Author Report for: Zhang PNo contact information in database for Zhang P
Fan X, Zhang P, Fan M, Jiang P, Leng Y Ref: Bioprocess Biosyst Eng, :, 2023 : PubMed ESTHER: Fan_2023_Bioprocess.Biosyst.Eng__ PubMedSearch: Fan 2023 Bioprocess.Biosyst.Eng PubMedID: 37329348 Abstract Acidified oil is obtained from by-product of crops oil refining industry, which is considered as a low-cost material for fatty acid production. Hydrolysis of acidified oil by lipase catalysis for producing fatty acid is a sustainable and efficient bioprocess that is an alternative of continuous countercurrent hydrolysis. In this study, lipase from Candida rugosa (CRL) was immobilized on magnetic Fe(3)O(4)@SiO(2) via covalent binding strategy for highly efficient hydrolysis of acidified soybean oil. FTIR, XRD, SEM and VSM were used to characterize the immobilized lipase (Fe(3)O(4)@SiO(2)-CRL). The enzyme properties of the Fe(3)O(4)@SiO(2)-CRL were determined. Fe(3)O(4)@SiO(2)-CRL was used to catalyze the hydrolysis of acidified soybean oil to produce fatty acids. Catalytic reaction conditions were studied, including amount of catalyst, reaction time, and water/oil ratio. The results of optimization indicated that the hydrolysis rate reached 98% under 10 wt.% (oil) of catalyst, 3:1 (v/v) of water/oil ratio, and 313 K after 12 h. After 5 cycles, the hydrolysis activity of Fe(3)O(4)@SiO(2)-CRL remained 55%. Preparation of fatty acids from high-acid-value by-products through biosystem shows great industrial potential. Title: Development of biodegradable nanogels for lipase accelerated drug release of 5-aminolevulinic acid Liu X, Zhang Y, Zhang P, Ge K, Zhang R, Sun Y, Sheng Y, Bradley M Ref: Colloids Surf B Biointerfaces, 225:113268, 2023 : PubMed ESTHER: Liu_2023_Colloids.Surf.B.Biointerfaces_225_113268 PubMedSearch: Liu 2023 Colloids.Surf.B.Biointerfaces 225 113268 PubMedID: 36989818 Abstract Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an important approach for the treatment of some skin diseases and cancers. A major defect of this approach is that it is difficult for 5-ALA to accumulate around lesions in deeper regions of tissue, resulting in poor conversion to the active fluorophore and photodynamic efficiencies. Because of their targeting and controlled release abilities, nanogel carriers could solve this problem. In this paper, nanogels were prepared by using micro-emulsion polymerization with various biodegradable polyester crosslinkers (L-lactide and sigma-caprolactone). The swelling and degradation properties and entrapment efficiency, drug loading and drug release ability of the nanogels were investigated. Nanogels co-cultured with skin cancer cells (A2058) allowed the efficiency of the PDT in vitro to be demonstrated. The results showed that the swelling rate of hydrogels reduced with increasing crosslinker levels, which caused a slow-down in the release of 5-ALA, but lipase accelerated degradation of nanogels increased 5-ALA concentrations in tumor cells and leading to higher PDT efficiency. It was proved by in vivo experiment indicating that the development of skin cancer tissues were efficiently inhibited by the 5-ALA loaded nanogels. Title: Organophosphate Level Evaluation for the Poisoning Treatment by Enzyme Activation Regeneration Strategy with Oxime-Functionalized ZIF-8 Nanoparticles Shen A, Hao X, Li M, Zhao Y, Li Z, Hou L, Duan R, Zhang P, Zhang L, Yang Y Ref: Analytical Chemistry, :, 2023 : PubMed ESTHER: Shen_2023_Anal.Chem__ PubMedSearch: Shen 2023 Anal.Chem PubMedID: 37358141 Abstract In this work, two nanometal-organic frameworks (NMOFs) of ZIF-8-1 and ZIF-8-2 were designed and synthesized with a "missing linker" defects strategy by using Oxime-1 and Oxime-2 as coligands, respectively. ZIF-8-2 exhibited an excellent performance in comparison to that of ZIF-8-1 in activating and regenerating the activity of BChE suppressed by demeton-S-methyl (DSM) and could rapidly detoxify DSM in poisoned serum samples within 24 min. Additionally, the synthesized fluorescence probe of IND-BChE with high quantum yields, large Stokes shifts, and superior water solubility could be used for the detection of both butyrylcholinesterase (BChE) and DSM in a lower LOD of 0.63 mU/mL (BChE) and 0.086 microg/mL (DSM). By the difference in fluorescent intensity of IND-BChE with and without ZIF-8-2, a highly linear relationship of IND-BChE with DSM concentration was found (R(2) = 0.9889), and the LOD was 0.073 microg/mL. In addition, an intelligent detection platform of ZIF-8-2@IND-BChE@agarose hydrogel combined with a smartphone formed a point-of-care test for DSM -poisoned serum samples and also realized satisfactory results. Unlike other detection methods of nerve agents, this assay first combined an NMOF reactivator for detoxification and detection of BChE enzyme activity and then quantification of OP nerve agents, which was of great significance in treatment of organophosphate poisoning. Title: Systematic assessment of cyflumetofen toxicity in soil-earthworm (Eisenia fetida) microcosms Shi L, Zhang P, Xu J, Wu X, Pan X, He L, Dong F, Zheng Y Ref: J Hazard Mater, 452:131300, 2023 : PubMed ESTHER: Shi_2023_J.Hazard.Mater_452_131300 PubMedSearch: Shi 2023 J.Hazard.Mater 452 131300 PubMedID: 37002996 Abstract Cyflumetofen was widely applied in agriculture with its excellent acaricidal effect. However, the impact of cyflumetofen on the soil non-target organism earthworm (Eisenia fetida) is unclear. This study aimed to elucidate the bioaccumulation of cyflumetofen in soil-earthworm systems and the ecotoxicity of earthworms. The highest concentration of cyflumetofen enriched by earthworms was found on the 7th day. Long-term exposure of earthworms to the cyflumetofen (10 mg/kg) could suppress protein content and increases Malondialdehyde content leading to severe peroxidation. Transcriptome sequencing analysis demonstrated that catalase and superoxide-dismutase activities were significantly activated while genes involved in related signaling pathways were significantly upregulated. In terms of detoxification metabolic pathways, high concentrations of cyflumetofen stimulated the number of Differentially-Expressed-Genes involved in the detoxification pathway of the metabolism of glutathione. Identification of three detoxification genes (LOC100376457, LOC114329378, and JGIBGZA-33J12) had synergistic detoxification. Additionally, cyflumetofen promoted disease-related signaling pathways leading to higher disease risk, affecting the transmembrane capacity and cell membrane composition, ultimately causing cytotoxicity. Superoxide-Dismutase in oxidative stress enzyme activity contributed more to detoxification. Carboxylesterase and glutathione-S-transferase activation play a major detoxification role in high-concentration treatment. Altogether, these results contribute to a better understanding of toxicity and defense mechanisms involved in long-term cyflumetofen exposure in earthworms. Title: Efficacy and Safety of Plasma Exchange Combined with Hemoperfusion in the Treatment of Organophosphorus Poisoning: A Meta-Analysis Yao Z, Wang P, Fu Q, Song Q, Wang W, Liu A, Zhang P Ref: Blood Purif, :1, 2023 : PubMed ESTHER: Yao_2023_Blood.Purif__1 PubMedSearch: Yao 2023 Blood.Purif 1 PubMedID: 37302392 Abstract INTRODUCTION: The aim of the study was to systematically evaluate the efficacy and safety of plasma exchange combined with hemoperfusion in the treatment of organophosphorus poisoning. METHODS: PubMed, Embase, the Cochrane Library, China National Knowledge Internet, Wanfang database, and Weipu database were searched for articles about this subject. Literature screening and selection were conducted in strict accordance with the inclusion and exclusion criteria. RESULTS: 14 randomized controlled trials with 1,034 participants were included in this meta-analysis study, including 518 cases in plasma exchange combined with hemoperfusion group (the combination treatment group) and 516 cases in hemoperfusion group (the control group). Compared with the control group, the combination treatment group was associated with a higher effective rate (relative risk [RR] = 1.20, 95% confidence interval [CI] [1.11, 1.30], p < 0.00001) and lower fatality rate (RR = 0.28, 95% CI [0.15, 0.52], p< 0.0001); reduced TNF-alpha (standardized mean difference [SMD] = -1.95, 95% CI [-2.42, -1.48], p < 0.00001), IL-6 (SMD = -1.94, 95% CI [-3.08, -0.80], p = 0.0009), and C-reactive protein (CRP) (SMD = -1.94, 95% CI [-2.86, -1.03], p < 0.0001); shorten coma time (SMD = -1.99, 95% CI [-2.75, -1.24], p < 0.00001), recovery time of cholinesterase activity (SMD = -1.71, 95% CI [-1.90, -1.53], p < 0.00001), and hospital stay (SMD = -1.29, 95% CI [-1.59, -0.98], p < 0.00001). The incidence of complications in the combination treatment group such as liver and kidney damage (RR = 0.30, 95% CI [0.18, 0.50], p < 0.00001), pulmonary infection (RR = 0.29, 95% CI [0.18, 0.47], p < 0.00001), and intermediate syndrome (RR = 0.32, 95% CI [0.21, 0.49], p < 0.00001) was lower than that in the control group. CONCLUSIONS: The current evidence suggests that the combination of plasma exchange with hemoperfusion therapy can reduce the mortality of patients with organophosphorus poisoning, shorten the recovery time of cholinesterase activity and the time of coma, reduce the average length of hospital stay, and reduce the levels of IL-6, TNF-alpha, and CRP, but high-quality randomized double-blind controlled trials are still required to confirm the current findings in the future. Title: Near-infrared ratiometric fluorescent strategy for butyrylcholinesterase activity and its application in the detection of pesticide residue in food samples and biological imaging Yuan W, Wan C, Zhang J, Li Q, Zhang P, Zheng K, Zhang Q, Ding C Ref: Spectrochim Acta A Mol Biomol Spectrosc, 297:122719, 2023 : PubMed ESTHER: Yuan_2023_Spectrochim.Acta.A.Mol.Biomol.Spectrosc_297_122719 PubMedSearch: Yuan 2023 Spectrochim.Acta.A.Mol.Biomol.Spectrosc 297 122719 PubMedID: 37043836 Abstract Butyrylcholinesterase (BChE) is an essential esterase synthesized by the liver, and its level is considered as a vital index for health evaluation. Therefore, it is of great need to develop a highly sensitive and selective tool to monitor BChE activity, which remains a considerable challenge on account of its usage in complex biological systems. A near-infrared (NIR) fluorescent probe was elaborated in this work, employing cyanine backbone to provide the intrinsic NIR fluorescence and avoid interference from bioluminescence. There presented an intriguing structural transformation upon the sensing event to shrink the conjugation in this protocol, leading to an eye-catching fluorescence change from NIR (816 nm) to red (637 nm) region, which gave rise to the proposed ratiometric assay. After an overall investigation, this receptor was verified to be applicable in a wide bio-area with ratiometric pattern, including the cellular level and slice platform. It was worth mentioning that this receptor was also discovered to be capable of monitoring pesticide dichlorvos (DDVP) residue in food samples with high sensitivity and accuracy, with significant potential to be developed as an alternative candidate for monitoring environmental pollution. Title: Molecular mechanism of miRNA-23a in sepsis-induced lung injury Zhang P, Huang Q, Liao P, Sun S, Yang J Ref: Am J Transl Res, 15:3900, 2023 : PubMed ESTHER: Zhang_2023_Am.J.Transl.Res_15_3900 PubMedSearch: Zhang 2023 Am.J.Transl.Res 15 3900 PubMedID: 37434814 Abstract OBJECTIVE: MicroRNA-23a-3p (miR-23a) is a novel gene regulator involved in inflammation. This study aimed to explore the molecular mechanism of miR-23a in sepsis-induced lung injury both in vitro and in vivo. METHODS: Lipopolysaccharide (LPS)- and ATP-stimulated human myeloid leukemia mononuclear cells (THP-1) and Human Bronchial Epithelial Cells (BEAS-2B) cell lines were used, while cecal ligation and puncture (CLP)-induced sepsis BABL/c mice were constructed. The mRNA expression levels of interleukin (IL)-18, IL-1beta, and miR-23a were determined, and Western blotting was used to measure CXCR4/PTEN/PI3K/AKT signaling. The concentrations of cytokines and Nod-like receptor family pyrin domain-containing 3 (NLRP3) were determined using an enzyme-linked immunosorbent assay. Lung tissue of mice was subjected to hematoxylin-eosin staining for examining myocardial injury. RESULTS: MiR-23a inhibited NLRP3 inflammasome activation in LPS- and ATP-stimulated THP-1 and BEAS-2B cells (P<0.05). Overexpression of miR-23a decreased the lactate dehydrogenase release rate in the cells (P<0.05). Meanwhile, miR-23a overexpression decreased the concentration and gene expression of IL-1beta and IL-18 in CXCR4 positive cells (P<0.05). Conversely, miR-23a knockdown increased the concentration and gene expression of IL-1beta and IL-18 (P<0.05). Additionally, PTEN and p53 proteins were up-regulated in miR-23a mimic group and down-regulated in miR-23a inhibitor group (P<0.05). Furthermore, miR-23a expression was decreased in sepsis-induced lung injury mice (P<0.05). MiR-23a overexpression reduced the sepsis-induced lung injury probably by inhibiting acetylcholinesterase activity and expression levels of IL-1beta, IL-18, capase-1, and NLRP3 (P<0.05). CONCLUSION: miR-23a can significantly alleviate sepsis-induced lung injury in CLP-induced septic mice and LPS-stimulated cell lines by suppressing NLRP3 inflammasome activation and inflammatory response, while promoting the CXCR4/PTEN/PI3K/AKT pathway. Title: Effects of the deletion and substitution of thioesterase on bacillomycin D synthesis Zhang P, Lv Z, Lu Z, Ma W, Bie X Ref: Biotechnol Lett, 45:981, 2023 : PubMed ESTHER: Zhang_2023_Biotechnol.Lett_45_981 PubMedSearch: Zhang 2023 Biotechnol.Lett 45 981 PubMedID: 37266877 Abstract OBJECTIVES: The importance of thioesterase domains on bacillomycin D synthesis and the ability of different thioesterase domains to selectively recognize and catalyze peptide chain hydrolysis and cyclization were studied by deleting and substituting thioesterase domains. RESULTS: No bacillomycin D analogs were found in the thioesterase-deleted strain fmbJ-deltaTE, indicating that the TE domain was essential for bacillomycin D synthesis. Then the thioesterase in bacillomycin D synthetases was replaced by the thioesterase in bacillomycin F, iturin A, mycosubtilin, plipastatin and surfactin synthetases. Except for fmbJ-S-TE, all others were able to synthesize bacillomycin D homologs because a suitable recombination site was selected, which maintained the integrity of NRPSs. In particular, the yield of bacillomycin D in fmbJ-IA-TE, fmbJ-M-TE and fmbJ-P-TE was significantly increased. CONCLUSION: This study expands our understanding of the TE domain in bacillomycin D synthetases and shows that thioesterase has excellent potential in the chemical-enzymatic synthesis of natural products or their analogs. Title: Neurexin-beta Mediates the Synaptogenic Activity of Amyloid Precursor Protein Cvetkovska V, Ge Y, Xu Q, Li S, Zhang P, Craig AM Ref: Journal of Neuroscience, :, 2022 : PubMed ESTHER: Cvetkovska_2022_J.Neurosci__ PubMedSearch: Cvetkovska 2022 J.Neurosci PubMedID: 36261284 Abstract In addition to its role in Alzheimer's disease, amyloid precursor protein (APP) has physiological roles in synapse development and function. APP induces presynaptic differentiation when presented to axons but the mechanism is unknown. Here we show that APP binds neurexin to mediate this synaptogenic activity. APP specifically binds beta not alpha neurexins modulated by splice site 4. Binding to neurexin heparan sulfate glycan and LNS protein domains is required for high affinity interaction and for full-length APP to recruit axonal neurexin. The synaptogenic activity of APP is abolished by triple knockdown of neurexins in hippocampal neurons pooled from male and female rats. Based on these and previous results, our model is that a dendritic-axonal trans dimer of full-length APP binds to axonal neurexin-beta to promote synaptic differentiation and function. Furthermore, soluble sAPPs also bind neurexin-beta and inhibit its interaction with neuroligin-1, raising the possibility that disruption of neurexin function by altered levels of full-length APP and its cleavage products may contribute to early synaptic deficits in Alzheimer's disease.SIGNIFICANCE STATEMENT:The prevailing model for the basis of Alzheimer's disease is the amyloid cascade triggered by altered cleavage of amyloid precursor protein (APP). APP also has physiological roles at the synapse but the molecular basis for its synaptic functions are not well understood. Here, we show that APP binds the presynaptic organizing protein neurexin-beta and that neurexin is essential for the synaptogenic activity of APP. Furthermore, soluble APP forms generated by APP cleavage also bind neurexin-beta and can block interaction with transmembrane synaptogenic ligands of neurexin. These findings reveal a role for neurexin-APP interaction in synapse development and raise the possibility that disruptions of neurexin function may contribute to synaptic and cognitive deficits in the critical early stage of Alzheimer's disease. Title: Tissue-specific accumulation, depuration, and effects of perfluorooctanoic acid on fish: Influences of aqueous pH and sex Dong H, Lu G, Wang X, Zhang P, Yang H, Yan Z, Liu J, Jiang R Ref: Sci Total Environ, :160567, 2022 : PubMed ESTHER: Dong_2022_Sci.Total.Environ__160567 PubMedSearch: Dong 2022 Sci.Total.Environ 160567 PubMedID: 36455738 Abstract Perfluorooctanoic acid (PFOA) is widely distributed in nature, particularly in aquatic environments. Its bioaccumulation and toxicity in aquatic organisms can be affected by both the chemical status of PFOA in water and the physiology of the organism. However, research on the patterns of these effects is scarce. In this study, we investigated the influence of aqueous pH (pH 6, acidic; pH 7.5, neutral; pH 9, basic) and fish sex on PFOA uptake, clearance, and biochemical effects in crucian carp (C. auratus) using flow-through exposure. In the 17-d kinetic experiment, PFOA bioaccumulation adhered to a uniform first-order model in which PFOA uptake rates from water to blood and liver in acidic conditions were faster than those in other conditions, indicating possible acidic pH influence on PFOA uptake. PFOA clearance rates in these compartments of males were slower than in females, which was attributed to the notably stronger expression of Oat2 (organic anion transporter 2, responsible for reabsorption) in the kidneys of males. Similar responses were observed for peroxisome proliferation-related biomarkers at different pH levels and in different sexes. These biochemical responses were driven by the internal concentrations of PFOA. The inhibition acetylcholinesterase activity in the fish brain was closely linked to changes in P-glycoprotein content, demonstrating a protective relationship. Collectively, an aqueous pH lower than 7.5 might affect the uptake of PFOA by fish. The clearance discrepancies between the sexes highlight the importance of anion carriers for ionizable organic compounds in aquatic organisms. Title: Novel and Potent Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease from Natural (+/-)-7,8-Dihydroxy-3-methyl-isochroman-4-one Li X, Jia Y, Li J, Zhang P, Li T, Lu L, Yao H, Liu J, Zhu Z, Xu J Ref: Molecules, 27:3090, 2022 : PubMed ESTHER: Li_2022_Molecules_27_3090 PubMedSearch: Li 2022 Molecules 27 3090 PubMedID: 35630563 Abstract Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (+/-)-7,8-dihydroxy-3-methyl-isochroman-4-one [(+/-)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound 10a [(Z)-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound 10a was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound 10a exhibited low cytotoxicity and moderate anti-Abeta aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood-brain barrier with high penetration. These findings show that compound 10a was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD. Title: Discovery of novel hybrids containing clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease Li X, Li T, Zhang P, Lu L, Sun Y, Zhang B, Allen S, White L, Phillips J and Xu J <2 more author(s)> Li X, Li T, Zhang P, Lu L, Sun Y, Zhang B, Allen S, White L, Phillips J, Zhu Z, Yao H, Xu J (- 2) Ref: Eur Journal of Medicinal Chemistry, 244:114841, 2022 : PubMed ESTHER: Li_2022_Eur.J.Med.Chem_244_114841 PubMedSearch: Li 2022 Eur.J.Med.Chem 244 114841 PubMedID: 36257284 Inhibitor(s) related to this paper: Compound19n-quinolinol Abstract Based on the multitarget strategy, a series of novel clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC(50) = 0.11 microM), appropriate metal chelating functions, modulation of AChE- and metal-induced Abeta aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 microM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD(50) = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Abeta(1-42)-induced) and suppressed inflammation induced by Abeta(1-42) in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease. Title: Highly Selective Detection of Paraoxon in Food Based on the Platform of Cu Nanocluster/MnO(2) Nanosheets Liu S, Zhang P, Miao Y, Li C, Shi YE, Liu J, Lv YK, Wang Z Ref: Nanomaterials (Basel), 12:, 2022 : PubMed ESTHER: Liu_2022_Nanomaterials.(Basel)_12_ PubMedSearch: Liu 2022 Nanomaterials.(Basel) 12 PubMedID: 35564138 Abstract Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a detection platform was developed by integrating Cu nanoclusters (Cu NCs) with MnO(2) nanosheets, where the fluorescence of Cu NCs was effectively quenched. Upon introducing butyrylcholinesterase and butyrylcholine into the system, their hydrolysate, thiocholine, leads to the decomposition of the platform through a reaction between the MnO(2) nanosheets and thiol groups on thiocholine. The electron-rich groups on thiocholine can further promote the fluorescence intensity of Cu NCs through host-guest interactions. Adding paraoxon results in the failure of fluorescence recovery and further promotion, which could be utilized for the quantitative detection of paraoxon, and a limit of detection as low as 0.22 ng/mL can be achieved. The detection platform shows strong tolerance to common interference species, which endows its applications for the detection of paraoxon in vegetables and fruit. These presented results not only open a new door for the functionalization of metal nanoclusters but also offer an inspiring strategy for analytic techniques in nanomedicine and environmental science. Title: Natural Antioxidants, Tyrosinase and Acetylcholinesterase Inhibitors from Cercis glabra Leaves Lou Y, Xu T, Cao H, Zhao Q, Zhang P, Shu P Ref: Molecules, 27:, 2022 : PubMed ESTHER: Lou_2022_Molecules_27_ PubMedSearch: Lou 2022 Molecules 27 PubMedID: 36557801 Abstract Cercis glabra is a plant belonging to the legume family, whose flowers and barks are commonly used as food and traditional Chinese medicines. However, its leaves are usually disposed of as wastes. This research comprehensively investigated the bioactive constituents of C. glabra leaves, and two new phenolic, ceroffesters A-B (1-2) and thirteen known compounds (3-15) were isolated. Their structures were elucidated by spectroscopic methods such as nuclear magnetic resonance (1D NMR and 2D NMR), high-resolution electrospray ionization mass spectra (HR-ESI-MS), optical rotatory dispersion (ORD) and electronic circular dichroism (ECD). All of them were assessed for their antioxidant activities through ABTS, DPPH and PTIO methodologies, and evaluated for inhibitory activities against two enzymes (mushroom tyrosinase and acetylcholinesterase). As a result, compounds 3-6, 10 and 13 exhibited evident antioxidant activities. Meanwhile, compounds 5, 10 and 13 showed the most potent tyrosinase inhibitory activities, with IC(50) of 0.64, 0.65 and 0.59 mM, and compared with the positive control of 0.63 mM (kojic acid). In the initial concentration of 1 mg/mL, compounds 3, 5 and 6 demonstrated moderate inhibitory activities against acetylcholinesterase with 85.27 +/- 0.06%, 83.65 +/- 0.48% and 82.21 +/- 0.09%, respectively, compared with the positive control of 91.17 +/- 0.23% (donepezil). These bioactive components could be promising antioxidants, tyrosinase and acetylcholinesterase inhibitors. Title: Structurally diverse steroids from an endophyte of Aspergillus tennesseensis 1022LEF attenuates LPS-induced inflammatory response through the cholinergic anti-inflammatory pathway Su JC, Pan Q, Xu X, Wei X, Lei X, Zhang P Ref: Chemico-Biological Interactions, 362:109998, 2022 : PubMed ESTHER: Su_2022_Chem.Biol.Interact_362_109998 PubMedSearch: Su 2022 Chem.Biol.Interact 362 109998 PubMedID: 35649461 Abstract The emerging cholinergic anti-inflammatory pathway plays a key role in regulating inflammation. Steroids are known to possess remarkable anti-inflammatory activity. However, the links between steroids and the cholinergic anti-inflammatory pathway remain unidentified. In this study, eight steroids (1-8) featuring five different structural types were characterized from an endophytic fungus Aspergillus tennesseensis 1022LEF, and were subsequently evaluated for their potential role in regulating the cholinergic anti-inflammatory pathway. As a result, compound 8, with the best potency, showed remarkable anti-inflammatory activity at the nanomolar to low micromolar level. Further pharmacological study indicated that 8 notably increased alpha7nAchR expression and inhibited the activation of its down-stream signaling pathways. Collectively, the present study not only highlighted the potential correlation between steroids and the cholinergic anti-inflammatory pathway, but also identified 8 as a dual-functional modulator via directly inhibition to acetylcholinesterase as well as up-regulation of alpha7nAchR expression. Title: Ratiometric imaging of butyrylcholinesterase activity in mice with nonalcoholic fatty liver using an AIE-based fluorescent probe Xiang C, Xiang J, Yang X, Li C, Zhou L, Jiang D, Peng Y, Xu Z, Deng G and Gong P <3 more author(s)> Xiang C, Xiang J, Yang X, Li C, Zhou L, Jiang D, Peng Y, Xu Z, Deng G, Zhu B, Zhang P, Cai L, Gong P (- 3) Ref: J Mater Chem B, :, 2022 : PubMed ESTHER: Xiang_2022_J.Mater.Chem.B__ PubMedSearch: Xiang 2022 J.Mater.Chem.B PubMedID: 35583194 Abstract Butyrylcholinesterase (BChE) is an essential human biomarker which is related to liver and neurodegenerative diseases. It is of great significance to develop a fluorescent probe that can image BChE in vitro and in vivo. Unfortunately, most fluorescent probes that are based on a single change in fluorescence intensity are susceptible to environmental interference. Therefore, we reported an easily available ratiometric fluorescent probe, TB-BChE, with aggregation-induced emission (AIE) characteristics for ratiometric imaging of BChE. TB-BChE demonstrated excellent sensitivity (LOD = 39.24 ng mL(-1)) and specificity for BChE. Moreover, we have successfully studied the ratiometric imaging of TB-BChE to BChE in a nonalcoholic fatty liver disease model. These results indicated that TB-BChE is expected to become a powerful analysis tool for butyrylcholinesterase research in basic medicine and clinical applications. Title: Response of xenobiotic biodegradation and metabolic genes in Tribolium castaneum following eugenol exposure Zhang Y, Gao S, Zhang P, Sun H, Lu R, Yu R, Li Y, Zhang K, Li B Ref: Mol Genet Genomics, :, 2022 : PubMed ESTHER: Zhang_2022_Mol.Genet.Genomics__ PubMedSearch: Zhang 2022 Mol.Genet.Genomics PubMedID: 35419714 Abstract Eugenol, a plant-derived component possessing small side effects, has an insecticidal activity to Tribolium castaneum; however, the underlying molecular mechanisms of eugenol acting on T. castaneum are currently unclear. Here, a nerve conduction carboxylesterase and a detoxifying glutathione S-transferase were significantly inhibited after eugenol exposure, resulting in the paralysis or death of beetles. Then, RNA-sequencing of eugenol-exposed and control samples identified 362 differentially expressed genes (DEGs), containing 206 up-regulated and 156 down-regulated genes. RNA-seq data were validated further by qRT-PCR. GO analysis revealed that DEGs were associated with 1308 GO terms of which the most enriched GO terms were catalytic activity, and integral component of membrane; KEGG pathway analysis showed that these DEGs were distributed in 151 different pathways, of which some pathways associated with metabolism of xenobiotics or drug were significantly enriched, which indicated that eugenol most likely disturbed the processes of metabolism, and detoxication. Moreover, several DEGs including Hexokinase type 2, Isocitrate dehydrogenase, and Cytochrome b-related protein, might participate in the respiratory metabolism of eugenol-exposed beetles. Some DEGs encoding CYP, UGT, GST, OBP, CSP, and ABC transporter were involved in the xenobiotic or drug metabolism pathway, which suggested that these genes of T. castaneum participated in the response to eugenol exposure. Additionally, TcOBPC11/ TcGSTs7, detected by qRT-PCR and RNA-interference against these genes, significantly increased the mortality of eugenol-treated T. castaneum, providing further evidence for the involvement of OBP/GST in eugenol metabolic detoxification in T. castaneum. These results aid eugenol insecticidal mechanisms and provide the basis of insect control. Title: Fine mapping of powdery mildew resistance gene MlWE74 derived from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in an NBS-LRR gene cluster Zhu K, Li M, Wu H, Zhang D, Dong L, Wu Q, Chen Y, Xie J, Lu P and Hua W <13 more author(s)> Zhu K, Li M, Wu H, Zhang D, Dong L, Wu Q, Chen Y, Xie J, Lu P, Guo G, Zhang H, Zhang P, Li B, Li W, Wang Q, Zhu J, Hu W, Guo L, Wang R, Yuan C, Li H, Liu Z, Hua W (- 13) Ref: Theor Appl Genet, :, 2022 : PubMed ESTHER: Zhu_2022_Theor.Appl.Genet__ PubMedSearch: Zhu 2022 Theor.Appl.Genet PubMedID: 35006335 Abstract Powdery mildew resistance gene MlWE74, originated from wild emmer wheat accession G-748-M, was mapped in an NBS-LRR gene cluster of chromosome 2BS. Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease. Wild emmer wheat (Triticum turgidum var. dicoccoides) is a valuable genetic resource for improving disease resistance in common wheat. A powdery mildew resistance gene was transferred to hexaploid wheat line WE74 from wild emmer accession G-748-M. Genetic analysis revealed that the powdery mildew resistance in WE74 is controlled by a single dominant gene, herein temporarily designated MlWE74. Bulked segregant analysis (BSA) and molecular mapping delimited MlWE74 to the terminal region of chromosome 2BS flanking by markers WGGBD412 and WGGBH346 within a genetic interval of 0.25 cM and corresponding to 799.9 kb genomic region in the Zavitan reference sequence. Sequence annotation revealed two phosphoglycerate mutase-like genes, an alpha/beta-hydrolases gene, and five NBS-LRR disease resistance genes that could serve as candidates for map-based cloning of MlWE74. The geographical location analysis indicated that MlWE74 is mainly distributed in Rosh Pinna and Amirim regions, in the northern part of Israel, where environmental conditions are favorable to the occurrence of powdery mildew. Moreover, the co-segregated marker WGGBD425 is helpful in marker-assisted transfer of MlWE74 into elite cultivars. Title: Bio-interaction of nano and bulk lanthanum and ytterbium oxides in soil system: Biochemical, genetic, and histopathological effects on Eisenia fetida Adeel M, Shakoor N, Hussain T, Azeem I, Zhou P, Zhang P, Hao Y, Rinklebe J, Rui Y Ref: J Hazard Mater, 415:125574, 2021 : PubMed ESTHER: Adeel_2021_J.Hazard.Mater_415_125574 PubMedSearch: Adeel 2021 J.Hazard.Mater 415 125574 PubMedID: 33756203 Abstract The massive application of rare earth elements (REEs) in electronic industries cause their inevitable release into the environment; however, its effects on soil biota remain largely unaddressed. We investigated the E. fetida detoxification potential of nano and bulk La(2)O(3) and Yb(2)O(3) and their potential impact on biochemical and genetic markers at 50, 100, 200, 500 and 1000 mg kg(-1) concentration. We found that earthworms bioremediate 3-15% La(2)O(3) and Yb(2)O(3) contaminated soil at low and medium levels, while this potential was limited at higher levels. Nano and bulk La(2)O(3) and Yb(2)O(3) treatment induced neurotoxicity in earthworm by inhibiting acetylcholinesterase by 49-65% and 22-36% at 500 and 1000 mg kg(-1), respectively. Nano La(2)O(3) proved to be highly detrimental, mainly through oxidative stress and subsequent failure of antioxidant system. Nano La(2)O(3) and Yb(2)O(3) at 100 mg kg(-1) significantly down-regulated the expression of annetocin mRNA in the parental and progeny earthworms by 50% and 20%, which is crucial for earthworm reproduction. Similarly, expression level of heat shock protein 70 (HSP70) and metallothionein was