Fan J

References (47)

Title : Annexin A6 mitigates neurological deficit in ischemia\/reperfusion injury by promoting synaptic plasticity - Wang_2024_CNS.Neurosci.Ther_30_e14639
Author(s) : Wang Y , Yang Z , Wang R , Zheng Y , Han Z , Fan J , Yan F , Liu P , Luo Y
Ref : CNS Neurosci Ther , 30 :e14639 , 2024
Abstract : AIMS: Alleviating neurological dysfunction caused by acute ischemic stroke (AIS) remains intractable. Given Annexin A6 (ANXA6)'s potential in promoting axon branching and repairing cell membranes, the study aimed to explore ANXA6's potential in alleviating AIS-induced neurological dysfunction. METHODS: A mouse middle cerebral artery occlusion model was established. Brain and plasma ANXA6 levels were detected at different timepoints post ischemia/reperfusion (I/R). We overexpressed and down-regulated brain ANXA6 and evaluated infarction volume, neurological function, and synaptic plasticity-related proteins post I/R. Plasma ANXA6 levels were measured in patients with AIS and healthy controls, investigating ANXA6 expression's clinical significance. RESULTS: Brain ANXA6 levels initially decreased, gradually returning to normal post I/R; plasma ANXA6 levels showed an opposite trend. ANXA6 overexpression significantly decreased the modified neurological severity score (p = 0.0109) 1 day post I/R and the infarction area at 1 day (p = 0.0008) and 7 day (p = 0.0013) post I/R, and vice versa. ANXA6 positively influenced synaptic plasticity, upregulating synaptophysin (p = 0.006), myelin basic protein (p = 0.010), neuroligin (p = 0.078), and tropomyosin-related kinase B (p = 0.150). Plasma ANXA6 levels were higher in patients with AIS (1.969 [1.228-3.086]) compared to healthy controls (1.249 [0.757-2.226]) (p < 0.001), that served as an independent risk factor for poor AIS outcomes (2.120 [1.563-3.023], p < 0.001). CONCLUSIONS: This study is the first to suggest that ANXA6 enhances synaptic plasticity and protects against transient cerebral ischemia.
ESTHER : Wang_2024_CNS.Neurosci.Ther_30_e14639
PubMedSearch : Wang_2024_CNS.Neurosci.Ther_30_e14639
PubMedID: 38380783

Title : MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior - Wang_2024_Neurosci.Bull__
Author(s) : Wang X , Lin D , Jiang J , Liu Y , Dong X , Fan J , Gong L , Shen W , Zeng L , Xu T , Jiang K , Connor SA , Xie Y
Ref : Neurosci Bull , : , 2024
Abstract : Synapse organizers are essential for the development, transmission, and plasticity of synapses. Acting as rare synapse suppressors, the MAM domain containing glycosylphosphatidylinositol anchor (MDGA) proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex. A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism. However, MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses. Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy. To address this, we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons. Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity. Functionally, evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs. At a behavioral level, memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of social deficits in autism, was similarly compromised. These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits, thereby optimizing this network for plasticity, cognition, and social behaviors.
ESTHER : Wang_2024_Neurosci.Bull__
PubMedSearch : Wang_2024_Neurosci.Bull__
PubMedID: 38321347

Title : The NLR immune receptor ADR1 and lipase-like proteins EDS1 and PAD4 mediate stomatal immunity in Nicotiana benthamiana and Arabidopsis - Wang_2023_Plant.Cell__
Author(s) : Wang H , Song S , Gao S , Yu Q , Zhang H , Cui X , Fan J , Xin X , Liu Y , Staskawicz B , Qi T
Ref : Plant Cell , : , 2023
Abstract : In the presence of pathogenic bacteria, plants close their stomata to prevent pathogen entry. Intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogenic effectors and activate effector-triggered immune responses. However, the regulatory and molecular mechanisms of stomatal immunity involving NLR immune receptors are unknown. Here, we show that the Nicotiana benthamiana RPW8-NLR central immune receptor ACTIVATED DISEASE RESISTANCE 1 (NbADR1), together with the key immune proteins ENHANCED DISEASE SUSCEPTIBILITY 1 (NbEDS1) and PHYTOALEXIN DEFICIENT 4 (NbPAD4), plays an essential role in bacterial pathogen- and flg22-induced stomatal immunity by regulating the expression of salicylic acid (SA) and abscisic acid (ABA) biosynthesis or response-related genes. NbADR1 recruits NbEDS1 and NbPAD4 in stomata to form a stomatal immune response complex. The transcription factor NbWRKY40e, in association with NbEDS1 and NbPAD4, modulates the expression of SA and ABA biosynthesis or response-related genes to influence stomatal immunity. NbADR1, NbEDS1, and NbPAD4 are required for the pathogen infection-enhanced binding of NbWRKY40e to the ISOCHORISMATE SYNTHASE 1 promoter. Moreover, the ADR1-EDS1-PAD4 module regulates stomatal immunity in Arabidopsis (Arabidopsis thaliana). Collectively, our findings show the pivotal role of the core intracellular immune receptor module ADR1-EDS1-PAD4 in stomatal immunity, which enables plants to limit pathogen entry.
ESTHER : Wang_2023_Plant.Cell__
PubMedSearch : Wang_2023_Plant.Cell__
PubMedID: 37851863

Title : A chloroplast diacylglycerol lipase modulates glycerolipid pathway balance in Arabidopsis - Yu_2023_Plant.J__
Author(s) : Yu L , Shen W , Fan J , Sah SK , Mavraganis I , Wang L , Gao P , Gao J , Zheng Q , Meesapyodsuk D , Yang H , Li Q , Zou J , Xu C
Ref : Plant J , : , 2023
Abstract : Two parallel pathways compartmentalized in the chloroplast and the endoplasmic reticulum (ER) contribute to thylakoid lipid synthesis in plants, but how these two pathways are coordinated during thylakoid biogenesis and remodeling remain unknown. We report here the molecular characterization of a homologous ADIPOSE TRIGLYCERIDE LIPASE-LIKE gene, previously referred to as ATGLL. The ATGLL gene is ubiquitously expressed throughout development and rapidly upregulated in response to a wide range of environmental cues. We show that ATGLL is a chloroplast non-regioselective lipase with a hydrolytic activity preferentially towards 16:0 of diacylglycerol (DAG). Comprehensive lipid profiling and radiotracer labeling studies revealed negative correlation of ATGLL expression and the relative contribution of the chloroplast lipid pathway to thylakoid lipid biosynthesis. Additionally, we show that genetic manipulation of ATGLL expression resulted in changes in triacylglycerol levels in leaves. We propose that ATGLL, through affecting the level of prokaryotic DAG in the chloroplast, plays important roles in balancing the two glycerolipid pathways and in maintaining lipid homeostasis in plants.
ESTHER : Yu_2023_Plant.J__
PubMedSearch : Yu_2023_Plant.J__
PubMedID: 37006186

Title : Comparison of chemical compositions, antioxidant activities, and acetylcholinesterase inhibitory activities between coffee flowers and leaves as potential novel foods - Shen_2023_Food.Sci.Nutr_11_917
Author(s) : Shen X , Nie F , Fang H , Liu K , Li Z , Li X , Chen Y , Chen R , Zheng T , Fan J
Ref : Food Sci Nutr , 11 :917 , 2023
Abstract : This study aimed to compare chemical compositions, antioxidant activities, and acetylcholinesterase inhibitory activities of coffee flowers (ACF) and coffee leaves (ACL) with green coffee beans (ACGB) of Coffea Arabica L. The chemical compositions were determined by employing high-performance liquid chromatography-mass spectroscopy (HPLC-MS) and gas chromatography-mass spectroscopy (GC-MS) techniques. Antioxidant effects of the components were evaluated using DPPH and ABTS radical scavenging assays, and the ferric reducing antioxidant power (FRAP) assay. Their acetylcholinesterase inhibitory activities were also evaluated. The coffee sample extracts contained a total of 214 components identified by HPLC-MS and belonged to 12 classes (such as nucleotides and amino acids and their derivatives, tannins, flavonoids, alkaloids, benzene, phenylpropanoids, and lipids.), where phenylpropanoids were the dominant component (>30%). The contents of flavonoids, alkaloids, saccharides, and carboxylic acid and its derivatives in ACF and ACL varied significantly (p < .05) compared to similar components in ACGB. Meanwhile, 30 differentially changed chemical compositions (variable importance in projection [VIP] > 1, p < .01 and fold change [FC] > 4, or <0.25), that determine the difference in characteristics, were confirmed in the three coffee samples. Furthermore, among 25 volatile chemical components identified by GC-MS, caffeine, n-hexadecanoic acid, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-methyl-phenol], and quinic acid were common in these samples with caffeine being the highest in percentage. In addition, ACL showed the significantly highest (p < .05) DPPH radical scavenging capacity with IC(50) value of 0.491 +/- 0.148 mg/ml, and acetylcholinesterase inhibitory activity with inhibition ratio 25.18 +/- 2.96%, whereas ACF showed the significantly highest (p < .05) ABTS radical scavenging activity with 36.413 +/- 1.523 mmol trolox/g Ex. The results suggested that ACL and ACF had potential values as novel foods in the future.
ESTHER : Shen_2023_Food.Sci.Nutr_11_917
PubMedSearch : Shen_2023_Food.Sci.Nutr_11_917
PubMedID: 36789063

