Lee M

References (44)

Title : Gemigliptin, a potent selective dipeptidyl peptidase 4 inhibitor, protects endothelial progenitor cells by oxidative stress via caspase-3 dependent pathway - Lee_2024_Biochem.Biophys.Rep_38_101673
Author(s) : Lee M , Tariq AR , Kim M
Ref : Biochem Biophys Rep , 38 :101673 , 2024
Abstract : Endothelial progenitor cells (EPCs) are exclusive players in vasculogenesis and endothelial regeneration. EPCs are of two types and their differentiation is mediated by different growth factors. A decrease in EPC number and function causes cardiovascular abnormalities and reduced angiogenesis. Various studies has documented a role of EPCs in diabetes. EPCs treatment with different drugs improve insulin secretion but causes other abnormalities. In vivo and in vitro studies have reported anti glycation effect of gemigliptin but no data is available on in vitro effect of gemigliptin on EPC number and functional credibility. The current study was aimed to find an in vitro effect of gemigliptin on EPC number and function along with an effective treatment dose of gemigliptin. EPCs were isolated, cultured and phenotypically characterized using Dil- AcLDL and ulex-lectin fluorescence staining. EPCs were then treated with different doses of Zemiglo and their viability analyzed with viability assay using water-soluble tetrazolium salt (WST-1), by Annexin V and Propidium Iodide (PI) staining, senescence-associated beta-galactosidase (SA-beta-gal) staining, western blot and Flow cytometric analysis of apoptotic signals. The results demonstrated that the isolated EPCs has typical endothelial phenotypes. And these EPCs were of two types based on morphology i.e., early and late EPCs. Gemigliptin dose dependently improved the EPCs morphology and increased EPCs viability, the most effective dose being the 20 microM. Gemigliptin at 10 microM, 20 microM and 50 microM significantly increased the BCL-2 levels and at 20 microM significantly decreased the Caspase-3 levels in EPCs. In conclusion, gemigliptin dose dependently effects the EPCs viability and morphology through Caspase-3 signaling. Our results are the first report of gemigliptin effect on EPC viability and morphology.
ESTHER : Lee_2024_Biochem.Biophys.Rep_38_101673
PubMedSearch : Lee_2024_Biochem.Biophys.Rep_38_101673
PubMedID: 38444735

Title : Potential function of loliolide as a novel blocker of epithelial-mesenchymal transition in colorectal and breast cancer cells - Yang_2023_Cell.Signal_105_110610
Author(s) : Yang MH , Ha IJ , Ahn J , Kim CK , Lee M , Ahn KS
Ref : Cell Signal , 105 :110610 , 2023
Abstract : Loliolide (LL), a naturally occurring monoterpenoid lactone isolated from Vicia tenuifolia Roth, can exhibit numerous pharmacological effects such as those related to anti-Parkinson, anti-oxidant, anti-cholinesterase, and anti-depressant. Epithelial-mesenchymal transition (EMT) plays a pivotal role in regulating tumor metastasis. CXCR4 and CXCR7 are G-protein-coupled receptors (GPRs), which can be stimulated by CXCL12. CXCL12/CXCR4/CXCXR7 axis can cause activation of multiple pathways including MAPKs, JAK/STAT pathway, and manganese superoxide dismutase (MnSOD) signaling. These events can initiate EMT process and induce cell invasion and migration. Here, we investigated whether LL can modulate the CXCR4 and CXCR7 and EMT process in colon cancer and breast cancer cells. We found that LL suppressed levels of CXCR4 and CXCR7, and exerted an inhibitory effect on these chemokines even after stimulation by CXCL12. LL suppressed expression of MnSOD and mesenchymal markers, whereas induced epithelial markers. In addition, LL significantly attenuated cellular invasion, migration, and metastasis. We noted that LL inhibited CXCR4/7 and EMT process even after stimulation of CXCL12 and MnSOD overexpression. Therefore, in this study, we provide evidences that targeting CXCR4/7 and MnSOD could inhibit the invasion, migration, and metastasis of cancer cells as well as negatively regulate the EMT process. Overall, our study suggested that LL might act as a potent suppressor of EMT process against colon and breast cancer cells.
ESTHER : Yang_2023_Cell.Signal_105_110610
PubMedSearch : Yang_2023_Cell.Signal_105_110610
PubMedID: 36707041

Title : Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade - Jiang_2022_ACS.Nano__
Author(s) : Jiang X , Lee M , Xia J , Luo T , Liu J , Rodriguez M , Lin W
Ref : ACS Nano , : , 2022
Abstract : Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core-shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33-50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.
ESTHER : Jiang_2022_ACS.Nano__
PubMedSearch : Jiang_2022_ACS.Nano__
PubMedID: 36382721

Title : Structural mechanism of muscle nicotinic receptor desensitization and block by curare - Rahman_2022_Nat.Struct.Mol.Biol_29_386
Author(s) : Rahman MM , Basta T , Teng J , Lee M , Worrell BT , Stowell MHB , Hibbs RE
Ref : Nat Struct Mol Biol , 29 :386 , 2022
Abstract : Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three-dimensional structure how agonists and antagonists alter nicotinic acetylcholine receptor conformation. We used the muscle-type receptor from the Torpedo ray to first define the structure of the receptor in a resting, activatable state. We then determined the receptor structure bound to the agonist carbachol, which stabilizes an asymmetric, closed channel desensitized state. We find conformational changes in a peripheral membrane helix are tied to recovery from desensitization. To probe mechanisms of antagonism, we obtained receptor structures with the active component of curare, a poison arrow toxin and precursor to modern muscle relaxants. d-Tubocurarine stabilizes the receptor in a desensitized-like state in the presence and absence of agonist. These findings define the transitions between resting and desensitized states and reveal divergent means by which antagonists block channel activity of the muscle-type nicotinic receptor.
ESTHER : Rahman_2022_Nat.Struct.Mol.Biol_29_386
PubMedSearch : Rahman_2022_Nat.Struct.Mol.Biol_29_386
PubMedID: 35301478

Title : Glycopyrrolate and the Management of Death Rattle in Patients with Myasthenia Gravis - Hindmarsh_2020_J.Palliat.Med__
Author(s) : Hindmarsh J , Everett P , Hindmarsh S , Lee M , Pickard J
Ref : J Palliat Med , : , 2020
Abstract : Death rattle commonly occurs at the end of life and is typically managed with anticholinergic agents. Myasthenia gravis is an autoimmune disorder characterized by fatigability of skeletal muscle, resulting from autoimmune destruction of acetylcholine receptors at the motor endplate. The condition is treated with acetylcholinesterase inhibitors, which potentiate the action of acetylcholine. Agents that antagonize acetylcholine activity (e.g., anticholinergic agents, such as glycopyrrolate) can, therefore, exacerbate myasthenia gravis. We discuss the case of a patient dying with myasthenia gravis that developed problematic "death rattle," and the successful use of glycopyrrolate in treating this symptom.
ESTHER : Hindmarsh_2020_J.Palliat.Med__
PubMedSearch : Hindmarsh_2020_J.Palliat.Med__
PubMedID: 31976808

Title : Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins - Rahman_2020_Neuron_106_952
Author(s) : Rahman MM , Teng J , Worrell BT , Noviello CM , Lee M , Karlin A , Stowell MHB , Hibbs RE
Ref : Neuron , 106 :952 , 2020
Abstract : The nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of alpha-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located -60 A from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes.
ESTHER : Rahman_2020_Neuron_106_952
PubMedSearch : Rahman_2020_Neuron_106_952
PubMedID: 32275860

