Du L

References (30)

Title : Design, Synthesis, and Bioactivities of N-Heterocyclic Ureas as Strigolactone Response Antagonists against Parasitic-Weed Seed Germination - Du_2024_J.Agric.Food.Chem__
Author(s) : Du L , Li X , Ding Y , Ma D , Yu C , Duan L
Ref : Journal of Agricultural and Food Chemistry , : , 2024
Abstract : The pernicious parasitism exhibited by root parasitic weeds such as Orobanche and Striga poses substantial peril to agricultural productivity and global food security. This deleterious phenomenon hinges upon the targeted induction of the signaling molecule strigolactones (SLs). Consequently, the identification of prospective SL antagonists holds significant promise in the realm of mitigating the infection of these pernicious weeds. In this study, we synthesized and characterized D12 based on a potent SL antagonist KK094. In vivo assay results demonstrated that D12 remarkably impedes the germination of Phelipanche aegyptiaca and Striga asiatica seeds, while also alleviating the inhibitory consequence of the SL analogue GR24 on hypocotyl elongation in Arabidopsis thaliana. The docking study and ITC assay indicated that D12 can interact strongly with the SL receptor protein, which may interfere with the binding of SL to the receptor protein as a result. In addition, the results of crop safety assessment tests showed that D12 had no adverse effects on rice seed germination and seedling growth and development. The outcomes obtained from the present study suggested that D12 exhibited promise as a prospective antagonist of SL receptors, thereby displaying substantial efficacy in impeding the seed germination process of root parasitic weeds, providing a promising basis for rational design and development of further Striga-specific herbicides.
ESTHER : Du_2024_J.Agric.Food.Chem__
PubMedSearch : Du_2024_J.Agric.Food.Chem__
PubMedID: 38593208

Title : Glutathione and Esterase Dual-Responsive Smart Nano-drug Delivery System Capable of Breaking the Redox Balance for Enhanced Tumor Therapy - Shen_2023_ACS.Appl.Mater.Interfaces__
Author(s) : Shen P , Zhang X , Ding N , Zhou Y , Wu C , Xing C , Zeng L , Du L , Yuan J , Kang Y
Ref : ACS Appl Mater Interfaces , : , 2023
Abstract : Conventional chemotherapy usually fails to achieve its intended effect because of the poor water solubility, poor tumor selectivity, and low tumor accumulation of chemotherapy drugs. The systemic toxicity of chemotherapy agents is also a problem that cannot be ignored. It is expected that smart nano-drug delivery systems that are able to respond to tumor microenvironments will provide better therapeutic outcomes with decreased side effects of chemotherapeutics. Nano-drug delivery systems capable of breaking the redox balance can also increase the sensitivity of tumor cells to chemotherapeutics. In this study, using polymer-containing disulfide bonds, ester bonds, and d-alpha-tocopherol polyethylene glycol succinate (TPGS), which can amplify reactive oxygen species (ROS) in tumor cells, we have successfully prepared a smart glutathione (GSH) and esterase dual-responsive nano-drug delivery system (DTX@PAMBE-SS-TPGS NPs) with the ability to deplete GSH as well as amplify ROS and effectively release an encapsulated chemotherapy drug (DTX) in tumor cells. The potential of DTX@PAMBE-SS-TPGS NPs for enhanced antitumor effects was thoroughly evaluated using in vitro as well as in vivo experiments. Our research offers a promising strategy for maximizing the efficacy of tumor therapy.
ESTHER : Shen_2023_ACS.Appl.Mater.Interfaces__
PubMedSearch : Shen_2023_ACS.Appl.Mater.Interfaces__
PubMedID: 37083309

Title : Research and progress of focused ultrasound in the treatment of Alzheimer's disease - Ma_2023_Front.Neurol_14_1323386
Author(s) : Ma X , Li T , Du L , Han T
Ref : Front Neurol , 14 :1323386 , 2023
Abstract : Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability of daily life as the cardinal symptoms, influencing the life quality of patients severely. There are currently approximately 46 million people living with Alzheimer's disease worldwide, and the number is expected to triple by 2050, which will pose a huge challenge for healthcare. At present, the Food and Drug Administration of the United States has approved five main drugs for the clinical treatment of Alzheimer's disease, which are cholinesterase inhibitors tacrine, galantamine, capalatine and donepezil, and N-methyl-d-aspartate receptor antagonist memantine, although these drugs have shown good efficacy in clinical trials, the actual clinical effect is less effective due to the existence of blood brain barrier. With the continuous development of ultrasound technology in recent years, focused ultrasound, as a non-invasive treatment technique, may target ultrasound energy to the deep brain for treatment without damaging the surrounding tissue. For the past few years, some studies could use focused ultrasound combined with microvesicles to induce blood brain barrier opening and targeted drug delivery to treat Alzheimer's disease, providing new opportunities for the treatment of Alzheimer's disease. This article reviews the application research and progress of focused ultrasound in the treatment of Alzheimer's disease, in order to provide new directions and ideas for the treatment of Alzheimer's disease.
ESTHER : Ma_2023_Front.Neurol_14_1323386
PubMedSearch : Ma_2023_Front.Neurol_14_1323386
PubMedID: 38187144

