Cao Y


Full name : Cao Yang

First name : Yang

Mail : Department of Medicinal and Biological Chemistry, Center for Drug Design and Development, College of Pharmacy, The University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio 43606

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Country : USA

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References (72)

Title : Regulation of soluble epoxide hydrolase in renal-associated diseases: insights from potential mechanisms to clinical researches - Gao_2024_Front.Endocrinol.(Lausanne)_15_1304547
Author(s) : Gao P , Cao Y , Ma L
Ref : Front Endocrinol (Lausanne) , 15 :1304547 , 2024
Abstract : In recent years, numerous experimental studies have underscored the pivotal role of soluble epoxide hydrolase (sEH) in renal diseases, demonstrating the reno-protective effects of sEH inhibitors. The nexus between sEH and renal-associated diseases has garnered escalating attention. This review endeavors to elucidate the potential molecular mechanisms of sEH in renal diseases and emphasize the critical role of sEH inhibitors as a prospective treatment modality. Initially, we expound upon the correlation between sEH and Epoxyeicosatrienoic acids (EETs) and also addressing the impact of sEH on other epoxy fatty acids, delineate prevalent EPHX2 single nucleotide polymorphisms (SNPs) associated with renal diseases, and delve into sEH-mediated potential mechanisms, encompassing oxidative stress, inflammation, ER stress, and autophagy. Subsequently, we delineate clinical research pertaining to sEH inhibition or co-inhibition of sEH with other inhibitors for the regulation of renal-associated diseases, covering conditions such as acute kidney injury, chronic kidney diseases, diabetic nephropathy, and hypertension-induced renal injury. Our objective is to validate the potential role of sEH inhibitors in the treatment of renal injuries. We contend that a comprehensive comprehension of the salient attributes of sEH, coupled with insights from clinical experiments, provides invaluable guidance for clinicians and presents promising therapeutic avenues for patients suffering from renal diseases.
ESTHER : Gao_2024_Front.Endocrinol.(Lausanne)_15_1304547
PubMedSearch : Gao_2024_Front.Endocrinol.(Lausanne)_15_1304547
PubMedID: 38425758

Title : Screening of Active Substances Regulating Alzheimer's Disease in Ginger and Visualization of the Effectiveness on 6-Gingerol Pathway Targets - Pan_2024_Foods_13_
Author(s) : Pan Y , Li Z , Zhao X , Du Y , Zhang L , Lu Y , Yang L , Cao Y , Qiu J , Qian Y
Ref : Foods , 13 : , 2024
Abstract : Ginger has been reported to potentially treat Alzheimer's disease (AD), but the specific compounds responsible for this biological function and their mechanisms are still unknown. In this study, a combination of network pharmacology, molecular docking, and dynamic simulation technology was used to screen active substances that regulate AD and explore their mechanisms. The TCMSP, GeneCards, OMIM, and DisGeNET databases were utilized to obtain 95 cross-targets related to ginger's active ingredients and AD as key targets. A functional enrichment analysis revealed that the pathways in which ginger's active substances may be involved in regulating AD include response to exogenous stimuli, response to oxidative stress, response to toxic substances, and lipid metabolism, among others. Furthermore, a drug-active ingredient-key target interaction network diagram was constructed, highlighting that 6-Gingerol is associated with 16 key targets. Additionally, a protein-protein interaction (PPI) network was mapped for the key targets, and HUB genes (ALB, ACTB, GAPDH, CASP3, and CAT) were identified. Based on the results of network pharmacology and cell experiments, 6-Gingerol was selected as the active ingredient for further investigation. Molecular docking was performed between 6-Gingerol and its 16 key targets, and the top three proteins with the strongest binding affinities (ACHE, MMP2, and PTGS2) were chosen for molecular dynamics analysis together with the CASP3 protein as the HUB gene. The findings indicate that 6-Gingerol exhibits strong binding ability to these disease targets, suggesting its potential role in regulating AD at the molecular level, as well as in abnormal cholinesterase metabolism and cell apoptosis, among other related regulatory pathways. These results provide a solid theoretical foundation for future in vitro experiments using actual cells and animal experiments to further investigate the application of 6-Gingerol.
ESTHER : Pan_2024_Foods_13_
PubMedSearch : Pan_2024_Foods_13_
PubMedID: 38397589

Title : Design, synthesis, and evaluation of dual-target inhibitors for the treatment of Alzheimer's disease - Zhai_2024_Arch.Pharm.(Weinheim)__e2300693
Author(s) : Zhai J , Hao C , Wang X , Cao Y , Pan Y , Zhou M , Sun J , Li C
Ref : Arch Pharm (Weinheim) , :e2300693 , 2024
Abstract : Abeta(1-42) and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC(50) = 0.05 +/- 0.02 microM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Abeta(1-42) and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl(3) -induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.
ESTHER : Zhai_2024_Arch.Pharm.(Weinheim)__e2300693
PubMedSearch : Zhai_2024_Arch.Pharm.(Weinheim)__e2300693
PubMedID: 38332316

Title : Direct detection of acetylcholinesterase by Fe(HCOO)(2.6)(OH)(0.3). H(2)O nanosheets with oxidase-like activity on a smartphone platform - Cao_2024_Talanta_274_126074
Author(s) : Cao Y , Chen Y , Zhou Y , Chen X , Peng J
Ref : Talanta , 274 :126074 , 2024
Abstract : Monitoring acetylcholinesterase (AChE) is crucial in clinical diagnosis and drug screening. Traditional methods for detecting AChE usually require the addition of intermediates like acetylthiocholine, which complicates the detection process and introduces interference risks. Herein, we develop a direct colorimetric assay based on alkaline iron formate nanosheets (Fe(HCOO)(2.6)(OH)(0.3).H(2)O NSs, Fef NSs) for the detection of AChE without any intermediates. The as-prepared Fef NSs exhibit oxidase-like activity, catalyzing the generation of O(2)(.-), (1)O(2) and .OH, which leads to a color change from colorless to blue when exposed to 3,3',5,5'-tetramethylbenzidine. AChE directly inhibits the oxidase-like activity of Fef NSs, resulting in a hindered color reaction, enabling the detection of AChE. The biosensor has a linear detection range of 0.1-30 mU/mL, with a minimum detection limit of 0.0083 mU/mL (S/N = 3), representing a 100-fold improvement in detection sensitivity over the traditional Ellman's method. Satisfactory results were obtained when analyzing real AChE samples. Attractively, a method for the quantitative detection of AChE by a smartphone is established based on the Fef NSs. This method enables instant acquisition of AChE concentrations, achieving real-time visualized detection.
ESTHER : Cao_2024_Talanta_274_126074
PubMedSearch : Cao_2024_Talanta_274_126074
PubMedID: 38608632

Title : Purification, identification and hypolipidemic activities of three novel hypolipidemic peptides from tea protein - Ye_2023_Food.Res.Int_165_112450
Author(s) : Ye H , Xu Y , Sun Y , Liu B , Chen B , Liu G , Cao Y , Miao J
Ref : Food Res Int , 165 :112450 , 2023
Abstract : In this study, hypolipidemic peptides were obtained from tea protein by enzymatic hydrolysis, ultrafiltration and high-performance liquid chromatography. Subsequently, the hypolipidemic peptides were identified by mass spectrometry and screened through molecular docking technology, and the hypolipidemic activities and mechanisms of the active peptides were explored. The results showed that the hydrolysate of hypolipidemic peptides obtained by pepsin hydrolysis for 3 h had good bile salt binding ability. After purification, identification and molecular docking screening, three novel hypolipidemic peptides FLF, IYF and QIF were obtained. FLF, IYF and QIF can interact with the receptor proteins 1LPB and 1F6W through hydrogen bonds, Pi-Pi bonds, hydrophobic interactions and van der Waals forces, thus exerting hypolipidemic activities. Activity studies showed that, compared with the positive controls, FLF, IYF and QIF had excellent sodium taurocholate binding abilities, pancreatic lipase inhibitory activities and cholesterol esterase inhibitory activities. Moreover, FLF, IYF and QIF can effectively inhibit lipogenic differentiation of 3T3-L1 preadipocytes, reduce intracellular lipid and low-density lipoprotein content and increase high-density lipoprotein content. These results indicated that the three novel hypolipidemic peptides screened in this study had excellent hypolipidemic activities and were expected to be used as natural-derived hypolipidemic active ingredients for the development and application in functional foods.
ESTHER : Ye_2023_Food.Res.Int_165_112450
PubMedSearch : Ye_2023_Food.Res.Int_165_112450
PubMedID: 36869471

Title : Theaflavin-3,3'-digallate ameliorates learning and memory impairments in mice with premature brain aging induced by D-galactose - Cao_2023_Physiol.Behav__114077
Author(s) : Cao Y , Zhang Y , Jia Z , Jia H , Sun Y , Yuan H , Bian Y , Xu B , Fu J , Qin F
Ref : Physiol Behav , :114077 , 2023
Abstract : Age-related neurodegenerative diseases accompanied by learning and memory deficits are growing in prevalence due to population aging. Cellular oxidative stress is a common pathomechanism in multiple age-related disorders, and various antioxidants have demonstrated therapeutic efficacy in patients or animal models. Many plants and plant extracts possess potent antioxidant activity, but the compounds responsible are frequently unknown. Identification and evaluation of these phytochemicals is necessary for optimal targeted therapy. A recent study identified theaflavin-3,3'-digallate (TFDG) as the most potent among a large series of phytochemical antioxidants. Here we examined if TFDG can mitigate learning and memory impairments in the D-galactose model of age-related neurodegeneration. Experimental mice were injected subcutaneously with D-galactose (120 mg/kg) for 56 days. In treatment groups, different doses of TFDG were administered daily by gavage starting on day 29 of D-galactose injection. Model mice exhibited poor learning and memory in the novel object recognition and Y-maze tests, reduced brain/body mass ratio, increased brain glutamate concentration and acetylcholinesterase activity, decreased brain acetylcholine concentration, and lower choline acetyltransferase, glutaminase, and glutamine synthetase activities. Activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were also reduced, while the concentration of malondialdehyde, a lipid peroxidation product, was elevated. Further, antioxidant genes Nrf2, Prx2, Gsh-px1, and Sod1 were downregulated in brain. Each one of these changes was dose-dependently reversed by TFDG. TFDG is an effective antioxidant response inducer and neuroprotectant that can restore normal neurotransmitter metabolism and ameliorate learning and memory dysfunction in the D-galactose model of age-related cognitive decline.
ESTHER : Cao_2023_Physiol.Behav__114077
PubMedSearch : Cao_2023_Physiol.Behav__114077
PubMedID: 36638877

Title : Population performance and detoxifying and protective enzyme activities of four thrips species feeding on flowers of Magnolia grandiflora (Ranunculales: Magnolia) - Cao_2023_Pest.Manag.Sci__
Author(s) : Cao Y , Qi G , Jiang F , Meng Y , Wang C , Gu Z , Gao Y , Reitz SR , Li C
Ref : Pest Manag Sci , : , 2023
Abstract : BACKGROUND: Different thrips species can co-occur on the same flowers with different dominance degrees. To accurately evaluate the population performance on different thrips species on Magnolia grandiflora flowers, we investigated the diversity of thrips species and their population dynamics both in the field and laboratory. In addition, the activities of detoxifying and protective enzymes in thrips were also measured. RESULTS: Field investigations revealed that four thrips species (Thrips hawaiiensis, Thrips flavidulus, Frankliniella occidentalis, and Thrips coloratus) were coexisted on M. grandiflora flowers. They were ranked, from highest population density to lowest, as follows: T. hawaiiensis > T. flavidulus > F. occidentalis > T. coloratus. In laboratory investigations, the species were ranked, from fastest developmental rates to slowest, as follows: F. occidentalis > T. hawaiiensis > T. flavidulus > T. coloratus; and from largest population size to smallest, as follows: T. hawaiiensis > F. occidentalis > T. flavidulus > T. coloratus. Biochemistry assays showed that the four species differed in their activities of detoxifying enzymes (carboxylesterase, glutathione-S-transferase, and cytochrome P450) and protective enzymes (superoxide dismutase, peroxidase) in both laboratory and field strains. CONCLUSION: Differences in population performance among these four thrips on M. grandiflora may be related to their activity levels of physiological enzymes. The variations in thrips population performance between the field and the laboratory could be due to differences in environmental conditions. T. hawaiiensis showed a strong host preference for M. grandiflora, and thus it has the potential to be a dangerous pest in horticultural plants. This article is protected by copyright. All rights reserved.
ESTHER : Cao_2023_Pest.Manag.Sci__
PubMedSearch : Cao_2023_Pest.Manag.Sci__
PubMedID: 37085951

Title : Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae) - Wang_2023_J.Insect.Sci_23_19
Author(s) : Wang J , Cao Y , Lai B , Liu Y , Li C , Bu C
Ref : J Insect Sci , 23 :19 , 2023
Abstract : The two-spotted spider mite, Tetranychus urticae Koch, has a broad host plant range and presents an extreme capacity for developing pesticide resistance, becoming a major economic pest in agriculture. Anticholinesterase insecticides still account for a big part of global insecticide sales. However, there is a growing concern about the serious resistance problems of anticholinesterase insecticides and their nontarget toxicity. In this study, structure-based virtual screening was performed to discover selective AChE inhibitors from the ChemBridge database, and 39 potential species-specific AChE inhibitor were obtained targeting T. urticae AChE, but not human AChE. Among them, compound No. 8 inhibited AChE from T. urticae, but not from human, and had an inhibitory activity comparable to that of eserine. Compound No. 8 had dose-dependent toxicity to T. urticae in glass slide-dipping assay and had significant mite control effects in a pot experiment, but required a high concentration to achieve similar control effects to spirodiclofen. The toxicity evaluation suggested that compound No. 8 had no acute toxicity on pollinator honey bees and natural predator N. californicus and did not affect strawberry growth in our assay. Compound No. 8 is a potential lead compound for developing novel acaricides with reduced nontarget toxicity.
ESTHER : Wang_2023_J.Insect.Sci_23_19
PubMedSearch : Wang_2023_J.Insect.Sci_23_19
PubMedID: 37578847
Gene_locus related to this paper: 9acar-m9t420