Title : Administering Neostigmine as a Subcutaneous Infusion: A Case Report of a Patient Dying With Myasthenia Gravis - Hindmarsh_2019_J.Palliat.Care__825859719869353
Author(s) : Hindmarsh J , Woods E , Lee M , Pickard J
Ref : J Palliat Care , :825859719869353 , 2019
Abstract : BACKGROUND: Abrupt withdrawal of pharmacological therapies for myasthenia gravis can exacerbate muscle weakness and even trigger myasthenic crisis. Such medications should ideally be continued, but how this can be achieved in patients approaching the end of life, particularly when enteral administration is compromised, has not been defined. CASE HISTORY: An 83-year-old man with a history of generalized myasthenia gravis and palliative metastatic anal adenocarcinoma was admitted to his local hospital with general decline, where he was considered by more than one physician to be actively dying from his cancer. In the days preceding admission, the patient had not taken his medications consistently, including the acetylcholinesterase inhibitor, pyridostigmine, for the management of his myasthenia gravis. CASE MANAGEMENT AND OUTCOME: Reintroduction of the patient's usual myasthenia therapy improved his clinical condition to the point where he was no longer thought to be dying. When enteral administration of pyridostigmine was no longer possible, the patient was successfully converted to neostigmine, which was administered as a continuous subcutaneous infusion. CONCLUSION: Undertreated myasthenia gravis can lead to a rapid deterioration in a patient's clinical condition, and such patients may be mistakenly diagnosed as dying. Undertreated myasthenia gravis should therefore be considered as a potentially reversible cause of acute deterioration, especially in patients with complex comorbidities. The use of neostigmine as a continuous subcutaneous infusion may have a role in the management of such patients, particularly when enteral administration of acetylcholinesterase inhibitors is no longer possible.
ESTHER : Hindmarsh_2019_J.Palliat.Care__825859719869353
PubMedSearch : Hindmarsh_2019_J.Palliat.Care__825859719869353
PubMedID: 31411109

Title : Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last Decade - Savelieff_2019_Chem.Rev_119_1221
Author(s) : Savelieff MG , Nam G , Kang J , Lee HJ , Lee M , Lim MH
Ref : Chem Rev , 119 :1221 , 2019
Abstract : Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.
ESTHER : Savelieff_2019_Chem.Rev_119_1221
PubMedSearch : Savelieff_2019_Chem.Rev_119_1221
PubMedID: 30095897

Title : Therapeutic strategies for congenital myasthenic syndromes - Lee_2018_Ann.N.Y.Acad.Sci_1412_129
Author(s) : Lee M , Beeson D , Palace J
Ref : Annals of the New York Academy of Sciences , 1412 :129 , 2018
Abstract : To date, more than 25 genes have been implicated in the etiology of the congenital myasthenic syndromes (CMS), and an ever-growing phenotypic landscape is now encountered in the CMS clinic. Unlike the autoimmune form of myasthenia, there is no role for immunomodulatory agents in the treatment of CMS. The present-day drug repertoire comprises acetylcholinesterase inhibitors (mainly pyridostigmine), 3,4-diaminopyridine (3,4-DAP), ephedrine, salbutamol/albuterol, open-channel blockers (fluoxetine, quinidine), or a combination of these. These are prescribed by the specialist in an off-label manner, as there is no drug currently licensed for the treatment of these rare diseases. The effective pharmacological agent varies according to the genetic form of CMS, and it is important to realize that an agent that provides benefit in one CMS subtype can be harmful in another. In addition, the time to treatment response is variable and tends to be commensurate with the drug used. Here, we summarize for the clinician the therapeutic strategies employed in this ever-evolving disease spectrum. We also address the barriers to treatment and discuss the treatment of CMS in pregnancy.
ESTHER : Lee_2018_Ann.N.Y.Acad.Sci_1412_129
PubMedSearch : Lee_2018_Ann.N.Y.Acad.Sci_1412_129
PubMedID: 29381222

Title : Structural Effect of Thioureas on the Detection of Chemical Warfare Agent Simulants - Ha_2017_ACS.Sens_2_1146
Author(s) : Ha S , Lee M , Seo HO , Song SG , Kim KS , Park CH , Kim IH , Kim YD , Song C
Ref : ACS Sens , 2 :1146 , 2017
Abstract : The ability to rapidly detect, identify, and monitor chemical warfare agents (CWAs) is imperative for both military and civilian defense. Since most CWAs and their simulants have an organophosphonate group, which is a hydrogen (H)-bond acceptor, many H-bond donors have been developed to effectively bind to the organophosphonate group. Although thioureas have been actively studied as an organocatalyst, they are relatively less investigated in CWA detection. In addition, there is a lack of studies on the structure-property relationship for gas phase detection. In this study, we synthesized various thioureas of different chemical structures, and tested them for sensing dimethylmethylphosphonate (DMMP), a CWA simulant. Molecular interaction between DMMP and thiourea was measured by (1)H NMR titration and supported by density functional theory (DFT) calculations. Strong H-bond donor ability of thiourea may cause self-aggregation, and CH-pi interaction can play an important role in the DMMP detection. Gas-phase adsorption of DMMP was also measured using a quartz crystal microbalance (QCM) and analyzed using the simple Langmuir isotherm, showing the importance of structure-induced morphology of thioureas on the surface.
ESTHER : Ha_2017_ACS.Sens_2_1146
PubMedSearch : Ha_2017_ACS.Sens_2_1146
PubMedID: 28776366

Title : 1H-NMR-based metabolomic study on toxicity of methomyl and methidathion in fish - Yoon_2016_J.Environ.Sci.Health.B__1
Author(s) : Yoon D , Kim S , Lee M , Yoon C
Ref : J Environ Sci Health B , :1 , 2016
Abstract : A 1H-nuclear magnetic resonance (NMR) spectroscopy with multivariate analysis was applied to detect the toxicity of antiacetylcholinesterase insecticides, methomyl (methyl (1E)-N-(methylcarbamoyloxy)ethanimidothioate) and methidathion (3-(dimethoxyphosphinothioyl sulfanylmethyl)-5-methoxy-1,3,4-thiadiazol-2-one), using zebrafish (Danio rerio) and Chinese bleak (Aphyocypris chinensis). Generally, methomyl and methidathion have been believed not to highly accumulate in fish tissues. However, these pesticides showed their toxicity by altering patterns of whole-body metabolites in neurotransmitter balance, energy metabolism, oxidative stress, and muscle maintenance in low concentrations. We used Pearson correlation analysis to contextualize the metabolic markers in pesticide treated groups. We observed that the positive correlations of choline with acetate and betaine in untreated control were shifted to null correlations showing acetylcholinesterase specific toxicity. This research demonstrated the applicability and potential of NMR metabolomics in detecting toxic effects of insecticide with a modicum of concentrations in aquatic environment.
ESTHER : Yoon_2016_J.Environ.Sci.Health.B__1
PubMedSearch : Yoon_2016_J.Environ.Sci.Health.B__1
PubMedID: 27715651

Title : Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma - Capello_2015_J.Natl.Cancer.Inst_107_
Author(s) : Capello M , Lee M , Wang H , Babel I , Katz MH , Fleming JB , Maitra A , Tian W , Taguchi A , Hanash SM
Ref : J Natl Cancer Inst , 107 : , 2015
Abstract : BACKGROUND: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy.
METHODS: CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided.
RESULTS: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). CONCLUSION: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
ESTHER : Capello_2015_J.Natl.Cancer.Inst_107_
PubMedSearch : Capello_2015_J.Natl.Cancer.Inst_107_
PubMedID: 26025324