Title : Insecticidal Activity of a Component, (-)-4-Terpineol, Isolated from the Essential Oil of Artemisia lavandulaefolia DC. against Plutella xylostella (L.) - Huang_2022_Insects_13_
Author(s) : Huang X , Du L , Liu T , Ma R , Liu X , Yuan H , Liu S
Ref : Insects , 13 : , 2022
Abstract : Plutella xylostella (L.) is one of the most serious pests of cruciferous vegetables. Our previous work demonstrated that the essential oil of Artemisia lavandulaefolia DC. exhibits promising insecticidal activities against P. xylostella. This study further characterizes the key components that are responsible for the insecticidal effect. In total, 47 compounds (96.52% of the total compounds) were identified from the total oil using GC-MS, and the major compounds were eucalyptol (21.57%), D(+)-camphor (17.33%), (-)-4-terpineol (9.96%) and caryophyllene oxide (10.96%). Among them, (-)-4-terpineol showed significantly larvicidal and fumigant activities against P. xylostella. The LD(50) of (-)-4-terpineol was 43.15 mg/mL at 12 h and 31.22 mg/mL at 24 h for 3rd instar larvae, and the LC(50) for adults was 8.34 mg/mL at 12 h and 7.35 mg/mL at 24 h. In addition, the adults treated with (-)-4-terpineol showed varying degrees of inhibitory activity toward glutathione S-transferase, catalase, acetylcholinesterase and Na(+)/K(+)-ATPase at different post-treatment intervals and concentrations. The results indicate that (-)-4-terpineol has promising insecticidal activities against P. xylostella, and it has good inhibitory effects on the four enzymes of P. xylostella adults.
ESTHER : Huang_2022_Insects_13_
PubMedSearch : Huang_2022_Insects_13_
PubMedID: 36555036

Title : Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry - Wan_2020_J.Virol_94_
Author(s) : Wan Y , Shang J , Sun S , Tai W , Chen J , Geng Q , He L , Chen Y , Wu J , Shi Z , Zhou Y , Du L , Li F
Ref : J Virol , 94 : , 2020
Abstract : Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.
ESTHER : Wan_2020_J.Virol_94_
PubMedSearch : Wan_2020_J.Virol_94_
PubMedID: 31826992

Title : Functional characterization of Vib-PT, an aromatic prenyltransferase involved in the biosynthesis of vibralactone from Stereum vibrans - Bai_2020_Appl.Environ.Microbiol__
Author(s) : Bai N , Li GH , Luo SL , Du L , Hu QY , Xu HK , Zhang KQ , Zhao PJ
Ref : Applied Environmental Microbiology , : , 2020
Abstract : Vibralactone, a hybrid compound derived from phenols and a prenyl group, is a strong pancreatic lipase inhibitor with a rare fused bicyclic beta-lactone skeleton. Recently, researcher reported a vibralactone derivative (compound C1) that caused inhibition of pancreatic lipase with a half-maximal inhibitory concentration of 14 nM determined by structure-based optimization, suggesting a potential candidate as a new anti-obesity treatment. In the present study, we sought to identify the main gene encoding prenyltransferase in Stereum vibrans, which is responsible for the prenylation of phenol leading to vibralactone synthesis. Two RNA silencing transformants of identified gene (vib-PT) were obtained through Agrobacterium tumefaciens-mediated transformation. Compared to wild-type strains, the transformants showed a decrease in vib-PT expression ranging from 11.0% to 56.0% at 5, 10, and 15 days in reverse transcription-quantitative PCR (RT-qPCR) analysis and along with a reduction in primary vibralactone production of 37% to 64% at 15 and 21 days, respectively, as determined using ultra-high-performance liquid chromatography mass spectrometry analysis. A soluble and enzymatically active fusion Vib-PT protein was obtained by expressing vib-PT in Escherichia coli, and the enzyme's optimal reaction conditions and catalytic efficiency (Km /Kcat ) were determined. In vitro experiments established that Vib-PT catalyzed the C-prenylation at C-3 of 4-hydroxy-benzaldehyde and the O-prenylation at the 4-hydroxy of 4-hydroxy-benzenemethanol in the presence of dimethylallyl diphosphate. Moreover, Vib-PT shows promiscuity towards aromatic compounds and prenyl donors. .IMPORTANCE Vibralactone is a lead compound with a novel skeleton structure that shows strong inhibitory activity against pancreatic lipase. Vibralactone is not encoded by the genome directly, but is rather synthesized from phenol, followed by prenylation and other enzyme reactions. Here, we used an RNA silencing approach to identify and characterize a prenyltransferase in a basidiomycetes species that is responsible for the synthesis of vibralactone. The identified gene, vib-PT, was expressed in E. coli to obtain a soluble and enzymatically active fusion Vib-PT protein. In vitro characterization of the enzyme demonstrated the catalytic mechanism of prenylation and broad substrate range for different aromatic acceptors and prenyl donors. These characteristics highlight the possibility of Vib-PT to generate prenylated derivatives of aromatics and other compounds as improved bioactive agents or potential prodrugs.
ESTHER : Bai_2020_Appl.Environ.Microbiol__
PubMedSearch : Bai_2020_Appl.Environ.Microbiol__
PubMedID: 32144102

Title : Compartmentalized biosynthesis of mycophenolic acid - Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305
Author(s) : Zhang W , Du L , Qu Z , Zhang X , Li F , Li Z , Qi F , Wang X , Jiang Y , Men P , Sun J , Cao S , Geng C , Wan X , Liu C , Li S
Ref : Proc Natl Acad Sci U S A , 116 :13305 , 2019
Abstract : Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and beta-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB' as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the endoplasmic reticulum-bound oxygenase MpaB' and P450-hydrolase fusion enzyme MpaDE', and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH'. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal beta-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis.
ESTHER : Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305
PubMedSearch : Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305
PubMedID: 31209052
Gene_locus related to this paper: penbr-mpaH , penbr-mpac

