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Sample records for lipid analogues act

  1. Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation.

    PubMed

    Bellmann-Sickert, Kathrin; Elling, Christian E; Madsen, Andreas N; Little, Paul B; Lundgren, Karsten; Gerlach, Lars-Ole; Bergmann, Ralf; Holst, Birgitte; Schwartz, Thue W; Beck-Sickinger, Annette G

    2011-04-28

    The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.

  2. Enzymatic synthesis of lipid II and analogues.

    PubMed

    Huang, Lin-Ya; Huang, Shih-Hsien; Chang, Ya-Chih; Cheng, Wei-Chieh; Cheng, Ting-Jen R; Wong, Chi-Huey

    2014-07-28

    The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I.

    PubMed

    Siricilla, Shajila; Mitachi, Katsuhiko; Skorupinska-Tudek, Karolina; Swiezewska, Ewa; Kurosu, Michio

    2014-09-15

    Translocase I (MraY/MurX) is an essential enzyme in growth of the vast majority of bacteria that catalyzes the transformation from UDP-MurNAc-pentapeptide (Park's nucleotide) to prenyl-MurNAc-pentapeptide (lipid I), the first membrane-anchored peptidoglycan precursor. MurX has received considerable attention in the development of new tuberculosis (TB) drugs due to the fact that the MurX inhibitors kill exponentially growing Mycobacterium tuberculosis (Mtb) much faster than clinically used TB drugs. Lipid I isolated from Mtb contains the C50-prenyl unit that shows very poor water solubility; thus, this chemical characteristic of lipid I renders MurX enzyme assays impractical for screening and lacks reproducibility of the enzyme assays. We have established a scalable chemical synthesis of Park's nucleotide-N(ε)-dansylthiourea 2 that can be used as a MurX enzymatic substrate to form lipid I analogues. In our investigation of the minimum structure requirement of the prenyl phosphate in the MraY/MurX-catalyzed lipid I analogue synthesis with 2, we found that neryl phosphate (C10 phosphate) can be recognized by MraY/MurX to generate the water-soluble lipid I analogue in quantitative yield under the optimized conditions. Here, we report a rapid and robust analytical method for quantifying MraY/MurX inhibitory activity of library molecules. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Biosynthesis of A Water-Soluble Lipid I Analogue and A Convenient Assay for Translocase I

    PubMed Central

    Skorupinska-Tudek, Karolina; Swiezewska, Ewa; Kurosu, Michio

    2014-01-01

    Translocase I (MraY/MurX) is an essential enzyme in growth of the vast majority of bacteria that catalyzes the transformation from UDP-MurNAc-pentapeptide (Park’s nucleotide) to prenyl-MurNAc-pentapeptide (lipid I), the first membrane-anchored peptidoglycan precursor. MurX has been received considerable attentions to the development of new TB drugs due to the fact that the MurX inhibitors kill exponentially growing Mycobacterium tuberculosis (Mtb) much faster than clinically used TB drugs. Lipid I isolated from Mtb contains the C50-prenyl unit that shows very poor water-solubility, and thus, this chemical characteristic of lipid I renders MurX enzyme assays impractical for screening and lacks reproducibility of the enzyme assays. We have established a scalable chemical synthesis of Park’s nucleotide-Nε-dansylthiourea 2 that can be used as a MurX enzymatic substrate to form lipid I analogues. In our investigation of minimum structure requirement of the prenyl phosphate in the MraY/MurX-catalyzed lipid I analogue synthesis with 2, we found that neryl phosphate (C10-phosphate) can be recognized by MraY/MurX to generate the water-soluble lipid I analogue in quantitative yield under the optimized conditions. Herein, we report a rapid and robust analytical method for quantifying MraY/MurX inhibitory activity of library molecules. PMID:24939461

  5. Structure-activity investigation on the gene transfection properties of cardiolipin mimicking gemini lipid analogues.

    PubMed

    Bajaj, Avinash; Paul, Bishwajit; Kondaiah, Paturu; Bhattacharya, Santanu

    2008-06-01

    A structure-activity relationship has been explored on the gene transfection efficiencies of cardiolipin mimicking gemini lipid analogues upon variation of length and hydrophilicity of the spacer between the cationic ammonium headgroups and lipid hydrocarbon chain lengths. All the gemini lipids were found to be highly superior in gene transfer abilities as compared to their monomeric lipid and a related commercially available formulation. Pseudoglyceryl gemini lipids bearing an oxyethylene (-CH2-(CH2-O-CH2)m-CH2-) spacer were found to be superior gene transfecting agents as compared to those bearing polymethylene (-CH2)m-) spacers. The major characteristic feature of the present set of gemini lipids is their serum compatibility, which is most often the major hurdle in liposome-mediated gene delivery.

  6. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

    NASA Astrophysics Data System (ADS)

    Tran, Anh T.; Watson, Emma E.; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J.; Giltrap, Andrew M.; Pang, Angel; Wong, Weng Ruh; Linington, Roger G.; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A.; West, Nicholas P.; Bugg, Timothy D. H.; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Crick, Dean C.; Britton, Warwick J.; Payne, Richard J.

    2017-03-01

    Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

  7. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

    PubMed Central

    Tran, Anh T.; Watson, Emma E.; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J.; Giltrap, Andrew M.; Pang, Angel; Wong, Weng Ruh; Linington, Roger G.; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A.; West, Nicholas P.; Bugg, Timothy D. H.; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Crick, Dean C.; Britton, Warwick J.; Payne, Richard J.

    2017-01-01

    Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis. PMID:28248311

  8. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.

    PubMed

    Tran, Anh T; Watson, Emma E; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J; Giltrap, Andrew M; Pang, Angel; Wong, Weng Ruh; Linington, Roger G; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A; West, Nicholas P; Bugg, Timothy D H; Tod, Julie; Dowson, Christopher G; Roper, David I; Crick, Dean C; Britton, Warwick J; Payne, Richard J

    2017-03-01

    Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

  9. Artepillin C isoprenomics: design and synthesis of artepillin C isoprene analogues as lipid peroxidation inhibitor having low mitochondrial toxicity.

    PubMed

    Uto, Yoshihiro; Ae, Shutaro; Koyama, Daisuke; Sakakibara, Mitsutoshi; Otomo, Naoki; Otsuki, Mamoru; Nagasawa, Hideko; Kirk, Kenneth L; Hori, Hitoshi

    2006-08-15

    We designed and synthesized isoprene analogues of artepillin C, a major component of Brazilian propolis, and investigated the inhibitory activity on lipid peroxidation of rat liver mitochondria (RLM) and RLM toxicity based on isoprenomics. We succeeded in the synthesis of artepillin C isoprene analogues using regioselective prenylation within the range from 22% to 53% total yield. Reactivity of artepillin C and its isoprene analogues with ABTS (2,2'-Azinobis(3-ethylbenzothiazoline-6-sulfonate)) radical cations showed only a slight difference among the molecules. The isoprene side-chain elongation analogues of artepillin C showed almost the same inhibitory activity against RLM lipid peroxidation as artepillin C. Artepillin C and its isoprene analogues had very weak RLM uncoupling activity. Moreover, artepillin C and its isoprene analogues exhibited a lower inhibitory activity against adenosine 5'-triphosphate (ATP) synthesis by about two orders of magnitude than the effective inhibitory activity against RLM lipid peroxidation. From these results we conclude that artepillin C isoprene analogues could be potent lipid peroxidation inhibitors having low mitochondrial toxicity. We also conclude that elongation of the isoprene side chain of artepillin C to increase lipophilicity had little influence on the inhibitory activity toward RLM lipid peroxidation.

  10. Imidazolium-Based Lipid Analogues and Their Interaction with Phosphatidylcholine Membranes.

    PubMed

    Wang, Da; de Jong, Djurre H; Rühling, Andreas; Lesch, Volker; Shimizu, Karina; Wulff, Stephanie; Heuer, Andreas; Glorius, Frank; Galla, Hans-Joachim

    2016-12-06

    4,5-Dialkylated imidazolium lipid salts are a new class of lipid analogues showing distinct biological activities. The potential effects of the imidazolium lipids on artificial lipid membranes and the corresponding membrane interactions was analyzed. Therefore, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was employed to create an established lipid monolayer model and a bilayer membrane. Mixed monolayers of DPPC and 4,5-dialkylimidazolium lipids differing by their alkyl chain length (C7, C11, and C15) were characterized by surface pressure-area (π-A) isotherms using a Wilhelmy film balance in combination with epifluorescence microscopy. Monolayer hysteresis for binary mixtures was examined by recording triplicate consecutive compression-expansion cycles. The lipid miscibility and membrane stability of DPPC/imidazolium lipids were subsequently evaluated by the excess mean molecular area (ΔA(ex)) and the excess Gibbs free energy (ΔG(ex)) of mixing. Furthermore, the thermotropic behavior of mixed liposomes of DPPC/imidazolium lipids was investigated by differential scanning calorimetry (DSC). The C15-imidazolium lipid (C15-IMe·HI) forms a thermodynamically favored and kinetically reversible Langmuir monolayer with DPPC and exhibits a rigidification effect on both DPPC monolayer and bilayer structures at low molar fractions (X ≤ 0.3). However, the incorporation of the C11-imidazolium lipid (C11-IMe·HI) causes the formation of an unstable and irreversible Langmuir-Gibbs monolayer with DPPC and disordered DPPC liposomes. The C7-imidazolium lipid (C7-IMe·HI) displays negligible membrane activity. To better understand these results on a molecular level, all-atom molecular dynamics (MD) simulations were performed. The simulations yield two opposing molecular mechanisms governing the different behavior of the three imidazolium lipids: a lateral ordering effect and a free volume/stretching effect. Overall, our study provides the first evidence that the membrane

