Gao F

References (62)

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 : Personalized venlafaxine dose prediction using artificial intelligence technology: a retrospective analysis based on real-world data - Liu_2024_Int.J.Clin.Pharm__
Author(s) : Liu Y , Yu Z , Ye X , Zhang J , Hao X , Gao F , Yu J , Zhou C
Ref : Int J Clin Pharm , : , 2024
Abstract : BACKGROUND: Venlafaxine dose regimens vary considerably between individuals, requiring personalized dosing. AIM: This study aimed to identify dose-related influencing factors of venlafaxine through real-world data analysis and to construct a personalized dose model using advanced artificial intelligence techniques. METHOD: We conducted a retrospective study on patients with depression treated with venlafaxine. Significant variables were selected through a univariate analysis. Subsequently, the predictive performance of seven models (XGBoost, LightGBM, CatBoost, GBDT, ANN, TabNet, and DT) was compared. The algorithm that demonstrated optimal performance was chosen to establish the dose prediction model. Model validation used confusion matrices and ROC analysis. Additionally, a dose subgroup analysis was conducted. RESULTS: A total of 298 patients were included. TabNet was selected to establish the venlafaxine dose prediction model, which exhibited the highest performance with an accuracy of 0.80. The analysis identified seven crucial variables correlated with venlafaxine daily dose, including blood venlafaxine concentration, total protein, lymphocytes, age, globulin, cholinesterase, and blood platelet count. The area under the curve (AUC) for predicting venlafaxine doses of 75 mg, 150 mg, and 225 mg were 0.90, 0.85, and 0.90, respectively. CONCLUSION: We successfully developed a TabNet model to predict venlafaxine doses using real-world data. This model demonstrated substantial predictive accuracy, offering a personalized dosing regimen for venlafaxine. These findings provide valuable guidance for the clinical use of the drug.
ESTHER : Liu_2024_Int.J.Clin.Pharm__
PubMedSearch : Liu_2024_Int.J.Clin.Pharm__
PubMedID: 38733475

Title : Structural and functional reorganization of inhibitory synapses by activity-dependent cleavage of neuroligin-2 - Xu_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2314541121
Author(s) : Xu N , Cao R , Chen SY , Gou XZ , Wang B , Luo HM , Gao F , Tang AH
Ref : Proc Natl Acad Sci U S A , 121 :e2314541121 , 2024
Abstract : Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABA(A) receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.
ESTHER : Xu_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2314541121
PubMedSearch : Xu_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2314541121
PubMedID: 38657049

Title : Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis - Zhu_2023_J.Neuroinflammation_20_17
Author(s) : Zhu D , Zhang J , Hashem J , Gao F , Chen C
Ref : J Neuroinflammation , 20 :17 , 2023
Abstract : BACKGROUND: 2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid. Inhibition of 2-AG metabolism by inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that degrades 2-AG in the brain, produces anti-inflammatory and neuroprotective effects in neurodegenerative diseases. However, the molecular mechanisms underlying these beneficial effects are largely unclear. METHODS: Hippocampal and cortical cells were isolated from cell type-specific MAGL knockout (KO) mice. Single-cell RNA sequencing was performed by 10 x Genomics platform. Cell Ranger, Seurat (v3.2) and CellChat (1.1.3) packages were used to carry out data analysis. RESULTS: Using single-cell RNA sequencing analysis, we show here that cell type-specific MAGL KO mice display distinct gene expression profiles in the brain. Inactivation of MAGL results in robust changes in expression of immune- and inflammation-related genes in microglia and astrocytes. Remarkably, upregulated expression of chemokines in microglia is more pronounced in mice lacking MAGL in astrocytes. In addition, expression of genes that regulate other cellular functions and Wnt signaling in astrocytes is altered in MAGL KO mice. CONCLUSIONS: Our results provide transcriptomic evidence that cell type-specific inactivation of MAGL induces differential expression of immune-related genes and other fundamental cellular pathways in microglia and astrocytes. Upregulation of the immune/inflammatory genes suggests that tonic levels of immune/inflammatory vigilance are enhanced in microglia and astrocytes, particularly in microglia, by inhibition of 2-AG metabolism, which likely contribute to anti-inflammatory and neuroprotective effects produced by inactivation of MAGL in neurodegenerative diseases.
ESTHER : Zhu_2023_J.Neuroinflammation_20_17
PubMedSearch : Zhu_2023_J.Neuroinflammation_20_17
PubMedID: 36717883

Title : Palladium-catalyzed synthesis and acetylcholinesterase inhibitory activity evaluation of 1-arylhuperzine A derivatives - Xu_2023_J.Asian.Nat.Prod.Res__1
Author(s) : Xu JB , Miao SX , Gao F , Wan LX
Ref : J Asian Nat Prod Res , :1 , 2023
Abstract : A series of arylated huperzine A (HPA) derivatives (1-24) were efficiently synthesized in good yields (45-88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer's disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.
ESTHER : Xu_2023_J.Asian.Nat.Prod.Res__1
PubMedSearch : Xu_2023_J.Asian.Nat.Prod.Res__1
PubMedID: 37098899

Title : Insights into the Effects of Insecticides on Aphids (Hemiptera: Aphididae): Resistance Mechanisms and Molecular Basis - Kaleem_2023_Int.J.Mol.Sci_24_
Author(s) : Kaleem Ullah RM , Gao F , Sikandar A , Wu H
Ref : Int J Mol Sci , 24 : , 2023
Abstract : With the passage of time and indiscreet usage of insecticides on crops, aphids are becoming resistant to their effect. The different classes of insecticides, including organophosphates, carbamates, pyrethroids and neonicotinoids, have varied effects on insects. Furthermore, the molecular effects of these insecticides in aphids, including effects on the enzymatic machinery and gene mutation, are resulting in aphid resistance to the insecticides. In this review, we will discuss how aphids are affected by the overuse of pesticides, how resistance appears, and which mechanisms participate in the resistance mechanisms in various aphid species as significant crop pests. Gene expression studies were analyzed using the RNA-Seq technique. The stress-responsive genes were analyzed, and their expression in response to insecticide administration was determined. Putative insecticide resistance-related genes, cytochrome P450, glutathione S-transferase, carboxylesterase CarEs, ABC transporters, cuticle protein genes, and trypsin-related genes were studied. The review concluded that if insecticide-susceptible aphids interact with ample dosages of insecticides with sublethal effects, this will result in the upregulation of genes whose primary role is to detoxify insecticides. In the past decade, certain advancements have been observed regarding insecticide resistance on a molecular basis. Even so, not much is known about how aphids detoxify the insecticides at molecular level. Thus, to attain equilibrium, it is important to observe the manipulation of pest and insect species with the aim of restoring susceptibility to insecticides. For this purpose, this review has included critical insights into insecticide resistance in aphids.
ESTHER : Kaleem_2023_Int.J.Mol.Sci_24_
PubMedSearch : Kaleem_2023_Int.J.Mol.Sci_24_
PubMedID: 37047722

Title : In-situ growth of SnO(2) nanoparticles on Nb(2)CT(x) nanosheets as highly sensitive electrochemical sensing platform for organophosphorus pesticide detection - Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
Author(s) : Guo W , Liang L , Zhao Y , Zhao C , Lu X , Cao Y , Gao F
Ref : Colloids Surf B Biointerfaces , 224 :113238 , 2023
Abstract : In this study, the SnO(2)/Nb(2)CT(x) MXene nanocomposite containing 0D/2D interfaces was prepared by situ growth strategy of one-step hydrothermal method. A SnO(2)/Nb(2)CT(x) MXene based acetylcholinesterase (AChE) biosensor was constructed for pesticide detection. Highly conductive Nb(2)CT(x) MXene, acting as substrate material, restrained the agglomeration of nanoparticles (NPs) and accelerated electron migration due to the confinement effect and well-known accordion-like layered structure. In addition, SnO(2) anchored on both sides of the Nb(2)CT(x) MXene nanosheets effectively provided a large surface area, abundant surface groups and active sites, which preserved numbers of electrons at the interface of the heterojunction. The SnO(2)/Nb(2)CT(x) MXene hybrids with outstanding conductivity, good biocompatibility and structural stability were beneficial for AChE immobilization. Under the optimized conditions, as-fabricated electrochemical biosensor demonstrated superior performance with linear detection range of 5.1 x 10(-14) - 5.1 x 10(-7) M for chlorpyrifos, along with the limit of detection (LOD) down to 5.1 x 10(-14) M (calculated for 10% inhibition). Furthermore, it is highly expected that this biosensor can be applied for the detection of other organophosphorus pesticides in the environment, providing an effective nanoplatform in biosensing field.
ESTHER : Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
PubMedSearch : Guo_2023_Colloids.Surf.B.Biointerfaces_224_113238
PubMedID: 36870270

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 : Glycine and N-Acetylcysteine (GlyNAC) Combined with Body Weight Support Treadmill Training Improved Spinal Cord and Skeletal Muscle Structure and Function in Rats with Spinal Cord Injury - Xu_2023_Nutrients_15_
Author(s) : Xu X , Du HY , Talifu Z , Zhang CJ , Li ZH , Liu WB , Liang YX , Xu XL , Zhang JM , Yang DG , Gao F , Du LJ , Yu Y , Jing YL , Li JJ
Ref : Nutrients , 15 : , 2023
Abstract : Skeletal muscle atrophy is a frequent complication after spinal cord injury (SCI) and can influence the recovery of motor function and metabolism in affected patients. Delaying skeletal muscle atrophy can promote functional recovery in SCI rats. In the present study, we investigated whether a combination of body weight support treadmill training (BWSTT) and glycine and N-acetylcysteine (GlyNAC) could exert neuroprotective effects, promote motor function recovery, and delay skeletal muscle atrophy in rats with SCI, and we assessed the therapeutic effects of the double intervention from both a structural and functional viewpoint. We found that, after SCI, rats given GlyNAC alone showed an improvement in Basso-Beattie-Bresnahan (BBB) scores, gait symmetry, and results in the open field test, indicative of improved motor function, while GlyNAC combined with BWSTT was more effective than either treatment alone at ameliorating voluntary motor function in injured rats. Meanwhile, the results of the skeletal muscle myofiber cross-sectional area (CSA), hindlimb grip strength, and acetylcholinesterase (AChE) immunostaining analysis demonstrated that GlyNAC improved the structure and function of the skeletal muscle in rats with SCI and delayed the atrophication of skeletal muscle.
ESTHER : Xu_2023_Nutrients_15_
PubMedSearch : Xu_2023_Nutrients_15_
PubMedID: 37960231

