Fu Y

References (49)

Title : Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial - Wang_2024_Diabetes.Obes.Metab__
Author(s) : Wang W , Guo X , Zhang C , Ning T , Ma G , Huang Y , Jia R , Zhou D , Cao M , Zhang T , Yao L , Yuan J , Chen L , Wang Y , Jiang C , Dong X , Chen M , Gu Q , Zhang L , Fu Y , Pan T , Bi Y , Song W , Xu J , Lu W , Sun X , Ye Z , Zhang D , Peng L , Lin X , Dai W , Wang Q , Yang W
Ref : Diabetes Obes Metab , : , 2024
Abstract : AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.
ESTHER : Wang_2024_Diabetes.Obes.Metab__
PubMedSearch : Wang_2024_Diabetes.Obes.Metab__
PubMedID: 38221859 || 38618970

Title : Structure-activity relationship of Caulerpa lentillifera polysaccharide in inhibiting lipid digestion - You_2024_Int.J.Biol.Macromol__129435
Author(s) : You Y , Song C , Fu Y , Sun Y , Wen C , Zhu B , Song S
Ref : Int J Biol Macromol , :129435 , 2024
Abstract : Caulerpa lentillifera polysaccharide (CLP) has been characterized as a sulfated polysaccharide which can effectively inhibit lipid digestion. However, little information was known regarding its inhibitory mechanisms. In the present study, desulfation and degradation were conducted to prepare the derivatives of CLP, and a series of chemical and spectroscopic methods were used to elucidate the structure-activity relationship of CLP on the inhibitory effect of lipid digestion. Results revealed that CLP possessed excellent binding capacities for sodium cholate, sodium glycocholate, and sodium taurocholate. In addition, CLP can effectively inhibit lipase activity by quenching the fluorescence intensity, changing the secondary structure, and decreasing the UV-Vis absorbance. Of note, sulfate groups in CLP took a vital role in inhibiting lipase activity, while the molecular weight of CLP showed a positive correlation with the binding activities of bile acids. Furthermore, adding CLP into the whey protein isolate (WPI) emulsion system also impeded lipid digestion, indicating that CLP can be a potential reduced-fat nutraceutical used in food emulsion systems.
ESTHER : You_2024_Int.J.Biol.Macromol__129435
PubMedSearch : You_2024_Int.J.Biol.Macromol__129435
PubMedID: 38228205

Title : Optimization of Extraction Process and Analysis of Biological Activity of Flavonoids from Leaves of Cultivated 'Qi-Nan' Agarwood - Li_2024_Molecules_29_
Author(s) : Li Q , Wei P , Li Y , Fu Y
Ref : Molecules , 29 : , 2024
Abstract : Currently, the planting of 'Qi-Nan' is continuously increasing, yet a substantial amount of 'Qi-Nan' leaves have not been properly exploited. To improve the 'Qi-Nan' tree 's utilization value, 'Qi-Nan' leaves were used as a raw material. An ultrasound-assisted method was performed to obtain the flavonoids from the 'Qi-Nan' leaves, followed by optimization of the extraction factors using a one-way and response surface methodology to enhance the extraction of flavonoids. Subsequently, the composition of the flavonoids, as well as their bioactive abilities, were analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and in vitro activity testing methods. The findings demonstrated that a 1:50 material-to-liquid ratio, 60% ethanol concentration, and ultrasound-assisted extraction time of 30 min were the ideal procedures for extracting flavonoids (flavonoid content: 6.68%). Meanwhile, the 'Qi-Nan' leaves possessed the antioxidant and medicinal potential to prevent diabetes and Alzheimer 's disease, as evidenced by the semi-inhibitory concentrations (IC50 values) of flavonoid extracts for scavenging DPPH() free radicals, scavenging ABTS(+) free radicals, inhibiting acetylcholinesterase, and inhibiting alpha-glucosidase, which were 12.64 microg/mL, 66.58 microg/mL, 102.31 microg/mL, and 38.76 microg/mL, respectively, which indicated that the 'Qi-Nan' leaves possessed the properties of antioxidant and medicinal potential for the prevention of Alzheimer 's disease and diabetes.
ESTHER : Li_2024_Molecules_29_
PubMedSearch : Li_2024_Molecules_29_
PubMedID: 38675648

Title : Preparation of functional oils rich in phytosterol esters and diacylglycerols by enzymatic transesterification - Shi_2024_Food.Chem_448_139100
Author(s) : Shi W , Li H , Fu Y , Tang X , Yu J , Wang X
Ref : Food Chem , 448 :139100 , 2024
Abstract : Phytosterol esters (PEs) and diacylglycerols (DAGs) have various health benefits in humans. In this study, PEs and DAGs were synthesized by lipase-catalyzed transesterification between a natural oil and phytosterols. First, commercial lipases were screened for transesterification and were further verified using multiple-ligand molecular docking. AYS "Amano" (a lipase from Candida rugosa) was found to be the optimum lipase. Subsequently, the enzymatic transesterification conditions were optimized. The optimized conditions were determined to be a 1:2 M ratio of phytosterols to oil, 100 mmol/L phytosterols, and 9 % AYS "Amano", and 50 degreesC for 24 h in 20 mL n-hexane. Under these conditions, over 70 % of phytosterols were converted to PEs. In this study, an efficient enzymatic process was developed to produce value-added functional oils rich in PEs and DAGs, with PEs content <= 31.6 %, DAGs content <= 11.2 %, acid value >= 0.91 mg KOH/g, and peroxide value >= 2.38 mmol/kg.
ESTHER : Shi_2024_Food.Chem_448_139100
PubMedSearch : Shi_2024_Food.Chem_448_139100
PubMedID: 38552457

Title : Enzymatic synthesis of branched chain fatty acid-enriched structured triacylglycerols via esterification with glycerol - Huang_2023_Food.Chem_429_136943
Author(s) : Huang Y , Li H , Wang Z , Fu Y , Chen Y , Wang X
Ref : Food Chem , 429 :136943 , 2023
Abstract : While branched-chain fatty acids (BCFA)-enriched triacylglycerols (TAG) has various health benefits, its preparation has not been reported. This study aimed to synthesize high-purity BCFA-enriched structured TAG. First, BCFA was enriched from lanolin through saponification, calcification, and urea complexation. Next, BCFA-enriched TAG was synthesized by enzymatic esterification of BCFA and glycerol. Then, lipases were screened by molecular docking and practical experiments, which suggested that Lipozyme 435 was the best lipase for esterification since it had the lowest binding energy. Structured TAG containing 92.23% BCFA was synthesized under conditions optimized by single-factor experiments. Furthermore, molecular distillation was adapted to remove excess fatty acids and small molecule impurities. Finally, high-purity BCFA-enriched structured lipid containing 70.26% TAG was obtained. Overall, this study successfully developed a method for synthesizing BCFA-enriched structured TAG, which holds great promise for applications in value-added foods.
ESTHER : Huang_2023_Food.Chem_429_136943
PubMedSearch : Huang_2023_Food.Chem_429_136943
PubMedID: 37517224

Title : How Closely Does Induced Agarwood's Biological Activity Resemble That of Wild Agarwood? - Ma_2023_Molecules_28_
Author(s) : Ma S , Huang M , Fu Y , Qiao M , Li Y
Ref : Molecules , 28 : , 2023
Abstract : Continuous innovation in artificially-induced agarwood technology is increasing the amount of agarwood and substantially alleviating shortages. Agarwood is widely utilized in perfumes and fragrances; however, it is unclear whether the overall pharmacological activity of induced agarwood can replace wild agarwood for medicinal use. In this study, the volatile components, total chromone content, and the differences in the overall activities of wild agarwood and induced agarwood, including the antioxidant, anti-acetylcholinesterase, and anti-glucosidase activity were all determined. The results indicated that both induced and wild agarwood's chemical makeup contains sesquiterpenes and 2-(2-phenylethyl)chromones. The total chromone content in generated agarwood can reach 82.96% of that in wild agarwood. Induced agarwood scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)) radicals and inhibited acetylcholinesterase activity and alpha-glucosidase activity with IC(50) values of 0.1873 mg/mL, 0.0602 mg/mL, 0.0493 mg/mL, and 0.2119 mg/mL, respectively, reaching 80.89%, 93.52%, 93.52%, and 69.47% of that of wild agarwood, respectively. Accordingly, the results distinguished that induced agarwood has the potential to replace wild agarwood in future for use in medicine because it has a similar chemical makeup to wild agarwood and has comparable antioxidant, anti-acetylcholinesterase, and anti-glucosidase capabilities.
ESTHER : Ma_2023_Molecules_28_
PubMedSearch : Ma_2023_Molecules_28_
PubMedID: 37049682

