Dong H

References (46)

Title : Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression - Hao_2024_Eur.J.Med.Chem_268_116285
Author(s) : Hao Q , Shi J , Zhang Z , Yang G , Zhi Y , Wang K , Ma D , Fu S , Dong H , Zhi Z , Zhang W , Li T , Wang J
Ref : Eur Journal of Medicinal Chemistry , 268 :116285 , 2024
Abstract : Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC(50) = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.
ESTHER : Hao_2024_Eur.J.Med.Chem_268_116285
PubMedSearch : Hao_2024_Eur.J.Med.Chem_268_116285
PubMedID: 38428273

Title : Iontronic Photoelectrochemical Biorecognition Probing - Dong_2024_ACS.Sens__
Author(s) : Dong H , Wang HY , Xu YT , Zhang X , Chen HY , Xu JJ , Zhao WW
Ref : ACS Sens , : , 2024
Abstract : Herein, the first iontronic photoelectrochemical (PEC) biorecognition probing is devised by rational engineering of a dual-functional bioconjugate, i.e., a light-sensitive intercalated structural DNA, as a smart gating module confined within a nanotip, which could respond to both the incident light and biotargets of interest. Light stimulation of the bioconjugate could intensify the negative charge at the nano-orifice to sustain enhanced ionic current. The presence of proteins (e.g., acetylcholinesterase, AChE) or nucleic acids (e.g., microRNA (miR)-10b) could lead to bioconjugate release with altered ionic signaling. The practical applicability of the methodology is confirmed by AChE detection in human serum and miR-10b detection in single cells.
ESTHER : Dong_2024_ACS.Sens__
PubMedSearch : Dong_2024_ACS.Sens__
PubMedID: 38258286

Title : Dual-Mode Ratiometric Electrochemical and Turn-On Fluorescent Detection of Butyrylcholinesterase Utilizing a Single Probe for the Diagnosis of Alzheimer's Disease - Dong_2023_Anal.Chem_95_8340
Author(s) : Dong H , Zhao L , Wang T , Chen Y , Hao W , Zhang Z , Hao Y , Zhang C , Wei X , Zhang Y , Zhou Y , Xu M
Ref : Analytical Chemistry , 95 :8340 , 2023
Abstract : Biomarkers detection in blood with high accuracy is crucial for the diagnosis and treatment of many diseases. In this study, the proof-of-concept fabrication of a dual-mode sensor based on a single probe (Re-BChE) using a dual-signaling electrochemical ratiometric strategy and a "turn-on" fluorescent method is presented. The probe Re-BChE was synthesized in a single step and demonstrated dual mode response toward butyrylcholinesterase (BChE), a promising biomarker of Alzheimer's disease (AD). Due to the specific hydrolysis reaction, the probe Re-BChE demonstrated a turn-on current response for BChE at -0.28 V, followed by a turn-off current response at -0.18 V, while the fluorescence spectrum demonstrated a turn-on response with an emission wavelength of 600 nm. The developed ratiometric electrochemical sensor and fluorescence detection demonstrated high sensitivity with BChE concentrations with a low detection limit of 0.08 microg mL(-1) and 0.05 microg mL(-1), respectively. Importantly, the dual-mode sensor presents the following advantages: (1) dual-mode readout can correct the impact of systematic or background error, thereby achieving more accurate results; (2) the responses of dual-mode readout originate from two distinct mechanisms and relatively independent signal transduction, in which there is no interference between two signaling routes. Additionally, compared with the reported single-signal electrochemical assays for BChE, both redox potential signals were detected in the absence of biological interference within a negative potential window. Furthermore, it was discovered that the outcomes of direct dual-mode electrochemical and fluorescence quantifications of the level of BChE in serum were in agreement with those obtained from the use of commercially available assay kits for BChE sensing. This method has the potential to serve as a useful point-of-care tool for the early detection of AD.
ESTHER : Dong_2023_Anal.Chem_95_8340
PubMedSearch : Dong_2023_Anal.Chem_95_8340
PubMedID: 37192372

Title : SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice - Xiang_2022_Cell.Death.Dis_13_638
Author(s) : Xiang L , Wu Q , Sun H , Miao X , Lv Z , Liu H , Chen L , Gu Y , Chen J , Zhou S , Jiang H , Du S , Zhou Y , Dong H , Fan Y , Miao S , Lu Q , Chang L , Wang H , Lu Y , Xu X , Wang W , Huang Z
Ref : Cell Death Dis , 13 :638 , 2022
Abstract : Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1(PV)-CKO) mice. SARM1(PV)-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1(PV)-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1(PV)-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1(PV)-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.
ESTHER : Xiang_2022_Cell.Death.Dis_13_638
PubMedSearch : Xiang_2022_Cell.Death.Dis_13_638
PubMedID: 35869039

Title : Cirrhosinones A-H, 24-hydroxy cevanine-type alkaloids from Fritillariacirrhosa - Dong_2022_Phytochemistry_197_113129
Author(s) : Dong H , Zhang Y , Wai Ming T , Wang S , Li J , Fu S , Zhang Q , Zeng K , Tu P , Liang H
Ref : Phytochemistry , 197 :113129 , 2022
Abstract : Eight undescribed isosteroidal alkaloids cirrhosinones A-H (1-8), along with six known isosteroidal alkaloids (9-14), were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were determined by HRESIMS and 2D NMR analysis, and their absolute configurations were established by X-ray analysis. Compounds 1-8 possessed a typical cevanine-type alkaloid skeleton with a hydroxyl group rarely substituted at C-24 and compounds 4-8 possessed rare 7alpha or 7beta-hydroxyl groups. This was the first report of both C-7 and C-24 hydroxyl groups substituted cevanine-type alkaloids. In addition, an approach for distinguishing D/E cis and trans conformations of cevanine-type alkaloids by (1)H NMR data was developed. Moreover, the correlations between the relative configurations of 3-OH, 7-OH, 22-C, 24-OH, and 25-Me and the (1)H NMR and (13)C NMR data were also summarized. Compounds 1-9 exhibited moderate NO inhibitory activities in LPS-stimulated BV-2 cells at the concentration of 40 microM. The acetylcholinesterase inhibitory activities of compounds 1-7 and 9-10 were also evaluated and none of them showed acetylcholinesterase inhibitory activities at the concentrations of 20-80 microM.
ESTHER : Dong_2022_Phytochemistry_197_113129
PubMedSearch : Dong_2022_Phytochemistry_197_113129
PubMedID: 35176308

Title : Tissue-specific accumulation, depuration, and effects of perfluorooctanoic acid on fish: Influences of aqueous pH and sex - Dong_2022_Sci.Total.Environ__160567
Author(s) : Dong H , Lu G , Wang X , Zhang P , Yang H , Yan Z , Liu J , Jiang R
Ref : Sci Total Environ , :160567 , 2022
Abstract : Perfluorooctanoic acid (PFOA) is widely distributed in nature, particularly in aquatic environments. Its bioaccumulation and toxicity in aquatic organisms can be affected by both the chemical status of PFOA in water and the physiology of the organism. However, research on the patterns of these effects is scarce. In this study, we investigated the influence of aqueous pH (pH 6, acidic; pH 7.5, neutral; pH 9, basic) and fish sex on PFOA uptake, clearance, and biochemical effects in crucian carp (C. auratus) using flow-through exposure. In the 17-d kinetic experiment, PFOA bioaccumulation adhered to a uniform first-order model in which PFOA uptake rates from water to blood and liver in acidic conditions were faster than those in other conditions, indicating possible acidic pH influence on PFOA uptake. PFOA clearance rates in these compartments of males were slower than in females, which was attributed to the notably stronger expression of Oat2 (organic anion transporter 2, responsible for reabsorption) in the kidneys of males. Similar responses were observed for peroxisome proliferation-related biomarkers at different pH levels and in different sexes. These biochemical responses were driven by the internal concentrations of PFOA. The inhibition acetylcholinesterase activity in the fish brain was closely linked to changes in P-glycoprotein content, demonstrating a protective relationship. Collectively, an aqueous pH lower than 7.5 might affect the uptake of PFOA by fish. The clearance discrepancies between the sexes highlight the importance of anion carriers for ionizable organic compounds in aquatic organisms.
ESTHER : Dong_2022_Sci.Total.Environ__160567
PubMedSearch : Dong_2022_Sci.Total.Environ__160567
PubMedID: 36455738