Title : Effect of thiamethoxam on the behavioral profile alteration and toxicity of adult zebrafish at environmentally relevant concentrations - Yang_2022_Sci.Total.Environ_858_159883
Author(s) : Yang J , Guo C , Luo Y , Fan J , Wang W , Yin X , Xu J
Ref : Sci Total Environ , 858 :159883 , 2022
Abstract : Thiamethoxam (THM) is a commercial neonicotinoid insecticide with broad-spectrum insecticidal activity. It has been widely detected in the aquatic environment, but its behavioral toxicity on aquatic organisms received limited attention. In this study, adult zebrafish were exposed to THM at three levels (0.1, 10, and 1000 g/L) for 45 days to investigate its effect on their ecological behavior, histopathology, bioaccumulation, and stress response. The bioconcentration factor in zebrafish brain was significantly higher (p < 0.05) at low concentration of THM (0.1 g/L) than in other treatment groups. In terms of individual behavior, the locomotor activity, aggregation, and social activity of fish were enhanced after THM exposure, but the memory of the food zone was disturbed and abnormal swimming behavior was observed. THM exposure caused brain tissue necrosis, erythrocyte infiltration, cloudy swelling, and other pathological changes in brain tissue and affected the concentrations of acetylcholinesterase and cortisol related to neurotoxicity. The condition factor and organ coefficients (brain, heart, and intestine) of zebrafish were markedly impacted by THM treatment at 0.1 and 1000 g/L, respectively. This finding showed that THM was more harmful to fish behavior than lethality, reproduction, and growth, and a behavioral study can be a useful tool for ecological risk assessment.
ESTHER : Yang_2022_Sci.Total.Environ_858_159883
PubMedSearch : Yang_2022_Sci.Total.Environ_858_159883
PubMedID: 36356732

Title : Enantioselective neurotoxicity and oxidative stress effects of paclobutrazol in zebrafish (Danio rerio) - Guo_2022_Pestic.Biochem.Physiol_185_105136
Author(s) : Guo D , Luo L , Kong Y , Kuang Z , Wen S , Zhao M , Zhang W , Fan J
Ref : Pestic Biochem Physiol , 185 :105136 , 2022
Abstract : Paclobutrazol is a widely used chiral plant growth regulator and its enantioselective toxicity in aquatic organisms is less explored till now. Herein, the enantioselective neurotoxicity of paclobutrazol mediated by oxidative stress in zebrafish were investigated. The oxidative stress parameters and neurotoxic biomarkers changed significantly in each exposure group, and paclobutrazol showed enantioselective toxicity in zebrafish. Firstly, (2R, 3R)-paclobutrazol exhibited a stronger oxidative stress in zebrafish than (2S, 3S)-enantiomer (P < 0.05). Then, activities of acetylcholinesterase, calcineurin, and total nitric oxide synthase in (2R, 3R)-paclobutrazol treatments were 0.61-0.89, 1.24-1.53, and 1.21-1.35-fold stronger (P < 0.05) than those in (2S, 3S)-enantiomer treatments, respectively. Next, the content variations of four neurotransmitters in zebrafish exposed to (2R, 3R)-paclobutrazol were significantly larger than those in (2S, 3S)-enantiomer treatments (P < 0.05). Moreover, (2R, 3R)-paclobutrazol had stronger binding with the receptors than (2S, 3S)-enantiomer through molecular docking. The integrated biomarker response values further demonstrated that (2R, 3R)-paclobutrazol showed stronger toxicity to zebrafish than (2S, 3S)-enantiomer. Furthermore, the neurotoxicity of paclobutrazol can be interpreted as the mediating effect of oxidative stress in zebrafish through correlation analysis, and an adverse outcome pathway for the nervous system in zebrafish induced by paclobutrazol was proposed. This work will greatly extend our understanding on the enantioselective toxic effects of paclobutrazol in aquatic organisms.
ESTHER : Guo_2022_Pestic.Biochem.Physiol_185_105136
PubMedSearch : Guo_2022_Pestic.Biochem.Physiol_185_105136
PubMedID: 35772839

Title : Enantioselective acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole in zebrafish (Danio rerio) - Guo_2022_Environ.Sci.Pollut.Res.Int__
Author(s) : Guo D , He R , Luo L , Zhang W , Fan J
Ref : Environ Sci Pollut Res Int , : , 2022
Abstract : Uniconazole is a widely used plant growth retardant in the agricultural field. However, toxicological effects of uniconazole in aquatic ecosystem at chiral level are still unclear. Herein, acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole enantiomers were investigated through using zebrafish as a model. (R)-Uniconazole possessed 1.16-fold greater acute toxicity to zebrafish than (S)-enantiomer. Then, integrated biomarker response values of oxidative stress parameters in zebrafish exposed to (R)-uniconazole were about 1.27~1.53 times greater than those treated by (S)-uniconazole, revealing that (R)-uniconazole could result in more significant adverse effects than (S)-uniconazole. Subsequently, the results of acetylcholinesterase activity of experimental fish demonstrated a state of inhibition-activation-inhibition after 14-day exposure to uniconazole, and a significant enantioselective neurotoxicity of uniconazole was observed in zebrafish after exposure for 4 and 7 days (p < 0.05). Moreover, thyroxine and triiodothyronine contents in (R)-uniconazole-exposed zebrafish were 0.89-fold (p=0.007) and 0.80-fold (p=0.007) than those in (S)-enantiomer-treated group, respectively. Furthermore, molecular docking results between uniconazole enantiomers and thyroid hormone receptors revealed that (R)-uniconazole was more tightly bound than (S)-uniconazole to the receptors. Briefly, our findings provide favorable information for ecological risk assessments of chiral agrochemicals in the environment and health of aquatic organisms.
ESTHER : Guo_2022_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Guo_2022_Environ.Sci.Pollut.Res.Int__
PubMedID: 35119633

Title : Whole-body insulin resistance and energy expenditure indices, serum lipids, and skeletal muscle metabolome in a state of lipoprotein lipase overexpression - Nishida_2021_Metabolomics_17_26
Author(s) : Nishida Y , Nishijima K , Yamada Y , Tanaka H , Matsumoto A , Fan J , Uda Y , Tomatsu H , Yamamoto H , Kami K , Kitajima S , Tanaka K
Ref : Metabolomics , 17 :26 , 2021
Abstract : INTRODUCTION: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. OBJECTIVES: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. METHODS: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. RESULTS: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). CONCLUSION: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression.
ESTHER : Nishida_2021_Metabolomics_17_26
PubMedSearch : Nishida_2021_Metabolomics_17_26
PubMedID: 33594546

Title : The Cutinase Bdo_10846 Play an Important Role in the Virulence of Botryosphaeria dothidea and in Inducing the Wart Symptom on Apple Plant - Dong_2021_Int.J.Mol.Sci_22_
Author(s) : Dong BZ , Zhu XQ , Fan J , Guo LY
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Botryosphaeria dothidea is a pathogen with worldwide distribution, infecting hundreds of species of economically important woody plants. It infects and causes various symptoms on apple plants, including wart and canker on branches, twigs, and stems. However, the mechanism of warts formation is unclear. In this study, we investigated the mechanism of wart formation by observing the transection ultrastructure of the inoculated cortical tissues at various time points of the infection process and detecting the expression of genes related to the pathogen pathogenicity and plant defense response. Results revealed that wart induced by B. dothidea consisted of proliferous of phelloderm cells, the newly formed secondary phellem, and the suberized phelloderm cells surrounding the invading mycelia. The qRT-PCR analysis revealed the significant upregulation of apple pathogenesis-related and suberification-related genes and a pathogen cutinase gene Bdo_10846. The Bdo_10846 knockout transformants showed reduced cutinase activity and decreased virulence. Transient expression of Bdo_10846 in Nicotiana benthamiana induced ROS burst, callose formation, the resistance of N. benthamiana to Botrytis cinerea, and significant upregulation of the plant pathogenesis-related and suberification-related genes. Additionally, the enzyme activity is essential for the induction. Virus-induced gene silencing demonstrated that the NbBAK1 and NbSOBIR1 expression were required for the Bdo_10846 induced defense response in N. benthamiana. These results revealed the mechanism of wart formation induced by B. dothidea invasion and the important roles of the cutinase Bdo_10846 in pathogen virulence and in inducing plant immunity.
ESTHER : Dong_2021_Int.J.Mol.Sci_22_
PubMedSearch : Dong_2021_Int.J.Mol.Sci_22_
PubMedID: 33673023
Gene_locus related to this paper: 9pezi-Bdo10846