Title : The phospholipase effector Tle1(Vc) promotes Vibrio cholerae virulence by killing competitors and impacting gene expression - Liu_2023_Gut.Microbes_15_2241204
Author(s) : Liu M , Wang H , Liu Y , Tian M , Wang Z , Shu RD , Zhao MY , Chen WD , Fu Y
Ref : Gut Microbes , 15 :2241204 , 2023
Abstract : Vibrio cholerae utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner. However, the impact of T6SS and its secreted effectors on physiological behavior remains poorly understood. In this study, we present Tle1(Vc), a phospholipase effector in atypical pathogenic V. cholerae E1 that is secreted by T6SS via its interaction with VgrG1(E1). Tle1(Vc) contains a DUF2235 domain and belongs to the Tle1 (type VI lipase effector) family. Bacterial toxicity assays, lipase activity assays and site-directed mutagenesis revealed that Tle1(Vc) possessed phospholipase A(1) activity and phospholipase A(2) activity, and that Tle1(Vc)-induced toxicity required a serine residue (S356) and two aspartic acid residues (D417 and D496). Cells intoxication with Tle1(Vc) lead to membrane depolarization and alter membrane permeability. Tli1(tox-), a cognate immunity protein, directly interacts with Tle1(Vc) to neutralize its toxicity. Moreover, Tle1(Vc) can kill multiple microorganisms by T6SS and promote in vivo fitness of V. cholerae through mediating antibacterial activity. Tle1(Vc) induces bacterial motility by increasing the expression of flagellar-related genes independently of functional T6SS and the tit-for-tat (TFT) response, where Pseudomonas aeruginosa uses its T6SS-H1 cluster to counterattack other offensive attackers. Our study also demonstrated that the physical puncture of E1 T6SS can induce a moderate TFT response, which is essential to the Tle1(Vc)-mediated strong TFT response, maximizing effector functions. Overall, our study characterized the antibacterial mechanism of phospholipase effector Tle1(Vc) and its multiple physiological significance.
ESTHER : Liu_2023_Gut.Microbes_15_2241204
PubMedSearch : Liu_2023_Gut.Microbes_15_2241204
PubMedID: 37526354

Title : Characteristics of CXE family of Salvia miltiorrhiza and identification of interactions between SmGID1s and SmDELLAs - Li_2023_Plant.Physiol.Biochem_206_108140
Author(s) : Li Y , Pang Q , Li B , Fu Y , Guo M , Zhang C , Tian Q , Hu S , Niu J , Wang S , Wang D , Wang Z
Ref : Plant Physiol Biochem , 206 :108140 , 2023
Abstract : Carboxylesterase (CXE) is a class of hydrolases that contain an alpha/beta folding domain, which plays critical roles in plant growth, development, and stress responses. Based on the genomic and transcriptomic data of Salvia miltiorrhiza, the SmCXE family was systematically analyzed using bioinformatics. The results revealed 34 SmCXE family members in S. miltiorrhiza, and the SmCXE family could be divided into five groups (Group I, Group II, Group III, Group IV, and Group V). Cis-regulatory elements indicated that the SmCXE promoter region contained tissue-specific and development-related, hormone-related, stress-related, and photoresponsive elements. Transcriptome analysis revealed that the expression levels of SmCXE2 were highest in roots and flowers (SmCXE8 was highest in stems and SmCXE19 was highest in leaves). Further, two GA receptors SmCXE1 (SmGID1A) and SmCXE2 (SmGID1B) were isolated from the SmCXE family, which are homologous to other plants. SmGID1A and SmGID1B have conserved HGGSF motifs and active amino acid sites (Ser-Asp-Val/IIe), which are required to maintain their GA-binding activities. SmGID1A and SmGID1B were significantly responsive to gibberellic acid (GA(3)) and methyl jasmonate (MeJA) treatment. A subcellular assay revealed that SmCXE1 and SmCXE2 resided within the nucleus. SmGID1B can interact with SmDELLAs regardless of whether GA(3) exists, whereas SmGID1A can only interact with SmDELLAs in the presence of GA(3). A Further assay showed that the GRAS domain mediated the interactions between SmGID1s and SmDELLAs. This study lays a foundation for further elucidating the role of SmCXE in the growth and development of S. miltiorrhiza.
ESTHER : Li_2023_Plant.Physiol.Biochem_206_108140
PubMedSearch : Li_2023_Plant.Physiol.Biochem_206_108140
PubMedID: 38134738
Gene_locus related to this paper: salmi-SmCXE1 , salmi-SmCXE2 , salmi-SmCXE3 , salmi-SmCXE4 , salmi-SmCXE5 , salmi-SmCXE6 , salmi-SmCXE7 , salmi-SmCXE8 , salmi-SmCXE9 , salmi-SmCXE10 , salmi-SmCXE11 , salmi-SmCXE12 , salmi-SmCXE13 , salmi-SmCXE14 , salmi-SmCXE15 , salmi-SmCXE16 , salmi-SmCXE17 , salmi-SmCXE18 , salmi-SmCXE19 , salmi-SmCXE20 , salmi-SmCXE21 , salmi-SmCXE22 , salmi-SmCXE23 , salmi-SmCXE24 , salmi-SmCXE25 , salmi-SmCXE26 , salmi-SmCXE27 , salmi-SmCXE28 , salmi-SmCXE29 , salmi-SmCXE30 , salmi-SmCXE31 , salmi-SmCXE32 , salmi-SmCXE33 , salmi-SmCXE34

Title : Sclerotinia sclerotiorum SsCut1 Modulates Virulence and Cutinase Activity - Gong_2022_J.Fungi.(Basel)_8_
Author(s) : Gong Y , Fu Y , Xie J , Li B , Chen T , Lin Y , Chen W , Jiang D , Cheng J
Ref : J Fungi (Basel) , 8 : , 2022
Abstract : The plant cuticle is one of the protective layers of the external surface of plant tissues. Plants use the cuticle layer to reduce water loss and resist pathogen infection. Fungi release cell wall-degrading enzymes to destroy the epidermis of plants to achieve the purpose of infection. Sclerotinia sclerotiorum secretes a large amount of cutinase to disrupt the cuticle layer of plants during the infection process. In order to further understand the role of cutinase in the pathogenic process of S. sclerotiorum, the S. sclerotiorum cutinsae 1 (SsCut1) gene was cloned and analyzed. The protein SsCut1 contains the conserved cutinase domain and a fungal cellulose-binding domain. RT-qPCR results showed that the expression of SsCut1 was significantly upregulated during infection. Split-Marker recombination was utilized for the deletion of the SsCut1 gene, deltaSsCut1 mutants showed reduced cutinase activity and virulence, but the deletion of the SsCut1 gene had no effect on the growth rate, colony morphology, oxalic acid production, infection cushion formation and sclerotial development. Complementation with the wild-type SsCut1 allele restored the cutinase activity and virulence to the wild-type level. Interestingly, expression of SsCut1 in plants can trigger defense responses, but it also enhanced plant susceptibility to SsCut1 gene knock-out mutants. Taken together, our finding demonstrated that the SsCut1 gene promotes the virulence of S. sclerotiorum by enhancing its cutinase activity.
ESTHER : Gong_2022_J.Fungi.(Basel)_8_
PubMedSearch : Gong_2022_J.Fungi.(Basel)_8_
PubMedID: 35628781
Gene_locus related to this paper: scls1-a7erz9

Title : Fluorescence-activated droplet sorting of PET degrading microorganisms - Qiao_2022_J.Hazard.Mater_424_127417
Author(s) : Qiao Y , Hu R , Chen D , Wang L , Wang Z , Yu H , Fu Y , Li C , Dong Z , Weng YX , Du W
Ref : J Hazard Mater , 424 :127417 , 2022
Abstract : Enzymes that can decompose synthetic plastics such as polyethylene terephthalate (PET) are urgently needed. Still, a bottleneck remains due to a lack of techniques for detecting and sorting environmental microorganisms with vast diversity and abundance. Here, we developed a fluorescence-activated droplet sorting (FADS) pipeline for high-throughput screening of PET-degrading microorganisms or enzymes (PETases). The pipeline comprises three steps: generation and incubation of droplets encapsulating single cells, picoinjection of fluorescein dibenzoate (FDBz) as the fluorogenic probe, and screening of droplets to obtain PET-degrading cells. We characterized critical factors associated with this method, including specificity and sensitivity for discriminating PETase from other enzymes. We then optimized its performance and compatibility with environmental samples. The system was used to screen a wastewater sample from a PET textile mill. We successfully obtained PET-degrading species from nine different genera. Moreover, two putative PETases from isolates Kineococcus endophyticus Un-5 and Staphylococcus epidermidis Un-C2-8 were genetically derived, heterologously expressed, and preliminarily validated for PET-degrading activities. We speculate that the FADS pipeline can be widely adopted to discover new plastic-degrading microorganisms and enzymes in various environments and may be utilized in the directed evolution of degrading enzymes using synthetic biology.
ESTHER : Qiao_2022_J.Hazard.Mater_424_127417
PubMedSearch : Qiao_2022_J.Hazard.Mater_424_127417
PubMedID: 34673397