Title : Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV - Jiang_2018_Emerg.Microbes.Infect_7_77
Author(s) : Jiang Y , Zhao G , Song N , Li P , Chen Y , Guo Y , Li J , Du L , Jiang S , Guo R , Sun S , Zhou Y
Ref : Emerg Microbes Infect , 7 :77 , 2018
Abstract : The pathogenesis of highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) remains poorly understood. In a previous study, we established an hDPP4-transgenic (hDPP4-Tg) mouse model in which MERS-CoV infection causes severe acute respiratory failure and high mortality accompanied by an elevated secretion of cytokines and chemokines. Since excessive complement activation is an important factor that contributes to acute lung injury after viral infection, in this study, we investigated the role of complement in MERS-CoV-induced lung damage. Our study showed that complement was excessively activated in MERS-CoV-infected hDPP4-Tg mice through observations of increased concentrations of the C5a and C5b-9 complement activation products in sera and lung tissues, respectively. Interestingly, blocking C5a production by targeting its receptor, C5aR, alleviated lung and spleen tissue damage and reduced inflammatory responses. More importantly, anti-C5aR antibody treatment led to decreased viral replication in lung tissues. Furthermore, compared with the sham treatment control, apoptosis of splenic cells was less pronounced in the splenic white pulp of treated mice, and greater number of proliferating splenic cells, particularly in the red pulp, was observed. These data indicate that (1) dysregulated host immune responses contribute to the severe outcome of MERS; (2) excessive complement activation, triggered by MERS-CoV infection, promote such dysregulation; and (3) blockade of the C5a-C5aR axis lead to the decreased tissue damage induced by MERS-CoV infection, as manifested by reduced apoptosis and T cell regeneration in the spleen. Therefore, the results of this study suggest a new strategy for clinical intervention and adjunctive treatment in MERS-CoV cases.
ESTHER : Jiang_2018_Emerg.Microbes.Infect_7_77
PubMedSearch : Jiang_2018_Emerg.Microbes.Infect_7_77
PubMedID: 29691378

Title : Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants - Tai_2017_J.Virol_91_
Author(s) : Tai W , Wang Y , Fett CA , Zhao G , Li F , Perlman S , Jiang S , Zhou Y , Du L
Ref : J Virol , 91 : , 2017
Abstract : Middle East respiratory syndrome coronavirus (MERS-CoV) binds to cellular receptor dipeptidyl peptidase 4 (DPP4) via the spike (S) protein receptor-binding domain (RBD). The RBD contains critical neutralizing epitopes and serves as an important vaccine target. Since RBD mutations occur in different MERS-CoV isolates and antibody escape mutants, cross-neutralization of divergent MERS-CoV strains by RBD-induced antibodies remains unknown. Here, we constructed four recombinant RBD (rRBD) proteins with single or multiple mutations detected in representative human MERS-CoV strains from the 2012, 2013, 2014, and 2015 outbreaks, respectively, and one rRBD protein with multiple changes derived from camel MERS-CoV strains. Like the RBD of prototype EMC2012 (EMC-RBD), all five RBDs maintained good antigenicity and functionality, the ability to bind RBD-specific neutralizing monoclonal antibodies (MAbs) and the DPP4 receptor, and high immunogenicity, able to elicit S-specific antibodies. They induced potent neutralizing antibodies cross-neutralizing 17 MERS pseudoviruses expressing S proteins of representative human and camel MERS-CoV strains identified during the 2012-2015 outbreaks, 5 MAb escape MERS-CoV mutants, and 2 live human MERS-CoV strains. We then constructed two RBDs mutated in multiple key residues in the receptor-binding motif (RBM) of RBD and demonstrated their strong cross-reactivity with anti-EMC-RBD antibodies. These RBD mutants with diminished DPP4 binding also led to virus attenuation, suggesting that immunoevasion after RBD immunization is accompanied by loss of viral fitness. Therefore, this study demonstrates that MERS-CoV RBD is an important vaccine target able to induce highly potent and broad-spectrum neutralizing antibodies against infection by divergent circulating human and camel MERS-CoV strains. IMPORTANCE: MERS-CoV was first identified in June 2012 and has since spread in humans and camels. Mutations in its spike (S) protein receptor-binding domain (RBD), a key vaccine target, have been identified, raising concerns over the efficacy of RBD-based MERS vaccines against circulating human and camel MERS-CoV strains. Here, we constructed five vaccine candidates, designated 2012-RBD, 2013-RBD, 2014-RBD, 2015-RBD, and Camel-RBD, containing single or multiple mutations in the RBD of representative human and camel MERS-CoV strains during the 2012-2015 outbreaks. These RBD-based vaccine candidates maintained good functionality, antigenicity, and immunogenicity, and they induced strong cross-neutralizing antibodies against infection by divergent pseudotyped and live MERS-CoV strains, as well as antibody escape MERS-CoV mutants. This study provides impetus for further development of a safe, highly effective, and broad-spectrum RBD-based subunit vaccine to prevent MERS-CoV infection.
ESTHER : Tai_2017_J.Virol_91_
PubMedSearch : Tai_2017_J.Virol_91_
PubMedID: 27795425