Title : Inhibiting beta-Amyloid-Associated Alzheimer's Pathogenesis In Vitro and In Vivo by a Multifunctional Dimeric Bis(12)-hupyridone Derived from Its Natural Analogue - Hu_2015_J.Mol.Neurosci_55_1014
Author(s) : Hu S , Wang R , Cui W , Zhang Z , Mak SH , Xu D , Choi C , Tsim KWK , Carlier PR , Lee M , Han Y
Ref : Journal of Molecular Neuroscience , 55 :1014 , 2015
Abstract : Fibrillar aggregates of beta-amyloid protein (Abeta) is the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit the formation of Abeta fibrils and block Abeta fibrils-associated toxicity may have therapeutic potential to combat AD. Bis(12)-hupyridone (B12H) is a multifunctional homodimer derived from huperzine A, which is an anti-AD drug in China. In the current study, the inhibitory effect of B12H on the formation of Abeta fibrils and their associated toxicity was investigated both in vitro and in vivo. By using Thioflavin T fluorescence assay, we found that B12H (0.3-3 muM) directly inhibited Abeta fibrils formation following co-incubation of B12H and Abeta1-40 at 37 degrees C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Abeta1-40 fibrils formation. Moreover, B12H markedly reduced Abeta1-40-induced cytotoxicity in cultured SH-SY5Y cells, as evidenced by the increase in cell viability, the decrease in lactate dehydrogenase release, and the reduction of apoptotic nuclei. Most importantly, B12H (0.2 and 0.4 mg/kg) reduced intracerebroventricular Abeta1-40 infusion-induced cognitive and memory impairments in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with increasing choline acetyltransferase activity and decreasing acetylcholinesterase activity. Collectively, our study provided novel sights into the potential application of B12H in AD treatment.
ESTHER : Hu_2015_J.Mol.Neurosci_55_1014
PubMedSearch : Hu_2015_J.Mol.Neurosci_55_1014
PubMedID: 25407821

Title : Fucoidan protects hepatocytes from apoptosis and inhibits invasion of hepatocellular carcinoma by up-regulating p42\/44 MAPK-dependent NDRG-1\/CAP43 - Cho_2015_Acta.Pharm.Sin.B_5_544
Author(s) : Cho Y , Yoon JH , Yoo JJ , Lee M , Lee DH , Cho EJ , Lee JH , Yu SJ , Kim YJ , Kim CY
Ref : Acta Pharm Sin B , 5 :544 , 2015
Abstract : Fucoidan is a traditional Chinese medicine suggested to possess anti-tumor effects. In this study the anti-metastatic effects of fucoidan were investigated in vitro in human hepatocellular carcinoma (HCC) cells (Huh-7 and SNU-761) under normoxic and hypoxic conditions and in vivo using a distant liver metastasis model involving injection of MH134 cells into spleen via the portal vein. Its ability to protect hepatocytes against bile acid (BA)-induced apoptosis was investigated in primary hepatocytes. Fucoidan was found to suppress the invasion of HCC cells through up-regulation of p42/44 MAPK-dependent NDRG-1/CAP43 and partly, under normoxic conditions, through up-regulation of p42/44 MAPK-dependent VMP-1 expression. It also significantly decreased liver metastasis in vivo. As regards its hepatoprotective effect, fucoidan decreased BA-induced hepatocyte apoptosis as shown by the attenuation of caspase-8, and -7 cleavages and suppression of the mobilization of caspase-8 and Fas associated death domain (FADD) into the death-inducing signaling complex. In summary, fucoidan displays inhibitory effects on proliferation of HCC cells and protective effects on hepatocytes. The results suggest fucoidan is a potent suppressor of tumor invasion with hepatoprotective effects.
ESTHER : Cho_2015_Acta.Pharm.Sin.B_5_544
PubMedSearch : Cho_2015_Acta.Pharm.Sin.B_5_544
PubMedID: 26713269

Title : Volatile Profiling of Aromatic Traditional Medicinal Plant, Polygonum minus in Different Tissues and Its Biological Activities - Ahmad_2014_Molecules_19_19220
Author(s) : Ahmad R , Baharum SN , Bunawan H , Lee M , Mohd Noor N , Rohani ER , Ilias N , Zin NM
Ref : Molecules , 19 :19220 , 2014
Abstract : The aim of this research was to identify the volatile metabolites produced in different organs (leaves, stem and roots) of Polygonum minus, an important essential oil producing crop in Malaysia. Two methods of extraction have been applied: Solid Phase Microextraction (SPME) and hydrodistillation coupled with Gas Chromatography-Mass Spectrometry (GC-MS). Approximately, 77 metabolites have been identified and aliphatic compounds contribute significantly towards the aroma and flavour of this plant. Two main aliphatic compounds: decanal and dodecanal were found to be the major contributor. Terpenoid metabolites were identified abundantly in leaves but not in the stem and root of this plant. Further studies on antioxidant, total phenolic content, anticholinesterase and antimicrobial activities were determined in the essential oil and five different extracts. The plant showed the highest DPPH radical scavenging activity in polar (ethanol) extract for all the tissues tested. For anti-acetylcholinesterase activity, leaf in aqueous extract and methanol extract showed the best acetylcholinesterase inhibitory activities. However, in microbial activity, the non-polar extracts (n-hexane) showed high antimicrobial activity against Methicillin-resistant Staphylococcus aureus (MRSA) compared to polar extracts. This study could provide the first step in the phytochemical profiles of volatile compounds and explore the additional value of pharmacology properties of this essential oil producing crop Polygonum minus.
ESTHER : Ahmad_2014_Molecules_19_19220
PubMedSearch : Ahmad_2014_Molecules_19_19220
PubMedID: 25420073

Title : LCAT deficiency does not impair amyloid metabolism in APP\/PS1 mice - Stukas_2014_J.Lipid.Res_55_1721
Author(s) : Stukas S , Freeman L , Lee M , Wilkinson A , Ossoli A , Vaisman B , Demosky S , Chan J , Hirsch-Reinshagen V , Remaley AT , Wellington CL
Ref : J Lipid Res , 55 :1721 , 2014
Abstract : A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating beta-amyloid (Abeta) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Abeta clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Abeta or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Abeta clearance.
ESTHER : Stukas_2014_J.Lipid.Res_55_1721
PubMedSearch : Stukas_2014_J.Lipid.Res_55_1721
PubMedID: 24950691
Gene_locus related to this paper: mouse-lcat

Title : Enzymatic biodiesel synthesis in semi-pilot continuous process in near-critical carbon dioxide - Lee_2013_Appl.Biochem.Biotechnol_171_1118
Author(s) : Lee M , Lee D , Cho J , Kim S , Park C
Ref : Appl Biochem Biotechnol , 171 :1118 , 2013
Abstract : A semi-pilot continuous process (SPCP) for enzymatic biodiesel synthesis utilizing near-critical carbon dioxide (NcCO) as the reaction medium was developed with the aim of reducing the reaction time and alleviating the catalyst inhibition by methanol. Biodiesel synthesis was evaluated in both lab-scale and semi-pilot scale reactors (batch and continuous reactors). In a SPCP, the highest conversion (~99.9 %) in four and a half hours was observed when three-step substrate (methanol) addition (molar ratio [oil/methanol] = 1:1.3) was used and the reaction mixture containing enzyme (Lipozyme TL IM, 20 wt.% of oil) was continuously mixed (agitation speed = 300 rpm) at 30 degreeC and 100 bar in a CO environment. The biodiesel produced from canola oil conformed to the fuel standard (EU) even without additional downstream processing, other than glycerol separation and drying.
ESTHER : Lee_2013_Appl.Biochem.Biotechnol_171_1118
PubMedSearch : Lee_2013_Appl.Biochem.Biotechnol_171_1118
PubMedID: 23536250