significantly upregulated in both generations at medium exposure level. Histological observations showed that nano REEs at 200 mg kg(-1) induced drastic changes in the intestinal epithelium and typhlosole of E. fetida. To date, our results enhance the understanding of interaction between REEs and earthworms. Title: Resolution of (R,S)-1-(4-methoxyphenyl)ethanol by lipase-catalyzed stereoselective transesterification and the process optimization He B, Tang F, Sun C, Su J, Wu B, Chen Y, Xiao Y, Zhang P, Tang K Ref: Chirality, :, 2021 : PubMed ESTHER: He_2021_Chirality__ PubMedSearch: He 2021 Chirality PubMedID: 34904761 Abstract An efficient lipase-catalyzed stereoselective transesterification reaction system was established for resolution of 1-(4-methoxyphenyl)ethanol (MOPE) enantiomers. A series of lipases were tested and compared. The immobilized lipase Novozym 40086 is selected as the best choice. The effects of organic solvent, acyl donor, time and temperature on substrate conversion (c), and optical purity of the remaining substrate (ee(S) ) were investigated. Response surface methodology and central composite design were employed to evaluate the effect of some important factors and to optimize the process. Under the optimized conditions including solvent of n-hexane, acyl donor of vinyl acetate, temperature of 35 degreesC, substrate molar ratio of 1:6, enzyme dosage of 20 mg, and reaction time of 2.5 h, ee(S) of 99.87% with c of 56.71% is achieved. The use of alkane solvent and immobilized enzyme, the mild reaction conditions, and the reduced reaction time make the system promising in industrial application. Title: ABHD15 promotes cell viability, glycolysis, and inhibits apoptosis in cardiomyocytes under hypoxia Huang G, Guo X, Guo J, Zhang P, Liang W, Bai C, Zhang Y Ref: Nutr Metab Cardiovasc Dis, 31:681, 2021 : PubMed ESTHER: Huang_2021_Nutr.Metab.Cardiovasc.Dis_31_681 PubMedSearch: Huang 2021 Nutr.Metab.Cardiovasc.Dis 31 681 PubMedID: 33257193 Abstract BACKGROUND AND AIMS: Myocardial infarction (MI) has been an important heart disease affecting human health. The aim of this study was to investigate the regulatory effect of abhydrolase domain containing 15 (ABHD15) on hypoxic cardiomyocytes. METHODS AND RESULTS: Hypoxic cardiomyocytes are commonly used as an vitro model for the study of MI. We found that cardiomyocyte viability was decreased under hypoxia, but cell glucose uptake, insulin receptor phosphorylation level and apoptosis were increased. Interestingly, ABHD15 expression was up-regulated in hypoxia-induced cardiomyocytes. Then, we identified the function of ABHD15 in hypoxic cardiomyocytes by using ABHD15 overexpression vector or short interfering RNA (siRNA) against ABHD15. The results showed that overexpression of ABHD15 promoted hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation (p-IR), and inhibited cell apoptosis. However, knockdown of ABHD15 attenuated hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation, and promoted apoptosis. Moreover, we found that ABHD15 promoted glucose transporter 4 (GLUT4) expression, translocation and enhance rate-limiting enzyme activation of glycolysis, thereby affecting glucose uptake. Furthermore, our study suggested that ABHD15 may affect the viability and apoptosis of hypoxic cardiomyocytes through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 signaling pathways, respectively. When the phosphorylation of IR, Raf or ERK was blocked by inhibitors, the protective effect of overexpressing ABHD15 on the viability of hypoxic cardiomyocytes was eliminated. Furthermore, inhibiting the phosphorylation of IR, AKT or Bcl2 abolished the inhibitory effect of overexpressing ABHD15 on hypoxic cardiomyocyte apoptosis. CONCLUSION: ABHD15 regulated myocardial cell viability, glycolysis, and apoptosis under hypoxia, providing a novel potential therapeutic strategy for MI. Title: 3D-Printed, Portable, Fluorescent-Sensing Platform for Smartphone-Capable Detection of Organophosphorus Residue Using Reaction-Based Aggregation Induced Emission Luminogens Jiao Z, Guo Z, Huang X, Yang J, Huang J, Liu Y, Liu G, Zhang P, Song C, Tang BZ Ref: ACS Sens, :, 2021 : PubMed ESTHER: Jiao_2021_ACS.Sens__ PubMedSearch: Jiao 2021 ACS.Sens PubMedID: 34406746 Abstract Development of an easy-to-use, low-cost, household device can help the consumer quickly identify an organophosphorus (OP) residue concentration level. In this work, we demonstrate a 3D-printed, portable, fluorescent-sensing platform for smartphone-capable detection of OPs in vegetables. For development of the proposed device, we utilize the smartphone for capturing the strong thiol-activated fluorescence, which was produced by hydrolysis of OPs in the presence of alkali. The thiol-responsive AIEgen (maleimide-functionalized tetraphenylethylene) was non-emissive in both solution and the solid state but could be readily lighted up by the click addition of thiol to its MI pendant. An android application "Detection" has been developed on the basis of the gray value to analyze the different concentration levels of OPs in vegetable samples. The gray value was linearly related with the concentration of five kinds of organophosphorus residue, ranging from 0 to 20 microg/mL. It was also applied for determination of OPs residue in the leaves of cowpea, celery, and Chinese cabbage. Different from acetylcholinesterase enzyme-based sensors for poor stability under high temperature, the proposed method was a direct detection method for OPs and can be used for rapid monitoring of OPs residue concentration levels before LC-MS analysis. Title: Effect of extrusion technology on hempseed (Cannabis sativa L.) oil cake: Polyphenol profile and biological activities Leonard W, Zhang P, Ying D, Xiong Y, Fang Z Ref: J Food Sci, :, 2021 : PubMed ESTHER: Leonard_2021_J.Food.Sci__ PubMedSearch: Leonard 2021 J.Food.Sci PubMedID: 34176120 Abstract Effects of extrusion with varying barrel temperature, moisture content, and screw speed on hempseed oil cake were studied for the first time. Extrusion at lower moisture (30%) and higher screw speed (300 rpm) significantly increased the proportion of free polyphenols, flavonoids, and phenylpropionamide content, and alpha -glucosidase and acetylcholinesterase inhibition activities. Full factorial design confirmed the three-way interactions among all extrusion parameters for all chemical assays with the bound phenolic fraction, total flavonoid content, and DPPH inhibition activity of the free phenolic fraction. HPLC-DAD-ESI-QTOF-MS/MS analysis tentatively identified 26 phenylpropionamides, and the contents of N-trans-caffeoyltyramine (66.26 microg/g) and total phenylpropionamides (85.77 microg/g) were significantly increased after extrusion at the lower moisture and higher screw speed extrusion conditions. The higher alpha -glucosidase inhibition activity at higher screw speed could be due to the N-trans-caffeoyltyramine (r = 0.99, p < 0.01), while the AChE inhibition activity appeared to be influenced more by the cannabisins A-C, M (r > 0.8, p < 0.01). PRACTICAL APPLICATION: Hempseed oil cake is a byproduct of oil extraction, with high protein and high fiber contents. The results of this research could be used directly in food industry to improve the nutritional and commercial value of hempseed oil cake by extrusion technology. Title: PKA and AMPK Signaling Pathways Differentially Regulate Luteal Steroidogenesis Przygrodzka E, Hou X, Zhang P, Plewes MR, Franco R, Davis JS Ref: Endocrinology, :, 2021 : PubMed ESTHER: Przygrodzka_2021_Endocrinology__ PubMedSearch: Przygrodzka 2021 Endocrinology PubMedID: 33502468 Abstract Luteinizing hormone via protein kinase A (PKA) triggers ovulation and formation of the corpus luteum, which arises from the differentiation of follicular granulosa and theca cells into large and small luteal cells, respectively. The small and large luteal cells produce progesterone, a steroid hormone required for establishment and maintenance of pregnancy. We recently reported on the importance of hormone sensitive lipase (HSL, also known as LIPE) and lipid droplets for appropriate secretory function of the corpus luteum. These lipid-rich intracellular organelles store cholesteryl esters, which can be hydrolyzed by HSL to provide cholesterol, the main substrate necessary for progesterone synthesis. In the present study, we analyzed dynamic post-translational modifications of HSL mediated by PKA and AMP-activated protein kinase (AMPK) as well as their effects on steroidogenesis in luteal cells. Our results revealed that AMPK acutely inhibits the stimulatory effects of LH/PKA on progesterone production without reducing levels of STAR, CYP11A1 and HSD3B proteins. Exogenous cholesterol reversed the negative effects of AMPK on LH-stimulated steroidogenesis, suggesting that AMPK regulates cholesterol availability in luteal cells. AMPK evoked inhibitory phosphorylation of HSL (Ser565). In contrast, LH/PKA decreased phosphorylation of AMPK at Thr172, a residue required for its activation. Additionally, LH/PKA increased phosphorylation of HSL at Ser563, which is crucial for enzyme activation, and decreased inhibitory phosphorylation of HSL at Ser565. The findings indicate that LH and AMPK exert opposite post-translational modifications of HSL, presumptively regulating cholesterol availability for steroidogenesis. Title: In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer's Disease Uras G, Manca A, Zhang P, Markus Z, Mack N, Allen S, Bo M, Xu S, Xu J and Zhu Z <1 more author(s)> Uras G, Manca A, Zhang P, Markus Z, Mack N, Allen S, Bo M, Xu S, Xu J, Georgiou M, Zhu Z (- 1) Ref: Front Neurosci, 15:691222, 2021 : PubMed ESTHER: Uras_2021_Front.Neurosci_15_691222 PubMedSearch: Uras 2021 Front.Neurosci 15 691222 PubMedID: 34276297 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. Title: Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J, Qin S, Li X, Allen S and Xu J <4 more 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 (- 4) Ref: Journal of Medicinal Chemistry, :, 2021 : PubMed ESTHER: Yao_2021_J.Med.Chem__ PubMedSearch: Yao 2021 J.Med.Chem PubMedID: 34024109 Inhibitor(s) related to this paper: ACHE-GSK-3-27g 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. Title: Fluorescent Determination of Butyrylcholinesterase Activity and Its Application in Biological Imaging and Pesticide Residue Detection Zhang Q, Fu C, Guo X, Gao J, Zhang P, Ding C Ref: ACS Sens, :, 2021 : PubMed ESTHER: Zhang_2021_ACS.Sens__ PubMedSearch: Zhang 2021 ACS.Sens PubMedID: 33503372 Abstract Butyrylcholinesterase (BChE) is an essential human cholinesterase relevant to liver conditions and neurodegenerative diseases, which makes it a pivotal biomarker of health. It therefore remains challenging and highly desired to elaborate efficient chemical tools for BChE with simple operations and satisfactory working performance. In this work, a background-free detection strategy was built by virtue of the judicious coupling of a specific BChE-enzymatic reaction and in situ cyclization. High sensitivity with a low limit of detection (LOD) of 0.075 microg/mL could be readily achieved from the blank background and the as-produced emissive indicators, and the specific reaction site contributed to the high selectivity over other bio-species even acetylcholinesterase (AChE). In addition to the multifaceted spectral experiments to verify the sensing mechanism, this work assumed comprehensive studies on the application. The bio-investigation ranged from cells to an organism, declaring a noteworthy prospect in disease diagnosis, especially for Alzheimer's disease (AD), a common neurodegenerative disease with over-expressed BChE. Moreover, its excellent work for inhibition efficacy elucidation was also proved with the accuracy IC(50) of tacrine for BChE (8.6 nM), giving rise to an expanded application for trace pesticide determination. Title: AND-Logic Strategy for Accurate Analysis of Alzheimer's Disease via Fluorescent Probe Lighted Up by Two Specific Biomarkers Zhang P, Fu C, Liu H, Guo X, Zhang Q, Gao J, Chen W, Yuan W, Ding C Ref: Analytical Chemistry, :, 2021 : PubMed ESTHER: Zhang_2021_Anal.Chem__ PubMedSearch: Zhang 2021 Anal.Chem PubMedID: 34353021 Abstract Alzheimer's disease (AD) has become a global threat to the elderly health with a short survival time after diagnosis. Due to the asymptomatic stage during the early development, patients are usually diagnosed at the middle or late stage. Therefore, an efficient tool for AD early diagnosis deserves considerable attention, which could make a significant contribution to the treatment intervention. A fluorescent probe has been widely applied for detecting and visualizing species of interest in vitro and in vivo, and the proper reaction between the probe and analytes is responsible for the fluorescence change to provide a lighting-on or ratiometric responsive pattern with satisfactory sensing behavior. In this work, we report the first attempt to build up an AND-logic probe P2 for AD accuracy diagnosis taking butyrylcholinesterase (BChE) and reactive oxygen species (ROSs) as dual targets. Upon the co-stimulation by these two factors through enzymatic hydrolysis and redox reaction, the NIR emission could be readily turned on. This AND sensing pattern avoided the false-positive response effectively, and other diseases sharing one biomarker could hardly induce a NIR fluorescence response. The sensing assay has also been confirmed to be feasible in vitro and in vivo with good sensibility and selectivity. It is worth mentioning that the probe structure has been optimized in terms of the linkage length. This study shows that probe P2 with a connecting arm of medium length (one methylene, n = 1) has superior sensing performance, promising to provide a reference for the relative structure design. Title: Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease Zhang P, Wang Z, Mou C, Zou J, Xie Y, Liu Z, Benjamin Naman C, Mao Y, Wei J and Cui W <11 more author(s)> Zhang P, Wang Z, Mou C, Zou J, Xie Y, Liu Z, Benjamin Naman C, Mao Y, Wei J, Huang X, Dong J, Yang M, Wang N, Jin H, Liu F, Lin D, Liu H, Zhou F, He S, Zhang B, Cui W (- 11) Ref: Bioorg Chem, 116:105387, 2021 : PubMed ESTHER: Zhang_2021_Bioorg.Chem_116_105387 PubMedSearch: Zhang 2021 Bioorg.Chem 116 105387 PubMedID: 34628225 Inhibitor(s) related to this paper: Tacrine-dipicolylamine-13a Abstract Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an beta-amyloid (Abeta) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Abeta(1-42) aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Abeta(1-42) pentamers. Moreover, 13a effectively attenuated Abeta(1-42) oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD. Title: Cadmium exposure affects growth performance, energy metabolism, and neuropeptide expression in Carassius auratus gibelio Cai Y, Yin Y, Li Y, Guan L, Zhang P, Qin Y, Wang Y Ref: Fish Physiol Biochem, 46:187, 2020 : PubMed ESTHER: Cai_2020_Fish.Physiol.Biochem_46_187 PubMedSearch: Cai 2020 Fish.Physiol.Biochem 46 187 PubMedID: 31612298 Abstract Cadmium (Cd) is the most abundant heavy metal in aquatic environments and is easily detected on a global scale. Carassius auratus gibelio is a common aquaculture species. The aim of this study was to explore the toxic effects of 1, 2, and 4 mg/L Cd on the energy metabolism, growth performance, and neurological responses of C. gibelio. After 30 days of exposure, Cd concentrations in the liver and brain were significantly increased in Cd-exposed groups. Low-level Cd exposure (1 mg/L) increased weight and length gains, as well as food intake, in the fish. Acetylcholinesterase activity decreased significantly in the Cd-exposed groups. Energy metabolism levels (as reflected by oxygen consumption, ammonia excretion rate, and swimming activity), as well as serum T3 and T4 levels, increased significantly in the fish exposed to 1 mg/L Cd. However, energy metabolism and serum T3/T4 levels decreased significantly in the 4-mg/L Cd group. Neuropeptide gene expression levels in brain were consistent with the observed changes in food intake. In the Cd-exposed groups, the expression levels of neuropeptide Y (NPY), apelin, and metallothionein (MT) increased significantly, while those of pro-opinmelanocortin (POMC), ghrelin, and corticotrophin-releasing factor (CRF) decreased significantly. Our data suggested that in fish, low doses of Cd might increase food intake, as well as weight and length gains, but high doses of Cd might have the opposite