Title : Cholinesterase homozygous genotype as susceptible biomarker of hypertriglyceridemia for pesticide-exposed agricultural workers - Zhou_2021_Biomarkers__1
Author(s) : Zhou X , Zhang M , Wang Y , Xia H , Zhu L , Li G , Rong L , Dong H , Chen R , Tang S , Yu M
Ref : Biomarkers , :1 , 2021
Abstract : PURPOSE: Dyslipidemia is an emerging metabolic disorder among pesticide-exposed agricultural workers, and this study was aimed to explore biomarkers of hypertriglyceridemia susceptibility. METHODS: This cross-sectional study recruited 72 pesticide-exposed subjects and 78 non-exposed controls. Lipid profile, cholinesterase activity, and thyroid hormones were analyzed with routine assays. Six loci, including rs11206244 and rs2235544 for deiodinase 1, rs12885300 and rs225014 for deiodinase 2, rs1803274 for butyrylcholinesterase, and rs3757869 for acetylcholinesterase were genotyped using an improved multiplex ligation detection reaction technique. RESULTS: Pesticide-exposed subjects showed higher levels of triglyceride than controls (p = 0.009), although there were comparable cholinesterase activity and genotype frequencies of all six loci between pesticide-exposed subjects and controls. Pesticide-exposed subjects with homozygous genotype of cholinesterasehad increased triglyceride levels than controls (p < 0.05). The percentage of hypertriglyceridemia was 28.6% and 8.8% for pesticide-exposed subjects and controls with homozygous butyrylcholinesterase genotype (p = 0.007) and 20.8% and 14.3% with homozygous acetylcholinesterase genotype (p = 0.792), respectively. Multivariate logistic regression analyses found that odds ratio of hypertriglyceridemia is 21.92 and 4.56 for pesticide-exposed subjects with homozygous genotype of butyrylcholinesterase (p = 0.001) and acetylcholinesterase (p = 0.036), respectively. CONCLUSIONS: Cholinesterase homozygous genotype might be a potential susceptible biomarker in screening pesticide-exposed agricultural workers vulnerable to hypertriglyceridemia.
ESTHER : Zhou_2021_Biomarkers__1
PubMedSearch : Zhou_2021_Biomarkers__1
PubMedID: 33617373

Title : Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway - Wang_2021_Planta.Med__
Author(s) : Wang D , Ren Y , Sun W , Gong J , Zou X , Dong H , Xu L , Wang K , Lu F
Ref : Planta Med , : , 2021
Abstract : Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1beta and TNF-alpha in the serum and downregulated nuclear factor kappaB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.
ESTHER : Wang_2021_Planta.Med__
PubMedSearch : Wang_2021_Planta.Med__
PubMedID: 33682914

Title : Binding Peptide-Guided Immobilization of Lipases with Significantly Improved Catalytic Performance Using Escherichia coli BL21(DE3) Biofilms as a Platform - Dong_2021_ACS.Appl.Mater.Interfaces__
Author(s) : Dong H , Zhang W , Xuan Q , Zhou Y , Zhou S , Huang J , Wang P
Ref : ACS Appl Mater Interfaces , : , 2021
Abstract : Developing novel immobilization methods to maximize the catalytic performance of enzymes has been a permanent pursuit of scientific researchers. Engineered Escherichia coli biofilms have attracted great concern as surface display platforms for enzyme immobilization. However, current biological conjugation methods, such as the SpyTag/SpyCatcher tagging pair, that immobilize enzymes onto E. coli biofilms seriously hamper enzymatic performance. Through phage display screening of lipase-binding peptides (LBPs) and co-expression of CsgB (nucleation protein of curli nanofibers) and LBP2-modified CsgA (CsgALBP2, major structural subunit of curli nanofibers) proteins, we developed E. coli BL21::deltaCsgA-CsgB-CsgALBP2 (LBP2-functionalized) biofilms as surface display platforms to maximize the catalytic performance of lipase (Lip181). After immobilization onto LBP2-functionalized biofilm materials, Lip181 showed increased thermostability, pH, and storage stability. Surprisingly, the relative activity of immobilized Lip181 increased from 8.43 to 11.33 U/mg through this immobilization strategy. Furthermore, the highest loading of lipase on LBP2-functionalized biofilm materials reached up to 27.90 mg/g of wet biofilm materials, equivalent to 210.49 mg/g of dry biofilm materials, revealing their potential as a surface with high enzyme loading capacity. Additionally, immobilized Lip181 was used to hydrolyze phthalic acid esters, and the hydrolysis rate against dibutyl phthalate was up to 100%. Thus, LBP2-mediated immobilization of lipases was demonstrated to be far more advantageous than the traditional SpyTag/SpyCatcher strategy in maximizing enzymatic performance, thereby providing a better alternative for enzyme immobilization onto E. coli biofilms.
ESTHER : Dong_2021_ACS.Appl.Mater.Interfaces__
PubMedSearch : Dong_2021_ACS.Appl.Mater.Interfaces__
PubMedID: 33499600

Title : Detoxification enzymes associated with butene-fipronil resistance in Epacromius coerulipes - Jin_2020_Pest.Manag.Sci_76_227
Author(s) : Jin Y , Gao Y , Zhang H , Wang L , Yang K , Dong H
Ref : Pest Manag Sci , 76 :227 , 2020
Abstract : BACKGROUND: Epacromius coerulipes is a widely distributed locust pest species. Chemical control is the main method used to kill locusts; however, this can result in the selection of locusts with resistance to chemical pesticides. Therefore, the study of resistance is of great significance for the sustainable management of locusts. RESULTS: In this study, to investigate the relationship between detoxification enzymes and butene-fipronil resistance in E. coerulipes, resistant strains of the locust were compared with sensitive strains. The synergism of synergistic agents was significantly enhanced, and the activities of multifunctional oxidase, carboxylesterase, and glutathione sulfur transferase were significantly increased. Transcriptome sequencing revealed 226 detoxification enzyme genes and 23 upregulated genes. Neighbor-joining was used to construct a phylogenetic tree of related gene families, which included 59 P450 genes, 52 carboxylesterases (CarE) genes, and 25 glutathione S-transferase (GST) genes. Reverse transcription polymerase chain reaction (RT-PCR) analysis results of overexpressed genes in the resistant population combined with a phylogenetic tree showed that four P450 genes belonged to the CYP6, CYP4, CYP18 and CYP302 families, two CarE genes belonged to Clade A families, and one GST gene belonged to the Sigma family. These family members were annotated as detoxification enzyme genes of metabolic insecticide in the transcriptome databases. CONCLUSIONS: This study showed that P450, CarE and GST together resulted in moderate resistance to butene-fipronil in locusts. The analysis revealed several overexpressed detoxification enzyme genes that will be the focus of future studies on the mechanism of resistance to butene-fipronil. (c) 2019 Society of Chemical Industry.
ESTHER : Jin_2020_Pest.Manag.Sci_76_227
PubMedSearch : Jin_2020_Pest.Manag.Sci_76_227
PubMedID: 31150148