Title : Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain - Jarcho_2013_Pain_154_987
Author(s) : Jarcho JM , Feier NA , Bert A , Labus JA , Lee M , Stains J , Ebrat B , Groman SM , Tillisch K , Brody AL , London ED , Mandelkern MA , Mayer EA
Ref : Pain , 154 :987 , 2013
Abstract : Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [(18)F]SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS.
ESTHER : Jarcho_2013_Pain_154_987
PubMedSearch : Jarcho_2013_Pain_154_987
PubMedID: 23582152

Title : Aspergillus luchuensis, an industrially important black Aspergillus in East Asia - Hong_2013_PLoS.One_8_e63769
Author(s) : Hong SB , Lee M , Kim DH , Varga J , Frisvad JC , Perrone G , Gomi K , Yamada O , Machida M , Houbraken J , Samson RA
Ref : PLoS ONE , 8 :e63769 , 2013
Abstract : Aspergilli known as black- and white-koji molds which are used for awamori, shochu, makgeolli and other food and beverage fermentations, are reported in the literature as A. luchuensis, A. awamori, A. kawachii, or A. acidus. In order to elucidate the taxonomic position of these species, available ex-type cultures were compared based on morphology and molecular characters. A. luchuensis, A. kawachii and A. acidus showed the same banding patterns in RAPD, and the three species had the same rDNA-ITS, beta-tubulin and calmodulin sequences and these differed from those of the closely related A. niger and A. tubingensis. Morphologically, the three species are not significantly different from each other or from A. niger and A. tubingensis. It is concluded that A. luchuensis, A. kawachii and A. acidus are the same species, and A. luchuensis is selected as the correct name based on priority. Strains of A. awamori which are stored in National Research Institute of Brewing in Japan, represent A. niger (n = 14) and A. luchuensis (n = 6). The neotype of A. awamori (CBS 557.65 = NRRL 4948) does not originate from awamori fermentation and it is shown to be identical with the unknown taxon Aspergillus welwitschiae. Extrolite analysis of strains of A. luchuensis showed that they do not produce mycotoxins and therefore can be considered safe for food and beverage fermentations. A. luchuensis is also frequently isolated from meju and nuruk in Korea and Puerh tea in China and the species is probably common in the fermentation environment of East Asia. A re-description of A. luchuensis is provided because the incomplete data in the original literature.
ESTHER : Hong_2013_PLoS.One_8_e63769
PubMedSearch : Hong_2013_PLoS.One_8_e63769
PubMedID: 23723998
Gene_locus related to this paper: aspaw-AXE1

Title : Genome Sequence of Dehalobacter UNSWDHB, a Chloroform-Dechlorinating Bacterium - Deshpande_2013_Genome.Announc_1_e00720
Author(s) : Deshpande NP , Wong YK , Manefield M , Wilkins MR , Lee M
Ref : Genome Announc , 1 : , 2013
Abstract : The chloroform-respiring bacterium Dehalobacter UNSWDHB was isolated from subsurface soil contaminated with a mixture of organohalides, including chloroform. Here, we present its 3.2-Mb genome.
ESTHER : Deshpande_2013_Genome.Announc_1_e00720
PubMedSearch : Deshpande_2013_Genome.Announc_1_e00720
PubMedID: 24051315
Gene_locus related to this paper: 9firm-w0ejt1

Title : Improved high-pressure enzymatic biodiesel batch synthesis in near-critical carbon dioxide - Lee_2012_Bioprocess.Biosyst.Eng_35_105
Author(s) : Lee M , Lee D , Cho JK , Cho J , Han J , Park C , Kim S
Ref : Bioprocess Biosyst Eng , 35 :105 , 2012
Abstract : The enzymatic synthesis of biodiesel by a high-pressure semi-continuous process in near-critical carbon dioxide (NcCO(2)) was studied. Biodiesel synthesis was evaluated in both batch and semi-continuous systems to develop an effective process. Batch processing demonstrated the advantageous properties of NcCO(2) as an alternative reaction medium. Three immobilized lipases (Novozym 435, Lipozyme RM IM, and Lipozyme TL IM from Novozymes) were tested, with Lipozyme TL IM the most effective, showing the highest conversion. Biodiesel conversion from several edible and non-edible oil feedstocks reached >92%. Higher conversion (99.0%) was obtained in a shorter time by employing repeated batch processes with optimized conditions: 44.3 g (500 mM) canola oil, a substrate molar ratio (methanol:oil) of 3:1, an enzyme loading of 20 wt% (of the oil used), at 30 degreeC, 100 bar, and 300 rpm agitation. The enzyme maintained 80.2% of its initial stability after being reused eight times. These results suggest that this method produces biodiesel energy-efficiently and environment-friendly.
ESTHER : Lee_2012_Bioprocess.Biosyst.Eng_35_105
PubMedSearch : Lee_2012_Bioprocess.Biosyst.Eng_35_105
PubMedID: 21989636

Title : Improvement of enzymatic biodiesel production by controlled substrate feeding using silica gel in solvent free system - Lee_2011_Enzyme.Microb.Technol_49_402
Author(s) : Lee M , Lee J , Lee D , Cho J , Kim S , Park C
Ref : Enzyme Microb Technol , 49 :402 , 2011
Abstract : A silica gel-based substrate feeding system was developed to prevent methanol inhibiting the catalyst during enzymatic biodiesel synthesis. In the system, silica gel swelled upon methanol addition and subsequently released it in a controlled manner to prevent excess methanol affecting the enzyme. Biodiesel was synthesized by the enzymatic transesterification of canola oil with methanol. For this reaction, enzyme loading, methanol/oil molar ratio, silica gel dosage, glycerol content, and methanol feeding method were tested using commercial immobilized enzymes (Novozym 435 and Lipozyme RM IM from Novozymes). The results showed that conversion was highest with controlled substrate feeding rather than direct methanol addition, suggesting that the method developed here can easily prevent enzyme inhibition by limiting methanol concentration to an acceptable level.
ESTHER : Lee_2011_Enzyme.Microb.Technol_49_402
PubMedSearch : Lee_2011_Enzyme.Microb.Technol_49_402
PubMedID: 22112567

Title : Enzymatic coproduction of biodiesel and glycerol carbonate from soybean oil and dimethyl carbonate - Seong_2011_Enzyme.Microb.Technol_48_505
Author(s) : Seong PJ , Jeon BW , Lee M , Cho DH , Kim DK , Jung KS , Kim SW , Han SO , Kim YH , Park C
Ref : Enzyme Microb Technol , 48 :505 , 2011
Abstract : The enzymatic coproduction of biodiesel and glycerol carbonate by the transesterification of soybean oil was studied using lipase as catalyst in organic solvent. To produce biodiesel and glycerol carbonate simultaneously, experiments were designed sequentially. Enzyme screening, the molar ratio of dimethyl carbonate (DMC) to soybean oil, reaction temperature and solvent effects were investigated. The results of enzyme screening, at 100 g/L Novozym 435 (immobilized Candida antarctica lipase B), biodiesel and glycerol carbonate showed conversions of 58.7% and 50.7%, respectively. The optimal conditions were 60 degreeC, 100 g/L Novozym 435, 6.0:1 molar ratio with tert-butanol as solvent: 84.9% biodiesel and 92.0% glycerol carbonate production was achieved.
ESTHER : Seong_2011_Enzyme.Microb.Technol_48_505
PubMedSearch : Seong_2011_Enzyme.Microb.Technol_48_505
PubMedID: 22113023
Gene_locus related to this paper: canar-LipB