effect. These effects might be a result of neurohumoral regulation. Long-term exposure to low doses of Cd might cause weight gain and affect food intake. Title: Novel Cinnamoylated Flavoalkaloids Identified in Tea with Acetylcholinesterase Inhibition Effect Gaur R, Ke JP, Zhang P, Yang Z, Bao GH Ref: Journal of Agricultural and Food Chemistry, :, 2020 : PubMed ESTHER: Gaur_2020_J.Agric.Food.Chem__ PubMedSearch: Gaur 2020 J.Agric.Food.Chem PubMedID: 32053361 Abstract 3-O-cinnamoylepicatechin (1) was synthesized along with four flavoalkaloids, (-)-6-(5'''S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (2), (-)-6-(5'''R)-N-ethyl-2-pyrrolidinone--3-O-cinnamoylepicatechin (3), (-)-8-(5'''S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (4), and (-)-8-(5'''R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (5) via esterification of epicatechin followed by phenolic Mannich reaction of 1 with theanine in the presence of heat. The new compounds 1-5 were detected in leaves of three tea cultivars, Fuding-Dabai, Huangjingui, and Zimudan with the help of ultra performance liquid chromatography hyphenated with photodiode array detector and electrospray ionization high resolution mass spectrometry (UPLC-PDA-ESI-HRMS), suggesting that they are naturally occurring in tea leaves. The structures of the novel natural products were characterized by one and two dimensional nuclear magnetic resonance (1D and 2D NMR) and mass spectroscopy. Compounds 1-5 were then evaluated for their acetylcholinesterase (AChE) inhibitory effect (IC50 = 0.12 - 1.02 muM). The availability of the synthesized epicatechin derivatives 1-5 via synthetic route enabled the first unequivocal identification of these derivatives as tea secondary metabolites and made it possible to determine their content in the tea material as well as the diverse bioactivities. Title: Extrusion improves the phenolic profile and biological activities of hempseed (Cannabis sativa L.) hull Leonard W, Zhang P, Ying D, Xiong Y, Fang Z Ref: Food Chem, 346:128606, 2020 : PubMed ESTHER: Leonard_2020_Food.Chem_346_128606 PubMedSearch: Leonard 2020 Food.Chem 346 128606 PubMedID: 33388667 Abstract The impact of extrusion at different barrel temperature and screw speed on the hempseed hull was investigated. The extrusion treatments showed significant (p < 0.05) increase in total phenolic content, proportion of free phenolic compounds, and DPPH and ABTS radical scavenging activities. At low screw speed (150 rpm), significantly (p < 0.05) higher alpha-glucosidase and acetylcholinesterase inhibition activities were observed in the extruded samples. The full factorial model revealed a significant interaction between extrusion parameters on total phenolic/flavonoid content and antioxidant activities for free fraction, and alpha-glucosidase and acetylcholinesterase inhibition for whole fraction. A total of 26 phenylpropionamides, including hydroxycinnamic acid amides and lignanamides, were identified by HPLC-ESI-QTOF-MS/MS. HPLC-DAD analysis showed a 25-78% increase in total phenylpropionamide content in hempseed hull after extrusion. Pearson's correlation displayed significant (p < 0.05) positive correlation of N-trans-caffeoyltyramine, the most abundant phenylpropionamide, with all biological activities (r = 0.832-0.940). Title: Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity Oku S, Feng H, Connor S, Toledo A, Zhang P, Zhang Y, Thoumine O, Zhang C, Craig AM Ref: Elife, 9:, 2020 : PubMed ESTHER: Oku_2020_Elife_9_ PubMedSearch: Oku 2020 Elife 9 PubMedID: 32915137 Abstract Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated by neuroligin-1. We propose that the A1 insert could be a target for alleviating the consequences of deleterious NLGN1/3 mutations, supported by assays with the autism-linked neuroligin-1-P89L mutant. An enrichment of neuroligin-1 A1 in GABAergic neuron types suggests a role in synchrony of cortical circuits. Altogether, these data reveal an unusual mode by which neuroligin splicing controls synapse development through protein-glycan interaction and identify it as a potential therapeutic target. Title: Formation and characterization of lipid droplets of the bovine corpus luteum Talbott HA, Plewes MR, Krause C, Hou X, Zhang P, Rizzo WB, Wood JR, Cupp AS, Davis JS Ref: Sci Rep, 10:11287, 2020 : PubMed ESTHER: Talbott_2020_Sci.Rep_10_11287 PubMedSearch: Talbott 2020 Sci.Rep 10 11287 PubMedID: 32647143 Abstract Establishment and maintenance of pregnancy depends on progesterone synthesized by luteal tissue in the ovary. Our objective was to identify the characteristics of lipid droplets (LDs) in ovarian steroidogenic cells. We hypothesized that LDs are a major feature of steroidogenic luteal cells and store cholesteryl esters. Whole bovine tissues, isolated ovarian steroidogenic cells (granulosa, theca, small luteal, and large luteal), and isolated luteal LDs were assessed for LD content, LD-associated proteins and lipid analyses. Bovine luteal tissue contained abundant lipid droplets, LD-associated perilipins 2/3/5, hormone-sensitive lipase, and 1-acylglycerol-3-phosphate O-acyltransferase ABHD5. Luteal tissue was enriched in triglycerides (TGs) compared to other tissues, except for adipose tissue. Luteal cells were distinguishable from follicular cells by the presence of LDs, LD-associated proteins, and increased TGs. Furthermore, LDs from large luteal cells were numerous and small; whereas, LDs from small luteal cells were large and less numerous. Isolated LDs contained nearly all of the TGs and cholesteryl esters present in luteal tissue. Isolated luteal LDs were composed primarily of TG, with lesser amounts of cholesteryl esters, diglyceride and other phospholipids. Bovine luteal LDs are distinct from LDs in other bovine tissues, including follicular steroidogenic cells. Title: Cadinane- and drimane-type sesquiterpenoids produced by Paecilomyces sp. TE-540, an endophyte from Nicotiana tabacum L., are acetylcholinesterase inhibitors Xu K, Zhou Q, Li XQ, Luo T, Yuan XL, Zhang ZF, Zhang P Ref: Bioorg Chem, 104:104252, 2020 : PubMed ESTHER: Xu_2020_Bioorg.Chem_104_104252 PubMedSearch: Xu 2020 Bioorg.Chem 104 104252 PubMedID: 32911187 Abstract Sesquiterpenoids with diverse skeleton types are regarded as potential lead compounds in pharmacological and other applications. Herein, we report the discovery of two new cadinane-type sesquiterpenoids, paecilacadinol A (1) and B (2); two new drimane-type sesquiterpenoids, ustusol D (3) and ustusol E (4); and six known analogs (5-10) from the endophytic fungus Paecilomyces sp. TE-540, enriching the structural diversity of naturally occurring sesquiterpenoids. Their planar structures were determined on the basis of detailed interpretation of 1D and 2D NMR spectroscopy and HRESIMS data, while their stereochemical structures were established by X-ray crystallographic analyses for 1 and 3-8 and theoretical calculations for 2. Notably, compounds 1 and 2 represent novel examples of cadinane-type sesquiterpenoids with ether bonds formed by intramolecular dehydration. Compounds 5 and 6 showed moderate activities against acetylcholinesterase (AChE), with IC(50) values of 43.02 +/- 6.01 and 35.97 +/- 2.12 muM, respectively. Docking analysis predicted that 5 bound well in the catalytic pocket of AChE via hydrophobic interactions with Trp84, Gly117, Ser122, and Tyr121 residues, while 6 was located with Asp72 and Ser122 residues. Title: Copper(II) complex as a turn on fluorescent sensing platform for acetylcholinesterase activity with high sensitivity Zhang P, Fu C, Xiao Y, Zhang Q, Ding C Ref: Talanta, 208:120406, 2020 : PubMed ESTHER: Zhang_2020_Talanta_208_120406 PubMedSearch: Zhang 2020 Talanta 208 120406 PubMedID: 31816742 Abstract Acetylcholinesterase (AChE) is an important enzyme associated with many nervous diseases, demonstrating the great need for smarter sensing platform with improved sensitivity, selectivity and simplified operation. A "turn on" fluorometric assay is described herein for AChE activity detection, according to the specific enzyme catalyzed reaction of acetylcholine (ATCh) by AChE, which generates thiocholine (TCh) as the product. The well-designed fluorescent probe HBTP possesses ESIPT (Excited State Intramolecular Proton Transfer) nature, leading to a larger Stokes shift, which could be quenched upon coordination with Cu(2+). The fluorescence-silent HBTP-Cu(2+) complex could be broken by TCh generated from reaction of ATCh with AChE, giving rise to HBTP release which originates from competitive coordination of TCh with Cu(2+). This complex probe HBTP-Cu(2+) offers a limit detection as low as 0.02 mUmL(-1), which is lower than most reported literatures. Furthermore, both HBTP-Cu(2+) and HBTP show little toxicity to live cells and is available in visualizing cellular AChE activity. Title: Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice Zhou Y, Wu X, Ye L, Bai Y, Zhang H, Xuan Z, Feng Y, Zhang P, Chen Y and Cui W <2 more author(s)> Zhou Y, Wu X, Ye L, Bai Y, Zhang H, Xuan Z, Feng Y, Zhang P, Chen Y, Yan Y, Zhu B, Cui W (- 2) Ref: Metabolic Brain Disease, :, 2020 : PubMed ESTHER: Zhou_2020_Metab.Brain.Dis__ PubMedSearch: Zhou 2020 Metab.Brain.Dis PubMedID: 31916204 Abstract Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3beta (pSer9-GSK3beta) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD. Title: Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J and Sang Z <1 more author(s)> Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J, Lu X, Sang Z (- 1) Ref: Eur Journal of Medicinal Chemistry, 183:111737, 2019 : PubMed ESTHER: Bai_2019_Eur.J.Med.Chem_183_111737 PubMedSearch: Bai 2019 Eur.J.Med.Chem 183 111737 PubMedID: 31581002 Abstract A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50=1.3+/-0.01muM) and butyrylcholinesterase (IC50=1.2+/-0.09muM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57+/-0.01muM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Abeta1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu(2+)-induced Abeta1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Abeta1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD. Title: Characterization and identification of ferulic acid esterase-producing Lactobacillus species isolated from Elymus nutans silage and their application in ensiled alfalfa Ding ZT, Xu DM, Bai J, Li FH, Adesogan AT, Zhang P, Yuan XJ, Guo XS Ref: J Appl Microbiol, 127:985, 2019 : PubMed ESTHER: Ding_2019_J.Appl.Microbiol_127_985 PubMedSearch: Ding 2019 J.Appl.Microbiol 127 985 PubMedID: 31287933 Abstract AIMS: Ferulic acid esterase (FAE)-producing Lactobacillus species isolated from ensiled Elymus nutans growing on the Qinghai-Tibetan plateau were characterized, and effects of their application to the alfalfa ensiling process and the evidence to synergic effect between cellulase and FAE were investigated. METHODS AND RESULTS: The results of 16S rRNA gene sequence and species-specific polymerase chain reaction amplification showed that two screened strains with high FAE activity were Lactobacillus plantarum A1 (LP) and L. brevis A3 (LBr). The optimum temperature and pH for the LP and LBr was 37 degrees C and 6.4 respectively. The FAE exhibited a good stability at temperatures between 25 and 50 degrees C and at pH values of 5.0-7.0. The two strains and a commercial cellulase (CE) were applied as additives to alfalfa silage. After 60 days of ensiling, the lactic acid in the control and CE groups were significantly lower than those of the other treatment groups. The neutral detergent fibre and acid detergent fibre contents in the LP group were significantly lower than those observed in the other groups. At the same time, the combination of CE and FAE-producing lactic acid bacteria synergistically improved the fermentation quality of the silage. CONCLUSIONS: The addition of the FAE-producing strain of L. plantarum A1 to alfalfa silage improved its fermentation quality, and reduced the fibre content of the silage. SIGNIFICANCE AND IMPACT OF THE STUDY: The screened homo-fermentative and FAE-producing strain of L. plantarum A1 could be a candidate strain in improving fermentation quality and fibre digestibility of ensiled forages. Title: Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer's Disease: in Vitro and in Vivo Evidence Pan H, Qiu H, Zhang K, Zhang P, Liang W, Yang M, Mou C, Lin M, He M and Cui W <8 more author(s)> Pan H, Qiu H, Zhang K, Zhang P, Liang W, Yang M, Mou C, Lin M, He M, Xiao X, Zhang D, Wang H, Liu F, Li Y, Jin H, Yan X, Liang H, Cui W (- 8) Ref: ACS Chem Neurosci, 10:4741, 2019 : PubMed ESTHER: Pan_2019_ACS.Chem.Neurosci_10_4741 PubMedSearch: Pan 2019 ACS.Chem.Neurosci 10 4741 PubMedID: 31639294 Abstract Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a beta-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and beta-amyloid (Abeta) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Abeta oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Abeta-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood-brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment. Title: Interspecies variation of clopidogrel hydrolysis in liver microsomes from various manmmals Wang YQ, Shang XF, Wang L, Zhang P, Zou LW, Song YQ, Hao DC, Fang SQ, Ge GB, Tang H Ref: Chemico-Biological Interactions, :108871, 2019 : PubMed ESTHER: Wang_2019_Chem.Biol.Interact__108871 PubMedSearch: Wang 2019 Chem.Biol.Interact 108871 PubMedID: 31669218 Abstract Clopidogrel, a clinically used antiplatelet agent, can be readily hydrolyzed by human carboxylesterase 1A (CES1A) to release an inactive metabolite clopidogrel carboxylic acid (CCA). In this study, clopidogrel was used as a tool substrate to investigate the interspecies variation of clopidogrel hydrolysis in hepatic microsomes from various mammals including human and six laboratory animals (such as mouse, rat, rabbit, beagle dog, minipig and cynomolgus monkey). The results demonstrated that clopidogrel could be hydrolyzed into CCA by all tested hepatic microsomes from human or other mammals, but the hydrolytic rates greatly varied among species. Inhibition assays demonstrated that BNPP (an inactivator of mammalian CES) strongly inactivated clopidogrel hydrolytic activity in all tested hepatic microsomes, suggested that mammalian CES were major contributor(s) responsible for clopidogrel hydrolysis in hepatic preparations from all above-mentioned species. By contrast, the response of a reversible inhibitor of human CES1A on clopidogrel hydrolysis in these liver preparations varied significantly among different species. Moreover, the enzymatic kinetics and the apparent kinetic parameters of clopidogrel hydrolysis in hepatic microsomes from various animal species were evaluated and compared to each other. These findings provide crucial information for deeply understanding the differences in catalytic behaviors of mammalian CES, which will be very helpful for choosing suitable laboratory animal(s) for whole tests of CES1A substrate-drugs. Title: Synthesis and biological evaluation of 3-arylcoumarins as potential anti-Alzheimer's disease agents Yang J, Zhang P, Hu Y, Liu T, Sun J, Wang X Ref: J Enzyme Inhib Med Chem, 34:651, 2019 : PubMed ESTHER: Yang_2019_J.Enzyme.Inhib.Med.Chem_34_651 PubMedSearch: Yang 2019 J.Enzyme.Inhib.Med.Chem 34 651 PubMedID: 30746966 Abstract Alzheimer's disease, a neurodegenerative illness, has the extremely complex pathogenesis. Accumulating evidence indicates there is a close relationship between several enzymes and Alzheimer's disease. Various substituted 3-arylcoumarin derivatives were synthesised, and their in vitro activity, including cholinesterase inhibitory activity, monoamine oxidase inhibitory activity, and antioxidant activity were investigated. Most of the compounds exhibited high activity; therefore 3-arylcoumarin compounds have the potential as drug candidates for the treatment of Alzheimer's disease. Title: A sensitive amperometric AChE-biosensor for organophosphate pesticides detection based on conjugated polymer and Ag-rGO-NH2 nanocomposite Zhang P, Sun T, Rong S, Zeng D, Yu H, Zhang Z, Chang D, Pan H Ref: Bioelectrochemistry, 127:163, 2019 : PubMed ESTHER: Zhang_2019_Bioelectrochemistry_127_163 PubMedSearch: Zhang 2019 Bioelectrochemistry 127 163 PubMedID: 30831354 Abstract Long-term accumulation of organophosphate pesticides in environment presents a potential hazard to human and animal health. Towards this, a highly sensitive amperometric AChE-biosensor based on conjugated polymer and Ag-rGO-NH2 nanocomposite has been successfully