Title : Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis - Fu_2022_Genes.(Basel)_13_
Author(s) : Fu Y , Zhao D , Zhou Y , Lu J , Kang L , Jiang X , Xu R , Ding Z , Zou Y
Ref : Genes (Basel) , 13 : , 2022
Abstract : Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein-protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape's three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARalpha), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARalpha, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment.
ESTHER : Fu_2022_Genes.(Basel)_13_
PubMedSearch : Fu_2022_Genes.(Basel)_13_
PubMedID: 35886059

Title : Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain - Du_2022_Acta.Pharm.Sin.B_12_1377
Author(s) : Du F , Cao R , Chen L , Sun J , Shi Y , Fu Y , Hammock BD , Zheng Z , Liu Z , Chen G
Ref : Acta Pharm Sin B , 12 :1377 , 2022
Abstract : Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (+/-)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.
ESTHER : Du_2022_Acta.Pharm.Sin.B_12_1377
PubMedSearch : Du_2022_Acta.Pharm.Sin.B_12_1377
PubMedID: 35530144

Title : Ethanol and its nonoxidative metabolites promote acute liver injury by inducing ER stress, adipocyte death and lipolysis - Park_2022_Cell.Mol.Gastroenterol.Hepatol__
Author(s) : Park SH , Seo W , Xu MJ , Mackowiak B , Lin Y , He Y , Fu Y , Hwang S , Kim SJ , Guan Y , Feng D , Yu L , Lehner R , Liangpunsakul S , Gao B
Ref : Cell Mol Gastroenterol Hepatol , : , 2022
Abstract : BACKGROUND & AIMS: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease (ALD). However, the underlying mechanisms remain elusive. We investigated if oxidative and non-oxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influence the development of acute liver injury in a single ethanol binge model. METHODS & RESULTS: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. Oral administration of a single dose of ethanol induced acute liver injury and hepatic ER stress in chow- or HFD-fed mice. Disruption of the alcohol dehydrogenase 1 (Adh1) gene elevated blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the aldehyde dehydrogenase 2 (Aldh2) gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies revealed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, increased adipocyte death and lipolysis, contributing to acute liver injury. Elevated serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice post ethanol gavage with higher levels in Adh1 knockout mice than that in wild-type mice. Deletion of the carboxylesterase 1d (Ces1d) gene in mice markedly reduced acute ethanol-induced elevation of blood FAEE levels with slight but significant reduction of serum aminotransferase levels. CONCLUSION: Ethanol and its non-oxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.
ESTHER : Park_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedSearch : Park_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedID: 36243320

Title : A novel pomegranate-inspired bifunctional electrode materials design for acetylcholinesterase biosensor and methanol oxidation reaction - Wei_2022_Bioelectrochemistry_145_108094
Author(s) : Wei W , Tang H , Dong S , Fu Y , Huang T
Ref : Bioelectrochemistry , 145 :108094 , 2022
Abstract : A pomegranate-inspired bifunctional electrode material based on Ni/NiO nanoparticle embedded in nitrogen-doped, partially graphitized carbon framework (Ni/NiO@NPGC) was designed and prepared for the construction of novel electrochemical biosensor and methanol oxidation reaction (MOR). Profiting from itsspecialstructureandfunction, Ni/NiO@NPGC was employed as a matrix immobilizing acetylcholinesterase (AChE) for methyl parathion (MP) sensor. The developed biosensor was proved to have wide linear range (1.0 x 10(-14)-1.0 x 10(-8) g mL(-1)), low detection limit (3.5 x 10(-15) g mL(-1)), and good stability for the determination of MP in practical samples. In addition, the Ni/NiO@NPGC electrode exhibited high electrocatalytic activity (specific activity 73.1 mA cm(-2)) and durability for the MOR in alkaline medium. The results were mainly attributed to the pomegranate-like architecture structure with pyridinic N and carbon frame of Ni/NiO@NPGC, which ensured the electrochemical activities of all nanoparticles and immobilization of enzyme. In addition, the metal oxide was well dispersed to prevent from self-agglomeration and kept mass transfer paths. The work provides a reference for the development of high-performance bifunctional electrode material for the biosensor and MOR.
ESTHER : Wei_2022_Bioelectrochemistry_145_108094
PubMedSearch : Wei_2022_Bioelectrochemistry_145_108094
PubMedID: 35299151

Title : Recombinant AcMNPV-gp64-EGFP and synergist triphenyl phosphate, an effective combination against Spodoptera frugiperda - Jiao_2022_Biotechnol.Lett__
Author(s) : Jiao R , Fu Y
Ref : Biotechnol Lett , : , 2022
Abstract : OBJECTIVES: AcMNPV is a kind of microbial insecticide that can significantly relieve the resistance of Spodoptera frugiperda to chemical pesticides. TPP is a widely used synergist, which can reduce the use of pesticides by inhibiting carboxylesterase. It is emergently needed to develop a biological control way of Spodoptera frugiperda. RESULTS: GP64 mediates low-pH-triggered membrane fusion during entry by endocytosis and participates in AcMNPV particle budding. We explored the synergistic anti-insect activity of AcMNPV-gp64-EGFP and TPP. AcMNPV-gp64-EGFP could increase progeny virus proliferation and accelerate the transcription of 38k and vp39 genes. TPP could inhibit the carboxylesterase activity in the midgut of Spodoptera frugiperda larvae infected with AcMNPV-gp64-EGFP and enhance the virulence of AcMNPV-gp64-EGFP to Spodoptera frugiperda. CONCLUSIONS: TPP targeted carboxylesterase inhibition so that AcMNPV-gp64-EGFP could escape the antiviral response in insect hosts. It provided a novel strategy for the prevention of Spodoptera frugiperda.
ESTHER : Jiao_2022_Biotechnol.Lett__
PubMedSearch : Jiao_2022_Biotechnol.Lett__
PubMedID: 35922646

Title : Nuclear access of DNlg3 c-terminal fragment and its function in regulating innate immune response genes - Xie_2022_Biochem.Biophys.Res.Commun_641_93
Author(s) : Xie H , Liu S , Fu Y , Cheng Q , Wang P , Bi CL , Wang R , Chen MM , Fang M
Ref : Biochemical & Biophysical Research Communications , 641 :93 , 2022
Abstract : Neuroligins (NLGNs) are one of the autism susceptibility genes, however, the mechanism that how dysfunction of NLGNs leads to Autism remains unclear. More and more studies have shown that the transcriptome alteration may be one of the important factors to generate Autism. Therefore, we are very concerned about whether Neuroligins would affect transcriptional regulation, which may at last lead to Autism. As a single-transmembrane receptor, proteolytic cleavage is one of the most important posttranslational modifications of NLGN proteins. In this study, we demonstrated the existence of DNlg3 C-terminal fragment. Studies in the S2 cells and HEK293T cells showed the evidence for nuclear access of the DNlg3 C-terminal fragment. Then we identified the possible targets of DNlg3 C-terminal fragment after its nuclear access by RNA-seq. The bioinformatics analysis indicated the transcriptome alteration between dnlg3 null flies and wild type flies focused on genes for the innate immune responses. These results were consistent with the infection hypotheses for autism. Our study revealed the nuclear access ability of DNlg3 c-terminal fragment and its possible function in transcriptional regulation of the innate immune response genes. This work provides the new links between synaptic adhesion molecule NLGNs and immune activation, which may help us to get a deeper understanding on the relationship between NLGNs and Autism.
ESTHER : Xie_2022_Biochem.Biophys.Res.Commun_641_93
PubMedSearch : Xie_2022_Biochem.Biophys.Res.Commun_641_93
PubMedID: 36525929