Title : The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of alpha7*nAChR function - Araud_2011_Biochem.Pharmacol_82(8)_904
Author(s) : Araud T , Graw S , Berger R , Lee M , Neveu E , Bertrand D , Leonard S
Ref : Biochemical Pharmacology , 82 :904 , 2011
Abstract : The human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the alpha7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of alpha7*nAChR, as measured by binding of the ligand [(125)I]-alpha-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of alpha7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with alpha7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.
ESTHER : Araud_2011_Biochem.Pharmacol_82(8)_904
PubMedSearch : Araud_2011_Biochem.Pharmacol_82(8)_904
PubMedID: 21718690

Title : Higher post-absorptive skeletal muscle LPL activity in African American vs. non-Hispanic White pre-menopausal women - Berk_2008_Obesity.(Silver.Spring)_16_199
Author(s) : Berk ES , Johnson JA , Lee M , Zhang K , Boozer CN , Pi-Sunyer FX , Fried SK , Albu JB
Ref : Obesity (Silver Spring) , 16 :199 , 2008
Abstract : OBJECTIVE: Higher post-absorptive post-heparin plasma lipoprotein lipase (LPL) activity has been reported in African Americans as compared to non-Hispanic whites but differences in tissue-specific LPL activity are unclear. METHODS AND PROCEDURES: Post-absorptive skeletal muscle (SM)-LPL (vastus lateralis ) and subcutaneous abdominal adipose tissue (AT)-LPL activity was measured in overweight, sedentary African American females (n = 11) as well as in their non-Hispanic white counterparts (n = 6) during a period of controlled low fat (30%) diet (for 10 days) combined with physical activity (for days 8-10). Post-absorptive substrate utilization was measured on day 10; fasting blood levels and SM and AT biopsies were obtained on day 11.
RESULTS: African Americans had significantly greater post-absorptive SM-LPL activity (P = 0.04) when compared to non-Hispanic whites. There were no significant differences in post-absorptive AT-LPL activity, free fatty acids, and systemic fat oxidation or respiratory quotient between African American and white non-Hispanic women in this study (P > 0.2 for all). DISCUSSION: During a controlled low fat (30%) diet post-absorptive vastus lateralis SM-LPL activity is higher in sedentary pre-menopausal African American as compared to non-Hispanic white women.
ESTHER : Berk_2008_Obesity.(Silver.Spring)_16_199
PubMedSearch : Berk_2008_Obesity.(Silver.Spring)_16_199
PubMedID: 18223635

Title : 5-I A-85380 and TC-2559 differentially activate heterologously expressed alpha4beta2 nicotinic receptors - Zwart_2006_Eur.J.Pharmacol_539_10
Author(s) : Zwart R , Broad LM , Xi Q , Lee M , Moroni M , Bermudez I , Sher E
Ref : European Journal of Pharmacology , 539 :10 , 2006
Abstract : The neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunits expressed in heterologous expression systems assemble into at least two distinct subunit stoichiometries of alpha4beta2 receptor. The (alpha4)2(beta2)3 stoichiometry is about 100-fold more sensitive to acetylcholine than the (alpha4)3(beta2)2 stoichiometry. In order to investigate if agonists in general distinguish high- and low-affinity alpha4beta2 nicotinic acetylcholine receptors, we have expressed human alpha4 and beta2 nicotinic acetylcholine receptor subunits in two different expression systems. The relative amounts of alpha4beta2 nicotinic acetylcholine receptors with high- and low-affinity for acetylcholine were manipulated by (a) injecting the subunit cDNAs at different alpha:beta ratios into Xenopus oocytes and (b) by culturing HEK-293 cells stably expressing alpha4beta2 nicotinic acetylcholine receptors overnight at different temperatures. The sensitivities of the alpha4beta2 nicotinic acetylcholine receptors to the agonists acetylcholine, 5-I A-85380, and TC-2559 were investigated using the voltage-clamp technique on Xenopus oocytes and using a fluorescent imaging plate reader to measure calcium responses from HEK-293 cells. Like acetylcholine, 5-I A-85380 produced biphasic concentration-response curves and the high-affinity component became larger when the cells were manipulated to produce a greater proportion of (alpha4)2(beta2)3 nicotinic acetylcholine receptors. Interestingly, under all circumstances, TC-2559 produced monophasic concentration-response curves. In oocytes injected with alpha4 and beta2 subunits in the 1:1 ratio the maximum effect of TC-2559 was 28% of that of acetylcholine. The EC50 for TC-2559 was not changed when oocytes were manipulated to express exclusively (alpha4)2(beta2)3 nicotinic acetylcholine receptors, however, the maximum effect of TC-2559 was dramatically enhanced. These results suggest that TC-2559 is a selective agonist of the (alpha4)2(beta2)3 nicotinic acetylcholine receptor stoichiometry.
ESTHER : Zwart_2006_Eur.J.Pharmacol_539_10
PubMedSearch : Zwart_2006_Eur.J.Pharmacol_539_10
PubMedID: 16674940

Title : Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators - Broad_2006_J.Pharmacol.Exp.Ther_318_1108
Author(s) : Broad LM , Zwart R , Pearson KH , Lee M , Wallace L , McPhie GI , Emkey R , Hollinshead SP , Dell CP , Baker SR , Sher E
Ref : Journal of Pharmacology & Experimental Therapeutics , 318 :1108 , 2006
Abstract : Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha1beta1gammadelta, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7) expressed in mammalian cells or Xenopus oocytes. At alpha2beta4, alpha4beta2, alpha4beta4, and alpha7, but not alpha1beta1gammadelta, alpha3beta2, or alpha3beta4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-d-aspartate receptors or voltage-gated Na(+) and Ca(2+) channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at alpha4beta2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [(3)H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.
ESTHER : Broad_2006_J.Pharmacol.Exp.Ther_318_1108
PubMedSearch : Broad_2006_J.Pharmacol.Exp.Ther_318_1108
PubMedID: 16738207

Title : Cellular sterol ester synthesis in plants is performed by an enzyme (phospholipid:sterol acyltransferase) different from the yeast and mammalian acyl-CoA:sterol acyltransferases - Banas_2005_J.Biol.Chem_280_34626
Author(s) : Banas A , Carlsson AS , Huang B , Lenman M , Banas W , Lee M , Noiriel A , Benveniste P , Schaller H , Bouvier-Nave P , Stymne S
Ref : Journal of Biological Chemistry , 280 :34626 , 2005
Abstract : A gene encoding a sterol ester-synthesizing enzyme was identified in Arabidopsis. The cDNA of the Arabidopsis gene At1g04010 (AtPSAT) was overexpressed in Arabidopsis behind the cauliflower mosaic virus 35S promoter. Microsomal membranes from the leaves of overexpresser lines catalyzed the transacylation of acyl groups from phosphatidylethanolamine to sterols. This activity correlated with the expression level of the AtPSAT gene, thus demonstrating that this gene encodes a phospholipid:sterol acyltransferase (PSAT). Properties of the AtPSAT were examined in microsomal fractions from the tissues of an overexpresser. The enzyme did not utilize neutral lipids, had the highest activity with phosphatidylethanolamine, had a 5-fold preference for the sn-2 position, and utilized both saturated and unsaturated fatty acids. Various sterols and sterol intermediates, including triterpenic precursors, were acylated by the PSAT, whereas other triterpenes were not. Sterol selectivity studies showed that the enzyme is activated by end product sterols and that sterol intermediates are preferentially acylated by the activated enzyme. This indicates that PSAT both regulates the pool of free sterols as well as limits the amount of free sterol intermediates in the membranes. Two T-DNA insertion mutants in the AtPSAT gene, with strongly reduced (but still measurable) levels of sterol esters in their tissues, had no detectable PSAT activity in the microsomal fractions, suggesting that Arabidopsis possess other enzyme(s) capable of acylating sterols. The AtPSAT is the only intracellular enzyme found so far that catalyzes an acyl-CoA-independent sterol ester formation. Thus, PSAT has a similar physiological function in plant cells as the unrelated acyl-CoA:sterol acyltransferase has in animal cells.
ESTHER : Banas_2005_J.Biol.Chem_280_34626
PubMedSearch : Banas_2005_J.Biol.Chem_280_34626
PubMedID: 16020547
Gene_locus related to this paper: arath-LCAT2

