Xu S

References (70)

Title : Inhibition of soluble epoxide hydrolase enhances the dentin-pulp complex regeneration mediated by crosstalk between vascular endothelial cells and dental pulp stem cells - Kong_2024_J.Transl.Med_22_61
Author(s) : Kong L , Li J , Bai Y , Xu S , Zhang L , Chen W , Gao L , Wang F
Ref : J Transl Med , 22 :61 , 2024
Abstract : BACKGROUND: Revascularization and restoration of normal pulp-dentin complex are important for tissue-engineered pulp regeneration. Recently, a unique periodontal tip-like endothelial cells subtype (POTCs) specialized to dentinogenesis was identified. We have confirmed that TPPU, a soluble epoxide hydrolase (sEH) inhibitor targeting epoxyeicosatrienoic acids (EETs) metabolism, promotes bone growth and regeneration by angiogenesis and osteogenesis coupling. We hypothesized that TPPU could also promote revascularization and induce POTCs to contribute to pulp-dentin complex regeneration. Here, we in vitro and in vivo characterized the potential effect of TPPU on the coupling of angiogenesis and odontogenesis and investigated the relevant mechanism, providing new ideas for pulp-dentin regeneration by targeting sEH. METHODS: In vitro effects of TPPU on the proliferation, migration, and angiogenesis of dental pulp stem cells (DPSCs), human umbilical vein endothelial cells (HUVECs) and cocultured DPSCs and HUVECs were detected using cell counting kit 8 (CCK8) assay, wound healing, transwell, tube formation and RT-qPCR. In vivo, Matrigel plug assay was performed to outline the roles of TPPU in revascularization and survival of grafts. Then we characterized the VEGFR2 + POTCs around odontoblast layer in the molar of pups from C57BL/6 female mice gavaged with TPPU. Finally, the root segments with DPSCs mixed with Matrigel were implanted subcutaneously in BALB/c nude mice treated with TPPU and the root grafts were isolated for histological staining. RESULTS: In vitro, TPPU significantly promoted the migration and tube formation capability of cocultured DPSCs and HUVECs. ALP and ARS staining and RT-qPCR showed that TPPU promoted the osteogenic and odontogenic differentiation of cultured cells, treatment with an anti-TGF-beta blocking antibody abrogated this effect. Knockdown of HIF-1alpha in HUVECs significantly reversed the effect of TPPU on the expression of angiogenesis, osteogenesis and odontogenesis-related genes in cocultured cells. Matrigel plug assay showed that TPPU increased VEGF/VEGFR2-expressed cells in transplanted grafts. TPPU contributed to angiogenic-odontogenic coupling featured by increased VEGFR2 + POTCs and odontoblast maturation during early dentinogenesis in molar of newborn pups from C57BL/6 female mice gavaged with TPPU. TPPU induced more dental pulp-like tissue with more vessels and collagen fibers in transplanted root segment. CONCLUSIONS: TPPU promotes revascularization of dental pulp regeneration by enhancing migration and angiogenesis of HUVECs, and improves odontogenic differentiation of DPSCs by TGF-beta. TPPU boosts the angiogenic-odontogenic coupling by enhancing VEGFR2 + POTCs meditated odontoblast maturation partly via upregulating HIF-1alpha, which contributes to increasing pulp-dentin complex for tissue-engineered pulp regeneration.
ESTHER : Kong_2024_J.Transl.Med_22_61
PubMedSearch : Kong_2024_J.Transl.Med_22_61
PubMedID: 38229161

Title : Nanoliposome-Mediated Encapsulation of Chlorella Oil for the Development of a Controlled-Release Lipid-Lowering Formulation - Tu_2024_Foods_13_
Author(s) : Tu L , Zeng J , Bai X , Wu Z , Wu J , Xu S
Ref : Foods , 13 : , 2024
Abstract : Chlorella oil nanoliposomes (CO-NLP) were synthesized through ultrasonic injection with ethanol, and their physicochemical properties and hypolipidemic efficacy were systematically investigated. The results revealed that the mean particle size of CO-NLP was 86.90 nm and the encapsulation efficiency (EE) was 92.84%. Storage conditions at 4 degreesC were conducive to the stability of CO-NLP, maintaining an EE of approximately 90% even after 10 days of storage. The release profile of CO-NLP adhered more closely to the first-order kinetic model during in vitro assessments, exhibiting a slower release rate compared to free microalgae oil. In simulated in vitro digestion experiments, lipolytic reactions of CO-NLP were observed during intestinal digestion subsequent to nanoliposome administration. Notably, the inhibitory effect of CO-NLP on cholesterol esterase activity was measured at 85.42%. Additionally, the average fluorescence intensity of nematodes in the CO-NLP group was 52.17% lower than in the control group at a CO-NLP concentration of 500 microg/mL, which suggests a pronounced lipid-lowering effect of CO-NLP. Therefore, the CO-NLP exhibited characteristics of small and uniform particle size, elevated storage stability, gradual release during intestinal digestion, and a noteworthy hypolipidemic effect. These findings designate CO-NLP as a novel lipid-lowering active product, demonstrating potential for the development of functional foods.
ESTHER : Tu_2024_Foods_13_
PubMedSearch : Tu_2024_Foods_13_
PubMedID: 38201186

Title : Metabolic engineering of Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids - Dong_2024_Metab.Eng__
Author(s) : Dong G , Zhao Y , Ding W , Xu S , Zhang Q , Zhao H , Shi S
Ref : Metab Eng , : , 2024
Abstract : Odd-numbered fatty acids (FAs) have been widely used in nutrition, agriculture, and chemical industries. Recently, some studies showed that they could be produced from bacteria or yeast, but the products are almost exclusively odd-numbered long-chain FAs. Here we report the design and construction of two biosynthetic pathways in Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids (OMFAs) via ricinoleic acid and 10-hydroxystearic acid, respectively. The production of OMFAs was enabled by introducing a hydroxy fatty acid cleavage pathway, including an alcohol dehydrogenase from Micrococcus luteus, a Baeyer-Villiger monooxygenase from Pseudomonas putida, and a lipase from Pseudomonas fluorescens. These OMFA biosynthetic pathways were optimized by eliminating the rate-limiting step, generating heptanoic acid, 11-hydroxyundec-9-enoic acid, nonanoic acid, and 9-hydroxynonanoic acid at 7.83 mg/L, 9.68 mg/L, 9.43 mg/L and 13.48 mg/L, respectively. This work demonstrates the biological production of OMFAs in a sustainable manner in S. cerevisiae.
ESTHER : Dong_2024_Metab.Eng__
PubMedSearch : Dong_2024_Metab.Eng__
PubMedID: 38325640

Title : Effects of age and tissue of Juniperus sabina L. on its phytochemical characteristics, anti-cholinesterase, antidiabetes, and anti-drug resistant bacteria activities - Xu_2023_Front.Plant.Sci_14_1174922
Author(s) : Xu S , Chen Q , Luo N , Yang J , Li D
Ref : Front Plant Sci , 14 :1174922 , 2023
Abstract : Juniperus sabina L. is used in the traditional Chinese medicine (TCM) system to prevent or treat various diseases. However, only the leaves and branches are used as medicinal parts. The aim of this study was to compare the chemical characteristics of different tissues (leaves, branches, stems, and roots) of J. sabina at different ages by HPLC-MS and to evaluate the biological activity (enzyme inhibition, anti-drug-resistant bacteria). Total phenol (TPC) and total lignan (TLC) contents in J. sabina were determined by Folin-Ciocalteu method and UV spectrophotometry, respectively. High levels of total phenols (87.16 mg GAE/g dry weight) and total lignans (491.24 mg PPT/g dry weight) were detected in fifteen annual J. sabina roots and current year leaves, respectively. Eleven compounds, of which six were phenolic compounds and five were lignans, were identified and quantified by HPLC/HPLC-MS. Statistical analysis showed that the distribution and content of the detected compounds showed considerable variation among ages and tissues, and that the current year leaves of fifteen annual J. sabina could be used as a potential application site for the source of podophyllotoxin. Acetylcholinesterase (AChE) inhibitory activity was found to be the highest on the extracts of fifteen annual J. sabina current year leaves (47.37 microg/mL), while the highest inhibition towards butyrylcholinesterase (BChE) was observed for the extracts of seven annual J. sabina previous year leaves (136.3 microg/mL). And the second annual J. sabina current year stem's extracts showed the best antidiabetic activity (anti-alpha-glucosidase, 62.59 microg/mL). In addition, the extracts of fifteen annual J. sabina roots (47.37 microg/mL) showed the highest anti-MRSA activity (31.25 microg/mL). Redundancy analysis (RDA) was conducted to clarify the factors affecting the biological activity of J. sabina, and its results showed that epicatechin and matairesinol showed positive promotion. This study provides a new perspective for understanding the chemical differences and comprehensive utilization of different tissues of J. sabina.
ESTHER : Xu_2023_Front.Plant.Sci_14_1174922
PubMedSearch : Xu_2023_Front.Plant.Sci_14_1174922
PubMedID: 37731973

Title : Repetitive transcranial magnetic stimulation may be superior to drug therapy in the treatment of Alzheimer's disease: A systematic review and Bayesian network meta-analysis - Wei_2023_CNS.Neurosci.Ther__
Author(s) : Wei N , Liu H , Ye W , Xu S , Lu C , Dai A , Hou T , Zeng X , Wu J , Chen J
Ref : CNS Neurosci Ther , : , 2023
Abstract : BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation therapy that is primarily used to treat a variety of neuropsychiatric conditions. Recently, previous research reports stated that rTMS have the characteristics of neurorestorative in Alzheimer's disease (AD). However, the relevant clinical research evidence has not been fully summarized. METHODS: This article performed a network meta-analysis of individual participant data from eligible studies searched in PubMed, Embase, and the Cochrane Library from inception to March 31, 2022. The drug treatments involved were acetylcholinesterase inhibitors (AChEIs), N-methyl-d-aspartate (NMDA), anti-amyloid-beta (Abeta), and some new targeted therapeutic drugs. RESULTS: A total of 15, 548 individuals with AD disease in 57 randomized clinical trials (RCTs) were included in this meta-analysis. The results indicated that the patients who received rTMS treatment (standard mean difference [SMD]: 0.65; 95% confidence interval [CI]: 0.22-1.07) had a better MMSE score than placebo. Treatment outcome analysis showed that, compared with multiple pharmacological interventions, rTMS acquired the greatest probability rank with the best cognitive improvement in MMSE score [the surface under the cumulative ranking curve (SUCRA) 93.3%] and ADAS-cog score (SUCRA 86.7%). At the same time, rTMS treatment had the lowest rank in the adverse events (SUCRA 24.1%) except for the placebo group (SUCRA 19.1%). CONCLUSION: Compared with the current clinical drug treatment, rTMS demonstrated better cognitive function improvement and fewer adverse events in AD patients. Therefore, rTMS shows broad prospects in the treatment of Alzheimer's disease, and it is worth being widely popularized in clinic.
ESTHER : Wei_2023_CNS.Neurosci.Ther__
PubMedSearch : Wei_2023_CNS.Neurosci.Ther__
PubMedID: 37088953