  11. Lipid-lowering effects of farnesylquinone and related analogues from the marine-derived Streptomyces nitrosporeus.

    PubMed

    Liu, Dong; Yang, Aigang; Wu, Chongming; Guo, Peng; Proksch, Peter; Lin, Wenhan

    2014-11-15

    Bioassay-guided fractionation of the fermentation broth of Arctic Streptomyces nitrosporeus YBH10-5 resulted in the isolation of seven new compounds named nitrosporeunols A-G (1-7), together with seven known analogues (8-14). Their structures were determined based on extensive spectroscopic analysis. Compounds 1-14 were evaluated for the lowering lipid effects, while two compounds (10 and 12) remarkably decreased lipid levels including total cholesterol (TC) and triglycerides (TG) in HepG2 cells. Quantitative realtime PCR and Western blot indicated that farnesylquinone (12) increased the expression of the key proteins including peroxisome proliferator-activated receptor-α (PPARα), peroxisome proliferator-activated receptor-γ, and coactivator 1α (PGC-1α), as well as their downstream genes carnitine palmitoyltransterase-1 (CPT-1), acyl-coenzyme A oxidase 1 (ACOX), malonyl CoA decarboxylase 1 (MCD1), pyruvate dehydrogenase kinase 4 (PDK4), and cholesterol 7α -hydroxylase (CYP7A1). Luciferase assay showed that 12 increased the transcriptional activity of PPARα, while its lipid-lowering effect was abolished by PPARα inhibitor, MK886, in HepG2 cells. These findings suggested that 12 is a potent lipid-lowering agent which may decrease lipid levels through upregulation of PPARα pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Budget Impact of Long-Acting Insulin Analogues: The Case in Brazil

    PubMed Central

    da Silva, Everton Nunes; Pereira, Maurício G

    2016-01-01

    Background Long-acting insulin analogues for type 1 diabetes (T1D) treatment have been available on the Brazilian market since 2002. However, the population cannot access the analogues through the public health system. Objective To estimate the incremental budget impact of long-acting insulin analogues coverage for T1D patients in the Brazilian public health system compared to NPH insulin. Methods We performed a budget impact analysis of a five-year period. The eligible population was projected using epidemiological data from the International Diabetes Federation estimates for patients between 0–14 and 20–79 years old. The prevalence of T1D was estimated in children, and the same proportion was applied to the 15-19-year-old group due to a gap in epidemiological information. We considered 4,944 new cases per year and a 34.61/100,000 inhabitants mortality rate. Market share for long-acting insulin analogues was assumed as 20% in the first year, reaching 40% in the fifth year. The mean daily dose was taken from clinical trials. We calculated the bargaining power of the Ministry of Health by dividing the price paid for human insulin in the last purchase by the average regulated price. We performed univariate and multivariate sensitivity analyses. Results The incremental budget impact of long-acting insulin analogues was US$ 28.6 million in the first year, and reached US$ 58.7 million in the fifth year. The total incremental budget impact was US$ 217.9 million over the five-year period. The sensitivity analysis showed that the percentage of T1D among diabetic adults and the insulin analogue price were the main factors that affected the budget impact. Conclusions The cost of the first year of long-acting insulin analogue coverage would correspond to 0.03% of total public health expenditure. The main advantage of this study is that it identifies potential bargaining power because it features more realistic profiles of resource usage, once centralized purchasing is

  13. Budget Impact of Long-Acting Insulin Analogues: The Case in Brazil.

    PubMed

    Laranjeira, Fernanda O; Silva, Everton Nunes da; Pereira, Maurício G

    2016-01-01

    Long-acting insulin analogues for type 1 diabetes (T1D) treatment have been available on the Brazilian market since 2002. However, the population cannot access the analogues through the public health system. To estimate the incremental budget impact of long-acting insulin analogues coverage for T1D patients in the Brazilian public health system compared to NPH insulin. We performed a budget impact analysis of a five-year period. The eligible population was projected using epidemiological data from the International Diabetes Federation estimates for patients between 0-14 and 20-79 years old. The prevalence of T1D was estimated in children, and the same proportion was applied to the 15-19-year-old group due to a gap in epidemiological information. We considered 4,944 new cases per year and a 34.61/100,000 inhabitants mortality rate. Market share for long-acting insulin analogues was assumed as 20% in the first year, reaching 40% in the fifth year. The mean daily dose was taken from clinical trials. We calculated the bargaining power of the Ministry of Health by dividing the price paid for human insulin in the last purchase by the average regulated price. We performed univariate and multivariate sensitivity analyses. The incremental budget impact of long-acting insulin analogues was US$ 28.6 million in the first year, and reached US$ 58.7 million in the fifth year. The total incremental budget impact was US$ 217.9 million over the five-year period. The sensitivity analysis showed that the percentage of T1D among diabetic adults and the insulin analogue price were the main factors that affected the budget impact. The cost of the first year of long-acting insulin analogue coverage would correspond to 0.03% of total public health expenditure. The main advantage of this study is that it identifies potential bargaining power because it features more realistic profiles of resource usage, once centralized purchasing is established as an economically sustainable strategy

  14. Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

    PubMed

    Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa

    2013-11-01

    Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.

  15. Reversible inhibition of central precocious puberty with a long acting GnRH analogue.

    PubMed Central

    Ward, P S; Ward, I; McNinch, A W; Savage, D C

    1985-01-01

    A 7 year old girl with precocious puberty was treated with buserelin, a long acting analogue of gonadotrophin releasing hormone. Spontaneous and stimulated gonadotrophin secretion became prepubertal but returned to pubertal values when buserelin was withdrawn, suggesting that normal sexual maturation should follow cessation of treatment. PMID:3931565

  16. Bilayer/cytoskeleton interactions in lipid-symmetric erythrocytes assessed by a photoactivable phospholipid analogue

    SciTech Connect

    Pradhan, D.; Schlegel, R.A. ); Williamson, P. )

    1991-08-06

    Two mechanisms have been proposed for maintenance of transbilayer phospholipid asymmetry in the erythrocyte plasma membrane, one involving specific interactions between the aminophospholipids of the inner leaflet of the bilayer and the cytoskeleton, particularly spectrin, and the other involving the aminophospholipid translocase. If the former mechanism is correct, then erythrocytes which have lost their asymmetric distribution of phospholipids should display altered bilayer/cytoskeleton interactions. To test this possibility, normal erythrocytes, erythrocytes from patients with chronic myelogenous leukemia or sickle disease, and lipid-symmetric and -asymmetric erythrocyte ghosts were labeled with the radioactive photoactivable analogue of phosphatidylethanolamine, 2-(2-azido-4-nitrobenzoyl)-1-acyl-sn-glycero-3-phospho({sup 14}C) ethanolamine (({sup 14}C)AzPE), previously shown to label cytoskeletal proteins from the bilayer. The labeling pattern of cytoskeletal proteins in pathologic erythrocytes and lipid-asymmetric erythrocyte ghosts was indistinguishable from normal erythrocytes, indicating that the probe detects no differences in bilayer/cytoskeleton interactions in these cells. In contrast, in lipid-symmetric erythrocyte ghosts, labeling of bands 4.1 and 4.2 and actin, and to a lesser extent ankyrin, by ({sup 14}C)AzPE was considerably reduced. Significantly, however, labeling of spectrin was unaltered in the lipid-symmetric cells. These results do not support a model in which spectrin is involved in the maintenance of an asymmetric distribution of phospholipids in erythrocytes.

  17. Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues (PIAs) in NSCLC cells

    PubMed Central

    Zhang, Chunyu; Elkahloun, Abdel G.; Liao, Hongling; Delaney, Shannon; Saber, Barbara; Morrow, Betsy; Gills, Joell J.; Hollander, M. Christine; Prendergast, George C.; Dennis, Phillip A.

    2011-01-01

    Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIAs) are analogues of the products of PI3K that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of 5 active PIAs and the PI3K inhibitor LY294002 (LY) was performed in NSCLC cells using high-density oligonucleotide arrays. Gene ontology analysis revealed genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, while genes involved in DNA replication, repair and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into 3 groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3 and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB) and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity. PMID:21551261

  18. MODULATING LPS SIGNAL TRANSDUCTION AT THE LPS RECEPTOR COMPLEX WITH SYNTHETIC LIPID A ANALOGUES

    PubMed Central

    White, Aileen F. B.; Demchenko, Alexei V.