Title : Biological uptake, depuration and biochemical effects of diclofenac and carbamazepine in Carassius carassius - Nkoom_2020_Ecotoxicol.Environ.Saf_205_111106
Author(s) : Nkoom M , Lu G , Liu J , Dong H
Ref : Ecotoxicology & Environmental Safety , 205 :111106 , 2020
Abstract : The uptake and depuration kinetics of diclofenac and carbamazepine alone at an environmentally relevant nominal concentration of 2 mug/L and in combination at a concentration ratio of 1:1 with total concentration of 4 mug/L were evaluated in Carassius carassius after 7 d uptake and depuration. Also, the biochemical effects of both drugs alone at nominal concentrations of 2 and 10 mug/L as well as in combination with total concentrations of 4 and 20 mug/L were investigated in Carassius carassius after 7 d exposure followed by 10 d recovery. In the single treatments, steady-state BCFs measured after the 7 d exposure were 73.05, 49.71, 38.01 and 24.93 L/kg for diclofenac and 9.25, 8.99, 5.29 and 4.11 L/kg for carbamazepine in the liver, brain, gill and muscle of Carassius carassius, respectively. Comparatively lower BCFs were measured in the tissues of Carassius carassius for both drugs in the combined treatments. Acetylcholinesterase activity in the brain was significantly induced by diclofenac while carbamazepine and the mixtures significantly inhibited it during all the exposure days as well as after the 10 d recovery in all treatments. This indicates that Carassius carassius could not recover from the neurotoxic effects caused by carbamazepine unlike the inductive effect caused by diclofenac which was recoverable after 10 days. A significant increase in the activities of 7-ethoxyresorufin O-deethylase and glutathione s-transferase for individual and mixed pharmaceuticals suggest that metabolism and detoxification of both drugs took place in the liver of Carassius carassius. Also, a significant increase in the activities of superoxide dismutase, catalase, glutathione reductase and malondialdehyde contents in the individual and mixture treatments mean that the antioxidant defence system of Carassius carassius was triggered to fight against oxidative stress but lipid peroxidation still occurred. However, Carassius carassius recovered from all these increases (superoxide dismutase, catalase, glutathione reductase and malondialdehyde) after the 10 d recovery, suggesting that oxidative damage is reversible. Our results indicate that both drugs at environmentally relevant concentrations might cause adverse effects in Carassius carassius and other fish species.
ESTHER : Nkoom_2020_Ecotoxicol.Environ.Saf_205_111106
PubMedSearch : Nkoom_2020_Ecotoxicol.Environ.Saf_205_111106
PubMedID: 32818877

Title : Biofilm polysaccharide display platform: A natural, renewable, and biocompatible material for improved lipase performance - Dong_2020_J.Agric.Food.Chem__
Author(s) : Dong H , Zhang W , Wang Y , Liu D , Wang P
Ref : Journal of Agricultural and Food Chemistry , : , 2020
Abstract : Most of microorganisms can form biofilms, which makes biofilms become an abundant bioresource to be exploited. Due to the application limitations of current immobilization methods onto biofilms, we developed an immobilization method called the Biofilm Polysaccharides Display (BPD) strategy while maintaining the native biofilm structure and catalytic microenvironment of C. acetobutylicum B3. Lipase Lip181 showed significant improvements in stability after chemical immobilization. For example, immobilized Lip181 retained 74.23% of its original activity after incubation for 14 days while free Lip181 was totally deactivated. In addition, immobilized Lip181 maintained high residual activity (pH 5.0pH 11.0), which showed improved resistance to pH changes. Notably, this method did not decrease but slightly increased the relative activity of Lip181 from 6.39 to 6.78 U/mg. Immobilized Lip181 was used to prepare cinnamyl acetate, and it showed a maximum yield of 85.09%. Overall, this biofilm immobilization method may promote the development of biocatalysis and biofilm materials.
ESTHER : Dong_2020_J.Agric.Food.Chem__
PubMedSearch : Dong_2020_J.Agric.Food.Chem__
PubMedID: 31927950

Title : Bioconcentration of the antiepileptic drug carbamazepine and its physiological and biochemical effects on Daphnia magna - Nkoom_2019_Ecotoxicol.Environ.Saf_172_11
Author(s) : Nkoom M , Lu G , Liu J , Yang H , Dong H
Ref : Ecotoxicology & Environmental Safety , 172 :11 , 2019
Abstract : Owing to its persistence, carbamazepine an antiepileptic drug is regularly detected in the aquatic environment. The motive for our research was to assess the bioconcentration, physiological and biochemical effects of carbamazepine in Daphnia magna. A 48h aqueous exposure of carbamazepine yielded bioconcentration factors of 202.56 and 19.95 in Daphnia magna for the respective nominal treatments of 5 and 100microg/L. Apparently, the inhibition of the capability of Daphnia magna to obtain food attributable to carbamazepine exposure will reduce their fitness to reproduce as well as to grow. Also, a significant alteration in the phototactic behaviour of Daphnia magna exposed to carbamazepine is maladaptive since it will increase their chance of being preyed upon in the surface water during daylight. Again, a significant decline in the acetylcholinesterase activity observed herein brings to light the neurotoxicity of carbamazepine to Daphnia magna. Moreover, significant inhibition of the superoxide dismutase, catalase and glutathione reductase activities coupled with the simultaneous induction of the malondialdehyde content imply that carbamazepine evoked a life-threatening oxidative stress that overpowered the antioxidant defence system of Daphnia magna. These observations confirm that carbamazepine can accumulate and consequently cause negative physiological and biochemical changes to wild Daphnia magna populations.
ESTHER : Nkoom_2019_Ecotoxicol.Environ.Saf_172_11
PubMedSearch : Nkoom_2019_Ecotoxicol.Environ.Saf_172_11
PubMedID: 30669069

Title : Molecular and phenotypic responses of male crucian carp (Carassius auratus) exposed to perfluorooctanoic acid - Dong_2019_Sci.Total.Environ_653_1395
Author(s) : Dong H , Lu G , Yan Z , Liu J , Ji Y
Ref : Sci Total Environ , 653 :1395 , 2019
Abstract : Perfluorooctanoic acid (PFOA) has long been produced and widely used due to its excellent water and oil repellent properties. However, this trend has facilitated to the ubiquitous existence of PFOA in environmental matrix, and the potential ecotoxicity on aquatic organisms has not been fully elucidated. To study the tissue-specific bioconcentration and the nervous system- and energy-related biochemical effects of PFOA, as well as the phenotypic alterations by this chemical, male crucian carp (Carassius auratus) were exposed to gradient concentrations of PFOA (nominal 0.2, 10, 500 and 25,000mug/L) in a flow-through apparatus for 7days. PFOA was enriched in tissues following an order of blood>kidney>/=liver>gill>brain>muscle. The bioconcentration factors ranged from 0.1 to 60.4. Acetylcholinesterase activity in the fish brain was inhibited, while liver carboxylesterase was induced in most cases and attenuated with time. The acyl-CoA oxidase activity was dose-dependently elevated and accompanied by a decline of ATP contents. PFOA treatments also inhibited the activity of the electron transport system (ETS). At the transcriptional level, ETS component complexes II and IV were concordantly depressed, and ATP synthesis was also downregulated. The mRNA level of peroxisome proliferator activated receptor alpha was increasingly upregulated, with related downstream genes upregulated in varying degrees. The phenotypes showed patterns of increased liver pathology and reduced swimming activity. In summary, PFOA leads to adverse effects in Carassius auratus related to multiple aspects, which may be associated with the nervous system, fundamental energy metabolism and other unpredictable factors. The results obtained in this study are expected to help clarify the PFOA toxic mechanisms on energy relevance.
ESTHER : Dong_2019_Sci.Total.Environ_653_1395
PubMedSearch : Dong_2019_Sci.Total.Environ_653_1395
PubMedID: 30759578

Title : Bioconcentration, behavioral, and biochemical effects of the non-steroidal anti-inflammatory drug diclofenac in Daphnia magna - Nkoom_2019_Environ.Sci.Pollut.Res.Int_26_5704
Author(s) : Nkoom M , Lu G , Liu J , Dong H , Yang H
Ref : Environ Sci Pollut Res Int , 26 :5704 , 2019
Abstract : The non-steroidal anti-inflammatory drug (NSAID) diclofenac is one of the most frequently studied as well as controversially discussed pharmaceutically active drug on the subject of its relevance to the environment. This study was conducted to assess the bioconcentration potential of diclofenac and its behavioral and biochemical effects in Daphnia magna. The bioconcentration factors of diclofenac determined after 48 h of aqueous exposure in Daphnia magna were 70.94 and 8.02 for the nominal exposure concentrations of 5 and 100 mug/L, respectively. Diclofenac exposure obviously decreased the filtration and ingestion rates of the daphnids. A significant increase of the acetylcholinesterase activity that was observed in this study indicates that diclofenac might not have neurobehavioral toxicity in Daphnia magna. Significant induction of malondialdehyde content is an indication of overproduction of reactive oxygen species leading to oxidative damage in daphnids after diclofenac exposure. Moreover, significant inhibition of the superoxide dismutase, catalase, and glutathione reductase activities implies that the antioxidant defense system of Daphnia magna was overwhelmed. Also, significant inhibition of glutathione s-transferase activity might point to the fact that the enzyme was not capable to detoxify diclofenac in Daphnia magna. These findings indicate that diclofenac can accumulate and consequently stimulate behavioral and biochemical disturbances in Daphnia magna.
ESTHER : Nkoom_2019_Environ.Sci.Pollut.Res.Int_26_5704
PubMedSearch : Nkoom_2019_Environ.Sci.Pollut.Res.Int_26_5704
PubMedID: 30612359