Title : Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke - Yu_2023_J.Am.Heart.Assoc_12_e026901
Author(s) : Yu D , Liang N , Zebarth J , Shen Q , Ozzoude M , Goubran M , Rabin JS , Ramirez J , Scott CJM , Gao F , Bartha R , Symons S , Haddad SMH , Berezuk C , Tan B , Kwan D , Hegele RA , Dilliott AA , Nanayakkara ND , Binns MA , Beaton D , Arnott SR , Lawrence-Dewar JM , Hassan A , Dowlatshahi D , Mandzia J , Sahlas D , Casaubon L , Saposnik G , Otoki Y , Lanctot KL , Masellis M , Black SE , Swartz RH , Taha AY , Swardfager W
Ref : J Am Heart Assoc , 12 :e026901 , 2023
Abstract : Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME]sand 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME]sand 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imagingscriteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared withsparticipants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (beta=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (beta=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (beta=0.364, P<0.001; beta=0.362, P<0.001) and white matter MRI-visible perivascular spaces (beta=0.302, P=0.011; beta=0.314, P=0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (beta=0.439, P=0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (beta=-0.277, P=0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.
ESTHER : Yu_2023_J.Am.Heart.Assoc_12_e026901
PubMedSearch : Yu_2023_J.Am.Heart.Assoc_12_e026901
PubMedID: 36583428

Title : The porous hollow cobalt-based oxides encapsulated with bimetallic PdAu Nanoparticles of electrochemical biosensor for highly sensitive pesticides detection - Zhao_2023_Nanotechnology__
Author(s) : Zhao Y , Liang L , Guo W , Lu X , Zhao C , Gao F
Ref : Nanotechnology , : , 2023
Abstract : Efficient and portable electrochemical biosensors are received to evaluation of pesticides in the environment, which can make great significance for food safety. In this study, the Co-based oxides with a kind of hierarchical porous hollow and nanocages were constructed, in which the materials (Co3O4-NC) were encapsulated with PdAu nanoparticles (NPs). Due to the unique porous structure, the changeable valence state of cobalt and the synergistic effect of bimetallic PdAuNPs, PdAu@Co3O4-NC possessed excellent electron pathways, and showed more exposed active sites. Accordingly, the porous Co-based oxides have been applied to construct an acetylcholinesterase (AChE) electrochemical biosensor, which showed good performance for organophosphorus pesticides (OPs) detection. The optimum biosensing platform based on nanocomposites was applied to exhibit highly sensitive determination of omethoate and chlorpyrifos, with the relative low detection limit of 6.125 x 10-15 M and 5.10 x 10-13 M, respectively. And a wide detection range of 6.125 x 10-15 ~ 6.125 x 10-6 M and 5.10 x 10-13 ~ 5.10 x 10-6 M for these two pesticides were achieved. Therefore, the PdAu@Co3O4-NC may represent a powerful tool for ultrasensitive sensing of OPs, and have great potential application.
ESTHER : Zhao_2023_Nanotechnology__
PubMedSearch : Zhao_2023_Nanotechnology__
PubMedID: 37054697

Title : Core-shell ZnO@CoO nitrogen doped nano-composites as highly sensitive electrochemical sensor for organophosphate pesticides detection - Li_2023_Anal.Biochem__115422
Author(s) : Li Z , Lu X , Liu G , Yang L , Gao F
Ref : Analytical Biochemistry , :115422 , 2023
Abstract : Core-shell ZIF-8@ZIF-67 was synthesized by growing a cobalt-based ZIF-67 on a ZIF-8 seed particle. Herein, through selective etching of the ZIF-8@ZIF-67 core and subsequent direct carbonization, core-shell hollow ZnO@CoO nitrogen-doped nanoporous carbon (HZnO@CoO-NPC) nanocomposites were prepared. HZnO@CoO-NPCs possessed a high nitrogen content, large surface area, high degree of graphitization and excellent electrical conductivity, all of which were attributed to successfully integrating the unique advantages of ZIF-8 and ZIF-67. HZnO@CoO-NPCs were used to assemble acetylcholinesterase (AChE) biosensors for organophosphorus pesticides (OPs) detection. The low detection limit of 2.74 x 10(-13) M for chlorpyrifos and 7.6 x 10(-15) M for parathion-methyl demonstrated the superior sensing performance. The results showed that the electrochemical biosensor constructed by HZnO@CoO-NPC provided a sensitive and efficient electrochemical strategy for OPs detection.
ESTHER : Li_2023_Anal.Biochem__115422
PubMedSearch : Li_2023_Anal.Biochem__115422
PubMedID: 38070664

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 : A stable enzyme sensor via embedding enzymes into zeolitic imidazolate frameworks for pesticide determination - Zhao_2022_Anal.Biochem__114628
Author(s) : Zhao Y , Lu X , Gao F
Ref : Analytical Biochemistry , :114628 , 2022
Abstract : The stability of biosensors is of significant importance for practical applications, and the natural biomineralization processes in living organisms have inspired us from a new perspective. In this work, acetylcholinesterase (AChE) was embedded into zeolitic imidazolate framework-8 carriers (with negligible cytotoxicity) via biomimetic mineralization, being demonstrated to be a stable strategy for enzyme immobilization. When further coupled with the conductive and catalytic Au nanoparticles, the biocomposites were explored as electrochemical pesticide detection biosensor, which showed favorable analytical performance, and improved stability comparing with other biosensors. This work provides a new strategy for the reasonable design of stable biosensors for different analytes monitoring.
ESTHER : Zhao_2022_Anal.Biochem__114628
PubMedSearch : Zhao_2022_Anal.Biochem__114628
PubMedID: 35257680

Title : Design, synthesis and insecticidal activity and mechanism research of Chasmanthinine derivatives - Song_2022_Sci.Rep_12_15290
Author(s) : Song Z , Li X , Xu K , Sun G , Yang L , Huang L , Liu J , Yin P , Huang S , Gao F , Zhou X , Chen L
Ref : Sci Rep , 12 :15290 , 2022
Abstract : Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC(50) = 0.10 mg/cm(2)) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC(50) = 12.87 microM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection.
ESTHER : Song_2022_Sci.Rep_12_15290
PubMedSearch : Song_2022_Sci.Rep_12_15290
PubMedID: 36088472

Title : Sublethal Effects of Thiamethoxam on Biological Traits and Detoxification Enzyme Activities in the Small Brown Planthopper, Laodelphax striatellus (Falln) - Cai_2022_J.Econ.Entomol__
Author(s) : Cai Y , Dou T , Gao F , Wang G , Dong Y , Song N , An S , Yin X , Liu X , Ren Y
Ref : J Econ Entomol , : , 2022
Abstract : The small brown planthopper (Laodelphax striatellus (Falln), Hemiptera: Delphacidae), is an important agricultural pest of rice, and neonicotinoid insecticides are commonly used for controlling L. striatellus. However, the sublethal effects of thiamethoxam on L. striatellus remain relatively unknown. In this study, an age-stage life table procedure was used to evaluate the sublethal effects of thiamethoxam on the biological parameters of L. striatellus. Additionally, activities of carboxylesterase, glutathione S-transferase, and cytochrome P450 monooxygenase in the third instar nymphs were analyzed. The results indicated that the survival time of F0 adults and the fecundity of female adults decreased significantly after the third instar nymphs were treated with sublethal concentrations of thiamethoxam (LC15 0.428 mg/liter and LC30 0.820 mg/liter). The developmental duration, adult preoviposition period, total preoviposition period, and mean generation time of the F1 generation increased significantly, whereas the fecundity of the female adults, intrinsic rate of increase (ri), and finite rate of increase (Lambda) decreased significantly. The oviposition period was significantly shorter for the insects treated with LC30 than for the control insects. Neither sublethal concentrations had significant effects on the adult longevity, net reproduction rate (R0), or gross reproduction rate (GRR) of the F1 generation. The activities of carboxylesterase, glutathione-S-transferase, and cytochrome P450 monooxygenase increased significantly after the thiamethoxam treatments. These results indicate that sublethal concentrations of thiamethoxam can inhibit L. striatellus population growth and enhance detoxification enzyme activities.
ESTHER : Cai_2022_J.Econ.Entomol__
PubMedSearch : Cai_2022_J.Econ.Entomol__
PubMedID: 36351784

Title : Ternary heterostructures of 1D\/2D\/2D CuCo(2)S(4)\/CuS\/Ti(3)C(2) MXene: Boosted amperometric sensing for chlorpyrifos - Mi_2022_J.Hazard.Mater_438_129419
Author(s) : Mi Y , Zhao Y , Chen J , Li X , Yang Y , Gao F
Ref : J Hazard Mater , 438 :129419 , 2022
Abstract : Multicomponent heterogeneous Ti(3)C(2) transition metal carbide (MXene)-based materials are receiving extensive research attention due to their interesting synergistic interactions and catalytic properties. However, the morphology-controllable synthesis of heterostructures as structural stabilizers for Ti(3)C(2) MXene remains a challenge owing the complicated synthesis procedure. In this work, a kind of ternary heterogeneous nanomaterials CuCo(2)S(4)/CuS/Ti(3)C(2) MXene with a nanorod/nanoplate/nanosheet hybrid architecture is constructed through a one-step low-temperature solvothermal method. The well-designed ternary one-dimensional (1D)/two-dimensional (2D)/2D CuCo(2)S(4)/CuS/Ti(3)C(2) MXene heteromaterials exhibit synergistic improvements in substrate-catalyzed reactions for electrochemical acetylcholinesterase (AChE) biosensor. The Michaelis-Menten constant for the Nafion/AChE/CuCo(2)S(4)/CuS/Ti(3)C(2) MXene/GCE biosensor is 228 microM, which is smaller than ones reported in previous literatures, indicating a higher affinity of the fabricated enzyme biosensor to acetylthiocholine chloride. The biosensor exhibits a well linear relationship with chlorpyrifos concentration ranging from 2.852 x 10(-12) M to 2.852 x 10(-6) M. The multicomponent 1D/2D/2D CuCo(2)S(4)/CuS/Ti(3)C(2) MXene heteromaterial may shine a light in more electrochemical applications.
ESTHER : Mi_2022_J.Hazard.Mater_438_129419
PubMedSearch : Mi_2022_J.Hazard.Mater_438_129419
PubMedID: 35780734

Title : Two new C18-diterpenoid alkaloids from Aconitum leucostomum Worosch - Zhou_2022_Chem.Biodivers__
Author(s) : Zhou X , Yang HB , Luo YY , Xu JB , Liu Y , Gao F , Huang S , Chen L
Ref : Chem Biodivers , : , 2022
Abstract : Two new lappaconitine-type C18-diterpenoid alkaloids, named as leucostosines C (1) and D (2), together with six known compounds (3-8), were isolated from the roots of Aconitum leucostomum Worosch. Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, NMR spectra and X-ray experiments. Leucostosine C is the first diterpenoid alkaloid bearing the 7-amino group. The isolated compounds were tested for the acetylcholinesterase (AChE) inhibitory effect and neuroprotective activity, none of them showed significant activities.
ESTHER : Zhou_2022_Chem.Biodivers__
PubMedSearch : Zhou_2022_Chem.Biodivers__
PubMedID: 36094326