Title : Soluble epoxide hydrolase deficiency promotes liver regeneration and ameliorates liver injury in mice by regulating angiocrine factors and angiogenesis - Deng_2023_Biochim.Biophys.Acta.Gen.Subj__130394
Author(s) : Deng W , Hu T , Xiong W , Jiang X , Cao Y , Li Z , Jiang H , Wang X
Ref : Biochimica & Biophysica Acta Gen Subj , :130394 , 2023
Abstract : BACKGROUND: Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear. METHODS: This study used sEH-deficient (sEH(-/-)) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for alpha-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting. RESULTS: sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH(-/-) mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH(-/-) mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH(-/-) compared to WT mice. Furthermore, sEH deficiency attenuated CCl(4)-induced acute liver injury and reduced fibrosis in both CCl(4) and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH(-/-) mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH(-/-) BDL mice had more Ki67-positive cells in the liver than WT BDL mice. CONCLUSIONS: sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage.
ESTHER : Deng_2023_Biochim.Biophys.Acta.Gen.Subj__130394
PubMedSearch : Deng_2023_Biochim.Biophys.Acta.Gen.Subj__130394
PubMedID: 37315719

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

Title : Novel N(1) or N(9) modified alpha-carboline analogues as potential ligands in Alzheimer's disease therapy: Synthesis and neurobiological activity evaluation - Dan_2023_Bioorg.Chem_133_106378
Author(s) : Dan W , Cao Y , Sun Y , Zhang J , Liu J , Gao J , Han R , Dai J
Ref : Bioorg Chem , 133 :106378 , 2023
Abstract : A series of new alpha-carboline analogues modified at N(1) or N(9) positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC(50) = 1.45 microM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-kappaB signaling pathway by decreasing the phosphorylation of IkappaB-alpha and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H(2)O(2)-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC(50) of 0.77 microM. Overall, this work provided some lead compounds based on alpha-carboline used for AD therapy.
ESTHER : Dan_2023_Bioorg.Chem_133_106378
PubMedSearch : Dan_2023_Bioorg.Chem_133_106378
PubMedID: 36736035

Title : Carnosic acid ameliorated Abeta-mediated (amyloid-beta peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer's Model - Chen_2022_Food.Funct__
Author(s) : Chen Y , Wang Y , Qin Q , Zhang Y , Xie L , Xiao J , Cao Y , Su Z
Ref : Food Funct , : , 2022
Abstract : Amyloid-beta peptide (Abeta)-induced cholinergic system and mitochondrial dysfunction are major risk factors for Alzheimer's disease (AD). Our previous studies found that carnosic acid (CA), an important polyphenol antioxidant, could significantly delay Abeta(1-42)-mediated acute paralysis. However, many details and underlying mechanisms of CA's neuroprotection against Abeta-induced cholinergic system defects and mitochondrial dysfunction remain unclear. Herein, we deeply investigated the effects and the possible mechanisms of CA-mediated protection against Abeta toxicity in vivo through several AD Caenorhabditis elegans strains. The results showed CA delayed age-related paralysis and Abeta deposition, and significantly protected neurons from Abeta-induced toxicity. CA might downgrade the expression of ace-1 and ace-2 genes, and upregulate cha-1 and unc-17 genes to inhibit acetylcholinesterase activity and relieve Abeta-caused cholinergic system defects. Furthermore, CA might also ameliorate Abeta-induced mitochondrial imbalance and oxidative stress through up-regulating the expression of phb-1, phb-2, eat-3, and drp-1 genes. The enhancements of the cholinergic system and mitochondrial function might be the reasons for the amelioration of Abeta-mediated toxicity and Abeta aggregation mediated by CA. These findings have helped us to understand the CA anti-Abeta activity in C. elegans and the potential mechanism of action.
ESTHER : Chen_2022_Food.Funct__
PubMedSearch : Chen_2022_Food.Funct__
PubMedID: 35357374

Title : Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China - Cao_2022_Front.Neurol_13_1034243
Author(s) : Cao Y , Yu F , Lyu Y , Lu X
Ref : Front Neurol , 13 :1034243 , 2022
Abstract : Alzheimer's disease is the most common neurodegenerative disease. Prior to 2017, National Medical Products Administration approved only four drugs to treat Alzheimer's disease, including three cholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist. We queried to better understand Alzheimer's drug development over the past 5 years and found 16 promising candidates that have entered late-stage trials and analyzed their impact on clinical treatment of Alzheimer's disease in China. The 16 compounds selected include disease-modifying therapies and symptomatic therapies. The research and development pipeline now focuses on disease-modifying therapies such as gantenerumab, aducanumab, ALZ-801, ALZT-OP1, donanemab, lecanemab, simufilam, NE3107, semaglutide, and GV-971, which could put an end to the situation where Alzheimer's patients in China have no effective treatment alternatives. The reuse of drugs or combinations currently under investigation for the psychiatric treatment of Alzheimer's disease, including AXS-05, AVP-786, nabilone, brexpiprazole, methylphenidate, and pimavanserin, could provide physicians with additional treatment options. Although most of these drugs have not been explored in China yet, due to the current development trend in this field in China, it is expected that China will be involved in research on these drugs in the future.
ESTHER : Cao_2022_Front.Neurol_13_1034243
PubMedSearch : Cao_2022_Front.Neurol_13_1034243
PubMedID: 36457865

Title : Diagnosis of Alzheimer's Disease and In Situ Biological Imaging via an Activatable Near-Infrared Fluorescence Probe - Yang_2022_Anal.Chem__
Author(s) : Yang Y , Zhang L , Wang J , Cao Y , Li S , Qin W , Liu Y
Ref : Analytical Chemistry , : , 2022
Abstract : Alzheimer's disease (AD) is a common neurodegenerative disease that makes the brain nervous system degenerate rapidly and is accompanied by some special cognitive and behavioral dysfunction. Recently, butyrylcholinesterase (BChE) was reported as an important enzyme, whose activity can provide predictive value for timely discovery and diagnosis of AD. Therefore, it is indispensable to design a detection tool for selective and rapid response toward BChE. In this study, we developed a novel near-infrared fluorescent probe (Chy-1) for the detection of BChE activity. An excellent sensitivity, good biocompatibility, and lower limit of detection (LOD) of 0.12 ng/mL made the probe extremely specific for BChE, which was successfully used in biological imaging. What is more, Chy-1 can not only clearly distinguish tumor from normal cells but also forms a clear boundary between the normal and cancer tissues due to the obvious difference in fluorescence intensity produced via in situ spraying. Most important of all, Chy-1 was also successfully applied to track the BChE activity in AD mouse models. Based on this research, the novel probe may be a powerful tool for clinical diagnosis and therapy of tumor and neurodegenerative diseases.
ESTHER : Yang_2022_Anal.Chem__
PubMedSearch : Yang_2022_Anal.Chem__
PubMedID: 36121878

Title : The CEL-HYB1 Hybrid Allele Promotes Digestive Enzyme Misfolding and Pancreatitis in Mice - Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
Author(s) : Mao XT , Zou WB , Cao Y , Wang YC , Deng SJ , Cooper DN , Ferec C , Li ZS , Chen JM , Liao Z
Ref : Cell Mol Gastroenterol Hepatol , : , 2022
Abstract : BACKGROUND & AIMS: A hybrid allele that originated from homologous recombination between CEL and its pseudogene (CELP), CEL-HYB1 increases the risk of chronic pancreatitis (CP). Although suggested to cause digestive enzyme misfolding, definitive in vivo evidence for this postulate has been lacking. METHODS: CRISPR-Cas9 was used to generate humanized mice harboring the CEL-HYB1 allele on a C57BL/6J background. Humanized CEL mice and C57BL/6J mice were used as controls. Pancreata were collected and analyzed by histology, immunohistochemistry, immunoblotting and transcriptomics. Isolated pancreatic acini were cultured in vitro to measure the secretion and aggregation of CEL-HYB1. Mice were given caerulein injections to induce acute pancreatitis (AP) and CP. RESULTS: Pancreata from mice expressing CEL-HYB1 developed pathological features characteristic of focal pancreatitis that included acinar atrophy and vacuolization, inflammatory infiltrates and fibrosis in a time-dependent manner. CEL-HYB1 expression in pancreatic acini led to decreased secretion and increased intracellular aggregation, and triggered endoplasmic reticulum stress compared with CEL. The autophagy levels of pancreata from mice expressing CEL-HYB1 changed at different developmental stages; some aged CEL-HYB1 mice exhibited an accumulation of large autophagic vesicles and impaired autophagy in acinar cells. Administration of caerulein increased the severity of AP/CP in mice expressing CEL-HYB1 compared to control mice, accompanied by higher levels of endoplasmic reticulum stress. CONCLUSIONS: Expression of a humanized form of CEL-HYB1 in mice promotes endoplasmic reticulum stress and pancreatitis through a misfolding-dependent pathway. Impaired autophagy appears to be involved in the pancreatic injury in aged CEL-HYB1 mice. These mice have the potential to be used as a model to identify therapeutic targets for CP.
ESTHER : Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedSearch : Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedID: 35398595

Title : PRDX6: A protein bridging S-palmitoylation and diabetic neuropathy - Cao_2022_Front.Endocrinol.(Lausanne)_13_992875
Author(s) : Cao Y , Wang W , Zhan X , Zhang Y
Ref : Front Endocrinol (Lausanne) , 13 :992875 , 2022
Abstract : Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes. It can affect both the peripheral and central nervous systems, leading to pain, decreased motility, cognitive decline, and dementia. S-palmitoylation is a reversible posttranslational lipid modification, and its dysregulation has been implicated in metabolic syndrome, cancers, neurological disorders, and infections. However, the role of S-palmitoylation in diabetic neuropathy remains unclear. Here we demonstrate a potential association between activating protein palmitoylation and diabetic neuropathy. We compared the proteomic data of lumbar dorsal root ganglia (DRG) of diabetes mice and palmitoylome profiling data of the HUVEC cell line. The mapping results identified peroxiredoxin-6 (PRDX6) as a novel target in diabetic neuropathy, whose biological mechanism was associated with S-palmitoylation. Bioinformatic prediction revealed that PRDX6 had two palmitoylation sites, Cys47 and Cys91. Immunofluorescence results indicated PRDX6 translocating between the cytoplasm and cell membrane. Protein function analysis proposed that increased palmitoylation could competitively inhibit the formation of disulfide-bond between Cys47 and Cys91 and change the spatial topology of PRDX6 protein. Cl(-)HCO3(-) anion exchanger 3 (AE3) was one of the AE family members, which was proved to express in DRG. AE3 activity evoked Cl(-) influx in neurons which was generally associated with increased excitability and susceptibility to pain. We demonstrated that the S-palmitoylation status of Cys47 could affect the interaction between PRDX6 and the C-terminal domain of AE3, thereby regulating the activity of AE3 anion exchanger enzyme in the nervous system. The results highlight a central role for PRDX6 palmitoylation in protection against diabetic neuropathy.
ESTHER : Cao_2022_Front.Endocrinol.(Lausanne)_13_992875
PubMedSearch : Cao_2022_Front.Endocrinol.(Lausanne)_13_992875
PubMedID: 36120430

Title : Anti-Alzheimer's disease active components screened out and identified from Hedyotis diffusa combining bioaffinity ultrafiltration LC-MS with acetylcholinesterase - Li_2022_J.Ethnopharmacol__115460
Author(s) : Li J , Yang G , Shi W , Fang X , Han L , Cao Y
Ref : J Ethnopharmacol , :115460 , 2022
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis diffusa is a traditional ethnomedicinal plant in local communities in northeastern Asia and used to treat inflammation, nervous breakdown, among others. In recent years, it has been applied in the treatment of Alzheimer's disease (AD), while the specific chemical components responsible for the activity remain need to be explored. AIM OF THE STUDY: To prepare, screen and identify the potential anti-AD active components from Hedyotis diffusa. MATERIALS AND METHODS: The acetylcholinesterase (AChE) inhibitory activity of four different extracts of Hedyotis diffusa were initially assessed using a spectrophotometric Ellman's method. A more accurate LC-MS/MS screening method combining functional enzyme assay and affinity ultrafiltration (AU) screening assay was developed and applied for the screening of natural compound inhibitors of AChE from Hedyotis diffusa. The binding mode were further investigated between protein and ligands via molecular docking. Subsequently, CL4176, a transgenic nematode model for AD, was used for activity validation of one of these components. RESULTS: N-butanol extract of Hedyotis diffusa (NHD) appeared significant inhibitory activities on AChE, were chosen to delve deeper. Five bioactive components targeting AChE were screened out and identified using AU coupled to liquid chromatography-mass spectrometry. Molecular docking technique further confirmed the results of the screening assay. Finally, qurecetin-3-O-sophoroside (QS) was confirmed as a potent anti-AD agent by in vivo experiments in C. elegans. CONCLUSION: This study explores a new idea for screening anti-AD active components from traditional medicine. The findings provide a molecular structure and bioactivity basis for future potential applications of Hedyotis diffusa in medical industries.
ESTHER : Li_2022_J.Ethnopharmacol__115460
PubMedSearch : Li_2022_J.Ethnopharmacol__115460
PubMedID: 35714878