Title : Application and design of esterase-responsive nanoparticles for cancer therapy - Dong_2019_Drug.Deliv_26_416
Author(s) : Dong H , Pang L , Cong H , Shen Y , Yu B
Ref : Drug Deliv , 26 :416 , 2019
Abstract : Nanoparticles have been developed for tumor treatment due to the enhanced permeability and retention effects. However, lack of specific cancer cells selectivity results in low delivery efficiency and undesired side effects. In that case, the stimuli-responsive nanoparticles system designed for the specific structure and physicochemical properties of tumors have attracted more and more attention of researchers. Esterase-responsive nanoparticle system is widely used due to the overexpressed esterase in tumor cells. For a rational designed esterase-responsive nanoparticle, ester bonds and nanoparticle structures are the key characters. In this review, we overviewed the design of esterase-responsive nanoparticles, including ester bonds design and nano-structure design, and analyzed the fitness of each design for different application. In the end, the outlook of esterase-responsive nanoparticle is looking forward.
ESTHER : Dong_2019_Drug.Deliv_26_416
PubMedSearch : Dong_2019_Drug.Deliv_26_416
PubMedID: 30929527

Title : Bioconcentration and effects of hexabromocyclododecane exposure in crucian carp (Carassius auratus) - Dong_2018_Ecotoxicology_27_313
Author(s) : Dong H , Lu G , Yan Z , Liu J , Yang H , Nkoom M
Ref : Ecotoxicology , 27 :313 , 2018
Abstract : As a cycloaliphatic brominated flame retardant, hexabromocyclododecane (HBCD) has been widely used in building thermal insulation and fireproof materials. However, there is little information on the bioconcentration as well as effects with respect to HBCD exposure in the aquatic environment. To investigate the bioconcentration of HBCD in tissues (muscle and liver) and its biochemical and behavioural effects, juvenile crucian carp (Carassius auratus) were exposed to different concentrations of technical HBCD (nominal concentrations, 2, 20, 200 mug/L) for 7 days, using a flow-through exposure system. HBCD was found to concentrate in the liver and muscle with a terminal concentration of 0.60 +/- 0.22 mug/g lw (lipid weight) and 0.18 +/- 0.02 mug/g lw, respectively, at an environmentally-relevant concentration (2 mug/L). The total thyroxine and total triiodothyronine in the fish plasma were lowered as a result of exposure to the HBCD. Acetylcholinesterase activity in the brain was increased, while swimming activity was inhibited and shoaling inclination was enhanced after exposure to 200 mug/L HBCD. Feeding rate was suppressed in the 20 and 200 mug/L treatment groups. In summary, HBCD concentrations 10-100x higher than the current environmentally-relevant exposures induced adverse effects in the fish species tested in this study. These results suggest that increasing environmental concentrations and/or species with higher sensitivity than carp might be adversely affected by HBCD.
ESTHER : Dong_2018_Ecotoxicology_27_313
PubMedSearch : Dong_2018_Ecotoxicology_27_313
PubMedID: 29404869

Title : Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration - Kukreja_2018_J.Neurosci_38_6045
Author(s) : Kukreja L , Shahidehpour R , Kim G , Keegan J , Sadleir KR , Russell T , Csernansky J , Mesulam M , Vassar RJ , Wang L , Dong H , Geula C
Ref : Journal of Neuroscience , 38 :6045 , 2018
Abstract : Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.
ESTHER : Kukreja_2018_J.Neurosci_38_6045
PubMedSearch : Kukreja_2018_J.Neurosci_38_6045
PubMedID: 29807909

Title : Biological effects of citalopram in a suspended sediment-water system on Daphnia magna - Yang_2017_Environ.Sci.Pollut.Res.Int_24_21180
Author(s) : Yang H , Lu G , Yan Z , Liu J , Ma B , Dong H
Ref : Environ Sci Pollut Res Int , 24 :21180 , 2017
Abstract : Suspended sediment (SPS) plays an important role in the aquatic ecosystems. Selective serotonin uptake inhibitors (SSRIs) are commonly used antidepressants and are frequently detected in aquatic environments. However, the biological effects of SSRIs in the presence of SPS are not well understood. To fill this gap, an SPS-water system was constructed to investigate the effects of citalopram (CIT) on Daphnia magna in the presence of SPS with different concentrations (0.1, 0.5, 1 g l(-1)) and organic carbon contents (0.5, 1, 1.5, 2%). A dialysis bag was applied in the exposure system to control the same dissolved concentration of CIT and prevent SPS from entering into the bag. The dissolved CIT concentration obviously decreased in the SPS-water system during the exposure period. The presence of SPS significantly increased the immobilization of D. magna, and the immobilization rates were positively correlated with the SPS concentration and negatively correlated with the organic carbon content in SPS. For a single exposure, CIT significantly increased superoxide dismutase (SOD) activity and inhibited acetylcholinesterase (AChE) activity in D. magna, while SPS itself did not change the SOD and AChE activities. In the SPS-water system, SOD activity was significantly suppressed, indicating that the SPS-CIT combination could result in oxidative damage. However, SPS did not enhance the neurotoxicity of D. magna that was induced by CIT. These results suggest that SPS exerts a vital role on the biological effects of CIT and the contaminants sorbed on SPS should be taken into consideration.
ESTHER : Yang_2017_Environ.Sci.Pollut.Res.Int_24_21180
PubMedSearch : Yang_2017_Environ.Sci.Pollut.Res.Int_24_21180
PubMedID: 28733820

Title : Clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning and prognosis analysis after rescue - Dong_2017_Medicine.(Baltimore)_96_e7237
Author(s) : Dong H , Weng YB , Zhen GS , Li FJ , Jin AC , Liu J
Ref : Medicine (Baltimore) , 96 :e7237 , 2017
Abstract : This study reports the clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning, and analyzes the prognosis after rescue.The general data of 68 patients with severe organophosphorus poisoning treated in our hospital were retrospectively analyzed. These patients were divided into 2 groups: treatment group, and control group. Patients in the control group received routine emergency treatment, while patients in the treatment group additionally received hemoperfusion plus hemodialysis on the basis of routine emergency treatment. The curative effects in these 2 groups and the prognosis after rescue were compared.Compared with the control group, atropinization time, recovery time of cholinesterase activity, recovery time of consciousness, extubation time, and length of hospital stay were shorter (P < .05); the total usage of atropine was significantly lower (P < .05); Glasgow Coma Score was significantly higher (P < .05); acute physiology and chronic health score (APACHE II) was significantly lower (P < .05); and mortality and poisoning rebound rate was significantly lower (P < .05) in the treatment group.Hemoperfusion and hemodialysis on the basis of routine emergency treatment for critical patients with organophosphorus poisoning can improve rescue outcomes and improve the prognosis of patients, which should be popularized.
ESTHER : Dong_2017_Medicine.(Baltimore)_96_e7237
PubMedSearch : Dong_2017_Medicine.(Baltimore)_96_e7237
PubMedID: 28640122

Title : Whole-Cell Biocatalytic Synthesis of Cinnamyl Acetate with a Novel Esterase from the DNA Library of Acinetobacter hemolyticus - Dong_2017_J.Agric.Food.Chem_65_2120
Author(s) : Dong H , Secundo F , Xue C , Mao X
Ref : Journal of Agricultural and Food Chemistry , 65 :2120 , 2017
Abstract : Cinnamyl acetate has a wide application in the flavor and fragrance industry because of its sweet, balsamic, and floral odor. Up to now, lipases have been mainly used in enzyme-mediated synthesis of cinnamyl acetate, whereas esterases are used in only a few cases. Moreover, the use of purified enzymes is often a disadvantage, which leads to increases of the production costs. In this paper, a genomic DNA library of Acinetobacter hemolyticus was constructed, and a novel esterase (EstK1) was identified. After expression in Escherichia coli, the whole-cell catalyst of EstK1 displayed high transesterification activity to produce cinnamyl acetate in nonaqueous systems. Furthermore, under optimal conditions (vinyl acetate as acyl donor, isooctane as solvent, molar ratio 1:4, temperature 40 degrees C), the conversion ratio of cinnamyl alcohol could be up to 94.1% at 1 h, and it reached an even higher level (97.1%) at 2 h.
ESTHER : Dong_2017_J.Agric.Food.Chem_65_2120
PubMedSearch : Dong_2017_J.Agric.Food.Chem_65_2120
PubMedID: 28220703