Title : Epigallocatechin-3-Gallate Provides Protection Against Alzheimer's Disease-Induced Learning and Memory Impairments in Rats - Nan_2021_Drug.Des.Devel.Ther_15_2013
Author(s) : Nan S , Wang P , Zhang Y , Fan J
Ref : Drug Des Devel Ther , 15 :2013 , 2021
Abstract : PURPOSE: Recent evidence has highlighted the anti-inflammatory properties of the constituent of Green Tea Polyphenols (GTP), epigallocatechin-3-gallate (EGCG) which has been suggested to exert a neuroprotective effect on Alzheimer's disease (AD). The current study aimed to elucidate the effect of EGCG on memory function in rats with AD. METHODS: AD rat models were initially established through an injection with Abeta 25-35 solution, followed by gavage with EGCG at varying doses to determine the effect of EGCG on learning and cognitive deficits in AD. Morris water maze test was conducted to evaluate the spatial memory function of the rats. Immunohistochemistry and Western blot analysis were performed to identify Tau phosphorylation. The expression of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA and protein in rat hippocampus was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Acetylcholinesterase (AchE) activity, Abeta1-42 expression and Ach content were all detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: EGCG intervention brought about a decrease in the escape latency period while increasing the time at the target quadrant among the AD rats. EGCG decreased the hyperphosphorylation of Tau in hippocampus. BACE1 expression and activity as well as the expression of Abeta1-42 were suppressed by EGCG. Moreover, EGCG promoted Ach content by diminishing the activity of AchE. CONCLUSION: The current study demonstrates that EGCG may diminish the hyperphosphorylation of the Tau protein, downregulate BACE1 and Abeta1-42 expression to improve the antioxidant system and learning and memory function of rats with AD.
ESTHER : Nan_2021_Drug.Des.Devel.Ther_15_2013
PubMedSearch : Nan_2021_Drug.Des.Devel.Ther_15_2013
PubMedID: 34012254

Title : Endothelial Lipase Exerts its Anti-Atherogenic Effect through Increased Catabolism of beta-VLDLs - Yan_2020_J.Atheroscler.Thromb__
Author(s) : Yan H , Niimi M , Wang C , Chen Y , Zhou H , Matsuhisa F , Nishijima K , Kitajima S , Zhang B , Yokomichi H , Nakajima K , Murakami M , Zhang J , Chen YE , Fan J
Ref : J Atheroscler Thromb , : , 2020
Abstract : AIM: Endothelial lipase (EL) plays an important role in lipoprotein metabolism. Our recent study showed that increased hepatic expression of EL attenuates diet-induced hypercholesterolemia, thus subsequently reducing atherosclerosis in transgenic (Tg) rabbits. However, it is yet to be determined whether increased EL activity itself per se is anti-atherogenic or whether the anti-atherogenic effect of EL is exclusively dependent on its lipid-lowering effect. METHODS: To determine the mechanisms underlying EL-mediated anti-atherogenic effect, we fed Tg and non-Tg rabbits diets containing different amounts of cholesterol to make their plasma cholesterol levels similarly high. Sixteen weeks later, we examined their lipoprotein profiles and compared their susceptibility to atherosclerosis. RESULTS: With Tg and non-Tg rabbits having hypercholesterolemia, the plasma lipids and lipoprotein profiles were observed to be similar, while pathological examinations revealed that lesion areas of both aortic and coronary atherosclerosis of Tg rabbits were not significantly different from non-Tg rabbits. Moreover, Tg rabbits exhibited faster clearance of DiI-labeled beta-VLDLs than non-Tg rabbits. CONCLUSION: The results of our study suggest that the enhancement of beta-VLDL catabolism is the major mechanism for atheroprotective effects of EL in Tg rabbits.
ESTHER : Yan_2020_J.Atheroscler.Thromb__
PubMedSearch : Yan_2020_J.Atheroscler.Thromb__
PubMedID: 32448826

Title : Reduced insecticide sensitivity of the wheat aphid Sitobion miscanthi after infection by the secondary bacterial symbiont Hamiltonella defensa - Li_2020_Pest.Manag.Sci_77_1936
Author(s) : Li Q , Sun J , Qin Y , Fan J , Zhang Y , Tan X , Hou M , Chen J
Ref : Pest Manag Sci , 77 :1936 , 2020
Abstract : BACKGROUND: Bacterial symbionts in insects, especially aphids, have a major influence on host adaptation. The authors previously showed that infection with the secondary symbiont Hamiltonella defensa increases the fitness of the wheat aphid Sitobion miscanthi, yielding increases in fitness parameters such as adult weight and offspring number. However, whether H. defensa affects the sensitivity of host aphids to insecticides remains unknown. RESULTS: We tested the effects of H. defensa on host aphid susceptibility to the insecticides chlorpyrifos methyl, imidacloprid, cyantraniliprole and acetamiprid. Our results showed that compared with Hamiltonella-free aphid clones, Hamiltonella-infected aphid clones exhibited lower sensitivity to most of the tested insecticides at low concentrations. Quantitative PCR showed that the density of H. defensa in the infected clones was slightly decreased at 24 h but then sharply increased until the late stage after treatment with the different insecticides. H. defensa in the host aphids was detected by fluorescence in situ hybridization and was localized to the aphid hindgut. The levels of the detoxification enzymes acetylcholinesterase (AChE), glutathione transferase (GST) and carboxylesterase (CarE) were significantly higher in the Hamiltonella-infected clones than in the Hamiltonella-free clones. CONCLUSIONS: The findings indicated that infection with H. defensa reduced aphid sensitivity to the investigated insecticides at low concentrations, potentially by increasing detoxification enzyme activity in the host. Therefore, symbiont-mediated insecticide resistance should be taken into account when performing resistance-monitoring studies. Studies of symbiont-mediated insecticide resistance may enhance our understanding of the emergence of insecticide resistance in agricultural systems. This article is protected by copyright. All rights reserved.
ESTHER : Li_2020_Pest.Manag.Sci_77_1936
PubMedSearch : Li_2020_Pest.Manag.Sci_77_1936
PubMedID: 33300163

Title : Modulation of hippocampal neuronal resilience during aging by the Hsp70\/Hsp90 co-chaperone STI1 - Lackie_2020_J.Neurochem_153_727
Author(s) : Lackie RE , Razzaq AR , Farhan SMK , Qiu LR , Moshitzky G , Beraldo FH , Lopes MH , Maciejewski A , Gros R , Fan J , Choy WY , Greenberg DS , Martins VR , Duennwald ML , Lerch JP , Soreq H , Prado VF , Prado MAM
Ref : Journal of Neurochemistry , 153 :727 , 2020
Abstract : Chaperone networks are dysregulated with aging, but whether compromised Hsp70/Hsp90 chaperone function disturbs neuronal resilience is unknown. Stress-inducible phosphoprotein 1 (STI1; STIP1; HOP) is a co-chaperone that simultaneously interacts with Hsp70 and Hsp90, but whose function in vivo remains poorly understood. We combined in-depth analysis of chaperone genes in human datasets, analysis of a neuronal cell line lacking STI1 and of a mouse line with a hypomorphic Stip1 allele to investigate the requirement for STI1 in aging. Our experiments revealed that dysfunctional STI1 activity compromised Hsp70/Hsp90 chaperone network and neuronal resilience. The levels of a set of Hsp90 co-chaperones and client proteins were selectively affected by reduced levels of STI1, suggesting that their stability depends on functional Hsp70/Hsp90 machinery. Analysis of human databases revealed a subset of co-chaperones, including STI1, whose loss of function is incompatible with life in mammals, albeit they are not essential in yeast. Importantly, mice expressing a hypomorphic STI1 allele presented spontaneous age-dependent hippocampal neurodegeneration and reduced hippocampal volume, with consequent spatial memory deficit. We suggest that impaired STI1 function compromises Hsp70/Hsp90 chaperone activity in mammals and can by itself cause age-dependent hippocampal neurodegeneration in mice. Cover Image for this issue: doi: 10.1111/jnc.14749.
ESTHER : Lackie_2020_J.Neurochem_153_727
PubMedSearch : Lackie_2020_J.Neurochem_153_727
PubMedID: 31562773

Title : Increasing Structural Diversity of Natural Products by Michael Addition with ortho-Quinone Methide as the Acceptor - Liao_2020_J.Org.Chem_85_1298
Author(s) : Liao G , Fan J , Ludwig-Radtke L , Backhaus K , Li SM
Ref : J Org Chem , 85 :1298 , 2020
Abstract : The active form of clavatol, ortho-quinone methide, can be generated from hydroxyclavatol in an aqueous system and used as a highly reactive intermediate for coupling with diverse natural products under very mild conditions. These include flavonoids, hydroxynaphthalenes, coumarins, xanthones, anthraquinones, phloroglucinols, phenolic acids, indole derivatives, tyrosine analogues, and quinolines. The clavatol moiety was mainly attached via C-C bonds to the ortho- or para-positions of phenolic hydroxyl/amino groups and the C2-position of the indole ring.
ESTHER : Liao_2020_J.Org.Chem_85_1298
PubMedSearch : Liao_2020_J.Org.Chem_85_1298
PubMedID: 31860310
Gene_locus related to this paper: pencr-clae , pencr-clah

Title : HEV-LFS : A novel scoring model for patients with hepatitis E virus-related liver failure - Wu_2019_J.Viral.Hepat_26_1334
Author(s) : Wu J , Guo N , Zhang X , Xiong C , Liu J , Xu Y , Fan J , Yu J , Zhao X , Liu B , Wang W , Zhang J , Cao H , Li L
Ref : J Viral Hepat , 26 :1334 , 2019
Abstract : A noninvasive assessment method for acute or acute-on-chronic liver failure in patients with hepatitis E virus (HEV) infection is urgently needed. We aimed to develop a scoring model for diagnosing HEV patients who developed liver failure (HEV-LF) at different stages. A cross-sectional set of 350 HEV-LF patients were identified and enrolled, and the Guidelines for Diagnosis and Treatment of Liver Failure in China and the Asian Pacific Association for the Study of the Liver were adopted as references. HEV-LFS , a novel scoring model that incorporates data on cholinesterase (CHE), urea nitrogen (UREA), platelets and international normalized ratio was developed using a derived dataset. For diagnosing HEV-LF stages F1 to F3, the HEV-LFS scoring model (F1: 0.87; F2: 0.90; F3: 0.92) had a significantly higher AUROC than did the CLIF-C-ACLFs (F1: 0.65; F2: 0.56; F3: 0.51) and iMELD (F1: 0.70; F2: 0.57; F3: 0.51) scoring models, of which the HEV-LFS scoring model had the best sensitivity and specificity. In addition, the HEV-LFS scoring model was correlated with mortality, length of hospitalization and ICU stay. As the GDTLF score increased, the CHE level decreased and the UREA increased gradually. Encouragingly, a calibration curve showed good agreement between the derivation and validation sets. Notably, we also established a nomogram to facilitate the practical operability of the HEV-LFS scoring model in clinical settings. In conclusion, both CHE and UREA may be indicators for HEV-LF patients. The HEV-LFS scoring model is an efficient and accessible model for classifying HEV-LF at different stages.
ESTHER : Wu_2019_J.Viral.Hepat_26_1334
PubMedSearch : Wu_2019_J.Viral.Hepat_26_1334
PubMedID: 31294523