Title : MERS-CoV spike protein: a key target for antivirals - Du_2017_Expert.Opin.Ther.Targets_21_131
Author(s) : Du L , Yang Y , Zhou Y , Lu L , Li F , Jiang S
Ref : Expert Opin Ther Targets , 21 :131 , 2017
Abstract : INTRODUCTION: The continual Middle East respiratory syndrome (MERS) threat highlights the importance of developing effective antiviral therapeutics to prevent and treat MERS coronavirus (MERS-CoV) infection. A surface spike (S) protein guides MERS-CoV entry into host cells by binding to cellular receptor dipeptidyl peptidase-4 (DPP4), followed by fusion between virus and host cell membranes. MERS-CoV S protein represents a key target for developing therapeutics to block viral entry and inhibit membrane fusion. Areas covered: This review illustrates MERS-CoV S protein's structure and function, particularly S1 receptor-binding domain (RBD) and S2 heptad repeat 1 (HR1) as therapeutic targets, and summarizes current advancement on developing anti-MERS-CoV therapeutics, focusing on neutralizing monoclonal antibodies (mAbs) and antiviral peptides. Expert opinion: No anti-MERS-CoV therapeutic is approved for human use. Several S-targeting neutralizing mAbs and peptides have demonstrated efficacy against MERS-CoV infection, providing feasibility for development. Generally, human neutralizing mAbs targeting RBD are more potent than those targeting other regions of S protein. However, emergence of escape mutant viruses and mAb's limitations make it necessary for combining neutralizing mAbs recognizing different neutralizing epitopes and engineering them with improved efficacy and reduced cost. Optimization of the peptide sequences is expected to produce next-generation anti-MERS-CoV peptides with improved potency.
ESTHER : Du_2017_Expert.Opin.Ther.Targets_21_131
PubMedSearch : Du_2017_Expert.Opin.Ther.Targets_21_131
PubMedID: 27936982

Title : A recombinant receptor-binding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection - Tai_2016_Virology_499_375
Author(s) : Tai W , Zhao G , Sun S , Guo Y , Wang Y , Tao X , Tseng CK , Li F , Jiang S , Du L , Zhou Y
Ref : Virology , 499 :375 , 2016
Abstract : Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) was first identified in 2012, and it continues to threaten human health worldwide. No MERS vaccines are licensed for human use, reinforcing the urgency to develop safe and efficacious vaccines to prevent MERS. MERS-CoV spike protein forms a trimer, and its receptor-binding domain (RBD) serves as a vaccine target. Nevertheless, the protective efficacy of RBD in its native trimeric form has never been evaluated. In this study, a trimeric protein, RBD-Fd, was generated by fusing RBD with foldon trimerization motif. It bound strongly to the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), and elicited robust RBD-specific neutralizing antibodies in mice, maintaining long-term neutralizing activity against MERS-CoV infection. RBD-Fd potently protected hDPP4 transgenic mice from lethal MERS-CoV challenge. These results suggest that MERS-CoV RBD in its trimeric form maintains native conformation and induces protective neutralizing antibodies, making it a candidate for further therapeutic development.
ESTHER : Tai_2016_Virology_499_375
PubMedSearch : Tai_2016_Virology_499_375
PubMedID: 27750111

Title : Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease - Tao_2016_J.Virol_90_57
Author(s) : Tao X , Garron T , Agrawal AS , Algaissi A , Peng BH , Wakamiya M , Chan TS , Lu L , Du L , Jiang S , Couch RB , Tseng CT
Ref : J Virol , 90 :57 , 2016
Abstract : UNLABELLED: Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID50) and lethal dose (LD50) of virus were estimated to be <1 and 10 TCID50 of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID50/LD50 determinations, and all were fully immune to challenge with 100 LD50 of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD50 of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10(5) LD50 of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research. IMPORTANCE: Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing hCD26/DPP4 viral receptor uniformly succumbed to death within 6 days, making it difficult to evaluate host responses to infection and disease. We further characterized this model by determining both the ID50 and the LD50 of MERS-CoV in order to establish both an infection model and a lethal model for MERS and followed this by investigating the antibody responses and immunity of the mice that survived MERS-CoV infection. Using the estimated LD50 and ID50 data, we dissected the kinetics of viral tissue distribution and pathology in mice challenged with 10 LD50 of virus and utilized the model for preclinical evaluation of a vaccine and drug for treatment of MERS-CoV infection. This further-characterized transgenic mouse model will be useful for advancing MERS research.
ESTHER : Tao_2016_J.Virol_90_57
PubMedSearch : Tao_2016_J.Virol_90_57
PubMedID: 26446606

Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema - Chen_2016_J.Med.Chem_59_2674
Author(s) : Chen X , Wang K , Xu W , Ma Q , Chen M , Du L , Mo M , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 59 :2674 , 2016
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
ESTHER : Chen_2016_J.Med.Chem_59_2674
PubMedSearch : Chen_2016_J.Med.Chem_59_2674
PubMedID: 26927682
Gene_locus related to this paper: human-PLA2G7

Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors - Chen_2015_J.Med.Chem_58_8529
Author(s) : Chen X , Xu W , Wang K , Mo M , Zhang W , Du L , Yuan X , Xu Y , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 58 :8529 , 2015
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
ESTHER : Chen_2015_J.Med.Chem_58_8529
PubMedSearch : Chen_2015_J.Med.Chem_58_8529
PubMedID: 26479945
Gene_locus related to this paper: human-PLA2G7

Title : Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus - Yang_2015_J.Virol_89_9119
Author(s) : Yang Y , Liu C , Du L , Jiang S , Shi Z , Baric RS , Li F
Ref : J Virol , 89 :9119 , 2015
Abstract : To understand how Middle East respiratory syndrome coronavirus (MERS-CoV) transmitted from bats to humans, we compared the virus surface spikes of MERS-CoV and a related bat coronavirus, HKU4. Although HKU4 spike cannot mediate viral entry into human cells, two mutations enabled it to do so by allowing it to be activated by human proteases. These mutations are present in MERS-CoV spike, explaining why MERS-CoV infects human cells. These mutations therefore played critical roles in the bat-to-human transmission of MERS-CoV, either directly or through intermediate hosts.
ESTHER : Yang_2015_J.Virol_89_9119
PubMedSearch : Yang_2015_J.Virol_89_9119
PubMedID: 26063432