Title : Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice - Harris_2015_Toxicol.Appl.Pharmacol_286_102
Author(s) : Harris TR , Bettaieb A , Kodani S , Dong H , Myers R , Chiamvimonvat N , Haj FG , Hammock BD
Ref : Toxicol Appl Pharmacol , 286 :102 , 2015
Abstract : Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress.
ESTHER : Harris_2015_Toxicol.Appl.Pharmacol_286_102
PubMedSearch : Harris_2015_Toxicol.Appl.Pharmacol_286_102
PubMedID: 25827057

Title : Interaction of Acetylcholinesterase with Neurexin-1beta regulates Glutamatergic Synaptic stability in Hippocampal neurons - Xiang_2014_Mol.Brain_7_15
Author(s) : Xiang YY , Dong H , Yang BB , MacDonald JF , Lu WY
Ref : Mol Brain , 7 :15 , 2014
Abstract : BACKGROUND: Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses.
RESULTS: The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O-glycosylated neurexin-1beta, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE.
CONCLUSIONS: Excessive glycosylated AChE could competitively disrupt a subset of the neurexin-neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration.
ESTHER : Xiang_2014_Mol.Brain_7_15
PubMedSearch : Xiang_2014_Mol.Brain_7_15
PubMedID: 24594013

Title : Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy - Lee_2014_J.Med.Chem_57_7016
Author(s) : Lee KS , Liu JY , Wagner KM , Pakhomova S , Dong H , Morisseau C , Fu SH , Yang J , Wang P , Ulu A , Mate CA , Nguyen LV , Hwang SH , Edin ML , Mara AA , Wulff H , Newcomer ME , Zeldin DC , Hammock BD
Ref : Journal of Medicinal Chemistry , 57 :7016 , 2014
Abstract : Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
ESTHER : Lee_2014_J.Med.Chem_57_7016
PubMedSearch : Lee_2014_J.Med.Chem_57_7016
PubMedID: 25079952
Gene_locus related to this paper: human-EPHX2

Title : Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation - Morisseau_2014_J.Lipid.Res_55_1131
Author(s) : Morisseau C , Wecksler AT , Deng C , Dong H , Yang J , Lee KS , Kodani SD , Hammock BD
Ref : J Lipid Res , 55 :1131 , 2014
Abstract : Epoxy FAs (EpFAs) are important lipid mediators that are mainly metabolized by soluble epoxide hydrolase (sEH). Thus, sEH inhibition is a promising therapeutic target to treat numerous ailments. Several sEH polymorphisms result in amino acid substitutions and alter enzyme activity. K55R and R287Q are associated with inflammatory, cardiovascular, and metabolic diseases. R287Q seems to affect sEH activity through reducing formation of a catalytically active dimer. Thus, understanding how these SNPs affect the selectivity of sEH for substrates and inhibitors is of potential clinical importance. We investigated the selectivity of four sEH SNPs toward a series of EpFAs and inhibitors. We found that the SNPs alter the catalytic activity of the enzyme but do not alter the relative substrate and inhibitor selectivity. We also determined their dimer/monomer constants (KD/M). The WT sEH formed a very tight dimer, with a KD/M in the low picomolar range. Only R287Q resulted in a large change of the KD/M. However, human tissue concentrations of sEH suggest that it is always in its dimer form independently of the SNP. These results suggest that the different biologies associated with K55R and R287Q are not explained by alteration in dimer formation or substrate selectivity.
ESTHER : Morisseau_2014_J.Lipid.Res_55_1131
PubMedSearch : Morisseau_2014_J.Lipid.Res_55_1131
PubMedID: 24771868

Title : Soluble Epoxide Hydrolase Deficiency Inhibits Dextran Sulfate Sodium-induced Colitis and Carcinogenesis in Mice - Zhang_2013_Anticancer.Res_33_5261
Author(s) : Zhang W , Li H , Dong H , Liao J , Hammock BD , Yang GY
Ref : Anticancer Research , 33 :5261 , 2013
Abstract : Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH(-/-) mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62+/-20.91 mm(3) vs. 22.42+/-11.22 mm(3)), and a significant number of pre-cancerous dysplasia (3+/-1.18 vs. 2+/-0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH(-/-) mice (44.7%+/-24.9% vs. 20.2%+/-16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1beta and TNF-alpha expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/ dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis.
ESTHER : Zhang_2013_Anticancer.Res_33_5261
PubMedSearch : Zhang_2013_Anticancer.Res_33_5261
PubMedID: 24324059

Title : Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model - Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
Author(s) : Chen L , Fan C , Zhang Y , Bakri M , Dong H , Morisseau C , Maddipati KR , Luo P , Wang CY , Hammock BD , Wang MH
Ref : Prostaglandins Other Lipid Mediat , 104-105 :42 , 2013
Abstract : Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and anti-apoptotic mediators. In the present study, we determined the effects of the inhibition of sEH on glucose homeostasis and islet damage in mice treated with streptozotocin (STZ), a model of chemical-induced diabetes. STZ increased daily water intake and decreased visceral (spleen and pancreas) weight in mice; sEH inhibition in STZ mice decreased water intake, but did not affect visceral weight. Hyperglycemia induced by STZ treatment in mice was attenuated by inhibiting sEH. The beneficial effects of sEH inhibition were accompanied, after 2 and 4 weeks of initial administration, by improving glucose tolerance. In contrast, sEH inhibition did not affect insulin tolerance. Using LC/MS analysis, neither STZ nor STZ plus sEH inhibition affected pancreatic and plasma ratios of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), an index of EETs levels. Western blot analysis showed that mouse cytochrome P450 (CYP) 2C enzymes are the major epoxygenases in islets. On day 5 after initial STZ treatment, STZ induced islet cell apoptosis, while sEH inhibition in STZ mice significantly reduced islet cell apoptosis. These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet beta-cell damage and improves glucose homeostasis in STZ-induced diabetes.
ESTHER : Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
PubMedSearch : Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
PubMedID: 23247129

Title : Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-\/-) mice - Zhang_2012_Dig.Dis.Sci_57_2580
Author(s) : Zhang W , Yang AL , Liao J , Li H , Dong H , Chung YT , Bai H , Matkowskyj KA , Hammock BD , Yang GY
Ref : Digestive Diseases & Sciences , 57 :2580 , 2012
Abstract : BACKGROUND: Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation. AIMS: To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(-/-) mice.
METHODS: Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(-/-) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel.
RESULTS: Compared to IL-10 (-/-) mice, sEH inhibition or sEH deficiency in IL-10(-/-) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-gamma, TNF-alpha, and MCP-1, as well VCAM-1 and NF-kB/IKK-alpha signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB(4) and 5-HETE. CONCLUSION: These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (-/-) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.
ESTHER : Zhang_2012_Dig.Dis.Sci_57_2580
PubMedSearch : Zhang_2012_Dig.Dis.Sci_57_2580
PubMedID: 22588244