Title : Stereodivergent Protein Engineering of a Lipase To Access All Possible Stereoisomers of Chiral Esters with Two Stereocenters - Xu_2019_J.Am.Chem.Soc_141_7934
Author(s) : Xu J , Cen Y , Singh W , Fan J , Wu L , Lin X , Zhou J , Huang M , Reetz MT , Wu Q
Ref : Journal of the American Chemical Society , 141 :7934 , 2019
Abstract : Enzymatic stereodivergent synthesis to access all possible product stereoisomers bearing multiple stereocenters is relatively undeveloped, although enzymes are being increasingly used in both academic and industrial areas. When two stereocenters and thus four stereoisomeric products are involved, obtaining stereodivergent enzyme mutants for individually accessing all four stereoisomers would be ideal. Although significant success has been achieved in directed evolution of enzymes in general, stereodivergent engineering of one enzyme into four highly stereocomplementary variants for obtaining the full complement of stereoisomers bearing multiple stereocenters remains a challenge. Using Candida antarctica lipase B (CALB) as a model, we report the protein engineering of this enzyme into four highly stereocomplementary variants needed for obtaining all four stereoisomers in transesterification reactions between racemic acids and racemic alcohols in organic solvents. By generating and screening less than 25 variants of each isomer, we achieved >90% selectivity for all of the four possible stereoisomers in the model reaction. This difficult feat was accomplished by developing a strategy dubbed "focused rational iterative site-specific mutagenesis" (FRISM) at sites lining the enzyme's binding pocket. The accumulation of single mutations by iterative site-specific mutagenesis using a restricted set of rationally chosen amino acids allows the formation of ultrasmall mutant libraries requiring minimal screening for stereoselectivity. The crystal structure of all stereodivergent CALB variants, flanked by MD simulations, uncovered the source of selectivity.
ESTHER : Xu_2019_J.Am.Chem.Soc_141_7934
PubMedSearch : Xu_2019_J.Am.Chem.Soc_141_7934
PubMedID: 31023008
Gene_locus related to this paper: canar-LipB

Title : Protective role of phenylethanoid glycosides, Torenoside B and Savatiside A, in Alzheimer's disease - Ji_2019_Exp.Ther.Med_17_3755
Author(s) : Ji S , Li S , Zhao X , Kang N , Cao K , Zhu Y , Peng P , Fan J , Xu Q , Yang S , Liu Y
Ref : Exp Ther Med , 17 :3755 , 2019
Abstract : The current study assessed the efficacy of two phenylethanoid glycosides (PhGs), Torenoside B (TB) and Savatiside A (SA), in the treatment of Alzheimer's disease (AD). The effects of TB and SA compounds were first assessed following amyloid beta (Abeta)25-35 induction in SH-SY5Y cells at a range of concentrations. Their effects on cell viability and reactive oxygen species (ROS) were determined by performing MTT and dichlorofluorescin diacetate assays, respectively. The concentration of intracellular Ca(2+) was determined using Fluo-3AM to stain SH-SY5Y cells. SA and TB treatments were also assessed in Abeta25-35-induced mice. Y-maze and Morris water maze methods were utilized to assess murine learning and memory capability. The pathological changes of murine hippocampi was determined using H&E and Nissl staining. In addition, biochemical parameters associated with intracellular reactive oxygen pathways including Maleic dialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), acetylcholinesterase (AChE) and Calnexin were also assessed. TB and SA treatment in Abeta25-35-induced SH-SY5Y cells resulted in the restoration of cell morphology, an increase of SOD and GSH-Px activity, a decrease in ROS, Ca(2+) and MDA content, and a decrease in Calnexin expression. Furthermore, SA or TB treatment administered to Abeta25-35-induced mice improved their spatial/non-spatial learning and memory capabilities. The efficacy of treatment was also supported by a marked change in the morphological structure of pyramidal neurons in the CA1 areas of murine hippocampi, as well as an increase of SOD and GSH-Px activity. Treatment also resulted in a decrease in MDA content, AchE activity and Calnexin expression in murine hippocampal tissue. As potential AD treatment drugs, SA and TB compounds have been demonstrated to alleviate the oxidative stress induced by Abeta25-35 via the regulation of intracellular calcium homeostasis and Calnexin, preventing AD development.
ESTHER : Ji_2019_Exp.Ther.Med_17_3755
PubMedSearch : Ji_2019_Exp.Ther.Med_17_3755
PubMedID: 30988761

Title : Peniphenone and Penilactone Formation in Penicillium crustosum via 1,4-Michael Additions of ortho-Quinone Methide from Hydroxyclavatol to gamma-Butyrolactones from Crustosic Acid - Fan_2019_J.Am.Chem.Soc_141_4225
Author(s) : Fan J , Liao G , Kindinger F , Ludwig-Radtke L , Yin WB , Li SM
Ref : Journal of the American Chemical Society , 141 :4225 , 2019
Abstract : Penilactones A and B consist of a gamma-butyrolactone and two clavatol moieties. We identified two separate gene clusters for the biosynthesis of these key building blocks in Penicillium crustosum. Gene deletion, feeding experiments, and biochemical investigations proved that a nonreducing PKS ClaF is responsible for the formation of clavatol and the PKS-NRPS hybrid TraA is involved in the formation of crustosic acid, which undergoes decarboxylation and isomerization to the predominant terrestric acid. Both acids are proposed to be converted to gamma-butyrolactones with involvement of a cytochrome P(450) ClaJ. Oxidation of clavatol to hydroxyclavatol by a nonheme Fe(II)/2-oxoglutarate-dependent oxygenase ClaD and its spontaneous dehydration to an ortho-quinone methide initiate the two nonenzymatic 1,4-Michael addition steps. Spontaneous addition of the methide to the gamma-butyrolactones led to peniphenone D and penilactone D, which undergo again stereospecific attacking by methide to give penilactones A/B.
ESTHER : Fan_2019_J.Am.Chem.Soc_141_4225
PubMedSearch : Fan_2019_J.Am.Chem.Soc_141_4225
PubMedID: 30811183
Gene_locus related to this paper: pencr-clae , pencr-clah

Title : Increased Hepatic Expression of Endothelial Lipase Inhibits Cholesterol Diet-Induced Hypercholesterolemia and Atherosclerosis in Transgenic Rabbits - Wang_2017_Arterioscler.Thromb.Vasc.Biol_37_1282
Author(s) : Wang C , Nishijima K , Kitajima S , Niimi M , Yan H , Chen Y , Ning B , Matsuhisa F , Liu E , Zhang J , Chen YE , Fan J
Ref : Arterioscler Thromb Vasc Biol , 37 :1282 , 2017
Abstract : OBJECTIVE: Endothelial lipase (EL) is a key determinant in plasma high-density lipoprotein-cholesterol. However, functional roles of EL on the development of atherosclerosis have not been clarified. We investigated whether hepatic expression of EL affects plasma lipoprotein metabolism and cholesterol diet-induced atherosclerosis. APPROACH AND
RESULTS: We generated transgenic (Tg) rabbits expressing the human EL gene in the liver and then examined the effects of EL expression on plasma lipids and lipoproteins and compared the susceptibility of Tg rabbits with cholesterol diet-induced atherosclerosis with non-Tg littermates. On a chow diet, hepatic expression of human EL in Tg rabbits led to remarkable reductions in plasma levels of total cholesterol, phospholipids, and high-density lipoprotein-cholesterol compared with non-Tg controls. On a cholesterol-rich diet for 16 weeks, Tg rabbits exhibited significantly lower hypercholesterolemia and less atherosclerosis than non-Tg littermates. In Tg rabbits, gross lesion area of aortic atherosclerosis was reduced by 52%, and the lesions were characterized by fewer macrophages and smooth muscle cells compared with non-Tg littermates.
CONCLUSIONS: Increased hepatic expression of EL attenuates cholesterol diet-induced hypercholesterolemia and protects against atherosclerosis.
ESTHER : Wang_2017_Arterioscler.Thromb.Vasc.Biol_37_1282
PubMedSearch : Wang_2017_Arterioscler.Thromb.Vasc.Biol_37_1282
PubMedID: 28546217
Gene_locus related to this paper: human-LIPG