Title : Plasma-Soluble Dipeptidyl Peptidase 4 and Risk of Major Cardiovascular Events After Ischemic Stroke: Secondary Analysis of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) - You_2022_Neurology__
Author(s) : You S , Miao M , Lu Z , Bao A , Du J , Che B , Xu T , Zhong C , Cao Y , Liu CF , Zhang Y , He J
Ref : Neurology , : , 2022
Abstract : BACKGROUND AND OBJECTIVES: Recent studies have suggested that plasma soluble dipeptidyl peptidase-4 (sDPP4) have important physiological effects, which may influence the prognosis of ischemic stroke. Our study aimed to examine the relationship between plasma sDDP4 levels and long-term clinical outcomes among acute ischemic stroke patients. METHODS: Secondary analysis was conducted among 3,564 participants (2,270 men and 1,294 women) from the China Antihypertensive Trial in Acute Ischemic Stroke with baseline measurement of plasma sDPP4 levels. We evaluated the associations between plasma sDPP4 levels and 2-year clinical outcomes using logistic regression and Cox regression models. We further investigated the predictive utility of sDPP4 by calculating net reclassification index (NRI) and integrated discrimination improvement (IDI). RESULTS: The highest plasma sDPP4 quartile was associated with lower risk of cardiovascular events (HR 0.62, 95% CI 0.45-0.87), recurrent stroke (HR 0.70, 95% CI 0.49-0.99), all-cause mortality (HR 0.62, 95% CI 0.44-0.87), stroke-specific mortality (HR 0.65, 95% CI 0.44-0.94) and poor functional outcomes (OR 0.66, 95% CI 0.53-0.82) at 2 years compared with the lowest sDPP4 category in multivariable models. The addition of plasma sDPP4 to conventional risk factors model significantly improved risk prediction of all outcomes. DISCUSSION: In this study, we found that higher plasma sDPP4 levels in acute ischemic stroke patients were associated with decreased risks of cardiovascular events, recurrent stroke, all-cause mortality, and poor functional outcomes after ischemic stroke. These findings suggest that plasma sDPP4 may be a potential prognostic marker for initial risk stratification in patients with acute ischemic stroke.
ESTHER : You_2022_Neurology__
PubMedSearch : You_2022_Neurology__
PubMedID: 35654589

Title : 5-Methyltetrahydrofolate Alleviates Memory Impairment in a Rat Model of Alzheimer's Disease Induced by D-Galactose and Aluminum Chloride - Zhang_2022_Int.J.Environ.Res.Public.Health_19_
Author(s) : Zhang Z , Wu H , Qi S , Tang Y , Qin C , Liu R , Zhang J , Cao Y , Gao X
Ref : Int J Environ Research Public Health , 19 : , 2022
Abstract : The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl(3)) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl(3) to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid beta-protein 1-42 (Abeta(1-42)) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of beta-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl(3)-exposed rat model of AD. The inhibition of Abeta(1-42) and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible.
ESTHER : Zhang_2022_Int.J.Environ.Res.Public.Health_19_
PubMedSearch : Zhang_2022_Int.J.Environ.Res.Public.Health_19_
PubMedID: 36554305

Title : A GRN Autocrine-Dependent FAM135B\/AKT\/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression - Dong_2021_Cancer.Res_81_910
Author(s) : Dong D , Zhang W , Xiao W , Wu Q , Cao Y , Gao X , Huang L , Wang Y , Chen J , Wang W , Zhan Q
Ref : Cancer Research , 81 :910 , 2021
Abstract : Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC. SIGNIFICANCE: These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.
ESTHER : Dong_2021_Cancer.Res_81_910
PubMedSearch : Dong_2021_Cancer.Res_81_910
PubMedID: 33323378
Gene_locus related to this paper: human-FAM135B

Title : Effect of superabsorbent polymers (SAP) and metal organic frameworks (MOF) wiping sandwich patch on human skin decontamination and detoxification in vitro - Cao_2021_Toxicol.Lett_337_7
Author(s) : Cao Y , Hui X , Maibach HI
Ref : Toxicol Lett , 337 :7 , 2021
Abstract : Most chemical warfare agents partition rapidly into stratum corneum (SC) and subsequently slowly diffuse through - or are retained in the membrane. Since chemicals can interact with SC components during the process, skin decontamination poses a challenging yet important problem. To address these issues, we have developed a new method in combination with wet and dry decon technologies with new materials for emergency or delayed contamination scenarios. An in vitro human skin diffusion system was employed to model various dermal exposures of radiolabeled chemical warfare simulants, followed by surface decontamination with metal organic frameworks (MOFs), super-absorbent polymers (SAP), and/or dermal decontamination gel (DDGel). All samples measured for radioactive recovery and acetylcholinesterase activity to ascertain relative decon efficacy. Results demonstrated powerful water absorption of SAP, strong catalysis of UiO-66 MOF, and decon enhancement of pre-wetting surface contaminants. SAP had no interfering interactions with MOF yet provided additional benefits as porosity and reactivity that allowed for fast liquidized chemical transportation, absorption, and degeneration. We then designed a cotton-based SAP/MOF patch that worked cooperatively in decontamination and detoxification. Together with pre-wet, SAP/MOF wipe, and DDGel applications, maximum effect was observed in early and/or extended dermal exposure, and no "wash-in" effect occurred.
ESTHER : Cao_2021_Toxicol.Lett_337_7
PubMedSearch : Cao_2021_Toxicol.Lett_337_7
PubMedID: 33197554

Title : 3D origami paper-based ratiometric fluorescent microfluidic device for visual point-of-care detection of alkaline phosphatase and butyrylcholinesterase - Zhu_2021_Biosens.Bioelectron_196_113691
Author(s) : Zhu Y , Tong X , Wei Q , Cai G , Cao Y , Tong C , Shi S , Wang F
Ref : Biosensors & Bioelectronics , 196 :113691 , 2021
Abstract : On-site multiplex enzyme detection is crucial for diagnosis, therapeutics and prognostic. To date, it is still a daunting challenge to develop portable, low-cost, and efficient multi-enzyme detection methods. Herein, a novel sample-in-result-out platform integrating ratiometric fluorescent assays with 3D origami microfluidic paper-based device (microPAD) was developed for simultaneous visual point-of-care testing (POCT) of alkaline phosphatase (ALP) and butyrylcholinesterase (BChE). Cascade catalytic reaction with the same two fluorescent signal indicators was rationally designed to ratiometric fluorescent detection of ALP and BChE: substrate of ALP (pyrophosphate) and product of BChE (thiocholine) can strongly complex with Cu(2+), Cu(2+) oxidizes o-phenylenediamine to fluorescent 2,3-diaminophenazine (oxOPD) (emission, 565 nm), oxOPD quenches the fluorescence of carbon dots (CDs, emission at 445 nm) via inner filter effect, thus oxOPD/CDs values are relevant to ALP and BChE activities. Then 3D origami microPAD composing of four layers and two parallel channels was fabricated and simply prepared by one-step plotting with black oil-based marker and specific metal molds. After simple folding and unfolding neighboring layers to sequentially initiate reactions of pre-loaded reagents, fluorescent images on the detection zone can be captured by smartphone and analyzed by red-green-blue software for quantitative analysis. Under optimal conditions, the proposed platform was successfully performed to detect ALP and BChE with activity difference at 3 orders of magnitude in human serum samples without any pretreatment procedures. Excellent selectivity, good precision, favorable linear range, and high accuracy were exhibited. Importantly, the platform opens a promising horizon for high-throughput POCT of multiplex biomarkers.
ESTHER : Zhu_2021_Biosens.Bioelectron_196_113691
PubMedSearch : Zhu_2021_Biosens.Bioelectron_196_113691
PubMedID: 34637993

Title : Can Organophosphates and Carbamates Cause Synergisms by Inhibiting Esterases Responsible for Biotransformation of Pyrethroids? - Cao_2021_Environ.Sci.Technol__
Author(s) : Cao Y , Ibanez Navarro A , Perrella L , Cedergreen N
Ref : Environ Sci Technol , : , 2021
Abstract : Hydrolysis catalyzed by general esterases (GEs) is the most efficient route for hydrolyzation of pyrethroid insecticides. Organophosphate (OP) and carbamate (CB) insecticides are known to inhibit GEs in addition to acetylcholinesterase (AChE), which is their main target. We hypothesize that synergies can be induced by OPs and CBs when mixed with pyrethroids, due to their inhibition of GE-dependent detoxification of pyrethroids. To test this hypothesis, we conducted mixture toxicity experiments with Daphnia magna using alpha-cypermethrin (alpha-cyp) in combination with the noninsecticidal OP tetraisopropyl pyrophosphoramide (iso-OMPA) and five AChE inhibitors diazinon, chlorpyrifos, chlorfenviphos, parathion, and aldicarb. In addition, the in vivo GE activity inhibition was measured for all compounds. Up to 10-fold synergy was found between alpha-cyp and iso-OMPA, and the degree of synergy correlated linearly with the inhibition of the GE activity. No synergy, however, was found in any of the insecticide mixtures nor was the GE activity inhibited within the nonlethal concentration range tested. It was concluded that the effect of the insecticides on AChE occurred at lower concentrations than their effect on GEs, making the daphnids become immobilized before any synergistic effects on mortality could be observed. The implications of the findings are discussed from a risk assessment perspective.
ESTHER : Cao_2021_Environ.Sci.Technol__
PubMedSearch : Cao_2021_Environ.Sci.Technol__
PubMedID: 33470798

Title : Acetylcholinesterase target sites for developing environmentally friendly insecticides against Tetranychus urticae (Acari: Tetranychidae) - Li_2021_Exp.Appl.Acarol__
Author(s) : Li C , Cao Y , Yang J , Li M , Li B , Bu C
Ref : Exp Appl Acarol , : , 2021
Abstract : The non-target toxicity and resistance problems of acetylcholinesterase (AChE) insecticides, such as organophosphates and carbamates, are of growing concern. To explore the potential targets for achieving inhibitor selectivity, the AChE structures at or near the catalytic pocket of Tetranychus urticae (TuAChE), honey bees, and humans were compared. The entrances to the AChE catalytic pocket differ significantly because of their different peripheral sites. The role of these potential mite-specific sites in AChE function was further elucidated by site-directed mutagenesis of these sites and then examining the catalytic activities of TuAChE mutants. The spider mite E(316), H(369), and V(105) active sites are important for AChE function. By further analyzing their physostigmine inhibitory properties and the detailed interaction between physostigmine and TuAChE, the peripheral site H(369) locating near the gorge entrance, and S(154) at the oxyanion hole, affects substrate and inhibitor trafficking. The discovery of conserved mite-specific residues in Tetranychus will enable the development of safer, effective pesticides that target residues present only in mite AChEs, potentially offering effective control against this important agricultural pest.
ESTHER : Li_2021_Exp.Appl.Acarol__
PubMedSearch : Li_2021_Exp.Appl.Acarol__
PubMedID: 33914192

Title : Long-Wavelength Ratiometric Fluorescent Probe for the Early Diagnosis of Diabetes - Wang_2021_Anal.Chem_93_11461
Author(s) : Wang J , Zhang L , Qu Y , Yang Y , Cao T , Cao Y , Iqbal A , Qin W , Liu Y
Ref : Analytical Chemistry , 93 :11461 , 2021
Abstract : Diabetes is a metabolic disease caused by high blood sugar. Patients are often suffering from high blood pressure and arteriosclerosis, which may even evolve into liver disease, kidney disease, and other diabetic complications. Dipeptide peptidase IV (DPP-IV) plays an important role in regulating blood sugar levels and is one of the targets for the diagnosis and treatment of diabetes. Here, a long-wavelength ratiometric fluorescent probe DCDHFNH(2)-dpp4 for detecting DPP-IV was designed and synthesized. DCDHFNH(2)-dpp4 was used to detect DPP-IV in healthy, tumor-bearing, and diabetic mice, and only diabetic mice showed strong fluorescence signals. In organ imaging, it is found that DPP-IV is relatively enriched in the liver of diabetic mice. In addition, probe DCDHFNH(2)-dpp4 also exhibited a significant ratiometric fluorescence signal in the serum of diabetic mice. Therefore, the fluorescent probe DCDHFNH(2)-dpp4 has shown outstanding potential in the early diagnosis of diabetes, and DCDHFNH(2)-dpp4 is hopeful to be applied to actual clinical medicine.
ESTHER : Wang_2021_Anal.Chem_93_11461
PubMedSearch : Wang_2021_Anal.Chem_93_11461
PubMedID: 34369744

Title : A ratiometric fluorescence strategy based on inner filter effect for Cu(2+)-mediated detection of acetylcholinesterase - Li_2021_Mikrochim.Acta_188_385
Author(s) : Li Y , Liang H , Lin B , Yu Y , Wang Y , Zhang L , Cao Y , Guo M
Ref : Mikrochim Acta , 188 :385 , 2021
Abstract : A novel ratiometric fluorescence strategy for detection of acetylcholestinerase (AChE) is proposed based on carbon nitride quantum dots (g-CNQD) and the complex (PA) formed between phenylboronic acid (PBA) and alizarin red S (ARS). PA showed fluorescence at 598 nm and quenched the fluorescence of g-CNQD at 438 nm. Through UV-visible absorption, fluorescence, and fluorescence lifetime measurements, the quenching effect was demonstrated as inner filter effect (IFE). When Cu(2+) was added, the coordination of ARS and Cu(2+) decreased the fluorescence of PA at 598 nm and recovered that of g-CNQD at 438 nm. In the presence of AChE it catalyzed the hydrolysis of acetylthiocholine (ATCh) to produce thiocholine (TCh) which competed with ARS for binding to Cu(2+); thus, the fluorescence at 598 nm increased and that at 438 nm decreased again. Under the mediation of Cu(2+), the fluorescence ratio F(598)/F(438) of PA-CNQD probe had good linear relationship with AChE concentration in the range 0.5-15 mU/mL with a detection limit of 0.36 mU/mL. The method was successfully applied to the determination of AChE in human serum and the screening of inhibitors.
ESTHER : Li_2021_Mikrochim.Acta_188_385
PubMedSearch : Li_2021_Mikrochim.Acta_188_385
PubMedID: 34664146