Title : Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats - Guglielmino_2012_Am.J.Physiol.Heart.Circ.Physiol_303_H853
Author(s) : Guglielmino K , Jackson K , Harris TR , Vu V , Dong H , Dutrow G , Evans JE , Graham J , Cummings BP , Havel PJ , Chiamvimonvat N , Despa S , Hammock BD , Despa F
Ref : American Journal of Physiology Heart Circ Physiol , 303 :H853 , 2012
Abstract : Glycemic regulation improves myocardial function in diabetic patients, but finding optimal therapeutic strategies remains challenging. Recent data have shown that pharmacological inhibition of soluble epoxide hydrolase (sEH), an enzyme that decreases the endogenous levels of protective epoxyeicosatrienoic acids (EETs), improves glucose homeostasis in insulin-resistant mice. Here, we tested whether the administration of sEH inhibitors preserves cardiac myocyte structure and function in hyperglycemic rats. University of California-Davis-type 2 diabetes mellitus (UCD-T2DM) rats with nonfasting blood glucose levels in the range of 150-200 mg/dl were treated with the sEH inhibitor 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU) for 6 wk. Administration of APAU attenuated the progressive increase of blood glucose concentration and preserved mitochondrial structure and myofibril morphology in cardiac myocytes, as revealed by electron microscopy imaging. Fluorescence microscopy with Ca(2+) indicators also showed a 40% improvement of cardiac Ca(2+) transients in treated rats. Sarcoplasmic reticulum Ca(2+) content was decreased in both treated and untreated rats compared with control rats. However, treatment limited this reduction by 30%, suggesting that APAU may protect the intracellular Ca(2+) effector system. Using Western blot analysis on cardiac myocyte lysates, we found less downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the main route of Ca(2+) reuptake in the sarcoplasmic reticulum, and lower expression of hypertrophic markers in treated versus untreated UCD-T2DM rats. In conclusion, APAU enhances the therapeutic effects of EETs, resulting in slower progression of hyperglycemia, efficient protection of myocyte structure, and reduced Ca(2+) dysregulation and SERCA remodeling in hyperglycemic rats. The results suggest that sEH/EETs may be an effective therapeutic target for cardioprotection in insulin resistance and diabetes.
ESTHER : Guglielmino_2012_Am.J.Physiol.Heart.Circ.Physiol_303_H853
PubMedSearch : Guglielmino_2012_Am.J.Physiol.Heart.Circ.Physiol_303_H853
PubMedID: 22865388

Title : Active screen plasma surface modification of polycaprolactone to improve cell attachment - Fu_2012_J.Biomed.Mater.Res.B.Appl.Biomater_100_314
Author(s) : Fu X , Sammons RL , Bertoti I , Jenkins MJ , Dong H
Ref : J Biomed Mater Res B Appl Biomater , 100 :314 , 2012
Abstract : To tailor polycaprolactone (PCL) surface properties for biomedical applications, film samples of PCL were surface modified by the active screen plasma nitriding (ASPN) technique. The chemical composition and structure were characterized by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The wettability of the surface modified polymers was investigated by contact angle and surface energy methods. Biocompatibility of the prepared PCL samples was evaluated in vitro using MC3T3-E1 osteoblast-like cells. The degradability was assessed by determining the self-degradation rate (catalyzed by lipase). The results show that ASPN surface modification can effectively improve osteoblast cell adhesion and spreading on the surface of PCL. The main change in chemical composition is the exchange of some carboxyl groups on the surface for hydroxyl groups. The active-screen plasma nitriding technique has been found to be an effective and practical method to effectively improve osteoblast cell adhesion and spreading on the PCL surface. Such changes have been attributed to the increase in wettablity and generation of new hydroxyl groups by plasma treatment. After active-screen plasma treatment, the PCL film is still degradable, but the enzymatic degradation rate is slower compared with untreated PCL film.
ESTHER : Fu_2012_J.Biomed.Mater.Res.B.Appl.Biomater_100_314
PubMedSearch : Fu_2012_J.Biomed.Mater.Res.B.Appl.Biomater_100_314
PubMedID: 22179939

Title : Complete genome sequence of Clostridium acetobutylicum DSM 1731, a solvent-producing strain with multireplicon genome architecture - Bao_2011_J.Bacteriol_193_5007
Author(s) : Bao G , Wang R , Zhu Y , Dong H , Mao S , Zhang Y , Chen Z , Li Y , Ma Y
Ref : Journal of Bacteriology , 193 :5007 , 2011
Abstract : Clostridium acetobutylicum is an important microorganism for solvent production. We report the complete genome sequence of C. acetobutylicum DSM 1731, a genome with multireplicon architecture. Comparison with the sequenced type strain C. acetobutylicum ATCC 824, the genome of strain DSM1731 harbors a 1.7-kb insertion and a novel 11.1-kb plasmid, which might have been acquired during evolution.
ESTHER : Bao_2011_J.Bacteriol_193_5007
PubMedSearch : Bao_2011_J.Bacteriol_193_5007
PubMedID: 21742891
Gene_locus related to this paper: cloab-q97db4 , cloac-pnbae

Title : Complete genome sequences of Mycobacterium tuberculosis strains CCDC5079 and CCDC5080, which belong to the Beijing family - Zhang_2011_J.Bacteriol_193_5591
Author(s) : Zhang Y , Chen C , Liu J , Deng H , Pan A , Zhang L , Zhao X , Huang M , Lu B , Dong H , Du P , Chen W , Wan K
Ref : Journal of Bacteriology , 193 :5591 , 2011
Abstract : Mycobacterium tuberculosis is one of most prevalent pathogens in the world. Drug-resistant strains of this pathogen caused by the excessive use of antibiotics have long posed serious threats to public health worldwide. A broader picture of drug resistance mechanisms at the genomic level can be obtained only with large-scale comparative genomic methodology. Two closely related Beijing family isolates, one resistant to four first-line drugs (CCDC5180) and one sensitive to them (CCDC5079), were completely sequenced. These sequences will serve as valuable references for further drug resistance site identification studies and could be of great importance for developing drugs targeting these sites.
ESTHER : Zhang_2011_J.Bacteriol_193_5591
PubMedSearch : Zhang_2011_J.Bacteriol_193_5591
PubMedID: 21914894
Gene_locus related to this paper: myctu-cut3 , myctu-cutas1 , myctu-cutas2 , myctu-Rv0160c , myctu-Rv1069c , myctu-RV1215C , myctu-Rv2045c , myctu-RV3452 , myctu-RV3724 , myctu-Rv3802c , myctu-y0571

Title : Tacrine treatment at high dose suppresses the recognition memory in juvenile and adult mice with attention to hepatotoxicity - Pan_2011_Basic.Clin.Pharmacol.Toxicol_108_421
Author(s) : Pan SY , Guo BF , Zhang Y , Yu Q , Yu ZL , Dong H , Ye Y , Han YF , Ko KM
Ref : Basic Clin Pharmacol Toxicol , 108 :421 , 2011
Abstract : It is well established that cholinergic over-stimulation can interfere with memory processes. The aim of this study was to evaluate the effect of tacrine, an acetylcholinesterase inhibitor, on recognition memory as well as the associated hepatotoxicity in juvenile (20-day-old) and adult (100-day-old) ICR male mice. Recognition memory was assessed by open-field test and step-through task without footshocks for three sessions between 08:00 and 13:00, with a 24-hr retention interval. Tacrine (10 or 40 mumol/kg) or vehicle was administered (s.c.) 20 min. prior to the first session. During the acquisition session, tacrine suppressed the open-field behaviours, including locomotor activity, rearing, grooming and defecation (by 77-100%) in mice of both ages. During the recall (observable in both ages) and re-recall (observable in juvenile mice) session, the locomotor activity and rearing number were significantly increased, indicative of impairment in recognition memory, in mice treated with tacrine 40 mumol/kg. During the training trial, tacrine decreased the step-through number in mice of both ages. In contrast, during the retention and re-retention trials, the step-through number was increased (by 92% and 93%, respectively), indicative of impairment in step-through memory, in juvenile but not adult mice treated with tacrine 40 mumol/kg. Tacrine 40 mumol/kg elevated the serum alanine aminotransferase (ALT) activity (by 135%) in juvenile mice, but reduced the ALT activity (by 42%) in adult mice. The results indicated that 20-day-old mice seemed to be more sensitive than 100-day-old mice to tacrine-induced impairment in recognition memory and the associated liver damage.
ESTHER : Pan_2011_Basic.Clin.Pharmacol.Toxicol_108_421
PubMedSearch : Pan_2011_Basic.Clin.Pharmacol.Toxicol_108_421
PubMedID: 21232021