developed. First, 4, 7-di (furan-2-yl) benzo thiadiazole (FBThF) was electrochemically polymerized on the electrode surface. Then, Ag-rGO-NH2 nanocomposite and acetylcholinesterase (AChE) are modified on the polymer membrane surface. In this way, a novel amperometric AChE-biosensor was successfully prepared. The as-prepared biosensor possessed excellent conductivity, catalytic activity, and biocompatibility which were attributed to the synergistic effects of poly(FBThF) and Ag-rGO-NH2 and provided a hydrophilic surface for AChE adhesion. Under optimized conductions, the linear range was 0.099-9.9mugL(-1) with a regression coefficient of 0.9947 for malathion, 0.0206-2.06mugL(-1) with a regression coefficient of 0.9969 for trichlorfon. The detection limit is calculated to be about 0.032mugL(-1) for malathion and 0.001mugL(-1) for trichlorfon (S/N=3). Moreover, the biosensor exhibited acceptable reproducibility and long-term stability, which makes it possible to provide a novel and promising tool for analysis of organophosphate pesticides. Title: Multi-target design strategies for the improved treatment of Alzheimer's disease Zhang P, Xu S, Zhu Z, Xu J Ref: Eur Journal of Medicinal Chemistry, 176:228, 2019 : PubMed ESTHER: Zhang_2019_Eur.J.Med.Chem_176_228 PubMedSearch: Zhang 2019 Eur.J.Med.Chem 176 228 PubMedID: 31103902 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. Title: Two transcription factors cooperatively regulate DHN melanin biosynthesis and development in Pestalotiopsis fici Zhang P, Zhou S, Wang G, An Z, Liu X, Li K, Yin WB Ref: Molecular Microbiology, 112:649, 2019 : PubMed ESTHER: Zhang_2019_Mol.Microbiol_112_649 PubMedSearch: Zhang 2019 Mol.Microbiol 112 649 PubMedID: 31116900 Gene_locus related to this paper: pesfw-pfmab, pesfw-pfmae Abstract Fungal 1,8-dihydroxynaphthalene (DHN) melanin plays important roles in UV protection, oxidative stress and pathogenesis. However, knowledge of the regulatory mechanisms of its biosynthesis is limited. Previous studies showed two transcription factors, PfmaF and PfmaH, located in the DHN melanin biosynthetic gene cluster (Pfma) in Pestalotiopsis fici. In this study, deletion of PfmaH resulted in loss of melanin and affected conidia cell wall integrity. Specifically, PfmaH directly regulates the expression of scytalone dehydratase, which catalyzes the transition of scytalone to T(3) HN. However, PfmaF disruption using CRISPR/Cas9 system affected neither DHN melanin distribution nor conidia cell wall integrity in P. fici. Unexpectedly, overexpression of PfmaF leads to heavy pigment accumulation in P. fici hyphae. Transcriptome and qRT-PCR analyses provide insight into the roles of PfmaF and PfmaH in DHN melanin regulation. PfmaH, as a pathway specific regulator, mainly regulates melanin biosynthesis that contributes to cell wall development. Furthermore, PfmaF functions as a broad regulator to stimulate PfmaH expression in melanin production, secondary metabolism as well as fungal development. Title: The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z Ref: Bioorganic & Medicinal Chemistry Lett, 29:126625, 2019 : PubMed ESTHER: Zhu_2019_Bioorg.Med.Chem.Lett_29_126625 PubMedSearch: Zhu 2019 Bioorg.Med.Chem.Lett 29 126625 PubMedID: 31444085 Abstract A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC(50) value of 2.9 microM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu(2+) complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC(50) = 6.8 microM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease. Title: CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P and Wang W <7 more author(s)> Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P, Qu Y, Zhang Z, Yang Z, Xiang Y, Zhang W, Wang S, Shao W, Wang W (- 7) Ref: Biomed Pharmacother, 107:1496, 2018 : PubMed ESTHER: Feng_2018_Biomed.Pharmacother_107_1496 PubMedSearch: Feng 2018 Biomed.Pharmacother 107 1496 PubMedID: 30257367 Abstract CXCL5 is showed a surprisingly elevated profile and implicated in tumorigenesis in several tumors. However, the expression and function of CXCL5 in uterine cervix cancer (UCC) remain largely unknown. The current study aimed to elucidate the expression pattern of CXCL5 in human UCC tissues and Hela cervix cancer cell, as well as its functions in Hela cells. Our data showed that CXCL5 and its receptor CXCR2 were expressed by Hela uterine cervix cancer cells. CXCL5 was upregulated in UCC tissues, and its overexpression was positively correlated with age, but did not correlate with clinical stages and tumor infiltration. Exogenous administration of CXCL5 and CXCL5 overexpression contributed to proliferation and migration activities of Hela cells in vitro, consistent with this, CXCL5 overexpression also promoted growth of Hela cells in a nude mouse xenograft model. At the gene level, CXCL5 overexpression regulated the expression of tumor-related genes including ERK, p-ERK, AKT, p-AKT, DIABOL, NUMB, NDRG3 and CXCR2. Taken together, CXCL5 may contribute to a dominant role in UCC progression and sever as a potential molecular therapeutic target for UCC. Title: Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X and Yi W <2 more author(s)> Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X, Ji H, Zhang C, Yi W (- 2) Ref: Molecules, 23:, 2018 : PubMed ESTHER: Wu_2018_Molecules_23_ PubMedSearch: Wu 2018 Molecules 23 PubMedID: 30301153 Abstract A series of novel ligustrazine derivatives 8a(-)r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 x 10(6); for 8r, IC50 BuChE/IC50 AChE = 1.32 x 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Abeta aggregation, with IC50 values of 17.36 microM and 49.14 microM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 muM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. Title: Duplication of a Pks gene cluster and subsequent functional diversification facilitate environmental adaptation in Metarhizium species Zeng G, Zhang P, Zhang Q, Zhao H, Li Z, Zhang X, Wang C, Yin WB, Fang W Ref: PLoS Genet, 14:e1007472, 2018 : PubMed ESTHER: Zeng_2018_PLoS.Genet_14_E1007472 PubMedSearch: Zeng 2018 PLoS.Genet 14 E1007472 PubMedID: 29958281 Gene_locus related to this paper: metaq-pks1, metra-pks2, metmf-pks2, metaf-pks1, metbs-pks2, metas-pks1, metaq-pks2 Abstract The ecological importance of the duplication and diversification of gene clusters that synthesize secondary metabolites in fungi remains poorly understood. Here, we demonstrated that the duplication and subsequent diversification of a gene cluster produced two polyketide synthase gene clusters in the cosmopolitan fungal genus Metarhizium. Diversification occurred in the promoter regions and the exon-intron structures of the two Pks paralogs (Pks1 and Pks2). These two Pks genes have distinct expression patterns, with Pks1 highly expressed during conidiation and Pks2 highly expressed during infection. Different upstream signaling pathways were found to regulate the two Pks genes. Pks1 is positively regulated by Hog1-MAPK, Slt2-MAPK and Mr-OPY2, while Pks2 is positively regulated by Fus3-MAPK and negatively regulated by Mr-OPY2. Pks1 and Pks2 have been subjected to positive selection and synthesize different secondary metabolites. PKS1 is involved in synthesis of an anthraquinone derivative, and contributes to conidial pigmentation, which plays an important role in fungal tolerance to UV radiation and extreme temperatures. Disruption of the Pks2 gene delayed formation of infectious structures and increased the time taken to kill insects, indicating that Pks2 contributes to pathogenesis. Thus, the duplication of a Pks gene cluster and its subsequent functional diversification has increased the adaptive flexibility of Metarhizium species. Title: Evolutionary history of Coleoptera revealed by extensive sampling of genes and species Zhang SQ, Che LH, Li Y, Dan L, Pang H, Slipinski A, Zhang P Ref: Nat Commun, 9:205, 2018 : PubMed ESTHER: Zhang_2018_Nat.Commun_9_205 PubMedSearch: Zhang 2018 Nat.Commun 9 205 PubMedID: 29335414 Abstract Beetles (Coleoptera) are the most diverse and species-rich group of insects, and a robust, time-calibrated phylogeny is fundamental to understanding macroevolutionary processes that underlie their diversity. Here we infer the phylogeny and divergence times of all major lineages of Coleoptera by analyzing 95 protein-coding genes in 373 beetle species, including ~67% of the currently recognized families. The subordinal relationships are strongly supported as Polyphaga (Adephaga (Archostemata, Myxophaga)). The series and superfamilies of Polyphaga are mostly monophyletic. The species-poor Nosodendridae is robustly recovered in a novel position sister to Staphyliniformia, Bostrichiformia, and Cucujiformia. Our divergence time analyses suggest that the crown group of extant beetles occurred ~297 million years ago (Mya) and that ~64% of families originated in the Cretaceous. Most of the herbivorous families experienced a significant increase in diversification rate during the Cretaceous, thus suggesting that the rise of angiosperms in the Cretaceous may have been an 'evolutionary impetus' driving the hyperdiversity of herbivorous beetles. Title: Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships Zhang P, Lu H, Peixoto RT, Pines MK, Ge Y, Oku S, Siddiqui TJ, Xie Y, Wu W and Craig AM <8 more author(s)> Zhang P, Lu H, Peixoto RT, Pines MK, Ge Y, Oku S, Siddiqui TJ, Xie Y, Wu W, Archer-Hartmann S, Yoshida K, Tanaka KF, Aricescu AR, Azadi P, Gordon MD, Sabatini BL, Wong ROL, Craig AM (- 8) Ref: Cell, 174:1450, 2018 : PubMed ESTHER: Zhang_2018_Cell_174_1450 PubMedSearch: Zhang 2018 Cell 174 1450 PubMedID: 30100184 Abstract Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. Title: A cryptic pigment biosynthetic pathway uncovered by heterologous expression is essential for conidial development in Pestalotiopsis fici Zhang P, Wang X, Fan A, Zheng Y, Liu X, Wang S, Zou H, Oakley BR, Keller NP, Yin WB Ref: Molecular Microbiology, 105:469, 2017 : PubMed ESTHER: Zhang_2017_Mol.Microbiol_105_469 PubMedSearch: Zhang 2017 Mol.Microbiol 105 469 PubMedID: 28517364 Gene_locus related to this paper: pesfw-pfmab, pesfw-pfmae Abstract Spore pigmentation is very common in the fungal kingdom. The best studied pigment in fungi is melanin which coats the surface of single cell spores. What and how pigments function in a fungal species with multiple cell conidia is poorly understood. Here, we identified and deleted a polyketide synthase (PKS) gene PfmaE and showed that it is essential for multicellular conidial pigmentation and development in a plant endophytic fungus, Pestalotiopsis fici. To further characterize the melanin pathway, we utilized an advanced Aspergillus nidulans heterologous system for the expression of the PKS PfmaE and the Pfma gene cluster. By structural elucidation of the pathway metabolite scytalone in A. nidulans, we provided chemical evidence that the Pfma cluster synthesizes DHN melanin. Combining genetic deletion and combinatorial gene expression of Pfma cluster genes, we determined that the putative reductase PfmaG and the PKS are sufficient for the synthesis of scytalone. Feeding scytalone back to the P. fici deltaPfmaE mutant restored pigmentation and multicellular adherence of the conidia. These results cement a growing understanding that pigments are essential not simply for protection of spores from biotic and abiotic stresses but also for spore structural development. Title: Butyrylcholinesterase nanocapsule as a long circulating bioscavenger with reduced immune response Zhang P, Jain P, Tsao C, Sinclair A, Sun F, Hung HC, Bai T, Wu K, Jiang S Ref: J Control Release, 230:73, 2016 : PubMed ESTHER: Zhang_2016_J.Control.Release_230_73 PubMedSearch: Zhang 2016 J.Control.Release 230 73 PubMedID: 27063423 Abstract Butyrylcholinesterase (BChE) is the most promising bioscavenger candidate to treat or prevent organophosphate (OP) poisoning. However, the clinical application of BChE is limited by two obstacles: an inadequate circulation half-life and limited sources for production. Although several modification technologies including glycosylation and PEGylation have been developed to improve its pharmacokinetics, none of them have been able to outperform blood-derived native BChE. In this work, we designed a long-circulating bioscavenger nanogel by coating equine serum-derived BChE with a zwitterionic polymer gel layer. This zwitterionic gel coating protected BChE from denaturation and degradation under harsh conditions. Notably, the nanocapsule exhibited a long circulation half-life of ~45h, a three-fold increase from the unmodified native version, enabling both therapeutic and prophylactic applications. In addition, the gel coating reduced the immunogenicity of equine BChE, unlocking the possibility to use non-human derived BChE as an OP bioscavenger in humans. Title: (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-beta aggregation with high antioxidant potency for Alzheimer's therapy Cheng S, Zheng W, Gong P, Zhou Q, Xie Q, Yu L, Zhang P, Chen L, Li J and Chen H <1 more author(s)> Cheng S, Zheng W, Gong P, Zhou Q, Xie Q, Yu L, Zhang P, Chen L, Li J, Chen J, Chen H (- 1) Ref: Bioorganic & Medicinal Chemistry, 23:3110, 2015 : PubMed ESTHER: Cheng_2015_Bioorg.Med.Chem_23_3110 PubMedSearch: Cheng 2015 Bioorg.Med.Chem 23 3110 PubMedID: 26025073 Abstract The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-beta (Abeta) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Abeta self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Title: Genome sequencing of adzuki bean (Vigna angularis) provides insight into high starch and low fat accumulation and domestication Yang K, Tian Z, Chen C, Luo L, Zhao B, Wang Z, Yu L, Li Y, Sun Y and Wan P <17 more author(s)> Yang K, Tian Z, Chen C, Luo L, Zhao B, Wang Z, Yu L, Li Y, Sun Y, Li W, Chen Y, Zhang Y, Ai D, Zhao J, Shang C, Ma Y, Wu B, Wang M, Gao L, Sun D, Zhang P, Guo F, Wang W, Wang J, Varshney RK, Ling HQ, Wan P (- 17) Ref: Proc Natl Acad Sci U S A, 112:13213, 2015 : PubMed ESTHER: Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_13213 PubMedSearch: Yang 2015 Proc.Natl.Acad.Sci.U.S.A 112 13213 PubMedID: 26460024 Gene_locus related to this paper: phaan-a0a0l9ttq5, phaan-a0a0l9vh69, phaan-a0a0l9vh89, phaan-a0a0s3tc53, vigrr-a0a1s3v914, phaan-a0a0s3s998, phaan-a0a0s3siv8, phaan-a0a0l9uys5, phaan-a0a0s3rp07, phaan-a0a0s3rbq0, vigrr-a0a1s3tul4, phaan-a0a0s3smk7, phaan-a0a0s3slm9, phaan-a0a0l9ujf5, phaan-a0a0l9til9, phaan-a0a0l9uqr2, phaan-a0a0l9v1m8, phaan-a0a0l9uc60, phaan-a0a0l9ucr8 Abstract Adzuki bean (Vigna angularis), an important legume crop, is grown in more than 30 countries of the world. The seed of adzuki bean, as an important source of starch, digestible protein, mineral elements, and vitamins, is widely used foods for at least a billion people. Here, we generated a high-quality draft genome sequence of adzuki bean by whole-genome shotgun sequencing. The assembled contig sequences reached to 450 Mb (83% of the genome) with an N50 of 38 kb, and the total scaffold sequences were 466.7 Mb with an N50 of 1.29 Mb. Of them, 372.9 Mb of scaffold sequences were assigned to the 11 chromosomes of adzuki bean by using a single nucleotide polymorphism genetic map. A total of 34,183 protein-coding genes were predicted. Functional analysis revealed that significant differences in starch and fat content between adzuki bean and soybean were likely due to transcriptional abundance, rather than copy number variations, of the genes related to starch and oil synthesis. We detected strong selection signals in domestication by the population analysis of 50 accessions including 11 wild, 11 semiwild, 17 landraces, and 11 improved varieties. In addition, the semiwild accessions were illuminated to have a closer relationship to the cultigen accessions than the wild type, suggesting that the semiwild adzuki bean might be a preliminary landrace and play some roles in the adzuki bean domestication. The genome sequence of adzuki bean will facilitate the identification of agronomically important genes and accelerate the improvement of adzuki bean. Title: Inhibitory Synapses Get Madd for Neuroligin Zhang P, Craig AM Ref: Neuron, 86:1321, 2015 : PubMed ESTHER: Zhang_2015_Neuron_86_1321 PubMedSearch: Zhang 2015 Neuron 86 1321 PubMedID: 26087158 Abstract The mechanisms mediating the appropriate clustering of neurotransmitter receptors opposite release sites are poorly understood. Two studies in this issue of Neuron, Maro et al. (2015) and Tu et al. (2015), identify a new extracellular