Title : 6-(2-Phenylethyl)nicotine: a novel nicotinic cholinergic receptor ligand - Ramunno_2005_Bioorg.Med.Chem.Lett_15_3237
Author(s) : Ramunno A , Dukat M , Lee M , Young R , El-Zahabi M , Damaj MI , Martin B , Glennon RA
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :3237 , 2005
Abstract : 6-(2-Phenylethyl)nicotine (1b; K(i)=15 nM) was unexpectedly found to bind at alpha4beta2 nicotinic cholinergic (nACh) receptors. Although this compound failed to produce nicotine-like agonist action in several functional assays, 1b antagonized the antinociceptive effects of nicotine (mouse tail-flick assay) in a dose-dependent fashion when administered via an intrathecal route.
ESTHER : Ramunno_2005_Bioorg.Med.Chem.Lett_15_3237
PubMedSearch : Ramunno_2005_Bioorg.Med.Chem.Lett_15_3237
PubMedID: 15925512

Title : The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine - Weiner_2004_Psychopharmacology.(Berl)_177_207
Author(s) : Weiner DM , Meltzer HY , Veinbergs I , Donohue EM , Spalding TA , Smith TT , Mohell N , Harvey SC , Lameh J , Nash N , Vanover KE , Olsson R , Jayathilake K , Lee M , Levey AI , Hacksell U , Burstein ES , Davis RE , Brann MR
Ref : Psychopharmacology (Berl) , 177 :207 , 2004
Abstract : RATIONALE: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND
METHODS: To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.
RESULTS: Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.
CONCLUSIONS: The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.
ESTHER : Weiner_2004_Psychopharmacology.(Berl)_177_207
PubMedSearch : Weiner_2004_Psychopharmacology.(Berl)_177_207
PubMedID: 15258717

Title : 3-(4-Aminobutyn-1-yl)pyridines: binding at alpha 4 beta 2 nicotinic cholinergic receptors - Dogruer_2004_Bioorg.Med.Chem.Lett_14_523
Author(s) : Dogruer D , Lee M , Dukat M , Damaj MI , Martin BR , Glennon RA
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :523 , 2004
Abstract : The binding of a series pyridylbutynylamines 6 was examined at alpha4beta2 nACh receptors. Structural modifications, comparing 6 with pyridyl ethers 2, did not consistently result in parallel effects on receptor affinity, suggesting possible differences in their modes of binding. Furthermore, the binding of amine 6a seemed to be accounted for by the newer vector pharmacophore models.
ESTHER : Dogruer_2004_Bioorg.Med.Chem.Lett_14_523
PubMedSearch : Dogruer_2004_Bioorg.Med.Chem.Lett_14_523
PubMedID: 14698195

Title : Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice - Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
Author(s) : Hellstrom-Lindahl E , Court J , Keverne J , Svedberg M , Lee M , Marutle A , Thomas A , Perry E , Bednar I , Nordberg A
Ref : European Journal of Neuroscience , 19 :2703 , 2004
Abstract : Ten days treatment with nicotine reduced insoluble amyloid A beta 1-40 and Alpha beta 1-42 peptides by 80% in the cortex of 9-month-old APPsw mice, which is more than that observed in 14.5-month-old mice following nicotine treatment for 5.5 months. A reduction in A beta associated with cerebral vessels was observed in addition to that deposited as parenchymal plaques after 5.5 months treatment. The diminution in A beta peptides observed was not accompanied by changes in brain alpha, beta or gamma secretase-like activities, NGF or BDNF protein expression measured in brain homogenates. A significant increase in sAPP was observed after nicotine treatment of SH-SY5Yneuroblastoma cells that could be blocked by the nicotinic antagonist mecamylamine. Attenuation of elevated [(125)I]-alpha bungarotoxin binding (alpha 7) in APPsw mice was observed after 5.5 months nicotine treatment. Both these observations suggest that the reduction in insoluble A beta by nicotine might be in part mediated via the alpha 7 nicotinic receptor. Further studies are required to identify potential mechanisms of the nicotine's amyloid-reducing effect.
ESTHER : Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
PubMedSearch : Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
PubMedID: 15147304

Title : Regulation of cholinergic neurotransmitter phenotypes. -
Author(s) : Salvaterra PM , Lee M , Song S
Ref : Cholinergic Mechanisms, CRC Press :193 , 2004
PubMedID:

Title : A comparison of the binding of three series of nicotinic ligands - Lee_2002_Bioorg.Med.Chem.Lett_12_1989
Author(s) : Lee M , Dukat M , Liao L , Flammia D , Damaj MI , Martin B , Glennon RA
Ref : Bioorganic & Medicinal Chemistry Lett , 12 :1989 , 2002
Abstract : A total of 24 aryl-substituted analogues of nicotine (1a) and two related series of nicotinic ligands, aminomethylpyridines 3 and ether analogues 8, were examined to determine if they bind at alpha4beta2 nACh receptors in a common manner. A modest correlation (r=0.785) was found between the affinities of the nicotine analogues and derivatives of 3, but little correlation (r=0.348) was found with analogues 8. However, a modest correlation (r=0.742) exists between the binding of analogues 3 and 8. It seems that 1-series and 8-series compounds bind differently but that the 3-series compounds share some intermediate binding similarity with both.
ESTHER : Lee_2002_Bioorg.Med.Chem.Lett_12_1989
PubMedSearch : Lee_2002_Bioorg.Med.Chem.Lett_12_1989
PubMedID: 12113825

Title : Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw) - Nordberg_2002_J.Neurochem_81_655
Author(s) : Nordberg A , Hellstrom-Lindahl E , Lee M , Johnson M , Mousavi M , Hall R , Perry E , Bednar I , Court J
Ref : Journal of Neurochemistry , 81 :655 , 2002
Abstract : Alzheimer's disease neuropathology is characterised by beta-amyloid plaques and neurofibrillary tangles. Inhibition of beta-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain beta-amyloid deposits, with nicotine in drinking fluid (200 microg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid beta peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid beta peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid beta peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.
ESTHER : Nordberg_2002_J.Neurochem_81_655
PubMedSearch : Nordberg_2002_J.Neurochem_81_655
PubMedID: 12065674