Title : Enhancement of Fear Extinction Memory and Resistance to Age-Related Cognitive Decline in Butyrylcholinesterase Knockout Mice and (R)-Bambuterol Treated Mice - Liu_2021_Biology.(Basel)_10_
Author(s) : Liu W , Cao Y , Lin Y , Tan KS , Zhao H , Guo H , Tan W
Ref : Biology (Basel) , 10 : , 2021
Abstract : Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer's disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3-10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline.
ESTHER : Liu_2021_Biology.(Basel)_10_
PubMedSearch : Liu_2021_Biology.(Basel)_10_
PubMedID: 34062954

Title : In vitro gastrointestinal digestibility of phytosterol oleogels: influence of self-assembled microstructures on emulsification efficiency and lipase activity - Dong_2020_Food.Funct_11_9503
Author(s) : Dong L , Lv M , Gao X , Zhang L , Rogers M , Cao Y , Lan Y
Ref : Food Funct , 11 :9503 , 2020
Abstract : The objective of this study was to investigate the influence of self-assembled microstructure on lipid digestibility in phytosterol (gamma-oryzanol and beta-sitosterol) oleogels. Different molar ratios of gamma-oryzanol and beta-sitosterol yielded a variety of crystal morphologies; the resulting gels were tested for their lipid emulsification efficiency, release rate of free fatty acids (FFAs) during lipolysis, and their effect on lipase behavior. Results indicated that oleogels were harder to emulsify when compared to oil samples. The emulsification efficiencly was affected by both the gel strength and crystal morphology of the self-assembled structures within phytosterol oleogels. In oil emulsions, intestinal digestion resulted in more extensive lipid droplet coalescence with increased particle size when compared to oleogel emulsions. The FFA release rate suggested that the extent of lipid digestion was correlated to the emulsification efficiency. The interfacial binding of lipase indicated that the amount of lipase adsorption was positively correlated to the interface area created during the emulsification process. Finally, isothermal titration calorimetry results indicated that self-assembled structures within these oleogels physically obstructed the interaction between lipase and lipid. Ultimately, this led to lower reaction rate during gastrointestinal digestion. Collectively, these results may have important implications in designing oleogel systems with controlled lipid digestibility as well as controlling the bioavailability of delivered lipid-soluble bioactive compounds.
ESTHER : Dong_2020_Food.Funct_11_9503
PubMedSearch : Dong_2020_Food.Funct_11_9503
PubMedID: 32955534

Title : Pharmacological Mechanisms Underlying the Neuroprotective Effects of Alpinia oxyphylla Miq. on Alzheimer's Disease - Xu_2020_Int.J.Mol.Sci_21_
Author(s) : Xu J , Wang F , Guo J , Xu C , Cao Y , Fang Z , Wang Q
Ref : Int J Mol Sci , 21 : , 2020
Abstract : Alpinia oxyphylla Miq. (i.e., A. oxyphylla), a traditional Chinese medicine, can exert neuroprotective effects in ameliorating mild cognitive impairment and improving the pathological hallmarks of Alzheimer's disease (AD). Here, 50 active compounds and 164 putative targets were collected and identified with 251 clinically tested AD-associated target proteins using network pharmacology approaches. Based on the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichments, the compound-target-pathway-disease/protein-protein interaction network constructions, and the network topological analysis, we concluded that A. oxyphylla may have neuroprotective effects by regulating neurotransmitter function, as well as brain plasticity in neuronal networks. Moreover, closely-related AD proteins, including the amyloid-beta precursor protein, the estrogen receptor 1, acetylcholinesterase, and nitric oxide synthase 2, were selected as the bottleneck nodes of network for further verification by molecular docking. Our analytical results demonstrated that terpene, as the main compound of A. oxyphylla extract, exerts neuroprotective effects, providing new insights into the development of a natural therapy for the prevention and treatment of AD.
ESTHER : Xu_2020_Int.J.Mol.Sci_21_
PubMedSearch : Xu_2020_Int.J.Mol.Sci_21_
PubMedID: 32197305

Title : Biomonitoring of polycyclic aromatic hydrocarbons (PAHs) from Manila clam Ruditapes philippinarum in Laizhou, Rushan and Jiaozhou, bays of China, and investigation of its relationship with human carcinogenic risk - Sun_2020_Mar.Pollut.Bull_160_111556
Author(s) : Sun J , Pan L , Cao Y , Li Z
Ref : Mar Pollut Bull , 160 :111556 , 2020
Abstract : This study examined the marine environment and seafood safety using chemical monitoring and multiple biomarkers. Samples were collected from three bays on the Shandong Peninsula in China, Laizhou, Rushan and Jiaozhou, in March, May, August, and October of 2018 and 2019. The polycyclic aromatic hydrocarbon (PAH) concentrations in sediments and tissue samples from the clam Ruditapes philippinarum and multiple biomarkers were measured. All the sampling sites were found to be medium-PAH-contaminated areas (100-1000 ng/g d.w.). According to the correlation analysis, ethoxyresorufin-o-deethylase (EROD) and superoxide dismutase (SOD) activity in the clam's digestive gland were sensitive to PAHs (p < .05), but the incremental lifetime cancer risk (ILCR) was lower than the priority risk level (10(-4)) at most sampling sites. EROD, SOD and acetylcholinesterase activity exhibited significant correlations with the ILCR values (p < .01), suggesting that they may serve as good indicators for assessing safe seafood consumption levels for human beings.
ESTHER : Sun_2020_Mar.Pollut.Bull_160_111556
PubMedSearch : Sun_2020_Mar.Pollut.Bull_160_111556
PubMedID: 32836194

Title : A ratiometric fluorescence probe based on graphene quantum dots and o-phenylenediamine for highly sensitive detection of acetylcholinesterase activity - Ye_2020_Mikrochim.Acta_187_511
Author(s) : Ye M , Lin B , Yu Y , Li H , Wang Y , Zhang L , Cao Y , Guo M
Ref : Mikrochim Acta , 187 :511 , 2020
Abstract : By using graphene quantum dots (GQDs) and o-phenylenediamine (OPD), a ratiometric fluorescence probe was designed for the highly sensitive and selective detection of AChE. GQDs with strong fluorescence were synthesized by the one-step hydrothermal method. The optimal emission wavelength of GQDs was 450 nm at the excitation wavelength of 375 nm. MnO(2) nanosheets with a wide absorption band of 300-600 nm were prepared at room temperature. Because of the extensive overlap between the absorption spectrum of MnO(2) nanosheets and the excitation and emission spectra of GQDs, the fluorescence of GQDs at 450 nm was efficiently quenched by the inner-filter effect. Meanwhile, due to the peroxidase-like activity of MnO(2) nanosheets, OPD was catalytically oxidized to 2,3-diaminophenazine (oxOPD), a yellow fluorescent substance with a new emission peak at 572 nm. When AChE was present, the substrate acetylthiocholine (ATCh) was hydrolyzed to thiocholine (TCh) that is capable of decomposing MnO(2) nanosheets. Therefore, the quench of GQDs and the oxidation of OPD by MnO(2) nanosheets were suppressed, resulting in the fluorescence recovery of GQDs at 450 nm, while the fluorescence decrease of oxOPD at 572 nm. Utilizing the fluorescence intensity ratio F(450)/F(572) as the signal readout, the ratiometric fluorescence method was established to detect AChE activity. The ratio F(450)/F(572) against the AChE concentration demonstrated two linear relationships in the range 0.1-2.0 and 2.0-4.5 mU mL(-1) with a detection limit of 0.09 mU mL(-1). The method was applied to the detection of positive human serum samples and the analysis of the inhibitor neostigmine. Due to the advantages of high sensitivity, favorable selectivity, and strong anti-interference, the method possesses an application prospect in clinical diagnosis of AChE and the screening of inhibitors. Graphical abstract Schematic presentation of a ratiometric fluorescence method for the detection of acetylcholinesterase (AChE). The fluorescence of graphene quantum dots (GQDs) is quenched and o-phenylenediamine (OPD) is oxidized to generate fluorescent product 2,3-diaminophenazine (oxOPD) by MnO(2) nanosheets. When AChE is present, acetylthiocholine iodide (ATCh) is hydrolyzed to thiocholine (TCh) with reducibility for decomposing MnO(2) nanosheets. Due to the decomposition of MnO(2) nanosheets, the quenching of GQDs and oxidation of OPD are suppressed. The fluorescence of GQDs at 450 nm is enhanced, while the fluorescence of oxOPD at 572 nm is reduced. The fluorescence intensity ratio F(450)/F(572) is used to establish the ratiometric fluorescence method for AChE activity.
ESTHER : Ye_2020_Mikrochim.Acta_187_511
PubMedSearch : Ye_2020_Mikrochim.Acta_187_511
PubMedID: 32833082

Title : Correlation analysis between CARMEN variants and alcohol-induced osteonecrosis of the femoral head in the Chinese population - Guo_2020_BMC.Musculoskelet.Disord_21_547
Author(s) : Guo Y , Cao Y , Gong S , Zhang S , Hou F , Zhang X , Hu J , Yang Z , Yi J , Luo D , Chen X , Song J
Ref : BMC Musculoskelet Disord , 21 :547 , 2020
Abstract : BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a complicated disease associated with trauma, hormone abuse and excessive alcohol consumption. Polymorphisms of long non-coding RNAs have been also linked with the development of ONFH. Our research aimed to explore the relationship between CARMEN (Cardiac Mesoderm Enhancer-Associated Non-Coding RNA) variants and ONFH risk. METHODS: Our study used Agena MassARRAY Assay to genotype 6 selected single nucleotide polymorphisms (SNPs) in 731 participants (308 alcohol-induced ONFH patients and 423 controls). We used odds ratios (ORs) and 95% confidence intervals (CIs) to calculate the effect of gene polymorphisms on the occurrence of alcohol-induced ONFH by logistic regression analysis and haplotype analysis. RESULTS: Our overall analysis illustrated that rs13177623 and rs12654195 had an association with a reduced risk of ONFH after adjustment for age and gender. We also found that rs13177623, rs12654195 and rs11168100 were associated with a decreased susceptibility to alcohol-induced ONFH in people <=45 years. In addition, the necrotic sites stratification analysis showed that rs12654195 was only found to be related to alcohol-induced ONFH risk in the recessive model. In patients with different clinical stages, rs353300 was observed to be associated with a higher incidence of ONFH. Individuals with different genotypes of rs13177623, rs12654195 and rs11168100 had significantly different clinical parameters (cholinesterase, globulin, percentage of neutrophils and the absolute value of lymphocytes). CONCLUSIONS: Our data provided new light on the association between CARMEN polymorphisms and alcohol-induced ONFH risk in the Chinese Han population.
ESTHER : Guo_2020_BMC.Musculoskelet.Disord_21_547
PubMedSearch : Guo_2020_BMC.Musculoskelet.Disord_21_547
PubMedID: 32799824

Title : Dipeptidyl Peptidase-4 Is a Target Protein of Epigallocatechin-3-Gallate - Hou_2020_Biomed.Res.Int_2020_5370759
Author(s) : Hou H , Wang Y , Li C , Wang J , Cao Y
Ref : Biomed Res Int , 2020 :5370759 , 2020
Abstract : Epigallocatechin-3-gallate (EGCG), a major active ingredient in green tea, has various health benefits. It affects glucose metabolism, but the mechanism is not well understood. This study aimed to identify targets of EGCG related to glucose metabolism. The core fragment of EGCG is a flavonoid. The flavonoid scaffold was used as a substructure to find proteins cocrystallized with flavonoids in the Protein Data Bank. The proteins identified were screened in PubMed for known relationships with diabetes. Dipeptidyl peptidase-4 (DPP4; PDB 5J3J) was identified following this approach. By molecular docking, the interactions of EGCG and DPP4 were assessed. To test the stability of the interactions between EGCG and DPP4, molecular dynamics simulation for 100 ns was performed using Desmond software. In vitro, the concentration of EGCG required to inhibit DPP4 activity by 50% (the IC50 value) was 28.42 muM. These data provide a theoretical basis for intervention in glucose metabolism with EGCG.
ESTHER : Hou_2020_Biomed.Res.Int_2020_5370759
PubMedSearch : Hou_2020_Biomed.Res.Int_2020_5370759
PubMedID: 32104696

Title : Neuroprotective effects of the aerial parts of Polygala tenuifolia Willd extract on scopolamine-induced learning and memory impairments in mice - Wang_2020_Biomed.Rep_13_37
Author(s) : Wang X , Zhang D , Song W , Cai CF , Zhou Z , Fu Q , Yan X , Cao Y , Fang M
Ref : Biomed Rep , 13 :37 , 2020
Abstract : Alzheimer's disease is a common neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. Aerial parts of Polygala tenuifolia Willd (APT) is a traditional Chinese medicine used for the treatment of amnesia. The present study aimed to investigate the protective effects of APT on scopolamine-induced learning and memory impairments in mice. Scopolamine-induced mice were used to determine the effects of APT on learning and memory impairment. Mice were orally administered with APT (25, 50 and 100 mg/kg) and piracetam (750 mg/kg) for 14 days, and intraperitoneally injected with scopolamine (2 mg/kg) from days 8 to 14. Morris water maze and step-down tests were performed to evaluate learning and memory. Levels of acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), interleukin (IL)-1beta, IL-10 and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex were measured by ELISA. Superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) were measured via biochemical detection. The results demonstrated that APT ameliorated learning and memory impairment in scopolamine-induced mice. Correspondingly, APT significantly increased ACh and ChAT levels in the hippocampus and prefrontal cortex of scopolamine-induced mice. Additionally, treatment with APT significantly increased BDNF and IL-10 levels, and decreased IL-1beta and AChE levels in the same mice. Furthermore, APT significantly increased SOD activity and GSH content, and decreased MDA levels in brain tissue. These results indicated that APT may ameliorate learning and memory impairment by regulating cholinergic activity, promoting BDNF and inhibiting neuroinflammation and oxidative stress.
ESTHER : Wang_2020_Biomed.Rep_13_37
PubMedSearch : Wang_2020_Biomed.Rep_13_37
PubMedID: 32874571