Title : Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus - Zhao_2015_PLoS.One_10_e0145561
Author(s) : Zhao G , Jiang Y , Qiu H , Gao T , Zeng Y , Guo Y , Yu H , Li J , Kou Z , Du L , Tan W , Jiang S , Sun S , Zhou Y
Ref : PLoS ONE , 10 :e0145561 , 2015
Abstract : The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.
ESTHER : Zhao_2015_PLoS.One_10_e0145561
PubMedSearch : Zhao_2015_PLoS.One_10_e0145561
PubMedID: 26701103

Title : Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus - Yang_2014_Proc.Natl.Acad.Sci.U.S.A_111_12516
Author(s) : Yang Y , Du L , Liu C , Wang L , Ma C , Tang J , Baric RS , Jiang S , Li F
Ref : Proc Natl Acad Sci U S A , 111 :12516 , 2014
Abstract : Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes approximately 36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5. We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells. Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes' capability to adapt to human cells for cross-species transmissions.
ESTHER : Yang_2014_Proc.Natl.Acad.Sci.U.S.A_111_12516
PubMedSearch : Yang_2014_Proc.Natl.Acad.Sci.U.S.A_111_12516
PubMedID: 25114257

Title : Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development - Du_2013_J.Virol_87_9939
Author(s) : Du L , Zhao G , Kou Z , Ma C , Sun S , Poon VK , Lu L , Wang L , Debnath AK , Zheng BJ , Zhou Y , Jiang S
Ref : J Virol , 87 :9939 , 2013
Abstract : A novel human Middle East respiratory syndrome coronavirus (MERS-CoV) caused outbreaks of severe acute respiratory syndrome (SARS)-like illness with a high mortality rate, raising concerns of its pandemic potential. Dipeptidyl peptidase-4 (DPP4) was recently identified as its receptor. Here we showed that residues 377 to 662 in the S protein of MERS-CoV specifically bound to DPP4-expressing cells and soluble DPP4 protein and induced significant neutralizing antibody responses, suggesting that this region contains the receptor-binding domain (RBD), which has a potential to be developed as a MERS-CoV vaccine.
ESTHER : Du_2013_J.Virol_87_9939
PubMedSearch : Du_2013_J.Virol_87_9939
PubMedID: 23824801

Title : A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines - Du_2013_PLoS.One_8_e81587
Author(s) : Du L , Kou Z , Ma C , Tao X , Wang L , Zhao G , Chen Y , Yu F , Tseng CT , Zhou Y , Jiang S
Ref : PLoS ONE , 8 :e81587 , 2013
Abstract : An emerging respiratory infectious disease with high mortality, Middle East respiratory syndrome (MERS), is caused by a novel coronavirus (MERS-CoV). It was first reported in 2012 in Saudi Arabia and has now spread to eight countries. Development of effective therapeutics and vaccines is crucial to save lives and halt the spread of MERS-CoV. Here, we show that a recombinant protein containing a 212-amino acid fragment (residues 377-588) in the truncated receptor-binding domain (RBD: residues 367-606) of MERS-CoV spike (S) protein fused with human IgG Fc fragment (S377-588-Fc) is highly expressed in the culture supernatant of transfected 293T cells. The purified S377-588-Fc protein efficiently binds to dipeptidyl peptidase 4 (DPP4), the receptor of MERS-CoV, and potently inhibited MERS-CoV infection, suggesting its potential to be further developed as a therapeutic modality for treating MERS-CoV infection and saving the patients' lives. The recombinant S377-588-Fc is able to induce in the vaccinated mice strong MERS-CoV S-specific antibodies, which blocks the binding of RBD to DPP4 receptor and effectively neutralizes MERS-CoV infection. These findings indicate that this truncated RBD protein shows promise for further development as an effective and safe vaccine for the prevention of MERS-CoV infection.
ESTHER : Du_2013_PLoS.One_8_e81587
PubMedSearch : Du_2013_PLoS.One_8_e81587
PubMedID: 24324708

Title : Elucidating the biosynthetic pathway for vibralactone: a pancreatic lipase inhibitor with a fused bicyclic beta-lactone -
Author(s) : Zhao PJ , Yang YL , Du L , Liu JK , Zeng Y
Ref : Angew Chem Int Ed Engl , 52 :2298 , 2013
PubMedID: 23339115

Title : Putative conformations of the receptor-binding domain in S protein of hCoV-EMC in complex with its receptor dipeptidyl peptidase-4 -
Author(s) : Jiang S , Lu L , Du L , Debnath AK
Ref : J Infect , 67 :156 , 2013
PubMedID: 23603488

Title : Metabonomics analysis of urine and plasma from rats given long-term and low-dose dimethoate by ultra-performance liquid chromatography-mass spectrometry - Feng_2012_Chem.Biol.Interact_199_143
Author(s) : Feng Z , Sun X , Yang J , Hao D , Du L , Wang H , Xu W , Zhao X , Sun C
Ref : Chemico-Biological Interactions , 199 :143 , 2012
Abstract : This study assessed the effects of long-term low-dose dimethoate administration to rats by ultra-performance liquid chromatography-mass spectrometry UPLC-MS Dimethoate 0.04 0.12 and 0.36mg/kg body weight/day was administered daily to male Wistar rats through their drinking water for 24weeks Significant changes in serum clinical chemistry were observed in the middle and high-dose groups UPLC-MS revealed evident separate clustering among the different dose groups using global metabolic profiling by supervised partial least squares-discriminant analysis Metabonomic analysis showed alterations in a number of metabolites 12 from urine and 13 from plasma such as l-tyrosine dimethylthiophosphate DMTP dimethyldithiophosphate DMDTP citric acid uric acid suberic acid glycylproline allantoin isovalerylglutamic acid and kinds of lipids The results suggest that long-term low-dose exposure to dimethoate can cause disturbances in liver function antioxidant and nervous systems as well as the metabolisms of lipids glucose fatty acids amino acids and collagen in rats DMTP and DMDTP which had the most significant changes among all other studied biomarkers were considered as early sensitive biomarkers of exposure to dimethoate The other aforementioned proposed toxicity biomarkers in metabonomic analysis may be useful in the risk assessment of the toxic effects of dimethoate Metabonomics as a systems toxicology approach was able to provide comprehensive information on the dynamic process of dimethoate induced toxicity In addition the results indicate that metabonomic approach could detect systemic toxic effects at an earlier stage compared to clinical chemistry The combination of metabonomics and clinical chemistry made the toxicity of dimethoate on rats more comprehensive.
ESTHER : Feng_2012_Chem.Biol.Interact_199_143
PubMedSearch : Feng_2012_Chem.Biol.Interact_199_143
PubMedID: 22884955