Title : Redox regulation of soluble epoxide hydrolase by 15-deoxy-delta-prostaglandin J2 controls coronary hypoxic vasodilation - Charles_2011_Circ.Res_108_324
Author(s) : Charles RL , Burgoyne JR , Mayr M , Weldon SM , Hubner N , Dong H , Morisseau C , Hammock BD , Landar A , Eaton P
Ref : Circulation Research , 108 :324 , 2011
Abstract : RATIONALE: 15-Deoxy-Delta-prostaglandin (15d-PG)J(2) is an electrophilic oxidant that dilates the coronary vasculature. This lipid can adduct to redox active protein thiols to induce oxidative posttranslational modifications that modulate protein and tissue function. OBJECTIVE: To investigate the role of oxidative protein modifications in 15d-PGJ(2)-mediated coronary vasodilation and define the distal signaling pathways leading to enhanced perfusion. METHODS AND RESULTS: Proteomic screening with biotinylated 15d-PGJ(2) identified novel vascular targets to which it adducts, most notably soluble epoxide hydrolase (sEH). 15d-PGJ(2) inhibited sEH by specifically adducting to a highly conserved thiol (Cys521) adjacent to the catalytic center of the hydrolase. Indeed a Cys521Ser sEH "redox-dead" mutant was resistant to 15d-PGJ(2)-induced hydrolase inhibition. 15d-PGJ(2) dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ(2) and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ(2)-mediated vasodilation was blocked by the EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE). Additionally, the coronary vasculature of sEH-null mice was basally dilated compared to wild-type controls and failed to vasodilate in response to 15d-PGJ(2). Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ(2) adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia. CONCLUSION: This represents a new paradigm for the regulation of sEH by an endogenous lipid, which is integral to the fundamental physiological response of coronary hypoxic vasodilation.
ESTHER : Charles_2011_Circ.Res_108_324
PubMedSearch : Charles_2011_Circ.Res_108_324
PubMedID: 21164107

Title : Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase - Hwang_2011_J.Med.Chem_54_3037
Author(s) : Hwang SH , Wagner KM , Morisseau C , Liu JY , Dong H , Wecksler AT , Hammock BD
Ref : Journal of Medicinal Chemistry , 54 :3037 , 2011
Abstract : A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.
ESTHER : Hwang_2011_J.Med.Chem_54_3037
PubMedSearch : Hwang_2011_J.Med.Chem_54_3037
PubMedID: 21434686

Title : Effects of donepezil on amyloid-beta and synapse density in the Tg2576 mouse model of Alzheimer's disease - Dong_2009_Brain.Res_1303_169
Author(s) : Dong H , Yuede CM , Coughlan CA , Murphy KM , Csernansky JG
Ref : Brain Research , 1303 :169 , 2009
Abstract : Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the treatment of Alzheimer's disease (AD). Although extensive studies have demonstrated the symptomatic efficacy of donepezil treatment in patients with AD, the effects of donepezil, if any, on the AD process are not known. In this study, we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition or confer neuronal protection in a mouse model of AD. We used quantitative light and electron microscopy to investigate the effects of long-term administration (from 3 to 9 months of age for 6 months of treatment) of donepezil (1, 2, 4 mg/kg, in drinking water) on tissue amyloid-beta (Abeta) protein, plaque deposition, synaptic protein (synaptophysin), and synapse density in the hippocampus of Tg2576 mice. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Abeta(1-40) and Abeta(1-42), Abeta plaque number, and burden at the study end point in Tg2576 mice. The dose of 4 mg/kg of donepezil also significantly increased synaptic density in the molecular layer of the dentate gyrus in Tg2576 mice. However, a significant change of the synaptophysin-positive bouton in the hippocampus was not observed. These results suggest that a higher dose of donepezil may have a measurable impact on tissue level of Abeta protein and plaque deposition and may prevent synapse loss in the Tg2576 mouse model of AD.
ESTHER : Dong_2009_Brain.Res_1303_169
PubMedSearch : Dong_2009_Brain.Res_1303_169
PubMedID: 19799879

Title : Analyses of associations between three positionally cloned asthma candidate genes and asthma or asthma-related phenotypes in a Chinese population - Zhou_2009_BMC.Med.Genet_10_123
Author(s) : Zhou H , Hong X , Jiang S , Dong H , Xu X
Ref : BMC Med Genet , 10 :123 , 2009
Abstract : BACKGROUND: Six asthma candidate genes, ADAM33, NPSR1, PHF11, DPP10, HLA-G, and CYFIP2, located at different chromosome regions have been positionally cloned following the reported linkage studies. For ADAM33, NPSR1, and CYFIP2, the associations with asthma or asthma-related phenotypes have been studied in East Asian populations such as Chinese and Japanese. However, for PHF11, DPP10, and HLA-G, none of the association studies have been conducted in Asian populations. Therefore, the aim of the present study is to test the associations between these three positionally cloned genes and asthma or asthma-related phenotypes in a Chinese population.
METHODS: Two, five, and two single nucleotide polymorphisms (SNPs) in the identified top regions of PHF11, DPP10, and HLA-G, respectively, were genotyped in 1183 independent samples. The study samples were selected based on asthma affectation status and extreme values in at least one of the following three asthma-related phenotypes: total serum immunoglobulin E levels, bronchial responsiveness test, and skin prick test. Both single SNP and haplotype analyses were performed.
RESULTS: We found that DPP10 was significantly associated with bronchial hyperresponsiveness (BHR) and BHR asthma after the adjustment for multiple testing; while the associations of PHF11 with positive skin reactions to antigens and the associations of HLA-G with BHR asthma were only nominally significant. CONCLUSION: Our study is the first one to provide additional evidence that supports the roles of DPP10 in influencing asthma or BHR in a Chinese population.
ESTHER : Zhou_2009_BMC.Med.Genet_10_123
PubMedSearch : Zhou_2009_BMC.Med.Genet_10_123
PubMedID: 19951440
Gene_locus related to this paper: human-DPP10

Title : Comparison studies of tacrine and bis7-tacrine on the suppression of scopolamine-induced behavioral changes and inhibition of acetylcholinesterase in mice - Pan_2009_Pharmacology_83_294
Author(s) : Pan SY , Yu ZL , Xiang CJ , Dong H , Fang HY , Ko KM
Ref : Pharmacology , 83 :294 , 2009
Abstract : Effects of the cholinesterase inhibitors tacrine and bis(7)- tacrine (0.25-20 micromol/kg, s.c.) on locomotor activity and passive-avoidance response were investigated in mice treated with scopolamine (SCP, 1 or 5 micromol/kg, i.p.), using an open-field test and step-through task with a 24-hour retention interval. Drugs were given 30 min prior to the first session. During the acquisition session, SCP treatment increased the locomotor activity (10-16%). Tacrine, but not bis(7)-tacrine, cotreatment significantly reduced the locomotor activity by 23 or 27%, when compared with the SCP-treated control mice. In the step-through task, tacrine or bis(7)-tacrine coadministration dose-dependently attenuated the increase in the number of footshocks (by 50 or 58%) in SCP-treated mice. The lowest dose of tacrine and bis(7)-tacrine for prolonging the retention latency (up to 500%) in SCP-treated mice was 5 and 1 micromol/kg, respectively. Tacrine and bis(7)-tacrine inhibited brain acetylcholinesterase (AChE) activity 15 min (but not 30 min) after the drug administration in mice. At the same dose of 20 micromol/kg, the bis(7)-tacrine-induced AChE inhibition in serum was 14-fold higher than that of tacrine. The results indicated that bis(7)-tacrine was less potent than tacrine in causing motor dysfunction. However, bis(7)-tacrine was more potent than tacrine in the cognitive enhancement of SCP-induced memory loss and in AChE inhibition.
ESTHER : Pan_2009_Pharmacology_83_294
PubMedSearch : Pan_2009_Pharmacology_83_294
PubMedID: 19365154

Title : Anti-dementia drugs and hippocampal-dependent memory in rodents - Yuede_2007_Behav.Pharmacol_18_347
Author(s) : Yuede CM , Dong H , Csernansky JG
Ref : Behav Pharmacol , 18 :347 , 2007
Abstract : Abnormalities in hippocampal structure and function are characteristics of early Alzheimer's disease (AD). Behavioral tests measuring hippocampal-dependent memory in rodents are often used to evaluate novel treatments for AD and other dementias. In this study, we review the effects of drugs marketed for the treatment of AD, such as the acetylcholinesterase inhibitors, donepezil, rivastigmine, galantamine and the N-methyl-D-aspartic acid antagonist, memantine, in rodent models of memory impairment. We also briefly describe the effects of novel treatments for cognitive impairment in rodent models of memory impairment, and discuss issues concerning the selection of the animal model and behavioral tests. Suggestions for future research are offered.
ESTHER : Yuede_2007_Behav.Pharmacol_18_347
PubMedSearch : Yuede_2007_Behav.Pharmacol_18_347
PubMedID: 17762506