Title : Expression and characterization of two glucuronoyl esterases from Thielavia terrestris and their application in enzymatic hydrolysis of corn bran - Tang_2019_Appl.Microbiol.Biotechnol_103_3037
Author(s) : Tang J , Long L , Cao Y , Ding S
Ref : Applied Microbiology & Biotechnology , 103 :3037 , 2019
Abstract : The thermophilic fungus Thielavia terrestris when cultured on cellulose produces a cocktail of thermal hydrolases with potential application in saccharification of lignocellulosic biomass and other biotechnological areas. Glucuronoyl esterases are considered to play a unique role as accessory enzymes in lignocellulosic material biodegradation by cleaving the covalent ester linkage between 4-O-methyl-D-glucuronic acid (MeGlcA) and lignin in lignin-carbohydrate complexes (LCCs). Two glucuronoyl esterases from T. terrestris named TtGE1 and TtGE2 were expressed in Pichia pastoris. Both esterases displayed features of thermophilic enzymes, with the optimal temperature at 45 degrees C and 55 degrees C. TtGE1 and TtGE2 exhibited activity towards methyl (4-nitrophenyl beta-D-glucopyranosid) uronate (Me-GlcA-pNP) but no catalytic activity to benzyl-D-glucuronate (BnzGlcA), indicating the difference in substrate specificity from previously studied fungal GEs. A substantial increase in the release of monomeric sugars and glucuronic acid from autohydrolysis of corn bran was observed by the supplementing TtGEs into commercial xylanase; the results clearly demonstrated that the TtGEs played a significant role in this degradation process. This research on TtGEs enriches our knowledge of this novel class of fungal GEs. These newly characterized TtGEs could be used as promising accessory enzymes to improve the hydrolysis efficiency of commercial enzymes in saccharification of lignocellulosic materials due to their thermophilic characteristics.
ESTHER : Tang_2019_Appl.Microbiol.Biotechnol_103_3037
PubMedSearch : Tang_2019_Appl.Microbiol.Biotechnol_103_3037
PubMedID: 30762074
Gene_locus related to this paper: thite-g2r8b5 , thite-g2rcm8

Title : Effect and Safety of Huannao Yicong Formula () in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Double-Blinded, Donepezil-Controlled Trial - Yang_2019_Chin.J.Integr.Med_25_574
Author(s) : Yang Y , Liu JP , Fang JY , Wang HC , Wei Y , Cao Y , Liu JG , Liu LT , Li H
Ref : Chin J Integr Med , 25 :574 , 2019
Abstract : OBJECTIVE: To assess the effect and safety of Huannao Yicong Formula (, HYF) in the treatment of patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Sixty patients with mild-tomoderate AD were evenly randomized into HYF group and donepezil group with the random number method. Patients in the HYF group took 5 g of HYF granules twice daily and 5 mg placebo of donepezil once daily. Patients in the donepezil group took 5 mg donepezil once daily and 5 g placebo of HYF granules twice daily. The intervention lasted for 6 months. Clinical researchers, participants and statisticians were blinded to the treatment assignment throughout the study. The primary outcomes were scores of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Montreal Cognitive Assessment (MoCA) test and Mini-Mental State Exam (MMSE). The serum levels of acetylcholinesterase (AchE) and amyloid-beta protein 42 (Abeta42) were detected with enzymelinked immunosorbent assay kits. The scale assessments were conducted at baseline, the 3rd and 6th months of treatment, respectively. Biochemistry tests were conducted at baseline and the 6th month of treatment. RESULTS: A total of 52 patients completed the trial, 28 in HYF group and 24 in donepezil group. Compared with the baseline, HYF and donepezil signifificantly decreased the total scores of ADAS-Cog and CM-SS, and signifificantly increased the scores of MoCA and MMSE after 6-month treatment (all P<0.01). Both treatments remarkably reduced the serum levels of AchE and Abeta42 (both P<0.05). The CM-SS total effective rate of HYF was signifificantly higher than donepezil [75.00% (21/28) vs. 54.17% (13/24), P<0.05]. No severe adverse events were observed in both groups. CONCLUSION: HYF is effective and safe for improving the cognitive function in mildto-moderate AD patients. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-IOR-17011746)].
ESTHER : Yang_2019_Chin.J.Integr.Med_25_574
PubMedSearch : Yang_2019_Chin.J.Integr.Med_25_574
PubMedID: 30109588

Title : Linarin improves the dyskinesia recovery in Alzheimer's disease zebrafish by inhibiting the acetylcholinesterase activity - Pan_2019_Life.Sci_222_112
Author(s) : Pan H , Zhang J , Wang Y , Cui K , Cao Y , Wang L , Wu Y
Ref : Life Sciences , 222 :112 , 2019
Abstract : BACKGROUND: Due to complex pathogenesis of Alzheimer's disease (AD), currently there is no effective disease-modifying treatment. Acetylcholinesterase (AChE) has introduced itself as an important target for AD therapy. Linarin as the representative active ingredient of flavonoid glycoside in Flos chrysanthemi indici has been found to have anti-acetylcholinesterase effect. AIMS: The present study intended to explore the potential effect of linarin for treatment of AD. MAIN METHODS: In this study, molecular docking simulation was used to evaluate whether linarin could dock with AChE and decipher the mechanism of linarin as an AChE inhibitor. After molecular docking simulation, AlCl3-induced Alzheimer's disease zebrafish model was established. Effects of linarin on treating AD zebrafish dyskinesia and AChE inhibition were compared with donepezil (DPZ) which was used as a positive control drug. KEY FINDINGS: Molecular docking simulation showed that linarin plays a critical role in AChE inhibition by binding AChE active sites. The experiments illustrated that the dyskinesia recovery rate of AD zebrafish could be significantly improved by linarin. The dyskinesia recovery and AChE inhibition rate were 88.0% and 74.5% respectively, while those of DPZ were 79.3% and 43.6%. SIGNIFICANCE: These findings provide evidences for supporting linarin to be developed into an AD drug by inhibiting the activity of AChE.
ESTHER : Pan_2019_Life.Sci_222_112
PubMedSearch : Pan_2019_Life.Sci_222_112
PubMedID: 30802512

Title : Traditional Chinese Medicine Shenmayizhi Decoction Ameliorates Memory And Cognitive Impairment Induced By Scopolamine Via Preventing Hippocampal Cholinergic Dysfunction In Rats - Wu_2019_Neuropsychiatr.Dis.Treat_15_3167
Author(s) : Wu Q , Cao Y , Liu M , Liu F , Brantner AH , Yang Y , Wei Y , Zhou Y , Wang Z , Ma L , Wang F , Pei H , Li H
Ref : Neuropsychiatr Dis Treat , 15 :3167 , 2019
Abstract : Purpose: Clinical trials have illustrated that Shenmayizhi decoction (SMYZ) could improve the cognitive functions in patients with dementia. However, the mechanism needs to be explored. Methods: Fifty adult male rats (Wistar strain) were divided into five groups equally and randomly, including control, model, and SMYZ of low dose, medium dose and high dose. Rats in each group received a daily gavage of respective treatment. Rats in control and model group were administrated by the same volume of distilled water. Memory impairment was induced by intraperitoneal administration of scopolamine (0.7 mg/kg) for 5 continuous days. Four weeks later, Morris water maze (MWM) was performed to evaluate the spatial memory in all rats. Then, rats were sacrificed and the hippocampus was removed for further tests. Furthermore, Western blot analysis was employed to assess the levels of acetylcholine M1 receptor (M1), acetylcholine M2 receptor (M2), acetylcholinesterase (AChE) and cholineacetyltransferase (ChAT). AChE and ChAT activities were determined. Results: The SMYZ decoction significantly improved behavioral performance of rats in high dose. The SMYZ decoction in three doses exhibited anti-acetylcholinesterase activity. In addition, a high dose of SMYZ promoted ChAT activity. Moreover, a high dose of SMYZ increased the level of ChAT and declined the level of AChE assessed by Western blotting. Besides, an increased level of M1 receptor was found after treatment. Conclusion: Shenmayizhi decoction could mitigate scopolamine-induced cognitive deficits through the preventative effect on cholinergic system dysfunction.
ESTHER : Wu_2019_Neuropsychiatr.Dis.Treat_15_3167
PubMedSearch : Wu_2019_Neuropsychiatr.Dis.Treat_15_3167
PubMedID: 31814724

Title : A comparative study of acetylcholinesterase and general-esterase activity assays using different substrates, in vitro and in vivo exposures and model organisms - Cao_2019_Ecotoxicol.Environ.Saf__109954
Author(s) : Cao Y , Herrero-Nogareda L , Cedergreen N
Ref : Ecotoxicology & Environmental Safety , :109954 , 2019
Abstract : Acetylcholinesterase (AChE) and general-esterase (GE) activities are important to understand detoxification processes of xenobiotics. The assays to quantify them have employed different substrates, inhibitors, types of experiments (in vitro and in vivo) and model organisms. The aim of this work was to give a systematic overview of the effect of the above factors on the outcome of AChE and GE activity measurements. We showed that AChE activity could be measured with the substrate acetylthiocholine iodide (AChI) but not with acetylcholine bromide (AChB) and only in in vitro assays. For GE activity, Michaelis-Menten kinetics differed between the substrates 4-methylumbellifery butyrate (4-MUB) and 1-naphtyl acetate (1-NA) in the measurements of in vitro activity, but their inhibition curves and IC50 values for the general inhibitor tetraisopropyl pyrophosphoramide (iso-OMPA) were similar, confirming that both substrates targeted the same group of enzymes. The GE substrate 4-MUB was applicable both in vitro and in vivo, while 1-NA was only applicable in vitro due to its high acute toxicity. When comparing the zooplankton crustacean Daphnia magna and the sediment dwelling Chironomus riparius, the latter had a four-fold higher maximal AChE activity (Vmax) and a higher susceptibility to the AChE inhibitor BW284c51 (four-fold lower 50% inhibitory concentration, IC50), but a lower maximal GE activity and lower susceptibility to iso-OMPA (higher IC50), indicating significant species differences between in C. riparius and D. magna. We conclude that both choice of substrate and exposure method matters for the outcome of esterase assays and that esterase compositions between species may vary significantly.
ESTHER : Cao_2019_Ecotoxicol.Environ.Saf__109954
PubMedSearch : Cao_2019_Ecotoxicol.Environ.Saf__109954
PubMedID: 31759743

Title : ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5 - Cao_2019_Nat.Chem.Biol_15_1232
Author(s) : Cao Y , Qiu T , Kathayat RS , Azizi SA , Thorne AK , Ahn D , Fukata Y , Fukata M , Rice PA , Dickinson BC
Ref : Nat Chemical Biology , 15 :1232 , 2019
Abstract : S-Palmitoylation is a reversible lipid post-translational modification that has been observed on mitochondrial proteins, but both the regulation and functional consequences of mitochondrial S-palmitoylation are poorly understood. Here, we show that perturbing the 'erasers' of S-palmitoylation, acyl protein thioesterases (APTs), with either pan-active inhibitors or a mitochondrial-targeted APT inhibitor, diminishes the antioxidant buffering capacity of mitochondria. Surprisingly, this effect was not mediated by the only known mitochondrial APT, but rather by a resident mitochondrial protein with no known endogenous function, ABHD10. We show that ABHD10 is a member of the APT family of regulatory proteins and identify peroxiredoxin-5 (PRDX5), a key antioxidant protein, as a target of ABHD10 S-depalmitoylase activity. We then find that ABHD10 regulates the S-palmitoylation status of the nucleophilic active site residue of PRDX5, providing a direct mechanistic connection between ABHD10-mediated S-depalmitoylation of PRDX5 and its antioxidant capacity.
ESTHER : Cao_2019_Nat.Chem.Biol_15_1232
PubMedSearch : Cao_2019_Nat.Chem.Biol_15_1232
PubMedID: 31740833
Gene_locus related to this paper: human-ABHD10 , mouse-abhda

Title : Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes - Kathayat_2018_Nat.Commun_9_334
Author(s) : Kathayat RS , Cao Y , Elvira PD , Sandoz PA , Zaballa ME , Springer MZ , Drake LE , Macleod KF , van der Goot FG , Dickinson BC
Ref : Nat Commun , 9 :334 , 2018
Abstract : The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of "erasers" of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells. Using mitoDPPs, we discover active S-depalmitoylation in mitochondria, in part mediated by APT1, an S-depalmitoylase previously thought to reside in the cytosol and on the Golgi apparatus. We also find that perturbation of long-chain acyl-CoA cytoplasm and mitochondrial regulatory proteins, respectively, results in selective responses from cytosolic and mitochondrial S-depalmitoylases. Altogether, this work reveals that mitochondrial S-palmitoylation is actively regulated by "eraser" enzymes that respond to alterations in mitochondrial lipid homeostasis.
ESTHER : Kathayat_2018_Nat.Commun_9_334
PubMedSearch : Kathayat_2018_Nat.Commun_9_334
PubMedID: 29362370
Gene_locus related to this paper: human-LYPLA1

Title : A Human DPP4-Knockin Mouse's Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV - Fan_2018_Viruses_10_
Author(s) : Fan C , Wu X , Liu Q , Li Q , Liu S , Lu J , Yang Y , Cao Y , Huang W , Liang C , Ying T , Jiang S , Wang Y
Ref : Viruses , 10 : , 2018
Abstract : Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.
ESTHER : Fan_2018_Viruses_10_
PubMedSearch : Fan_2018_Viruses_10_
PubMedID: 30142928