Title : Crystal structures of herbicide-detoxifying esterase reveal a lid loop affecting substrate binding and activity - Liu_2023_Nat.Commun_14_4343
Author(s) : Liu B , Wang W , Qiu J , Huang X , Qiu S , Bao Y , Xu S , Ruan L , Ran T , He J
Ref : Nat Commun , 14 :4343 , 2023
Abstract : SulE, an esterase, which detoxifies a variety of sulfonylurea herbicides through de-esterification, provides an attractive approach to remove environmental sulfonylurea herbicides and develop herbicide-tolerant crops. Here, we determined the crystal structures of SulE and an activity improved mutant P44R. Structural analysis revealed that SulE is a dimer with spacious binding pocket accommodating the large sulfonylureas substrate. Particularly, SulE contains a protruding beta hairpin with a lid loop covering the active site of the other subunit of the dimer. The lid loop participates in substrate recognition and binding. P44R mutation altered the lid loop flexibility, resulting in the sulfonylurea heterocyclic ring repositioning to a relative stable conformation thus leading to dramatically increased activity. Our work provides important insights into the molecular mechanism of SulE, and establish a solid foundation for further improving the enzyme activity to various sulfonylurea herbicides through rational design.
ESTHER : Liu_2023_Nat.Commun_14_4343
PubMedSearch : Liu_2023_Nat.Commun_14_4343
PubMedID: 37468532
Gene_locus related to this paper: 9rhiz-g9i933

Title : Sublethal effect of chlorpyrifos on predatory behavior and physiology of Eocanthecona furcellata (Hemiptera: Pentatomidae) - Xu_2023_J.Econ.Entomol__
Author(s) : Xu S , Yao Q , Quan L , Dong Y , Chen B , Zeng D
Ref : J Econ Entomol , : , 2023
Abstract : Insecticides have been known to reduce the predation efficacy of natural enemies. However, the mechanism of the sublethal effect of insecticides on the functional response of predators remains unclear. This study investigated the sublethal effects of the broad-spectrum insecticide chlorpyrifos on the predatory bug Eocanthecona furcellata (Wolff), which is a potential biological control agent against pests in integrated pest management (IPM) programs. After exposure to a sublethal concentration of chlorpyrifos, the predation capacity and the maximum predatory number of E. furcellata increased by 11.27 and 15.26%, respectively, with prey handling time decreased by 15.07%, and the searching efficiency increased by 5.88-12.61%. Additionally, the intraspecific interference effect was enhanced. Glutathione S-transferase (GST) activity was significantly decreased after 12- to 60-h treatment. At 12 h after treatment, the expression levels of GST gene (GST3), acetylcholinesterase gene (AChE), and cytochrome P450 monooxygenasegene (cyp6B1) were significantly up-regulated by 1.47-, 1.48-, and 2.05-fold, respectively, while GST gene (GST1) was significantly down-regulated by 16.67-fold. These results indicated that a sublethal chlorpyrifos concentration inhibited the GST activity and stimulated the predatory behavior of E. furcellata. The results will advance our understanding of the toxicological mechanism of predatory stink bug responses to insecticides and predict chlorpyrifos' effects on predators in an IPM program.
ESTHER : Xu_2023_J.Econ.Entomol__
PubMedSearch : Xu_2023_J.Econ.Entomol__
PubMedID: 37978042

Title : Biochemical toxicity and transcriptome aberration induced by dinotefuran in Bombyx mori - Xu_2022_Environ.Pollut__119562
Author(s) : Xu S , Hao Z , Li Y , Zhou Y , Shao R , Chen R , Zheng M , Xu Y , Wang H
Ref : Environ Pollut , :119562 , 2022
Abstract : Dinotefuran is a third-generation neonicotinoid pesticide and is increasingly used in agricultural production, which has adverse effects on nontarget organisms. However, the research on the impact of dinotefuran on nontarget organisms is still limited. Here the toxic effects of dinotefuran on an economic lepidopteran model insect, Bombyx mori, were investigated. Exposure to different doses of dinotefuran caused physiological disorders or death. Cytochrome P450, glutathione S-transferase, carboxylesterase, and UDP glycosyl-transferase activities were induced in the fat body at early stages after dinotefuran exposure. By contrast, only glutathione S-transferase activity was increased in the midgut. To overcome the lack of sensitivity of the biological assays at the individual organism level, RNA sequencing was performed to measure differential expressions of mRNA from silkworm larvae after dinotefuran exposure. Differential gene expression profiling revealed that various detoxification enzyme genes were significantly increased after dinotefuran exposure, which was consistent with the upregulation of the detoxifying enzyme. The global transcriptional pattern showed that the physiological responses induced by dinotefuran toxicity involved multiple cellular processes, including energy metabolism, oxidative stress, detoxification, and other fundamental physiological processes. Many metabolism processes, such as carbon metabolism, fatty acid biosynthesis, pyruvate metabolism, and the citrate cycle, were partially repressed in the midgut or fat body. Furthermore, dinotefuran significantly activated the MAPK/CREB, CncC/Keap1, PI3K/Akt, and Toll/IMD pathways. The links between physiological, biochemical toxicity and comparative transcriptomic analysis facilitated the systematic understanding of the integrated biological toxicity of dinotefuran. This study provides a holistic view of the toxicity and detoxification metabolism of dinotefuran in silkworm and other organisms.
ESTHER : Xu_2022_Environ.Pollut__119562
PubMedSearch : Xu_2022_Environ.Pollut__119562
PubMedID: 35659910

Title : Maternal Low-Protein Diet during Puberty and Adulthood Aggravates Lipid Metabolism of Their Offspring Fed a High-Fat Diet in Mice - Huang_2022_Nutrients_14_
Author(s) : Huang X , Zhuo Y , Jiang D , Zhu Y , Fang Z , Che L , Lin Y , Xu S , Hua L , Zou Y , Huang C , Li L , Wu D , Feng B
Ref : Nutrients , 14 : , 2022
Abstract : A maternal low-protein (LP) diet during gestation and/or lactation results in metabolic syndrome in their offspring. Here, we investigated the effect of maternal LP diet during puberty and adulthood on the metabolic homeostasis of glucose and lipids in offspring. Female mice were fed with normal-protein (NP) diet or a LP diet for 11 weeks. Male offspring were then fed with a high-fat diet (NP-HFD and LP-HFD groups) or standard chow diet (NP-Chow and LP-Chow groups) for 4 months. Results showed that maternal LP diet during puberty and adulthood did not alter the insulin sensitivity and hepatic lipid homeostasis of their offspring under chow diet, but aggravated insulin resistance, hepatic steatosis, and hypercholesterolemia of offspring in response to a post-weaning HFD. Accordingly, transcriptomics study with offspring's liver indicated that several genes related to glucose and lipid metabolism, including lipoprotein lipase (Lpl), long-chain acyl-CoA synthetase 1 (Acsl1), Apoprotein A1 (Apoa1), major urinary protein 19 (Mup19), cholesterol 7alpha hydroxylase (Cyp7a1) and fibroblast growth factor 1 (Fgf1), were changed by maternal LP diet. Taken together, maternal LP diet during puberty and adulthood could disarrange the expression of metabolic genes in the liver of offspring and aggravate insulin resistance and hepatic steatosis in offspring fed a HFD.
ESTHER : Huang_2022_Nutrients_14_
PubMedSearch : Huang_2022_Nutrients_14_
PubMedID: 36235710

Title : Novel inhibitors of AChE and Abeta aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease - Liu_2022_Eur.J.Med.Chem_235_114305
Author(s) : Liu Y , Uras G , Onuwaje I , Li W , Yao H , Xu S , Li X , Phillips J , Allen S , Gong Q , Zhang H , Zhu Z , Liu J , Xu J
Ref : Eur Journal of Medicinal Chemistry , 235 :114305 , 2022
Abstract : A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Abeta aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC(50) = 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents.
ESTHER : Liu_2022_Eur.J.Med.Chem_235_114305
PubMedSearch : Liu_2022_Eur.J.Med.Chem_235_114305
PubMedID: 35339839

Title : Engineering an Ag\/Au bimetallic nanoparticle-based acetylcholinesterase SERS biosensor for in situ sensitive detection of organophosphorus pesticide residues in food - Xu_2022_Anal.Bioanal.Chem__
Author(s) : Xu S , Li M , Li X , Jiang Y , Yu L , Zhao Y , Wen L , Xue Q
Ref : Anal Bioanal Chem , : , 2022
Abstract : Developing simple, efficient, and inexpensive method for trace amount organophosphorus pesticides' (OPs) detection with high sensitivity and specificity is of significant importance for guaranteeing food safety. Herein, an Ag/Au bimetallic nanoparticle-based acetylcholinesterase (AChE) surface-enhanced Raman scattering (SERS) biosensor was constructed for in situ simple and sensitive detection of pesticide residues in food. The principle of this biosensor exploited 4-mercaptophenylboronic acid (4-MPBA)-modified Ag/Au bimetallic nanoprobes as SERS signal probe to improve sensitivity and stability. The combination of AChE and choline oxidase (CHO) can hydrolyze acetylcholine (ATCh) to generate H(2)O(2). The product of H(2)O(2) selectively oxidizes the boronate ester of 4-MPBA, decreasing the Raman intensity of the B-O symmetric stretching. In the presence of OPs, it could inhibit the production of H(2)O(2) by destroying the AChE activity, so the reduction of the SERS signal was also alleviated. Based on the principle, an Ag/Au bimetallic nanoparticle-based AChE SERS sensor was established without any complicated pretreatments. Benefiting from the synergistic effects of Ag/Au bimetallic hybrids, a linear detection range from 5x10(-9) to 5x10(-4) M was achieved with a limit of detection down to 1.7x10(-9) M using parathion-methyl (PM) as the representative model of OPs. Moreover, the SERS biosensor uses readily available reagents and is simple to implement. Importantly, the proposed SERS biosensor was used to quantitatively analyze OP residues in apple peels. The levels of OPs detected in real samples by this method were consistent with those obtained using gas chromatography-mass spectrometry (GC-MS), suggesting the proposed assay has great potential applications for OPs in situ detection in food safety fields.
ESTHER : Xu_2022_Anal.Bioanal.Chem__
PubMedSearch : Xu_2022_Anal.Bioanal.Chem__
PubMedID: 36333614

Title : Juniperus sabina L. as a Source of Podophyllotoxins: Extraction Optimization and Anticholinesterase Activities - Xu_2022_Int.J.Mol.Sci_23_
Author(s) : Xu S , Li X , Liu S , Tian P , Li D
Ref : Int J Mol Sci , 23 : , 2022
Abstract : Juniperus sabina L. (J. sabina) has been an important plant in traditional medicine since ancient times. Its needles are rich in podophyllotoxin, a precursor compound to anti-tumor drugs. However, no systematic research has been done on J. sabina as a source of podophyllotoxins or their biological action. Hence, extracts of podophyllotoxin and deoxypodophyllotoxin were the main optimization targets using the Box-Behnken design (BBD) and response surface methodology (RSM). The total phenol content and antioxidant activity of J. sabina needle extract were also optimized. Under the optimal process conditions (ratio of material to liquid (RLM) 1:40, 90% methanol, and ultrasonic time 7 min), the podophyllotoxin extraction rate was 7.51 mg/g DW, the highest level reported for Juniperus spp. distributed in China. To evaluate its biological potential, the neuroprotective acetyl- and butyrylcholinease (AChE and BChE) inhibitory abilities were tested. The needle extract exhibited significant anti-butyrylcholinesterase activity (520.15 mg GALE/g extract), which correlated well with the high levels of podophyllotoxin and deoxypodophyllotoxin. This study shows the potential medicinal value of J. sabina needles.
ESTHER : Xu_2022_Int.J.Mol.Sci_23_
PubMedSearch : Xu_2022_Int.J.Mol.Sci_23_
PubMedID: 36142118