Title : Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling - Farchi_2007_Neurodegener.Dis_4_171
Author(s) : Farchi N , Ofek K , Podoly E , Dong H , Xiang YY , Diamant S , Livnah O , Li J , Hochner B , Lu WY , Soreq H
Ref : Neurodegener Dis , 4 :171 , 2007
Abstract : BACKGROUND: Peripheral anionic site (PAS) blockade of acetylcholinesterase (AChE) notably affects neuronal activity and cyto-architecture, however, the mechanism(s) involved are incompletely understood.
OBJECTIVE: We wished to specify the PAS extracellular effects on specific AChE mRNA splice variants, delineate the consequent cellular remodeling events, and explore the inhibitory effects on interchanging RACK1 interactions.
METHODS: We exposed rat hippocampal cultured neurons to BW284C51, the peripheral anionic site inhibitor of AChE, and to the non-selective AChE active site inhibitor, physostigmine for studying the neuronal remodeling of AChE mRNA expression and trafficking.
RESULTS: BW284C51 induced overexpression of both AChE splice variants, yet promoted neuritic translocation of the normally rare AChE-R, and retraction of AChE-S mRNA in an antisense-suppressible manner. BW284C51 further caused modest decreases in the expression of the scaffold protein RACK1 (receptor for activated protein kinase betaII), followed by drastic neurite retraction of both RACK1 and the AChE homologue neuroligin1, but not the tubulin-associated MAP2 protein. Accompanying BW284C51 effects involved decreases in the Fyn kinase and membrane insertion of the glutamate receptor NR2B variant and impaired glutamatergic activities of treated cells. Intriguingly, molecular modeling suggested that direct, non-catalytic competition with Fyn binding by the RACK1-interacting AChE-R variant may be involved.
CONCLUSIONS: Our findings highlight complex neuronal AChE-R/RACK1 interactions and are compatible with the hypothesis that peripheral site AChE inhibitors induce RACK1-mediated neuronal remodeling, promoting suppressed glutamatergic neurotransmission.
ESTHER : Farchi_2007_Neurodegener.Dis_4_171
PubMedSearch : Farchi_2007_Neurodegener.Dis_4_171
PubMedID: 17596712

Title : Dipeptidyl peptidase IV inhibitors derived from beta-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole, or pyrazole - Ashton_2005_Bioorg.Med.Chem.Lett_15_2253
Author(s) : Ashton WT , Sisco RM , Dong H , Lyons KA , He H , Doss GA , Leiting B , Patel RA , Wu JK , Marsilio F , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :2253 , 2005
Abstract : A series of beta-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC50=26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.
ESTHER : Ashton_2005_Bioorg.Med.Chem.Lett_15_2253
PubMedSearch : Ashton_2005_Bioorg.Med.Chem.Lett_15_2253
PubMedID: 15837304

Title : Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer's disease - Dong_2005_Psychopharmacology.(Berl)_181_145
Author(s) : Dong H , Csernansky CA , Martin MV , Bertchume A , Vallera D , Csernansky JG
Ref : Psychopharmacology (Berl) , 181 :145 , 2005
Abstract : RATIONALE: Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer's disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of beta-amyloid (Abeta) and behavioral deficits during adulthood are useful for investigating this question. OBJECTIVES: The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Abeta plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9-10 months of age, Tg2576-transgenic [Tg(+)] mice develop Abeta plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(-)] mice.
METHODS: Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Abeta plaque number was quantified.
RESULTS: Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Abeta plaques.
CONCLUSIONS: These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Abeta plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.
ESTHER : Dong_2005_Psychopharmacology.(Berl)_181_145
PubMedSearch : Dong_2005_Psychopharmacology.(Berl)_181_145
PubMedID: 15778881

Title : Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice - Csernansky_2005_Neuropsychopharmacology_30_2135
Author(s) : Csernansky JG , Martin M , Shah R , Bertchume A , Colvin J , Dong H
Ref : Neuropsychopharmacology , 30 :2135 , 2005
Abstract : Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (ie physostigmine-0.03, 0.10, or 0.30 mg/kg; donepezil-0.10, 0.30, or 1.00 mg/kg; or galantamine-0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that AChE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia.
ESTHER : Csernansky_2005_Neuropsychopharmacology_30_2135
PubMedSearch : Csernansky_2005_Neuropsychopharmacology_30_2135
PubMedID: 15956997

Title : Excessive expression of acetylcholinesterase impairs glutamatergic synaptogenesis in hippocampal neurons - Dong_2004_J.Neurosci_24_8950
Author(s) : Dong H , Xiang YY , Farchi N , Ju W , Wu Y , Chen L , Wang Y , Hochner B , Yang B , Soreq H , Lu WY
Ref : Journal of Neuroscience , 24 :8950 , 2004
Abstract : Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated protein-protein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic beta-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of beta-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.
ESTHER : Dong_2004_J.Neurosci_24_8950
PubMedSearch : Dong_2004_J.Neurosci_24_8950
PubMedID: 15483114

Title : A complete gene cluster from Streptomyces nanchangensis NS3226 encoding biosynthesis of the polyether ionophore nanchangmycin - Sun_2003_Chem.Biol_10_431
Author(s) : Sun Y , Zhou X , Dong H , Tu G , Wang M , Wang B , Deng Z
Ref : Chemical Biology , 10 :431 , 2003
Abstract : The PKS genes for biosynthesis of the polyether nanchangmycin are organized to encode two sets of proteins (six and seven ORFs, respectively), but are separated by independent ORFs that encode an epimerase, epoxidase, and epoxide hydrolase, and, notably, an independent ACP. One of the PKS modules lacks a corresponding ACP. We propose that the process of oxidative cyclization to form the polyether structure occurs when the polyketide chain is still anchored on the independent ACP before release. 4-O-methyl-L-rhodinose biosynthesis and its transglycosylation involve four putative genes, and regulation of nanchangmycin biosynthesis seems to involve activation as well as repression. In-frame deletion of a KR6 domain generated the nanchangmycin aglycone with loss of 4-O-methyl-L-rhodinose and antibacterial activity, in agreement with the assignments of the PKS domains catalyzing specific biosynthetic steps.
ESTHER : Sun_2003_Chem.Biol_10_431
PubMedSearch : Sun_2003_Chem.Biol_10_431
PubMedID: 12770825
Gene_locus related to this paper: strna-NANE

Title : Complete genome sequence of the oral pathogenic Bacterium porphyromonas gingivalis strain W83 - Nelson_2003_J.Bacteriol_185_5591
Author(s) : Nelson KE , Fleischmann RD , DeBoy RT , Paulsen IT , Fouts DE , Eisen JA , Daugherty SC , Dodson RJ , Durkin AS , Gwinn M , Haft DH , Kolonay JF , Nelson WC , Mason T , Tallon L , Gray J , Granger D , Tettelin H , Dong H , Galvin JL , Duncan MJ , Dewhirst FE , Fraser CM
Ref : Journal of Bacteriology , 185 :5591 , 2003
Abstract : The complete 2,343,479-bp genome sequence of the gram-negative, pathogenic oral bacterium Porphyromonas gingivalis strain W83, a major contributor to periodontal disease, was determined. Whole-genome comparative analysis with other available complete genome sequences confirms the close relationship between the Cytophaga-Flavobacteria-Bacteroides (CFB) phylum and the green-sulfur bacteria. Within the CFB phyla, the genomes most similar to that of P. gingivalis are those of Bacteroides thetaiotaomicron and B. fragilis. Outside of the CFB phyla the most similar genome to P. gingivalis is that of Chlorobium tepidum, supporting the previous phylogenetic studies that indicated that the Chlorobia and CFB phyla are related, albeit distantly. Genome analysis of strain W83 reveals a range of pathways and virulence determinants that relate to the novel biology of this oral pathogen. Among these determinants are at least six putative hemagglutinin-like genes and 36 previously unidentified peptidases. Genome analysis also reveals that P. gingivalis can metabolize a range of amino acids and generate a number of metabolic end products that are toxic to the human host or human gingival tissue and contribute to the development of periodontal disease.
ESTHER : Nelson_2003_J.Bacteriol_185_5591
PubMedSearch : Nelson_2003_J.Bacteriol_185_5591
PubMedID: 12949112
Gene_locus related to this paper: 9gamm-q4a538 , porgi-DPP , porgi-q7mtk3 , porgi-q7mu18 , porgi-q7mub3 , porgi-q7muw6 , porgi-q7mvp4 , porgi-q7mwa7 , porgi-q7mx03