Title : Simultaneous CSM-TACE with CalliSpheres() and partial splenic embolization using 8spheres() for hepatocellular carcinoma with hypersplenism: Early prospective multicenter clinical outcome - Zhou_2022_Front.Oncol_12_998500
Author(s) : Zhou J , Feng Z , Liu S , Li X , Liu Y , Gao F , Shen J , Zhang YW , Zhao GS , Zhang M
Ref : Front Oncol , 12 :998500 , 2022
Abstract : BACKGROUND: Primary hepatocellular carcinoma is often complicated with hepatitis and liver cirrhosis. Some patients develop different degrees of splenomegaly, hypersplenism and hypohepatia due to the aggravation of liver cirrhosis, which to some extent interfere with the treatment of tumors and even affect the prognosis of patients. In this study, we prospectively evaluate the efficacy and safety of simultaneous CalliSpheres((a)) microspheres transcatheter arterial chemoembolization (CSM-TACE) and partial splenic embolization (PSE) using 8spheres((a)) for hepatocellular carcinoma (HCC) with hypersplenism. METHODS: Ninety consecutive HCC patients with hypersplenism who underwent CSM-TACE were selected: 32 patients in CSM-TACE+PSE group, and 58 patients in CSM-TACE group. The peripheral blood cell counts (leukocyte, platelet (PLT), liver function and red blood cell (RBC)), CSM-TACE and/or PSE related complications, and the tumor control rate at 1 month after CSM-TACE were compared. The survival time and prognostic factors were also observed. RESULTS: Before CSM-TACE, there were no significant differences in sex, age, Child-Pugh grade, tumor size, and alpha-fetoprotein (AFP) between the two groups. After CSM-TACE, the PLT and white blood cell (WBC) counts in CSM-TACE+PSE group were significantly higher than those in the CSM-TACE group (P<0.05). There were no significant differences in RBC before and after treatment (P > 0.05). In the CSM-TACE group, there were no significant differences in WBC, PLT, and RBC before and after treatment (P > 0.05). There was no significant difference in liver function at 1 month after treatment between the two groups. The cholinesterase (CHE) level in the CSM-TACE+PSE group after CSM-TACE+PSE was obviously higher than that before CSM-TACE+PSE and higher than that in the CSM-TACE group (P<0.05). However, the level of CHE returned to the preoperative level 1 month after CSM-TACE in the CSM-TACE group. The objective response rate (ORR) and median overall survival (OS) in the CSM-TACE+PSE group were higher than those in the CSM-TACE group (P<0.05). The adverse reactions of the two groups were fever, abdominal pain, stomach discomfort, nausea, and vomiting, and no serious complications occurred. The degree of abdominal pain and fever in the experimental group was lower than that in the control group (P > 0.05). CONCLUSIONS: Simultaneous CSM-TACE and PSE using domestic embolization particles for HCC with hypersplenism have good safety and efficacy and has a low incidence of PSE-related adverse events, it is conducive to improving liver function reserve, and can further improve the median OS.
ESTHER : Zhou_2022_Front.Oncol_12_998500
PubMedSearch : Zhou_2022_Front.Oncol_12_998500
PubMedID: 36530976

Title : Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer's Disease - Hashem_2021_Mol.Neurobiol__
Author(s) : Hashem J , Hu M , Zhang J , Gao F , Chen C
Ref : Molecular Neurobiology , : , 2021
Abstract : Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates beta-amyloid (Abeta) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3beta and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARgamma in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.
ESTHER : Hashem_2021_Mol.Neurobiol__
PubMedSearch : Hashem_2021_Mol.Neurobiol__
PubMedID: 33939165

Title : Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives - Wan_2021_ACS.Omega_6_9960
Author(s) : Wan LX , Zhen YQ , He ZX , Zhang Y , Zhang L , Li X , Gao F , Zhou XL
Ref : ACS Omega , 6 :9960 , 2021
Abstract : A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC(50) values of 1.77 and 1.48 microM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC(50) value of 5.16 microM). Compound 3o also displayed anti-BuChE activity with an IC(50) value of 19.00 microM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H(2)O(2)-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer's disease.
ESTHER : Wan_2021_ACS.Omega_6_9960
PubMedSearch : Wan_2021_ACS.Omega_6_9960
PubMedID: 33869976

Title : A new diterpenoid alkaloid from Delphinium gyalanum C. Marquand & Airy Shaw - Li_2021_Nat.Prod.Res__1
Author(s) : Li X , Ye M , Gao F , Zhou X , Chen L , Huang S
Ref : Nat Prod Res , :1 , 2021
Abstract : A new C(19)-diterpenoid alkaloid named gyalanutine A (1) and fourteen known compounds 2-15 were isolated from the plant of Delphinium gyalanum C. Marquand & Airy Shaw. Compound 1 displayed an unusual lycoctonine-type C(19)-diterpenoid alkaloid skeleton with the cleavage of N-C(19) and C(7)-C(17) bonds, and the construction of the N-C(7) bond. Structures were identified by multiple spectroscopic analyses including 1 D, 2 D NMR, IR and HR-ESI-MS. Compounds were tested for acetylcholinesterase inhibitory and anti-inflammatory activity.
ESTHER : Li_2021_Nat.Prod.Res__1
PubMedSearch : Li_2021_Nat.Prod.Res__1
PubMedID: 34241556

Title : Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis - Wang_2021_Front.Immunol_12_753247
Author(s) : Wang S , Yang H , Guo R , Wang L , Zhang Y , Lv J , Zhao X , Zhang J , Fang H , Zhang Q , Yang J , Cui X , Gao P , Chang T , Gao F
Ref : Front Immunol , 12 :753247 , 2021
Abstract : This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.
ESTHER : Wang_2021_Front.Immunol_12_753247
PubMedSearch : Wang_2021_Front.Immunol_12_753247
PubMedID: 34956185

Title : Pd-Catalyzed Direct Modification of an Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of alpha-Aryl Donepezil Analogues - Wan_2021_ACS.Omega_6_23347
Author(s) : Wan LX , Miao SX , He ZX , Li X , Zhou XL , Gao F
Ref : ACS Omega , 6 :23347 , 2021
Abstract : Palladium/BuAd(2)P efficiently catalyzed the direct alpha-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H(2)O(2)-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).
ESTHER : Wan_2021_ACS.Omega_6_23347
PubMedSearch : Wan_2021_ACS.Omega_6_23347
PubMedID: 34549134

Title : Endocannabinoid Metabolism and Traumatic Brain Injury - Zhu_2021_Cells_10_
Author(s) : Zhu D , Gao F , Chen C
Ref : Cells , 10 : , 2021
Abstract : Traumatic brain injury (TBI) represents a major cause of morbidity and disability and is a risk factor for developing neurodegenerative diseases, including Alzheimer's disease (AD). However, no effective therapies are currently available for TBI-induced AD-like disease. Endocannabinoids are endogenous lipid mediators involved in a variety of physiological and pathological processes. The compound 2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid with profound anti-inflammatory and neuroprotective properties. This molecule is predominantly metabolized by monoacylglycerol lipase (MAGL), a key enzyme degrading about 85% of 2-AG in the brain. Studies using animal models of inflammation, AD, and TBI provide evidence that inactivation of MAGL, which augments 2-AG signaling and reduces its metabolites, exerts neuroprotective effects, suggesting that MAGL is a promising therapeutic target for neurodegenerative diseases. In this short review, we provide an overview of the inhibition of 2-AG metabolism for the alleviation of neuropathology and the improvement of synaptic and cognitive functions after TBI.
ESTHER : Zhu_2021_Cells_10_
PubMedSearch : Zhu_2021_Cells_10_
PubMedID: 34831202

Title : Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of N-Aryl Huperzine A Analogues - Miao_2021_J.Nat.Prod_84_2374
Author(s) : Miao SX , Wan LX , He ZX , Zhou XL , Li X , Gao F
Ref : Journal of Natural Products , 84 :2374 , 2021
Abstract : The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of N-(hetero)aryl analogues (1-32) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the N-aryl-huperzine A (N-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in in vitro experiments. Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (30) displayed the most potent AChE inhibition activity, with an IC(50) value of 1.5 microM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H(2)O(2)-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.
ESTHER : Miao_2021_J.Nat.Prod_84_2374
PubMedSearch : Miao_2021_J.Nat.Prod_84_2374
PubMedID: 34445873

Title : Four New Diterpenoid Alkaloids from The Roots of Aconitum coreanum - Xu_2020_Chem.Biodivers_17_e1900600
Author(s) : Xu JB , Luo YY , Huang S , Gao F , Zhou XL
Ref : Chem Biodivers , 17 :e1900600 , 2020
Abstract : Four new hetisine-type C20 -diterpenoid alkaloids, named as coreanines A-D (1-4), were isolated from the roots of Aconitum coreanum, together with thirteen known alkaloids (5-17). Their structures were elucidated by extensive spectroscopic methods including IR, HR-ESI-MS and NMR techniques. All the isolated compounds were screened for the acetylcholinesterase (AChE) inhibitory effects, and none of them showed considerable inhibitory activity.
ESTHER : Xu_2020_Chem.Biodivers_17_e1900600
PubMedSearch : Xu_2020_Chem.Biodivers_17_e1900600
PubMedID: 31793197

Title : Enantioselective synthesis of a chiral intermediate of himbacine analogs by Burkholderia cepacia lipase A - Chen_2020_Biotechnol.Lett_42_2643
Author(s) : Chen Y , Gao F , Zheng G , Gao S
Ref : Biotechnol Lett , 42 :2643 , 2020
Abstract : The enantiomers of (4R/S)-4-hydroxy-N, N-diphenyl-2-pentynamide are key chiral synthons for the synthesis of thrombin receptor antagonists such as vorapaxar. In this paper, we report the enzymatic preparation of enantiomerically enriched (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide using lipase A from Burkholderia cepacia ATCC 25416 as the catalyst. First, the lipase gene (lipA) and its chaperone gene (lipB) was cloned and expressed in Escherichia coli system. After purification, lipase A activation was performed with the assistance of foldase lipase B. Enzyme assay revealed that the activated lipase A showed the optimal catalytic activity at 60 degC and pH 7. The effects of various metals on the activity were investigated and results demonstrated that most of the metals inhibited the activity. To further improve the catalytic outcome, two-phase reaction was studied, and n-hexane proved to be a good organic solvent for the combination system. Using the optimize conditions, (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide with 94.5% ee value and 48.93% conversion ratio was achieved. Our investigation on this lipase reveals lipase A as a promising biocatalyst for producing chiral propargyl alcohol for preparation of novel himbacine analogs.
ESTHER : Chen_2020_Biotechnol.Lett_42_2643
PubMedSearch : Chen_2020_Biotechnol.Lett_42_2643
PubMedID: 32691184

Title : Diterpenoid alkaloids from Aconitum anthoroideum that offer protection against MPP(+)-Induced apoptosis of SH-SY5Y cells and acetylcholinesterase inhibitory activity - Huang_2020_Phytochemistry_178_112459
Author(s) : Huang S , Zhang JF , Chen L , Gao F , Zhou XL
Ref : Phytochemistry , 178 :112459 , 2020
Abstract : Nine unprecedented diterpenoid alkaloid, including a diterpenoid alkaloid featuring a diterpenoid moiety, anthoroidine A; one bisditerpenoid alkaloid joined with a carbon-carbon single bond, anthoroidine B; three racemulosine-type C(20)-diterpenoid alkaloids, anthoroidines C-E; one hetidine-type C(20)-diterpenoid alkaloid, anthoroidine F; and three hetisine-type C(20)-diterpenoid alkaloids, anthoroidines G-I, together with ten known diterpenoid alkaloids were isolated from Aconitum anthoroideum DC. Their structures were established via detailed spectroscopic analyses. Most of the isolated compounds along with five known diterpenoid alkaloids obtained in a previous study were screened for neuroprotective activities and acetylcholinesterase inhibitory effects. Nominine showed potent protective activity against MPP(+)-induced apoptosis in SH-SY5Y cells, with a rescue rate of 34.4% (50 muM). Rotundifosine F showed a significant inhibitory activity against AChE (IC(50) = 0.3 muM). The structure-activity relationship of these alkaloids is also briefly discussed.
ESTHER : Huang_2020_Phytochemistry_178_112459
PubMedSearch : Huang_2020_Phytochemistry_178_112459
PubMedID: 32888673

