 10.5 min. Although the number of nicotinic receptor binding sites measured with (+/-)-[(3)H]epibatidine was increased during the chronic treatment with nicotine, no increase in function was detected.
ESTHER : Meyer_2001_Mol.Pharmacol_60_568
PubMedSearch : Meyer_2001_Mol.Pharmacol_60_568
PubMedID: 11502889

Title : [125\/123I] 5-Iodo-3-pyridyl ethers. syntheses and binding to neuronal nicotinic acetylcholine receptors - Fan_2001_Nucl.Med.Biol_28_911
Author(s) : Fan H , Scheffel UA , Rauseo P , Xiao Y , Dogan AS , Yokoi F , Hilton J , Kellar KJ , Wong DF , Musachio JL
Ref : Nucl Med Biol , 28 :911 , 2001
Abstract : Three 3-pyridyl ether nicotinic ligands-(S)-5-Iodo-3-[(2-pyrrolidinyl)-methoxy]pyridine (5-iodo-A-85865), (S)-5-Iodo-3-[1-(methyl)-2-pyrrolidinyl-methoxy]pyridine (5-Iodo-A-84543), and (S)-5-iodo-3-[1-methyl-(2-azetidinyl)-methoxy]pyridine (5-iodo-N-Me-A-85380) were labeled with I-125/I-123, and their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated. The most promising ligand, [123/125I] 5-iodo-A-85865, showed approximately 65% inhibition of radioactivity uptake in thalamus in mice pretreated with cytisine. Preliminary SPECT imaging studies with [123I] 5-iodo-A-85865 revealed a distribution profile consistent with nAChRs (thalamus > frontal cortex > cerebellum) and a more rapid pharmacokinetic profile relative to azetidinyl 3-pyridyl ether based ligands.
ESTHER : Fan_2001_Nucl.Med.Biol_28_911
PubMedSearch : Fan_2001_Nucl.Med.Biol_28_911
PubMedID: 11711310

Title : Neuronal nicotinic acetylcholine receptor alpha3 subunit protein in rat brain and sympathetic ganglion measured using a subunit-specific antibody: regional and ontogenic expression - Yeh_2001_J.Neurochem_77_336
Author(s) : Yeh JJ , Yasuda RP , Davila-Garcia MI , Xiao Y , Ebert S , Gupta T , Kellar KJ , Wolfe BB
Ref : Journal of Neurochemistry , 77 :336 , 2001
Abstract : A synthetic peptide corresponding to the C-terminus of the alpha 3 subunit of the rat neuronal nicotinic acetylcholine receptor (nAChR) was used to generate a rabbit polyclonal alpha 3 antibody. The specificity of this antibody was characterized by immunoblotting, immunohistochemical and immunoprecipitation techniques. Using this antibody, the relative densities of the alpha 3 subunit were quantitatively determined in different brain regions and in superior cervical ganglion (SCG). Among these regions, SCG, interpeduncular nucleus (IPN) and pineal gland showed the highest levels of alpha 3 protein expression. Habenula and superior colliculi had intermediate levels of expression. Low levels were found in cerebral cortex, hippocampus and cerebellum. The ontogenic profile of the alpha 3 subunit in the SCG was also determined. The alpha 3 protein level is low at postnatal day (P 1), but increases rapidly during the first seven postnatal days. This level then plateaus and remains stable through postnatal day 35. These findings suggest that neuronal nAChRs containing the alpha 3 subunit participate in important roles in specific regions of the rat brain and the SCG.
ESTHER : Yeh_2001_J.Neurochem_77_336
PubMedSearch : Yeh_2001_J.Neurochem_77_336
PubMedID: 11279289

Title : Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors - Hernandez_2000_J.Pharmacol.Exp.Ther_293_962
Author(s) : Hernandez SC , Bertolino M , Xiao Y , Pringle KE , Caruso FS , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 293 :962 , 2000
Abstract : Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.
ESTHER : Hernandez_2000_J.Pharmacol.Exp.Ther_293_962
PubMedSearch : Hernandez_2000_J.Pharmacol.Exp.Ther_293_962
PubMedID: 10869398

Title : Liquid chromatographic studies with immobilized neuronal nicotinic acetylcholine receptor stationary phases: effects of receptor subtypes, pH and ionic strength on drug-receptor interactions - Wainer_1999_J.Chromatogr.B.Biomed.Sci.Appl_724_65
Author(s) : Wainer IW , Zhang Y , Xiao Y , Kellar KJ
Ref : Journal of Chromatography B Biomed Sci Appl , 724 :65 , 1999
Abstract : Nicotinic acetylcholine receptor (nAChR) alpha3-subunits, beta4-subunits, alpha3/beta4-subunit combination and alpha4/beta2-subunit combination were immobilized on chromatographic stationary phases and the binding affinities of the different nAChR subtypes were chromatographically evaluated. The observed relative binding affinities of epibatidine were alpha4/beta2>alpha3/beta4 and epibatidine did not bind at alpha3-subunits and beta4-subunits. No significant difference in binding affinities was observed on the alpha4/beta2 nAChRs immobilized in immobilized artificial membrane (IAM) particles and those sterically immobilized on Superdex 200 beads. The effects of mobile phase pH and ionic strength on the binding affinities of the alpha3/beta4 nAChRs support were also investigated. The results are consistent with the proposed ligand-nAChR binding model in which a cationic center exists at the binding site.
ESTHER : Wainer_1999_J.Chromatogr.B.Biomed.Sci.Appl_724_65
PubMedSearch : Wainer_1999_J.Chromatogr.B.Biomed.Sci.Appl_724_65
PubMedID: 10202958