Title : Enhanced Production of (S)-2-arylpropionic Acids by Protein Engineering and Whole-Cell Catalysis - Liu_2021_Front.Bioeng.Biotechnol_9_697677
Author(s) : Liu X , Zhao M , Fan X , Fu Y
Ref : Front Bioeng Biotechnol , 9 :697677 , 2021
Abstract : Esterases are important biocatalysts for chemical synthesis. Several bHSL family esterases have been used to prepare (S)-2-arylpropionic acids with stronger anti-inflammatory effects via kinetic resolution. Here, we presented the discovery of key residues that controlled the enantioselectivity of bHSL family esterases to ethyl 2-arylpropionates, through careful analysis of the structural information and molecular docking. A new bHSL family esterase, Est924, was identified as a promising catalyst for kinetic resolution of racemic ethyl 2-arylpropionates with slight (R)-stereopreference. Using Est924 as the starting enzyme, protein engineering was conducted at hotspots, and the substitution of A203 was proved to enhance the enantioselectivity. The stereopreference of the mutant M1 (A203W) was inverted to ethyl (S)-2-arylpropionates, and this stereopreference was further improved in variant M3 (I202F/A203W/G208F). In addition, the optimal variant, M3, was also suitable for the resolution of ibuprofen ethyl ester and ketoprofen ethyl ester, and their efficient (S)-isomers were synthesized. Next, the whole-cell catalyst harboring M3 was used to prepare (S)-ketoprofen. (S)-ketoprofen with 86%ee was produced by whole-cell catalyst with a single freeze-thaw cycle, and the cells could be reused for at least five cycles. Our results suggested that Est924 variants could kinetically resolve economically important racemates for industrial production and further offer the opportunity for the rational design of enzyme enantioselectivity. Moreover, it is an economical process to prepare optically pure (S)-ketoprofen and (S)-naproxen by using an engineered strain harboring M3 as the catalyst.
ESTHER : Liu_2021_Front.Bioeng.Biotechnol_9_697677
PubMedSearch : Liu_2021_Front.Bioeng.Biotechnol_9_697677
PubMedID: 34307324
Gene_locus related to this paper: 9zzzz-Est924

Title : The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression - Li_2021_Eur.J.Med.Chem_229_114045
Author(s) : Li X , Li J , Huang Y , Gong Q , Fu Y , Xu Y , Huang J , You H , Zhang D , Mao F , Zhu J , Wang H , Zhang H
Ref : Eur Journal of Medicinal Chemistry , 229 :114045 , 2021
Abstract : Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT(1A) receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT(1A) receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression.
ESTHER : Li_2021_Eur.J.Med.Chem_229_114045
PubMedSearch : Li_2021_Eur.J.Med.Chem_229_114045
PubMedID: 34922191

Title : Reshaping the active pocket of esterase Est816 for resolution of economically important racemates - Liu_2021_Catal.Sci.Technol__
Author(s) : Liu X , Zhao M , Fan XJ , Fu Y
Ref : Catal Sci Technol , : , 2021
Abstract : Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with high E values were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.
ESTHER : Liu_2021_Catal.Sci.Technol__
PubMedSearch : Liu_2021_Catal.Sci.Technol__
Gene_locus related to this paper: 9bact-i6yrg4

Title : Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate - Zhou_2021_J.Med.Chem_64_1844
Author(s) : Zhou Y , Fu Y , Yin W , Li J , Wang W , Bai F , Xu S , Gong Q , Peng T , Hong Y , Zhang D , Liu Q , Xu Y , Xu HE , Zhang H , Jiang H , Liu H
Ref : Journal of Medicinal Chemistry , 64 :1844 , 2021
Abstract : The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
ESTHER : Zhou_2021_J.Med.Chem_64_1844
PubMedSearch : Zhou_2021_J.Med.Chem_64_1844
PubMedID: 33570950
Gene_locus related to this paper: human-ACHE

Title : Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China - Li_2020_Ecotoxicol.Environ.Saf_196_110548
Author(s) : Li Y , Fu Y , Hu K , Zhang Y , Chen J , Zhang S , Zhang B , Liu Y
Ref : Ecotoxicology & Environmental Safety , 196 :110548 , 2020
Abstract : As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer.
ESTHER : Li_2020_Ecotoxicol.Environ.Saf_196_110548
PubMedSearch : Li_2020_Ecotoxicol.Environ.Saf_196_110548
PubMedID: 32278140

Title : One-pot cascade synthesis of benzopyrans and dihydropyrano[c]chromenes catalyzed by lipase TLIM - Fu_2020_Bioorg.Chem_99_103888
Author(s) : Fu Y , Lu Z , Ma X , Fang K , He X , Xu H , Hu Y
Ref : Bioorg Chem , 99 :103888 , 2020
Abstract : Lipase TLIM was reported to be an efficient, commercially available and reusable catalyst for the Knoevenagel-Michael cascade reactions of aldehydes, malononitrile/ethyl cyanoacetate and 4-hydroxycoumarin/1, 3-cyclohexanedione/dimedone in aqueous DMSO. This methodology presents many superiorities such as simple procedure, mild reaction conditions, commercially available and reusable catalyst, high substrate applicability, the ability to be scaled up, and good to excellent yields.
ESTHER : Fu_2020_Bioorg.Chem_99_103888
PubMedSearch : Fu_2020_Bioorg.Chem_99_103888
PubMedID: 32388204

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 : Bio-\/Nanoimmobilization Platform Based on Bioinspired Fibrin-Bone@Polydopamine-Shell Adhesive Composites for Biosensing - Zhang_2019_ACS.Appl.Mater.Interfaces_11_47311
Author(s) : Zhang L , Liu Z , Zha S , Liu G , Zhu W , Xie Q , Li Y , Ying Y , Fu Y
Ref : ACS Appl Mater Interfaces , 11 :47311 , 2019
Abstract : Inspired by blood coagulation and mussel adhesion, we report novel adhesive fibrin-bone@polydopamine (PDA)-shell composite matrix as highly efficient immobilization platform for biomacromolecules and nanomaterials. Fibrin, as a bioglue, and PDA, as a chemical adhesive, are integrated in a one-pot simultaneous polymerization consisting of biopolymerization of fibrinogen and chemical polymerization of dopamine. Fibrin fibers act as adhesive bones to construct scaffold, while PDA coat on the scaffold to form adhesive shell, generating 3D porous composite matrix with unique bone@shell structure. Two types of enzymes (glucose oxidase and acetylcholinesterase) and Au nanoparticles were adopted as respective model biomolecules and nanomaterials to investigate the immobilization capability of the matrix. The bionanocomposites showed high efficiency in capturing nanoparticles and enzymes, as well as significant mass-transfer and biocatalysis efficiencies. Therefore, the bionanocomposites exhibited significant potential in biosensing of glucose and paraoxon with limits of detection down to 5.2 muM and 4 ppt, respectively. The biological-chemical-combined polymerization strategy and composite platform with high immobilization capacity and mass-transfer efficiency open up a novel way for the preparation of high-performance bionanocomposites for various applications, in particular, biosensing.
ESTHER : Zhang_2019_ACS.Appl.Mater.Interfaces_11_47311
PubMedSearch : Zhang_2019_ACS.Appl.Mater.Interfaces_11_47311
PubMedID: 31742992

Title : Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson's Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage - Zou_2018_Aging.Dis_9_51
Author(s) : Zou J , Chen Z , Liang C , Fu Y , Wei X , Lu J , Pan M , Guo Y , Liao X , Xie H , Wu D , Li M , Liang L , Wang P , Wang Q
Ref : Aging Dis , 9 :51 , 2018
Abstract : Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson's disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores' distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD.
ESTHER : Zou_2018_Aging.Dis_9_51
PubMedSearch : Zou_2018_Aging.Dis_9_51
PubMedID: 29392081

Title : Increased NDRG1 expression attenuate trophoblast invasion through ERK\/MMP-9 pathway in preeclampsia - Fu_2017_Placenta_51_76
Author(s) : Fu Y , Wei J , Dai X , Ye Y
Ref : Placenta , 51 :76 , 2017
Abstract : OBJECTIVE: The aim of this study was to investigate the expression of N-myc downstream-regulated gene1(NDRG1)in the placentas of pregnancies complicated with early-onset and late-onset preeclampsia (PE) and its underlying mechanism on the pathophysiology of PE.
METHODS: The expressions of NDRG-1 in placentas of pregnancies complicated with early-onset PE and late-onset PE were detected using immunohistochemistry, western blot assays and fluorescence quantitative PCR. The expressions of MMP-2, MMP-9 and ERK1/2 protein were detected by western blot analysis and cell invasion assay was performed using transwell chambers in NDRG1 silenced JEG-3 cells.
RESULTS: Compared with the normal term pregnancies, the expression of both NDRG1 mRNA and protein were significantly high in placentas from PE, and the expression of NDRG1 in early-onset PE was higher than that in late-onset PE. In NDRG1-silenced JEG-3 cells, MMP-2, MMP-9 and phosphorylation of ERK1/2 protein increased obviously and the number of cells that penetrated the membrane increased. CONCLUSION: Upregulation of NDRG1 is associated with impaired trophoblast invasion in PE by inhibition ERK/MMP-2 and MMP-9 Pathway.
ESTHER : Fu_2017_Placenta_51_76
PubMedSearch : Fu_2017_Placenta_51_76
PubMedID: 28292472