Title : Lighting-up breast cancer cells by a near-infrared fluorescent probe based on KIAA1363 enzyme-targeting - Fan_2017_Chem.Commun.(Camb)_53_4857
Author(s) : Fan J , Guo S , Wang S , Kang Y , Yao Q , Wang J , Gao X , Wang H , Du J , Peng X
Ref : Chem Commun (Camb) , 53 :4857 , 2017
Abstract : The first NIR KIAA1363-targeting probe, NB-AX, specifically and instantly featured an "off-on" switch upon gradual addition of KIAA1363 over all kinds of other biomolecules, and its detection limit was initially calculated to be 0.58 mug mL(-1) (3delta/k). The probe was also able to be used in ultrafast distinguishing of breast cancer cells from normal cells in fluorescence imaging and applied in tissue imaging and tumor imaging in vivo.
ESTHER : Fan_2017_Chem.Commun.(Camb)_53_4857
PubMedSearch : Fan_2017_Chem.Commun.(Camb)_53_4857
PubMedID: 28421217
Gene_locus related to this paper: human-NCEH1

Title : Seco-pregnane glycosides from the stems of Epigynum auritum - Gao_2016_Nat.Prod.Res__1
Author(s) : Gao F , Yao YC , Wan Z , Cai SB , Fan J , Zhao TR , Cao JX , Cheng GG
Ref : Nat Prod Res , :1 , 2016
Abstract : Chemical investigation of the stems of Epigynum auritum led to the isolation and identification of a novel 16,17-seco pregnane glycoside, epigynoside D, along with other three known compounds (2-4). The structure of compound 1 was elucidated by means of spectroscopic analysis, including HRESIMS, 1D and 2D NMR experiments. All isolated compounds were tested for their in vitro cytotoxic, immunological and anti-acetylcholinesterase activities.
ESTHER : Gao_2016_Nat.Prod.Res__1
PubMedSearch : Gao_2016_Nat.Prod.Res__1
PubMedID: 27931111

Title : The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to beta-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment - Ostapchenko_2015_J.Neurosci_35_15157
Author(s) : Ostapchenko VG , Chen M , Guzman MS , Xie YF , Lavine N , Fan J , Beraldo FH , Martyn AC , Belrose JC , Mori Y , MacDonald JF , Prado VF , Prado MAM , Jackson MF
Ref : Journal of Neuroscience , 35 :15157 , 2015
Abstract : In Alzheimer's disease, accumulation of soluble oligomers of beta-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca(2+)-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with beta-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2alpha, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for beta-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2(-/-) neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2(-/-)/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the importance of TRPM2 for beta-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease. SIGNIFICANCE STATEMENT: Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric beta-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved age-dependent spatial memory deficits observed in Alzheimer's mice. Our results reveal the importance of TRPM2 for neuronal toxicity and memory impairments in an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the development of therapeutic agents effective in the treatment of dementia.
ESTHER : Ostapchenko_2015_J.Neurosci_35_15157
PubMedSearch : Ostapchenko_2015_J.Neurosci_35_15157
PubMedID: 26558786

Title : Quantitative Proteomics Analysis of the Hepatitis C Virus Replicon High-Permissive and Low-Permissive Cell Lines - Ye_2015_PLoS.One_10_e0142082
Author(s) : Ye F , Xin Z , Han W , Fan J , Yin B , Wu S , Yang W , Yuan J , Qiang B , Sun W , Peng X
Ref : PLoS ONE , 10 :e0142082 , 2015
Abstract : Chronic hepatitis C virus (HCV) infection is one of the leading causes of severe hepatitis. The molecular mechanisms underlying HCV replication and pathogenesis remain unclear. The development of the subgenome replicon model system significantly enhanced study of HCV. However, the permissiveness of the HCV subgenome replicon greatly differs among different hepatoma cell lines. Proteomic analysis of different permissive cell lines might provide new clues in understanding HCV replication. In this study, to detect potential candidates that might account for the differences in HCV replication. Label-free and iTRAQ labeling were used to analyze the differentially expressed protein profiles between Huh7.5.1 wt and HepG2 cells. A total of 4919 proteins were quantified in which 114 proteins were commonly identified as differentially expressed by both quantitative methods. A total of 37 differential proteins were validated by qRT-PCR. The differential expression of Glutathione S-transferase P (GSTP1), Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), carboxylesterase 1 (CES1), vimentin, Proteasome activator complex subunit1 (PSME1), and Cathepsin B (CTSB) were verified by western blot. And over-expression of CTSB or knock-down of vimentin induced significant changes to HCV RNA levels. Additionally, we demonstrated that CTSB was able to inhibit HCV replication and viral protein translation. These results highlight the potential role of CTSB and vimentin in virus replication.
ESTHER : Ye_2015_PLoS.One_10_e0142082
PubMedSearch : Ye_2015_PLoS.One_10_e0142082
PubMedID: 26544179

Title : Comparative proteomic analysis of Bombyx mori hemocytes treated with destruxin A - Fan_2014_Arch.Insect.Biochem.Physiol_86_33
Author(s) : Fan J , Han P , Chen X , Hu Q , Ye M
Ref : Archives of Insect Biochemistry & Physiology , 86 :33 , 2014
Abstract : Destruxin A (DA), a cyclodepsipeptidic secondary metabolite of the entomopathogenic fungus, Metarhizium anisopliae, is an important anti-immunity agent against insect hemocytes. To understand the mechanism of the molecular responses to DA, fifth-instar larvae of the silkworm, Bombyx mori, were injected with 2 mug of DA. The proteomics of hemocytes were then investigated using two-dimensional electrophoresis and mass spectrometry, and validated qPCR. As a result, a total of 47 differently expressed protein spots were detected and 22 proteins in 26 spots were identified. There are eight immunity-related proteins, including three downregulated proteins (antitrypsin isoform 3, p50 protein, and calreticulin precursor) and five upregulated proteins (C-type lectin 10 precursor, serine proteinase-like protein, paralytic peptide, PPO-1, and PPO-2). Four resistance- and/or stress-related proteins (arginine kinase, carboxylesterase clade H, member 1, aminoacylase, and thiol peroxiredoxin) were upregulated. Ten proteins with other or unknown functions were also recorded. Five selected proteins were verified with qPCR. These results provide new insights into the molecular mechanism of host immune response to DA challenge.
ESTHER : Fan_2014_Arch.Insect.Biochem.Physiol_86_33
PubMedSearch : Fan_2014_Arch.Insect.Biochem.Physiol_86_33
PubMedID: 24719308

Title : Comparative analyses of lipoprotein lipase, hepatic lipase, and endothelial lipase, and their binding properties with known inhibitors - Wang_2013_PLoS.One_8_e72146
Author(s) : Wang Z , Li S , Sun L , Fan J , Liu Z
Ref : PLoS ONE , 8 :e72146 , 2013
Abstract : The triglyceride lipase gene subfamily plays a central role in lipid and lipoprotein metabolism. There are three members of this subfamily: lipoprotein lipase, hepatic lipase, and endothelial lipase. Although these lipases are implicated in the pathophysiology of hyperlipidemia and atherosclerosis, their structures have not been fully solved. In the current study, we established homology models of these three lipases, and carried out analysis of their activity sites. In addition, we investigated the kinetic characteristics for the catalytic residues using a molecular dynamics simulation strategy. To elucidate the molecular interactions and determine potential key residues involved in the binding to lipase inhibitors, we analyzed the binding pockets and binding poses of known inhibitors of the three lipases. We identified the spatial consensus catalytic triad "Ser-Asp-His", a characteristic motif in all three lipases. Furthermore, we found that the spatial characteristics of the binding pockets of the lipase molecules play a key role in ligand recognition, binding poses, and affinities. To the best of our knowledge, this is the first report that systematically builds homology models of all the triglyceride lipase gene subfamily members. Our data provide novel insights into the molecular structures of lipases and their structure-function relationship, and thus provides groundwork for functional probe design towards lipase-based therapeutic inhibitors for the treatment of hyperlipidemia and atherosclerosis.
ESTHER : Wang_2013_PLoS.One_8_e72146
PubMedSearch : Wang_2013_PLoS.One_8_e72146
PubMedID: 23991054

Title : ChAT-ChR2-EYFP Mice Have Enhanced Motor Endurance But Show Deficits in Attention and Several Additional Cognitive Domains - Kolisnyk_2013_J.Neurosci_33_10427
Author(s) : Kolisnyk B , Guzman MS , Raulic S , Fan J , Magalhaes AC , Feng G , Gros R , Prado VF , Prado MAM
Ref : Journal of Neuroscience , 33 :10427 , 2013
Abstract : Acetylcholine (ACh) is an important neuromodulator in the nervous system implicated in many forms of cognitive and motor processing. Recent studies have used bacterial artificial chromosome (BAC) transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches. We report that a mouse line used for this purpose also carries several copies of the vesicular acetylcholine transporter gene (VAChT), which leads to overexpression of functional VAChT and consequently increased cholinergic tone. We demonstrate that these mice have marked improvement in motor endurance. However, they also present severe cognitive deficits, including attention deficits and dysfunction in working memory and spatial memory. These results suggest that increased VAChT expression may disrupt critical steps in information processing. Our studies demonstrate that ChAT-ChR2-EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice.
ESTHER : Kolisnyk_2013_J.Neurosci_33_10427
PubMedSearch : Kolisnyk_2013_J.Neurosci_33_10427
PubMedID: 23785154