Title : Activation and Ca2+ permeation of stably transfected alpha3\/beta4 neuronal nicotinic acetylcholine receptor - Zhang_1999_Mol.Pharmacol_55_970
Author(s) : Zhang J , Xiao Y , Abdrakhmanova G , Wang W , Cleemann L , Kellar KJ , Morad M
Ref : Molecular Pharmacology , 55 :970 , 1999
Abstract : The alpha3/beta4 rat neuronal nicotinic acetylcholine receptor, stably transfected in human embryonic kidney cells, was examined using the whole-cell-clamp technique and 2-dimensional confocal imaging. Application of agonists (nicotine, cytisine, epibatidine) activated a large (100-200 pA/pF) inwardly rectifying monovalent current, with little current at voltages between 0 and +40 mV. Rapid application of nicotine and cytisine indicated EC50 values of congruent with22 and congruent with64 microM, respectively, and suggested second order binding kinetics (Hill coefficient approximately 2). The time constant of desensitization (decay) of nicotine-activated current was concentration-dependent (typically approximately 10 s at 30 microM versus approximately 1.0 s at 100-1000 microM), but not voltage-dependent and was significantly smaller than the approximately 200 s reported for the alpha3/beta4 receptor expressed in Xenopus oocytes. Nicotine-activated current was rapidly and reversibly blocked by coapplication of mecamylamine and d-tubocurarine. At -80 mV holding potentials, the current was also suppressed by approximately 25% either upon complete removal or elevation of Ca2+ to 10 mM. Total replacement of Na+ by Ca2+ also completely blocked the current. On the other hand, evidence for permeation of Ca2+ was indicated by increased inward current at -40 mV upon elevation of Ca2+ from 2 to 10 mM, as well as a rise in the cytosolic Ca2+ proportional to the current carried by the receptor. These findings are consistent with the idea that Ca2+, in addition to its channel-permeating properties, may also regulate the receptor from an extracellular site. Our results suggest that the alpha3/beta4 neuronal nicotinic acetylcholine receptor, when stably expressed in human embryonic kidney 293 cells, has desensitization kinetics and Ca2+ regulatory mechanisms somewhat different from those described for the receptor expressed in Xenopus oocytes.
ESTHER : Zhang_1999_Mol.Pharmacol_55_970
PubMedSearch : Zhang_1999_Mol.Pharmacol_55_970
PubMedID: 10347237

Title : Pharmacology of neuronal nicotinic acetylcholine recceptors: effects of acute and chronic nicotine - Kellar_1999_Nicotine.Tob.Res_1 Suppl 2_S117
Author(s) : Kellar KJ , Davila-Garcia MI , Xiao Y
Ref : Nicotine Tob Res , 1 Suppl 2 :S117 , 1999
Abstract : Neuronal nicotinic acetylcholine receptors mediate nicotine's diverse effects on the brain, spinal cord and autonomic nervous system. These receptors are composed of alpha and beta subunits. Eight different alpha and three different beta subunits have been identified in vertebrate nervous systems, giving rise to the possibility of multiple subtypes of nicotinic receptors, defined by their constituent subunits. The pharmacological and channel conductance properties of the recombinant receptor subtypes studied in cellular expression systems differ from one another. In addition, the regulation of the receptor density and function during and after acute and chronic exposure to nicotine appears to differ among the subtypes. The predominant receptor subtypes in specific brain regions and peripheral neurons are beginning to be identified and their characteristics studied using new ligands and methods. As more is learned of the differences among the receptor subtypes, it should be possible to identify which specific subtype mediates a specific function within the nervous system and which subtypes are associated with the reinforcing and addictive actions of nicotine.
ESTHER : Kellar_1999_Nicotine.Tob.Res_1 Suppl 2_S117
PubMedSearch : Kellar_1999_Nicotine.Tob.Res_1 Suppl 2_S117
PubMedID: 11768167