Title : A Fluorescent Probe with Improved Water Solubility Permits the Analysis of Protein S-Depalmitoylation Activity in Live Cells - Qiu_2018_Biochemistry_57_221
Author(s) : Qiu T , Kathayat RS , Cao Y , Beck MW , Dickinson BC
Ref : Biochemistry , 57 :221 , 2018
Abstract : S-Palmitoylation is an abundant lipid post-translational modification that is dynamically installed on and removed from target proteins to regulate their activity and cellular localization. A dearth of tools for studying the activities and regulation of protein S-depalmitoylases, thioesterase "erasers" of protein cysteine S-palmitoylation, has contributed to an incomplete understanding of the role of dynamic S-palmitoylation in regulating proteome lipidation. Recently, we developed "depalmitoylation probes" (DPPs), small molecule probes that become fluorescent upon S-depalmitoylase enzymatic activity. To be suitable for application in live cells, the first-generation DPPs relied on a shorter lipid substrate (C8 vs naturally occurring C16), which enhanced solubility and cell permeability. However, the use of an unnatural lipid substrate on the probes potentially limits the utility of the approach. Herein, we present a new member of the DPP family, DPP-5, which features an anionic carboxylate functional group that increases the probe water solubility. The enhanced water solubility of DPP-5 permits the use of a natural, palmitoylated substrate (C16), rather than a surrogate lipid. We show that DPP-5 is capable of monitoring endogenous S-depalmitoylases in live mammalian cells and that it can reveal changes in S-depalmitoylation levels due to lipid stress. DPP-5 should prove to be a useful new tool for probing the regulation of proteome lipidation through dynamic S-depalmitoylation.
ESTHER : Qiu_2018_Biochemistry_57_221
PubMedSearch : Qiu_2018_Biochemistry_57_221
PubMedID: 29023093

Title : A pH responsive AIE probe for enzyme assays - Shi_2018_Analyst_143_741
Author(s) : Shi L , Liu Y , Wang Q , Wang T , Ding Y , Cao Y , Li Z , Wei H
Ref : Analyst , 143 :741 , 2018
Abstract : By combining leucine (Leu) and tetraphenylethene (TPE), a pH-sensitive aggregation induced emission (AIE) probe TPE-Leu was developed. The aliphatic amine in TPE-Leu was more easily protonated under acidic conditions, which made TPE-Leu more water soluble. Therefore, the protonated AIE probe showed weak fluorescence under acidic conditions. When the pH was changed to basic conditions, it showed strong fluorescence due to the hydrophobic nature of TPE-Leu. We demonstrated that the probe showed high selectivity toward pH changes with the coexistence of other potential species such as metal ions, redox agents, and biomolecules. In contrast, TPE-NH2 did not exhibit obvious pH-sensitive properties. Moreover, TPE-Leu was further utilized to develop a sensitive and selective sensing platform for urease and acetylcholinesterase (AChE) detection. The current study not only provides a new strategy for designing pH-sensitive fluorescent probes for bioassays but also broadens the applications of AIE probes.
ESTHER : Shi_2018_Analyst_143_741
PubMedSearch : Shi_2018_Analyst_143_741
PubMedID: 29323362

Title : Modification-free carbon dots as turn-on fluorescence probe for detection of organophosphorus pesticides - Lin_2018_Food.Chem_245_1176
Author(s) : Lin B , Yan Y , Guo M , Cao Y , Yu Y , Zhang T , Huang Y , Wu D
Ref : Food Chem , 245 :1176 , 2018
Abstract : It is important to detect pesticides residues due to the concern over food safety. In this work, the burning ash of waste paper was used as carbon source to synthesize carbon dots (C-dots). The fluorescence of obtained C-dots could been turn off by Fe(3+) which was from Fe(2+) oxidized by H2O2, organophosphorus pesticides could effectively inhibit the production of H2O2 by destroying the acetylcholinesterase activity, so the fluorescence of C-dots hold turning on in the presence of organophosphorus pesticides. Based on above principle that the fluorescence intensity of C-dots was proportional to the pesticides concentration, take chlorpyrifos for example, a universal method for pesticides detection was established. The linear range was 0.01-1.0mug/mL with detection limit of 3ng/mL. The method was reliable and sensitive to actual samples. The imaging of chlorpyrifos on cabbages leaves indicated this method could be used for visualization detection of organophosphorus pesticides in vegetables.
ESTHER : Lin_2018_Food.Chem_245_1176
PubMedSearch : Lin_2018_Food.Chem_245_1176
PubMedID: 29287338

Title : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis - Qin_2018_Biomed.Chromatogr__e4320
Author(s) : Qin Y , Kang A , Zhou G , Wang H , Wei W , Cao Y , Chen Y , Wang J , Shi Y , Tang Y , Jiang J
Ref : Biomedical Chromatography , :e4320 , 2018
Abstract : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan (CPT-11) has long been proposed to be responsible for its anti-tumor activity and toxicity, like delayed-onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we choose rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describes an sensitive and versatile UHPLC-MS/MS method for simultaneously quantify CPT-11 and its metabolites, including SN-38 and SN-38G. Meanwhile, we have adopted the method to investigate the pharmacokinetic or metabolism behavior of CPT-11 in the above biological samples. Calibration curves for all bio-matrices showed desirable linearity (r(2) >0.99). The intra-day and inter-day precision (RSD, %) were within 15 % and the excellent accuracy (RE, %) was between 2.96% and 14.12%. In addition, the specificity, matrix effect and extraction recovery were all meet the requirements of biological sample analysis. We have successfully applied this method to investigating pharmacokinetic of irinotecan in different biological samples, which mediated by carboxylesterase and UDP-glucuronosyltransferases. And this method could be emplyed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.
ESTHER : Qin_2018_Biomed.Chromatogr__e4320
PubMedSearch : Qin_2018_Biomed.Chromatogr__e4320
PubMedID: 29920713

Title : Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE - Xiao_2016_Cell.Death.Dis_7_e2521
Author(s) : Xiao YT , Wang J , Lu W , Cao Y , Cai W
Ref : Cell Death Dis , 7 :e2521 , 2016
Abstract : Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-alpha. Further studies showed that miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-alpha production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.
ESTHER : Xiao_2016_Cell.Death.Dis_7_e2521
PubMedSearch : Xiao_2016_Cell.Death.Dis_7_e2521
PubMedID: 27977009

Title : Overexpression of CXCL3 can enhance the oncogenic potential of prostate cancer - Gui_2016_Int.Urol.Nephrol_48_701
Author(s) : Gui SL , Teng LC , Wang SQ , Liu S , Lin YL , Zhao XL , Liu L , Sui HY , Yang Y , Liang LC , Wang ML , Li XY , Cao Y , Li FY , Wang WQ
Ref : International Urology & Nephrology , 48 :701 , 2016
Abstract : PURPOSE: CXCL3 and its receptor CXCR2 were considered to play particularly important roles in the progression of malignancies. However, the investigations about CXCL3/CXCR2 axis in prostate cancer have been poorly involved. Herein we firstly reported our studies on the expression and biological roles of CXCL3 and CXCR2 in prostate cancer. METHODS: Expression levels of CXCL3 and CXCR2 in prostate cancer cell lines (PC-3, DU145 and LNCaP), immortalized prostate stromal cell line (WPMY-1) and immortalized prostate epithelial cell line (RWPE-1) were investigated by RT-PCR, ELISA and western blot, whereas expression levels of CXCL3 in a prostate tissue microarray were detected by immunohistochemistry. Cell counting kit-8 and transwell assays were, respectively, utilized to determine the effects of exogenous CXCL3 on the cell proliferation and migration. We further examined whether CXCL3 could regulate the expression of genes correlated with prostate tumorigenesis by RT- PCR. RESULTS: Elevated expression of CXCR2 was detected in DU145, LNCaP and RWPE-1. Moreover, high-level CXCL3 can be secreted by PC-3 and RWPE-1, and CXCL3 protein expression level in tissue microarray is concordant with prostate cancer metastasis. Exogenous CXCL3 does not contribute to proliferation, but has a significant effect on migration of prostate cancer cells and RWPE-1. Finally, our data showed that exogenous CXCL3 can regulate the expression of genes including ERK, TP73, NUMB, BAX and NDRG3. CONCLUSION: Our findings suggest that CXCL3 and its receptor CXCR2 are overexpressed in prostate cancer cells, prostate epithelial cells and prostate cancer tissues, which may play multiple roles in prostate cancer progression and metastasis.
ESTHER : Gui_2016_Int.Urol.Nephrol_48_701
PubMedSearch : Gui_2016_Int.Urol.Nephrol_48_701
PubMedID: 26837773

Title : Functional Characterization of a Novel Marine Microbial Esterase and its Utilization in the Enantioselective Preparation of (R)-Methyl 2-Chloropropionate - Cao_2016_Appl.Biochem.Biotechnol_180_210
Author(s) : Cao Y , Deng D , Sun A , Zhang Y , Hu Y
Ref : Appl Biochem Biotechnol , 180 :210 , 2016
Abstract : Chiral 2-chloropropanoic acids and their ester derivatives are crucial intermediates in the synthesis of many chemicals, especially herbicides. The enzymatic synthesis of chiral 2-chloropropanoic acids and their ester derivatives by esterases was not easily achieved, because the structural difference between the two enantiomers was too small to be recognized by esterases. Herein, we report the expression and functional characterization of one novel low temperature-resistant esterase EST12-7 identified from the genome of Pseudonocardia antitumoralis SCSIO 01299 isolated from the sediments of the South China Sea. Biocatalyst EST12-7 could hydrolyze racemic methyl 2-chloropropinate and generate optically pure (R)-methyl 2-chloropropinate with high enantiomeric excess (>99 %) and conversion (>49 %) after process optimization. Notably, the addition of different surfactants and using surfactants of different concentrations in the kinetic resolution catalyzed by EST12-7 could greatly affect the enantiomeric excess and conversion rate of product (R)-methyl 2-chloropropinate.
ESTHER : Cao_2016_Appl.Biochem.Biotechnol_180_210
PubMedSearch : Cao_2016_Appl.Biochem.Biotechnol_180_210
PubMedID: 27118550
Gene_locus related to this paper: 9pseu-a0a0p0s9g4

Title : Novel and selective acetylcholinesterase inhibitors for Tetranychus cinnabarinus (Acari: Tetranychidae) - Bu_2015_Insect.Biochem.Mol.Biol_66_129
Author(s) : Bu C , Peng B , Cao Y , Wang X , Chen Q , Li J , Shi G
Ref : Insect Biochemistry & Molecular Biology , 66 :129 , 2015
Abstract : The carmine spider mite, Tetranychus cinnabarinus (Acari: Tetranychidae), is an economically important and extremely polyphagous herbivorous pest, with the title of "resistance champion" among arthropods. Anticholinesterase insecticides such as organophosphate and carbamate account for more than one-third of global insecticide sales. The non-target toxicity and resistance problem of organophosphate and carbamate have become of growing concern, which may be due to the fact that they target the ubiquitous catalytic serine residue of acetylcholinesterase (AChE) in mammals, birds, and beneficial insects. In this study, the structural differences between T. cinnabarinus AChE and human AChE, at or near the catalytic pocket, were illustrated. From the SPECS chemical lead-compound database, 55 AChE inhibitor candidates were screened for high affinity for T. cinnabarinus AChE, but low affinity for human AChE, using the DOCK 6 and AutoDock Vina software. Three of the fifty-five candidates had inhibitory activity greater than that of the reversible AChE inhibitor eserine, with no observed inhibitory activities against human AChE. Two of the three had toxicity to T. cinnabarinus comparable to that of natural insecticidal pyrethrins. However, their potency is low compared with that of etoxazole, and further work is needed to optimize their potency. The selectivity of the three compounds over human and mite AChE may be due to their interaction with the mite-specific residues, as analyzed by Cyscore. The three compounds are potential lead compounds for development of novel acaricides against T. cinnabarinus with reduced toxicity to non-target species and a low propensity for resistance.
ESTHER : Bu_2015_Insect.Biochem.Mol.Biol_66_129
PubMedSearch : Bu_2015_Insect.Biochem.Mol.Biol_66_129
PubMedID: 26520174

Title : Cloning and Characterization of the Acetylcholinesterase1 Gene of Tetranychus cinnabarinus (Acari: Tetranychidae) - Bu_2015_J.Econ.Entomol_108_769
Author(s) : Bu CY , Feng XJ , Wang XQ , Cao Y , Wang YN , Chen Q , Gao P , Peng B , Li JL , Han JY , Shi GL
Ref : J Econ Entomol , 108 :769 , 2015
Abstract : The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is a major agriculture pest. It can be found worldwide, has an extensive host plant range, and has shown resistance to pesticides. Organophosphate and carbamate insecticides account for more than one-third of all insecticide sales. Insecticide resistance and the toxicity of organophosphate and carbamate insecticides to mammals have become a growing concern. Acetylcholinesterase (AChE) is the major targeted enzyme of organophosphate and carbamate insecticides. In this study, we fully cloned, sequenced and characterized the ace1 gene of T. cinnabarinus, and identified the differences between T. cinnabarinus AChE1, Tetranychus urticae Koch AChE1, and human AChE1. Resistance-associated target-site mutations were displayed by comparing the AChE amino acid sequences and their AChE three-dimensional (3D) structures of the insecticide-susceptible strains of T. cinnabarinus and T. urticae to that of a T. urticae-resistant strain. We identified variation in the active-site gorge and the sites interacting with gorge residues by comparing AChE1 3D structures of T. cinnabarinus, T. urticae, and humans, though their 3D structures were similar. Furthermore, the expression profile of T. cinnabarinus AChE, at the different developmental stages, was determined by quantitative real-time polymerase chain reaction; the transcript levels of AChE were higher in the larvae stage than in other stages. The changes in AChE expression between different developmental stages may be related to their growth habits and metabolism characteristics. This study may offer new insights into the problems of insecticide resistance and insecticide toxicity of nontarget species.
ESTHER : Bu_2015_J.Econ.Entomol_108_769
PubMedSearch : Bu_2015_J.Econ.Entomol_108_769
PubMedID: 26470189
Gene_locus related to this paper: 9acar-m9t420