effector for neuroligin in GABAergic postsynaptic differentiation. Title: Association between EPHX1 rs1051740 and lung cancer susceptibility: a meta-analysis Zhang P, Zhang Y, Yang H, Li W, Chen X, Long F Ref: Int J Clin Exp Med, 8:17941, 2015 : PubMed ESTHER: Zhang_2015_Int.J.Clin.Exp.Med_8_17941 PubMedSearch: Zhang 2015 Int.J.Clin.Exp.Med 8 17941 PubMedID: 26770388 Abstract BACKGROUND: Microsomal epoxide hydrolase 1 (EPHX1) may play an important role in epigenetic change and DNA repair concerned with lung cancer. Several studies have investigated the association between EPHX1 rs1051740 and lung cancer risk, but there is no consensus. Therefore, we performed a meta-analysis to further identify the relationship. Title: Alkaloids from the bulbs of Lycoris longituba and their neuroprotective and acetylcholinesterase inhibitory activities Zhu YY, Li X, Yu HY, Xiong YF, Zhang P, Pi HF, Ruan HL Ref: Arch Pharm Res, 38:604, 2015 : PubMed ESTHER: Zhu_2015_Arch.Pharm.Res_38_604 PubMedSearch: Zhu 2015 Arch.Pharm.Res 38 604 PubMedID: 25219454 Abstract Three novel alkaloids (1-3), together with nineteen known ones (4-22), were isolated from the bulbs of Lycoris longituba. Their structures were elucidated on the basis of extensive spectroscopic analyses, which belong to several Amaryllidaceae alkaloid skeletons. Among them, the harmane-type alkaloids (the new compound 1 and the known compounds 5, 6 and 7) were found for the first time from Lycoris genus. The isolates were tested for their neuroprotective activities against CoCl2, H2O2 and Abeta25-35-induced SH-SY5Y cell injuries, and the majority of them exhibited neuroprotective activities of different degrees. The acetylcholinesterase (AChE) inhibitory activities of the isolated alkaloids were also evaluated, while compounds 12, 14-20 and 22 exhibited extremely significant AChE inhibitory activities. Title: Whole-genome sequence of a flatfish provides insights into ZW sex chromosome evolution and adaptation to a benthic lifestyle Chen S, Zhang G, Shao C, Huang Q, Liu G, Zhang P, Song W, An N, Chalopin D and Wang J <34 more author(s)> Chen S, Zhang G, Shao C, Huang Q, Liu G, Zhang P, Song W, An N, Chalopin D, Volff JN, Hong Y, Li Q, Sha Z, Zhou H, Xie M, Yu Q, Liu Y, Xiang H, Wang N, Wu K, Yang C, Zhou Q, Liao X, Yang L, Hu Q, Zhang J, Meng L, Jin L, Tian Y, Lian J, Yang J, Miao G, Liu S, Liang Z, Yan F, Li Y, Sun B, Zhang H, Zhu Y, Du M, Zhao Y, Schartl M, Tang Q, Wang J (- 34) Ref: Nat Genet, 46:253, 2014 : PubMed ESTHER: Chen_2014_Nat.Genet_46_253 PubMedSearch: Chen 2014 Nat.Genet 46 253 PubMedID: 24487278 Gene_locus related to this paper: cynse-a0a3p8wch2, cynse-a0a3p8vd14, cynse-a0a3p8w747, cynse-a0a3p8wq40, cynse-a0a3p8wul3, cynse-a0a3p8vqr4, cynse-a0a3p8vmz4 Abstract Genetic sex determination by W and Z chromosomes has developed independently in different groups of organisms. To better understand the evolution of sex chromosomes and the plasticity of sex-determination mechanisms, we sequenced the whole genomes of a male (ZZ) and a female (ZW) half-smooth tongue sole (Cynoglossus semilaevis). In addition to insights into adaptation to a benthic lifestyle, we find that the sex chromosomes of these fish are derived from the same ancestral vertebrate protochromosome as the avian W and Z chromosomes. Notably, the same gene on the Z chromosome, dmrt1, which is the male-determining gene in birds, showed convergent evolution of features that are compatible with a similar function in tongue sole. Comparison of the relatively young tongue sole sex chromosomes with those of mammals and birds identified events that occurred during the early phase of sex-chromosome evolution. Pertinent to the current debate about heterogametic sex-chromosome decay, we find that massive gene loss occurred in the wake of sex-chromosome 'birth'. Title: Determination of tacrine-6-ferulic acid in rat plasma by LC-MS/MS and its application to pharmacokinetics study Sun X, Zhang P, Pi R, Zhou Y, Deng X, Xie Z, Liao Q Ref: Biomedical Chromatography, 28:1352, 2014 : PubMed ESTHER: Sun_2014_Biomed.Chromatogr_28_1352 PubMedSearch: Sun 2014 Biomed.Chromatogr 28 1352 PubMedID: 24706520 Abstract Tacrine, as a drug for treating Alzheimer's disease (AD), has low efficacy owing to its single function and serious side effects. However, tacrine-6-ferulic acid (T6FA), the dimer which added ferulic acid to tacrine, has been found to be a promising multifunctional drug candidate for AD and much more potent and selective on acetylcholinesterase (AChE) than tacrine. The aim of the present work was to develop and validate an LC-MS/MS method with electrospray ionization for the quantification of T6FA in rat plasma using tacrine-3-ferulic acid (T3FA) as internal standard and to examine its application for pharmacokinetic study in rats. Following a single liquid-liquid extraction with ethyl acetate, chromatographic separation was achieved at 25 degrees C on a BDS Hypersil C18 column with a mobile phase composed of 1% formic acid and methonal (30:70, v/v) at a flow rate of 0.2 mL/min. Quantification was achieved by monitoring the selected ions at m/z 474.2 --> 298.1 for T6FA and m/z 432.2 --> 199.0 for T3FA. The method was validated to be rapid, specific, accurate and precise over the concentration range of 0.5-1000.0 ng/mL in rat samples. Furthermore, it was successfully applied for the pharmacokinetic measurement of T6FA with an oral administration at 40 mg/kg to rats. Copyright (c) 2014 John Wiley & Sons, Ltd. Title: Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs Zhou M, Liu M, He X, Yu H, Wu D, Yao Y, Fan S, Zhang P, Shi W, Zhong B Ref: Molecules, 19:19718, 2014 : PubMed ESTHER: Zhou_2014_Molecules_19_19718 PubMedSearch: Zhou 2014 Molecules 19 19718 PubMedID: 25438082 Inhibitor(s) related to this paper: SN-38 Abstract In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo. Title: [Protective effect of oligosaccharides from Morinda officinalis on beta-amyloid-induced dementia rats] Chen DL, Zhang P, Lin L, Zhang HM, Liu SH Ref: Zhongguo Zhong Yao Za Zhi, 38:1306, 2013 : PubMed ESTHER: Chen_2013_Zhongguo.Zhong.Yao.Za.Zhi_38_1306 PubMedSearch: Chen 2013 Zhongguo.Zhong.Yao.Za.Zhi 38 1306 PubMedID: 23944057 Abstract OBJECTIVE: To observe the effect of oligosaccharides of Morinda officinalis (OMO) on beta-amyloid-induced dementia rats, and study its pharmacological mechanism in treatment of dementia. METHOD: The dementia model rats were established by injecting Abeta25-35 10 microLg into bilateral hippocampus. OMO high-dose (60 mg . kg-1 . d-1) group, OMO low-dose (20 mg . kg-1 . d-1 ) groups, the blank group, the sham operation group and the positive donepezil HC1 group (0. 125 mg kg-1 . d-1) were designed for the experiment. They were continuously administered with drugs at the 15th day after operation for 25 days. Kit microplate method was used to detect the contents of super oxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione reductase (GSH-Px), acetylcholine (ACh) , acetylcholinesterase (AChE) and Na+ /K+ -ATPase. RESULT: Compared with the model group, all of administration groups showed higher SOD, CAT and GSH-Px levels, and lower MDA in the brain tissues. Besides, they also showed rise in the activities of ACh and Na+ /K+ -ATPase. CONCLUSION: OMO can ameliorate on beta-amyloid-induced dementia rats by enhancing oxidation resistance, activating brain energy metabolism and improving the injury of cholinergic system. Title: The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells Shi L, Chang X, Zhang P, Coba MP, Lu W, Wang K Ref: Hum Mol Genet, 22:3749, 2013 : PubMed ESTHER: Shi_2013_Hum.Mol.Genet_22_3749 PubMedSearch: Shi 2013 Hum.Mol.Genet 22 3749 PubMedID: 23710042 Abstract Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases. Title: Exposure to a Cutinase-like Serine Esterase Triggers Rapid Lysis of Multiple Mycobacterial Species Yang Y, Bhatti A, Ke D, Gonzalez-Juarrero M, Lenaerts A, Kremer L, Guerardel Y, Zhang P, Ojha AK Ref: Journal of Biological Chemistry, 288:382, 2013 : PubMed ESTHER: Yang_2013_J.Biol.Chem_288_382 PubMedSearch: Yang 2013 J.Biol.Chem 288 382 PubMedID: 23155047 Abstract Mycobacteria are shaped by a thick envelope made of an array of uniquely structured lipids and polysaccharides. However, the spatial organization of these molecules remains unclear. Here, we show that exposure to an esterase from Mycobacterium smegmatis (Msmeg_1529), hydrolyzing the ester linkage of trehalose dimycolate in vitro, triggers rapid and efficient lysis of Mycobacterium tuberculosis, Mycobacterium bovis BCG, and Mycobacterium marinum. Exposure to the esterase immediately releases free mycolic acids, while concomitantly depleting trehalose mycolates. Moreover, lysis could be competitively inhibited by an excess of purified trehalose dimycolate and was abolished by a S124A mutation affecting the catalytic activity of the esterase. These findings are consistent with an indispensable structural role of trehalose mycolates in the architectural design of the exposed surface of the mycobacterial envelope. Importantly, we also demonstrate that the esterase-mediated rapid lysis of M. tuberculosis significantly improves its detection in paucibacillary samples. Title: Predictors of rapid cognitive decline in Alzheimer's disease: results from the Australian imaging, biomarkers and lifestyle (AIBL) study of ageing Sona A, Zhang P, Ames D, Bush AI, Lautenschlager NT, Martins RN, Masters CL, Rowe CC, Szoeke C and Ellis KA <1 more author(s)> Sona A, Zhang P, Ames D, Bush AI, Lautenschlager NT, Martins RN, Masters CL, Rowe CC, Szoeke C, Taddei K, Ellis KA (- 1) Ref: Int Psychogeriatr, 24:197, 2012 : PubMed ESTHER: Sona_2012_Int.Psychogeriatr_24_197 PubMedSearch: Sona 2012 Int.Psychogeriatr 24 197 PubMedID: 21749739 Abstract BACKGROUND: The AIBL study, which commenced in November 2006, is a two-center prospective study of a cohort of 1112 volunteers aged 60+. The cohort includes 211 patients meeting NINCDS-ADRDA criteria for Alzheimer's disease (AD) (180 probable and 31 possible). We aimed to identify factors associated with rapid cognitive decline over 18 months in this cohort of AD patients. METHODS: We defined rapid cognitive decline as a drop of 6 points or more on the Mini-Mental State Examination (MMSE) between baseline and 18-month follow-up. Analyses were also conducted with a threshold of 4, 5, 7 and 8 points, as well as with and without subjects who had died or were too severely affected to be interviewed at 18 months and after, both including and excluding subjects whose AD diagnosis was "possible" AD. We sought correlations between rapid cognitive decline and demographic, clinical and biological variables. RESULTS: Of the 211 AD patients recruited at baseline, we had available data for 156 (73.9%) patients at 18 months. Fifty-one patients were considered rapid cognitive decliners (32.7%). A higher Clinical Dementia Rating scale (CDR) and higher CDR "sum of boxes" score at baseline were the major predictors of rapid cognitive decline in this population. Furthermore, using logistic regression model analysis, patients treated with a cholinesterase inhibitor (CheI) had a higher risk of being rapid cognitive decliners, as did males and those of younger age. CONCLUSIONS: Almost one third of patients satisfying established research criteria for AD experienced rapid cognitive decline. Worse baseline functional and cognitive status and treatment with a CheI were the major factors associated with rapid cognitive decline over 18 months in this population. Title: Multiple genome alignments facilitate development of NPCL markers: a case study of tetrapod phylogeny focusing on the position of turtles Shen XX, Liang D, Wen JZ, Zhang P Ref: Molecular Biology Evolution, 28:3237, 2011 : PubMed ESTHER: Shen_2011_Mol.Biol.Evol_28_3237 PubMedSearch: Shen 2011 Mol.Biol.Evol 28 3237 PubMedID: 21680872 Gene_locus related to this paper: pelsi-BCHE Abstract In recent years, the increasing availability of genomic resources has provided an opportunity to develop phylogenetic markers for phylogenomics. Efficient methods to search for candidate markers from the huge number of genes within genomic data are particularly needed in the era of phylogenomics. Here, rather than using the traditional approach of comparing genomes of two distantly related taxa to develop conserved primers, we take advantage of the multiple genome alignment resources from the the University of California-San Cruz Genome Browser and present a simple and straightforward bioinformatic approach to automatically screen for candidate nuclear protein-coding locus (NPCL) markers. We tested our protocol in tetrapods and successfully obtained 21 new NPCL markers with high success rates of polymerase chain reaction amplification (mostly over 80%) in 16 diverse tetrapod taxa. These 21 newly developed markers together with two reference genes (RAG1 and mitochondrial 12S-16S) are used to infer the higher level relationships of tetrapods, with emphasis on the debated position of turtles. Both maximum likelihood (ML) and Bayesian analyses on the concatenated data combining the 23 markers (21,137 bp) yield the same tree, with ML bootstrap values over 95% and Bayesian posterior probability equaling 1.0 for most nodes. Species tree estimation using the program BEST without data concatenation produces similar results. In all analyses, turtles are robustly recovered as the sister group of Archosauria (birds and crocodilians). The jackknife analysis on the concatenated data showed that the minimum sequence length needed to robustly resolve the position of turtles is 13-14 kb. Based on the large 23-gene data set and the well-resolved tree, we also estimated evolutionary timescales for tetrapods with the popular Bayesian method MultiDivTime. Most of the estimated ages among tetrapods are similar to the average estimates of the previous dating studies summarized by the book The Timetree of Life. Title: Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques Yan G, Zhang G, Fang X, Zhang Y, Li C, Ling F, Cooper DN, Li Q, Li Y and Wang X <32 more author(s)> Yan G, Zhang G, Fang X, Zhang Y, Li C, Ling F, Cooper DN, Li Q, Li Y, van Gool AJ, Du H, Chen J, Chen R, Zhang P, Huang Z, Thompson JR, Meng Y, Bai Y, Wang J, Zhuo M, Wang T, Huang Y, Wei L, Li J, Wang Z, Hu H, Yang P, Le L, Stenson PD, Li B, Liu X, Ball EV, An N, Huang Q, Fan W, Zhang X, Wang W, Katze MG, Su B, Nielsen R, Yang H, Wang X (- 32) Ref: Nat Biotechnol, 29:1019, 2011 : PubMed ESTHER: Yan_2011_Nat.Biotechnol_29_1019 PubMedSearch: Yan 2011 Nat.Biotechnol 29 1019 PubMedID: 22002653 Gene_locus related to this paper: macfa-BCHE, macfa-g7nzc0, macfa-g7nze2, macfa-g7p4b9, macfa-g7pa87, macfa-g7pd01, macfa-g7q259, macfa-3neur, macfa-g8f585, macfa-KANSL3, macfa-q4r8p0, macfa-SPG21, macfa-TEX30, macmu-3neur, macmu-ACHE, macmu-BCHE, macmu-f6sz31, macmu-f6the6, macmu-f6zkq5, macmu-f7buk8, macmu-f7cfi8, macmu-f7flv1, macmu-f7ggk1, macmu-f7hir7, macmu-g7n054, macmu-g7npb8, macmu-g7nq39, macmu-KANSL3, macmu-TEX30, macfa-g7pgg6, macmu-g7n4x3, macfa-g7nzx2, macfa-g8f4f7, macmu-f7ba84, macfa-g7psx7, macmu-h9er02, macfa-g8f3k0, macfa-a0a2k5w1n7, macmu-g7mxj6, macfa-g7pbk1, macfa-a0a2k5urk5, macfa-a0a2k5wye4, macfa-g7pe14, macmu-f7hkw9, macmu-f7hm08, macmu-g7mke4, macfa-g7nxn9, macmu-a0a1d5rh04, macmu-h9fud6, macfa-g8f3e1, macfa-i7gcw6, macmu-f6qwx1, macmu-f7h4t2, macfa-a0a2k5wkd0, macfa-a0a2k5v7v4, macfa-g7p7y3, macfa-a0a2k5uqq3, macmu-i2cu80, macfa-g8f5i1, macmu-f7h550, macmu-f7gkb9, macfa-a0a2k5tui1 Abstract The nonhuman primates most commonly used in medical research are from the genus Macaca. To better understand the genetic differences between these animal models, we present high-quality draft genome sequences from two macaque species, the cynomolgus/crab-eating macaque and the Chinese rhesus macaque. Comparison with the previously sequenced Indian rhesus macaque reveals that all three macaques maintain abundant genetic heterogeneity, including millions of single-nucleotide substitutions and many insertions, deletions and gross chromosomal rearrangements. By assessing genetic regions with reduced variability, we identify genes in each macaque species that may have experienced positive selection. Genetic divergence patterns suggest that the cynomolgus macaque genome has been shaped by introgression after hybridization with the Chinese rhesus macaque. Macaque genes display a high degree of sequence similarity with human disease gene orthologs and drug targets. However, we identify several putatively