Title : Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents - Li_2016_J.Med.Chem_59_8326
Author(s) : Li X , Wang H , Lu Z , Zheng X , Ni W , Zhu J , Fu Y , Lian F , Zhang N , Li J , Zhang H , Mao F
Ref : Journal of Medicinal Chemistry , 59 :8326 , 2016
Abstract : Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 muM, SI > 196; 5t, IC50 = 0.067 muM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Abeta aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.
ESTHER : Li_2016_J.Med.Chem_59_8326
PubMedSearch : Li_2016_J.Med.Chem_59_8326
PubMedID: 27552582

Title : Use of a carboxylesterase inhibitor of phenylmethanesulfonyl fluoride to stabilize epothilone D in rat plasma for a validated UHPLC-MS\/MS assay - Yuan_2014_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_969C_60
Author(s) : Yuan L , Fu Y , Zhang D , Xia YQ , Peng Q , Aubry AF , Arnold ME
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 969C :60 , 2014
Abstract : A sensitive, accurate and rugged UHPLC-MS/MS method was developed and validated for the quantitation of Epothilone D (EpoD), a microtubule stabilizer in development for treatment of Alzeimer's disease, in rat plasma. The ester group in EpoD can be hydrolyzed by esterases in blood or plasma, which creates a stability concern for the bioanalysis of EpoD. Species differences in the stability of EpoD in plasma were observed. Carboxylesterases were identified as the likely esterases responsible for the hydrolysis of EpoD in plasma ex vivo, and the cause of the species different stability. Phenylmethanesulfonyl fluoride, a carboxylesterase inhibitor, was used to stabilize EpoD in rat blood during sample collection, processing, and storage. A systematic method screening and optimization strategy was used to improve the assay sensitivity and minimize potential bioanalytical risks. The stabilized plasma samples were extracted by liquid-liquid extraction. Chromatographic separation was achieved on an Acquity UPLC BEH Phenyl column with a gradient elution. EpoD and its stable isotope labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 0.100 to 100ng/mL was fitted to a 1/x2 weighted linear regression model. The intra-assay precision was within +/-3.6% CV and inter-assay precision was within +/-4.2% CV. The assay accuracy was within +/-8.3% of the nominal values. Assay recovery of EpoD was high ( approximately 90%) and matrix effect was minimal (1.02-1.05). EpoD was stable in stabilized rat plasma for at least 30h at room temperature, 180 days at -20 degrees C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in toxicology studies.
ESTHER : Yuan_2014_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_969C_60
PubMedSearch : Yuan_2014_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_969C_60
PubMedID: 25151331

Title : Synaptic proteins and receptors defects in autism spectrum disorders - Chen_2014_Front.Cell.Neurosci_8_276
Author(s) : Chen J , Yu S , Fu Y , Li X
Ref : Front Cell Neurosci , 8 :276 , 2014
Abstract : Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.
ESTHER : Chen_2014_Front.Cell.Neurosci_8_276
PubMedSearch : Chen_2014_Front.Cell.Neurosci_8_276
PubMedID: 25309321

Title : Casuarinines A-J, Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides - Tang_2013_J.Nat.Prod_76_1475
Author(s) : Tang Y , Fu Y , Xiong J , Li M , Ma GL , Yang GX , Wei BG , Zhao Y , Zhang HY , Hu JF
Ref : Journal of Natural Products , 76 :1475 , 2013
Abstract : Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE).
ESTHER : Tang_2013_J.Nat.Prod_76_1475
PubMedSearch : Tang_2013_J.Nat.Prod_76_1475
PubMedID: 23941108

Title : Discovery of novel 2,6-disubstituted pyridazinone derivatives as acetylcholinesterase inhibitors - Xing_2013_Eur.J.Med.Chem_63C_95
Author(s) : Xing W , Fu Y , Shi Z , Lu D , Zhang H , Hu Y
Ref : Eur Journal of Medicinal Chemistry , 63C :95 , 2013
Abstract : 2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BCHE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.
ESTHER : Xing_2013_Eur.J.Med.Chem_63C_95
PubMedSearch : Xing_2013_Eur.J.Med.Chem_63C_95
PubMedID: 23466605

Title : Three-dimensional ordered macroporous (3DOM) composite for electrochemical study on acetylcholinesterase inhibition induced by endogenous neurotoxin - Teng_2012_J.Phys.Chem.B_116_11180
Author(s) : Teng Y , Fu Y , Xu L , Lin B , Wang Z , Xu Z , Jin L , Zhang W
Ref : J Phys Chem B , 116 :11180 , 2012
Abstract : In this paper, an electrochemical acetylcholinesterase (AChE) inhibition assay based on three-dimensional ordered macroporous (3DOM) composite was conducted. The 3DOM composite was first fabricated on the glassy carbon electrode by electropolymerization of aniline in the presence of ionic liquid (IL) on a sacrificial silica nanospheres template. After the silica nanospheres were etched, an IL-doped polyaniline (IL-PANI) film with 3DOM morphology was formed. Then, gold nanoparticles (AuNPs) were decorated on the IL-PANI film by electrodeposition. The immobilized AChE on the 3DOM composite displayed favorable affinity to substrate acetylthiocholine chloride (ATCh), and the 3DOM composite showed excellent electrocatalytic effect on thiocholine, the hydrolysis product of ATCh. The presence of IL and AuNPs could improve the sensitivity by accelerating the electron transfer. The designed AChE biosensor was successfully applied to evaluate the AChE inhibition induced by endogenous neurotoxin 1(R),2N-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-NMSal]. The results demonstrate that (R)-NMSal exerts a considerable effect on AChE activity, and the inhibition is reversible. The developed method offers a new approach for AChE inhibition assay, which is of great benefit in understanding the mechanism behind neurotoxin-induced neurodegenerative disorders.
ESTHER : Teng_2012_J.Phys.Chem.B_116_11180
PubMedSearch : Teng_2012_J.Phys.Chem.B_116_11180
PubMedID: 22946763

Title : A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, in healthy subjects and patients - Huang_2010_Curr.Clin.Pharmacol_5_115
Author(s) : Huang F , Fu Y
Ref : Curr Clin Pharmacol , 5 :115 , 2010
Abstract : Galantamine is a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Following oral administration, galantamine is rapidly absorbed and reaches C(max) in approximately one hour for immediate release (IR) tablets and four hours for extended-release (ER) capsules. Food has no clinically important effects on the absorption of galantamine. Galantamine displays dose-proportional pharmacokinetics over a dose range of 8-32 mg and 8-24 mg for IR and ER formulations, respectively. The elimination half-life of galantamine is about 7-8 hours. Galantamine has low protein binding (28.3-33.8%) and has an apparent steady-state volume of distribution (V(ss)) of 193 L. Approximately 20-25% of the galantamine dose administered is excreted unchanged in urine. No clinically significant effects of age, gender, and race have been observed on galantamine pharmacokinetics. The exposures to galantamine in patients with moderate and severe renal impairment are 37% and 67% higher, respectively than in healthy subjects, whereas the exposure to galantamine is approximately 30% higher in patients with moderate hepatic impairment. Co-administration of galantamine with ketoconazole (CYP 3A4 strong inhibitor) or paroxetine (CYP 2D6 strong inhibitor) leads to a 30% and 40% increase, respectively, in galantamine exposure compared to galantamine given alone.
ESTHER : Huang_2010_Curr.Clin.Pharmacol_5_115
PubMedSearch : Huang_2010_Curr.Clin.Pharmacol_5_115
PubMedID: 20156150

Title : Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice - Dineley_2010_J.Neurosci.Res_88_2923
Author(s) : Dineley KT , Kayed R , Neugebauer V , Fu Y , Zhang W , Reese LC , Taglialatela G
Ref : Journal of Neuroscience Research , 88 :2923 , 2010
Abstract : Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice.
ESTHER : Dineley_2010_J.Neurosci.Res_88_2923
PubMedSearch : Dineley_2010_J.Neurosci.Res_88_2923
PubMedID: 20544830