Title : An outbreak of food-borne illness associated with methomyl-contaminated salt - Buchholz_2002_Jama_288_604
Author(s) : Buchholz U , Mermin J , Rios R , Casagrande TL , Galey F , Lee M , Quattrone A , Farrar J , Nagelkerke N , Werner SB
Ref : Jama , 288 :604 , 2002
Abstract : CONTEXT: On January 5, 1999, the California Department of Health Services was notified of the repeated occurrence (December 21, 1998, and January 2, 1999) of gastrointestinal tract illness among patrons at a Thai restaurant in central California. OBJECTIVE: To identify the source of the outbreak. DESIGN: Case-control study; microbiological and toxicological laboratory testing of samples of food, stool, and vomitus. SETTING: Thai food restaurant in central California. PARTICIPANTS: Patrons of the restaurant. A case (n = 107) was defined as dizziness, nausea, or vomiting occurring in a person who ate at the restaurant between December 20, 1998, and January 2, 1999, with onset of symptoms within 2 hours of eating. A control (n = 169) was a person who ate at the restaurant during the same period but reported no symptoms. MAIN OUTCOME MEASURES: Odds ratios (ORs) of illness associated with food exposures; ORs of shifts during which illness occurred associated with certain cooks; laboratory results. RESULTS: The median latency period was 40 minutes from beginning eating to first symptom and was 2 hours to onset of diarrhea. The median duration of symptoms was 6 hours. Twenty-six persons (24%) visited the emergency department or were treated by a physician; no person required hospitalization. Patients reported nausea (95%), dizziness (72%), abdominal cramps (58%), headache (52%), vomiting (51%), chills (48%), and diarrhea (46%). Fifty-one cases (48%) included dizziness, lightheadedness, or a feeling of disequilibrium as the initial symptom. Illness was statistically associated with several foods and ingredients, but no single dish or ingredient explained a substantial number of cases. The analysis of food exposures included salt added by cooks, as estimated by using the amount of salt in the recipe for each dish and the amount of each dish eaten by respondents. This association was stronger with increasing levels of salt: ORs for illness among persons who consumed more than 0.42 to 0.84, more than 0.84 to 1.25, and more than 1.25 tsp of salt added to foods in the kitchen were 1.9 (95% confidence interval [CI], 0.6-5.7), 3.0 (95% CI, 1.0-8.8), and 4.0 (95% CI, 1.3-13.5) compared with persons who consumed less than 0.42 tsp (P value for trend =.004). Methomyl, a highly toxic carbamate pesticide, was identified in a sample of vomitus (20 ppm) and in salt taken from containers in the storeroom (mean, 5600 ppm) and the stovetop (mean, 1425 ppm). The oral toxic dose causing illness in 50% of those exposed to methomyl was estimated to be 0.15 mg/kg of body weight (estimated range, 0.09-0.31 mg/kg of body weight). The presence of cook A was associated with shifts during which cases of illness occurred (OR, 10.4; 95% CI, 1.2-157.4). CONCLUSION: This outbreak of gastrointestinal illness was associated with the consumption of food seasoned with methomyl-contaminated salt. To allow rapid assessment for further investigational and control measures by health officials, physicians should report suspected outbreaks of illness to public health departments, however trivial the symptoms or cause may seem.
ESTHER : Buchholz_2002_Jama_288_604
PubMedSearch : Buchholz_2002_Jama_288_604
PubMedID: 12150672

Title : Upregulation of neuronal nicotinic receptor subunits alpha4, beta2, and alpha7 in transgenic mice overexpressing human acetylcholinesterase - Svedberg_2002_J.Mol.Neurosci_18_211
Author(s) : Svedberg MM , Svensson AL , Johnson M , Lee M , Cohen O , Court J , Soreq H , Perry E , Nordberg A
Ref : Journal of Molecular Neuroscience , 18 :211 , 2002
Abstract : Neuronal nicotinic receptor binding sites as well as mRNA levels encoding for subunits alpha4, beta2, and alpha7 were analysed in 3-mo-old transgenic mice generated with a neuronal overexpression of human acetylcholinesterase and in age-matched controls. The acetylcholinesterase transgenic mice display progressive cognitive impairment in spatial learning and memory. We here report a significantly increased [3H]epibatidine and [125I]alphabungarotoxin binding in the cortex and the caudate putamen of these mice. Quantitativein situ hybridization showed significant upregulation of mRNA corresponding to the nicotinic receptor subunits alpha4, beta2, and alpha7 in various brain regions in the transgenic mice compared to nontransgenic controls. Our results suggest that disruption of balanced cholinergic transmission by constitutive overexpression of acetylcholinesterase is accompanied by variable upregulation of several nicotinic receptor subtypes, in particular these associated with cholinergic terminals participating in compensatory response.
ESTHER : Svedberg_2002_J.Mol.Neurosci_18_211
PubMedSearch : Svedberg_2002_J.Mol.Neurosci_18_211
PubMedID: 12059039

Title : Phospholipid:diacylglycerol acyltransferase: an enzyme that catalyzes the acyl-CoA-independent formation of triacylglycerol in yeast and plants - Dahlqvist_2000_Proc.Natl.Acad.Sci.U.S.A_97_6487
Author(s) : Dahlqvist A , Stahl U , Lenman M , Banas A , Lee M , Sandager L , Ronne H , Stymne S
Ref : Proc Natl Acad Sci U S A , 97 :6487 , 2000
Abstract : Triacylglycerol (TAG) is known to be synthesized in a reaction that uses acyl-CoA as acyl donor and diacylglycerol (DAG) as acceptor, and which is catalyzed by the enzyme acyl-CoA:diacylglycerol acyltransferase. We have found that some plants and yeast also have an acyl-CoA-independent mechanism for TAG synthesis, which uses phospholipids as acyl donors and DAG as acceptor. This reaction is catalyzed by an enzyme that we call phospholipid:diacylglycerol acyltransferase, or PDAT. PDAT was characterized in microsomal preparations from three different oil seeds: sunflower, castor bean, and Crepis palaestina. We found that the specificity of the enzyme for the acyl group in the phospholipid varies between these species. Thus, C. palaestina PDAT preferentially incorporates vernoloyl groups into TAG, whereas PDAT from castor bean incorporates both ricinoleoyl and vernoloyl groups. We further found that PDAT activity also is present in yeast microsomes. The substrate specificity of this PDAT depends on the head group of the acyl donor, the acyl group transferred, and the acyl chains of the acceptor DAG. The gene encoding the enzyme was identified. The encoded PDAT protein is related to lecithin:cholesterol acyltransferase, which catalyzes the acyl-CoA-independent synthesis of cholesterol esters. However, budding yeast PDAT and its relatives in fission yeast and Arabidopsis form a distinct branch within this protein superfamily, indicating that a separate PDAT enzyme arose at an early point in evolution.
ESTHER : Dahlqvist_2000_Proc.Natl.Acad.Sci.U.S.A_97_6487
PubMedSearch : Dahlqvist_2000_Proc.Natl.Acad.Sci.U.S.A_97_6487
PubMedID: 10829075
Gene_locus related to this paper: yeast-pdat

Title : Smoking and schizophrenia: abnormal nicotinic receptor expression - Leonard_2000_Eur.J.Pharmacol_393_237
Author(s) : Leonard S , Breese C , Adams C , Benhammou K , Gault J , Stevens K , Lee M , Adler L , Olincy A , Ross R , Freedman R
Ref : European Journal of Pharmacology , 393 :237 , 2000
Abstract : Biological and genetic evidence suggests a role for the neuronal nicotinic receptors in the neuropathophysiology of schizophrenia. Nicotine normalizes an auditory evoked potential deficit seen in subjects who suffer from the disease. Nicotinic receptors with both high and low affinity for nicotine are decreased in postmortem brain of schizophrenics compared to control subjects. The chromosomal locus of the human alpha-7 gene (15q14) is linked to the gating deficit with a lod of 5.3, and antagonists of the alpha-7 receptor (alpha-bungarotoxin and methyllycaconitine) induce a loss of gating in rodents. We have cloned the human alpha-7 gene and found it to be partially duplicated proximal to the full-length gene. The duplication is expressed in both the brain and in peripheral blood cells of normal subjects, but is missing in some schizophrenic subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.
ESTHER : Leonard_2000_Eur.J.Pharmacol_393_237
PubMedSearch : Leonard_2000_Eur.J.Pharmacol_393_237
PubMedID: 10771019