dysfunctional genetic differences between the three macaque species, which may explain functional differences between them previously observed in clinical studies. Title: Genomic comparison of the ants Camponotus floridanus and Harpegnathos saltator Bonasio R, Zhang G, Ye C, Mutti NS, Fang X, Qin N, Donahue G, Yang P, Li Q and Liebig J <6 more author(s)> Bonasio R, Zhang G, Ye C, Mutti NS, Fang X, Qin N, Donahue G, Yang P, Li Q, Li C, Zhang P, Huang Z, Berger SL, Reinberg D, Wang J, Liebig J (- 6) Ref: Science, 329:1068, 2010 : PubMed ESTHER: Bonasio_2010_Science_329_1068 PubMedSearch: Bonasio 2010 Science 329 1068 PubMedID: 20798317 Gene_locus related to this paper: 9hyme-e1zye4, 9hyme-e2a0n6, 9hyme-e2a3j7, 9hyme-e2a4n5, 9hyme-e2a4n6, 9hyme-e2a8v4, 9hyme-e2a9y2, 9hyme-e2acx6, 9hyme-e2adw2, 9hyme-e2adw3, 9hyme-e2adw4, 9hyme-e2adw5, 9hyme-e2adw7, 9hyme-e2adw9, 9hyme-e2adx0, 9hyme-e2ai90, 9hyme-e2ajl7, 9hyme-e2ajl8, 9hyme-e2ajl9, 9hyme-e2am67, 9hyme-e2am68, 9hyme-e2any0, 9hyme-e2ara9, 9hyme-e2axr7, 9hyme-e2b2q4, 9hyme-e2b493, 9hyme-e2bc53, 9hyme-e2bft9, 9hyme-e2bfu1, 9hyme-e2bfu2, 9hyme-e2bi28, 9hyme-e2bn41, 9hyme-e2by80, 9hyme-e2c2j5, camfo-e1zwv0, camfo-e1zxk2, camfo-e1zze7, camfo-e2a1a9, camfo-e2a6b9, camfo-e2a925, camfo-e2af07, camfo-e2af09, camfo-e2ahe1, camfo-e2am62, camfo-e2ap71, camfo-e2aqx6, camfo-e2ar09, camfo-e2arj6, camfo-e2ask6, camfo-e2av24, camfo-e2axp8, camfo-e2az30, camfo-e2b0g1, camfo-e2b1u7, camfo-e2b1v1, harsa-e2b4e6, harsa-e2b4y5, harsa-e2b5u0, harsa-e2b6u3, harsa-e2b8w0, harsa-e2b8w2, harsa-e2b370, harsa-e2b563, harsa-e2bfn3, harsa-e2bh58, harsa-e2bh77, harsa-e2bnc8, harsa-e2bng4, harsa-e2bnh3, harsa-e2btb0, harsa-e2buf0, harsa-e2bva8, harsa-e2bwj6, harsa-e2bwn1, harsa-e2c1r6, harsa-e2c1r7, harsa-e2c5m6, harsa-e2c6m2, harsa-e2c618, camfo-e2ad05, harsa-e2ca28, camfo-e2a8t9, harsa-e2blx5, camfo-e1zxe8, harsa-e2bmi6, harsa-e2c8h0, camfo-e2a7b9, camfo-e1zyd7, camfo-e1zyd8, harsa-e2c2j9, harsa-e2bmu7, camfo-e2ax69, camfo-e2a482, harsa-e2c147 Abstract The organized societies of ants include short-lived worker castes displaying specialized behavior and morphology and long-lived queens dedicated to reproduction. We sequenced and compared the genomes of two socially divergent ant species: Camponotus floridanus and Harpegnathos saltator. Both genomes contained high amounts of CpG, despite the presence of DNA methylation, which in non-Hymenoptera correlates with CpG depletion. Comparison of gene expression in different castes identified up-regulation of telomerase and sirtuin deacetylases in longer-lived H. saltator reproductives, caste-specific expression of microRNAs and SMYD histone methyltransferases, and differential regulation of genes implicated in neuronal function and chemical communication. Our findings provide clues on the molecular differences between castes in these two ants and establish a new experimental model to study epigenetics in aging and behavior. Title: Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development Wilensky RL, Shi Y, Mohler ER, 3rd, Hamamdzic D, Burgert ME, Li J, Postle A, Fenning RS, Bollinger JG and Macphee CH <10 more author(s)> Wilensky RL, Shi Y, Mohler ER, 3rd, Hamamdzic D, Burgert ME, Li J, Postle A, Fenning RS, Bollinger JG, Hoffman BE, Pelchovitz DJ, Yang J, Mirabile RC, Webb CL, Zhang L, Zhang P, Gelb MH, Walker MC, Zalewski A, Macphee CH (- 10) Ref: Nat Med, 14:1059, 2008 : PubMed ESTHER: Wilensky_2008_Nat.Med_14_1059 PubMedSearch: Wilensky 2008 Nat.Med 14 1059 PubMedID: 18806801 Gene_locus related to this paper: human-PLA2G7 Abstract Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke. Title: Evolution of genes and genomes on the Drosophila phylogeny Clark AG, Eisen MB, Smith DR, Bergman CM, Oliver B, Markow TA, Kaufman TC, Kellis M, Gelbart W and MacCallum I <405 more author(s)> Clark AG, Eisen MB, Smith DR, Bergman CM, Oliver B, Markow TA, Kaufman TC, Kellis M, Gelbart W, Iyer VN, Pollard DA, Sackton TB, Larracuente AM, Singh ND, Abad JP, Abt DN, Adryan B, Aguade M, Akashi H, Anderson WW, Aquadro CF, Ardell DH, Arguello R, Artieri CG, Barbash DA, Barker D, Barsanti P, Batterham P, Batzoglou S, Begun D, Bhutkar A, Blanco E, Bosak SA, Bradley RK, Brand AD, Brent MR, Brooks AN, Brown RH, Butlin RK, Caggese C, Calvi BR, Bernardo de Carvalho A, Caspi A, Castrezana S, Celniker SE, Chang JL, Chapple C, Chatterji S, Chinwalla A, Civetta A, Clifton SW, Comeron JM, Costello JC, Coyne JA, Daub J, David RG, Delcher AL, Delehaunty K, Do CB, Ebling H, Edwards K, Eickbush T, Evans JD, Filipski A, Findeiss S, Freyhult E, Fulton L, Fulton R, Garcia AC, Gardiner A, Garfield DA, Garvin BE, Gibson G, Gilbert D, Gnerre S, Godfrey J, Good R, Gotea V, Gravely B, Greenberg AJ, Griffiths-Jones S, Gross S, Guigo R, Gustafson EA, Haerty W, Hahn MW, Halligan DL, Halpern AL, Halter GM, Han MV, Heger A, Hillier L, Hinrichs AS, Holmes I, Hoskins RA, Hubisz MJ, Hultmark D, Huntley MA, Jaffe DB, Jagadeeshan S, Jeck WR, Johnson J, Jones CD, Jordan WC, Karpen GH, Kataoka E, Keightley PD, Kheradpour P, Kirkness EF, Koerich LB, Kristiansen K, Kudrna D, Kulathinal RJ, Kumar S, Kwok R, Lander E, Langley CH, Lapoint R, Lazzaro BP, Lee SJ, Levesque L, Li R, Lin CF, Lin MF, Lindblad-Toh K, Llopart A, Long M, Low L, Lozovsky E, Lu J, Luo M, Machado CA, Makalowski W, Marzo M, Matsuda M, Matzkin L, McAllister B, McBride CS, McKernan B, McKernan K, Mendez-Lago M, Minx P, Mollenhauer MU, Montooth K, Mount SM, Mu X, Myers E, Negre B, Newfeld S, Nielsen R, Noor MA, O'Grady P, Pachter L, Papaceit M, Parisi MJ, Parisi M, Parts L, Pedersen JS, Pesole G, Phillippy AM, Ponting CP, Pop M, Porcelli D, Powell JR, Prohaska S, Pruitt K, Puig M, Quesneville H, Ram KR, Rand D, Rasmussen MD, Reed LK, Reenan R, Reily A, Remington KA, Rieger TT, Ritchie MG, Robin C, Rogers YH, Rohde C, Rozas J, Rubenfield MJ, Ruiz A, Russo S, Salzberg SL, Sanchez-Gracia A, Saranga DJ, Sato H, Schaeffer SW, Schatz MC, Schlenke T, Schwartz R, Segarra C, Singh RS, Sirot L, Sirota M, Sisneros NB, Smith CD, Smith TF, Spieth J, Stage DE, Stark A, Stephan W, Strausberg RL, Strempel S, Sturgill D, Sutton G, Sutton GG, Tao W, Teichmann S, Tobari YN, Tomimura Y, Tsolas JM, Valente VL, Venter E, Venter JC, Vicario S, Vieira FG, Vilella AJ, Villasante A, Walenz B, Wang J, Wasserman M, Watts T, Wilson D, Wilson RK, Wing RA, Wolfner MF, Wong A, Wong GK, Wu CI, Wu G, Yamamoto D, Yang HP, Yang SP, Yorke JA, Yoshida K, Zdobnov E, Zhang P, Zhang Y, Zimin AV, Baldwin J, Abdouelleil A, Abdulkadir J, Abebe A, Abera B, Abreu J, Acer SC, Aftuck L, Alexander A, An P, Anderson E, Anderson S, Arachi H, Azer M, Bachantsang P, Barry A, Bayul T, Berlin A, Bessette D, Bloom T, Blye J, Boguslavskiy L, Bonnet C, Boukhgalter B, Bourzgui I, Brown A, Cahill P, Channer S, Cheshatsang Y, Chuda L, Citroen M, Collymore A, Cooke P, Costello M, D'Aco K, Daza R, De Haan G, DeGray S, DeMaso C, Dhargay N, Dooley K, Dooley E, Doricent M, Dorje P, Dorjee K, Dupes A, Elong R, Falk J, Farina A, Faro S, Ferguson D, Fisher S, Foley CD, Franke A, Friedrich D, Gadbois L, Gearin G, Gearin CR, Giannoukos G, Goode T, Graham J, Grandbois E, Grewal S, Gyaltsen K, Hafez N, Hagos B, Hall J, Henson C, Hollinger A, Honan T, Huard MD, Hughes L, Hurhula B, Husby ME, Kamat A, Kanga B, Kashin S, Khazanovich D, Kisner P, Lance K, Lara M, Lee W, Lennon N, Letendre F, LeVine R, Lipovsky A, Liu X, Liu J, Liu S, Lokyitsang T, Lokyitsang Y, Lubonja R, Lui A, Macdonald P, Magnisalis V, Maru K, Matthews C, McCusker W, McDonough S, Mehta T, Meldrim J, Meneus L, Mihai O, Mihalev A, Mihova T, Mittelman R, Mlenga V, Montmayeur A, Mulrain L, Navidi A, Naylor J, Negash T, Nguyen T, Nguyen N, Nicol R, Norbu C, Norbu N, Novod N, O'Neill B, Osman S, Markiewicz E, Oyono OL, Patti C, Phunkhang P, Pierre F, Priest M, Raghuraman S, Rege F, Reyes R, Rise C, Rogov P, Ross K, Ryan E, Settipalli S, Shea T, Sherpa N, Shi L, Shih D, Sparrow T, Spaulding J, Stalker J, Stange-Thomann N, Stavropoulos S, Stone C, Strader C, Tesfaye S, Thomson T, Thoulutsang Y, Thoulutsang D, Topham K, Topping I, Tsamla T, Vassiliev H, Vo A, Wangchuk T, Wangdi T, Weiand M, Wilkinson J, Wilson A, Yadav S, Young G, Yu Q, Zembek L, Zhong D, Zimmer A, Zwirko Z, Alvarez P, Brockman W, Butler J, Chin C, Grabherr M, Kleber M, Mauceli E, MacCallum I (- 405) Ref: Nature, 450:203, 2007 : PubMed ESTHER: Clark_2007_Nature_450_203 PubMedSearch: Clark 2007 Nature 450 203 PubMedID: 17994087 Gene_locus related to this paper: droan-ACHE, droan-b3lx10, droan-b3lx75, droan-b3lxv7, droan-b3ly87, droan-b3lyh4, droan-b3lyh5, droan-b3lyh7, droan-b3lyh9, droan-b3lyi0, droan-b3lyi2, droan-b3lyi3, droan-b3lyi4, droan-b3lyj8, droan-b3lyj9, droan-b3lyx4, droan-b3lyx5, droan-b3lyx6, droan-b3lyx7, droan-b3lyx9, droan-b3lz72, droan-b3m1x3, droan-b3m2d4, droan-b3m3d9, droan-b3m4e3, droan-b3m5w1, droan-b3m6i7, droan-b3m7v2, droan-b3m9a5, droan-b3m9f4, droan-b3m9p3, droan-b3m254, droan-b3m259, droan-b3m260, droan-b3m262, droan-b3m524, droan-b3m635, droan-b3m845, droan-b3m846, droan-b3md01, droan-b3mdh7, droan-b3mdm6, droan-b3mdw8, droan-b3mee1, droan-b3mf47, droan-b3mf48, droan-b3mg94, droan-b3mgk2, droan-b3mgn6, droan-b3mii3, droan-b3mjk2, droan-b3mjk3, droan-b3mjk4, droan-b3mjk5, droan-b3mjl2, droan-b3mjl4, droan-b3mjl7, droan-b3mjl9, droan-b3mjm8, droan-b3mjm9, droan-b3mjs6, droan-b3mkr0, droan-b3ml20, droan-b3mly4, droan-b3mly5, droan-b3mly6, droan-b3mmm8, droan-b3mnb5, droan-b3mny9, droan-b3mtj5, droan-b3muw4, droan-b3muw8, droan-b3n0e7, droan-b3n2j7, droan-b3n247, droan-c5idb2, droer-ACHE, droer-b3n5c7, droer-b3n5d0, droer-b3n5d8, droer-b3n5d9, droer-b3n5t7, droer-b3n5y4, droer-b3n7d2, droer-b3n7d3, droer-b3n7d4, droer-b3n7k8, droer-b3n8e4, droer-b3n8f7, droer-b3n8f8, droer-b3n9e1, droer-b3n319, droer-b3n547, droer-b3n549, droer-b3n558, droer-b3n560, droer-b3n577, droer-b3n612, droer-b3nar5, droer-b3nb91, droer-b3nct9, droer-b3nd53, droer-b3ndh9, droer-b3ndq8, droer-b3ne66, droer-b3ne67, droer-b3ne97, droer-b3nfk3, droer-b3nfq9, droer-b3nim7, droer-b3nkn2, droer-b3nm11, droer-b3nmh4, droer-b3nmy2, droer-b3npx2, droer-b3npx3, droer-b3nq76, droer-b3nqg9, droer-b3nqm8, droer-b3nr28, droer-b3nrd3, droer-b3nst4, droer-b3nwa7, droer-b3nyp5.1, droer-b3nyp5.2, droer-b3nyp6, droer-b3nyp7, droer-b3nyp8, droer-b3nyp9, droer-b3nyq3, droer-b3nz06, droer-b3nz14, droer-b3nzj0, droer-b3p0c0, droer-b3p0c1, droer-b3p0c2, droer-b3p2x6, droer-b3p2x7, droer-b3p2x9, droer-b3p2y1, droer-b3p2y2, droer-b3p6d4, droer-b3p6d5, droer-b3p6w3, droer-b3p7b4, droer-b3p7h9, droer-b3p152, droer-b3p486, droer-b3p487, droer-b3p488, droer-b3p489, droer-EST6, droer-q670j5, drogr-ACHE, drogr-b4iwp3, drogr-b4iww3, drogr-b4iwy3, drogr-b4ixf7, drogr-b4ixh4, drogr-b4iyz5, drogr-b4j2s2, drogr-b4j2u8, drogr-b4j3u1, drogr-b4j3v3, drogr-b4j4g7, drogr-b4j4x9, drogr-b4j6e6, drogr-b4j9c9, drogr-b4j9y4, drogr-b4j156, drogr-b4j384, drogr-b4j605, drogr-b4j685, drogr-b4ja76, drogr-b4jay5, drogr-b4jcf0, drogr-b4jcf1, drogr-b4jdg6, drogr-b4jdg7, drogr-b4jdh6, drogr-b4jdz1, drogr-b4jdz2, drogr-b4jdz4, drogr-b4je66, drogr-b4je79, drogr-b4je82, drogr-b4je88, drogr-b4je89, drogr-b4je90, drogr-b4je91, drogr-b4jf76, drogr-b4jf79, drogr-b4jf80, drogr-b4jf81, drogr-b4jf82, drogr-b4jf83, drogr-b4jf84, drogr-b4jf85, drogr-b4jf87, drogr-b4jf91, drogr-b4jf92, drogr-b4jg66, drogr-b4jgh0, drogr-b4jgh1, drogr-b4jgr9, drogr-b4ji67, drogr-b4jls2, drogr-b4jnh9, drogr-b4jpc6, drogr-b4jpq3, drogr-b4jpx9, drogr-b4jql2, drogr-b4jrh5, drogr-b4jsb2, drogr-b4jth3, drogr-b4jti1, drogr-b4jul5, drogr-b4jur4, drogr-b4jvh3, drogr-b4jz00, drogr-b4jz03, drogr-b4jz04, drogr-b4jz05, drogr-b4jzh2, drogr-b4k0u2, drogr-b4k2r1, drogr-b4k234, drogr-b4k235, drome-BEM46, drome-CG3734, drome-CG9953, drome-CG11626, drome-GH02439, dromo-ACHE, dromo-b4k6a7, dromo-b4k6a8, dromo-b4k6q8, dromo-b4k6q9, dromo-b4k6r1, dromo-b4k6r3, dromo-b4k6r4, dromo-b4k6r5, dromo-b4k6r6, dromo-b4k6r7, dromo-b4k6r8, dromo-b4k6r9, dromo-b4k6s0, dromo-b4k6s1, dromo-b4k6s2, dromo-b4k9c7, dromo-b4k9d3, dromo-b4k571, dromo-b4k721, dromo-b4ka74, dromo-b4ka89, dromo-b4kaj4, dromo-b4kc20, dromo-b4kcl2, dromo-b4kcl3, dromo-b4kd55.1, dromo-b4kd55.2, dromo-b4kd56, dromo-b4kd57, dromo-b4kde1, dromo-b4kdg2, dromo-b4kdh4, dromo-b4kdh5, dromo-b4kdh6, dromo-A0A0Q9XDF2, dromo-b4kdh8.1, dromo-b4kdh8.2, dromo-b4kg04, dromo-b4kg05, dromo-b4kg06, dromo-b4kg16, dromo-b4kg44, dromo-b4kg90, dromo-b4kh20, dromo-b4kh21, dromo-b4kht7, dromo-b4kid3, dromo-b4kik0, dromo-b4kjx0, dromo-b4kki1, dromo-b4kkp6, dromo-b4kkp8, dromo-b4kkq8, dromo-b4kkr0, dromo-b4kkr3, dromo-b4kkr4, dromo-b4kks0, dromo-b4kks1, dromo-b4kks2, dromo-b4kla1, dromo-b4klv8, dromo-b4knt4, dromo-b4kp08, dromo-b4kp16, dromo-b4kqa6, dromo-b4kqa7, dromo-b4kqa8, dromo-b4kqh1, dromo-b4kst4, dromo-b4ksy6, dromo-b4kt84, dromo-b4ktf5, dromo-b4ktf6, dromo-b4kvl3, dromo-b4kvw2, dromo-b4kwv4, dromo-b4kwv5, dromo-b4kxz6, dromo-b4ky12, dromo-b4ky36, dromo-b4ky44, dromo-b4kzu7, dromo-b4l0n8, dromo-b4l4u5, dromo-b4l6l9, dromo-b4l084, drope-ACHE, drope-b4g3s6, drope-b4g4p7, drope-b4g6v4, drope-b4g8m0, drope-b4g8n6, drope-b4g8n7, drope-b4g9p2, drope-b4g815, drope-b4g816, drope-b4gat7, drope-b4gav5, drope-b4gb05, drope-b4gc08, drope-b4gcr3, drope-b4gdk2, drope-b4gdl9, drope-b4gdv9, drope-b4gei8, drope-b4gei9, drope-b4gej0, drope-b4ghz9, drope-b4gj62, drope-b4gj64, drope-b4gj74, drope-b4gkf4, drope-b4gkv2, drope-b4gky9, drope-b4gl76, drope-b4glf3, drope-b4gmt3, drope-b4gmt7, drope-b4gmt9, drope-b4gmu2, drope-b4gmu3, drope-b4gmu4, drope-b4gmu5, drope-b4gmu6, drope-b4gmu7, drope-b4gmv1, drope-b4gn08, drope-b4gpa7, drope-b4gq13, drope-b4grh7, drope-b4gsf9, drope-b4gsw4, drope-b4gsw5, drope-b4gsx2, drope-b4gsx7, drope-b4gsy6, drope-b4gsy7, drope-b4guj8, drope-b4gw36, drope-b4gzc2, drope-b4gzc6, drope-b4gzc7, drope-b4h4p9, drope-b4h5l3, drope-b4h6a0, drope-b4h6a8, drope-b4h6a9, drope-b4h6b0, drope-b4h7m7, drope-b4h462, drope-b4h601, drope-b4h602, drope-b4hay1, drope-b4hb18, drope-est5a, drope-est5b, drope-est5c, drops-ACHE, drops-b5dhd2, drops-b5dk96, drops-b5dpe3, drops-b5drp9, drops-b5dwa7, drops-b5dwa8, drops-b5dz85, drops-b5dz86, drops-est5a, drops-est5b, drops-q29bq2, drops-q29dd7, drops-q29ew0, drops-q291d5, drops-q291e8, drops-q293n1, drops-q293n4, drops-q293n5, drops-q293n6, drops-q294n6, drops-q294n7, drops-q294n9, drops-q294p4, drose-b4he97, drose-b4hfu2, drose-b4hg54, drose-b4hga0, drose-b4hgu9, drose-b4hgv0, drose-b4hgv3, drose-b4hgv4, drose-b4hhm8, drose-b4hhs6, drose-b4hie4, drose-b4him9, drose-b4hk63, drose-b4hkj5, drose-b4hr07, drose-b4hr81, drose-b4hre7, drose-b4hs13, drose-b4hsj9, drose-b4hsk0, drose-b4hsm8, drose-b4hvr5, drose-b4hwr7, drose-b4hwr8, drose-b4hwr9, drose-b4hws6, drose-b4hws7, drose-b4hwt0, drose-b4hwt2, drose-b4hwu1, drose-b4hwu2, drose-b4hxs9, drose-b4hxu4, drose-b4hxz1, drose-b4hyp8, drose-b4hyp9, drose-b4hyq0, drose-b4hyz4, drose-b4hyz5, drose-b4i1k8, drose-b4i2f3, drose-b4i2w5, drose-b4i4u3, drose-b4i4u7, drose-b4i4u9, drose-b4i4v0, drose-b4i4v1, drose-b4i4v4, drose-b4i4v5, drose-b4i4v6, drose-b4i4v7, drose-b4i4v8, drose-b4i4w0, drose-b4i7s6, drose-b4i133, drose-b4i857, drose-b4iam7, drose-b4iam9, drose-b4iaq6, drose-b4icf6, drose-b4icf7, drose-b4id80, drose-b4ifc5, drose-b4ihv9, drose-b4iie9, drose-b4ilj8, drose-b4in13, drose-b4inj9, drosi-ACHE, drosi-aes04a, drosi-b4nsh8, drosi-b4q3d7, drosi-b4q4w5, drosi-b4q4y7, drosi-b4q6h6, drosi-b4q7u2, drosi-b4q7u3, drosi-b4q9c6, drosi-b4q9c7, drosi-b4q9d3, drosi-b4q9d4, drosi-b4q9r0, drosi-b4q9r1, drosi-b4q9r3, drosi-b4q9s2, drosi-b4q9s3, drosi-b4q429, drosi-b4q530, drosi-b4q734, drosi-b4q782, drosi-b4q783, drosi-b4q942, drosi-b4qet1, drosi-b4qfv6, drosi-b4qge5, drosi-b4qgh5, drosi-b4qgs5, drosi-b4qhf3, drosi-b4qhf4, drosi-b4qhi5, drosi-b4qjr2, drosi-b4qjr3, drosi-b4qjv6, drosi-b4qk23, drosi-b4qk51, drosi-b4qlt1, drosi-b4qlz9, drosi-b4qmn9, drosi-b4qrq7, drosi-b4qs01, drosi-b4qs57, drosi-b4qs82, drosi-b4qs83, drosi-b4qs84, drosi-b4qs85, drosi-b4qs86, drosi-b4qsq1, drosi-b4quk6, drosi-b4qvg5, drosi-b4qvg6, drosi-b4qzn2, drosi-b4qzn3, drosi-b4qzn5, drosi-b4qzn7, drosi-b4qzn8, drosi-b4qzp2, drosi-b4qzp3, drosi-b4qzp4, drosi-b4qzp5, drosi-b4qzp6, drosi-b4qzp7, drosi-b4r1a4, drosi-b4r025, drosi-b4r207, drosi-b4r662, drosi-este6, drosi-q670k8, drovi-ACHE, drovi-b4lev2, drovi-b4lf33, drovi-b4lf51, drovi-b4lg54, drovi-b4lg72, drovi-b4lgc6, drovi-b4lgd5, drovi-b4lgg0, drovi-b4lgk5, drovi-b4lgn2, drovi-b4lh17, drovi-b4lh18, drovi-b4lk43, drovi-b4ll59, drovi-b4ll60, drovi-b4llm5, drovi-b4lln3, drovi-b4lmk4, drovi-b4lmp0, drovi-b4lnr4, drovi-b4lp47, drovi-b4lpd0, drovi-b4lps0, drovi-b4lqc6, drovi-b4lr00, drovi-b4lrp6, drovi-b4lrw2, drovi-b4lse7, drovi-b4lse9, drovi-b4lsf0, drovi-