Title : In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer's Disease - Uras_2021_Front.Neurosci_15_691222
Author(s) : Uras G , Manca A , Zhang P , Markus Z , Mack N , Allen S , Bo M , Xu S , Xu J , Georgiou M , Zhu Z
Ref : Front Neurosci , 15 :691222 , 2021
Abstract : Alzheimer's disease is a neurodegenerative disease characterized by disrupted memory, learning functions, reduced life expectancy, and locomotor dysfunction, as a result of the accumulation and aggregation of amyloid peptides that cause neuronal damage in neuronal circuits. In the current study, we exploited a transgenic Drosophila melanogaster line, expressing amyloid-beta peptides to investigate the efficacy of a newly synthesized acetylcholinesterase inhibitor, named XJP-1, as a potential AD therapy. Behavioral assays and confocal microscopy were used to characterize the drug effect on AD symptomatology and amyloid peptide deposition. The symptomatology induced in this particular transgenic model recapitulates the scenario observed in human AD patients, showing a shortened lifespan and reduced locomotor functions, along with a significant accumulation of amyloid plaques in the brain. XJP-1 treatment resulted in a significant improvement of AD symptoms and a reduction of amyloid plaques by diminishing the amyloid aggregation rate. In comparison with clinically effective AD drugs, our results demonstrated that XJP-1 has similar effects on AD symptomatology, but at 10 times lower drug concentration than donepezil. It also showed an earlier beneficial effect on the reduction of amyloid plaques at 10 days after drug treatment, as observed for donepezil at 20 days, while the other drugs tested have no such effect. As a novel and potent AChE inhibitor, our study demonstrates that inhibition of the enzyme AChE by XJP-1 treatment improves the amyloid-induced symptomatology in Drosophila, by reducing the number of amyloid plaques within the fruit fly CNS. Thus, compound XJP-1 has the therapeutic potential to be further investigated for the treatment of AD.
ESTHER : Uras_2021_Front.Neurosci_15_691222
PubMedSearch : Uras_2021_Front.Neurosci_15_691222
PubMedID: 34276297

Title : Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease - Yao_2021_J.Med.Chem__
Author(s) : Yao H , Uras G , Zhang P , Xu S , Yin Y , Liu J , Qin S , Li X , Allen S , Bai R , Gong Q , Zhang H , Zhu Z , Xu J
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC(50) = 51.1 nM; GSK-3beta: IC(50) = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
ESTHER : Yao_2021_J.Med.Chem__
PubMedSearch : Yao_2021_J.Med.Chem__
PubMedID: 34024109

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

Title : Toxic effects of the dinoflagellate Karenia mikimotoi on zebrafish (Danio rerio) larval behavior - Niu_2021_Harmful.Algae_103_101996
Author(s) : Niu X , Xu S , Yang Q , Xu X , Zheng M , Li X , Guan W
Ref : Harmful Algae , 103 :101996 , 2021
Abstract : Karenia mikimotoi is a toxic dinoflagellate that forms harmful blooms in coastal waters, threatening aquaculture worldwide. However, we do not know whether K. mikimotoi has a neurotoxic effect on aquatic animal behavior. Thus, this study investigated potential K. mikimotoi neurotoxicity in zebrafish larvae. Cells of K. mikimotoi were collected at the mid-exponential phase from a batch culture to prepare ruptured cell solutions (RCS). At 6 h post-fertilization (hpf), zebrafish embryos were exposed to different RCS concentrations (0, 10(2), 10(3), 10(4), and 2.5 x 10(4) cells mL(-1)). After 120 hpf, treated larvae were collected to analyze locomotor behavior; activities of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT); and expression of genes related to neurodevelopment. We found that RCS did not affect survival rate, but significantly decreased larval locomotion, as well as their AChE, SOD, and CAT activity. Additionally, the examination of the day-night behavioral experiment revealed RCS decreased locomotion only at night. Zebrafish larvae were also significantly hypoactive in response to light and sound stimulations. Of the neurodevelopment genes, three (th, neurog1, and neurod1) were downregulated, while two (bdnf and manf) were upregulated. Our study suggests that K. mikimotoi neurotoxicity occurs through causing oxidative damage, as well as disorders in the cholinergic system and nervous system development. The results provide new insight that K. mikimotoi in low abundance did not cause significant lethal effect but still exhibited significant neurotoxicity on aquatic animals.
ESTHER : Niu_2021_Harmful.Algae_103_101996
PubMedSearch : Niu_2021_Harmful.Algae_103_101996
PubMedID: 33980436

Title : Characterization and structural analysis of a thermophilic GH11 xylanase from compost metatranscriptome - Yi_2021_Appl.Microbiol.Biotechnol_105_7757
Author(s) : Yi Y , Xu S , Kovalevsky A , Zhang X , Liu D , Wan Q
Ref : Applied Microbiology & Biotechnology , 105 :7757 , 2021
Abstract : Xylanase is efficient for xylan degradation and widely applied in industries. We found a GH11 family xylanase (Xyn11A) with high thermostability and catalytic activity from compost metatranscriptome. This xylanase has the optimal reaction temperature at 80 degreesC with the activity of 2907.3 U/mg. The X-ray crystallographic structure shows a typical "right hand" architecture, which is the characteristics of the GH11 family enzymes. Comparing it with the mesophilic XYN II, a well-studied GH11 xylanase from Trichoderma reesei, Xyn11A is more compact with more H-bonds. Our mutagenic results show that the electrostatic interactions in the thumb and palm region of Xyn11A could result in its high thermostability and activity. Introducing a disulfide bond at the N-terminus further increased its optimal reaction temperature to 90 degreesC with augmented activity. KEY POINTS: A hyperthermophilic xylanase with high activity was discovered using the metatranscriptomic method. The mechanisms of thermophilicity and high activity were revealed using X-ray crystallography, mutagenesis, and molecular dynamics simulations. The thermostability and activity were further improved by introducing a disulfide bond.
ESTHER : Yi_2021_Appl.Microbiol.Biotechnol_105_7757
PubMedSearch : Yi_2021_Appl.Microbiol.Biotechnol_105_7757
PubMedID: 34553251

Title : Structurally various sorbicillinoids from the deep-sea sediment derived fungus Penicillium sp. SCSIO06871 - Pang_2020_Bioorg.Chem_107_104600
Author(s) : Pang X , Zhou X , Lin X , Yang B , Tian X , Wang J , Xu S , Liu Y
Ref : Bioorg Chem , 107 :104600 , 2020
Abstract : Two new hybrid sorbicillinoids (1 and 5), three new bisorbicillinoids (2-4), and three monomeric sorbicillinoids (6-8), along with eighteen known sorbicillinoids (9-26) were isolated from cultures of the deep-sea sediment derived fungus Penicillium sp. SCSIO06871. Their structures and absolute configurations were elucidated based upon the extensive spectroscopic analysis, X-ray crystallography analysis and the comparison of the experimental and calculated ECD data. Bisorbicillpyrone A (4) is the first example of bisorbicillinoid containing an alpha-pyrone derivative unit. All of the isolated compounds were evaluated for their antibacterial, antifungal and enzyme inhibitory activities against alpha-glycosidase and acetylcholinesterase (AChE) in vitro. Compound 6 displayed more potent inhibitory activity against alpha-glycosidase than acarbose with IC(50) value of 36.0 microM and compounds 4, 12, 18, 22, 23 exhibited moderate inhibitory activity with IC(50) values ranging from 115.8 to 208.5 microM. Compounds 10 and 22 showed weak enzyme inhibitory activities against AChE with 55.1% and 51.1% inhibitions at concentration of 50 microg/mL, respectively. Besides, compounds 11 and 12 exhibited significant antibacterial activities against Staphylococcus aureus with MIC values of 10.0 and 5.0 microg/mL, respectively. The hypothetical biosynthetic pathway of the isolated sorbicillinoids with three different structural types was discussed.
ESTHER : Pang_2020_Bioorg.Chem_107_104600
PubMedSearch : Pang_2020_Bioorg.Chem_107_104600
PubMedID: 33453645

Title : Patatin primary structural properties and effects on lipid metabolism - Wu_2020_Food.Chem__128661
Author(s) : Wu J , Wu Q , Yang D , Zhou M , Xu J , Wen Q , Cui Y , Bai Y , Xu S , Wang Z , Wang S
Ref : Food Chem , :128661 , 2020
Abstract : Patatin, the major protein found in potatoes, was purified and shows several isoforms. The essential amino acid content of patatin was ashighas 76%, indicating that it is a valuable protein source. Patatin was an O-linked glycoprotein that contained fucose monosaccharides, as well as mannose, rhamnose, glucose, galactose, xylose, and arabinose. Patatin had a fucosylated glycan structural feature, which strongly bound AAL (Aleuria aurantia Leukoagglutinin), a known fucose binding lectin. Moreover, thelipid metabolism regulatory effects of patatin on the fat catabolism, fat absorption, and inhibition of lipase activity were measured after high-fat feeding of zebrafish larvae. Results revealed that 37.0 g/mL patatin promoted 23% lipid decomposition metabolism. Meanwhile patatin could inhibite lipase activity and fat absorption, whose effects accounted for half that of a positive control drug. Our findings suggest that patatin, a fucosylated glycoprotein, could potentially be used as a naturalactiveconstituent with anti-obesity effects.
ESTHER : Wu_2020_Food.Chem__128661
PubMedSearch : Wu_2020_Food.Chem__128661
PubMedID: 33272761

Title : Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects - Han_2020_Eur.J.Med.Chem__113028
Author(s) : Han Y , Huang D , Xu S , Li L , Tian Y , Li S , Chen C , Li Y , Sun Y , Hou Y , Qin M , Gong P , Gao Z , Zhao Y
Ref : Eur Journal of Medicinal Chemistry , :113028 , 2020
Abstract : Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC(50) value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a "prodrug". In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
ESTHER : Han_2020_Eur.J.Med.Chem__113028
PubMedSearch : Han_2020_Eur.J.Med.Chem__113028
PubMedID: 33248848

Title : Chlorpyrifos-induced toxicity has no gender selectivity in the early fetal brain - Gu_2020_J.Environ.Sci.Health.B__1
Author(s) : Gu J , Xu S , Liu Y , Chen X
Ref : J Environ Sci Health B , :1 , 2020
Abstract : Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.
ESTHER : Gu_2020_J.Environ.Sci.Health.B__1
PubMedSearch : Gu_2020_J.Environ.Sci.Health.B__1
PubMedID: 32602772

Title : Multi-target design strategies for the improved treatment of Alzheimer's disease - Zhang_2019_Eur.J.Med.Chem_176_228
Author(s) : Zhang P , Xu S , Zhu Z , Xu J
Ref : Eur Journal of Medicinal Chemistry , 176 :228 , 2019
Abstract : Alzheimer's disease (AD) is a multifactorial syndrome resulting in profound misery and poses a substantial burden on human health, economy, and society throughout the world. Based on the numerous AD-related targets in the disease network, multi-target design strategy is a crucial direction to seek for enhanced therapy, and multi-target drugs have the ability to regulate more targets than single-target drugs, affecting the disease network with more potency. Herein, we highlight nine major targets associated with AD, which are acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (beta-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3beta), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), and phosphodiesterases (PDEs), and their respective relationship to the disease network. Furthermore, eleven multi-target design strategies classified by the involvement of AChE and related promising compounds for improved therapy of AD in recent years are described based on the nine major targets.
ESTHER : Zhang_2019_Eur.J.Med.Chem_176_228
PubMedSearch : Zhang_2019_Eur.J.Med.Chem_176_228
PubMedID: 31103902