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 : Effects of Different Dietary Flavonoids on Dipeptidyl Peptidase-IV Activity and Expression: Insights into Structure-Activity Relationship - Gao_2020_J.Agric.Food.Chem_68_12141
Author(s) : Gao F , Fu Y , Yi J , Gao A , Jia Y , Cai S
Ref : Journal of Agricultural and Food Chemistry , 68 :12141 , 2020
Abstract : The inhibitory effects of 30 dietary flavonoids on dipeptidyl peptidase-IV (DPP-IV) were investigated to illustrate their quantitative structure-activity relationship (QSAR) and further explore their inhibition at the cellular level. Results of in vitro experiment show that isorhamnetin-3-O-glucoside (IC(50), 6.53 +/- 0.280 microM) had the strongest inhibition followed by cyanidin-3-O-glucoside (IC(50), 8.26 +/- 0.143 microM) and isorhamnetin-3-O-rutinoside (IC(50), 8.57 +/- 0.422 microM). A 3D QSAR model [comparative molecular field analysis, q(2) = 0.502, optimum number of components (ONC) = 3, R(2) = 0.983, F = 404.378, standard error of estimation (SEE) = 0.070, and two descriptors; comparative similarity index analysis, q(2) = 0.580, ONC = 10, R(2) = 0.999, F = 1617.594, SEE = 0.022, and four descriptors] indicates that the DPP-IV inhibition of flavonoid was facilitated by crucial structural factors. Position 3 of ring C favored bulky, hydrogen bond acceptors and hydrophilic and electron-donating substituents. The presence of minor and electron-withdrawing groups at position 4' of ring B and positions 5 and 7 of ring A could improve DPP-IV inhibition. Moreover, the three flavonoids mentioned above could effectively suppress DPP-IV activity and expression in Caco-2 cells. This work may supply new insights into dietary flavonoids as DPP-IV inhibitors for controlling blood glucose.
ESTHER : Gao_2020_J.Agric.Food.Chem_68_12141
PubMedSearch : Gao_2020_J.Agric.Food.Chem_68_12141
PubMedID: 33063510

Title : Fifteen new diterpenoid alkaloids from the roots of Aconitum kirinense Nakai - Jiang_2020_Fitoterapia__104477
Author(s) : Jiang GY , Qin LL , Gao F , Huang S , Zhou XL
Ref : Fitoterapia , :104477 , 2020
Abstract : Extensive phytochemical investigation from the roots of Aconitum kirinense Nakai led to the identification of fifteen new compounds, including four ranaconitine type C18-diterpenoid alkaloids (kirisines A-D, 1-4), one lappaconitine type C18-diterpenoid alkaloid (kirisine E, 5), seven denudatine type C20-diterpenoid alkaloids (kirisines F-L, 6-12), and three napelline type C20-diterpenoid alkaloids (kirisines M-O, 13-15), together with 25 known ones. Their structures were elucidated by extensive spectroscopic analyses. Among them, compounds 1 and 2 are rare diterpenoid alkaloid with 9,14-methylenedioxy group, and the latter also has a rare chloro-substituent. The diterpenoid alkaloids isolated were C18, C19 and C20-category, which might provide further clues for understanding the chemotaxonomic significance of this plant. The isolated compounds were tested for neuroprotective activity and acetylcholinesterase inhibitory activity. Compounds 7, 18, 30 and 40 which exhibited moderate activity at 80muM against acetylcholinesterase.
ESTHER : Jiang_2020_Fitoterapia__104477
PubMedSearch : Jiang_2020_Fitoterapia__104477
PubMedID: 31927015

Title : Clinical analysis of Chinese anti-low-density-lipoprotein-receptor-associated protein 4 antibodies in patients with myasthenia gravis - Li_2019_Eur.J.Neurol_26_1296
Author(s) : Li M , Han J , Zhang Y , Lv J , Zhang J , Zhao X , Ren L , Fang H , Yang J , Cui X , Zhang Q , Li Q , Du Y , Gao F
Ref : Eur Journal of Neurology , 26 :1296 , 2019
Abstract : BACKGROUND AND PURPOSE: Low-density-lipoprotein-receptor-associated protein 4 (LRP4) autoantibodies have recently been detected in myasthenia gravis (MG), but little is known about the clinical characteristics associated with this serological type. In this study, the clinical features of Chinese patients with anti-LRP4 antibody-positive MG were characterized. METHODS: A total of 2172 MG serum samples were collected from patients in various parts of China. An enzyme-linked immunosorbent assay was used to detect acetylcholine receptor (AChR) antibody and titin antibody, and cell-based assays were used to detect muscle-specific kinase antibody and LRP4 antibody. Clinical data for patients with MG were collected from different provinces in China. RESULTS: In total, 16 (0.8%) patients with LRP4-MG were found amongst 2172 total patients, including three patients with AChR/LRP4-MG. Additionally, 13 (2.9%) patients with LRP4-MG were found amongst 455 patients with double seronegative MG. The ratio of males to females for these 13 patients was 1:1.6, and 53.8% patients were children. A total of 91.7% of cases exhibited initial ocular involvement, and 58.3% of cases exhibited simple eye muscle involvement. Responses to acetylcholinesterase inhibitors and prednisone were observed. CONCLUSION: The expanded sample confirmed that the positive rate of LRP4 antibodies in China is lower than that in western countries. Our results highlighted the differences between LRP4-MG and other antibody groups. Children and female patients with LRP4-MG have a higher prevalence, often involving the ocular muscles and limb muscles. The clinical symptoms are mild, and satisfactory responses to treatment are often achieved.
ESTHER : Li_2019_Eur.J.Neurol_26_1296
PubMedSearch : Li_2019_Eur.J.Neurol_26_1296
PubMedID: 31050101

Title : Exosomes Released from Rabies Virus-Infected Cells May be Involved in the Infection Process - Wang_2019_Virol.Sin_34_59
Author(s) : Wang J , Wu F , Liu C , Dai W , Teng Y , Su W , Kong W , Gao F , Cai L , Hou A , Jiang C
Ref : Virol Sin , 34 :59 , 2019
Abstract : Exosomes are cell-derived vesicles that are secreted by many eukaryotic cells. It has recently attracted attention as vehicles of intercellular communication. Virus-infected cells release exosomes, which contain viral proteins, RNA, and pathogenic molecules. However, the role of exosomes in virus infection process remains unclear and needs to be further investigated. In this study, we aimed to evaluate the effects of exosomes on rabies virus infection. OptiPrep density gradient centrifugation was used to isolate exosomes from rabies virus-infected cell culture supernatants. A rabies virus G protein enzyme-linked immunosorbent assay and acetylcholinesterase activity assays were performed to verify the centrifugation fractions. Exosomes were then characterized using transmission electron microscopy and Western blotting. Our results showed that rabies virus infection increased the release of exosomes. Treatment with GW4869 and si-Rab27a, two exosomal secretion inhibitors, inhibited exosome release. Furthermore, the inhibitors reduced the levels of extracellular and intracellular viral RNA. These data indicated that exosomes may participate in the viral infection process. Moreover, our results establish a basis for future research into the roles of exosomes in rabies virus infection and as potential targets for developing new antiviral strategies.
ESTHER : Wang_2019_Virol.Sin_34_59
PubMedSearch : Wang_2019_Virol.Sin_34_59
PubMedID: 30725320

Title : [Distribution characteristics and correlation analysis of antibody detection value in myasthenia gravis] - Liu_2019_Zhonghua.Yi.Xue.Za.Zhi_99_3221
Author(s) : Liu YL , Zheng YM , Luo JJ , Zhang W , Gao F , Yuan Y , Hao HJ
Ref : Zhonghua Yi Xue Za Zhi , 99 :3221 , 2019
Abstract : Objective: To determine the factors affecting distribution and magnitude of antibody detection value in myasthenia gravis (MG). Methods: A total of 406 MG patients diagnosed at Department of Neurology, Peking University First Hospital from May 2015 to November 2017 were included.All of them exhibited muscle fatigue with decreased response in repetitive nerve stimulation test. There were 200 males and 206 females whose ages ranged from 2 to 85 years old. According to clinical classification of MG recommended by Myasthenia Gravis Foundation of America (MGFA), patients assigned to class I to class V included 200,140, 46, 15 and 5 cases, respectively. There were 33 cases of thymic hyperplasia and 63 cases of thymoma confirmed by radiological or pathological findings. Quantile plots and quantile regression model were used to determine the effects of age, gender and MGFA classification, thymus disease on acetylcholine receptors (AChR)antibody, acetylcholinesterase (AChE) antibody, Titin antibody, ryanodine receptor (RyR) antibody and muscle-specific tyrosine kinase (MuSK) antibody detection values detected by enzyme-linked immunosorbent assay (ELISA). Results: MGFA classification had effects on distribution of AChR antibody level. There was a positive correlation between age and AChR antibody level(P<0.05). Negative correlation was found between age and AChE, Titin and RyR antibody level (P<0.05). No significant correlation was shown between any factors and MuSK antibody level(P>/=0.05). MGFA classification had a positive correlation with AChR antibody level (P<0.05) and no correlation with other antibody levels (P>0.05). Gender and thymus disease had no correlation with any tested antibody levels (P>0.05). Conclusion: MGFA classification has significant effects on distribution of AChR antibody level. Age and MGFA classification have positive correlation with AChR antibody level.
ESTHER : Liu_2019_Zhonghua.Yi.Xue.Za.Zhi_99_3221
PubMedSearch : Liu_2019_Zhonghua.Yi.Xue.Za.Zhi_99_3221
PubMedID: 31694116

Title : Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment - Yu_2019_Transl.Stroke.Res_10_522
Author(s) : Yu D , Hennebelle M , Sahlas DJ , Ramirez J , Gao F , Masellis M , Cogo-Moreira H , Swartz RH , Herrmann N , Chan PC , Pettersen JA , Stuss DT , Black SE , Taha AY , Swardfager W
Ref : Transl Stroke Res , 10 :522 , 2019
Abstract : White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (beta = - 0.473, p = 0.001, adjusted r(2) = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = - 0.50, 95% bootstrap confidence interval [- 0.99, - 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter.
ESTHER : Yu_2019_Transl.Stroke.Res_10_522
PubMedSearch : Yu_2019_Transl.Stroke.Res_10_522
PubMedID: 30443886