    2015-01-01

    Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization. PMID:25480508

  19. Structural organisation and phase behaviour of a stratum corneum lipid analogue: ceramide 3A.

    PubMed

    Garidel, Patrick

    2006-05-21

    The thermotropic phase behaviour and structural organisation of ceramide N-linoeoyl-phytosphingosine (ceramide 3A) is investigated by means of differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Its polymorphism and structural properties are compared with two ceramides of the type III class with various hydrocarbon chain saturation degrees. After hydration the main phase transition temperature of ceramide 3A is found at 76 degrees C with a phase transition enthalpy of +29 kJ mol(-1). Analysing the frequency of methylene stretching vibrations (by infrared spectroscopy) reveals that the fluidity (amount of trans-gauche isomers) is strongly increased for ceramide 3A compared to its stearoyl ceramide type III analogue. After lipid hydration, the acyl chains of all investigated phytosphingosine ceramides of type III adopt a hexagonal-like chain packing. The amide I and amide II vibrations are quite sensitive to the phase transition of the ceramide. The corresponding band analysis reveals strong inter- and intramolecular hydrogen bonds between the amide and hydroxyl groups in the ceramide head groups. The H-bonding network and conformation of the head group of ceramide 3A is only slightly influenced by hydration. The water penetration capacity of ceramide 3A is, however, considerably larger compared to other phytosphingosine derivatives. The structural and organisational properties of ceramides of type III class are discussed with respect to their physiological relevancies for the stratum corneum lipid barrier property of the skin.

  20. Significant antitumor effect of a synthetic lipid A analogue, DT-5461, on murine syngeneic tumor models.

    PubMed

    Kumazawa, E; Tohgo, A; Soga, T; Kusama, T; Osada, Y

    1992-01-01

    The antitumor effect of a synthetic lipid A analogue, DT-5461, was investigated using syngeneic tumor models in mice. Intravenous injection of DT-5461 into mice transplanted with solid tumors of MethA fibrosarcoma, MH134 hepatoma, MM46 mammary carcinoma, Lewis lung carcinoma (3LL), and colon adenocarcinomas 26 and 38 resulted in significant reductions in the weight of all tumors except Colon 26, with marked hemorrhagic necrosis of tumor tissues. Efficacy was almost equal to that of an Escherichia coli-type synthetic lipid A (compound 506), and also to those of some chemotherapeutics including Adriamycin, mitomycin C, fluorouracil and cisplatin. Furthermore, DT-5461 was more effective than other immunotherapeutics, including picibanil (OK-432) and lentinan. However, its antitumor effects were inferior to those of Adriamycin or OK-432 against the malignant ascites caused by intraperitoneal inoculation with MethA or with MH134 cells; life span was not prolonged by either intraperitoneal or intravenous administration. In addition, although DT-5461 showed direct inhibitory effects on the in vitro growth of MethA or MH134, these were much weaker than those of Adriamycin. These findings clearly indicated that DT-5461 with systemic administration is a highly effective antitumor agent on solid tumors, and suggest that the antitumor effect of DT-5461 with potent necrotizing activity might derive from indirect mechanisms related to the activation of host immune systems and not to the weak direct cytotoxicity.

  1. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    SciTech Connect

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

    2016-08-05

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.

  2. Structure-activity analysis of diffusible lipid electrophiles associated with phospholipid peroxidation: 4-hydroxynonenal and 4-oxononenal analogues.

    PubMed

    McGrath, Colleen E; Tallman, Keri A; Porter, Ned A; Marnett, Lawrence J

    2011-03-21

    Electrophile-mediated disruption of cell signal-ing is involved in the pathogenesis of several diseases including atherosclerosis and cancer. Diffusible and membrane bound lipid electrophiles are known to modify DNA and protein substrates and modulate cellular pathways including ER stress, antioxidant response, DNA damage, heat shock, and apoptosis. Herein we report on a structure-activity relationship for several electrophilic analogues of 4-hydroxynonenal (HNE) and 4-oxononenal (ONE) with regard to toxicity and anti-inflammatory activity. The analogues studied were the oxidation products of HNE and ONE, HNEA/ONEA, the in vivo hydrolysis products of oxidized phosphatidylcholine, COOH-HNE/COOH-ONE, and their methyl esters, COOMe-HNE/ONE. The reactivity of each compound toward N-acetylcysteine was determined and compared to the toxicity toward a human colorectal carcinoma cell line (RKO) and a human monocytic leukemia cell line (THP-1). Further analysis was performed in differentiated THP-1 macrophages to assess changes in macrophage activation and pro-inflammatory signaling in response to each lipid electrophile. HNE/ONE analogues inhibited THP-1 macrophage production of the pro-inflammatory cytokines, IL-6, IL-1β, and TNFα, after lipopolysaccharide (LPS)/IFNγ activation. Inhibition of cytokine production was observed at submicromolar concentrations of several analogues with as little as 30 min of exposure. Phagocytosis of fluorescent beads was also inhibited by lipid electrophile treatment. Lipid electrophiles related to HNE/ONE are both toxic and anti-inflammatory, but the anti-inflammatory effects in human macrophages are observed at nontoxic concentrations. Neither toxicity nor anti-inflammatory activity are strongly correlated to the reactivity of the model nucleophile, N-acetylcysteine.

  3. Drug uptake, lipid rafts, and vesicle trafficking modulate resistance to an anticancer lysophosphatidylcholine analogue in yeast.

    PubMed

    Cuesta-Marbán, Álvaro; Botet, Javier; Czyz, Ola; Cacharro, Luis M; Gajate, Consuelo; Hornillos, Valentín; Delgado, Javier; Zhang, Hui; Amat-Guerri, Francisco; Acuña, A Ulises; McMaster, Christopher R; Revuelta, José Luis; Zaremberg, Vanina; Mollinedo, Faustino

    2013-03-22

    The ether-phospholipid edelfosine, a prototype antitumor lipid (ATL), kills yeast cells and selectively kills several cancer cell types. To gain insight into its mechanism of action, we performed chemogenomic screens in the Saccharomyces cerevisiae gene-deletion strain collection, identifying edelfosine-resistant mutants. LEM3, AGP2, and DOC1 genes were required for drug uptake. Edelfosine displaced the essential proton pump Pma1p from rafts, inducing its internalization into the vacuole. Additional ATLs, including miltefosine and perifosine, also displaced Pma1p from rafts to the vacuole, suggesting that this process is a major hallmark of ATL cytotoxicity in yeast. Radioactive and synthetic fluorescent edelfosine analogues accumulated in yeast plasma membrane rafts and subsequently the endoplasmic reticulum. Although both edelfosine and Pma1p were initially located at membrane rafts, internalization of the drug toward endoplasmic reticulum and Pma1p to the vacuole followed different routes. Drug internalization was not dependent on endocytosis and was not critical for yeast cytotoxicity. However, mutants affecting endocytosis, vesicle sorting, or trafficking to the vacuole, including the retromer and ESCRT complexes, prevented Pma1p internalization and were edelfosine-resistant. Our data suggest that edelfosine-induced cytotoxicity involves raft reorganization and retromer- and ESCRT-mediated vesicular transport and degradation of essential raft proteins leading to cell death. Cytotoxicity of ATLs is mainly dependent on the changes they induce in plasma membrane raft-located proteins that lead to their internalization and subsequent degradation. Edelfosine toxicity can be circumvented by inactivating genes that then result in the recycling of internalized cell-surface proteins back to the plasma membrane.

  4. STED microscopy detects and quantifies liquid phase separation in lipid membranes using a new far-red emitting fluorescent phosphoglycerolipid analogue.

    PubMed

    Honigmann, Alf; Mueller, Veronika; Hell, Stefan W; Eggeling, Christian

    2013-01-01

    We have developed a bright, photostable, and far-red emitting fluorescent phosphoglycerolipid analogue to probe diffusion characteristics of lipids in membranes. The lipid analogue consists of a saturated (C18) phosphoethanolamine and a hydrophilic far-red emitting fluorescent dye (KK114) that is tethered to the head group by a long polyethylenglycol linker. In contrast to reported far-red emitting fluorescent lipid analogues, this one partitions predominantly into liquid ordered domains of phase-separated ternary bilayers. We performed fluorescence correlation spectroscopy with a super-resolution STED microscope (STED-FCS) to measure the lateral diffusion of the new lipid analogue in the liquid ordered (Lo) and disordered (Ld) phase. On a mica support, we observed micrometer large phases and found that the lipid analogue diffuses freely on all tested spatial scales (40-250 nm) in both the Ld and Lo phase with diffusion coefficients of 1.8 microm2 s(-1) and 0.7 microm2 s(-1) respectively. This indicates that the tight molecular packing of the Lo phase mainly slows down the diffusion rather than causing anomalous sub-diffusion. The same ternary mixture deposited on acid-cleaned glass forms Lo nanodomains of < 40 nm to 300 nm in diameter as only revealed by STED microscopy, which demonstrates the severe influence of interactions with the substrate on the sizes of domains in membranes. When averaging over different positions, STEd-FCS measurements on such glass supported membranes displayed anomalous sub-diffusion. This anomaly can be attributed to a transient partitioning of the lipid analogue into the nano-domains, where diffusion is slowed down. Our results suggest that STED-FCS in combination with a Lo-partitioning fluorescent lipid analogue can directly probe the presence of Lo nano-domains, which in the future should allow the study of potential lipid rafts in live-cell membranes.