Title : Genomic characterization of the Bacillus cereus sensu lato species: backdrop to the evolution of Bacillus anthracis - Zwick_2012_Genome.Res_22_1512
Author(s) : Zwick ME , Joseph SJ , Didelot X , Chen PE , Bishop-Lilly KA , Stewart AC , Willner K , Nolan N , Lentz S , Thomason MK , Sozhamannan S , Mateczun AJ , Du L , Read TD
Ref : Genome Res , 22 :1512 , 2012
Abstract : The key genes required for Bacillus anthracis to cause anthrax have been acquired recently by horizontal gene transfer. To understand the genetic background for the evolution of B. anthracis virulence, we obtained high-redundancy genome sequences of 45 strains of the Bacillus cereus sensu lato (s.l.) species that were chosen for their genetic diversity within the species based on the existing multilocus sequence typing scheme. From the resulting data, we called more than 324,000 new genes representing more than 12,333 new gene families for this group. The core genome size for the B. cereus s.l. group was approximately 1750 genes, with another 2150 genes found in almost every genome constituting the extended core. There was a paucity of genes specific and conserved in any clade. We found no evidence of recent large-scale gene loss in B. anthracis or for unusual accumulation of nonsynonymous DNA substitutions in the chromosome; however, several B. cereus genomes isolated from soil and not previously associated with human disease were degraded to various degrees. Although B. anthracis has undergone an ecological shift within the species, its chromosome does not appear to be exceptional on a macroscopic scale compared with close relatives.
ESTHER : Zwick_2012_Genome.Res_22_1512
PubMedSearch : Zwick_2012_Genome.Res_22_1512
PubMedID: 22645259
Gene_locus related to this paper: bacan-BA2392 , bacan-BA2607 , bacan-BA3703 , bacan-DHBF , bacce-c2zyv1 , bacce-BC0192 , bacce-BC1677 , bacce-BC1788 , bacce-BC2083 , bacce-BC2141 , bacce-BC2171 , bacce-BC2337 , bacce-BC2456 , bacce-BC2458 , bacce-BC3133 , bacce-BC3277 , bacce-BC4102 , bacce-BC4730 , bacce-BC4862 , bacce-BC5130 , bacce-BCE3188 , bacce-lipP , bacce-PHAC , bacce-q20cj0 , bacce-q72yu1 , baccr-pepx , bacmy-c3aae7 , bacwk-a9vqm8 , bacwk-a9vtw7 , bacce-c2w7k9 , bacce-c2wbn9 , bacce-c2wmc3 , bacce-c2xbm4 , bacmy-c3al45 , bacmy-c3b7j4 , 9baci-c3bv77 , bacce-c2qdt4

Title : The genome of melon (Cucumis melo L.) - Garcia-Mas_2012_Proc.Natl.Acad.Sci.U.S.A_109_11872
Author(s) : Garcia-Mas J , Benjak A , Sanseverino W , Bourgeois M , Mir G , Gonzalez VM , Henaff E , Camara F , Cozzuto L , Lowy E , Alioto T , Capella-Gutierrez S , Blanca J , Canizares J , Ziarsolo P , Gonzalez-Ibeas D , Rodriguez-Moreno L , Droege M , Du L , Alvarez-Tejado M , Lorente-Galdos B , Mele M , Yang L , Weng Y , Navarro A , Marques-Bonet T , Aranda MA , Nuez F , Pico B , Gabaldon T , Roma G , Guigo R , Casacuberta JM , Arus P , Puigdomenech P
Ref : Proc Natl Acad Sci U S A , 109 :11872 , 2012
Abstract : We report the genome sequence of melon, an important horticultural crop worldwide. We assembled 375 Mb of the double-haploid line DHL92, representing 83.3% of the estimated melon genome. We predicted 27,427 protein-coding genes, which we analyzed by reconstructing 22,218 phylogenetic trees, allowing mapping of the orthology and paralogy relationships of sequenced plant genomes. We observed the absence of recent whole-genome duplications in the melon lineage since the ancient eudicot triplication, and our data suggest that transposon amplification may in part explain the increased size of the melon genome compared with the close relative cucumber. A low number of nucleotide-binding site-leucine-rich repeat disease resistance genes were annotated, suggesting the existence of specific defense mechanisms in this species. The DHL92 genome was compared with that of its parental lines allowing the quantification of sequence variability in the species. The use of the genome sequence in future investigations will facilitate the understanding of evolution of cucurbits and the improvement of breeding strategies.
ESTHER : Garcia-Mas_2012_Proc.Natl.Acad.Sci.U.S.A_109_11872
PubMedSearch : Garcia-Mas_2012_Proc.Natl.Acad.Sci.U.S.A_109_11872
PubMedID: 22753475
Gene_locus related to this paper: cucme-a0a1s3cge4 , cucme-a0a1s3ct47 , cucme-a0a1s3bcl7 , cucsa-a0a0a0m228 , cucme-a0a1s3bnl4 , cucme-a0a1s3b1c9 , cucme-a0a1s3b1d4 , cucme-a0a1s3buy0 , cucme-a0a1s3bva9 , cucme-a0a1s3c6j4 , cucme-a0a1s3cky2 , cucme-a0a1s3clz8 , cucme-a0a1s3buy6 , cucme-a0a1s3bp26