b4lsn0, drovi-b4lsq5, drovi-b4lt32, drovi-b4ltr1, drovi-b4lui7, drovi-b4lui9, drovi-b4luj8, drovi-b4luk0, drovi-b4luk3, drovi-b4luk8, drovi-b4luk9, drovi-b4lul0, drovi-b4lve2, drovi-b4lxi9, drovi-b4lxj8, drovi-b4lyf3, drovi-b4lyq2, drovi-b4lyq3, drovi-b4lz07, drovi-b4lz13, drovi-b4lz14, drovi-b4lz15, drovi-b4m0j7, drovi-b4m0s0, drovi-b4m2b6, drovi-b4m4h7, drovi-b4m4h8, drovi-b4m4i0, drovi-b4m4i2, drovi-b4m4i3.A, drovi-b4m4i3.B, drovi-b4m4i4, drovi-b4m4i5, drovi-b4m4i6, drovi-b4m4i7, drovi-b4m4i8, drovi-b4m4i9, drovi-b4m4j2, drovi-b4m5a0, drovi-b4m5a1, drovi-b4m5a2, drovi-b4m6b9, drovi-b4m7k9, drovi-b4m9g9, drovi-b4m9h0, drovi-b4m564, drovi-b4m599, drovi-b4m918, drovi-b4mb87, drovi-b4mc71, drovi-b4mfa4, drowi-ACHE, drowi-b4mjb9, drowi-b4mkt7, drowi-b4mlc1, drowi-b4mp68, drowi-b4mqe9, drowi-b4mqf0.2, drowi-b4mqf1, drowi-b4mqf3, drowi-b4mqf4, drowi-b4mqf5, drowi-b4mqq6, drowi-b4mrd1, drowi-b4mrk3, drowi-b4mtl5, drowi-b4mug2, drowi-b4muj8, drowi-b4mv18, drowi-b4mw32, drowi-b4mw85, drowi-b4mwp2, drowi-b4mwp6, drowi-b4mwq5, drowi-b4mwr0, drowi-b4mwr8, drowi-b4mwr9, drowi-b4mwt1, drowi-b4mwz7, drowi-b4mxn5, drowi-b4my54, drowi-b4myg1, drowi-b4myh5, drowi-b4n0d4, drowi-b4n1a7, drowi-b4n1c8, drowi-b4n3s9, drowi-b4n3x7, drowi-b4n4x9, drowi-b4n4y0, drowi-b4n6m1, drowi-b4n6n0, drowi-b4n6n7, drowi-b4n6u6, drowi-b4n7s6, drowi-b4n7s7, drowi-b4n7s8, drowi-b4n899.1, drowi-b4n8a1, drowi-b4n8a2, drowi-b4n8a3, drowi-b4n8a4, drowi-b4n8a9, drowi-b4n023, drowi-b4n075, drowi-b4n543, drowi-b4n888, drowi-b4n889, drowi-b4n891, drowi-b4n893, drowi-b4n895, drowi-b4n897, drowi-b4n898, drowi-b4n899.2, drowi-b4nae3, drowi-b4ner8, drowi-b4ng76, drowi-b4nga7, drowi-b4ngb5, drowi-b4nhz9, drowi-b4nj18, drowi-b4nj19, drowi-b4nja7, drowi-b4nja8, drowi-b4nja9, drowi-b4njk8, drowi-b4nkc8, drowi-b4nky0, drowi-b4nl36, drowi-b4nm27, drowi-b4nn59, drowi-b4nnc1, drowi-b4nng1, drowi-b4nng2, droya-ACHE, droya-aes04, droya-b4itg2, droya-b4itg6, droya-b4itu9, droya-b4iuv4, droya-b4iuv5, droya-b4nxe6, droya-b4nxg5, droya-b4nxg6, droya-b4nxg8, droya-b4nxw4, droya-b4ny57, droya-b4ny58, droya-b4ny86, droya-b4nzz8, droya-b4p0b5, droya-b4p0q9, droya-b4p0r0, droya-b4p0r7, droya-b4p0r8, droya-b4p0r9, droya-b4p0s0, droya-b4p0s2, droya-b4p0t0, droya-b4p0t1, droya-b4p3h4, droya-b4p3x8, droya-b4p5g8, droya-b4p6c9, droya-b4p6l9, droya-b4p6r1, droya-b4p6r2, droya-b4p7u4, droya-b4p8w7, droya-b4p023, droya-b4p241, droya-b4p774, droya-b4pat9, droya-b4pbl1, droya-b4pd22, droya-b4pd70, droya-b4pdm8, droya-b4pet9, droya-b4pff9, droya-b4pga7, droya-b4pgu0, droya-b4pig3, droya-b4pjt8, droya-b4pka2, droya-b4plh2, droya-b4pma3, droya-b4pmv3, droya-b4pmv4, droya-b4pmv5, droya-b4pn92, droya-b4pp65, droya-b4ppc5, droya-b4ppc6, droya-b4ppc7, droya-b4ppc8, droya-b4pq03, droya-b4prg6B, droya-b4prg9, droya-b4prh3, droya-b4prh4, droya-b4prh6, droya-b4prh7, droya-b4psz8, droya-b4psz9, droya-b4pv22, droya-b4q0g5, droya-b4q246, droya-EST6, droya-q71d76, drowi-b4n7m9, drope-b4gkk1, droer-b3n5s3, drose-b4i1w5, drowi-a0a0q9x0t3, drogr-b4jvm7, dromo-b4ku70, drovi-b4mcn9, drovi-b4lty2, drogr-b4jdu1, drovi-a0a0q9wiq8, dromo-b4kf70, drosi-b2zi86, droya-b4p2y4, drose-b2zic5, droer-b3n895 Abstract Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species. Title: Crystal structure of homoserine O-acetyltransferase from Leptospira interrogans Wang M, Liu L, Wang Y, Wei Z, Zhang P, Li Y, Jiang X, Xu H, Gong W Ref: Biochemical & Biophysical Research Communications, 363:1050, 2007 : PubMed ESTHER: Wang_2007_Biochem.Biophys.Res.Commun_363_1050 PubMedSearch: Wang 2007 Biochem.Biophys.Res.Commun 363 1050 PubMedID: 17927957 Gene_locus related to this paper: lepin-METX Abstract Homoserine O-acetyltransferase (HTA, EC 2.3.1.31) initiates methionine biosynthesis pathway by catalyzing the transfer of acetyl group from acetyl-CoA to homoserine. This study reports the crystal structure of HTA from Leptospira interrogans determined at 2.2A resolution using selenomethionyl single-wavelength anomalous diffraction method. HTA is modular and consists of two structurally distinct domains--a core alpha/beta domain containing the catalytic site and a helical bundle called the lid domain. Overall, the structure fold belongs to alpha/beta hydrolase superfamily with the characteristic 'catalytic triad' residues in the active site. Detailed structure analysis showed that the catalytic histidine and serine are both present in two conformations, which may be involved in the catalytic mechanism for acetyl transfer. Title: Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Saha A, Wei H, Xu Y, Xiao YJ and Mukherjee AB <2 more author(s)> Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Saha A, Wei H, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB (- 2) Ref: Hum Mol Genet, 16:837, 2007 : PubMed ESTHER: Zhang_2007_Hum.Mol.Genet_16_837 PubMedSearch: Zhang 2007 Hum.Mol.Genet 16 837 PubMedID: 17341491 Gene_locus related to this paper: mouse-ppt Abstract In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid signal' for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA(2)-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology. Title: Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB Ref: Hum Mol Genet, 15:337, 2006 : PubMed ESTHER: Zhang_2006_Hum.Mol.Genet_15_337 PubMedSearch: Zhang 2006 Hum.Mol.Genet 15 337 PubMedID: 16368712 Gene_locus related to this paper: mouse-ppt Abstract Numerous proteins undergo modification by palmitic acid (S-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. Although palmitoylation is an essential modification, these proteins must also undergo depalmitoylation for their degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes palmitate residues facilitating the degradation of these proteins. Thus, inactivating mutations in the PPT1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood. Although rapidly progressing brain atrophy is the most dramatic pathological manifestation of INCL, the molecular mechanism(s) remains unclear. Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal. Further, we demonstrate that the level of growth-associated protein-43 (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in the abnormal accumulation of this protein in the ER. Consistent with these results, we found evidence for the activation of unfolded protein response (UPR) marked by elevated levels of phosphorylated translation initiation factor, eIF2alpha, increased expression of chaperone proteins such as glucose-regulated protein-78 and activation of caspase-12, a cysteine proteinase in the ER, mediating caspase-3 activation and apoptosis. Our results, for the first time, link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration in INCL and identify potential targets for therapeutic intervention in this uniformly fatal disease. Title: Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution Richards S, Liu Y, Bettencourt BR, Hradecky P, Letovsky S, Nielsen R, Thornton K, Hubisz MJ, Chen R and Gibbs RA <42 more author(s)> Richards S, Liu Y, Bettencourt BR, Hradecky P, Letovsky S, Nielsen R, Thornton K, Hubisz MJ, Chen R, Meisel RP, Couronne O, Hua S, Smith MA, Zhang P, Liu J, Bussemaker HJ, van Batenburg MF, Howells SL, Scherer SE, Sodergren E, Matthews BB, Crosby MA, Schroeder AJ, Ortiz-Barrientos D, Rives CM, Metzker ML, Muzny DM, Scott G, Steffen D, Wheeler DA, Worley KC, Havlak P, Durbin KJ, Egan A, Gill R, Hume J, Morgan MB, Miner G, Hamilton C, Huang Y, Waldron L, Verduzco D, Clerc-Blankenburg KP, Dubchak I, Noor MA, Anderson W, White KP, Clark AG, Schaeffer SW, Gelbart W, Weinstock GM, Gibbs RA (- 42) Ref: Genome Res, 15:1, 2005 : PubMed ESTHER: Richards_2005_Genome.Res_15_1 PubMedSearch: Richards 2005 Genome.Res 15 1 PubMedID: 15632085 Gene_locus related to this paper: drome-BEM46, drome-GH02439, drops-ACHE, drops-b5dhd2, drops-b5di70, drops-b5djn7, drops-b5dk96, drops-b5dm12, drops-b5dpe3, drops-b5drp9, drops-b5du62, drops-b5dud8, drops-b5dwa7, drops-b5dwa8, drops-b5dy09, drops-b5dz85, drops-b5dz86, drops-b5e1k7, drops-CG4390, drops-est5a, drops-est5b, drops-est5c, drops-nrtac, drops-q2lyp3, drops-q2lyp4, drops-q2lyu3, drops-q2lz68, drops-q2m0u9, drops-q2m169, drops-q28wj5, drops-q28wt2, drops-q28wt8, drops-q28zi3, drops-q28zz1, drops-q29a22, drops-q29ad8, drops-q29ad9, drops-q29ae0, drops-q29ae1, drops-q29ay7, drops-q29ay8, drops-q29ay9, drops-q29bq2, drops-q29br3, drops-q29d59, drops-q29dc9, drops-q29dd7, drops-q29dp4, drops-q29dw3, drops-q29dw4, drops-q29e16, drops-q29ew0, drops-q29f35, drops-q29f66, drops-q29fi0, drops-q29fw0, drops-q29fw9, drops-q29g93, drops-q29gb0, drops-q29gs6, drops-q29h54, drops-b5dmp7, drops-q29hd2, drops-q29hu2, drops-q29hu3, drops-q29hv0, drops-q29i09, drops-q29js9, drops-q29jt5, drops-q29jt6, drops-q29jy5, drops-q29k25, drops-q29kd5, drops-q29kd6, drops-q29ke5, drops-q29kq9, drops-q29kr1, drops-q29kr3, drops-q29kr5, drops-q29kr8, drops-q29kr9, drops-q29ks6, drops-q29kz0, drops-q29kz1, drops-q29l31, drops-q29lf8, drops-q29lv0, drops-q29m07, drops-q29m08, drops-q29m27, drops-q29m66, drops-q29m81, drops-q29mj7, drops-q29mv2, drops-q29mx0, drops-q29n87, drops-q29na5, drops-q29na6, drops-q29pe4, drops-q29pk4, drops-q290i1, drops-q290k3, drops-q290v8, drops-q290v9, drops-q290w0, drops-q290z8, drops-q291d5, drops-q291e8, drops-q291y3, drops-q292f5, drops-q292g6, drops-q293n1, drops-q293n4, drops-q293n5, drops-q293n6, drops-q293y7, drops-q294n3, drops-q294n6, drops-q294n7, drops-q294n9, drops-q294p0, drops-q294p1, drops-q294p3, drops-q294p4, drops-q294u9, drops-q295h3, drops-q296h2, drops-q296x1, drops-q296x2, drops-q297h5, drops-q298u8, drope-b4gkk1 Abstract We have sequenced the genome of a second Drosophila species, Drosophila pseudoobscura, and compared this to the genome sequence of Drosophila melanogaster, a primary model organism. Throughout evolution the vast majority of Drosophila genes have remained on the same chromosome arm, but within each arm gene order has been extensively reshuffled, leading to a minimum of 921 syntenic blocks shared between the species. A repetitive sequence is found in the D. pseudoobscura genome at many junctions between adjacent syntenic blocks. Analysis of this novel repetitive element family suggests that recombination between offset elements may have given rise to many paracentric inversions, thereby contributing to the shuffling of gene order in the D. pseudoobscura lineage. Based on sequence similarity and synteny, 10,516 putative orthologs have been identified as a core gene set conserved over 25-55 million years (Myr) since the pseudoobscura/melanogaster divergence. Genes expressed in the testes had higher amino acid sequence divergence than the genome-wide average, consistent with the rapid evolution of sex-specific proteins. Cis-regulatory sequences are more conserved than random and nearby sequences between the species--but the difference is slight, suggesting that the evolution of cis-regulatory elements is flexible. Overall, a pattern of repeat-mediated chromosomal rearrangement, and high coadaptation of both male genes and cis-regulatory sequences emerges as important themes of genome divergence between these species of Drosophila. Title: The genomic sequence of the accidental pathogen Legionella pneumophila Chien M, Morozova I, Shi S, Sheng H, Chen J, Gomez SM, Asamani G, Hill K, Nuara J and Russo JJ <27 more author(s)> Chien M, Morozova I, Shi S, Sheng H, Chen J, Gomez SM, Asamani G, Hill K, Nuara J, Feder M, Rineer J, Greenberg JJ, Steshenko V, Park SH, Zhao B, Teplitskaya E, Edwards JR, Pampou S, Georghiou A, Chou IC, Iannuccilli W, Ulz ME, Kim DH, Geringer-Sameth A, Goldsberry C, Morozov P, Fischer SG, Segal G, Qu X, Rzhetsky A, Zhang P, Cayanis E, de Jong PJ, Ju J, Kalachikov S, Shuman HA, Russo JJ (- 27) Ref: Science, 305:1966, 2004 : PubMed ESTHER: Chien_2004_Science_305_1966 PubMedSearch: Chien 2004 Science 305 1966 PubMedID: 15448271 Gene_locus related to this paper: legph-q5zsu4, legpa-q5x2r4, legpa-q5x3a5, legpa-q5x3d6, legpa-q5x4r4, legpa-q5x4t1, legpa-q5x5b2, legpa-q5x5z2, legpa-q5x7f5, legpa-q5x8e6, legpa-q5x8m4, legpa-q5x322, legpa-q5x405, legpa-q5x424, legpa-q5x473, legpa-q5x590, legpa-q5x611, legpa-q5x819, legpc-a5iar0, legph-q5zrh1, legph-q5zsb5, legph-q5zv00, legph-q5zwi8, legph-q5zze3, legpl-q5wtd3, legpl-q5wua5, legpl-q5wvw9, legpn-Q8KU34, legpn-Q8RNQ1, legpn-SBPA, legpn-i7i328, legpl-q5wsw9 Abstract We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets. Title: Large-scale cDNA transfection screening for genes related to cancer development and progression Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X and Gu J <15 more author(s)> Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X, Zhong F, He L, Yu J, Yao G, Jiang H, Qian L, Yu Y, Shu H, Chen X, Xu H, Guo M, Pan Z, Chen Y, Ge C, Yang S, Gu J (- 15) Ref: Proc Natl Acad Sci U S A, 101:15724, 2004 : PubMed ESTHER: Wan_2004_Proc.Natl.Acad.Sci.U.S.A_101_15724 PubMedSearch: Wan 2004 Proc.Natl.Acad.Sci.U.S.A 101 15724 PubMedID: 15498874 Abstract A large-scale assay was performed by transfecting 29,910 individual cDNA clones derived from human placenta, fetus, and normal liver tissues into human hepatoma cells and 22,926 cDNA clones into mouse NIH 3T3 cells. Based on the results of colony formation in hepatoma cells and foci formation in NIH 3T3 cells, 3,806 cDNA species (8,237 clones) were found to possess the ability of either stimulating or inhibiting cell growth. Among them, 2,836 (6,958 clones) were known genes, 372 (384 clones) were previously unrecognized genes, and 598 (895 clones) were unigenes of uncharacterized structure and function. A comprehensive analysis of the genes and the potential mechanisms for their involvement in the regulation of cell growth is provided. The genes were classified into four categories: I, genes related to the basic cellular mechanism for growth and survival; II, genes related to the cellular microenvironment; III, genes related to host-cell systemic regulation; and IV, genes of miscellaneous function. The extensive growth-regulatory activity of genes with such highly diversified functions suggests that cancer may be related to multiple levels of cellular and systemic controls. The present assay provides a direct genomewide functional screening method. It offers a better understanding of the basic machinery of oncogenesis, including previously undescribed systemic regulatory mechanisms, and also provides a tool for gene discovery with potential clinical applications. Title: Association between lipoprotein lipase (LPL) gene and blood lipids: a common variant for a common trait? Morabia A, Cayanis E, Costanza MC, Ross BM, Bernstein MS, Flaherty MS, Alvin GB, Das K, Morris MA and Gilliam TC <2 more author(s)> Morabia A, Cayanis E, Costanza MC, Ross BM, Bernstein MS, Flaherty MS, Alvin GB, Das K, Morris MA, Penchaszadeh GK, Zhang P, Gilliam TC (- 2) Ref: Genet Epidemiol, 24:309, 2003 : PubMed ESTHER: Morabia_2003_Genet.Epidemiol_24_309 PubMedSearch: Morabia 2003 Genet.Epidemiol 24 309 PubMedID: 12687649 Abstract S447X, a serine substitution by a stop codon on base 99 of exon 9 of the lipoprotein lipase (LPL) gene, has beneficial effects on blood lipids. Other LPL alleles are associated with lipid levels, but whether one of these variants predominates remains elusive. We performed a systematic survey to identify single-nucleotide polymorphisms (SNPs) in all 10 LPL exons and flanking regions by resequencing the gene in 95 subjects. Of 24 variants, 14 were common (> or = 3%). We assayed the common SNPs in 186 cases with atherogenic lipid profiles (low HDL, high LDL) and 185 nonatherogenic controls (high HDL, low LDL). Only S447X and exons 6 (base +73) and 10 (base -11) were individually associated with case-control status (P<0.05, adjusted for major nongenetic covariates with known lipid effects). There were no significant SNP x gender interactions. In adjusted multi-SNP and haplotypic analyses, S447X was interpretable as the sole predictor, with a 2-3-fold reduction in the odds of being atherogenic vs. nonatherogenic (adjusted OR, 0.39; 95% CI, 0.21-0.73). S447X and base -11 of exon 10 were statistically interchangeable because they are strongly associated (r=0.92, P<0.0001), but we posit that the LPL association with lipid profile is more likely attributable to the functional S447X rather than the nonfunctional exon 10 SNP. It appears that the S447X variant of LPL may be another rare example (like APOE4, factor V-Leiden, and PPAR gamma Pro12Ala) of a common variant predisposing to a common disorder. | |||||||
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