  5. Lipid analogues as potential drugs for the regulation of mitochondrial cell death

    PubMed Central

    Murray, Michael; Dyari, Herryawan Ryadi Eziwar; Allison, Sarah E; Rawling, Tristan

    2014-01-01

    The mitochondrion plays an important role in the production of energy as ATP, the regulation of cell viability and apoptosis, and the biosynthesis of major structural and regulatory molecules, such as lipids. During ATP production, reactive oxygen species are generated that alter the intracellular redox state and activate apoptosis. Mitochondrial dysfunction is a well-recognized component of the pathogenesis of diseases such as cancer. Understanding mitochondrial function, and how this is dysregulated in disease, offers the opportunity for the development of drug molecules to specifically target such defects. Altered energy metabolism in cancer, in which ATP production occurs largely by glycolysis, rather than by oxidative phosphorylation, is attributable in part to the up-regulation of cell survival signalling cascades. These pathways also regulate the balance between pro-and anti-apoptotic factors that may determine the rate of cell death and proliferation. A number of anti-cancer drugs have been developed that target these factors and one of the most promising groups of agents in this regard are the lipid-based molecules that act directly or indirectly at the mitochondrion. These molecules have emerged in part from an understanding of the mitochondrial actions of naturally occurring fatty acids. Some of these agents have already entered clinical trials because they specifically target known mitochondrial defects in the cancer cell. LINKED ARTICLES This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24111728

  6. Treatment of advanced pancreatic cancer with the long-acting somatostatin analogue lanreotide: in vitro and in vivo results

    PubMed Central

    Raderer, M; Hamilton, G; Kurtaran, A; Valencak, J; Haberl, I; Hoffmann, O; Kornek, G V; Vorbeck, F; Hejna, M H L; Virgolini, I; Scheithauer, W

    1999-01-01

    Fourteen patients with metastatic pancreatic adenocarcinoma were treated with the long-acting somatostatin (SST) analogue lanreotide. No objective response was obtained, and the median survival was 4 months (range 1.8–7 months). Pancreatic cancer could not be visualized by means of SST-receptor (R) scintigraphy in our patients. In vitro data also demonstrated absence of SSTR2 expression, suggesting pancreatic cancer not to be a potential target for treatment with SST analogues. © 1999 Cancer Research Campaign PMID:10027326

  7. LAPS-FSH: a new and effective long-acting follicle-stimulating hormone analogue for the treatment of infertility.

    PubMed

    Jung, Sunyoung; Park, Youngjin; Kim, YoungHoon; Kim, Yu Yon; Choi, Hyun-Ji; Son, Woo-Chan; Kwon, SeChang

    2014-10-01

    Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6µgkg(-1) follitropin β, 6, 12 or 42µgkg(-1) corifollitropin α or 3, 6 or 12µgkg(-1) long acting protein/peptide discovery-follicle-stimulating hormone (LAPS-FSH). As a result, the animals treated with 12µgkg(-1) LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs.

  8. Changes in cellular lipid synthesis of normal and neoplastic cells during cytolysis induced by alkyl lysophospholipid analogues.

    PubMed

    Herrmann, D B

    1985-09-01

    Susceptibility of eight different cell types of murine or human origins to alkyl lysophospholipid analogue (ALP)-induced cytolysis correlated well with a selective, dose-dependent inhibition of radiolabeled oleic acid incorporation into phosphatidylcholine (PC) and a concomitant stimulation of incorporation into neutral lipids (NL), mainly triacylglycerols. In resistant cells (murine macrophages, L929S, K562, and rMeth A) a counts per minute NL/counts per minute PC ratio of 0.8-1.0 was observed with 30 micrograms ALP/ml; in sensitive tumor targets (Meth A, HL60, YAC, and ABLS-8.1) values greater than 2.7 were found with 5-10 micrograms ALP/ml. Changes in lipid metabolism preceded cytolysis in Meth A fibrosarcoma cells. In degradation experiments the percentage of total lipid radioactivity in PC was reduced after 24 hours to 47% compared to that in controls in sensitive Meth A with 10 micrograms ALP/ml. The macrophage-PC was unaffected at the same concentration. Sensitivity to ALP was independent of cell proliferation. Resistance was not restricted to normal cells and was inducible in Meth A (and rMeth A).

  9. Effects of long-acting somatostatin analogues on redox systems in rat lens in experimental diabetes

    PubMed Central

    Kunjara, Sirilaksana; Greenbaum, A Leslie; Sochor, Milena; Flyvbjerg, Allan; Grønbaek, Henning; McLean, Patricia

    2014-01-01

    The effects of long-acting somatostatin analogues, angiopeptin (AGP) and Sandostatin (SMS), on the early decline in the lens content of glutathione (GSH), ATP and NADPH and increase in sorbitol were studied in STZ diabetic rats, and comparison was made with the effect of insulin. Three factors prompted this study: (i) the known increase in IGF-1 in ocular tissue in diabetes and antagonistic effect of somatostatins, (ii) the known effect of IGF-1 in increasing lens aldose reductase and (iii) the lack of effect of somatostatins on diabetic hyperglycaemia, the latter enabling a differentiation to be made between effects of hyperglycaemia per se and site(s) of IGF-1/somatostatins. All four metabolites studied showed a significant restoration towards the normal control level after 7 days of treatment with AGP and SMS, and AGP was more effective on levels of GSH and ATP. A significant correlation was found between GSH and ATP across all groups at 7 days treatment. The redox state changes in diabetes include both NADP+/NADPH and NAD+/NADH in the conversion of glucose to sorbitol and via sorbitol dehydrogenase to fructose with a linked decrease in ATP formation via NAD+/NADH regulation of the glycolytic pathway. The interlinked network of change includes the requirement for ATP in the synthesis of GSH. The present study points to possible loci of action of somatostatins in improving metabolic parameters in the diabetic rat lens via effects on aldose reductase and/or glucose transport at GLUT 3. PMID:24602114

  10. Efficacy of the long-acting repeatable formulation of the somatostatin analogue octreotide in postoperative dumping.

    PubMed

    Arts, Joris; Caenepeel, Philip; Bisschops, Raf; Dewulf, Dominiek; Holvoet, Lieselot; Piessevaux, Hubert; Bourgeois, Stefan; Sifrim, Daniel; Janssens, Jozef; Tack, Jan

    2009-04-01

    Several studies have established symptomatic and mechanistic benefits of the somatostatin analogue octreotide in patients with dumping syndrome, but clinical use is hampered by the requirement for subcutaneous administration 3 times daily. We compared the efficacy of subcutaneous octreotide with that of the long-acting repeatable (LAR) octreotide formulation, which is administered monthly, in patients with dumping syndrome. The study included 30 consecutive patients with postoperative dumping, evidenced by oral glucose tolerance test (OGTT) results and insufficient response to dietary measures. OGTT, dumping severity score (summary of scores 0-3 for 8 early and 6 late dumping symptoms), and quality-of-life data were evaluated at baseline, after 3 days of subcutaneous administration of octreotide (0.5 mg), and then after 3 monthly intramuscular injections of octreotide LAR (20 mg). Both formulations of octreotide significantly reduced total dumping severity scores (21.7 +/- 1.6 at baseline, 11.2 +/- 1.2 for subcutaneous and 14.0 +/- 1.8 for LAR formulations; P < .05). This reduction was associated with significant improvements in the increase in pulse rate (13.8 +/- 5.8 at baseline vs -0.3 +/- 2.2 and 1.9 +/- 1.7; P < .05) as well as the increase in hematocrit level (4.0 +/- 1.4 at baseline vs 0.3 +/- 0.9. and 0.4 +/- 1.0; P < .05), and the lowest glycemia level in the OGTT (54.1 +/- 6.7 at baseline vs 98.9 +/- 7.1 and 67.8 +/- 5.9; P < .05). LAR octreotide administration significantly improved patients' quality of life. Patients' evaluations of their overall treatment efficacy was higher on LAR compared with the subcutaneous formulation (83% vs 52%; P = .01). Gallbladder stones occurred in 4 patients. Monthly administration of LAR octreotide improves OGTT results, symptoms, and quality of life in patients with postoperative dumping.

  11. Large lipid-rich mammary analogue secretory carcinoma of parotid gland: An unusual case.

    PubMed

    Joshi, Prashant; Mridha, Asit Ranjan; Singh, Shuchita; Kinra, Prateek; Ray, Ruma; Thakar, Alok

    2015-01-01

    Mammary analogue secretory carcinoma (MASC) of the salivary gland is a malignant tumor which bears morphologic, immunohistochemical and molecular features similar to those of mammary secretory carcinoma. The tumor is considered as a low-grade malignancy perhaps slightly more aggressive than acinic cell carcinoma. High-grade transformation with recurrences, regional nodal involvement, metastases, and cancer-related death has been reported in a few cases. We report an unusual case of large MASC of the parotid gland in a young patient without regional lymph node involvement. To the best of our knowledge till date such a large MASC of the salivary gland has not been reported in the English literature.