Title : Effects of feed intake restriction during late pregnancy on the function, anti-oxidation capability and acute phase protein synthesis of ovine liver - Yang_2019_Asian-Australas.J.Anim.Sci_32_217
Author(s) : Yang H , Wang Y , Ma C , Sun C , Liu Y , Wu K , Li M , Borjigin G , Gao F
Ref : Asian-Australas J Anim Sci , 32 :217 , 2019
Abstract : OBJECTIVE: An experiment was conducted to investigate the effects of feed intake restriction during late pregnancy on the function, anti-oxidation capability and acute phase protein synthesis of ovine liver. METHODS: Eighteen time-mated ewes with singleton fetuses were allocated to three groups: restricted group 1 (RG1, 0.18 MJ ME/kg W0.75 d, n = 6), restricted group 2 (RG2, 0.33 MJ ME/kg W0.75 d), n = 6) and a control group (CG, ad libitum, 0.67 MJ ME/kg W0.75 d, n = 6). The feed restriction period was from 90 days to 140 days of pregnancy. RESULTS: The ewe's body weight, liver weights, water, and protein content of liver in the restricted groups were reduced compared with the CG group (p<0.05), but the liver fat contents in the RG1 group were higher than those of the CG group (p<0.05). The increased hepatic collagen fibers and reticular fibers were observed in the restricted groups with the reduction of energy intake. The concentrations of nonesterified free fatty acids in the RG1 and RG2 groups were higher than those of the CG group with the reduction of energy intake (p<0.05), but there were decreased concentrations of lipoprotein lipase and hepatic lipase in both restricted groups compared with the CG group (p<0.05). In addition, the increased concentrations of beta-hydroxybutyric acid, triglycerides, malondialdehyde, total antioxidant capacity and activities of superoxide dismutase activity and catalase were found in the RG1 group, and the concentrations of cholinesterase in the RG1 group were reduced compared with the CG group (p<0.05). For the concentrations of acute phase proteins, the C-reactive protein (CRP) in the RG1 group were reduced compared with the CG group, but there were no differences in haptoglobin relative to the controls (p>0.05). CONCLUSION: The fat accumulation, increased hepatic fibrosis, antioxidant imbalance and modified synthesis of acute phase proteins were induced in ewe's liver by maternal malnutrition during late pregnancy, which were detrimental for liver function to accommodate pregnancy.
ESTHER : Yang_2019_Asian-Australas.J.Anim.Sci_32_217
PubMedSearch : Yang_2019_Asian-Australas.J.Anim.Sci_32_217
PubMedID: 30056659

Title : MKK6 Functions in Two Parallel MAP Kinase Cascades in Immune Signaling - Lian_2018_Plant.Physiol_178_1284
Author(s) : Lian K , Gao F , Sun T , van Wersch R , Ao K , Kong Q , Nitta Y , Wu D , Krysan P , Zhang Y
Ref : Plant Physiol , 178 :1284 , 2018
Abstract : Arabidopsis (Arabidopsis thaliana) MAP KINASE (MPK) proteins can function in multiple MAP kinase cascades and physiological processes. For instance, MPK4 functions in regulating development as well as in plant defense by participating in two independent MAP kinase cascades: the MEKK1-MKK1/MKK2-MPK4 cascade promotes basal resistance against pathogens and is guarded by the NB-LRR protein SUMM2, whereas the ANPs-MKK6-MPK4 cascade plays an essential role in cytokinesis. Here, we report a novel role for MKK6 in regulating plant immune responses. We found that MKK6 functions similarly to MKK1/MKK2 and works together with MEKK1 and MPK4 to prevent autoactivation of SUMM2-mediated defense responses. Interestingly, loss of MKK6 or ANP2/ANP3 results in constitutive activation of plant defense responses. The autoimmune phenotypes of mkk6 and anp2 anp3 mutant plants can be largely suppressed by a constitutively active mpk4 mutant. Further analysis showed that the constitutive defense response in anp2 anp3 is dependent on the defense regulators PAD4 and EDS1, but not on SUMM2, suggesting that the ANP2/ANP3-MKK6-MPK4 cascade may be guarded by a TIR-NB-LRR protein. Our study shows that MKK6 has multiple functions in plant defense responses in addition to cytokinesis.
ESTHER : Lian_2018_Plant.Physiol_178_1284
PubMedSearch : Lian_2018_Plant.Physiol_178_1284
PubMedID: 30185442

Title : Ultra-thin bimetallic alloy nanowires with porous architecture\/monolayer MoS2 nanosheet as a highly sensitive platform for the electrochemical assay of hazardous omethoate pollutant - Song_2018_J.Hazard.Mater_357_466
Author(s) : Song D , Li Q , Lu X , Li Y , Wang Y , Gao F
Ref : J Hazard Mater , 357 :466 , 2018
Abstract : A novel electrochemical biosensor was designed for sensitive detection of organophosphate pesticides based on three-dimensional porous bimetallic alloy architecture with ultrathin nanowires (PdCo NWs, PdCu NWs, PdNi NWs) and monolayer MoS2 nanosheet (m-MoS2). The bimetallic alloy NWs/m-MoS2 nanomaterials were used as a sensing platform for electrochemical analysis of omethoate, a representative organophosphate pesticide, via acetylcholinesterase inhibition pathway. We demonstrated that all three bimetallic alloy NWs enhanced electrochemical responses of enzymatic biosensor, benefited from bimetallic synergistic action and porous structure. In particular, PdNi NWs outperformed other two bimetallic alloy. Moreover, PdNi NWs/m-MoS2 as an electronic transducer is superior to the corresponding biosensor in the absence of monolayer MoS2 nanosheet, which arise from synergistic signal amplification effect between different components. Under optimized conditions, the developed biosensor on the basis of PdNi NWs/m-MoS2 shows outstanding performance for the electrochemical assay of omethoate, such as a wide linear range (10(-13) M approximately 10(-7) M), a low detection limit of 0.05pM at a signal-to-noise ratio of 3, high sensitivity and long-time stability. The results demonstrate that bimetallic alloy NWs/m-MoS2 nanocomposites could be excellent transducers to promote electron transfer for the electrochemical reactions, holding great potentials in the construction of current and future biosensing devices.
ESTHER : Song_2018_J.Hazard.Mater_357_466
PubMedSearch : Song_2018_J.Hazard.Mater_357_466
PubMedID: 29935459

Title : Amorphous metal boride as a novel platform for acetylcholinesterase biosensor development and detection of organophosphate pesticides - Lu_2018_Nanotechnology_30_055501
Author(s) : Lu X , Li Y , Tao L , Song D , Wang Y , Gao F
Ref : Nanotechnology , 30 :055501 , 2018
Abstract : The exploration of new materials for modifying electrodes is important to advance electrochemical biosensors. Herein, we demonstrated that amorphous bimetallic boride material (Co-2Ni-B) prepared by a simple and facile aqueous reaction is an efficient matrix to immobilize acetylcholinesterase (AChE) to construct a biosensor for the determination of organophosphate pesticides. The effects of different composition and crystallinity on its electrochemical performance are investigated, and the optimization studies of the biological transducer were also discussed. Under optimal conditions, the fabricated sensor showed good analytical performance for the determination of chlorpyrifos with a low limit of detection (2.83 pM) and a wide linear range (3 pM-300 nM). The proposed biosensor also demonstrated high reproducibility, stability and accuracy. The impressive performance was due to the excellent conductivity and the unique amorphous bimetal-metalloid complex nanostructure. These results introduce a new class of promising materials as a robust platform for biosensor applications.
ESTHER : Lu_2018_Nanotechnology_30_055501
PubMedSearch : Lu_2018_Nanotechnology_30_055501
PubMedID: 30499458

Title : Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate - Hu_2017_Environ.Sci.Technol_51_4061
Author(s) : Hu W , Gao F , Zhang H , Hiromori Y , Arakawa S , Nagase H , Nakanishi T , Hu J
Ref : Environ Sci Technol , 51 :4061 , 2017
Abstract : 2-Ethylhexyl diphenyl phosphate (EHDPP), an organophosphate flame retardant (OPFR), is frequently detected in human blood. In this study, the sensitive dual-luciferase reporter gene assay and molecular docking were used to investigate the activation of EHDPP to human peroxisome proliferator-activated receptor gamma (PPARG). Results show that EHDPP exhibited stronger PPARG activation (EC(20): 2.04 microM) than triphenyl phosphate (TPhP) (EC(20): 2.78 microM). EHDPP upregulated the gene expression of 3beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD1) in human placental choriocarcinoma cells in a dose-dependent manner, and the lowest observable effective concentration was 10 microM, lower than that of TPhP (20 microM). EHDPP significantly altered progesterone secretion at a lower concentration (10 microM) than that of TPhP (20 microM), and both EHDPP and TPhP significantly promoted human chorionic gonadotropin (hCG) production at 20 microM. Furthermore, inactivation of PPARG by either a pharmacological inhibitor (GW9662) or small interfering RNA (siRNA) abolished the change in progesterone secretion and gene expression in the cells exposed to EHDPP, suggesting that the PPARG signaling pathway plays a role in the upregulation of progesterone by the two OPFRs. This is the first report to show that OPFRs can alter the biosynthesis of progesterone in the placenta, which could affect female reproduction and fetal development.
ESTHER : Hu_2017_Environ.Sci.Technol_51_4061
PubMedSearch : Hu_2017_Environ.Sci.Technol_51_4061
PubMedID: 28282128

Title : Palladium-copper nanowires-based biosensor for the ultrasensitive detection of organophosphate pesticides - Song_2017_Anal.Chim.Acta_982_168
Author(s) : Song D , Li Y , Lu X , Sun M , Liu H , Yu G , Gao F
Ref : Anal Chim Acta , 982 :168 , 2017
Abstract : A highly sensitive acetylcholinesterase (AChE) electrochemical biosensor for the quantitative determination of organophosphate pesticides (OPs) in vegetables and fruits based on palladium-copper nanowires (Pd-Cu NWs) was reported. AChE immobilized on the modified electrode could catalyze hydrolysis of acetylthiocholine chloride (ATCl), generating an irreversible oxidation peak. When exposed to the OPs, the activity of the AChE was inhibited and the current significantly decreased. The detection mechanism is based on the inhibition of AChE. The Pd-Cu NWs not only provide a large active surface area (0.268 +/- 0.01) cm2 for the immobilization of AChE, which was approximately 3.8 times higher than the bare glass carbon electrode, but also exhibit excellent electro-catalytic activity and remarkable electron mobility. The biosensor modified with Pd-Cu NWs displayed a good affinity to ATCl and catalyzed hydrolysis of ATCl, with a low Michaelis-Menten constant (KM) of 50.56 muM. Under optimized conditions, the AChE-Cs/Pd-Cu NWs/GCE biosensor detected malathion with wide linear ranges of 5-1000 ppt and 500-3000 ppb, and the low detection limit was 1.5 ppt (4.5 pM). In addition, the OPs biosensor has been applied to the analysis of malathion in commercial vegetable and fruit samples, with excellent recoveries in the range of 98.5%-113.5%. This work provides a simple, sensitive and effective platform for biosensors and exhibits future potential in practical application for the OPs assay.
ESTHER : Song_2017_Anal.Chim.Acta_982_168
PubMedSearch : Song_2017_Anal.Chim.Acta_982_168
PubMedID: 28734356