Title : Isolation and identification of antifungal peptides from Bacillus BH072, a novel bacterium isolated from honey - Zhao_2013_Microbiol.Res_168_598
Author(s) : Zhao X , Zhou ZJ , Han Y , Wang ZZ , Fan J , Xiao HZ
Ref : Microbiol Res , 168 :598 , 2013
Abstract : A bacterial strain BH072 isolated from a honey sample showed antifungal activity against mold. Based on morphological, biochemical, physiological tests, and analysis of 16S rDNA sequence, the strain was identified to be a new subspecies of Bacillus sp. It had a broad spectrum of antifungal activity against various mold, such as Aspergillus niger, Pythium, and Botrytis cinerea. Six pairs of antifungal genes primers were designed and synthesized, and ituA, hag, tasA genes were detected by PCR analysis. The remarkable antifungal activity could be associated with the co-production of these three peptides. One of them was purified by 30-40% ammonium sulfate precipitation, Sephadex G-75 gel filtration and anion exchange chromatography on D201 resin. The purified peptide was estimated to be 35.615 kDa and identified to be flagellin by micrOTOF-Q II. By using methanol extraction, another substance was isolated from fermentation liquor, and determined to be iturin with liquid chromatography-mass spectrometry (LC-MS) method. The third possible peptide encoded by tasA was not isolated in this study. The culture liquor displayed antifungal activity in a wide pH range (5.0-9.0) and at 40-100 degrees C. The result of the present work suggested that Bacillus BH072 might be a bio-control bacterium of research value.
ESTHER : Zhao_2013_Microbiol.Res_168_598
PubMedSearch : Zhao_2013_Microbiol.Res_168_598
PubMedID: 23545354
Gene_locus related to this paper: bacsu-YVAK

Title : Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits - Zhang_2012_J.Atheroscler.Thromb_19_213
Author(s) : Zhang J , Yu Y , Nakamura K , Koike T , Waqar AB , Zhang X , Liu E , Nishijima K , Kitajima S , Shiomi M , Qi Z , Yu J , Graham MJ , Crooke RM , Ishida T , Hirata K , Hurt-Camejo E , Chen YE , Fan J
Ref : J Atheroscler Thromb , 19 :213 , 2012
Abstract : AIM: Existing evidence suggests that endothelial lipase (EL) plays an important role in high-densitylipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit EL (rEL) expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits. METHODS: We cloned the rEL cDNA and analyzed the EL tissue expression using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization. We evaluated the effects of rEL antisense on plasma HDL levels. RESULTS: We found that rEL mRNA was highly expressed in cholesterol synthesis-related organs, including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in the elevation of plasma large HDLs. Furthermore, we demonstrated that rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits. CONCLUSIONS: rEL is expressed in multiple tissues and may have many physiological and pathophysiological functions, such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits.
ESTHER : Zhang_2012_J.Atheroscler.Thromb_19_213
PubMedSearch : Zhang_2012_J.Atheroscler.Thromb_19_213
PubMedID: 22240910

Title : Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization - Zhao_2011_Hepatology_53_493
Author(s) : Zhao Y , Wang X , Wang T , Hu X , Hui X , Yan M , Gao Q , Chen T , Li J , Yao M , Wan D , Gu J , Fan J , He X
Ref : Hepatology , 53 :493 , 2011
Abstract : UNLABELLED: Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3beta and lead to beta-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). CONCLUSION: For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.
ESTHER : Zhao_2011_Hepatology_53_493
PubMedSearch : Zhao_2011_Hepatology_53_493
PubMedID: 21274871

Title : DGAT1 and PDAT1 acyltransferases have overlapping functions in Arabidopsis triacylglycerol biosynthesis and are essential for normal pollen and seed development - Zhang_2009_Plant.Cell_21_3885
Author(s) : Zhang M , Fan J , Taylor DC , Ohlrogge JB
Ref : Plant Cell , 21 :3885 , 2009
Abstract : Triacylglycerol (TAG) biosynthesis is a principal metabolic pathway in most organisms, and TAG is the major form of carbon storage in many plant seeds. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the only acyltransferase enzyme that has been confirmed to contribute to TAG biosynthesis in Arabidopsis thaliana seeds. However, dgat1 null mutants display only a 20 to 40% decrease in seed oil content. To determine whether other enzymes contribute to TAG synthesis, candidate genes were expressed in TAG-deficient yeast, candidate mutants were crossed with the dgat1-1 mutant, and target genes were suppressed by RNA interference (RNAi). An in vivo role for phospholipid:diacylglycerol acyltransferase 1 (PDAT1; At5g13640) in TAG synthesis was revealed in this study. After failing to obtain double homozygous plants from crossing dgat1-1 and pdat1-2, further investigation showed that the dgat1-1 pdat1-2 double mutation resulted in sterile pollen that lacked visible oil bodies. RNAi silencing of PDAT1 in a dgat1-1 background or DGAT1 in pdat1-1 background resulted in 70 to 80% decreases in oil content per seed and in disruptions of embryo development. These results establish in vivo involvement of PDAT1 in TAG biosynthesis, rule out major contributions by other candidate enzymes, and indicate that PDAT1 and DGAT1 have overlapping functions that are essential for normal pollen and seed development of Arabidopsis.
ESTHER : Zhang_2009_Plant.Cell_21_3885
PubMedSearch : Zhang_2009_Plant.Cell_21_3885
PubMedID: 20040537
Gene_locus related to this paper: arath-At5g13640

Title : Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet - Zhang_2008_Circ.Res_102_250
Author(s) : Zhang X , Qi R , Xian X , Yang F , Blackstein M , Deng X , Fan J , Ross C , Karasinska J , Hayden MR , Liu G
Ref : Circulation Research , 102 :250 , 2008
Abstract : Large-scale epidemiological studies have revealed a strong association between hypertriglyceridemia and coronary arteriosclerotic disease. However, there are conflicting reports whether the severe hypertriglyceridemia caused by lipoprotein lipase (LPL) deficiency is pro- or antiatherogenic. To determine the effect of LPL deficiency on atherosclerosis, we pursued long-term observation of the development of atherosclerotic lesions in an LPL gene deficient mouse model. At 4 months of age, homozygous LPL-deficient mice exhibited severe hypertriglyceridemia but no signs of aortic atherosclerotic lesions. At >15 months of age, these mice developed foam cell-rich atherosclerotic lesions at the aortic root, whereas wild-type and heterozygous mice were lesion-free at the same age. Further investigation revealed that plasma malondialdehyde levels in >15-month-old LPL-deficient mice were significantly higher than those of heterozygous and wild-type mice. Electron spin resonance analysis showed a marked increase in oxidative susceptibility of chylomicrons from the aged LPL-deficient mice. Incubation of chylomicrons from >15-month-old LPL-deficient mice with cultured human umbilical vein endothelial cells showed significantly increased upregulation of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, markers of enhanced endothelial activation, and enhanced adherence of human THP-1 mononuclear cells. These results clearly demonstrate the occurrence of spontaneous atherosclerosis in aged LPL-deficient mice mediated by the oxidation of chylomicrons and the activation of vascular endothelial cells.
ESTHER : Zhang_2008_Circ.Res_102_250
PubMedSearch : Zhang_2008_Circ.Res_102_250
PubMedID: 18032735

Title : Sub-parts-per-billion level detection of dimethyl methyl phosphonate (DMMP) by quantum cascade laser photoacoustic spectroscopy - Mukherjee_2008_Appl.Opt_47_1543
Author(s) : Mukherjee A , Dunayevskiy I , Prasanna M , Go R , Tsekoun A , Wang X , Fan J , Patel CK
Ref : Appl Opt , 47 :1543 , 2008
Abstract : The need for the detection of chemical warfare agents (CWAs) is no longer confined to battlefield environments because of at least one confirmed terrorist attack, the Tokyo Subway [Emerg. Infect. Dis. 5, 513 (1999)] in 1995, and a suspected, i.e., a false-alarm of a CWA in the Russell Senate Office Building [Washington Post, 9 February 2006, p. B01]. Therefore, detection of CWAs with high sensitivity and low false-alarm rates is considered an important priority for ensuring public safety. We report a minimum detection level for a CWA simulant, dimethyl methyl phosphonate (DMMP), of <0.5 ppb (parts in 10(9)) by use of a widely tunable external grating cavity quantum cascade laser and photoacoustic spectroscopy. With interferents present in Santa Monica, California street air, we demonstrate a false-alarm rate of 1:10(6) at a detection threshold of 1.6 ppb.
ESTHER : Mukherjee_2008_Appl.Opt_47_1543
PubMedSearch : Mukherjee_2008_Appl.Opt_47_1543
PubMedID: 18382583

Title : Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice - Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
Author(s) : Wang J , Xian X , Huang W , Chen L , Wu L , Zhu Y , Fan J , Ross C , Hayden MR , Liu G
Ref : Arterioscler Thromb Vasc Biol , 27 :197 , 2007
Abstract : OBJECTIVE: Overexpression of lipoprotein lipase (LPL) in deendothelialized artery led to profound localized lipid deposition. In this study the role of LPL in atherogenesis in endothelial-intact carotid arteries was assessed in genetically hyperlipidemic LPL- and ApoE-deficient mice. METHODS AND RESULTS: Human wild-type LPL (hLPLwt), catalytically inactive LPL (hLPL194), or control alkaline phosphatase (hAP) were expressed in endothelial-intact carotid arteries via adenoviral vectors. Compared with Ad-hAP, lipid deposition in the arterial wall increased 10.0- and 5.1-fold for Ad-hLPLwt and Ad-hLPL194 in LPL-deficient mice, and 10.6- and 6.2-fold in ApoE-deficient mice, respectively. Vascular cell adhesion molecule-1 (VCAM-1) was upregulated in Ad-hLPLwt and Ad-hLPL194 transferred arteries. CONCLUSIONS: Endothelial cell associated LPL, either active or inactive, in the arterial wall is a strong proatherosclerotic factor in both LPL- and ApoE-deficient mice.
ESTHER : Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
PubMedSearch : Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
PubMedID: 17038632