  12. Incorporation of monodisperse oligoethyleneglycol amino acids into anticonvulsant analogues of galanin and neuropeptide y provides peripherally acting analgesics.

    PubMed

    Zhang, Liuyin; Klein, Brian D; Metcalf, Cameron S; Smith, Misty D; McDougle, Daniel R; Lee, Hee-Kyoung; White, H Steve; Bulaj, Grzegorz

    2013-02-04

    Delivery of neuropeptides into the central and/or peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogues containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogues Gal-B2-dPEG(24), Gal-R2-dPEG(24) and NPY-dPEG(24) displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG(24) was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG(24) and palmitic acids, respectively. All the dPEGylated analogues exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.

  13. Doping control analysis of intact rapid-acting insulin analogues in human urine by liquid chromatography-tandem mass spectrometry.

    PubMed

    Thevis, Mario; Thomas, Andreas; Delahaut, Philippe; Bosseloir, Alain; Schänzer, Wilhelm

    2006-03-15

    Insulin and related synthetic therapeutics have been prohibited by the World Anti-Doping Agency for athletes demonstrably not suffering from diabetes mellitus. The primary specimen for doping controls has been urine, but the renal excretion of intact human insulin as well as synthetic analogues such as the rapid-acting products Humalog LisPro, Novolog Aspart, and Apidra Glulisine has been reported negligible owing to metabolic degradation. Nevertheless, employing solid-phase extraction in combination with immunoaffinity purification followed by a top-down sequencing-based mass spectrometric approach, an assay was established allowing the identification of three intact rapid-acting synthetic insulins in doping control urine samples. A volume of 25 mL of urine was concentrated, insulin analogues were isolated from the concentrate by immunoaffinity chromatography, and the eluate was analyzed using microbore liquid chromatography/tandem mass spectrometry. Characteristic product ion spectra obtained from 5-fold protonated intact analytes as well as isolated insulin B-chains allowed the unambiguous identification of target analytes with detection limits of 0.05 ng/mL (9 fmol/mL). Moreover, assay validation demonstrated recoveries between 72 and 80% for Humalog LisPro, Novolog Aspart, and Apidra Glulisine, and assay precisions ranged from 9 to 16%. A reliable tool is provided that allows the qualitative determination of rapid-acting insulins in urine specimens collected for sports drug testing.

  14. Lipid antioxidants: how they may act in biological systems.

    PubMed Central

    Niki, E.

    1987-01-01

    Chain breaking antioxidants scavenge the chain carrying oxygen radicals and suppress the peroxidation of liposomal and biological membranes in aqueous dispersions. Vitamin E scavenges peroxyl radicals rapidly and its lateral diffusion is suggested to be fast, but its antioxidant efficiency in the liposomal and bio-membranes appears to be considerably smaller than in homogeneous solution. Water soluble chain breaking antioxidants, such as uric acid, cysteine, glutathione, and vitamin C, scavenge radicals in the aqueous region and suppress the peroxidation. However, they cannot scavenge the peroxyl radicals within the lipid region of the membranes. Nevertheless, vitamin C can interact with vitamin E radical, probably at membrane-water interface, and regenerate vitamin E. PMID:3307868

  15. Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis

    PubMed Central

    Schlager, Stefanie; Goeritzer, Madeleine; Jandl, Katharina; Frei, Robert; Vujic, Nemanja; Kolb, Dagmar; Strohmaier, Heimo; Dorow, Juliane; Eichmann, Thomas O.; Rosenberger, Angelika; Wölfler, Albert; Lass, Achim; Kershaw, Erin E.; Ceglarek, Uta; Dichlberger, Andrea; Heinemann, Akos; Kratky, Dagmar

    2015-01-01

    In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans’ anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl−/− mice exhibit Jordans’ anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl−/− mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl−/− mice. Mechanistically, ATGL−/− as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans’ anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases. PMID:26109679

  16. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    PubMed

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes.

  17. Noncompetitive and irreversible inhibition of xanthine oxidase by benzimidazole analogues acting at the functional flavin adenine dinucleotide cofactor.

    PubMed

    Skibo, E B

    1986-07-29

    Benzimidazole derivatives possessing a leaving group in the 2 alpha-position and either 4,7-dione, 4,7-diol, or 4,7-dimethoxy substituents were examined as inhibitors of buttermilk xanthine oxidase. The quinone and hydroquinone derivatives are not inhibitors of xanthine-oxygen reductase activity, even though the latter is a powerful alkylating agent. The methoxylated hydroquinones are linear noncompetitive inhibitors, the best of which is the 2 alpha-bromo analogue (Ki = 46 microM). During xanthine-oxygen reductase activity, the 2 alpha-bromo analogue irreversibly traps the reduced enzyme. Formation of a C(4a) adduct of the reduced functional FAD cofactor is postulated on the basis of UV-visible spectral evidence and reconstitution of the enzyme after removal of the altered FAD. A probable sequence of events is reversible binding at or near the reduced cofactor followed by adduct formation. It is concluded that potent tight binding inhibitors could be designed that act at the FAD cofactor rather than the purine active site.

  18. The role played by lipids unsaturation upon the membrane interaction of the Helicobacter pylori HP(2-20) antimicrobial peptide analogue HPA3.

    PubMed

    Mereuta, Loredana; Luchian, Tudor; Park, Yoonkynung; Hahm, Kyung-Soo

    2009-02-01

    The HPA3 peptide is an analogue of the linear antimicrobial peptide, HP(2-20), isolated from the N-terminal region of the Helicobacter pylori ribosomal protein, able to interact with zwitterionic lipid membranes and generate pores. Herein we focused on the importance of the degree of unsaturation of lipid acyl chains on HPA3 peptide-membrane interactions. Electrophysiology experiments carried out in reconstituted lipid membranes formed from phosphatidylcholines with one (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine - POPC) and two monounsaturated acyl chains (1,2-dioleoyl-sn-glycero-3-phosphocholine - DOPC) demonstrate that the lesser degree of the packing density of membrane lipids encountered in DOPC-based planar membranes greatly enhances the electric activity of pores created by the HPA3 peptide. Data derived from fluorescence spectroscopy experiments demonstrate that upon interaction with the bilayer, the HPA3 peptide translocates to the trans-side of the membrane. From the same experiments, we demonstrate that in the case of DOPC-based planar membranes, the net amount of HPA3 peptide which passes across the membrane and re-dissolves in the trans solution is almost 22% greater than POPC-based membranes. Such data further emphasize the modulatory role played by lipid acyl chain in determining antimicrobial peptides-lipids interactions, and demonstrate that small differences in unsaturation degree can impose a sizeable influence on HPA3 peptide activity.

  19. Carotenoids acts as reinforcers of the Acholeplasma laidlawii lipid bilayer.

    PubMed Central

    Rottem, S; Markowitz, O

    1979-01-01

    Acholeplasma laidlawii cells grown with oleic acid produced much more colored carotenoids than did cells grown with elaidic acid. The amount of carotenoids was decreased 80 to 90% by growing the cells with 0.05 M propionate, resulting in a marked increase in the mobility of both 5-doxylstearate and 12-doxylstearate incorporated into the membranes. The fatty acid composition of the propionate-grown cells differed from that of cells grown without propionate by containing odd-numbered rather than even-numbered saturated fatty acids, but the ratios of saturated to unsaturated fatty acids were the same. To determine whether the carotenoids are the cause for the restricted mobility in the membranes, the carotenoids were selectively removed from A. laidlawii membranes by incubating the membranes with phosphatidylcholine vesicles. The carotenoid-depleted membranes showed an increase in the mobility of the hydrocarbon chains of the spin-labeled fatty acids. Furthermore, the incorporation of carotenoids into artificial membrane vesicles restricted the mobility of the hydrocarbon chain. Our results support the notion that the carotenoids in A. laidlawii act as a rigid insert reinforcing the membrane bilayer. PMID:533770

  20. Lateral mobility of lipid analogues and GPI-anchored proteins in supported bilayers determined by fluorescent bead tracking.