Title : Lysophospholipases cooperate to mediate lipid homeostasis and lysophospholipid signaling - Wepy_2019_J.Lipid.Res_60_360
Author(s) : Wepy JA , Galligan JJ , Kingsley PJ , Xu S , Goodman MC , Tallman KA , Rouzer CA , Marnett LJ
Ref : J Lipid Res , 60 :360 , 2019
Abstract : Lysophospholipids (LysoPLs) are bioactive lipid species involved in cellular signaling processes and the regulation of cell membrane structure. LysoPLs are metabolized through the action of lysophospholipases, including lysophospholipase A1 (LYPLA1) and lysophospholipase A2 (LYPLA2). A new X-ray crystal structure of LYPLA2 compared with a previously published structure of LYPLA1 demonstrated near-identical folding of the two enzymes; however, LYPLA1 and LYPLA2 have displayed distinct substrate specificities in recombinant enzyme assays. To determine how these in vitro substrate preferences translate into a relevant cellular setting and better understand the enzymes' role in LysoPL metabolism, CRISPR-Cas9 technology was utilized to generate stable KOs of Lypla1 and/or Lypla2 in Neuro2a cells. Using these cellular models in combination with a targeted lipidomics approach, LysoPL levels were quantified and compared between cell lines to determine the effect of losing lysophospholipase activity on lipid metabolism. This work suggests that LYPLA1 and LYPLA2 are each able to account for the loss of the other to maintain lipid homeostasis in cells; however, when both are deleted, LysoPL levels are dramatically increased, causing phenotypic and morphological changes to the cells.
ESTHER : Wepy_2019_J.Lipid.Res_60_360
PubMedSearch : Wepy_2019_J.Lipid.Res_60_360
PubMedID: 30482805
Gene_locus related to this paper: human-LYPLA2

Title : Design, synthesis and molecular modeling of isothiochromanone derivatives as acetylcholinesterase inhibitors - Shuai_2019_Future.Med.Chem_11_2687
Author(s) : Shuai W , Li W , Yin Y , Yang L , Xu F , Xu S , Yao H , Zhu Z , Xu J
Ref : Future Med Chem , 11 :2687 , 2019
Abstract : Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.
ESTHER : Shuai_2019_Future.Med.Chem_11_2687
PubMedSearch : Shuai_2019_Future.Med.Chem_11_2687
PubMedID: 31596141

Title : Characterization of one novel microbial esterase WDEst9 and its use to make l-methyl lactate - Wang_2019_Biocatal.Biotransformation_37_190
Author(s) : Wang Y , Xu S , Li R , Sun A , Zhang Y , Sai K , Hu Y
Ref : Biocatalysis and Biotransformation , 37 :190 , 2019
Abstract : Chiral lactic acids and their ester derivatives are crucial building blocks and intermediates for the synthesis of a great variety of valuable functional materials and pharmaceuticals. Before our study, the reports about the enantioselective preparation of pure L-lactic acid and its ester derivatives through direct hydrolysis of racemic substrate were quite rare. Herein, we heterologously expressed and functionally characterized one novel microbial esterase WDEst9 from Dactylosporangium aurantiacum, which exhibited high resistance to diverse metal ions, organic solvents, surfactants, NaCl and KCl. We further utilized WDEst9 as a green biocatalyst in the kinetic resolution of (+/-)-methyl lactate through direct hydrolysis and generated L-methyl lactate with high enantiomeric excess (e.e. >99%) and high yield (>86%) after process optimization. Notably, the enantioselectivity of WDEst9 was opposite than that of two previously reported esterases PHE14 and BSE01701 that can generate D-methyl lactate though kinetic resolution of (+/-)-methyl lactate. Microbial esterase WDEst9 is a promising green biocatalyst in the preparation of valuable chiral chemicals and opens the door for the identification of useful industrial enzymes and biocatalysts from the genus Dactylosporangium.
ESTHER : Wang_2019_Biocatal.Biotransformation_37_190
PubMedSearch : Wang_2019_Biocatal.Biotransformation_37_190
Gene_locus related to this paper: 9actn-a0a2d1pk72

Title : Significant association between GPR50 hypomethylation and AD in males - Chen_2019_Mol.Med.Rep_20_1085
Author(s) : Chen W , Ji H , Li L , Xu C , Zou T , Cui W , Xu S , Zhou X , Duan S , Wang Q
Ref : Mol Med Rep , 20 :1085 , 2019
Abstract : Alzheimer's disease (AD) is a chronic neurodegenerative disease. G protein coupled receptor 50 (GPR50) is a candidate gene for AD. The present study was designed to determine the association between GPR50 methylation and AD. The methylation levels of the GPR50 promoter in 51 patients with AD and 61 healthy controls were determined by bisulfite pyrophosphate sequencing. All participants were Han Chinese, living in Ningbo. It was identified that the GPR50 promoter methylation level was significantly decreased in the male AD group compared with the male control group (9.15 vs. 16.67%, P=0.002). In addition, it was observed that the GPR50 methylation levels of the females was significantly increased compared with that of males in both the patients with AD and the healthy control group (AD patient group: 33.00 vs. 9.15%, P<0.0001; healthy control group: 29.41 vs. 16.67%, P<0.0001). This may be explained by the fact that GPR50 is located on the X chromosome. In addition, GPR50 methylation was positively correlated with plasma cholinesterase levels in female patients with AD (r=0.489, P=0.039). The present study demonstrated that hypomethylation of the GPR50 promoter in peripheral blood may be a potential biomarker for the diagnosis of AD in Chinese Han males.
ESTHER : Chen_2019_Mol.Med.Rep_20_1085
PubMedSearch : Chen_2019_Mol.Med.Rep_20_1085
PubMedID: 31173244

Title : Phosphodiesterase inhibitors say NO to Alzheimer's disease - Nabavi_2019_Food.Chem.Toxicol_134_110822
Author(s) : Nabavi SM , Talarek S , Listos J , Nabavi SF , Devi KP , Roberto de Oliveira M , Tewari D , Arguelles S , Mehrzadi S , Hosseinzadeh A , D'Onofrio G , Orhan IE , Sureda A , Xu S , Momtaz S , Farzaei MH
Ref : Food & Chemical Toxicology , 134 :110822 , 2019
Abstract : Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy.
ESTHER : Nabavi_2019_Food.Chem.Toxicol_134_110822
PubMedSearch : Nabavi_2019_Food.Chem.Toxicol_134_110822
PubMedID: 31536753

Title : ( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes - Liu_2018_J.Med.Chem_61_8639
Author(s) : Liu Y , Ji L , Eno M , Kudalkar S , Li AL , Schimpgen M , Benchama O , Morales P , Xu S , Hurst D , Wu S , Mohammad KA , Wood JT , Zvonok N , Papahatjis DP , Zhou H , Honrao C , Mackie K , Reggio P , Hohmann AG , Marnett LJ , Makriyannis A , Nikas SP
Ref : Journal of Medicinal Chemistry , 61 :8639 , 2018
Abstract : The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( Ki of 7.8 +/- 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 +/- 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.
ESTHER : Liu_2018_J.Med.Chem_61_8639
PubMedSearch : Liu_2018_J.Med.Chem_61_8639
PubMedID: 30196704

Title : Design, synthesis, biological evaluation, and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II) - Wang_2018_Chem.Biol.Drug.Des_91_756
Author(s) : Wang J , Wang C , Wu Z , Li X , Xu S , Liu J , Lan Q , Zhu Z , Xu J
Ref : Chemical Biology Drug Des , 91 :756 , 2018
Abstract : A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC50 value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents.
ESTHER : Wang_2018_Chem.Biol.Drug.Des_91_756
PubMedSearch : Wang_2018_Chem.Biol.Drug.Des_91_756
PubMedID: 29112799

Title : Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-alpha and IL-1beta in an Abeta25-35-induced Rat Model of Alzheimer's Disease - Li_2017_J.Alzheimers.Dis_56_1403
Author(s) : Li L , Xu S , Liu L , Feng R , Gong Y , Zhao X , Li J , Cai J , Feng N , Wang L , Wang X , Peng Y
Ref : J Alzheimers Dis , 56 :1403 , 2017
Abstract : The dyshomeostasis of transition metal ions, accumulation of amyloid-beta (Abeta) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Abeta species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Abeta aggregation in vitro and showed disassembly of Abeta aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Abeta25-35 were studied in rats. Compared to sham group, Abeta25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-alpha and IL-1beta). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Abeta25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-alpha and IL-1beta release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1beta production, but failed to block astrocyte activation and TNF-alpha production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.
ESTHER : Li_2017_J.Alzheimers.Dis_56_1403
PubMedSearch : Li_2017_J.Alzheimers.Dis_56_1403
PubMedID: 28157092

Title : The Role of AChE in Swimming Behavior of Daphnia magna: Correlation Analysis of Both Parameters Affected by Deltamethrin and Methomyl Exposure - Ren_2017_J.Toxicol_2017_3265727
Author(s) : Ren Q , Zhao R , Wang C , Li S , Zhang T , Ren Z , Yang M , Pan H , Xu S , Zhu J , Wang X
Ref : J Toxicol , 2017 :3265727 , 2017
Abstract : The unpredictable toxicity of insecticides may cause behavior disorder of biological organisms. In order to assess the role of acetylcholinesterase (AChE) in swimming behavior of Daphnia magna, a correlation analysis of both parameters in 24 h exposure of deltamethrin (DM) and methomyl (MT) was investigated. The behavior responses of D. magna in DM (13.36 mug/L and 33.40 mug/L) and MT (19.66 mug/L and 49.15 mug/L) suggested that recovery behavior in the adjustment phase was crucial, and behavior homeostasis provided them with an optimal way to achieve a wider tolerance against environmental stress. During the experiment, positive effects on AChE activity occurred in the beginning of the exposure. Even though the de novo synthesis of AChE in D. magna might help it recover, the AChE inhibition in different treatments could be observed. Some induction effects on AChE activity at the beginning of exposure occurred, and a 50% decrease may cause toxic effects on behavior. In most treatments, the results showed that both behavior strength and AChE activity stayed in the same field within a correlation circle. These results illustrated that the environmental stress caused by both DM and MT could inhibit AChE activity and subsequently induce a stepwise behavior response, though both pesticides affect it as direct and indirect inhibitors, respectively.
ESTHER : Ren_2017_J.Toxicol_2017_3265727
PubMedSearch : Ren_2017_J.Toxicol_2017_3265727
PubMedID: 29201050
Gene_locus related to this paper: dapul-ACHE1

Title : Does time difference of the acetylcholinesterase (AChE) inhibition in different tissues exist? A case study of zebra fish (Danio rerio) exposed to cadmium chloride and deltamethrin - Zhang_2017_Chemosphere_168_908
Author(s) : Zhang T , Yang M , Pan H , Li S , Ren B , Ren Z , Xing N , Qi L , Ren Q , Xu S , Song J , Ma J
Ref : Chemosphere , 168 :908 , 2017
Abstract : In order to illustrate time difference in toxic effects of cadmium chloride (CdCl2) and deltamethrin (DM), AChE activities were measured in different tissues, liver, muscle, brain, and gill, of Zebra fish (Danio rerio) across different concentrations in this research. The average AChE activity decreased comparing to 0.0 TU with DM (82.81% in 0.1 TU, 56.14% in 1.0 TU and 44.68% in 2.0 TU) and with CdCl2 (74.68% in 0.1 TU, 52.05% in 1.0 TU and 50.14% in 2.0 TU) showed an overall decrease with the increase of exposure concentrations. According to Self-Organizing Map (SOM), the AChE activities were characterized in relation with experimental conditions, showing an inverse relationship with exposure time. As the exposure time was longer, the AChE activities were correspondingly lower. The AChE inhibition showed time delay in sublethal treatments (0.1 TU) in different tissues: the AChE was first inhibited in brain by chemicals followed by gill, muscle and liver (brain > gill > muscle > liver). The AChE activity was almost inhibited synchronously in higher environmental stress (1.0 TU and 2.0 TU). As the AChE inhibition can induce abnormal of behavior movement, these results will be helpful to the mechanism of stepwise behavior responses according to the time difference in different tissues rather than the whole body AChE activity.
ESTHER : Zhang_2017_Chemosphere_168_908
PubMedSearch : Zhang_2017_Chemosphere_168_908
PubMedID: 27825714