Title : The sequence and de novo assembly of the giant panda genome - Li_2010_Nature_463_311
Author(s) : Li R , Fan W , Tian G , Zhu H , He L , Cai J , Huang Q , Cai Q , Li B , Bai Y , Zhang Z , Zhang Y , Wang W , Li J , Wei F , Li H , Jian M , Nielsen R , Li D , Gu W , Yang Z , Xuan Z , Ryder OA , Leung FC , Zhou Y , Cao J , Sun X , Fu Y , Fang X , Guo X , Wang B , Hou R , Shen F , Mu B , Ni P , Lin R , Qian W , Wang G , Yu C , Nie W , Wang J , Wu Z , Liang H , Min J , Wu Q , Cheng S , Ruan J , Wang M , Shi Z , Wen M , Liu B , Ren X , Zheng H , Dong D , Cook K , Shan G , Zhang H , Kosiol C , Xie X , Lu Z , Li Y , Steiner CC , Lam TT , Lin S , Zhang Q , Li G , Tian J , Gong T , Liu H , Zhang D , Fang L , Ye C , Zhang J , Hu W , Xu A , Ren Y , Zhang G , Bruford MW , Li Q , Ma L , Guo Y , An N , Hu Y , Zheng Y , Shi Y , Li Z , Liu Q , Chen Y , Zhao J , Qu N , Zhao S , Tian F , Wang X , Wang H , Xu L , Liu X , Vinar T , Wang Y , Lam TW , Yiu SM , Liu S , Huang Y , Yang G , Jiang Z , Qin N , Li L , Bolund L , Kristiansen K , Wong GK , Olson M , Zhang X , Li S , Yang H
Ref : Nature , 463 :311 , 2010
Abstract : Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
ESTHER : Li_2010_Nature_463_311
PubMedSearch : Li_2010_Nature_463_311
PubMedID: 20010809
Gene_locus related to this paper: ailme-ABH15 , ailme-ACHE , ailme-BCHE , ailme-d2gtv3 , ailme-d2gty9 , ailme-d2gu87 , ailme-d2gu97 , ailme-d2gve7 , ailme-d2gwu1 , ailme-d2gx08 , ailme-d2gyt0 , ailme-d2gz36 , ailme-d2gz37 , ailme-d2gz38 , ailme-d2gz39 , ailme-d2gz40 , ailme-d2h5r9 , ailme-d2h7b7 , ailme-d2h9c9 , ailme-d2h794 , ailme-d2hau7 , ailme-d2hau8 , ailme-d2hcd9 , ailme-d2hdi6 , ailme-d2heu6 , ailme-d2hga4 , ailme-d2hqw5 , ailme-d2hs98 , ailme-d2hsx4 , ailme-d2hti6 , ailme-d2htv3 , ailme-d2htz6 , ailme-d2huc7 , ailme-d2hwj8 , ailme-d2hwy7 , ailme-d2hxm1 , ailme-d2hyc8 , ailme-d2hyv2 , ailme-d2hz11 , ailme-d2hza3 , ailme-d2hzr4 , ailme-d2i1l4 , ailme-d2i2g8 , ailme-g1l7m3 , ailme-g1lu36 , ailme-g1m769 , ailme-g1mc29 , ailme-g1mdj8 , ailme-g1mdr5 , ailme-g1mfp4 , ailme-g1mfx5 , ailme-g1lj41 , ailme-g1lm28 , ailme-g1l3u1 , ailme-g1l7l1 , ailme-g1m5i3 , ailme-g1l2f6 , ailme-g1lji5 , ailme-g1lqk3 , ailme-g1l8s9 , ailme-d2h717 , ailme-d2h718 , ailme-d2h719 , ailme-d2h720 , ailme-g1m5v0 , ailme-g1m5y7 , ailme-g1lkt7 , ailme-g1l2a1 , ailme-g1lsc8 , ailme-g1lrp4 , ailme-d2gv02 , ailme-g1mik5 , ailme-g1ljr1 , ailme-g1lxw7 , ailme-d2h8b5 , ailme-d2h2r2 , ailme-d2h9w7 , ailme-g1meh3 , ailme-g1m719

Title : The B73 maize genome: complexity, diversity, and dynamics - Schnable_2009_Science_326_1112
Author(s) : Schnable PS , Ware D , Fulton RS , Stein JC , Wei F , Pasternak S , Liang C , Zhang J , Fulton L , Graves TA , Minx P , Reily AD , Courtney L , Kruchowski SS , Tomlinson C , Strong C , Delehaunty K , Fronick C , Courtney B , Rock SM , Belter E , Du F , Kim K , Abbott RM , Cotton M , Levy A , Marchetto P , Ochoa K , Jackson SM , Gillam B , Chen W , Yan L , Higginbotham J , Cardenas M , Waligorski J , Applebaum E , Phelps L , Falcone J , Kanchi K , Thane T , Scimone A , Thane N , Henke J , Wang T , Ruppert J , Shah N , Rotter K , Hodges J , Ingenthron E , Cordes M , Kohlberg S , Sgro J , Delgado B , Mead K , Chinwalla A , Leonard S , Crouse K , Collura K , Kudrna D , Currie J , He R , Angelova A , Rajasekar S , Mueller T , Lomeli R , Scara G , Ko A , Delaney K , Wissotski M , Lopez G , Campos D , Braidotti M , Ashley E , Golser W , Kim H , Lee S , Lin J , Dujmic Z , Kim W , Talag J , Zuccolo A , Fan C , Sebastian A , Kramer M , Spiegel L , Nascimento L , Zutavern T , Miller B , Ambroise C , Muller S , Spooner W , Narechania A , Ren L , Wei S , Kumari S , Faga B , Levy MJ , McMahan L , Van Buren P , Vaughn MW , Ying K , Yeh CT , Emrich SJ , Jia Y , Kalyanaraman A , Hsia AP , Barbazuk WB , Baucom RS , Brutnell TP , Carpita NC , Chaparro C , Chia JM , Deragon JM , Estill JC , Fu Y , Jeddeloh JA , Han Y , Lee H , Li P , Lisch DR , Liu S , Liu Z , Nagel DH , McCann MC , SanMiguel P , Myers AM , Nettleton D , Nguyen J , Penning BW , Ponnala L , Schneider KL , Schwartz DC , Sharma A , Soderlund C , Springer NM , Sun Q , Wang H , Waterman M , Westerman R , Wolfgruber TK , Yang L , Yu Y , Zhang L , Zhou S , Zhu Q , Bennetzen JL , Dawe RK , Jiang J , Jiang N , Presting GG , Wessler SR , Aluru S , Martienssen RA , Clifton SW , McCombie WR , Wing RA , Wilson RK
Ref : Science , 326 :1112 , 2009
Abstract : We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.
ESTHER : Schnable_2009_Science_326_1112
PubMedSearch : Schnable_2009_Science_326_1112
PubMedID: 19965430
Gene_locus related to this paper: maize-b4ffc7 , maize-b6u7e1 , maize-c0pcy5 , maize-c0pgf7 , maize-c0pgw1 , maize-c0pfl3 , maize-b4fpr7 , maize-k7vy73 , maize-a0a096swr3 , maize-k7v3i9 , maize-b6u9v9 , maize-a0a3l6e780 , maize-b4fv80 , maize-a0a1d6nse2 , maize-c4j9a1 , maize-k7uba1

Title : Identification and characterization of HTD2: a novel gene negatively regulating tiller bud outgrowth in rice - Liu_2009_Planta_230_649
Author(s) : Liu W , Wu C , Fu Y , Hu G , Si H , Zhu L , Luan W , He Z , Sun Z
Ref : Planta , 230 :649 , 2009
Abstract : Tiller number is highly regulated by controlling the formation of tiller bud and its subsequent outgrowth in response to endogenous and environmental signals. Here, we identified a rice mutant htd2 from one of the 15,000 transgenic rice lines, which is characterized by a high tillering and dwarf phenotype. Phenotypic analysis of the mutant showed that the mutation did not affect formation of tiller bud, but promoted the subsequent outgrowth of tiller bud. To isolate the htd2 gene, a map-based cloning strategy was employed and 17 new insertions-deletions (InDels) markers were developed. A high-resolution physical map of the chromosomal region around the htd2 gene was made using the F(2) and F(3) population. Finally, the gene was mapped in 12.8 kb region between marker HT41 and marker HT52 within the BAC clone OSJNBa0009J13. Cloning and sequencing of the target region from the mutant showed that the T-DNA insertion caused a 463 bp deletion between the promoter and first exon of an esterase/lipase/thioesterase family gene in the 12.8 kb region. Furthermore, transgenic rice with reduced expression level of the gene exhibited an enhanced tillering and dwarf phenotype. Accordingly, the esterase/lipase/thioesterase family gene (TIGR locus Os03g10620) was identified as the HTD2 gene. HTD2 transcripts were expressed mainly in leaf. Loss of function of HTD2 resulted in a significantly increased expression of HTD1, D10 and D3, which were involved in the strigolactone biosynthetic pathway. The results suggest that the HTD2 gene could negatively regulate tiller bud outgrowth by the strigolactone pathway.
ESTHER : Liu_2009_Planta_230_649
PubMedSearch : Liu_2009_Planta_230_649
PubMedID: 19579033
Gene_locus related to this paper: orysj-Q10QA5