    PubMed

    Fein, M; Unkeless, J; Chuang, F Y; Sassaroli, M; da Costa, R; Väänänen, H; Eisinger, J

    1993-07-01

    Lipid analogues and glycosylphosphatidylinositol (GPI)-anchored proteins incorporated in glass-supported phospholipid bilayers (SBL) were coupled to small (30 nm diameter) fluorescent beads whose motion in the liquid phase was tracked by intensified fluorescence video microscopy. Streptavidin (St), covalently attached to the carboxyl modified surface of the polystyrene bead, bound either the biotinylated membrane component, or a biotinylated monoclonal antibody (mAb) directed against a specific membrane constituent. The positions of the beads tethered to randomly diffusing membrane molecules were recorded at 0.2 sec intervals for about 1 min. The mean square displacement (rho) of the beads was found to be a linear function of diffusion time t, and the diffusion coefficient, D, was derived from the relation, rho(t) = 4Dt. The values of D for biotinylated phosphatidylethanolamine (Bi-PE) dispersed in an egg lecithin:cholesterol (80:20%) bilayer obtained by this methodology range from 0.05 to 0.6 micron 2/sec with an average of mean value of D = 0.26 micron 2/sec, similar to the value of mean value of D = 0.24 micron 2/sec for fluorescein-conjugated phosphatidylethanolamine (Fl-PE) linked to St-coupled beads by the anti-fluorescein mAb 4-4-20 or its Fab fragment. These values of D are comparable to those reported for Fl-PE linked to 30 nm gold particles but are several times lower than that of Fl-PE in the same planar bilayer as measured by fluorescence photobleaching recovery, D = 1.3 microns 2/sec. The mobilities of two GPI-anchored proteins in similar SBL were also determined by use of the appropriate biotinylated mAb and were found to be mean value of D = 0.25 and 0.56 micron 2/sec for the decay accelerating factor (DAF, CD55) and the human Fc gamma RIIIB (CD16) receptors, respectively. The methodology described here is suitable for tracking any accessible membrane component.

  1. Neurturin and a Glp-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats.

    PubMed

    Trevaskis, James L; Sacramento, Chester Bittencourt; Jouihan, Hani; Ali, Safina; Le Lay, John; Oldham, Stephanie; Bhagroo, Nicholas; Boland, Brandon B; Cann, Jennifer; Chang, Yuan; O'Day, Terrence; Howard, Victor; Reers, Christina; Winzell, Maria Sorhede; Smith, David M; Feigh, Michael; Barkholt, Pernille; Schreiter, Kay; Austen, Matthias; Andag, Uwe; Thompson, Simon; Jermutus, Lutz; Coghlan, Matthew P; Grimsby, Joseph; Dohrmann, Cord; Rhodes, Christopher J; Rondinone, Cristina M; Sharma, Arun

    2017-04-13

    Neurturin (NRTN), a member of the glial-derived neurotrophic factor (GDNF) family, was identified from an embryonic chicken pancreatic cDNA library in a screen for secreted factors. Here, we assessed the potential antidiabetic activities of NRTN relative to liraglutide, a GLP-1 receptor agonist, in Zucker diabetic fatty (ZDF) rats. Subcutaneous administration of NRTN to 8-week-old male ZDF rats prevented the development of hyperglycemia and improved metabolic parameters similar to liraglutide. NRTN treatment increased pancreatic insulin content and β-cell mass, and prevented deterioration of islet organization. However, unlike liraglutide-treated rats, NRTN-mediated improvements were not associated with reduced body weight or food intake. Acute NRTN treatment did not activate c-Fos expression in key feeding behavior and metabolic centers in ZDF rat brain or directly enhance glucose-stimulated insulin secretion from pancreatic β-cells. Treating 10-week-old ZDF rats with sustained hyperglycemia with liraglutide resulted in some alleviation of hyperglycemia, whereas NRTN was not as effective despite improving plasma lipids and fasting glucose levels. Interestingly, co-administration of NRTN and liraglutide normalized hyperglycemia and other metabolic parameters, demonstrating that combining therapies with distinct mechanism(s) can alleviate advanced diabetes. This emphasizes that therapeutic combinations can be more effective to manage diabetes in individuals with uncontrolled hyperglycemia.

  2. The clinical and nutritional implications of lipid-lowering drugs that act in the gastrointestinal tract.

    PubMed

    Sullivan, David R

    2005-02-01

    A new class of cholesterol-lowering therapy that reduces intestinal sterol absorption has recently been introduced. This increases the number of classes of lipid-lowering agents that directly affect gastrointestinal function and raises questions concerning the overall effect of these agents on absorption and nutritional status. A recent assessment notes a paucity of information concerning the factors that affect the bioavailability and intestinal absorption of lipophilic nutrients. By contrast, the specificity of the mechanisms of action of new drugs acting on the gastrointestinal tract may circumvent some of the detrimental effects on nutrient and drug bioavailability that have been noted with older forms of treatment. The clinical imperative for aggressive control of lipid and metabolic risk factors makes widespread use, alone or in combination, of lipid-lowering agents that affect the gastrointestinal tract seem increasingly likely. Whilst the opportunity for therapeutic synergy is attractive, care will be required to avoid interference with intestinal absorptive function.

  3. Use of insulin immunoassays in clinical studies involving rapid-acting insulin analogues: Bi-insulin IRMA preliminary assessment.

    PubMed

    Agin, Arnaud; Jeandidier, Nathalie; Gasser, Françoise; Grucker, Daniel; Sapin, Rémy

    2006-01-01

    In clinical studies involving rapid-acting analogues (RAAs), insulin immunoreactivity is frequently measured, including endogenous, regular insulin (RI) and RAA immunoreactivities. Such a procedure implies equivalent cross-reactivities of all insulins present in serum. Commercially available human insulin immunoassays have been widely used, but their limitations (including hemolysis and anti-insulin antibodies) were not fully investigated. The aims of our study were to compare cross-reactivities of RI and RAAs in buffer and in serum and to investigate insulin immunoassay pitfalls. Cross-reactivities were assessed using Bi-insulin IRMA (Schering Cis-Bio International) in phosphate-buffered saline (PBS)-1% bovine serum albumin (BSA) and in pools of sera spiked with RI and RAAs (lispro and aspart). To investigate the influence of hemolysis, a pool of sera spiked with RAA was mixed with a concentrated hemolysate (final hemoglobin concentration 10 g/L) and incubated for 3 h at room temperature. To determine interference by anti-insulin antibodies, insulin was removed using charcoal from 18 sera with anti-insulin antibodies and from 17 sera without detectable anti-insulin antibodies. These insulin-free samples were then spiked with RI and RAAs and the immunoreactivity was determined. Compared with buffer, cross-reactivity in serum for RI, lispro and aspart was lower (35%, 29% and 26% lower, respectively). Hemolysis degraded almost all RI and RAAs contained in the serum (>or=95%). Anti-insulin antibody interference was significant for RI and RAAs (p

  4. Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8.

    PubMed

    Deuis, Jennifer R; Dekan, Zoltan; Inserra, Marco C; Lee, Tzong-Hsien; Aguilar, Marie-Isabel; Craik, David J; Lewis, Richard J; Alewood, Paul F; Mobli, Mehdi; Schroeder, Christina I; Henriques, Sónia Troeira; Vetter, Irina

    2016-05-27

    The μO-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel NaV1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alanine-scanning mutagenesis, and identified residues important for its activity at human NaV1.8. A second round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at NaV1.8 and was analgesic in the mouse formalin assay. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness.

    PubMed

    Radermecker, Régis Pierre; Scheen, André Jacques

    2004-01-01

    Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open-label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast-acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well-educated diabetic patients.

  6. Single-molecule investigation of the interactions between reconstituted planar lipid membranes and an analogue of the HP(2-20) antimicrobial peptide

    SciTech Connect

    Mereuta, Loredana; Luchian, Tudor Park, Yoonkyung; Hahm, Kyung-Soo

    2008-09-05

    In this study, we employed electrophysiology experiments carried out at the single-molecule level to study the mechanism of action of the HPA3 peptide, an analogue of the linear antimicrobial peptide, HP(2-20), isolated from the N-terminal region of the Helicobacter pylori ribosomal protein. Amplitude analysis of currents fluctuations induced by HPA3 peptide at various potentials in zwitterionic lipid membranes reveal the existence of reproducible conductive states in the stochastic behavior of such events, which directly supports the existence of transmembrane pores induced the peptide. From our data recorded both at the single-pore and macroscopic levels, we propose that the HPA3 pore formation is electrophoretically facilitated by trans-negative transmembrane potentials, and HPA3 peptides translocate into the trans monolayers after forming the pores. We present evidence according to which the decrease in the membrane dipole potential of a reconstituted lipid membranes leads to an augmentation of the membrane activity of HPA3 peptides, and propose that a lower electric dipole field of the interfacial region of the membrane caused by phloretin facilitates the surface-bound HPA3 peptides to break free from one leaflet of the membrane, insert into the membrane and contribute to pore formation spanning the entire thickness of the membrane.

  7. Single-molecule investigation of the interactions between reconstituted planar lipid membranes and an analogue of the HP(2-20) antimicrobial peptide.

    PubMed

    Mereuta, Loredana; Luchian, Tudor; Park, Yoonkyung; Hahm, Kyung-Soo

    2008-09-05

    In this study, we employed electrophysiology experiments carried out at the single-molecule level to study the mechanism of action of the HPA3 peptide, an analogue of the linear antimicrobial peptide, HP(2-20), isolated from the N-terminal region of the Helicobacter pylori ribosomal protein. Amplitude analysis of currents fluctuations induced by HPA3 peptide at various potentials in zwitterionic lipid membranes reveal the existence of reproducible conductive states in the stochastic behavior of such events, which directly supports the existence of transmembrane pores induced the peptide. From our data recorded both at the single-pore and macroscopic levels, we propose that the HPA3 pore formation is electrophoretically facilitated by trans-negative transmembrane potentials, and HPA3 peptides translocate into the trans monolayers after forming the pores. We present evidence according to which the decrease in the membrane dipole potential of a reconstituted lipid membranes leads to an augmentation of the membrane activity of HPA3 peptides, and propose that a lower electric dipole field of the interfacial region of the membrane caused by phloretin facilitates the surface-bound HPA3 peptides to break free from one leaflet of the membrane, insert into the membrane and contribute to pore formation spanning the entire thickness of the membrane.