Title : Acetylcholinesterase biosensor for carbaryl detection based on interdigitated array microelectrodes - Gong_2014_Bioprocess.Biosyst.Eng_37_1929
Author(s) : Gong Z , Guo Y , Sun X , Cao Y , Wang X
Ref : Bioprocess Biosyst Eng , 37 :1929 , 2014
Abstract : In this study, an acetylcholinesterase (AChE) biosensor with superior accuracy and sensitivity was successfully developed based on interdigitated array microelectrodes (IAMs). IAMs have a series of parallel microband electrodes with alternating microbands connected together. Chitosan was used as the enzyme immobilization material, and AChE was used as the model enzyme for carbaryl detection to fabricate AChE biosensor. Electrochemical impedance spectroscopy was used in conjunction with the fabricated biosensor to detect pesticide residues. Based on the inhibition of pesticides on the AChE activity, using carbaryl as model compounds, the biosensor exhibited a wide range, low detection limit, and high stability. Moreover, the biosensor can also be used as a new promising tool for pesticide residue analysis.
ESTHER : Gong_2014_Bioprocess.Biosyst.Eng_37_1929
PubMedSearch : Gong_2014_Bioprocess.Biosyst.Eng_37_1929
PubMedID: 24770986

Title : Draft Genome Sequence of the Human-Pathogenic Bacterium Vibrio alginolyticus E0666 - Cao_2013_Genome.Announc_1_e00686
Author(s) : Cao Y , Liu XF , Zhang HL , Chen YJ , Hu CJ
Ref : Genome Announc , 1 : e00686 , 2013
Abstract : Vibrio alginolyticus is a Gram-negative halophilic bacterium with worldwide distribution. In this work, we report the draft genome sequence of a V. alginolyticus strain (E0666) isolated from Epinephelus coioides ascites in the Shantou city of Guangdong Province, China.
ESTHER : Cao_2013_Genome.Announc_1_e00686
PubMedSearch : Cao_2013_Genome.Announc_1_e00686
PubMedID: 23990586
Gene_locus related to this paper: vibse-d0m6m2

Title : Enzymatic synthesis of extremely pure triacylglycerols enriched in conjugated linoleic acids - Cao_2013_Molecules_18_9704
Author(s) : Cao Y , Wang W , Xu Y , Yang B , Wang Y
Ref : Molecules , 18 :9704 , 2013
Abstract : This work was objectively targeted to synthesize extremely pure triacylglycerols (TAG) enriched in conjugated linoleic acids (CLAs) for medical and dietetic purposes. Extremely pure CLA-enriched TAG was successfully synthesized by using the multi-step process: TAG was primarily synthesized by lipase-catalyzed esterification of CLA and glycerol and then the lower glycerides [monoacylglycerol (MAG) and diacylglycerol (DAG)] in the esterification mixtures was hydrolyzed to free fatty acids (FFAs) by a mono- and di-acylglycerol lipase (lipase SMG1), finally, the FFAs were further separated from TAG by low temperature (150 degreesC) molecular distillation. The operation parameters for the lipase SMG1-catalyzed hydrolysis were optimized using response surface methodology based on the central composite rotatable design (CCRD). The operation parameters included water content, pH and reaction temperature and all of these three parameters showed significant effects on the hydrolysis of lower glycerides. The optimal conditions were obtained with a water content of 66.4% (w/w, with respect to oil mass), pH at 5.7 and 1 h of reaction time at 19.6 degreesC. Under these conditions, the content of lower glycerides in the reaction mixture decreased from 45.2% to 0.3% and the purity of CLA-enriched TAG reached 99.7%. Further purification of TAG was accomplished by molecular distillation and the final CLA-enriched TAG product yielded 99.8% of TAG. These extremely pure CLA-enriched TAG would be used for in vivo studies in animals and humans in order to get specic information concerning CLA metabolism.
ESTHER : Cao_2013_Molecules_18_9704
PubMedSearch : Cao_2013_Molecules_18_9704
PubMedID: 23945644

Title : Genome Sequencing of Ralstonia solanacearum FQY_4, Isolated from a Bacterial Wilt Nursery Used for Breeding Crop Resistance - Cao_2013_Genome.Announc_1_e00125
Author(s) : Cao Y , Tian B , Liu Y , Cai L , Wang H , Lu N , Wang M , Shang S , Luo Z , Shi J
Ref : Genome Announc , 1 : , 2013
Abstract : Ralstonia solanacearum strain FQY_4 was isolated from a bacterial wilt nursery, which is used for breeding crops for Ralstonia resistance in China. Here, we report the complete genome sequence of FQY_4 and its comparison with other published R. solanacearum genomes, especially with the strains GMI1000 and Y45 in the same group.
ESTHER : Cao_2013_Genome.Announc_1_e00125
PubMedSearch : Cao_2013_Genome.Announc_1_e00125
PubMedID: 23661471
Gene_locus related to this paper: ralso-PCAD

Title : Synthesis of structured lipids by lipase-catalyzed interesterification of triacetin with camellia oil methyl esters and preliminary evaluation of their plasma lipid-lowering effect in mice - Cao_2013_Molecules_18_3733
Author(s) : Cao Y , Qi S , Zhang Y , Wang X , Yang B , Wang Y
Ref : Molecules , 18 :3733 , 2013
Abstract : Structured lipids (SLCTs triacylglycerols with short- and long-chain acyl residues) were synthesized by interesterification of triacetin and fatty acid methyl esters (FAMEs) from camellia oil, followed by molecular distillation for purification. Different commercial immobilized lipases (Lipozyme RM IM and Novozyme 435), the substrate molar ratios of FAMEs to triacetin, the reaction temperatures and the lipase amounts were studied for their efficiency in producing SLCTs. Results showed that Novozyme 435 was more suitable for this reaction system. Moreover, the optimal reaction conditions for the highest conversion of FAMEs and the highest LLS-TAGs (triacylglycerols with one short- and two long-chain acyl residues) yields were achieved at a molar ratio of FAMEs to triacetin of 3:1, 50 degreeC of reaction temperature and a lipase amount of 4% (w/v). Scale-up was conducted based on the optimized reaction conditions. Results showed that after 24 h of reaction , the conversion rate of FAMEs was 82.4% and the rate of disubstituted triacetin was 52.4 mol%. The final product yield rate was 94.6%. The effects of the synthesized SLCTs on the plasma lipid level of fasting mice were also studied. The SLCTs could effectively lessen the total triacylglycerol levels in plasma compared to the triacylglycerol group in fasting NIH mice. It suggested that this type of structured lipid might be beneficial for human health, especially for the prevention of obesity.
ESTHER : Cao_2013_Molecules_18_3733
PubMedSearch : Cao_2013_Molecules_18_3733
PubMedID: 23529033

Title : Changing the specificity of alpha-amino acid ester hydrolase toward para-hydroxyl cephalosporins synthesis by site-directed saturation mutagenesis - Ye_2012_Biotechnol.Lett_34_1719
Author(s) : Ye LJ , Wang L , Pan Y , Cao Y
Ref : Biotechnol Lett , 34 :1719 , 2012
Abstract : alpha-Amino acid ester hydrolases AEHs catalyze the synthesis of beta-lactam antibiotics containing an alpha-amino group with decreased activity toward antibiotics with a p-hydroxyl group The AEH gene from Xanthomonas rubrillineans was cloned and expressed in Escherichia coli Based on the crystal structure of the AEH and cefprozil complex 13 residues not directly involved in substrate recognition were mutated individually The resulting 1,300 mutants were screened for activity using cefprozil as a model product based on spectrophotometric assay in a 96-well format Mutants with improved cefprozil synthetic activity revealed the particular importance of positions 87 131 and 175 for specificity The mutant V131S with the highest initial rates of synthesis toward three p-hydroxyl cephalosporins showed 23 17 and 64 increase in maximum product accumulation of cefadroxil cefprozil and cefatrizine respectively.
ESTHER : Ye_2012_Biotechnol.Lett_34_1719
PubMedSearch : Ye_2012_Biotechnol.Lett_34_1719
PubMedID: 22648687

Title : Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils - Min_2012_Neurosci.Lett_510_29
Author(s) : Min D , Mao X , Wu K , Cao Y , Guo F , Zhu S , Xie N , Wang L , Chen T , Shaw C , Cai J
Ref : Neuroscience Letters , 510 :29 , 2012
Abstract : Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.
ESTHER : Min_2012_Neurosci.Lett_510_29
PubMedSearch : Min_2012_Neurosci.Lett_510_29
PubMedID: 22240104

Title : Two plate-based colorimetric assays for screening alpha-amino acid ester hydrolase with high synthesis\/hydrolysis ratio - Wang_2012_Enzyme.Microb.Technol_51_107
Author(s) : Wang L , Ye LJ , Pan Y , Cao Y
Ref : Enzyme Microb Technol , 51 :107 , 2012
Abstract : alpha-Amino acid ester hydrolases (AEHs) are enzymes of interest to the semi-synthesis of beta-lactam antibiotics with alpha-amino, such as cephalexin and cefaclor. An undesired side reaction, the hydrolysis of alpha-amino acid ester, had hindered applications in antibiotics synthesis. Although the enzymes' S/H ratio can be increased by protein engineering, such approaches require a suitable screening assay. Such a screening assay has not yet been described for AEHs. In this paper, we report a 96-well plate format screening procedure for AEHs based on two spectrophotometric assays. To reduce the hydrolysis reaction while maintaining synthesis activity, and to evaluate the effectiveness of the screening strategy, we introduced random mutations in part of the aeh gene from Xanthomonas rubrillineans by error-prone PCR. By a parallel plate-based screening strategy, three mutants with improved S/H ratio, R87L, T132N and N219I, were obtained.
ESTHER : Wang_2012_Enzyme.Microb.Technol_51_107
PubMedSearch : Wang_2012_Enzyme.Microb.Technol_51_107
PubMedID: 22664195

Title : Identification and characterization of (1R,6R)-2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate synthase in the menaquinone biosynthesis of Escherichia coli - Jiang_2008_Biochemistry_47_3426
Author(s) : Jiang M , Chen X , Guo ZF , Cao Y , Chen M , Guo Z
Ref : Biochemistry , 47 :3426 , 2008
Abstract : Menaquinone is a lipid-soluble molecule that plays an essential role as an electron carrier in the respiratory chain of many bacteria. We have previously shown that its biosynthesis in Escherichia coli involves a new intermediate, 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC), and requires an additional enzyme to convert this intermediate into (1 R,6 R)-2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC). Here, we report the identification and characterization of MenH (or YfbB), an enzyme previously proposed to catalyze a late step in menaquinone biosynthesis, as the SHCHC synthase. The synthase catalyzes a proton abstraction reaction that results in 2,5-elimination of pyruvate from SEPHCHC and the formation of SHCHC. It is an efficient enzyme ( k cat/ K M = 2.0 x 10 (7) M (-1) s (-1)) that provides a smaller transition-state stabilization than other enzymes catalyzing proton abstraction from carbon acids. Despite its lack of the proposed thioesterase activity, the SHCHC synthase is homologous to the well-characterized C-C bond hydrolase MhpC. The crystallographic structure of the Vibrio cholerae MenH protein closely resembles that of MhpC and contains a Ser-His-Asp triad typical of serine proteases. Interestingly, this triad is conserved in all MenH proteins and is essential for the SHCHC synthase activity. Mutational analysis found that the catalytic efficiency of the E. coli protein is reduced by 1.4 x 10 (3), 2.1 x 10 (5), and 9.3 x 10 (3) folds when alanine replaces serine, histidine, and aspartate of the triad, respectively. These results show that the SHCHC synthase is closely related to alpha/beta hydrolases but catalyzes a reaction mechanistically distinct from all known hydrolase reactions.
ESTHER : Jiang_2008_Biochemistry_47_3426
PubMedSearch : Jiang_2008_Biochemistry_47_3426
PubMedID: 18284213
Gene_locus related to this paper: ecoli-YFBB

Title : One-step purification of a fusion protein of glucagon-like peptide-1 and human serum albumin expressed in pichia pastoris by an immunomagnetic separation technique - Chen_2007_Biosci.Biotechnol.Biochem_71_2655
Author(s) : Chen J , Bai G , Cao Y , Gao Z , Zhang Q , Zhu Y , Yang W
Ref : Biosci Biotechnol Biochem , 71 :2655 , 2007
Abstract : Glucagon-like peptide-1 (GLP-1) has great therapeutic potential to treat diabetes type 2, mainly due to its unique glucose-dependent stimulation of insulin secretion profiles, but its clinical application is limited by its short half-life in vivo, which resultes from degradation by dipeptidyl peptidase IV and/or renal clearance. Developing long-acting GLP-1 analogs is therefore an important step toward using them therapeutically. In this study, the GLP-1/human serum albumin (HSA) fusion protein gene was cloned into the secretor type expression vector pPIC9K and subsequently expressed in Pichia pastoris. The expression quantity reached 58.5 mg/l in small-scale incubation. After optimization and characterization, the GLP-1/HSA fusion protein was successfully purified from the supernatant of the broth using immunomagnetic cellulose microspheres. HPLC showed that the purified GLP-1/HSA had an overall purity of 93.9%, and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) confirmed the fusion protein exhibited the expected molecular mass of 70 kDa. Furthermore, that analysis of in vivo activity indicated that GLP-1/HSA reduced the blood glucose level after intraperitoneal administration to Chinese Kunming mice in a dose-dependent manner, and the effects held significantly 4 h after administration. Overall, this study illustrates the development of a long-acting GLP-1/HSA fusion protein expressed in Pichia pastoris.
ESTHER : Chen_2007_Biosci.Biotechnol.Biochem_71_2655
PubMedSearch : Chen_2007_Biosci.Biotechnol.Biochem_71_2655
PubMedID: 17986790