Title : The genetic basis of laboratory adaptation in Caulobacter crescentus - Marks_2010_J.Bacteriol_192_3678
Author(s) : Marks ME , Castro-Rojas CM , Teiling C , Du L , Kapatral V , Walunas TL , Crosson S
Ref : Journal of Bacteriology , 192 :3678 , 2010
Abstract : The dimorphic bacterium Caulobacter crescentus has evolved marked phenotypic changes during its 50-year history of culture in the laboratory environment, providing an excellent system for the study of natural selection and phenotypic microevolution in prokaryotes. Combining whole-genome sequencing with classical molecular genetic tools, we have comprehensively mapped a set of polymorphisms underlying multiple derived phenotypes, several of which arose independently in separate strain lineages. The genetic basis of phenotypic differences in growth rate, mucoidy, adhesion, sedimentation, phage susceptibility, and stationary-phase survival between C. crescentus strain CB15 and its derivative NA1000 is determined by coding, regulatory, and insertion/deletion polymorphisms at five chromosomal loci. This study evidences multiple genetic mechanisms of bacterial evolution as driven by selection for growth and survival in a new selective environment and identifies a common polymorphic locus, zwf, between lab-adapted C. crescentus and clinical isolates of Pseudomonas aeruginosa that have adapted to a human host during chronic infection.
ESTHER : Marks_2010_J.Bacteriol_192_3678
PubMedSearch : Marks_2010_J.Bacteriol_192_3678
PubMedID: 20472802
Gene_locus related to this paper: caucn-b8h0s6 , caucn-b8h5p7 , caucn-b8h5w4 , caucr-CC0341 , caucr-CC0352 , caucr-CC0477 , caucr-CC0525 , caucr-CC0552 , caucr-CC0936 , caucr-CC1175 , caucr-CC1227 , caucr-CC1229 , caucr-CC1734 , caucr-CC1986 , caucr-CC2154 , caucr-CC2185 , caucr-CC2253 , caucr-CC2298 , caucr-CC2313 , caucr-CC2411 , caucr-CC2515 , caucr-CC2797 , caucr-CC3039 , caucr-CC3091 , caucr-CC3346 , caucr-CC3418 , caucr-CC3441 , caucr-CC3442 , caucr-CC3687 , caucr-CC3688 , caucr-CC3723 , caucr-PHAZ

Title : Genome sequence of Brucella abortus vaccine strain S19 compared to virulent strains yields candidate virulence genes - Crasta_2008_PLoS.One_3_e2193
Author(s) : Crasta OR , Folkerts O , Fei Z , Mane SP , Evans C , Martino-Catt S , Bricker B , Yu G , Du L , Sobral BW
Ref : PLoS ONE , 3 :e2193 , 2008
Abstract : The Brucella abortus strain S19, a spontaneously attenuated strain, has been used as a vaccine strain in vaccination of cattle against brucellosis for six decades. Despite many studies, the physiological and molecular mechanisms causing the attenuation are not known. We have applied pyrosequencing technology together with conventional sequencing to rapidly and comprehensively determine the complete genome sequence of the attenuated Brucella abortus vaccine strain S19. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with the published genome sequences of two virulent and closely related strains of B. abortus, 9-941 and 2308. The two S19 chromosomes are 2,122,487 and 1,161,449 bp in length. A total of 3062 genes were identified and annotated. Pairwise and reciprocal genome comparisons resulted in a total of 263 genes that were non-identical between the S19 genome and any of the two virulent strains. Amongst these, 45 genes were consistently different between the attenuated strain and the two virulent strains but were identical amongst the virulent strains, which included only two of the 236 genes that have been implicated as virulence factors in literature. The functional analyses of the differences have revealed a total of 24 genes that may be associated with the loss of virulence in S19. Of particular relevance are four genes with more than 60 bp consistent difference in S19 compared to both the virulent strains, which, in the virulent strains, encode an outer membrane protein and three proteins involved in erythritol uptake or metabolism.
ESTHER : Crasta_2008_PLoS.One_3_e2193
PubMedSearch : Crasta_2008_PLoS.One_3_e2193
PubMedID: 18478107
Gene_locus related to this paper: brume-BMEI0552 , brume-BMEI1594 , brume-BMEI1822 , brume-BMEII0047 , brume-dhE2 , brume-PCAD , brusu-BR0288

Title : Unique features of a highly pathogenic Campylobacter jejuni strain - Hofreuter_2006_Infect.Immun_74_4694
Author(s) : Hofreuter D , Tsai J , Watson RO , Novik V , Altman B , Benitez M , Clark C , Perbost C , Jarvie T , Du L , Galan JE
Ref : Infect Immun , 74 :4694 , 2006
Abstract : Campylobacter jejuni, a major human enteric pathogen, exhibits significant strain-to-strain differences which result in differences in pathogenic potential. C. jejuni 81-176 is a highly virulent strain that exhibits unique pathogenic features and is used by many research laboratories. We have determined the nucleotide sequence of its genome and compared it to the genomes of other sequenced C. jejuni strains. We identified a number of unique genetic features which may confer specific metabolic and pathogenic properties on this strain. We have also identified regions of the C. jejuni genome that are hot spots for the integration of horizontally acquired genetic material. This information should help the understanding of the pathogenesis of C. jejuni and, in particular, the unique features of this highly pathogenic strain.
ESTHER : Hofreuter_2006_Infect.Immun_74_4694
PubMedSearch : Hofreuter_2006_Infect.Immun_74_4694
PubMedID: 16861657
Gene_locus related to this paper: camje-q29xu7