Title : Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors - Shi_2009_Acta.Pharmacol.Sin_30_1195
Author(s) : Shi YF , Zhang HY , Wang W , Fu Y , Xia Y , Tang XC , Bai DL , He XC
Ref : Acta Pharmacol Sin , 30 :1195 , 2009
Abstract : AIM: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD).
METHODS: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BCHE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT.
RESULTS: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BCHE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BCHE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. CONCLUSION: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies.
ESTHER : Shi_2009_Acta.Pharmacol.Sin_30_1195
PubMedSearch : Shi_2009_Acta.Pharmacol.Sin_30_1195
PubMedID: 19578388

Title : Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase - Zhu_2009_Bioorg.Med.Chem_17_1600
Author(s) : Zhu Y , Xiao K , Ma L , Xiong B , Fu Y , Yu H , Wang W , Wang X , Hu D , Peng H , Li J , Gong Q , Chai Q , Tang X , Zhang H , Shen J
Ref : Bioorganic & Medicinal Chemistry , 17 :1600 , 2009
Abstract : To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.
ESTHER : Zhu_2009_Bioorg.Med.Chem_17_1600
PubMedSearch : Zhu_2009_Bioorg.Med.Chem_17_1600
PubMedID: 19162488

Title : Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor - Wang_2008_Cell.Mol.Neurobiol_28_245
Author(s) : Wang ZF , Yan J , Fu Y , Tang XC , Feng S , He XC , Bai DL
Ref : Cellular Molecular Neurobiology , 28 :245 , 2008
Abstract : (1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia.
ESTHER : Wang_2008_Cell.Mol.Neurobiol_28_245
PubMedSearch : Wang_2008_Cell.Mol.Neurobiol_28_245
PubMedID: 17786550

Title : Mapping and expression analysis of chicken NDRG1 and NDRG3 genes - Tian_2008_Biochem.Genet_46_677
Author(s) : Tian Y , Xu M , Fu Y , Yuan A , Wang D , Li G , Liu G , Lu L
Ref : Biochemical Genetics , 46 :677 , 2008
Abstract : N-myc downstream-regulated genes 1 and 3 (NDRG1 and NDRG3) are members of the alpha/beta hydrolase superfamily. Phylogenetic analysis of the family demonstrated that human NDRG1 and 3 belong to a subfamily. The mapping and gene expression patterns of these genes represent one step toward further investigation into their possible roles in the chicken (Gallus gallus). To map these genes in the chicken chromosome, a 6000 rads chicken-hamster radiation hybrid panel (ChickRH6) was used. Primers were designed according to the published human sequences for amplification of those two genes. We compared the corresponding human mRNA sequences with the predicted coding sequences of the chicken NDRG1 and 3 genes and found that the assembled contigs shared a high percentage of similarity with the human genes. PCR of samples from ChickRH6 revealed that the locations of NDRG1 and 3 are linked to the markers MYC (58 cRs away, LOD score 4.52) and SEQ0265 (10 cRs away, LOD score 17.81), respectively. This result adds two new markers to the chicken RH map, and it reinforces that the RH technique is indeed a powerful tool for mapping genes due to its rapidity, precision, convenience, and reproducibility. In addition, we detected the gene expression and distribution of chicken NDRG1 and 3 in seven tissues, including heart, liver, spleen, lung, muscle, brain, and thymus, by RT-PCR, and found that NDRG1 is relatively ubiquitously expressed in all the tested tissues and highly expressed in heart and liver, whereas NDRG3 is high in heart, muscle, and brain.
ESTHER : Tian_2008_Biochem.Genet_46_677
PubMedSearch : Tian_2008_Biochem.Genet_46_677
PubMedID: 18751885

Title : Huperzine A, a promising anti-Alzheimer?s agent, reduces staurosporine-induced apoptosis in NG108-15 cells. -
Author(s) : Xiao XQ , Wu DC , Gao Y , Fu Y , Lee NT , Ho WL , Tsim KWK , Han YF
Ref : Cholinergic Mechanisms, CRC Press :733 , 2004

Title : Up-regulation of brain nicotinic acetylcholine receptors in the rat during long-term self-administration of nicotine: disproportionate increase of the alpha6 subunit - Parker_2004_Mol.Pharmacol_65_611
Author(s) : Parker SL , Fu Y , McAllen K , Luo J , McIntosh JM , Lindstrom JM , Sharp BM
Ref : Molecular Pharmacology , 65 :611 , 2004
Abstract : In male rats continually self-administering nicotine (approximately 1.5 mg free base/kg/day), we found a significant increase of nicotinic acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas. A large increase of high-affinity Epb binding sites was apparent in the ventral tegmentum/substantia nigra, nucleus tractus solitarii, nucleus accumbens, thalamus/subthalamus, parietal cortex, hypothalamus, and amygdala. A smaller but significant up-regulation of high-affinity Epb sites was seen in the piriform cortex, hippocampus, caudate/putamen, and cerebellar cortex. The up-regulation of nAChRs, shown by immunoadsorption and Western blotting, involved alpha4, alpha6, and beta2 subunits. As a consequence of long-term self-administration of nicotine, the alpha6 immunoreactive (IR) binding of either labeled Epb or 125I-alpha-conotoxin MII increased to a much greater extent than did alpha4 or beta2 IR binding of Epb. In addition, the beta2 IR binding of Epb was consistently enhanced to a greater extent than was alpha4. These findings may reflect a larger surface membrane retention of alpha6-containing and, to some degree, beta2-containing nAChRs compared with alpha4-containing nAChRs during long-term self-administration of nicotine.
ESTHER : Parker_2004_Mol.Pharmacol_65_611
PubMedSearch : Parker_2004_Mol.Pharmacol_65_611
PubMedID: 14978239

Title : Effects of galantamine, a nicotinic allosteric potentiating ligand, on nicotine-induced catecholamine release in hippocampus and nucleus accumbens of rats - Sharp_2004_J.Pharmacol.Exp.Ther_309_1116
Author(s) : Sharp BM , Yatsula M , Fu Y
Ref : Journal of Pharmacology & Experimental Therapeutics , 309 :1116 , 2004
Abstract : Galantamine, a drug for treatment of Alzheimer's disease, is a novel cholinergic agent with a dual mode of action that inhibits acetylcholinesterase and allosterically modulates nicotinic cholinergic receptors (nAChRs). Nicotine stimulates catecholamine secretion, inducing hippocampal norepinephrine (NE) release, and improves memory consolidation. Thus, the effect of galantamine on nicotine-induced hippocampal NE secretion was investigated. This was compared with the effect of galantamine on nicotine-induced dopamine (DA) release within the nucleus accumbens of the same rat. Nicotine (0.025-0.09 mg/kg i.v.) dose dependently increased NE and DA levels in microdialysates from the hippocampus and nucleus accumbens, respectively, of freely moving rats. Pretreatment with galantamine (3.0 mg/kg s.c.) 3 h before nicotine either potentiated NE responses to doses of nicotine that were ineffective alone (0.025-0.045 mg/kg) or significantly enhanced (0.065 mg/kg) NE responses, whereas galantamine was ineffective when administered 2 or 4 h before nicotine. In contrast to its effects on NE, galantamine did not alter accumbal DA responses to any dose of nicotine. These selective effects of galantamine on nicotine-stimulated NE secretion may reflect differences in local neural circuits that use nAChRs to modulate hippocampal NE versus accumbal DA release.
ESTHER : Sharp_2004_J.Pharmacol.Exp.Ther_309_1116
PubMedSearch : Sharp_2004_J.Pharmacol.Exp.Ther_309_1116
PubMedID: 14769831

Title : Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation - Zhou_2001_Neurosci.Lett_306_53
Author(s) : Zhou J , Fu Y , Tang XC
Ref : Neuroscience Letters , 306 :53 , 2001
Abstract : Huperzine A (HupA) and donepezil, two novel selective acetylcholinesterase inhibitors available for Alzheimer's disease, were tested for their ability to alleviate injury from oxygen-glucose deprivation (OGD) in the rat pheochromocytoma line PC12 cells. OGD for 30 min triggered death in more than 50% of cells, along with major changes in morphology and biochemistry including elevated levels of lipid peroxide, superoxide disamutase activity and lactate. Cells pretreated for 2 h with HupA or donepezil showed improved survival and reduced biochemical and morphologic signs of toxicity (statistically significant over the range from 10 microM down to 1.0 and 0.1 microM, respectively). Our results indicated that HupA and donepezil protected PC12 cells against OGD-induced toxicity, most likely by alleviating disturbances of oxidative and energy metabolism.
ESTHER : Zhou_2001_Neurosci.Lett_306_53
PubMedSearch : Zhou_2001_Neurosci.Lett_306_53
PubMedID: 11403956