Title : Immobilized nicotinic receptor stationary phase for on-line liquid chromatographic determination of drug-receptor affinities - Zhang_1998_Anal.Biochem_264_22
Author(s) : Zhang Y , Xiao Y , Kellar KJ , Wainer IW
Ref : Analytical Biochemistry , 264 :22 , 1998
Abstract : Nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels which mediate nicotinic cholinergic transmission in the nervous system. A nAChR subtype composed of alpha3 and beta4 subunits (alpha3/beta4 subtype), prepared from a stably transfected KXalpha3beta4R2 cell line, has been immobilized in the phospholipid monolayer of an immobilized artificial membrane (IAM) liquid chromatography (LC) stationary phase. Approximately 60 mg of protein was immobilized per gram IAM particles. The resulting phase was used for the rapid on-line chromatographic determination of drug binding affinities to nAChRs. Relative binding affinities were determined by frontal chromatography for (+/-)-epibatidine (Kd: 0.27 +/- 0.05 nM) > A85380 (Kd: 17.2 +/- 0.5 nM) > (-)-nicotine (Kd: 88 +/- 33 nM) > carbachol (Kd: 1280 +/- 30 nM) > atropine (Kd: 14,570 +/- 2600 nM). These results are consistent with the affinity rank order obtained from binding assays using membrane homogenates. The immobilized receptor LC stationary phase was stable and reproducible. This approach opens up the possibility of the production of a variety of immobilized receptor LC stationary phases which may be used for direct determination of drug-receptor binding interactions and for the rapid on-line screening of combinatorial pools for drug candidates.
ESTHER : Zhang_1998_Anal.Biochem_264_22
PubMedSearch : Zhang_1998_Anal.Biochem_264_22
PubMedID: 9784183

Title : Rat alpha3\/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function - Xiao_1998_Mol.Pharmacol_54_322
Author(s) : Xiao Y , Meyer EL , Thompson JM , Surin A , Wroblewski J , Kellar KJ
Ref : Molecular Pharmacology , 54 :322 , 1998
Abstract : We stably transfected human kidney embryonic 293 cells with the rat neuronal nicotinic acetylcholine receptor (nAChR) alpha3 and beta4 subunit genes. This new cell line, KXalpha3 beta4R2, expresses a high level of the alpha3/beta4 receptor subtype, which binds (+/-)- [3H]epibatidine with a Kd value of 304+/-16 pM and a Bmax value of 8942 +/- 115 fmol/mg protein. Comparison of nicotinic drugs in competing for alpha3/beta4 receptor binding sites in this cell line and the binding sites in rat forebrain (predominantly alpha4/beta2 receptors) revealed marked differences in their Ki values, but similar rank orders of potency for agonists were observed, with the exception of anatoxin-A. The affinity of the competitive antagonist dihydro-beta-erythroidine is >7000 times higher at alpha4/beta2 receptors in rat forebrain than at the alpha3/beta4 receptors in these cells. The alpha3/beta4 nAChRs expressed in this cell line are functional, and in response to nicotinic agonists, 86Rb+ efflux was increased to levels 8-10 times the basal levels. Acetylcholine, (-)-nicotine, cytisine, carbachol, and (+/-)-epibatidine all stimulated 86Rb+ efflux, which was blocked by mecamylamine. The EC50 values for acetylcholine and (-)-nicotine to stimulate 86Rb+ effluxes were 114 +/- 24 and 28 +/- 4 microM, respectively. The rank order of potency of nicotinic antagonists in blocking the function of this alpha3/beta4 receptor was mecamylamine > d-tubocurarine > dihydro-beta-erythroidine > hexamethonium. Mecamylamine, d-tubocurarine, and hexamethonium blocked the function by a noncompetitive mechanism, whereas dihydro-beta-erythroidine blocked the function competitively. The KXalpha3 beta4R2 cell line should prove to be a very useful model for studying this subtype of nAChRs.
ESTHER : Xiao_1998_Mol.Pharmacol_54_322
PubMedSearch : Xiao_1998_Mol.Pharmacol_54_322
PubMedID: 9687574

Title : [125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors - Davila-Garcia_1997_J.Pharmacol.Exp.Ther_282_445
Author(s) : Davila-Garcia MI , Musachio JL , Perry DC , Xiao Y , Horti A , London ED , Dannals RF , Kellar KJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 282 :445 , 1997
Abstract : An analog of epibatidine (EB) was synthesized with an iodine atom in the 2 position of the pyridyl ring. This analog, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), as well as its two stereoisomers, displayed high affinity for neuronal nicotinic receptors; therefore, radioiodinated IPH, [125I]IPH, was synthesized with specific radioactivities consistently > 1000 Ci/mmol, and its properties as a radioligand for neuronal nicotinic receptors were evaluated. The characteristics of [125I]IPH binding in tissue homogenates appeared to be virtually identical to those reported for [3H]epibatidine binding; but the high specific radioactivity of [125I]IPH greatly facilitated measurements of nicotinic receptors in tissues with relatively low receptor densities and/or where tissues are in limited supply. Autoradiography with [125I]IPH provided clear localization of nicotinic receptors in brain and adrenal gland after film exposure times of < or = 2 days. We conclude that [125I]IPH will be a very useful radioligand for the study of neuronal nicotinic receptors in brain and in peripheral ganglia.
ESTHER : Davila-Garcia_1997_J.Pharmacol.Exp.Ther_282_445
PubMedSearch : Davila-Garcia_1997_J.Pharmacol.Exp.Ther_282_445
PubMedID: 9223586