Title : High-cholesterol diets impair short-term retention of memory in alloxan-induced diabetic mice, but not acquisition of memory nor retention of memory in prediabetic mice - Xie_2005_Life.Sci_77_481
Author(s) : Xie W , Du L
Ref : Life Sciences , 77 :481 , 2005
Abstract : Whether high-cholesterol diets (HCD) induce a high incidence of memory deficits in diabetes requires to be established; if so, whether they induce impairments of memory acquired in the pre-diabetic stage as well as in the diabetic stage also needs to be elucidated, and part of the related mechanisms involved in this dysfunction should be determined. The mice were grouped into: normal mice fed normal diets (NN), diabetic mice fed normal diets (DN), normal mice fed HCD (NH), and diabetic mice fed HCD (DH). Animals were subjected to Morris water maze testing: 1) Learning in the pre-diabetic stage and memory retrieval in the diabetic stage; 2) Learning and memory retrieval in the diabetic stage. Following water maze testing, biochemical parameters were estimated in the animals. The results showed that significant impairments of memory retrieval, acquired in the diabetic stage, were observed only in DH group, neither in DN nor NH group in a short term compared with NN group. Biochemical parameters including fasting blood glucose, lipid peroxidation productions and acetylcholinesterase activities in frontal cortex and hippocampus increased more rapidly in DH group than those in the rest. These results indicate that HCD impair the diabetic retention of memory, but neither the diabetic acquisition of memory nor the pre-diabetic retention of memory in diabetic mice in a short term. Controlled HCD may be a strategy to prevent the loss of memory in diabetic individuals after they have acquired new information.
ESTHER : Xie_2005_Life.Sci_77_481
PubMedSearch : Xie_2005_Life.Sci_77_481
PubMedID: 15904667

Title : An oxidation domain in the BlmIII non-ribosomal peptide synthetase probably catalyzing thiazole formation in the biosynthesis of the anti-tumor drug bleomycin in Streptomyces verticillus ATCC15003 - Du_2000_FEMS.Microbiol.Lett_189_171
Author(s) : Du L , Chen M , Sanchez C , Shen B
Ref : FEMS Microbiology Letters , 189 :171 , 2000
Abstract : We have previously proposed that the BlmIV and BlmIII non-ribosomal peptide synthetases are involved in the formation of the bithiazole moiety of the anti-tumor drug bleomycin in Streptomyces verticillus ATCC15003. We report here the identification and characterization of an oxidation domain in BlmIII. The oxidation domain shows local homology to a family of oxidoreductases and is present in all thiazole-forming non-ribosomal peptide synthetase modules known to date. Both the blmIII-Ox domain and blmIII gene were expressed in Escherichia coli, and the resulting BlmIII-Ox and BlmIII proteins were purified to homogeneity. The oxidation domain contains one molar equivalent of non-covalently bound FMN as a prosthetic group. These results provide experimental evidence for an oxidation domain within non-ribosomal peptide synthetases, suggesting that BlmIII-Ox probably catalyzes the thiazoline to thiazole oxidation in bleomycin biosynthesis.
ESTHER : Du_2000_FEMS.Microbiol.Lett_189_171
PubMedSearch : Du_2000_FEMS.Microbiol.Lett_189_171
PubMedID: 10930733
Gene_locus related to this paper: strve-Q9FB36 , 9actn-q9fb38

Title : The biosynthetic gene cluster for the antitumor drug bleomycin from Streptomyces verticillus ATCC15003 supporting functional interactions between nonribosomal peptide synthetases and a polyketide synthase - Du_2000_Chem.Biol_7_623
Author(s) : Du L , Sanchez C , Chen M , Edwards DJ , Shen B
Ref : Chemical Biology , 7 :623 , 2000
Abstract : BACKGROUND: The structural and catalytic similarities between modular nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) inspired us to search for a hybrid NRPS-PKS system. The antitumor drug bleomycin (BLM) is a natural hybrid peptide-polyketide metabolite, the biosynthesis of which provides an excellent opportunity to investigate intermodular communication between NRPS and PKS modules. Here, we report the cloning, sequencing, and characterization of the BLM biosynthetic gene cluster from Streptomyces verticillus ATCC15003. RESULTS: A set of 30 genes clustered with the previously characterized blmAB resistance genes were defined by sequencing a 85-kb contiguous region of DNA from S. verticillus ATCC15003. The sequenced gene cluster consists of 10 NRPS genes encoding nine NRPS modules, a PKS gene encoding one PKS module, five sugar biosynthesis genes, as well as genes encoding other biosynthesis, resistance, and regulatory proteins. The substrate specificities of individual NRPS and PKS modules were predicted based on sequence analysis, and the amino acid specificities of two NRPS modules were confirmed biochemically in vitro. The involvement of the cloned genes in BLM biosynthesis was demonstrated by bioconversion of the BLM aglycones into BLMs in Streptomyces lividans expressing a part of the gene cluster. CONCLUSION: The blm gene cluster is characterized by a hybrid NRPS-PKS system, supporting the wisdom of combining individual NRPS and PKS modules for combinatorial biosynthesis. The availability of the blm gene cluster has set the stage for engineering novel BLM analogs by genetic manipulation of genes governing BLM biosynthesis and for investigating the molecular basis for intermodular communication between NRPS and PKS in the biosynthesis of hybrid peptide-polyketide metabolites.
ESTHER : Du_2000_Chem.Biol_7_623
PubMedSearch : Du_2000_Chem.Biol_7_623
PubMedID: 11048953
Gene_locus related to this paper: strve-Q9FB36 , 9actn-q9fb38