Title : CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission - Jevsek_2006_Proc.Natl.Acad.Sci.U.S.A_103_6374
Author(s) : Jevsek M , Jaworski A , Polo-Parada L , Kim N , Fan J , Landmesser LT , Burden SJ
Ref : Proc Natl Acad Sci U S A , 103 :6374 , 2006
Abstract : The genes encoding several synaptic proteins, including acetylcholine receptors, acetylcholinesterase, and the muscle-specific kinase, MuSK, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site. Genetic analysis of mutant mice suggests that additional genes, expressed selectively by synaptic nuclei, might encode muscle-derived retrograde signals that regulate the differentiation of motor axon terminals. To identify candidate retrograde signals, we used a microarray screen to identify genes that are preferentially expressed in the synaptic region of muscle, and we analyzed one such gene, CD24, further. We show that CD24, which encodes a small, variably and highly glycosylated, glycosylphosphatidylinositol (GPI)-linked protein, is expressed preferentially by myofiber synaptic nuclei in embryonic and adult muscle, and that CD24 expression is restricted to the central region of muscle independent of innervation. Moreover, we show that CD24 has a role in presynaptic differentiation, because synaptic transmission is depressed and fails entirely, in a cyclical manner, after repetitive stimulation of motor axons in CD24 mutant mice. These deficits in synaptic transmission, which are accompanied by aberrant stimulus-dependent uptake of AM1-43 from axons, indicate that CD24 is required for normal presynaptic maturation and function. Because CD24 is also expressed in some neurons, additional experiments will be required to determine whether pre- or postsynaptic CD24 mediates these effects on presynaptic development and function.
ESTHER : Jevsek_2006_Proc.Natl.Acad.Sci.U.S.A_103_6374
PubMedSearch : Jevsek_2006_Proc.Natl.Acad.Sci.U.S.A_103_6374
PubMedID: 16606832

Title : Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall - Wu_2006_Atherosclerosis_187_65
Author(s) : Wu X , Wang J , Fan J , Chen M , Chen L , Huang W , Liu G
Ref : Atherosclerosis , 187 :65 , 2006
Abstract : Recent studies on mice demonstrated that lipoprotein lipase (LPL) located in the arterial wall might play a pro-atherogenic role. There are major differences between humans and mice in lipoprotein metabolism and in susceptibility to atherosclerosis. We have therefore used rabbits fed normal chow diet as a model to assess such localized effects by adenovirus-mediated gene transfer of human catalytically active wild type LPL (hLPLwt) and an inactive mutant (hLPL194) to balloon-injured carotid arteries. By morphometric analysis on cryosections stained with Oil Red O (ORO) we found 7- and 4-fold increases, respectively, of lipid deposition in the arterial walls 7 days after infection with adenovirus expressing hLPLwt or hLPL194, when compared with a virus expressing human alkaline phosphatase (hAP) as control. Macrophages were detected in the arteries expressing both forms of LPL, but apoB was only found in arteries expressing hLPLwt. Expression of the LPL gene products was transient and was gone after 2 weeks, but the accumulated lipid deposits remained between the neointimal and the media layers even after 8 weeks. Our data demonstrate that expression of LPL in the arterial wall (with or without lipase activity) leads to lipid accumulation in balloon-injured rabbit arteries, and could result in enhanced formation of atherosclerotic lesions.
ESTHER : Wu_2006_Atherosclerosis_187_65
PubMedSearch : Wu_2006_Atherosclerosis_187_65
PubMedID: 16191430

Title : High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits - Liu_2005_Metabolism_54_132
Author(s) : Liu E , Kitajima S , Higaki Y , Morimoto M , Sun H , Watanabe T , Yamada N , Fan J
Ref : Metabolism , 54 :132 , 2005
Abstract : Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism. To examine the hypothesis that increased LPL activity may alter insulin sensitivity, we investigated glucose metabolism and insulin sensitivity in transgenic (Tg) rabbits expressing the human LPL gene under the control of a I(2) -actin promoter. An intravenous glucose tolerance test showed that the plasma glucose clearance rate was not significantly different between Tg and non-Tg rabbits; however, the area under the curve for insulin and free fatty acids in Tg rabbits was significantly reduced compared with that of non-Tg rabbits (P < .05). Using the intravenous insulin tolerance test, we found that the area of under the curve of glucose of Tg rabbits was also significantly reduced (P < .01). Furthermore, euglycemic-hyperinsulinemic clamp test revealed that the mean glucose infusion rate in Tg rabbits was significantly higher than in non-Tg rabbits (P < .05). These results demonstrate that systemic overexpression of LPL increases whole-body insulin sensitivity and genetic manipulation of LPL genes may be a potential target for the treatment of diabetic patients.
ESTHER : Liu_2005_Metabolism_54_132
PubMedSearch : Liu_2005_Metabolism_54_132
PubMedID: 15562391

Title : Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase - Koike_2005_Cardiovasc.Res_65_524
Author(s) : Koike T , Liang J , Wang X , Ichikawa T , Shiomi M , Sun H , Watanabe T , Liu G , Fan J
Ref : Cardiovascular Research , 65 :524 , 2005
Abstract : OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency.
METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits.
RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits.
CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.
ESTHER : Koike_2005_Cardiovasc.Res_65_524
PubMedSearch : Koike_2005_Cardiovasc.Res_65_524
PubMedID: 15639492

Title : Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed Tg rabbits - Ichikawa_2005_Atherosclerosis_179_87
Author(s) : Ichikawa T , Liang J , Kitajima S , Koike T , Wang X , Sun H , Morimoto M , Shikama H , Watanabe T , Yamada N , Fan J
Ref : Atherosclerosis , 179 :87 , 2005
Abstract : Lipoprotein lipase (LPL) produced by macrophages is upregulated in the atherosclerotic lesions; however, it is not fully understood whether increased macrophage-derived LPL is pro-atherogenic. To examine the hypothesis that macrophage-derived LPL in the arterial wall enhances atherosclerotic lesion formation, we generated transgenic (Tg) rabbits that express the human LPL transgene under the control of the human scavenger receptor enhancer/promoter, which drives macrophage-specific expression of the human LPL gene. We fed Tg and non-Tg littermate rabbits a diet containing 0.3% cholesterol for 16 weeks and compared their lipoproteins and aortic atherosclerosis. We found that there was no difference in plasma lipid or lipoprotein profiles between Tg and non-Tg rabbits; however, atherosclerotic lesions were significantly increased in Tg compared to non-Tg rabbits. There was a 1.4-fold increase in total aortic en face lesions and a 2-fold increase in intimal lesions evaluated by image analysis system. Furthermore, immunohistochemical staining revealed that the increased atherosclerotic lesions present in Tg rabbits were characterized by marked accumulation of macrophage-derived foam cells and frequently associated with the deposition of oxidized LDL. These results support the notion that macrophage-derived LPL in the arterial wall is pro-atherogenic, possibly via the enhancement of foam cell formation during atherogenesis.
ESTHER : Ichikawa_2005_Atherosclerosis_179_87
PubMedSearch : Ichikawa_2005_Atherosclerosis_179_87
PubMedID: 15721013

Title : Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits - Kitajima_2004_Diabetologia_47_1202
Author(s) : Kitajima S , Morimoto M , Liu E , Koike T , Higaki Y , Taura Y , Mamba K , Itamoto K , Watanabe T , Tsutsumi K , Yamada N , Fan J
Ref : Diabetologia , 47 :1202 , 2004
Abstract : AIMS/HYPOTHESIS: Dysfunctions of lipoprotein lipase (LPL) have been found to be associated with dyslipidaemias, atherosclerosis, obesity and insulin resistance. There are two conflicting hypotheses regarding the roles of LPL in glucose metabolism and insulin resistance. Whether systemically increased LPL activity would be beneficial or detrimental to insulin sensitivity is yet to be resolved. To address this issue, we studied transgenic rabbits overexpressing human LPL transgene.
METHODS: LPL transgenic and control rabbits were fed a 10% high-fat diet (HFD) for 16 weeks. To evaluate glucose metabolism, we compared plasma levels of glucose and insulin in transgenic rabbits with control rabbits and performed an intravenous glucose tolerance test. In addition, we measured adipose tissue accumulation in HFD-fed rabbits.
RESULTS: Increased LPL activity in transgenic rabbits resulted in a significant reduction of plasma triglycerides and non-esterified fatty acids, but not in basal levels of glucose and insulin. HFD feeding induced an elevation of plasma glucose levels accompanied by hyperinsulinaemia in control rabbits, but was significantly inhibited in transgenic rabbits. The intravenous glucose tolerance test showed that transgenic rabbits had faster glucose clearance associated with lower levels of insulin secretion than control rabbits. In addition, there was a significant reduction of body adipose tissue in transgenic rabbits compared with in control rabbits fed an HFD. Scanning electron microscopic examination revealed that adipocytes in transgenic rabbits were predominately small cells. CONCLUSIONS/INTERPRETATION: Our results showed that systemically increased LPL activity improves insulin resistance and reduces adipose accumulation in transgenic rabbits, indicating that systemic elevation of LPL may have potential benefits for the treatment of insulin resistance and obesity.
ESTHER : Kitajima_2004_Diabetologia_47_1202
PubMedSearch : Kitajima_2004_Diabetologia_47_1202
PubMedID: 15221136