  8. Fluoride complexes of aluminium or beryllium act on G-proteins as reversibly bound analogues of the gamma phosphate of GTP.

    PubMed Central

    Bigay, J; Deterre, P; Pfister, C; Chabre, M

    1987-01-01

    Fluoride activation of G proteins requires the presence of aluminium or beryllium and it has been suggested that AIF4- acts as an analogue of the gamma-phosphate of GTP in the nucleotide site. We have investigated the action of AIF4- or of BeF3- on transducin (T), the G protein of the retinal rods, either indirectly through the activation of cGMP phosphodiesterase, or more directly through their effects on the conformation of transducin itself. In the presence of AIF4- or BeF3-, purified T alpha subunit of transducin activates purified cyclic GMP phosphodiesterase (PDE) in the absence of photoactivated rhodopsin. Activation is totally reversed by elution of fluoride or partially reversed by addition of excess T beta gamma. Activation requires that GDP or a suitable analogue be bound to T alpha: T alpha-GDP and T alpha-GDP alpha S are activable by fluorides, but not T alpha-GDP beta S, nor T alpha that has released its nucleotide upon binding to photoexcited rhodopsin. Analysis of previous works on other G proteins and with other nucleotide analogues confirm that in all cases fluoride activation requires that a GDP unsubstituted at its beta phosphate be bound in T alpha. By contrast with alumino-fluoride complexes, which can adopt various coordination geometries, all beryllium fluoride complexes are tetracoordinated, with a Be-F bond length of 1.55 A, and strictly isomorphous to a phosphate group. Our study confirms that fluoride activation of transducin results from a reversible binding of the metal-fluoride complex in the nucleotide site of T alpha, next to the beta phosphate of GDP, as an analogue of the gamma phosphate.(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. PMID:2826123

  9. 2,3-Dihydro-1-benzofuran-5-ols as analogues of alpha-tocopherol that inhibit in vitro and ex vivo lipid autoxidation and protect mice against central nervous system trauma.

    PubMed

    Grisar, J M; Bolkenius, F N; Petty, M A; Verne, J

    1995-02-03

    A series of alpha-tocopherol analogues was synthesized with potential therapeutic value for such pathological conditions as stroke and trauma. A set of criteria such as the inhibition of in vitro lipid peroxidation, superoxyl radical scavenging, and brain penetration, as measured by ex vivo inhibition of lipid peroxidation, was applied to select the most effective compound. 2,3-Dihydro-2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)methyl]-1 - benzofuran-5-ol dihydrochloride (22) was selected because of its superior antioxidant properties and better brain penetration. This compound also protected mice against the effects of head injury. The criteria thus turned out to be useful for the characterization of a neuroprotective analogue of alpha-tocopherol.

  10. A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents

    PubMed Central

    Tatarkiewicz, K; Hargrove, D M; Jodka, C M; Gedulin, B R; Smith, P A; Hoyt, J A; Lwin, A; Collins, L; Mamedova, L; Levy, O E; D’Souza, L; Janssen, S; Srivastava, V; Ghosh, S S; Parkes, D G

    2014-01-01

    Aim Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. Methods AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala2]GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu14] exenatide. Human GIP or [d-Ala2]GIP(1–42) were used for comparison. Results AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala2]GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala2]GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. Conclusions These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes. PMID:23859463

  11. Effects of rapid-acting insulin analogues insulin glulisine and insulin aspart on postprandial glycemic excursion with single bout of exercise in patients with type 2 diabetes.

    PubMed

    Tanaka, Nagaaki; Hiura, Yoshikazu

    2015-01-01

    The analogue insulin glulisine (Glu) shows both more rapid onset and shorter duration of action compared with the other rapid-acting insulin analogues. The current study investigates these properties in regard to the occurrence of hypoglycemia related to exercise. A randomized, single-center, open-label, crossover study was conducted in 12 hospitalized type 2 diabetes patients (all male, mean ± SD age of 51.9 ± 11.3 years; BMI: 25.5 ± 3.9 kg/m2; HbA1c: 11.2 ± 2.4 %). Glu or insulin aspart (Asp) was subcutaneously administered just before breakfast. Insulin dosage was determined as the usual dose of pre-prandial rapid-acting insulin for patients treated with insulin therapy or as 0.1 unit/kg for patients treated with oral anti-hyperglycemic agents. Sixty min after the start of eating, the patients began aerobic exercise on a bicycle ergometer for 30 min at 50% of maximum heart rate. Hypoglycemic episodes (plasma glucose level < 70 mg/dL with or without symptoms) were observed more frequently in Asp group (p < 0.05). Post-exercise plasma glucose levels at 90, 120, and 150 min were significantly lower in Asp group (p < 0.05). In patients with BMI < 25 kg/m2 (n = 6), post-exercise blood glucose levels were significantly lower in Asp group (p < 0.05), while in patients with BMI ≥ 25 kg/m2 (n = 6) the difference was not significant. Glu may therefore be a suitable choice of rapid-acting insulin for patients with type 2 diabetes who are at high risk of post-exercise hypoglycemia.

  12. Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact.

    PubMed

    Shah, Pratik; Rahman, Sofia A; McElroy, Sharon; Gilbert, Clare; Morgan, Kate; Hinchey, Louise; Senniappan, Senthil; Levy, Hannah; Amin, Rakesh; Hussain, Khalid

    2015-01-01

    Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic β cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life. © 2015 S. Karger AG, Basel.

  13. Self-reporter shikonin-Act-loaded solid lipid nanoparticle: formulation, physicochemical characterization and geno/cytotoxicity evaluation.

    PubMed

    Eskandani, Morteza; Nazemiyeh, Hossein

    2014-08-01

    Shikonin and some of its derivative have approved apoptotic potential in different human cancer cell lines, and moreover have a dominant fluorescent emission at ∼600nm. Here, to enhance shikonin-Act anti-proliferation properties, it was successfully incorporated in Solid Lipid Nanoparticles (SLNs) by the hot homogenization and entrapment efficiency (EE) of drug in SLNs was determined by ultrafiltration method. Scanning electron microscopy (SEM), laser diffractometry and zeta-sizer indicated that shikonin-Act-SLN were spherical and regular particles in the range of 70-120nm with polydispersity index (PI) of less than 0.10. The physical stability of shikonin-Act-loaded SLN in aqueous dispersion was evaluated in terms of size, PI, EE and drug leakage and the results showed that SLNs were stable upon storing three month. Long term in vitro release of the shikonin-Act was also approved. Cellular uptake of the shikonin-Act-SLN was examined by the in vitro fluorescent microscopy and facs flow cytometry analyses. In vivo rat imaging approved the penetrating capability of shikonin-Act-SLN emission through living tissues. In vitro anti-proliferation and genotoxicity evaluation by MTT and comet assay confirmed that shikonin-Act-SLN showed higher cytotoxic/antitumor potential than intact shikonin in terms of IC50 and DNA damage. This work provide sufficient information about improving of the therapeutic efficacy of the shikonin-Act, and also using of the shikonin-Act-SLN in bio-distribution studies during drug delivery investigation by incorporating in lipidic and colloidal drug delivery particles such as SLNs. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Pharmacokinetic and pharmacodynamic properties of a long-acting formulation of the new somatostatin analogue, lanreotide, in normal healthy volunteers.

    PubMed Central

    Kuhn, J M; Legrand, A; Ruiz, J M; Obach, R; De Ronzan, J; Thomas, F

    1994-01-01

    1. The aims of the study were to assess the pharmacokinetic parameters and the hormonal effects of the slow-release formulation of the somatostatin analogue (SR-L) in normal male volunteers. 2. Eight healthy males were studied. For the determination of basal values blood was sampled before the injection of vehicle and then every other hour for 8 h in order to measure plasma GH, prolactin (PRL), TSH, free thyroxin (fT4), insulin and glucagon levels. Plasma insulin-like growth factor 1 (IGF-1) levels were measured on a single sample. On day 1 of the study, 30 mg SR-L was administered intramuscularly. Blood was drawn just before injection and then every other hour for a period of 8 h. Thereafter, blood was sampled three times a week for 3 weeks in order to measure lanreotide, IGF-1, TSH, fT4 and PRL concentrations. Plasma GH was determined on days 6 and 11 of the study. 3. Plasma lanreotide concentrations rose to 38.3 +/- 4.1 ng ml-1 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng ml-1 until day 11 and reaching 0.92 +/- 0.28 ng ml-1 2 weeks after injection. The apparent plasma half-life and mean residence time were 4.52 +/- 0.50 and 5.48 +/- 0.51 days respectively. 4. By comparison with the control day, plasma insulin concentrations only decreased 2 h following injection, whereas plasma glucagon did not change at any time. 5. Plasma TSH concentrations were significantly (P < 0.01) reduced from 2 h to day 4 following SR-L injection.2+ ' PMID:7826822

  15. Analogue Gravity.

    PubMed

    Barceló, Carlos; Liberati, Stefano; Visser, Matt

    2011-01-01

    Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for) gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing) and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity).