Title : Rational Design of a Red-Emissive Fluorophore with AIE and ESIPT Characteristics and Its Application in Light-Up Sensing of Esterase - Peng_2017_Anal.Chem_89_3162
Author(s) : Peng L , Xu S , Zheng X , Cheng X , Zhang R , Liu J , Liu B , Tong A
Ref : Analytical Chemistry , 89 :3162 , 2017
Abstract : The development of red fluorophores with efficient solid-state emission is still challenging. Herein, a red fluorophore 1 with aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) characteristics is rationally designed and facilely synthesized by attaching an electron-donor diethylamine and an electron-acceptor maleonitrile group to salicyladazine. In contrast to many red fluorophores which undergo serious aggregation-caused quenching (ACQ), compound 1 emits bright red fluorescence (lambdaem = 650 nm, PhiF = 24.3%) in the solid state with a large Stokes shift of 174 nm. Interestingly, control compounds 2 and 3, which have similar structures as 1, exhibit obvious aggregation-caused quenching (ACQ) characteristics. The difference in the crystal structures of 1, 2, and 3 reveals that the interplanar spacing among molecules plays a decisive role in realizing the AIE characteristics of 1. Moreover, when the hydroxyl group of 1 was substituted by an esterase reactive acetoxyl, a fluorescence light-up probe 4 was developed for sensing of esterase based on the selective reaction between 4 and esterase to generate the AIE and ESIPT active molecule 1. The linear range for in vitro quantification of esterase is 0.01-0.15 U/mL with a detection limit of 0.005 U/mL. Probe 4 was also successfully applied to image esterase in mitochondria of living cells.
ESTHER : Peng_2017_Anal.Chem_89_3162
PubMedSearch : Peng_2017_Anal.Chem_89_3162
PubMedID: 28192960

Title : Preventative effects of fermented Chimonobambusa quadrangularis shoot on activated carbon-induced constipation - Li_2017_Exp.Ther.Med_13_1093
Author(s) : Li G , Zou X , Kuang G , Ren Y , Deng C , Lin Q , Zhao X , Xu S , Song JL
Ref : Exp Ther Med , 13 :1093 , 2017
Abstract : The present study aimed to determine the preventative effects of fermented Chimonobambusa quadrangularis shoot (FCQS) on activated carbon constipation in Kun Ming mice. FCQS has a more loose fiber tissue structure than unfermented fresh C. quadrangularis shoot (CQS), which is preferable for relieving constipation. In mice fed with FCQS for 9 days the time from consumption to their first black stool defecation (117 min) was shorter than the control group (192 min) and the CQS group (148 min); however, it was longer than the normal (85 min) and bisacodyl treatment (99 min) groups. The gastrointestinal transit of the FCQS group (73.8%) was increased, as compared with the control (37.9%) and CQS (61.7%) groups; however, it was decreased as compared with the normal (100%) and bisacodyl (88.3%) groups. By observing the hemotoxylin and eosin-stained section of mice intestine, it was demonstrated that FCQS reduced injury to the intestinal tract resulting from constipation and alleviated the damage caused to the intestinal villi over the effects observed in the CQS group. Furthermore, FCQS was also able to increase the serum levels of motilin, endothelin-1, vasoactive intestinal peptide and acetylcholinesterase compared with the control group. c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GDNF) mRNA and protein expression levels in the small intestinal cells of FCQS-fed mice were increased, as compared with CQS-fed mice. Transient receptor potential cation channel subfamily V member 1 (TRPV1) and nitric oxide synthase (NOS) expression levels of small intestinal cells of FCQS-fed mice were reduced, as compared with CQS-fed mice. These findings demonstrated that FCQS may induce improved preventative effects on constipation, compared with CQS.
ESTHER : Li_2017_Exp.Ther.Med_13_1093
PubMedSearch : Li_2017_Exp.Ther.Med_13_1093
PubMedID: 28450948

Title : Evolution of Digestive Enzymes and RNASE1 Provides Insights into Dietary Switch of Cetaceans - Wang_2016_Mol.Biol.Evol_33_3144
Author(s) : Wang Z , Xu S , Du K , Huang F , Chen Z , Zhou K , Ren W , Yang G
Ref : Molecular Biology Evolution , 33 :3144 , 2016
Abstract : Although cetaceans (whales, porpoises, and dolphins) have multi-chambered stomachs, feeding habits of modern cetaceans have dramatically changed from herbivorous to carnivorous. However, the genetic basis underlying this dietary switch remains unexplored. Here, we present the first systematic investigation of 10 digestive enzymes genes (i.e., CYP7A1, CTRC, LIPC, LIPF, PNLIP, PGC, PRSS1, SI, SLC5A1, and TMPRSS15) of representative cetaceans, and the evolutionary trajectory of RNASE1 in cetartiodactylans. Positive selections were detected with proteinases (i.e., CTRC, PRSS1, and TMPRSS15) and lipases (i.e., CYP7A1, LIPF, and PNLIP) suggesting that cetaceans have evolved an enhanced digestion capacity for proteins and lipids, the major nutritional components of their prey (fishes and invertebrates). In addition, it was found that RNASE1 gene duplicated after the cetartiodactylan speciation and two independent gene duplication events took place in Camelidae and Ruminantia. Positive selection was detected with RNASE1 of Camelidae and Bovidae, suggesting enhanced digestive efficiency in the ruminants. Remarkably, even though the ancestors of cetaceans were terrestrial artiodactyls that are herbivorous, modern cetaceans lost the pancreatic RNASE1 copy with digestive function, which is in accordance with the dietary change from herbivorous to carnivorous. In sum, this is the first study that provides new insights into the evolutionary mechanism of dietary switch in cetaceans.
ESTHER : Wang_2016_Mol.Biol.Evol_33_3144
PubMedSearch : Wang_2016_Mol.Biol.Evol_33_3144
PubMedID: 27651393
Gene_locus related to this paper: souch-a0a1d8i1n4

Title : The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors - Cox_2016_Bioorg.Med.Chem.Lett_26_2622
Author(s) : Cox JM , Chu HD , Kuethe JT , Gao YD , Scapin G , Eiermann G , He H , Li X , Lyons KA , Metzger J , Petrov A , Wu JK , Xu S , Sinha-Roy R , Weber AE , Biftu T
Ref : Bioorganic & Medicinal Chemistry Lett , 26 :2622 , 2016
Abstract : Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
ESTHER : Cox_2016_Bioorg.Med.Chem.Lett_26_2622
PubMedSearch : Cox_2016_Bioorg.Med.Chem.Lett_26_2622
PubMedID: 27106708
Gene_locus related to this paper: human-DPP4

Title : Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice - Huang_2016_ACS.Chem.Neurosci_7_1047
Author(s) : Huang L , Lin J , Xiang S , Zhao K , Yu J , Zheng J , Xu D , Mak SH , Hu S , Nirasha S , Wang C , Chen X , Zhang J , Xu S , Wei X , Zhang Z , Zhou D , Zhou W , Cui W , Han YF , Hu Z , Wang Q
Ref : ACS Chem Neurosci , 7 :1047 , 2016
Abstract : Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.
ESTHER : Huang_2016_ACS.Chem.Neurosci_7_1047
PubMedSearch : Huang_2016_ACS.Chem.Neurosci_7_1047
PubMedID: 27046396

Title : Protection against beta-amyloid-induced synaptic and memory impairments via altering beta-amyloid assembly by bis(heptyl)-cognitin - Chang_2015_Sci.Rep_5_10256
Author(s) : Chang L , Cui W , Yang Y , Xu S , Zhou WH , Fu HJ , Hu SQ , Mak SH , Hu JW , Wang Q , Pui-Yan Ma V , Chung-Lit Choi T , Dik-Lung Ma E , Tao L , Pang YP , Rowan MJ , Anwyl R , Han YF
Ref : Sci Rep , 5 :10256 , 2015
Abstract : beta-amyloid (Abeta) oligomers have been closely implicated in the pathogenesis of Alzheimer's disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Abeta oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Abeta oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Abeta oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Abeta assembly via directly inhibiting Abeta oligomers formation and reducing the amount of preformed Abeta oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Abeta, which confers stabilizing powers and assembly alteration effects on Abeta. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Abeta oligomers in mice. These results clearly demonstrated how dimeric agents prevent Abeta oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.
ESTHER : Chang_2015_Sci.Rep_5_10256
PubMedSearch : Chang_2015_Sci.Rep_5_10256
PubMedID: 26194093

Title : 'Obesity' is healthy for cetaceans? Evidence from pervasive positive selection in genes related to triacylglycerol metabolism - Wang_2015_Sci.Rep_5_14187
Author(s) : Wang Z , Chen Z , Xu S , Ren W , Zhou K , Yang G
Ref : Sci Rep , 5 :14187 , 2015
Abstract : Cetaceans are a group of secondarily adapted marine mammals with an enigmatic history of transition from terrestrial to fully aquatic habitat and subsequent adaptive radiation in waters around the world. Numerous physiological and morphological cetacean characteristics have been acquired in response to this drastic habitat transition; for example, the thickened blubber is one of the most striking changes that increases their buoyancy, supports locomotion, and provides thermal insulation. However, the genetic basis underlying the blubber thickening in cetaceans remains poorly explored. Here, 88 candidate genes associated with triacylglycerol metabolism were investigated in representative cetaceans and other mammals to test whether the thickened blubber matched adaptive evolution of triacylglycerol metabolism-related genes. Positive selection was detected in 41 of the 88 candidate genes, and functional characterization of these genes indicated that these are involved mainly in triacylglycerol synthesis and lipolysis processes. In addition, some essential regulatory genes underwent significant positive selection in cetacean-specific lineages, whereas no selection signal was detected in the counterpart terrestrial mammals. The extensive occurrence of positive selection in triacylglycerol metabolism-related genes is suggestive of their essential role in secondary adaptation to an aquatic life, and further implying that 'obesity' might be an indicator of good health for cetaceans.
ESTHER : Wang_2015_Sci.Rep_5_14187
PubMedSearch : Wang_2015_Sci.Rep_5_14187
PubMedID: 26381091
Gene_locus related to this paper: delle-a0a2y9m8t8 , lipve-a0a0n6wyt2

Title : Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson's Disease - Chen_2015_ACS.Chem.Neurosci_6_1708
Author(s) : Chen T , Hou R , Xu S , Wu C
Ref : ACS Chem Neurosci , 6 :1708 , 2015
Abstract : 1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer's disease (AD). In the present study, we tested the hypothesis that MPP+ promotes microglial M1 polarization and suppresses M2 polarization and that this can be restored by donepezil. Results indicate that MPP+ treatment in microglial BV2 cells promotes microglial polarization toward the M1 state. However, pretreatment with donepezil inhibited MPP+-induced M1 polarization in microglia by suppressing the release of interleukin (IL)-6, IL-1beta, or tumor necrosis factor (TNF)-alpha. Importantly, we found that MPP+ inhibited microglial M2 polarization by suppressing expression of Arg-1, Fizz1, and Ym1, which was also rescued by pretreatment with donepezil. In addition, IL-4-mediated induction of anti-inflammatory marker genes IL-10, IL-13, and transforming growth factor-beta2 (TGF-beta2) were significantly attenuated by MPP+ in BV2 cells, which was restored by pretreatment with donepezil in a concentration-dependent manner. Mechanistically, we found that the addition of MPP+ reduced the intensity of phosphorylated signal transducer and activator of transcription 6 (STAT6) but not total STAT6 in IL-4-stimulated BV2 cells. Importantly, pretreatment of microglial BV2 cells with donepezil 3 h prior to administration of MPP+ rescued the reduction of STAT6 phosphorylation induced by MPP+.
ESTHER : Chen_2015_ACS.Chem.Neurosci_6_1708
PubMedSearch : Chen_2015_ACS.Chem.Neurosci_6_1708
PubMedID: 26114860