Title : Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the PPARgamma pathway - Gao_2017_Toxicol.Appl.Pharmacol_327_23
Author(s) : Gao F , Hu W , Li Y , Shen H , Hu J
Ref : Toxicol Appl Pharmacol , 327 :23 , 2017
Abstract : Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARgamma pathway by either PPARgamma inhibitors or PPARgamma shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARgamma at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.
ESTHER : Gao_2017_Toxicol.Appl.Pharmacol_327_23
PubMedSearch : Gao_2017_Toxicol.Appl.Pharmacol_327_23
PubMedID: 28416457

Title : Association of PON1, P2Y12 and COX1 with Recurrent Ischemic Events in Patients with Extracranial or Intracranial Stenting - Li_2016_PLoS.One_11_e0148891
Author(s) : Li XQ , Ma N , Li XG , Wang B , Sun SS , Gao F , Mo DP , Song LG , Sun X , Liu L , Zhao XQ , Wang YL , Wang YJ , Zhao ZG , Miao ZR
Ref : PLoS ONE , 11 :e0148891 , 2016
Abstract : BACKGROUND AND PURPOSE: Short-term combined use of clopidogrel and aspirin improves cerebrovascular outcomes in patients with symptomatic extracranial or intracranial stenosis. Antiplatelet non-responsiveness is related to recurrent ischemic events, but the culprit genetic variants responsible for the non-responsiveness have not been well studied. We aimed to identify the genetic variants associated with poor clinical outcomes.
METHODS: Patients with symptomatic extracranial or intracranial stenosis scheduled for stenting and receiving dual antiplatelets (clopidogrel 75 mg and aspirin 100 mg daily) for at least 5 days before intervention were enrolled. Ischemic events including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality within 12 months follow-up were recorded. We examined the influence of genetic polymorphisms on treatment outcome in our patients.
RESULTS: A total of 268 patients were enrolled into our study and ischemic events were observed in 39 patients. For rs662 of paraoxonase 1 (PON1), allele C was associated with an increased risk of ischemic events (OR = 1.64, 95%CI = 1.03-2.62, P = 0.029). The A-allele carriers of rs2046934 of P2Y12 had a significant association with adverse events (OR = 2.01, 95%CI = 1.10-3.67, P = 0.041). The variant T-allele of cyclooxygenase-1 (COX1) rs1330344 significantly increased the risk of recurrent clinical events (OR = 1.85, 95%CI = 1.12-3.03, P = 0.017). The other single nucleotide polymorphism (SNP) had no association with ischemic events.
CONCLUSIONS: PON1, P2Y12 and COX1 polymorphisms were associated with poorer vascular outcomes. Testing for these polymorphisms may be valuable in the identification of patients at risk for recurrent ischemic events.
ESTHER : Li_2016_PLoS.One_11_e0148891
PubMedSearch : Li_2016_PLoS.One_11_e0148891
PubMedID: 26870959

Title : Seco-pregnane glycosides from the stems of Epigynum auritum - Gao_2016_Nat.Prod.Res__1
Author(s) : Gao F , Yao YC , Wan Z , Cai SB , Fan J , Zhao TR , Cao JX , Cheng GG
Ref : Nat Prod Res , :1 , 2016
Abstract : Chemical investigation of the stems of Epigynum auritum led to the isolation and identification of a novel 16,17-seco pregnane glycoside, epigynoside D, along with other three known compounds (2-4). The structure of compound 1 was elucidated by means of spectroscopic analysis, including HRESIMS, 1D and 2D NMR experiments. All isolated compounds were tested for their in vitro cytotoxic, immunological and anti-acetylcholinesterase activities.
ESTHER : Gao_2016_Nat.Prod.Res__1
PubMedSearch : Gao_2016_Nat.Prod.Res__1
PubMedID: 27931111

Title : Genome Sequence of Bacillus endophyticus and Analysis of Its Companion Mechanism in the Ketogulonigenium vulgare-Bacillus Strain Consortium - Jia_2015_PLoS.One_10_e0135104
Author(s) : Jia N , Du J , Ding MZ , Gao F , Yuan YJ
Ref : PLoS ONE , 10 :e0135104 , 2015
Abstract : Bacillus strains have been widely used as the companion strain of Ketogulonigenium vulgare in the process of vitamin C fermentation. Different Bacillus strains generate different effects on the growth of K. vulgare and ultimately influence the productivity. First, we identified that Bacillus endophyticus Hbe603 was an appropriate strain to cooperate with K. vulgare and the product conversion rate exceeded 90% in industrial vitamin C fermentation. Here, we report the genome sequencing of the B. endophyticus Hbe603 industrial companion strain and speculate its possible advantage in the consortium. The circular chromosome of B. endophyticus Hbe603 has a size of 4.87 Mb with GC content of 36.64% and has the highest similarity with that of Bacillus megaterium among all the bacteria with complete genomes. By comparing the distribution of COGs with that of Bacillus thuringiensis, Bacillus cereus and B. megaterium, B. endophyticus has less genes related to cell envelope biogenesis and signal transduction mechanisms, and more genes related to carbohydrate transport and metabolism, energy production and conversion, as well as lipid transport and metabolism. Genome-based functional studies revealed the specific capability of B. endophyticus in sporulation, transcription regulation, environmental resistance, membrane transportation, extracellular proteins and nutrients synthesis, which would be beneficial for K. vulgare. In particular, B. endophyticus lacks the Rap-Phr signal cascade system and, in part, spore coat related proteins. In addition, it has specific pathways for vitamin B12 synthesis and sorbitol metabolism. The genome analysis of the industrial B. endophyticus will help us understand its cooperative mechanism in the K. vulgare-Bacillus strain consortium to improve the fermentation of vitamin C.
ESTHER : Jia_2015_PLoS.One_10_e0135104
PubMedSearch : Jia_2015_PLoS.One_10_e0135104
PubMedID: 26248285
Gene_locus related to this paper: 9baci-a0a0h4kmj6

Title : Colorimetric and Phosphorimetric Dual-Signaling Strategy Mediated by Inner Filter Effect for Highly Sensitive Assay of Organophosphorus Pesticides - Zhang_2015_J.Agric.Food.Chem_63_8947
Author(s) : Zhang R , Li N , Sun J , Gao F
Ref : Journal of Agricultural and Food Chemistry , 63 :8947 , 2015
Abstract : We describe here a colorimetric and phosphorimetric dual-signaling strategy for sensitive assay of organophosphorus pesticides (OPPs). The principle for assay depends on the phenomenon that the phosphorescence of Mn-ZnS quantum dots (QDs) can be dramatically quenched by Au nanoparticles (AuNPs) through the inner filter effect (IFE) and the activity of acetylcholinesterase (AChE), an enzyme that catalytically hydrolyzes acetylthiocholine to thiocholine that can be inhibited by OPPs. By virtue of the variations of absorbance and phosphorescence of the analytical system, a dual-readout assay for OPPs has been proposed. The limits of detection for different OPPs including paraoxon, parathion, omethoate, and dimethyl dichlorovinyl phosphate (DDVP) are found to be 0.29, 0.59, 0.67, and 0.44 ng/L, respectively. The proposed assay was allowed to detect pesticides in real spiked samples and authentic contaminated apples with satisfactory results, suggesting its potential applications to detect pesticides in complicated samples.
ESTHER : Zhang_2015_J.Agric.Food.Chem_63_8947
PubMedSearch : Zhang_2015_J.Agric.Food.Chem_63_8947
PubMedID: 26411607

Title : Effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver - Gao_2014_Anim.Reprod.Sci_147_99
Author(s) : Gao F , Liu Y , Li L , Li M , Zhang C , Ao C , Hou X
Ref : Anim Reprod Sci , 147 :99 , 2014
Abstract : This study investigated the effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver. Eighteen ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.175MJMEkgBW(-0.75)d(-1), n=6), Restricted Group 2 (RG2, 0.33MJMEkgBW(-0.75)d(-1), n=6) and a Control Group (CG, ad libitum, 0.67MJMEkgBW(-0.75)d(-1), n=6). Fetuses were recovered at slaughter on d 140. Fetuses in the RG1 group exhibited decreased (P<0.05) liver weight, total antioxidant capacity (T-AOC), superoxide dismutase activity (SOD), cholinesterase (CHE), total protein (TP), globulin (GLB), and alanine transaminase (ALT). In addition, intermediate changes were found in the RG2 fetuses, including decreased liver weight, T-AOC and CHE (P<0.05). In contrast, increases in fetal hepatic collagen fibers and reticular fibers, glutathione peroxidase (GSH-Px), malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOs), monoamine oxidase (MAO), albumin (ALB)/GLB, aspartate transaminase (AST), and AST/ALT were found in the RG1 fetuses (P<0.05). The RG2 fetuses had increased fetal hepatic collagen fibers, NOs and MAO (P<0.05) relative to the control fetuses. These results indicate that impaired fetal hepatic growth, fibrosis, antioxidant imbalance and dysfunction were associated with maternal undernutrition.
ESTHER : Gao_2014_Anim.Reprod.Sci_147_99
PubMedSearch : Gao_2014_Anim.Reprod.Sci_147_99
PubMedID: 24852270

Title : Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 - Lu_2013_Nature_500_227
Author(s) : Lu G , Hu Y , Wang Q , Qi J , Gao F , Li Y , Zhang Y , Zhang W , Yuan Y , Bao J , Zhang B , Shi Y , Yan J , Gao GF
Ref : Nature , 500 :227 , 2013
Abstract : The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the molecular basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition.
ESTHER : Lu_2013_Nature_500_227
PubMedSearch : Lu_2013_Nature_500_227
PubMedID: 23831647
Gene_locus related to this paper: human-DPP4

Title : Role of PON2 in innate immune response in an acute infection model - Devarajan_2013_Mol.Genet.Metab_110_362
Author(s) : Devarajan A , Bourquard N , Grijalva VR , Gao F , Ganapathy E , Verma J , Reddy ST
Ref : Mol Genet Metab , 110 :362 , 2013
Abstract : N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) is a quorum-sensing molecule produced by gram-negative microbial pathogens such as Pseudomonas aeruginosa (PAO1). 3OC12-HSL is involved in the regulation of bacterial virulence factors and also alters the function of the host immune cells. Others and we have previously shown that paraoxonase 2 (PON2), a member of the paraoxonase gene family expressed in immune cells, hydrolyzes 3OC12-HSL. In this study, we examined i) whether macrophage PON2 participates in 3OC12-HSL hydrolysis, ii) the effect of PON2 deficiency in acute PAO1 infection in mice and iii) the effect of 3OC12-HSL on PON2 deficient (PON2-def) macrophages. When compared to wild type macrophages, both intact cells and membrane-enriched protein lysates obtained from PON2-def macrophages show a marked impairment in their ability to hydrolyze 3OC12-HSL. PON2 expression (message and protein) is not altered in response to 3OC12-HSL in macrophages. 3OC12-HSL treated PON2-def macrophages showed i) an increase in ER stress and oxidative stress, ii) defective phosphatidylinositol 3-kinase (PI3 kinase)/AKT activation, and iii) reduced phagocytosis function. Moreover, the nitration to phosphorylation ratio of Tyr458 in p85 protein, the regulatory subunit of PI3-kinase that has been correlated with the phagocytosis function of macrophages, was increased in PON2-def macrophages. Antioxidant treatment reversed the effects of PON2 deficiency in macrophage phagocytosis function. Furthermore, following administration of 1.6x10(7) CFU of PAO1, bacterial clearance was significantly reduced in the lungs (5.7 fold), liver (2.5 fold), and spleen (14.8 fold) of PON2-def mice when compared to wild type mice. Our results suggest that PON2 plays an important role in innate immune defense against PAO1 infection.
ESTHER : Devarajan_2013_Mol.Genet.Metab_110_362
PubMedSearch : Devarajan_2013_Mol.Genet.Metab_110_362
PubMedID: 23911207