Title : Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer - Guan_2000_Cancer.Res_60_749
Author(s) : Guan RJ , Ford HL , Fu Y , Li Y , Shaw LM , Pardee AB
Ref : Cancer Research , 60 :749 , 2000
Abstract : A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.
ESTHER : Guan_2000_Cancer.Res_60_749
PubMedSearch : Guan_2000_Cancer.Res_60_749
PubMedID: 10676663
Gene_locus related to this paper: human-NDRG1

Title : The DNA sequence of human chromosome 22 - Dunham_1999_Nature_402_489
Author(s) : Dunham I , Hunt AR , Collins JE , Bruskiewich R , Beare DM , Clamp M , Smink LJ , Ainscough R , Almeida JP , Babbage AK , Bagguley C , Bailey J , Barlow KF , Bates KN , Beasley OP , Bird CP , Blakey SE , Bridgeman AM , Buck D , Burgess J , Burrill WD , Burton J , Carder C , Carter NP , Chen Y , Clark G , Clegg SM , Cobley VE , Cole CG , Collier RE , Connor R , Conroy D , Corby NR , Coville GJ , Cox AV , Davis J , Dawson E , Dhami PD , Dockree C , Dodsworth SJ , Durbin RM , Ellington AG , Evans KL , Fey JM , Fleming K , French L , Garner AA , Gilbert JGR , Goward ME , Grafham DV , Griffiths MND , Hall C , Hall RE , Hall-Tamlyn G , Heathcott RW , Ho S , Holmes S , Hunt SE , Jones MC , Kershaw J , Kimberley AM , King A , Laird GK , Langford CF , Leversha MA , Lloyd C , Lloyd DM , Martyn ID , Mashreghi-Mohammadi M , Matthews LH , Mccann OT , Mcclay J , Mclaren S , McMurray AA , Milne SA , Mortimore BJ , Odell CN , Pavitt R , Pearce AV , Pearson D , Phillimore BJCT , Phillips SH , Plumb RW , Ramsay H , Ramsey Y , Rogers L , Ross MT , Scott CE , Sehra HK , Skuce CD , Smalley S , Smith ML , Soderlund C , Spragon L , Steward CA , Sulston JE , Swann RM , Vaudin M , Wall M , Wallis JM , Whiteley MN , Willey DL , Williams L , Williams SA , Williamson H , Wilmer TE , Wilming L , Wright CL , Hubbard T , Bentley DR , Beck S , Rogers J , Shimizu N , Minoshima S , Kawasaki K , Sasaki T , Asakawa S , Kudoh J , Shintani A , Shibuya K , Yoshizaki Y , Aoki N , Mitsuyama S , Roe BA , Chen F , Chu L , Crabtree J , Deschamps S , Do A , Do T , Dorman A , Fang F , Fu Y , Hu P , Hua A , Kenton S , Lai H , Lao HI , Lewis J , Lewis S , Lin S-P , Loh P , Malaj E , Nguyen T , Pan H , Phan S , Qi S , Qian Y , Ray L , Ren Q , Shaull S , Sloan D , Song L , Wang Q , Wang Y , Wang Z , White J , Willingham D , Wu H , Yao Z , Zhan M , Zhang G , Chissoe S , Murray J , Miller N , Minx P , Fulton R , Johnson D , Bemis G , Bentley D , Bradshaw H , Bourne S , Cordes M , Du Z , Fulton L , Goela D , Graves T , Hawkins J , Hinds K , Kemp K , Latreille P , Layman D , Ozersky P , Rohlfing T , Scheet P , Walker C , Wamsley A , Wohldmann P , Pepin K , Nelson J , Korf I , Bedell JA , Hillier L , Mardis E , Waterston R , Wilson R , Emanuel BS , Shaikh T , Kurahashi H , Saitta S , Budarf ML , McDermid HE , Johnson A , Wong ACC , Morrow BE , Edelmann L , Kim UJ , Shizuya H , Simon MI , Dumanski JP , Peyrard M , Kedra D , Seroussi E , Fransson I , Tapia I , Bruder CE , O'Brien KP
Ref : Nature , 402 :489 , 1999
Abstract : Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
ESTHER : Dunham_1999_Nature_402_489
PubMedSearch : Dunham_1999_Nature_402_489
PubMedID: 10591208
Gene_locus related to this paper: human-CES5A , human-SERHL2

Title : Cloning and characterization of a gene (LIP1) which encodes a lipase from the pathogenic yeast Candida albicans - Fu_1997_Microbiology_143 ( Pt 2)_331
Author(s) : Fu Y , Ibrahim AS , Fonzi W , Zhou X , Ramos CF , Ghannoum MA
Ref : Microbiology , 143 ( Pt 2) :331 , 1997
Abstract : Extracellular phospholipases are demonstrated virulence factors for a number of pathogenic microbes. The opportunistic pathogen Candida albicans is known to secrete phospholipases and these have been correlated with strain virulence. In an attempt to clone C. albicans genes encoding secreted phospholipases, Saccharomyces cerevisiae was transformed with a C. albicans genomic library and screened for lipolytic activity on egg-yolk agar plates, a traditional screen for phospholipase activity. Two identical clones were obtained which exhibited lipolytic activity. Nucleotide sequence analysis identified an ORF encoding a protein of 351 amino acid residues. Although no extensive homologies were identified, the sequence contained the Gly-X-Ser-X-Gly motif found in prokaryotic and eukaryotic lipases, suggesting a similar activity for the encoded protein. Indeed, culture supernatants from complemented yeast cells contained abundant hydrolytic activity against a triglyceride substrate and had no phospholipase activity. The data suggest that C. albicans, in addition to phospholipases, also has lipases. Southern blot analyses revealed that C. albicans may contain a lipase gene (LIP) family, and that a lipase gene(s) may be present in Candida parapsilosis, Candida tropicalis and Candida krusei, but not in Candida pseudotropicalis, Candida glabrata or S. cerevisiae. Northern blot analyses showed that expression of the LIP1 transcript, the cloned gene which encodes a lipase, was detected only when C. albicans was grown in media containing Tween 80, other Tweens or triglycerides as the sole carbon source, and not in Sabouraud Dextrose Broth or yeast/peptone/dextrose media. Additionally, carbohydrate supplementation inhibited LIP1 expression. Cloning this gene will allow the construction of LIP1-deficient null mutants which will be critical in determining the role of this gene in candidal virulence.
ESTHER : Fu_1997_Microbiology_143 ( Pt 2)_331
PubMedSearch : Fu_1997_Microbiology_143 ( Pt 2)_331
PubMedID: 9043110
Gene_locus related to this paper: canal-LIP1

Title : Singlet oxygen-mediated inactivation of acetylcholinesterase: a comparison of purified enzyme in solution and enzyme bound to K562 leukemia cells - Deadwyler_1997_Photochem.Photobiol_65_884
Author(s) : Deadwyler G , Sima PD , Fu Y , Kanofsky JR
Ref : Photochem Photobiol , 65 :884 , 1997
Abstract : We have compared the singlet oxygen-mediated inactivation of acetylcholinesterase (ACE) in solution with the inactivation of ACE on the surface of K562 leukemia cells. In solution, the actions of the singlet-oxygen quenchers, methionine, azide, disodium [N,N'-ethylenebis (5-sulfosalicylideneimminato)]nickelate(II) (Ni-chelate 1) and disodium [(N,N'-2,3-propionic acid)bis(5-sulfosal-icylideneimminato)] nickelate(II) (Ni-chelate 2) could be explained quantitatively by assuming their only mechanism of action was to quench singlet oxygen. The singlet oxygen quenchers, azide, Ni-chelate 1 and Ni-chelate 2, caused smaller inhibitions in the rate of singlet oxygen-mediated inactivation of ACE on K562 cells than ACE in solution. The effects of these quenchers and of deuterium oxide were interpreted using a mathematical model of singlet-oxygen quenching and diffusion to estimate the lifetime of singlet oxygen near the cell surface. The azide quenching data and the deuterium-oxide data gave lifetimes of 0.9 +/- 0.2 microsecond and 0.45 +/- 0.15 microsecond, respectively. The increases in ACE inactivation lifetime caused by the nickel chelates were anomalously large. The unexpectedly large quenching due to the nickel chelates may have been due to a nonuniform distribution of the chelates in the cytoplasm with a large concentration of the chelate near the cell membrane.
ESTHER : Deadwyler_1997_Photochem.Photobiol_65_884
PubMedSearch : Deadwyler_1997_Photochem.Photobiol_65_884
PubMedID: 9155262