Title : Prenatal exposure of guinea pigs to the organophosphorus pesticide chlorpyrifos disrupts the structural and functional integrity of the brain - Mullins_2015_Neurotoxicol_48_9
Author(s) : Mullins RJ , Xu S , Pereira EF , Pescrille JD , Todd SW , Mamczarz J , Albuquerque EX , Gullapalli RP
Ref : Neurotoxicology , 48 :9 , 2015
Abstract : This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (25 mg/kg, s.c.) or vehicle (peanut oil) once per day for 10 consecutive days, starting approximately on the 50th day of gestation. Cognitive behavior of female offspring was examined starting at 40-45 post-natal days (PND) using the Morris water maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T2-weighted anatomical scans and diffusion kurtosis imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of prenatal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment.
ESTHER : Mullins_2015_Neurotoxicol_48_9
PubMedSearch : Mullins_2015_Neurotoxicol_48_9
PubMedID: 25704171

Title : Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors - Wang_2015_Bioorg.Med.Chem.Lett_25_5212
Author(s) : Wang C , Wu Z , Cai H , Xu S , Liu J , Jiang J , Yao H , Wu X , Xu J
Ref : Bioorganic & Medicinal Chemistry Lett , 25 :5212 , 2015
Abstract : A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.
ESTHER : Wang_2015_Bioorg.Med.Chem.Lett_25_5212
PubMedSearch : Wang_2015_Bioorg.Med.Chem.Lett_25_5212
PubMedID: 26454504

Title : Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors - Xu_2015_Sci.Rep_5_14261
Author(s) : Xu S , Zhang T , Kompella SN , Yan M , Lu A , Wang Y , Shao X , Chi C , Adams DJ , Ding J , Wang C
Ref : Sci Rep , 5 :14261 , 2015
Abstract : Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting alphaD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of alphaD-GeXXA, GeXXA-CTD, retains inhibitory activity against the alpha9alpha10 nAChR subtype. Furthermore, we identified that His7 of the rat alpha10 nAChR subunit determines the species preference of alphaD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that alphaD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of alphaD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.
ESTHER : Xu_2015_Sci.Rep_5_14261
PubMedSearch : Xu_2015_Sci.Rep_5_14261
PubMedID: 26395518

Title : Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease - Zheng_2015_Pharm.Res_32_3837
Author(s) : Zheng X , Shao X , Zhang C , Tan Y , Liu Q , Wan X , Zhang Q , Xu S , Jiang X
Ref : Pharm Res , 32 :3837 , 2015
Abstract : PURPOSE: H102, a novel beta-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD).
METHODS: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia.
RESULTS: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa.
CONCLUSIONS: The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.
ESTHER : Zheng_2015_Pharm.Res_32_3837
PubMedSearch : Zheng_2015_Pharm.Res_32_3837
PubMedID: 26113236

Title : Alterations in activity and mRNA expression of acetylcholinesterase in the liver, kidney and gill of common carp exposed to atrazine and chlorpyrifos - Xing_2013_Environ.Toxicol.Pharmacol_35_47
Author(s) : Xing H , Wu H , Sun G , Zhang Z , Xu S , Li S
Ref : Environ Toxicol Pharmacol , 35 :47 , 2013
Abstract : Insecticides and herbicides are widely used in modern agricultural production. The intensive use of insecticide chlorpyrifos (CPF) and herbicide atrazine (ATR) has resulted in serious environmental problems. Herein, we investigated alteration in activity and mRNA levels of AChE in the liver, kidney and gill from common carp after 40d exposure to CPF and ATR alone or in combination and 20d recovery treatment. Results indicated that activity and mRNA levels of AChE at all high-dose groups have been significantly decreased after CPF and ATR alone or ATR/CPF mixture exposure, and the changes were improved in the end of recovery tests in varying degrees, the activity and gene expression of AChE in the joint toxicity of ATR and CPF groups were significantly lower than that in the single toxicant group. Our study suggests that the decrease of AChE activity observed at all high-dose groups (CPF and ATR alone or in combination) may be directly related to a lower AChE expression, and the joint toxicity of ATR and CPF is higher than ATR and CPF alone.
ESTHER : Xing_2013_Environ.Toxicol.Pharmacol_35_47
PubMedSearch : Xing_2013_Environ.Toxicol.Pharmacol_35_47
PubMedID: 23237783

Title : Does preconception paternal exposure to a physiologically relevant level of bisphenol A alter spatial memory in an adult rat? - Fan_2013_Horm.Behav_64_598
Author(s) : Fan Y , Ding S , Ye X , Manyande A , He D , Zhao N , Yang H , Jin X , Liu J , Tian C , Xu S , Ying C
Ref : Horm Behav , 64 :598 , 2013
Abstract : Bisphenol A (BPA) is a ubiquitous environmental endocrine disrupting compound (EDC); public health concerns have been fueled by findings that maternal BPA exposure can change sex differences in the brain and in some behaviors. We investigated whether a physiologically relevant dose of BPA ingested by male rats before conception would affect spatial memory and hippocampal acetylcholinesterase (AchE) in their adult offspring. Twenty-two 60-day-old male rats (F0) received either a BPA diet (50mug/kg/day) or vehicle alone for 10weeks before being mated with non-exposed females. The paternal rats and their forty adult offspring's (F1) behaviors were then examined in the Morris Water Maze (MWM) and their AchE activities in the hippocampus were evaluated. BPA exposure led to spatial memory deficits along with decreased AchE activities in the hippocampus (p=0.01) in adult F0 rats. This paternal exposure also induced impairment in spatial memory acquisition in both sexes while retention only in females in F1 rats, as well as abolished sex differences in the hippocampus AchE. Overall, these data provide new evidence that paternal BPA exposure, at a "safe" dose, may induce transgenerational alterations in spatial memory in a sex-specific manner.
ESTHER : Fan_2013_Horm.Behav_64_598
PubMedSearch : Fan_2013_Horm.Behav_64_598
PubMedID: 24005185

Title : Poster: Novel strategy of blocking nAChR revealed by dissecting a dimeric conotoxin alphaD-GeXXA -
Author(s) : Kompella SN , Xu S , Zhang T , Yan M , Shao X , Chi C , Ding J , Wang C , Adams DJ
Ref : Biochemical Pharmacology , 86 :1229 , 2013

Title : Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors - Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
Author(s) : Debenham JS , Graham TH , Verras A , Zhang Y , Clements MJ , Kuethe JT , Madsen-Duggan C , Liu W , Bhatt UR , Chen D , Chen Q , Garcia-Calvo M , Geissler WM , He H , Li X , Lisnock J , Shen Z , Tong X , Tung EC , Wiltsie J , Xu S , Hale JJ , Pinto S , Shen DM
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :6228 , 2013
Abstract : The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
ESTHER : Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
PubMedSearch : Debenham_2013_Bioorg.Med.Chem.Lett_23_6228
PubMedID: 24157366

Title : Surface Display of Recombinant Drosophila melanogaster Acetylcholinesterase for Detection of Organic Phosphorus and Carbamate Pesticides - Li_2013_PLoS.One_8_e72986
Author(s) : Li J , Qian B , Yin J , Wu S , Zhuan F , Xu S , Salazar JK , Zhang W , Wang H
Ref : PLoS ONE , 8 :e72986 , 2013
Abstract : Acetylcholinesterase (AChE) is commonly used for the detection of organophosphate (OP) and carbamate (CB) insecticides. However, the cost of this commercially available enzyme is high, making high-throughput insecticide detection improbable. In this study we constructed a new AChE yeast expression system in Saccharomyces cerevisiae for the expression of a highly reactive recombinant AChE originating from Drosophila melanogaster (DmAChE). Specifically, the coding sequence of DmAChE was fused with the 3'-terminal half of an alpha-agglutinin anchor region, along with an antigen tag for the detection of the recombinant protein. The target sequence was cloned into the yeast expression vector pYes-DEST52, and the signal peptide sequence was replaced with a glucoamylase secretion region for induced expression. The resultant engineered vector was transformed into S. cerevisiae. DmAChE was expressed and displayed on the cell surface after galactose induction. Our results showed that the recombinant protein displayed activity comparable to the commercial enzyme. We also detected different types of OP and CB insecticides through enzyme inhibition assays, with the expressed DmAChE showing high sensitivity. These results show the construction of a new yeast expression system for DmAChE, which can subsequently be used for detecting OP and CB insecticides with reduced economic costs.
ESTHER : Li_2013_PLoS.One_8_e72986
PubMedSearch : Li_2013_PLoS.One_8_e72986
PubMedID: 24039837

Title : Delayed hippocampal effects from a single exposure of prepubertal guinea pigs to sub-lethal dose of chlorpyrifos: a magnetic resonance imaging and spectroscopy study - Mullins_2013_Neurotoxicol_36_42
Author(s) : Mullins RJ , Xu S , Pereira EF , Mamczarz J , Albuquerque EX , Gullapalli RP
Ref : Neurotoxicology , 36 :42 , 2013
Abstract : This study was designed to test the hypothesis that in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) can detect in adulthood the neurotoxic effects of a single exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos. Twelve female guinea pigs were given either a single dose of chlorpyrifos (0.6xLD50 or 300mg/kg, sc) or peanut oil (vehicle; 0.5ml/kg, sc) at 35-40 days of age. One year after the exposure, the animals were tested in the Morris water maze. Three days after the end of the behavioral testing, the metabolic and structural integrity of the brain of the animals was examined by means of MRI/MRS. In the Morris water maze, the chlorpyrifos-exposed guinea pigs showed significant memory deficit. Although no significant anatomical differences were found between the chlorpyrifos-exposed guinea pigs and the control animals by in vivo MRI, the chlorpyrifos-exposed animals showed significant decreases in hippocampal myo-inositol concentration using MRS. The present results indicate that a single sub-lethal exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos can lead to long-term memory deficits that are accompanied by significant reductions in the levels of hippocampal myo-inositol.
ESTHER : Mullins_2013_Neurotoxicol_36_42
PubMedSearch : Mullins_2013_Neurotoxicol_36_42
PubMedID: 23411083

Title : The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors - Graham_2012_Bioorg.Med.Chem.Lett_22_658
Author(s) : Graham TH , Shen HC , Liu W , Xiong Y , Verras A , Bleasby K , Bhatt UR , Chabin RM , Chen D , Chen Q , Garcia-Calvo M , Geissler WM , He H , Lassman ME , Shen Z , Tong X , Tung EC , Xie D , Xu S , Colletti SL , Tata JR , Hale JJ , Pinto S , Shen DM
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :658 , 2012
Abstract : Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
ESTHER : Graham_2012_Bioorg.Med.Chem.Lett_22_658
PubMedSearch : Graham_2012_Bioorg.Med.Chem.Lett_22_658
PubMedID: 22079761
Gene_locus related to this paper: human-PRCP

Title : Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors - Shen_2011_Bioorg.Med.Chem.Lett_21_1299
Author(s) : Shen HC , Ding FX , Zhou C , Xiong Y , Verras A , Chabin RM , Xu S , Tong X , Xie D , Lassman ME , Bhatt UR , Garcia-Calvo MM , Geissler W , Shen Z , Chen D , SinhaRoy R , Hale JJ , Tata JR , Pinto S , Shen DM , Colletti SL
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :1299 , 2011
Abstract : A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.
ESTHER : Shen_2011_Bioorg.Med.Chem.Lett_21_1299
PubMedSearch : Shen_2011_Bioorg.Med.Chem.Lett_21_1299
PubMedID: 21315588
Gene_locus related to this paper: human-PRCP