Title : Identifying glucagon-like peptide-1 mimetics using a novel functional reporter gene high-throughput screening assay - Chen_2007_Peptides_28_928
Author(s) : Chen J , Bai G , Yang Y , Geng P , Cao Y , Zhu Y
Ref : Peptides , 28 :928 , 2007
Abstract : Glucagon-like peptide-1 (GLP-1) stimulates insulin and inhibits glucagon secretion and therefore could potentially be used to treat diabetes type II. However, its therapeutic use is limited by its short half-life in vivo, due mainly to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV). Developing GLP-1 analogs with greater bioactivity is therefore an important step toward using them therapeutically. Accordingly, we aimed to identify GLP-1 mimetic peptides by creating a high-throughput screening (HTS) assay of a phage displayed (PhD) peptide library. This assay was functionally based using the GLP-1 receptor (GLP-1R) gene. Rat GLP-1R cDNA was transfected into CHO/enhanced green fluorescent protein (EGFP) cells by lipofection. The resulting stable, recombinant cell line functionally expressed the GLP-1R and a cAMP-responsive EGFP reporter gene, to monitor receptor activation, and was used to screen a PhD dodecapeptide library. After four rounds of selection, 10 positive clones were selected based on functional evaluation and sequenced. Three sequences were obtained, corresponding to three different domains of GLP-1 (Group 1: 22-34; Group 2: 18-29; and Group 3: 6-17). The Group 3 peptide had the highest bioactivity, was synthesized, and designated KS-12. Importantly, KS-12 activated GLP-1R in vitro and reduced blood glucose levels in a dose-dependent manner when administered to Chinese Kunming mice. Although KS-12 was not as effective as GLP-1, it was significantly resistant to DPP-IV both in vitro and in vivo. Thus, this study provides a novel way to screen DPP-IV resistant agonist peptides of GLP-1 from a PhD peptide library using the functional reporter gene HTS assay.
ESTHER : Chen_2007_Peptides_28_928
PubMedSearch : Chen_2007_Peptides_28_928
PubMedID: 17267075

Title : [Separation and identification of down-regulated proteomics of intestinal mucosa in scalded rats] - Wang_2003_Zhonghua.Shao.Shang.Za.Zhi_19_275
Author(s) : Wang XJ , Sun YH , Ding QX , Feng Z , Cao Y
Ref : Zhonghua Shao Shang Za Zhi , 19 :275 , 2003
Abstract : OBJECTIVE: To explore the pathogenesis of postburn intestinal mucosal injury in scalded rats. METHODS: The rats inflicted with full thickness burn were employed as the model. The two-dimensional electrophoresis (2-DE) was employed to identify the down-regulating proteins from the differential proteins in scalded rats. Spot detection and matching were performed with Image Master 2D Elite. Mass spectrometry was performed on Bruker BIFLEX III TOF. RESULTS: There are 34 points of proteins in intestinal mucosa in scalded rats which were down-regulated at 6 and 12 postburn hours. Among them 22 proteins were employed for the identification and analysis. Mitochondrial aconitase, alpha-propionyl -CoA carboxylase heavy chain A of F1-ATPase in rat liver, Troponin short-chain of hydroxyacyl-coenzyme A dehydrogenase, alpha-subunit of P-electronic transferring flavoprotein (ETF) were down-regulating proteins correlated with mitochondria in intestinal mucosa in severely scalded rats. Triosephosphate isomerase 1 and cytosolic epoxide hydrolase were down-regulating proteins participated in metabolism of scalded rats. Fibromodulin, dynein-like protein, Troponin-2 and myosin light chain 3 alkali (MLC) were down-regulating proteins correlated with cellular skeletal protein. Glucocorticoid-inducible protein, nuclear factor1-B2, BRCA1, transcriptive factor EB (estradiol benzoate), beta2 subunit of G-protein, N-methyl-D-aspartate receptor1 (NMDAR) were down-regulating proteins participated in postburn regulation of intestinal mucosa in scalded rats. T-cell receptor-V-delta 6 and Ig heavy chain V region protein 1 were down-regulating proteins correlated with the immunomodulation of intestinal mucosa in scalded rats. CONCLUSION: The down-regulating proteins of intestinal mucosa in scalded rats exhibited close relationship with mitochondria.
ESTHER : Wang_2003_Zhonghua.Shao.Shang.Za.Zhi_19_275
PubMedSearch : Wang_2003_Zhonghua.Shao.Shang.Za.Zhi_19_275
PubMedID: 14687529

Title : C3,4 transfer for neurotization of C5,6 nerve roots in brachial plexus injury in a rabbit model - Cao_2003_J.Reconstr.Microsurg_19_265
Author(s) : Cao X , Li J , Cao Y , Cai J
Ref : J Reconstr Microsurg , 19 :265 , 2003
Abstract : To evaluate the root neurotization properties of extraplexal donor nerves, an avulsion injury model of brachial plexus was created and repaired by C 3,4 nerve-root transfers in the rabbit. Eighteen rabbits were divided into three groups. In Group 1 (n = 6), the right C 5,6 nerve roots were avulsed and bridged by a nerve graft taken from the femoral nerve, with C 3,4 as C 3 to C 5 and C 4 to C 6. In Group 2 (n = 6), the right C 5,6 nerve roots were cut and directly sutured end-to-end. Group 3 (n = 6) was a negative group, in which C 5,6 nerve roots were avulsed without repair. All three groups were positively controlled by the contralateral side. Postoperative behavior observation and anatomic, electrophysiologic studies were conducted 4 months later for comparison among groups. Axon existence was observed by acetylcholinesterase staining. Results showed that active motion was not found in all three groups by the end of the study. Extraplexal nerve transfer indeed was able to re-neurotize the avulsed nerve roots down to their target organ, but C 3,4 nerve transfer was weaker than direct end-to-end suture, in terms of neurotization ability. The authors conclude that "root or trunk repair" for avulsion injury of the brachial plexus is possible, provided that the donor nerve has enough fibers and the nerve regeneration ability is increased by modern moleculobiologic techniques.
ESTHER : Cao_2003_J.Reconstr.Microsurg_19_265
PubMedSearch : Cao_2003_J.Reconstr.Microsurg_19_265
PubMedID: 12858250

Title : Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders - Cao_2003_J.Med.Chem_46_4273
Author(s) : Cao Y , Zhang M , Wu C , Lee S , Wroblewski ME , Whipple T , Nagy PI , Takacs-Novak K , Balazs A , Toros S , Messer WS, Jr.
Ref : Journal of Medicinal Chemistry , 46 :4273 , 2003
Abstract : Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
ESTHER : Cao_2003_J.Med.Chem_46_4273
PubMedSearch : Cao_2003_J.Med.Chem_46_4273
PubMedID: 13678406

Title : Poster: Synthesis and biological evaluation of bivalent xanomeline analogs as M1 muscarinic agonists -
Author(s) : Messer WS, Jr. , Rajeswaran WG , Cao Y , Huang XP , Wroblewski ME , Nagy PI
Ref : Life Sciences , 68 :2625 , 2001

Title : Poster: Synthesis and biological evaluation of Bis[3-(3-alkoxy-1,2,sthiadiazole-4-yl)-1,2,s,6-tetrahydro-pyrid-1-yl] alkane dihydrochlorides as muscarinic agonists -
Author(s) : Cao Y , Wroblewski ME , Nagy PI , Messer WS, Jr.
Ref : Life Sciences , 68 :2625 , 2001

Title : [Role of endogenous cholinergic nerve in esophageal dysmotility with reflux esophagitis] - Cao_2001_Zhonghua.Nei.Ke.Za.Zhi_40_670
Author(s) : Cao Y , Xie P , Xing Y
Ref : Zhonghua Nei Ke Za Zhi , 40 :670 , 2001
Abstract : OBJECTIVE To study the role of endogenous cholinergic nerve in esophageal dysmotility with reflux esophagitis in a feline model METHODS In 16 healthy cats under ketamine anesthesia 20 mg/kg the abdominal parts of lower esophageal sphincter were cut open to establish the animal model for reflux esophagitis esophageal motility was measured respectively preoperation and post-esophagitis The activities of choline acetyltransferase CHAT and acetylcholinesterase(ACHE in medial and distal esophageal body muscle was measured respectively with spectrophotometry and compared to the normal cats(n 8 RESULTS Reflux esophagitis can make distal esophageal peristaltic amplitude decrease the distal esophageal peristaltic amplitude of cats with reflux esophagitis above LES 1 cm 22.65 16.53 mm Hg above LES 3 cm:(39.94 14.78 mm Hg P 0.0001 was significantly lower than that of normal cats above LES 1 cm 63.71 21.34 mm Hg above LES 3 cm 73.65 23.42 mm Hg and the conducting velocity of distal esophagus was slower than that of normal cats 1.04 0.36 cm/s vs 1.39 0.46 cm/s P 0.05 In the esophagus of reflux esophagitis group CHAT activity was lower in the model especially in the distal part 81.01 22.03 U/g vs 230.13 30.10 U/g P 0.0001 and ACHE activity remains unchanged CONCLUSION CHAT activity and pressure level were lower in the distal esophagus with reflux esophagitis compared to the normal cats This study supported that reflux esophagitis can results in dysmotility of the distal esophagus and the abnormality of endogenous cholinergic innervation is one of the important mechanisms as far as the disorder of esophageal movement in reflux esophagitis
ESTHER : Cao_2001_Zhonghua.Nei.Ke.Za.Zhi_40_670
PubMedSearch : Cao_2001_Zhonghua.Nei.Ke.Za.Zhi_40_670
PubMedID: 11769720

Title : Genome sequence of the plant pathogen and biotechnology agent Agrobacterium tumefaciens C58 - Goodner_2001_Science_294_2323
Author(s) : Goodner B , Hinkle G , Gattung S , Miller N , Blanchard M , Qurollo B , Goldman BS , Cao Y , Askenazi M , Halling C , Mullin L , Houmiel K , Gordon J , Vaudin M , Iartchouk O , Epp A , Liu F , Wollam C , Allinger M , Doughty D , Scott C , Lappas C , Markelz B , Flanagan C , Crowell C , Gurson J , Lomo C , Sear C , Strub G , Cielo C , Slater S
Ref : Science , 294 :2323 , 2001
Abstract : Agrobacterium tumefaciens is a plant pathogen capable of transferring a defined segment of DNA to a host plant, generating a gall tumor. Replacing the transferred tumor-inducing genes with exogenous DNA allows the introduction of any desired gene into the plant. Thus, A. tumefaciens has been critical for the development of modern plant genetics and agricultural biotechnology. Here we describe the genome of A. tumefaciens strain C58, which has an unusual structure consisting of one circular and one linear chromosome. We discuss genome architecture and evolution and additional genes potentially involved in virulence and metabolic parasitism of host plants.
ESTHER : Goodner_2001_Science_294_2323
PubMedSearch : Goodner_2001_Science_294_2323
PubMedID: 11743194
Gene_locus related to this paper: agrt5-a9cf94 , agrt5-a9cfa9 , agrt5-a9cfs8 , agrt5-a9cfu7 , agrt5-a9cie7 , agrt5-a9cj11 , agrt5-a9cjp2 , agrt5-a9cki2 , agrt5-a9ckr2 , agrt5-a9ckt2 , agrt5-a9cle4 , agrt5-a9clq8 , agrt5-a9clq9 , agrt5-q7cx24 , agrt5-q7d1j0 , agrt5-q7d1j3 , agrt5-q7d3m5 , agrt5-q7d3t6 , agrt5-y5261 , agrtu-ACVB , agrtu-ATTS , agrtu-ATU0253 , agrtu-ATU0403 , agrtu-ATU0841 , agrtu-ATU1045 , agrtu-ATU1102 , agrtu-ATU1572 , agrtu-ATU1617 , agrtu-ATU1826 , agrtu-ATU1842 , agrtu-ATU2061 , agrtu-ATU2126 , agrtu-ATU2171 , agrtu-ATU2409 , agrtu-ATU2452 , agrtu-ATU2481 , agrtu-ATU2497 , agrtu-ATU2576 , agrtu-ATU3428 , agrtu-ATU3651 , agrtu-ATU3652 , agrtu-ATU4238 , agrtu-ATU5190 , agrtu-ATU5193 , agrtu-ATU5275 , agrtu-ATU5296 , agrtu-ATU5348 , agrtu-ATU5389 , agrtu-ATU5446 , agrtu-ATU5495 , agrtu-CPO , agrtu-DHAA , agrtu-DLHH , agrtu-EPHA , agrtu-GRST , agrtu-PCA , agrtu-PCAD , agrtu-PHBC , agrtu-PTRB , agrt5-a9cji8

Title : Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists - Rajeswaran_2001_J.Med.Chem_44_4563
Author(s) : Rajeswaran WG , Cao Y , Huang XP , Wroblewski ME , Colclough T , Lee S , Liu F , Nagy PI , Ellis J , Levine BA , Nocka KH , Messer WS, Jr.
Ref : Journal of Medicinal Chemistry , 44 :4563 , 2001
Abstract : Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.
ESTHER : Rajeswaran_2001_J.Med.Chem_44_4563
PubMedSearch : Rajeswaran_2001_J.Med.Chem_44_4563
PubMedID: 11741475

Title : Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors - Messer_2000_Pharm.Acta.Helv_74_135
Author(s) : Messer WS, Jr. , Rajeswaran WG , Cao Y , Zhang HJ , el-Assadi AA , Dockery C , Liske J , O'Brien J , Williams FE , Huang XP , Wroblewski ME , Nagy PI , Peseckis SM
Ref : Pharm Acta Helv , 74 :135 , 2000
Abstract : Cholinergic neurons degenerate in Alzheimer's disease, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M1 muscarinic agonists. 5-(3-Ethyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102) stimulates M1 muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230-1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonist to M1 receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735-745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M1 receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129-1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M1 receptor affinity, selectivity and activity.
ESTHER : Messer_2000_Pharm.Acta.Helv_74_135
PubMedSearch : Messer_2000_Pharm.Acta.Helv_74_135
PubMedID: 10812950

Title : Poster: Activity of selective muscarinic agonists at human M1 receptors expressed at varying levels in A9 L cells -
Author(s) : Cao Y , Wise DD , Zhang H , Huang XP , Messer WS, Jr.
Ref : Life Sciences , 64 :571 , 1999