Title : Genome sequence of Acinetobacter baumannii MDR-TJ - Gao_2011_J.Bacteriol_193_2365
Author(s) : Gao F , Wang Y , Liu YJ , Wu XM , Lv X , Gan YR , Song SD , Huang H
Ref : Journal of Bacteriology , 193 :2365 , 2011
Abstract : Acinetobacter baumannii is a pathogenic species of bacteria, identified as an aerobic gram-negative bacterium, that is resistant to most antibiotics. In this study, the MDR-TJ strain was isolated at the Second Hospital of Tianjin Medical University, China, and was found to be resistant to penicillin, cephalosporins, aminoglycosides, quinolones, and also imipenem. The genome sequence of Acinetobacter baumannii strain MDR-TJ was determined by using a combination of 454 pyrosequencing and paired-end sequencing performed with the Roche Genome Sequencer FLX system to generate a scaffolded assembly.
ESTHER : Gao_2011_J.Bacteriol_193_2365
PubMedSearch : Gao_2011_J.Bacteriol_193_2365
PubMedID: 21398552
Gene_locus related to this paper: aciba-f5iht4 , aciba-a0a009wzt4

Title : A functional EDS1 ortholog is differentially regulated in powdery mildew resistant and susceptible grapevines and complements an Arabidopsis eds1 mutant - Gao_2010_Planta_231_1037
Author(s) : Gao F , Shu X , Ali MB , Howard S , Li N , Winterhagen P , Qiu W , Gassmann W
Ref : Planta , 231 :1037 , 2010
Abstract : Vitis vinifera (grapevine) is the most economically important deciduous fruit crop, but cultivated grapevine varieties lack adequate innate immunity to a range of devastating diseases. To identify genetic resources for grapevine innate immunity and understand pathogen defense pathways in a woody perennial plant, we focus in this study on orthologs of the central Arabidopsis thaliana defense regulator ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). The family of EDS1-like genes is expanded in grapevine, and members of this family were previously found to be constitutively upregulated in the resistant variety 'Norton' of the North American grapevine species Vitis aestivalis, while they were induced by Erysiphe necator, the causal agent of grapevine powdery mildew (PM), in the susceptible V. vinifera variety 'Cabernet Sauvignon'. Here, we determine the responsiveness of individual EDS1-like genes in grapevine to PM and salicylic acid, and find that EDS1-like paralogs are differentially regulated in 'Cabernet Sauvignon', while two are constitutively upregulated in 'Norton'. Sequencing of VvEDS1 and VaEDS1 cDNA and genomic clones revealed high conservation in the protein-encoding sequence and some divergence of the promoter sequence in the two grapevine varieties. Complementation of the Arabidopsis eds1-1 mutant showed that the EDS1-like gene with highest predicted amino acid sequence similarity to AtEDS1 from either grapevine varieties is a functional ortholog of AtEDS1. Together, our analyses show that differential susceptibility to PM is correlated with differences in EDS1 expression, not differences in EDS1 function, between resistant 'Norton' and susceptible 'Cabernet Sauvignon'.
ESTHER : Gao_2010_Planta_231_1037
PubMedSearch : Gao_2010_Planta_231_1037
PubMedID: 20145949
Gene_locus related to this paper: arath-eds1

Title : Detection of multiple antibodies in myasthenia gravis and its clinical significance - Wang_2010_Chin.Med.J.(Engl)_123_2555
Author(s) : Wang WW , Hao HJ , Gao F
Ref : Chinese Medical Journal (Engl) , 123 :2555 , 2010
Abstract : BACKGROUND: Antibodies against acetylcholine receptor, acetylcholinesterase, ryanodine receptor and titin have been found in patients with myasthenia gravis. However, the relations between these antibodies and character of myasthenia gravis are unknown. This study aimed to detect multiple antibodies in myasthenia gravis and to investigate its clinical significance. METHODS: These antibodies were detected by enzyme-linked immunoabsorbent assay in 89 cases of myasthenia gravis, 66 cases of other neurological diseases and 66 healthy controls. The incidences of antibodies were compared using the chi-square test. RESULTS: Acetylcholine receptor, acetylcholinesterase, titin and ryanodine receptor antibodies were detected in 53.9%, 20.2%, 64.0% and 55.0% of myasthenia gravis patients respectively, higher than in patients of other neurological diseases and controls groups. The combination of the four antibodies assays provided 94.4% sensitivity and 84.0% specificity for the diagnosis of myasthenia gravis. Acetylcholinesterase antibody occurred more frequently in acetylcholine receptor antibody negative patients with adverse reactions to neostigmine test. Titin antibody provided 82.1% sensitivity and 52.5% specificity for myasthenia gravis with thymoma. Incidences of titin and of ryanodine receptor antibody were higher in late onset myasthenia gravis than in early onset myasthenia gravis. The proportion of titin antibody positive patients increased with the severity of myasthenia gravis as graded by a modified Osserman scale. CONCLUSIONS: Testing for acetylcholine receptor, acetylcholinesterase, titin and ryanodine receptor antibodies can offer a better diagnostic method for myasthenia gravis than each antibody test alone. Titin antibody combined with computed tomography was better for the diagnosis of thymoma. Titin antibody occurred most frequently in severe myasthenia gravis.
ESTHER : Wang_2010_Chin.Med.J.(Engl)_123_2555
PubMedSearch : Wang_2010_Chin.Med.J.(Engl)_123_2555
PubMedID: 21034627

Title : Recent structural and mechanistic insights into endplate acetylcholine receptors - Sine_2008_Ann.N.Y.Acad.Sci_1132_53
Author(s) : Sine SM , Gao F , Lee WY , Mukhtasimova N , Wang HL , Engel AG
Ref : Annals of the New York Academy of Sciences , 1132 :53 , 2008
Abstract : Voluntary movement mediated by skeletal muscle relies on endplate acetylcholine receptors (AChR) to detect nerve-released ACh and depolarize the muscle fiber. Recent structural and mechanistic studies of the endplate AChR have catalyzed a leap in our understanding of the molecular steps in this chemical-to-electrical transduction process. Studies of acetylcholine binding protein (AChBP) give insight into ACh recognition, the first step in activation of the AChR. An atomic structural model of the Torpedo AChR at a resolution of 0.4 nm, together with single-ion channel recording methods, allow tracing of the link between the agonist binding event and gating of the ion channel, as well as determination of how the channel moves when it opens to allow flow of cations. Structural models of the human AChR enable precise mapping of disease-causing mutations, while studies of the speed with which single AChR channels open and close cast light on pathogenic mechanisms.
ESTHER : Sine_2008_Ann.N.Y.Acad.Sci_1132_53
PubMedSearch : Sine_2008_Ann.N.Y.Acad.Sci_1132_53
PubMedID: 18567853

Title : Strategic subcortical hyperintensities in cholinergic pathways and executive function decline in treated Alzheimer patients - Behl_2007_Arch.Neurol_64_266
Author(s) : Behl P , Bocti C , Swartz RH , Gao F , Sahlas DJ , Lanctot KL , Streiner DL , Black SE
Ref : Archives of Neurology , 64 :266 , 2007
Abstract : OBJECTIVE: To investigate changes in cognition, function, and behavior after 1 year in patients with Alzheimer disease being treated with cholinesterase inhibitors, in relation to the presence or absence of subcortical hyperintensities involving the cholinergic pathways. DESIGN: One-year prospective cohort study. SETTING: Memory Clinic, Sunnybrook Health Sciences Centre, University of Toronto. Patients Ninety patients with possible/probable Alzheimer disease who were being treated with cholinesterase inhibitors at baseline. INTERVENTIONS: Yearly standardized neuropsychological testing and brain magnetic resonance imaging (MRI). The Cholinergic Pathways Hyperintensities Scale (CHIPS) was applied to baseline MRIs to rate the severity of subcortical hyperintensities in cholinergic pathways. The consensus-derived Age-Related White Matter Changes (ARWMC) Rating Scale was used as a general measure of white matter disease burden. MAIN OUTCOME MEASURES: Tests of global cognition, function, and behavior and specific cognitive and functional domains. RESULTS: Patients in the low CHIPS group were equivalent to those in the high CHIPS group with regard to baseline demographic characteristics, cognitive severity, and vascular risk factors. After covarying age and education, no differences were found after 1 year in overall cognition, function, and behavior or on memory, language, and visuospatial tasks. Patients in the high CHIPS group showed improvement on executive function and working memory tasks compared with those in the low CHIPS group. For the ARWMC scale, groups with and without white matter abnormalities were equivalent on baseline demographics and in cognitive, functional, and behavioral outcomes. CONCLUSION: Cerebrovascular compromise of the cholinergic pathways may be a factor that contributes more selectively than does total white matter lesion burden to response to cholinergic therapy in Alzheimer disease, particularly on frontal/executive tasks.
ESTHER : Behl_2007_Arch.Neurol_64_266
PubMedSearch : Behl_2007_Arch.Neurol_64_266
PubMedID: 17296844

Title : Solution NMR of acetylcholine binding protein reveals agonist-mediated conformational change of the C-loop - Gao_2006_Mol.Pharmacol_70_1230
Author(s) : Gao F , Mer G , Tonelli M , Hansen SB , Burghardt TP , Taylor P , Sine SM
Ref : Molecular Pharmacology , 70 :1230 , 2006
Abstract : Previous X-ray crystallography, molecular dynamics simulation, fluorescence spectroscopy, and deuterium-hydrogen exchange of acetylcholine binding protein (AChBP) suggest that after binding of the agonist, the C-loop at the periphery of the binding site draws inward to cap the site and envelop the agonist. In this study, we use high-resolution solution NMR to monitor changes in the chemical environment of the C-loop without and with acetylcholine (ACh) bound. Substitution of [15N]cysteine for the native cysteines 123, 136, 187, and 188 provided intrinsic monitors of the chemical environments of the Cys- and C-loops, respectively. Two-dimensional transverse relaxation-optimized spectroscopy 15N-1H HSQC spectroscopy of apo-AChBP revealed seven well resolved cross-peaks for the group of cysteines. The spectrum of AChBP with Ser substituted for Cys 187 and 188 shows only two main cross-peaks, corresponding to Cys 123 and 136 from the Cys-loop, enabling resonance assignments. After binding of ACh, the five cross-peaks associated with cysteines from the C-loop condense into two predominant cross-peaks not observed in the spectrum from the apo protein, indicating a restricted range of conformations and change in chemical environment of the C-loop. The results show that isotopic cysteine can be incorporated into specified positions of AChBP expressed from a eukaryotic source, that the C-loop assumes multiple conformations without ACh, but that its conformation becomes restricted with ACh bound. The collective findings suggest a structural mechanism for agonist recognition in AChBP and related Cys-loop receptors.
ESTHER : Gao_2006_Mol.Pharmacol_70_1230
PubMedSearch : Gao_2006_Mol.Pharmacol_70_1230
PubMedID: 16847142