Title : Apelin decreases lipolysis via G(q), G(i), and AMPK-Dependent Mechanisms - Yue_2011_Endocrinology_152_59
Author(s) : Yue P , Jin H , Xu S , Aillaud M , Deng AC , Azuma J , Kundu RK , Reaven GM , Quertermous T , Tsao PS
Ref : Endocrinology , 152 :59 , 2011
Abstract : The release of free fatty acids (FFAs) from adipocytes (i.e. lipolysis) is increased in obesity and is a contributory factor to the development of insulin resistance. A recently identified adipokine, apelin, is up-regulated in states of obesity. Although apelin is secreted by adipocytes, its functions in them remain largely unknown. To determine whether apelin affects lipolysis, FFA, glycerol, and leptin levels, as well as abdominal adiposity, were measured at baseline and after reintroduction of exogenous apelin in apelin-null mice. To examine apelin's effects in vitro, isoproterenol-induced FFA/glycerol release, and hormone-sensitive lipase (HSL) and acetyl CoA carboxylase phosphorylation were investigated in 3T3-L1 cells and isolated wild-type adipocytes. Serum FFA, glycerol, and leptin concentrations, as well as abdominal adiposity, were significantly increased in apelin-null vs. wild-type mice; these changes were ameliorated in response to exogenous apelin. Apelin also reduced isoproterenol-induced FFA release in adipocytes isolated from wild-type but not APJ-null mice. In 3T3-L1 cells and isolated adipocytes, apelin attenuated isoproterenol-induced FFA/glycerol release. Apelin's inhibition was reversed by pertussis toxin, the G(q) inhibitor glycoprotein antagonist 2A, and the AMP-activated protein kinase inhibitors compound C and dorsomorphin. Apelin increased HSL phosphorylation at Ser-565 and also abrogated isoproterenol-induced HSL phosphorylation at Ser-563. Notably, apelin increased acetyl CoA carboxylase phosphorylation, suggesting AMPK activation. In conclusion, apelin negatively regulates lipolysis. Its actions may be mediated by pathways involving G(q), G(i), and AMP-activated protein kinase.
ESTHER : Yue_2011_Endocrinology_152_59
PubMedSearch : Yue_2011_Endocrinology_152_59
PubMedID: 21047945

Title : Elevated adipose triglyceride lipase in newly diagnosed type 2 diabetes mellitus with hypertension - Xu_2011_Am.J.Med.Sci_342_452
Author(s) : Xu S , Yang G , Yang M , Li S , Liu H , Li L
Ref : American Journal of Medicine Sci , 342 :452 , 2011
Abstract : INTRODUCTION: Adipose triglyceride lipase (ATGL) is a recently identified triacylglycerol lipase responsible for adiposity lipolysis. Its pathophysiologic role in humans remains unknown. MATERIAL AND METHODS: In this study, the authors investigated the levels of plasma ATGL among patients with type 2 diabetes mellitus (T2DM), patients with T2DM and hypertension and control subjects. They also assessed the association between plasma ATGL and body composition and metabolic parameters. RESULTS AND CONCLUSIONS: Plasma ATGL levels significantly increased in patients with T2DM and hypertension compared with those with T2DM (78.3 +/- 23.4 versus 65.1 +/- 22.8 mug/L, P < 0.01). No gender differences were found among plasma ATGL levels. Furthermore, they found that the plasma ATGL level was positively correlated with total cholesterol (r = 0.17, P < 0.05) and high-density lipoprotein C (r = 0.16, P < 0.05) in simple regression analysis of pooled data, whereas, in multiple stepwise regression analysis, diastolic blood pressure, total cholesterol and homeostasis model assessment of insulin resistance were independently related factors with plasma ATGL levels (Y = -13.662 + 0.343 x waist + 0.268 x diastolic blood pressure + 0.053 x 2hPin + 0.966 x homeostasis model assessment of insulin resistance). This work indicates the potential link of ATGL with the pathogenesis of insulin resistance and T2DM.
ESTHER : Xu_2011_Am.J.Med.Sci_342_452
PubMedSearch : Xu_2011_Am.J.Med.Sci_342_452
PubMedID: 21709540

Title : Integrated biomarker response index for the assessment of environmental stress of the Yangtze River (Nanjing section) - Wang_2010_Fish.Physiol.Biochem_36_1069
Author(s) : Wang C , Lu GH , Song WT , Xu S , Wang PF
Ref : Fish Physiol Biochem , 36 :1069 , 2010
Abstract : In the present study, multibiomarker effects of the river water of three representative sections in Nanjing section of the Yangtze River were investigated in goldfish (Carassius auratus). The organic toxicants were extracted from the water samples using solid phase extraction. Acetylcholinesterase (AChE), glutathione-S-transferase (GST), 7-ethoxyresorufin-O-deethylase (EROD), glutathione peroxidase (GPx) and Na+/K+-ATPase activities were determined after exposure of the extracted components. The fractions of water samples from three sections (Daqiao, Sanchahe and Jiangxinzhou) altered these enzymatic activities. With the change of the extracts polarity, the levels of AChE, GST, EROD, Na+/K+-ATPase activities were different. The responses of enzymatic activities were mostly significant for those exposures of intermediate polar components (50-80% methanol extracts) and weakly polar components (ether and ether/hexane extracts). It has been shown that toxicants were mainly concentrated in these fractions in the Yangtze River (Nanjing section). With regard to response for different sections, EROD and GST activities seem to be more sensitive biomarkers. Integrated biomarker response index (IBR) were calculated and used to evaluate an integrated impact of pollutants from different sampling sections. The order of negative biological effects of the three sections was Jiangxinzhou>Sanchahe>Daqiao. The wild fish living in Nanjing section of the Yangtze River were at potential ecological risk.
ESTHER : Wang_2010_Fish.Physiol.Biochem_36_1069
PubMedSearch : Wang_2010_Fish.Physiol.Biochem_36_1069
PubMedID: 20473565

Title : [Cloning, expression and characterization of a novel esterase from marine sediment microbial metagenomic library] - Xu_2010_Wei.Sheng.Wu.Xue.Bao_50_891
Author(s) : Xu S , Hu Y , Yuan A , Zhu B
Ref : Wei Sheng Wu Xue Bao , 50 :891 , 2010
Abstract : OBJECTIVE: To clone, express and characterize a novel esterase from marine sediment microbial metagenomic library.
METHODS: Using esterase segregation agar containing tributyrin, we obtained esterase positive fosmid clone FL10 from marine sediment microbial metagenomic library. This fosmid was partially digested with Sau3A I to construct the sublibrary, from which the esterase positive subclone pFLS10 was obtained. The full length of the esterase gene was amplified and cloned into the expressing vector pET28a, and the recombinant plasmid was transformed into E. coli BL21 cells. We analyse the enzyme activity and study the characterization of the esterase after its expression and purification.
RESULTS: An ORF (Open Reading Frame) of 924 bp was identified from the subclone pFLS10. Sequence analysis indicated that it showed 71% amino acid identity to esterase (ADA70030) from a marine sediment metagenomic library. The esterase is a novel low-temperature-active esterase and had highest lipolytic activity to the substrate of 4-nitrophenyl butyrate (C4). The optimum temperature of the esterase was 20 degrees C, the optimum pH was 7.5. The esterase in this study had good thermostability at 20 degrees C and good pH stability at pH8 -10. Significant increase in lipolytic activity was observed with addition of K+ and Mg2+, while decrease with Mn2+ etc. CONCLUSION: We obtained the novel esterase gene fls10 from the marine sediment microbial metagenomic library. The esterase had good thermostability and high lipolytic activity at low temperature and under basic conditions, which laid a basis for industrial application.
ESTHER : Xu_2010_Wei.Sheng.Wu.Xue.Bao_50_891
PubMedSearch : Xu_2010_Wei.Sheng.Wu.Xue.Bao_50_891
PubMedID: 20815235

Title : Alterations in mRNA expression of acetylcholinesterase in brain and muscle of common carp exposed to atrazine and chlorpyrifos - Xing_2010_Ecotoxicol.Environ.Saf_73_1666
Author(s) : Xing H , Han Y , Li S , Wang J , Wang X , Xu S
Ref : Ecotoxicology & Environmental Safety , 73 :1666 , 2010
Abstract : The uses of pesticides and herbicides have become an integral part of modern agricultural systems. The intensive use of pesticides chlorpyrifos (CPF) and herbicides atrazine (ATR) has resulted in serious environmental problems. Herein, we have developed real-time quantitative polymerase chain reaction assays for common carp (Cyprinus carpio L.) mRNA. The levels of AChE mRNA were evaluated in brain and muscle collected from common carp by treatment of ATR, CPF, and their mixture. The decreased transcription of AChE was detected in both tissues at different doses of the toxicants in the end of exposure tests, and the changes were improved in the end of recovery tests in varying degrees. It is suggested that transcription inhibition of AChE might be significant in long-playing single or associated exposure of ATR and CPF in common carp. Alteration in transcription of AChE caused by ATR, CPF, and their mixture could reveal the toxic mechanisms related to cholinergic signaling.
ESTHER : Xing_2010_Ecotoxicol.Environ.Saf_73_1666
PubMedSearch : Xing_2010_Ecotoxicol.Environ.Saf_73_1666
PubMedID: 20696475

Title : Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors - Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
Author(s) : Edmondson SD , Mastracchio A , Cox JM , Eiermann GJ , He H , Lyons KA , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Xu S , Zhu B , Thornberry NA , Roy RS , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :4097 , 2009
Abstract : A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
ESTHER : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedSearch : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedID: 19539471
Gene_locus related to this paper: human-DPP4

Title : Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement - Shen_2009_J.Med.Chem_52_5009
Author(s) : Shen HC , Ding FX , Wang S , Deng Q , Zhang X , Chen Y , Zhou G , Xu S , Chen HS , Tong X , Tong V , Mitra K , Kumar S , Tsai C , Stevenson AS , Pai LY , Alonso-Galicia M , Chen X , Soisson SM , Roy S , Zhang B , Tata JR , Berger JP , Colletti SL
Ref : Journal of Medicinal Chemistry , 52 :5009 , 2009
Abstract : 4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
ESTHER : Shen_2009_J.Med.Chem_52_5009
PubMedSearch : Shen_2009_J.Med.Chem_52_5009
PubMedID: 19645482

Title : Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors - Edmondson_2008_Bioorg.Med.Chem.Lett_18_2409
Author(s) : Edmondson SD , Wei L , Xu J , Shang J , Xu S , Pang J , Chaudhary A , Dean DC , He H , Leiting B , Lyons KA , Patel RA , Patel SB , Scapin G , Wu JK , Beconi MG , Thornberry NA , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :2409 , 2008
Abstract : The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
ESTHER : Edmondson_2008_Bioorg.Med.Chem.Lett_18_2409
PubMedSearch : Edmondson_2008_Bioorg.Med.Chem.Lett_18_2409
PubMedID: 18331795
Gene_locus related to this paper: human-DPP4