Title : Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis - Ichikawa_2004_Lab.Invest_84_715
Author(s) : Ichikawa T , Kitajima S , Liang J , Koike T , Wang X , Sun H , Okazaki M , Morimoto M , Shikama H , Watanabe T , Yamada N , Fan J
Ref : Lab Invest , 84 :715 , 2004
Abstract : Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3-0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (beta-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02-1.04 g/ml) and small LDLs (d=1.04-1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.
ESTHER : Ichikawa_2004_Lab.Invest_84_715
PubMedSearch : Ichikawa_2004_Lab.Invest_84_715
PubMedID: 15122303

Title : Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons - Scheiffele_2000_Cell_101_657
Author(s) : Scheiffele P , Fan J , Choih J , Fetter R , Serafini T
Ref : Cell , 101 :657 , 2000
Abstract : Most neurons form synapses exclusively with other neurons, but little is known about the molecular mechanisms mediating synaptogenesis in the central nervous system. Using an in vitro system, we demonstrate that neuroligin-1 and -2, postsynaptically localized proteins, can trigger the de novo formation of presynaptic structure. Nonneuronal cells engineered to express neuroligins induce morphological and functional presynaptic differentiation in contacting axons. This activity can be inhibited by addition of a soluble version of beta-neurexin, a receptor for neuroligin. Furthermore, addition of soluble beta-neurexin to a coculture of defined pre- and postsynaptic CNS neurons inhibits synaptic vesicle clustering in axons contacting target neurons. Our results suggest that neuroligins are part of the machinery employed during the formation and remodeling of CNS synapses.
ESTHER : Scheiffele_2000_Cell_101_657
PubMedSearch : Scheiffele_2000_Cell_101_657
PubMedID: 10892652
Gene_locus related to this paper: human-NLGN1 , human-NLGN2

Title : Transgenic rabbits expressing human lipoprotein lipase - Araki_2000_Cytotech_33_93
Author(s) : Araki M , Fan J , Challah M , Bensadoun A , Yamada N , Honda K , Watanabe T
Ref : Cytotechnology , 33 :93 , 2000
Abstract : To study the functions of lipoprotein lipase (LPL) in lipid and lipoprotein metabolism and the relationship between LPL and atherosclerosis, we generated transgenic rabbits expressing the human LPL gene. A total of 4045 Japanese whiterabbit embryos were microinjected with a 3.8-kb SalI/HindIII fragment containing the chicken beta-actin promoter, human LPL cDNA and rabbit beta-globin with poly (A) signals, and then transplanted into 116 recipient rabbits. Of the 166 pups born, six pups were transgenic as confirmed by Southern blot analysis. ANorthern blot analysis revealed that human LPL was expressed by a number of tissues including the heart, kidney, adrenal gland and intestine. One transgenic rabbit showed up to 3-foldincreased LPL activity in post-heparin plasma compared to thatin nontransgenic rabbits. Human LPL expression in various tissues of transgenic rabbits was further elucidated by in situ hybridization and immunostaining. Since rabbits are superior to mice as a model of atherosclerosis, this transgenicrabbit model should provide a valuable tool for the study of LPL in lipid metabolism and atherosclerosis.
ESTHER : Araki_2000_Cytotech_33_93
PubMedSearch : Araki_2000_Cytotech_33_93
PubMedID: 19002816

Title : Comparative genomes of Chlamydia pneumoniae and C. trachomatis - Kalman_1999_Nat.Genet_21_385
Author(s) : Kalman S , Mitchell W , Marathe R , Lammel C , Fan J , Hyman RW , Olinger L , Grimwood J , Davis RW , Stephens RS
Ref : Nat Genet , 21 :385 , 1999
Abstract : Chlamydia are obligate intracellular eubacteria that are phylogenetically separated from other bacterial divisions. C. trachomatis and C. pneumoniae are both pathogens of humans but differ in their tissue tropism and spectrum of diseases. C. pneumoniae is a newly recognized species of Chlamydia that is a natural pathogen of humans, and causes pneumonia and bronchitis. In the United States, approximately 10% of pneumonia cases and 5% of bronchitis cases are attributed to C. pneumoniae infection. Chronic disease may result following respiratory-acquired infection, such as reactive airway disease, adult-onset asthma and potentially lung cancer. In addition, C. pneumoniae infection has been associated with atherosclerosis. C. trachomatis infection causes trachoma, an ocular infection that leads to blindness, and sexually transmitted diseases such as pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy and epididymitis. Although relatively little is known about C. trachomatis biology, even less is known concerning C. pneumoniae. Comparison of the C. pneumoniae genome with the C. trachomatis genome will provide an understanding of the common biological processes required for infection and survival in mammalian cells. Genomic differences are implicated in the unique properties that differentiate the two species in disease spectrum. Analysis of the 1,230,230-nt C. pneumoniae genome revealed 214 protein-coding sequences not found in C. trachomatis, most without homologues to other known sequences. Prominent comparative findings include expansion of a novel family of 21 sequence-variant outer-membrane proteins, conservation of a type-III secretion virulence system, three serine/threonine protein kinases and a pair of parologous phospholipase-D-like proteins, additional purine and biotin biosynthetic capability, a homologue for aromatic amino acid (tryptophan) hydroxylase and the loss of tryptophan biosynthesis genes.
ESTHER : Kalman_1999_Nat.Genet_21_385
PubMedSearch : Kalman_1999_Nat.Genet_21_385
PubMedID: 10192388
Gene_locus related to this paper: chlpn-CPN0161 , chlpn-CPN0271 , chlpn-q9k1u7 , chlpn-q9z6x7 , chlpn-q9z6x9 , chlpn-q9z7z1

Title : Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis - Stephens_1998_Science_282_754
Author(s) : Stephens RS , Kalman S , Lammel C , Fan J , Marathe R , Aravind L , Mitchell W , Olinger L , Tatusov RL , Zhao Q , Koonin EV , Davis RW
Ref : Science , 282 :754 , 1998
Abstract : Analysis of the 1,042,519-base pair Chlamydia trachomatis genome revealed unexpected features related to the complex biology of chlamydiae. Although chlamydiae lack many biosynthetic capabilities, they retain functions for performing key steps and interconversions of metabolites obtained from their mammalian host cells. Numerous potential virulence-associated proteins also were characterized. Several eukaryotic chromatin-associated domain proteins were identified, suggesting a eukaryotic-like mechanism for chlamydial nucleoid condensation and decondensation. The phylogenetic mosaic of chlamydial genes, including a large number of genes with phylogenetic origins from eukaryotes, implies a complex evolution for adaptation to obligate intracellular parasitism.
ESTHER : Stephens_1998_Science_282_754
PubMedSearch : Stephens_1998_Science_282_754
PubMedID: 9784136
Gene_locus related to this paper: chltr-CT073 , chltr-CT136 , chltr-CT149 , chltr-CT206

Title : Hepatic lipase - Fan_1998_J.Atheroscler.Thromb_5_41
Author(s) : Fan J , Watanabe T
Ref : J Atheroscler Thromb , 5 :41 , 1998
Abstract : Hepatic lipase (HL) is an important enzyme that is involved in the metabolism of chylomicrons, intermediate density lipoproteins, and high density lipoproteins. HL may affect the liver uptake of remnant lipoproteins by modifying their compositions. HL also participates in the reverse cholesterol transport, thereby influencing the process of atherosclerosis. Several new functions of HL have recently been revealed. In this article, we review some of the recent progress based on studies using transgenic animals, with an emphasis on HL functions in remnant metabolism and atherosclerosis.
ESTHER : Fan_1998_J.Atheroscler.Thromb_5_41
PubMedSearch : Fan_1998_J.Atheroscler.Thromb_5_41
PubMedID: 10077457

Title : Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins - Fan_1994_Proc.Natl.Acad.Sci.U.S.A_91_8724
Author(s) : Fan J , Wang J , Bensadoun A , Lauer SJ , Dang Q , Mahley RW , Taylor JM
Ref : Proceedings of the National Academy of Sciences of the United States of America , 91 :8724 , 1994
Abstract : To elucidate the precise metabolic roles of hepatic lipase (HL), a human HL cDNA in a liver-specific expression vector was used to generate transgenic lines in the rabbit, an animal that normally expresses low levels of this enzyme. HL was detected in the plasma of all rabbits only after the administration of heparin; HL activity in transgenic rabbits was found at levels up to 80-fold greater than that in nontransgenic littermates. This increase in enzyme activity was associated with as much as a 5-fold decrease in total plasma cholesterol levels. Expression of the transgene resulted in a dramatic reduction in the level of large high density lipoproteins (HDL1 and HDL2) as well as dense HDL3. A reduction in the quantity of intermediate density lipoproteins (IDL) was also observed. These results demonstrate that HL functions in the metabolism of HDL and IDL, thereby playing a key role in plasma cholesterol homeostasis.
ESTHER : Fan_1994_Proc.Natl.Acad.Sci.U.S.A_91_8724
PubMedSearch : Fan_1994_Proc.Natl.Acad.Sci.U.S.A_91_8724
PubMedID: 8078949