Title : Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases - Perry_2000_Eur.J.Pharmacol_393_215
Author(s) : Perry E , Martin-Ruiz C , Lee M , Griffiths M , Johnson M , Piggott M , Haroutunian V , Buxbaum JD , Nasland J , Davis K , Gotti C , Clementi F , Tzartos SJ , Cohen O , Soreq H , Jaros E , Perry R , Ballard C , McKeith I , Court J
Ref : European Journal of Pharmacology , 393 :215 , 2000
Abstract : Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Abeta1-42, but not related to plaque or tangle densities. In contrast, alpha-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased alpha4 immunoreactivity in the cortex and lower densities of amyloid-beta plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not in nigro-striatal dopaminergic degeneration.
ESTHER : Perry_2000_Eur.J.Pharmacol_393_215
PubMedSearch : Perry_2000_Eur.J.Pharmacol_393_215
PubMedID: 10771016

Title : [(3)H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day - Benhammou_2000_Neuropharmacol_39_2818
Author(s) : Benhammou K , Lee M , Strook M , Sullivan B , Logel J , Raschen K , Gotti C , Leonard S
Ref : Neuropharmacology , 39 :2818 , 2000
Abstract : The principal sites for biological action of tobacco products are thought to be the nicotinic acetylcholine receptors (nAChR). Nicotinic receptor subunit genes, therefore, represent an important gene family for study in nicotine addiction. They are localized in both brain and in the periphery. In brain these receptors appear to function as modulators of synaptic transmission; the function of peripheral receptors is not known. Nicotinic receptor levels in human brain are regulated by smoking in a dose-dependent manner. In peripheral blood, nicotinic receptors are present on both lymphocytes and polymorphonuclear cells (PMN). We have compared [(3)H]nicotine binding in PMN isolated from smokers and non-smokers. [(3)H]nicotine binding was increased in smokers and was correlated, as in brain, with tobacco use. Expression of both mRNA and protein in lymphocytes and PMN, for a subset of nicotinic receptor subunits, suggests that these cell types contain both alpha4beta2 and alpha3beta4 receptors.
ESTHER : Benhammou_2000_Neuropharmacol_39_2818
PubMedSearch : Benhammou_2000_Neuropharmacol_39_2818
PubMedID: 11044752

Title : Alpha4 but not alpha3 and alpha7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer's disease - Martin-Ruiz_1999_J.Neurochem_73_1635
Author(s) : Martin-Ruiz CM , Court JA , Molnar E , Lee M , Gotti C , Mamalaki A , Tsouloufis T , Tzartos SJ , Ballard C , Perry RH , Perry EK
Ref : Journal of Neurochemistry , 73 :1635 , 1999
Abstract : Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to date it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal cortex of 14 AD cases and 15 age-matched control subjects was compared using immunoblotting with antibodies against recombinant peptides specific for alpha3, alpha4, and alpha7 subunits, in conjunction with [3H]epibatidine binding. Antibodies to alpha3, alpha4, and alpha7 produced one major band on western blots at 59, 51, and 57 kDa, respectively. [3H]Epibatidine binding and alpha4-like immunoreactivity (using antibodies against the extracellular domain and cytoplasmic loop of the alpha4 subunit) were reduced in AD cases compared with control subjects (p < 0.02) and with a subgroup of control subjects (n = 9) who did not smoke prior to death (p < 0.05) for the former two parameters. [3H]Epibatidine binding and cytoplasmic alpha4-like immunoreactivity were significantly elevated in a subgroup of control subjects (n = 4) known to have smoked prior to death (p < 0.05). There were no significant changes in alpha3- or alpha7-like immunoreactivity associated with AD or tobacco use. The selective involvement of alpha4 has implications for understanding the role of nicotinic receptors in AD and potential therapeutic targets.
ESTHER : Martin-Ruiz_1999_J.Neurochem_73_1635
PubMedSearch : Martin-Ruiz_1999_J.Neurochem_73_1635
PubMedID: 10501210

Title : Plasma lipoproteins in familial hepatic lipase deficiency - Connelly_1990_Arteriosclerosis_10_40
Author(s) : Connelly PW , Maguire GF , Lee M , Little JA
Ref : Arteriosclerosis , 10 :40 , 1990
Abstract : We have studied the lipoproteins, apolipoproteins, and postheparin lipase activities in an extended pedigree with familial hepatic lipase deficiency. A deficiency of hepatic lipase was found in three of five brothers and in one of their children. Triglyceride enrichment of low density and high density lipoproteins was identified as the constitutive phenotype. beta-very low density lipoprotein was observed in hepatic lipase-deficient subjects, but it was absent when the plasma triglyceride concentration was less than 1 mM/l. The hepatic lipase-deficient subjects had normal or elevated low density lipoprotein cholesterol and high density lipoprotein cholesterol concentrations. Hyperprebetalipoproteinemia, hyperbetalipoproteinemia, and hyperalphalipoproteinemia were observed in both affected and unaffected family members. Compared with the unaffected family members, the hepatic lipase-deficient subjects had no significant differences in very low density lipoprotein cholesterol, very low density lipoprotein triglyceride, or low density lipoprotein cholesterol. These observations are consistent with the presence of additional genes causing hyperlipidemia in this family, independent of the deficiency of hepatic lipase.
ESTHER : Connelly_1990_Arteriosclerosis_10_40
PubMedSearch : Connelly_1990_Arteriosclerosis_10_40
PubMedID: 2297346

Title : Localization of Drosophila neurons that contain choline acetyltransferase messenger RNA: an in situ hybridization study - Barber_1989_J.Comp.Neurol_280_533
Author(s) : Barber RP , Sugihara H , Lee M , Vaughn JE , Salvaterra PM
Ref : Journal of Comparative Neurology , 280 :533 , 1989
Abstract : In situ hybridization with radiolabeled complementary RNA (cRNA) probes was used to determine the location of the messenger RNA (mRNA) encoding choline acetyltransferase (ChAT) in Drosophila nervous system. Areas in the cell-rich cortical regions of the cerebrum and optic lobes hybridized with substantial concentrations of the probe. This contrasted with the cell-sparse neuropil areas where no significant concentrations of probe were observed. Although most of the cortical regions were substantially labeled, there were regions within all of the areas where labeling was sparse or nonexistent. For example in the lamina, even though the monopolar cell layer appeared to be heavily labeled, there were some neuronal profiles that were not associated with the probe. Moreover, the epithelial glia that form an arch of cell profiles subjacent to the monopolar cells were not labeled, nor were amacrine neurons in the apex of the lamina near the external optic chiasma. The highest concentration of probe (approximately 140 grains/400 microns2) was observed in the laminar monopolar cell region and the cerebral cortical rind. The next most heavily labeled region (approximately 90 grains/400 microns2) occurred over cortical cells of the medulla-lobula. In the peripheral nervous system, label over the antennal sensory neurons amounted to about 75 grains/400 microns2, and the retinular cell layer of the compound eye exhibited about 60 grains/400 microns2. The control probe did not hybridize in significant quantities in either cellular or noncellular regions. This study presents evidence that large numbers of Drosophila cortical and primary sensory neurons contain the messenger RNA necessary for the production of ChAT, the acetylcholine-synthesizing enzyme. Further, our findings provide baseline information for use in ontogenetic studies of cholinergic neurons in Drosophila, and they also provide normative data for studying the effects of mutant alleles at the Cha or Ace loci upon the transcription of ChAT messenger RNA.
ESTHER : Barber_1989_J.Comp.Neurol_280_533
PubMedSearch : Barber_1989_J.Comp.Neurol_280_533
PubMedID: 2496152