Title : Lipase-catalyzed selective synthesis of monolauroyl maltose using continuous stirred tank reactor - Liu_2008_Biotechnol.Lett_30_497
Author(s) : Liu Q , Jia C , Kim JM , Jiang P , Zhang X , Feng B , Xu S
Ref : Biotechnol Lett , 30 :497 , 2008
Abstract : Monolauroyl maltose was synthesized by an immobilized lipase that catalyzed condensation of maltose and lauric acid in acetone using a batch reactor or a continuous stirred tank reactor. Mono- and di-lauroyl maltoses were identified by FT-IR, (1)H NMR, (13)C NMR and MS. Monolauroyl maltose was selectively synthesized in a continuous stirred tank reactor and no diester was detected. The highest concentration of monolauroyl maltose at 28 mmol/l was obtained in 250 ml acetone when maltose was added at 4 g/d and the molar ratio of lauric acid to maltose was fixed at 4:1 at a flow rate of 0.15 ml/min for both influx and effluent without supplement of fresh molecular sieve.
ESTHER : Liu_2008_Biotechnol.Lett_30_497
PubMedSearch : Liu_2008_Biotechnol.Lett_30_497
PubMedID: 17968509

Title : Production of a novel recombinant Drosophila melanogaster acetylcholinesterase for detection of organophosphate and carbamate insecticide residues - Xu_2007_Biomol.Eng_24_253
Author(s) : Xu S , Wu A , Chen H , Xie Y , Xu Y , Zhang L , Li J , Zhang D
Ref : Biomol Eng , 24 :253 , 2007
Abstract : A novel recombinant Drosophila melanogaster acetylcholinesterase (R-DmAChE) produced in Pichia pastoris was first reported in this study. We cloned the DmAChE cDNA by reverse transcription PCR with removal of the signal for glycosylphosphatidylinositol (GPI) anchor attachment and the endogenous signal peptide coding sequence, and inserted it into P. pastoris vector pPIC9K under control of the alcohol oxidase gene AOX1 promoter (5'AOX1). The expression cassette of AChE cDNA was then introduced into methylotrophic yeast GS115 and several recombinant strains expressing R-DmAChE were obtained. The secreted R-DmAChE showed high stability in neutral phosphate buffer at 4 degrees C, and its kinetic parameters were identical to those of the native DmAChE. The bimolecular rate constants of R-DmAChE to dichlorvos, aldicarb and carbaryl were ranging from three to six times higher than of native DmAChE. Within six insecticides, the R-DmAChE was more sensitive than EeAChE, NbAChE and HuAChE. For 10 widely used insecticides, the IC50 values to the R-DmAChE were much lower than those to AChEs commonly used in China. With the R-DmAChE-based assay, samples spiked with three concentrations of pesticides caused enzymatic activity inhibition with R.S.D. of 0-13.7%. These results suggest that the R-DmAChE can be useful for detection of organophosphate and carbamate insecticide residues.
ESTHER : Xu_2007_Biomol.Eng_24_253
PubMedSearch : Xu_2007_Biomol.Eng_24_253
PubMedID: 17222583

Title : Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors - Cox_2007_Bioorg.Med.Chem.Lett_17_4579
Author(s) : Cox JM , Harper B , Mastracchio A , Leiting B , Sinha Roy R , Patel RA , Wu JK , Lyons KA , He H , Xu S , Zhu B , Thornberry NA , Weber AE , Edmondson SD
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :4579 , 2007
Abstract : Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
ESTHER : Cox_2007_Bioorg.Med.Chem.Lett_17_4579
PubMedSearch : Cox_2007_Bioorg.Med.Chem.Lett_17_4579
PubMedID: 17562364

Title : Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein - Chu_2007_J.Pharmacol.Exp.Ther_321_673
Author(s) : Chu XY , Bleasby K , Yabut J , Cai X , Chan GH , Hafey MJ , Xu S , Bergman AJ , Braun MP , Dean DC , Evers R
Ref : Journal of Pharmacology & Experimental Therapeutics , 321 :673 , 2007
Abstract : Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor recently approved for the treatment of type 2 diabetes, is excreted into the urine via active tubular secretion and glomerular filtration in humans. In this report, we demonstrate that sitagliptin is transported by human organic anion transporter hOAT3 (Km=162 microM), organic anion transporting polypeptide OATP4C1, and multidrug resistance (MDR) P-glycoprotein (Pgp), but not by human organic cation transporter 2 hOCT2, hOAT1, oligopeptide transporter hPEPT1, OATP2B1, and the multidrug resistance proteins MRP2 and MRP4. Our studies suggested that hOAT3, OATP4C1, and MDR1 Pgp might play a role in transporting sitagliptin into and out of renal proximal tubule cells, respectively. Sitagliptin did not inhibit hOAT1-mediated cidofovir uptake, but it showed weak inhibition of hOAT3-mediated cimetidine uptake (IC50=160 microM). hOAT3-mediated sitagliptin uptake was inhibited by probenecid, ibuprofen, furosemide, fenofibric acid, quinapril, indapamide, and cimetidine with IC50 values of 5.6, 3.7, 1.7, 2.2, 6.2, 11, and 79 microM, respectively. Sitagliptin did not inhibit Pgp-mediated transport of digoxin, verapamil, ritonavir, quinidine, and vinblastine. Cyclosporine A significantly inhibited Pgp-mediated transport of sitagliptin (IC50=1 microM). Our data indicate that sitagliptin is unlikely to be a perpetrator of drug-drug interactions with Pgp, hOAT1, or hOAT3 substrates at clinically relevant concentrations. Renal secretion of sitagliptin could be inhibited if coadministered with OAT3 inhibitors such as probenecid. However, the magnitude of interactions should be low, and the effects may not be clinically meaningful, due to the high safety margin of sitagliptin.
ESTHER : Chu_2007_J.Pharmacol.Exp.Ther_321_673
PubMedSearch : Chu_2007_J.Pharmacol.Exp.Ther_321_673
PubMedID: 17314201

Title : Disposition of the dipeptidyl peptidase 4 inhibitor sitagliptin in rats and dogs - Beconi_2007_Drug.Metab.Dispos_35_525
Author(s) : Beconi MG , Reed JR , Teffera Y , Xia YQ , Kochansky CJ , Liu DQ , Xu S , Elmore CS , Ciccotto S , Hora DF , Stearns RA , Vincent SH
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 35 :525 , 2007
Abstract : The pharmacokinetics, metabolism, and excretion of sitagliptin [MK-0431; (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine], a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [(14)C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.
ESTHER : Beconi_2007_Drug.Metab.Dispos_35_525
PubMedSearch : Beconi_2007_Drug.Metab.Dispos_35_525
PubMedID: 17220241

Title : (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]tr iazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Edmondson_2006_J.Med.Chem_49_3614
Author(s) : Edmondson SD , Mastracchio A , Mathvink RJ , He J , Harper B , Park YJ , Beconi M , Di Salvo J , Eiermann GJ , He H , Leiting B , Leone JF , Levorse DA , Lyons K , Patel RA , Patel SB , Petrov A , Scapin G , Shang J , Roy RS , Smith A , Wu JK , Xu S , Zhu B , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 49 :3614 , 2006
Abstract : A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]tr iazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
ESTHER : Edmondson_2006_J.Med.Chem_49_3614
PubMedSearch : Edmondson_2006_J.Med.Chem_49_3614
PubMedID: 16759103
Gene_locus related to this paper: human-DPP4

Title : Monitoring enzyme reaction and screening enzyme inhibitor based on MALDI-TOF-MS platform with a matrix of oxidized carbon nanotubes - Hu_2006_J.Am.Soc.Mass.Spectrom_17_1616
Author(s) : Hu L , Jiang G , Xu S , Pan C , Zou H
Ref : J Am Soc Mass Spectrom , 17 :1616 , 2006
Abstract : A matrix assisted laser desorption/ionization time-of-flight mass spectrometry platform for quantitatively monitoring enzyme activity and screening enzyme inhibitors has been demonstrated. The described method employs a new matrix of oxidized carbon nanotubes. Compared with the traditional fluorescence approach, this label-free method has the advantage of directly identifying the substrates and products in enzymatic reactions. Moreover, the method could be conveniently carried out with any commercial mass spectrometer without modification. We quantitatively monitored the acetylcholinesterase activity and screened acetylcholinesterase inhibitors with a detection rate of about 3.3 s per sample.
ESTHER : Hu_2006_J.Am.Soc.Mass.Spectrom_17_1616
PubMedSearch : Hu_2006_J.Am.Soc.Mass.Spectrom_17_1616
PubMedID: 16905330

Title : p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia - Guan_2003_J.Neurosci_23_7317
Author(s) : Guan Z , Kim JH , Lomvardas S , Holick K , Xu S , Kandel ER , Schwartz JH
Ref : Journal of Neuroscience , 23 :7317 , 2003
Abstract : At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinant Aplysia p38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.
ESTHER : Guan_2003_J.Neurosci_23_7317
PubMedSearch : Guan_2003_J.Neurosci_23_7317
PubMedID: 12917365

Title : Microglia and the early phase of immune surveillance in the axotomized facial motor nucleus: impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage-colony stimulating factor-deficient mice - Kalla_2001_J.Comp.Neurol_436_182
Author(s) : Kalla R , Liu Z , Xu S , Koppius A , Imai Y , Kloss CU , Kohsaka S , Gschwendtner A , Moller JC , Werner A , Raivich G
Ref : Journal of Comparative Neurology , 436 :182 , 2001
Abstract : Activation of microglia is among the first cellular changes in the injured CNS. However, little is known about their specific contribution to secondary damage or repair processes in neighboring neurons and nonneuronal cells or to the immune surveillance of the damaged tissue. Animal models with defective microglial response such as osteopetrosis provide an approach to explore these effects. Osteopetrosis (op) is an autosomal recessive mutation with a complete deficiency of the macrophage-colony stimulating factor (MCSF; CSF-1), an important mitogen for brain microglia. In the current study we examined the effects of this MCSF deficiency on the microglial reaction and the overall cellular response to nerve injury in the mouse axotomized facial motor nucleus. In the brain, MCSF receptor immunoreactivity was found only on microglia and was strongly up-regulated following injury. MCSF deficiency led to a failure of microglia to show a normal increase in early activation markers (thrombospondin, MCSF receptor, alpha M beta 2- and alpha 5 beta 1-integrins), to spread on the surface of axotomized motoneurons, and to proliferate after injury. Early recruitment of CD3(+) T-lymphocytes to the facial nucleus 24 hours after injury was reduced by 60%. In contrast, the neuronal and astrocyte response was not affected. There was a normal increase in the neuropeptides calcitonin gene-related peptide and galanin, neuronal c-JUN, and NADPH-diaphorase and a decrease in choline acetyltransferase and acetylcholinesterase. Astrocyte glial fibrillary acidic protein immunoreactivity also showed a normal increase. There was a normal influx of macrophages and granulocytes into the injured facial nerve. Synaptic stripping, neuronal survival, and speed of axonal regeneration were also not affected. The current results show a strong, selective effect of MCSF on the early activation of microglia and, indirectly, on lymphocyte recruitment. This early phase of microglial activation appears not to be involved in the process of repair following peripheral nerve injury. However, it is important in the initiation of inflammatory changes in the brain and in the interaction with the immune system.
ESTHER : Kalla_2001_J.Comp.Neurol_436_182
PubMedSearch : Kalla_2001_J.Comp.Neurol_436_182
PubMedID: 11438923

Title : Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans - Fire_1998_Nature_391_806
Author(s) : Fire A , Xu S , Montgomery MK , Kostas SA , Driver SE , Mello CC
Ref : Nature , 391 :806 , 1998
Abstract : Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene. Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts. RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression. Here we investigate the requirements for structure and delivery of the interfering RNA. To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually. After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference. The effects of this interference were evident in both the injected animals and their progeny. Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
ESTHER : Fire_1998_Nature_391_806
PubMedSearch : Fire_1998_Nature_391_806
PubMedID: 9486653