Title : Structural basis for epibatidine selectivity at desensitized nicotinic receptors - Pennington_2005_Mol.Pharmacol_67_123
Author(s) : Pennington RA , Gao F , Sine SM , Prince RJ
Ref : Molecular Pharmacology , 67 :123 , 2005
Abstract : The agonist binding sites of the fetal muscle nicotinic acetylcholine receptor are formed at the interfaces of alpha-subunits and neighboring gamma- and delta-subunits. When the receptor is in the nonconducting desensitized state, the alpha-gamma site binds the agonist epibatidine 200-fold more tightly than does the alpha-delta site. To determine the structural basis for this selectivity, we constructed gamma/delta-subunit chimeras, coexpressed them with complementary wild-type subunits in HEK 293 cells, and determined epibatidine affinity of the resulting complexes. The results reveal three determinants of epibatidine selectivity: gamma104-117/delta106-delta119, gamma164-171/delta166-177, and gammaPro190/deltaAla196. Point mutations reveal that three sequence differences within the gamma104-117/delta106-delta119 region are determinants of epibatidine selectivity: gammaLys104/deltaTyr106, gammaSer111/deltaTyr113, and gammaTyr117/deltaTyr119. In the delta-subunit, simultaneous mutation of these residues to their gamma equivalent produces high affinity, gamma-like epibatidine binding. However, converting gamma to delta affinity requires replacement of the gamma104-117 segment with delta sequence, suggesting interplay of residues in this region. The structural basis for epibatidine selectivity is explained by computational docking of epibatidine to a homology model of the alpha-gamma binding site.
ESTHER : Pennington_2005_Mol.Pharmacol_67_123
PubMedSearch : Pennington_2005_Mol.Pharmacol_67_123
PubMedID: 15496507

Title : Agonist-mediated conformational changes in acetylcholine-binding protein revealed by simulation and intrinsic tryptophan fluorescence - Gao_2005_J.Biol.Chem_280_8443
Author(s) : Gao F , Bren N , Burghardt TP , Hansen S , Henchman RH , Taylor P , McCammon JA , Sine SM
Ref : Journal of Biological Chemistry , 280 :8443 , 2005
Abstract : We delineated acetylcholine (ACh)-dependent conformational changes in a prototype of the nicotinic receptor ligand binding domain by molecular dynamics simulation and changes in intrinsic tryptophan (Trp) fluorescence. Prolonged molecular dynamics simulation of ACh-binding protein showed that binding of ACh establishes close register of Trps from adjacent subunits, Trp(143) and Trp(53), and draws the peripheral C-loop inward to occlude the entrance to the binding cavity. Close register of Trp(143) and Trp(53) was demonstrated by ACh-mediated quenching of intrinsic Trp fluorescence, elimination of quenching by mutation of one or both Trps to Phe, and decreased lifetime of Trp fluorescence by bound ACh. Occlusion of the binding cavity by the C-loop was demonstrated by restricted access of an extrinsic quencher of binding site Trp fluorescence by ACh. The collective findings showed that ACh initially establishes close register of conserved Trps from adjacent subunits and then draws the C-loop inward to occlude the entrance to the binding cavity.
ESTHER : Gao_2005_J.Biol.Chem_280_8443
PubMedSearch : Gao_2005_J.Biol.Chem_280_8443
PubMedID: 15591050

Title : Toward atomic-scale understanding of ligand recognition in the muscle nicotinic receptor - Sine_2004_Curr.Med.Chem_11_559
Author(s) : Sine SM , Wang HL , Gao F
Ref : Curr Med Chem , 11 :559 , 2004
Abstract : The nicotinic receptor at the motor endplate has served as a prototype for understanding structure, function and ligand recognition in the superfamily of pentameric ligand-gated ion channels. Yet despite this advanced state of knowledge, atomic-scale understanding of such elementary processes as ligand recognition has remained elusive owing to the lack of a high-resolution x-ray structure. However, the field has recently entered a state of rapid advancement following the discovery and atomic structural determination of the water-soluble acetylcholine binding protein (AChBP), a homolog of the receptor ligand binding domain. The AChBP structure provides the theoretical foundation for generating homology models of the corresponding receptor ligand binding domains within this structural family of receptors. Experimental assignment of residue equivalence between AChBP and receptor subunits subsequently yielded homology models ready for experimental testing. One such test is computational determination of ligand docking orientation in conjunction with mutagenesis of predicted contact residues and measurements of ligand binding affinity. Applied to different analogs of the competitive antagonist curare, docking computations that incorporate intrinsic protein flexibility reveal fundamentally distinct orientations of each analog bound to AChBP. The different contact residues predicted for each analog were tested and confirmed by mutagenesis of AChBP followed by measurements of ligand binding. By applying the same computational and experimental approaches to the adult human muscle AChR, we find that the two curare analogs also dock in distinctly different orientations. Thus subtle structural changes in the ligand, and by extension, structural differences in non-conserved residues among receptor subtypes and species, can dramatically alter the orientation of the bound ligand. The results have important implications for design of drugs targeting nicotinic receptors and members of the superfamily of pentameric ligand-gated ion channels.
ESTHER : Sine_2004_Curr.Med.Chem_11_559
PubMedSearch : Sine_2004_Curr.Med.Chem_11_559
PubMedID: 15032604

Title : Alpha-conotoxins ImI and ImII target distinct regions of the human alpha7 nicotinic acetylcholine receptor and distinguish human nicotinic receptor subtypes - Ellison_2004_Biochemistry_43_16019
Author(s) : Ellison M , Gao F , Wang HL , Sine SM , McIntosh JM , Olivera BM
Ref : Biochemistry , 43 :16019 , 2004
Abstract : The Conus peptides alpha-conotoxin ImI (alpha-ImI) and ImII (alpha-ImII) differ by only three of 11 residues in their primary sequences and yet are shown to inhibit the human alpha7 nicotinic acetylcholine receptor (nAChR) by targeting different sites. Mutations at both faces of the classical ligand binding site of the alpha7 nAChR strongly affect antagonism by alpha-ImI but not alpha-ImII. The effects of the mutations on alpha-ImI binding and functional antagonism are explained by computational docking of the NMR structure of alpha-ImI to a homology model of the ligand binding domain of the alpha7 nAChR. A distinct binding site for alpha-ImII is further demonstrated by its weakened antagonism for a chimeric receptor in which the membrane-spanning domains and intervening linkers of the alpha7 nAChR are replaced with the corresponding sequence from the serotonin type-3 receptor (5HT(3)). The two toxins also discriminate between different subtypes of human nicotinic receptors; alpha-ImII most strongly blocks the human alpha7 and alpha1beta1deltaepsilon receptor subtypes, while alpha-ImI most potently blocks the human alpha3beta2 subtype. Collectively, the data show that while alpha-ImI targets the classical competitive ligand binding site in a subtype selective manner, alpha-ImII is a probe of a novel inhibitory site in homomeric alpha7 nAChRs.
ESTHER : Ellison_2004_Biochemistry_43_16019
PubMedSearch : Ellison_2004_Biochemistry_43_16019
PubMedID: 15609996

Title : Curariform antagonists bind in different orientations to the nicotinic receptor ligand binding domain - Wang_2003_J.Biol.Chem_278_32284
Author(s) : Wang HL , Gao F , Bren N , Sine SM
Ref : Journal of Biological Chemistry , 278 :32284 , 2003
Abstract : Curariform alkaloids competitively inhibit muscle acetylcholine receptors (AChR) by bridging the alpha and non-alpha subunits that form the ligand-binding site. Here we delineate bound orientations of d-tubocurarine (d-TC) and its methylated derivative metocurine using mutagenesis, ligand binding measurements, and computational methods. When tested against a series of lysine mutations in the epsilon subunit, the two antagonists show marked differences in the consequences of the mutations on binding affinity. The mutations epsilon L117K, epsilon Y111K, and epsilon L109K decrease affinity of metocurine by up to 3 orders of magnitude but only slightly alter affinity of d-TC. At the alpha subunit face of the binding site, the mutation alpha Y198T decreases affinity of both antagonists, but alpha Y198F preferentially enhances affinity of d-TC. Computation of antagonist docking orientations, based on our structural model of the alpha-epsilon site of the human AChR, indicates distinct orientations of each antagonist; the flatter metocurine fits into a pocket formed principally by the epsilon subunit, whereas the more compact d-TC spans the narrower crevasse between alpha and epsilon subunits. The side chains of epsilon Tyr-111 and epsilon Thr-117 juxtapose one of two quaternary nitrogens in metocurine but are remote from the equivalent quaternary nitrogen in d-TC, which instead closely approaches alpha Tyr-198. The different docked orientations arise through tilt of the curariform scaffold by approximately 60 degrees normal to the nitrogen-nitrogen axis, together with a 20 degrees rotation about the axis. The overall mutagenesis and computational results show that despite their similar structures, d-TC and metocurine bind in distinctly different orientations to the adult human AChR.
ESTHER : Wang_2003_J.Biol.Chem_278_32284
PubMedSearch : Wang_2003_J.Biol.Chem_278_32284
PubMedID: 12799358

Title : Curariform antagonists bind in different orientations to acetylcholine-binding protein - Gao_2003_J.Biol.Chem_278_23020
Author(s) : Gao F , Bern N , Little A , Wang HL , Hansen SB , Talley TT , Taylor P , Sine SM
Ref : Journal of Biological Chemistry , 278 :23020 , 2003
Abstract : Acetylcholine-binding protein (AChBP) recently emerged as a prototype for relating structure to function of the ligand binding domain of nicotinic acetylcholine receptors (AChRs). To understand interactions of competitive antagonists at the atomic structural level, we studied binding of the curare derivatives d-tubocurarine (d-TC) and metocurine to AChBP using computational methods, mutagenesis, and ligand binding measurements. To account for protein flexibility, we used a 2-ns molecular dynamics simulation of AChBP to generate multiple snapshots of the equilibrated dynamic structure to which optimal docking orientations were determined. Our results predict a predominant docking orientation for both d-TC and metocurine, but unexpectedly, the bound orientations differ fundamentally for each ligand. At one subunit interface of AChBP, the side chain of Tyr-89 closely approaches a positively charged nitrogen in d-TC but is farther away from the equivalent nitrogen in metocurine, whereas, at the opposing interface, side chains of Trp-53 and Gln-55 closely approach the metocurine scaffold but not that of d-TC. The different orientations correspond to approximately 170 degrees rotation and approximately 30 degrees degree tilt of the curare scaffold within the binding pocket. Mutagenesis of binding site residues in AChBP, combined with measurements of ligand binding, confirms the different docking orientations. Thus structurally similar ligands can adopt distinct orientations at receptor binding sites, posing challenges for interpreting structure-activity relationships for many drugs.
ESTHER : Gao_2003_J.Biol.Chem_278_23020
PubMedSearch : Gao_2003_J.Biol.Chem_278_23020
PubMedID: 12682067