  16. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

    PubMed Central

    Wolin, Edward M; Jarzab, Barbara; Eriksson, Barbro; Walter, Thomas; Toumpanakis, Christos; Morse, Michael A; Tomassetti, Paola; Weber, Matthias M; Fogelman, David R; Ramage, John; Poon, Donald; Gadbaw, Brian; Li, Jiang; Pasieka, Janice L; Mahamat, Abakar; Swahn, Fredrik; Newell-Price, John; Mansoor, Wasat; Öberg, Kjell

    2015-01-01

    In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR. PMID:26366058

  17. Differential actions of the prostacyclin analogues treprostinil and iloprost and the selexipag metabolite, MRE-269 (ACT-333679) in rat small pulmonary arteries and veins.

    PubMed

    Orie, N N; Ledwozyw, A; Williams, D J; Whittle, B J; Clapp, L H

    2013-10-01

    The prostacyclin (IP) receptor agonists, treprostinil, iloprost and the selexipag metabolite, MRE-269 (ACT-333679) were evaluated in rat distal pulmonary blood vessels. Small pulmonary arteries and veins were pre-contracted with the thromboxane mimetic, U46619 (25 and 100nM, respectively), and relaxation determined with and without IP receptor antagonists, RO1138452 and RO3244794. In arteries, treprostinil was a more potent vasorelaxant than iloprost, while the efficacy of iloprost was greater. In pulmonary arteries, treprostinil-induced relaxation was essentially abolished by both IP antagonists (1μM), while responses to iloprost were partially inhibited. Both treprostinil and iloprost were equipotent, prominently relaxing pulmonary veins with responses being similarly and partially sensitive to IP antagonists. In contrast, RO1138452 failed to inhibit relaxations to MRE-269 in either pulmonary arteries or veins, suggesting no involvement of typical IP receptors. Thus, rat pulmonary tissues cannot be considered appropriate to assess classical IP receptors using the proposed highly selective non-prostanoid agonist MRE-269, contrasting with the IP receptor agonism profile of prostacyclin analogues, iloprost and treprostinil.

  18. Lipophorin acts as a shuttle of lipids to the milk gland during tsetse fly pregnancy.

    PubMed

    Benoit, Joshua B; Yang, Guangxiao; Krause, Tyler B; Patrick, Kevin R; Aksoy, Serap; Attardo, Geoffrey M

    2011-11-01

    During pregnancy in the viviparous tsetse fly, lipid mobilization is essential for the production of milk to feed the developing intrauterine larva. Lipophorin (Lp) functions as the major lipid transport protein in insects and closely-related arthropods. In this study, we assessed the role of Lp and the lipophorin receptor (LpR) in the lipid mobilization process during tsetse reproduction. We identified single gene sequences for GmmLp and GmmLpR from the genome of Glossinamorsitansmorsitans, and measured spatial and temporal expression of gmmlp and gmmlpr during the female reproductive cycle. Our results show that expression of gmmlp is specific to the adult fat body and larvae. In the adult female, gmmlp expression is constitutive. However transcript levels increase in the larva as it matures within the mother's uterus, reaching peak expression just prior to parturition. GmmLp was detected in the hemolymph of pregnant females and larvae, but not in the uterine fluid or larval gut contents ruling out the possibility of direct transfer of GmmLp from mother to offspring. Transcripts for gmmlpr were detected in the head, ovaries, midgut, milk gland/fat body, ovaries and developing larva. Levels of gmmlpr remain stable throughout the first and second gonotrophic cycles with a slight dip observed during the first gonotrophic cycle. GmmLpR was detected in multiple tissues, including the midgut, fat body, milk gland, spermatheca and head. Knockdown of gmmlp by RNA interference resulted in reduced hemolymph lipid levels, delayed oocyte development and extended larval gestation. Similar suppresion of gmmlpr did not significantly reduce hemolymph lipid levels or oogenesis duration, but did extend the duration of larval development. Thus, GmmLp function as the primary shuttle for lipids originating from the midgut and fat body to the ovaries and milk gland to supply resources for developing oocytes and larval nourishment, respectively. Once in the milk gland however, lipids

  19. Lipophorin acts as a shuttle of lipids to the milk gland during tsetse fly pregnancy

    PubMed Central

    Benoit, Joshua B.; Yang, Guangxiao; Krause, Tyler B.; Patrick, Kevin R.; Aksoy, Serap; Attardo, Geoffrey M.

    2011-01-01

    During pregnancy in the viviparous tsetse fly, lipid mobilization is essential for the production of milk to feed the developing intrauterine larva. Lipophorin (Lp) functions as the major lipid transport protein in insects and closely-related arthropods. In this study, we assessed the role of Lp and the lipophorin receptor (LpR) in the lipid mobilization process during tsetse reproduction. We identified single gene sequences for GmmLp and GmmLpR from the genome of Glossina morsitans morsitans, and measured spatial and temporal expression of gmmlp and gmmlpr during the female reproductive cycle. Our results show that expression of gmmlp is specific to the adult fat body and larvae. In the adult female, gmmlp expression is constitutive. However transcript levels increase in the larva as it matures within the mother’s uterus, reaching peak expression just prior to parturition. GmmLp was detected in the hemolymph of pregnant females and larvae, but not in the uterine fluid or larval gut contents ruling out the possibility of direct transfer of GmmLp from mother to offspring. Transcripts for gmmlpr were detected in the head, ovaries, midgut, milk gland/fat body, ovaries and developing larva. Levels of gmmlpr remain stable throughout the first and second gonotrophic cycles with a slight dip observed during the first gonotrophic cycle. GmmLpR was detected in multiple tissues, including the midgut, fat body, milk gland, spermatheca and head. Knockdown of gmmlp by RNA interference resulted in reduced hemolymph lipid levels, delayed oocyte development and extended larval gestation. Similar suppresion of gmmlpr did not significantly reduce hemolymph lipid levels or oogenesis duration, but did extend the duration of larval development. Thus, GmmLp and GmmLpR function as the primary shuttle for lipids originating from the midgut and fat body to the ovaries and milk gland to supply resources for developing oocytes and larval nourishment, respectively. Once in the milk gland

  20. LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver.

    PubMed

    Wang, Feng; Zhang, Xianfeng; Wang, Jiqiu; Chen, Maopei; Fan, Nengguang; Ma, Qinyun; Liu, Ruixin; Wang, Rui; Li, Xiaoying; Liu, Mingyao; Ning, Guang

    2014-04-01

    The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4(m/m)) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4(m/m) mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4(m/m) mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4(m/m) mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4(m/m) mice and primary Lgr4(m/m) hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.

  1. Macro- and microvascular outcomes in patients with type 2 diabetes treated with rapid-acting insulin analogues or human regular insulin: a retrospective database analysis.

    PubMed

    Rathmann, W; Schloot, N C; Kostev, K; Reaney, M; Zagar, A J; Haupt, A

    2014-02-01

    To investigate the risk of macro- and microvascular complications in patients with type 2 diabetes receiving rapid-acting insulin analogues (IA) or human regular insulin (HI).General practice diabetes patients with continuous prescription of any IA or HI for ≥3 years were selected from the German Disease Analyzer database (IMS Health). Logistic and Cox regression models were applied to analyze the incidence and time to onset of vascular outcomes (IA vs. HI).2764 patients on IA (insulin lispro, glulisine, aspart) and 4193 patients on HI were included (age, mean [SD]: 61.0 [11.3] and 64.7 [10.5] years, follow-up [Q1,Q3]: 4.6 [3.7,6.1] and 4.7 [3.7,5.9] years). No significant differences were detected between IA and HI regarding the incidence of vascular complications (OR [95%CI]: macrovascular 0.92 [0.72-1.18], microvascular 0.95 [0.77-1.17]) or regarding time to their onset, after adjustment for sex, age, comorbidities and time on IA/HI, or by propensity-score-based matching. However, in an additional short-term analysis (median [Q1,Q3] follow-up (IA 2.9 [1.2,4.6], HI 2.4 [0.8,4.4] years) of a larger sample (no continuous insulin treatment required) with more comorbidities, time to onset of macrovascular complications was significantly longer for AI than HI (HR 0.88 [0.81-0.97], p=0.009; microvascular complications: no difference).After long-term continuous treatment with IA or HI under real-life conditions, there was no different risk of macro- or microvascular complications, contradicting previous short-term analyses. Further prospective studies are needed to clarify whether selection bias may have been introduced by using strict entry criteria.

  2. Nanostructured self-assembly materials from neat and aqueous solutions of C18 lipid pro-drug analogues of Capecitabine—a chemotherapy agent. Focus on nanoparticulate cubosomes™ of the oleyl analogue

    SciTech Connect

    Gong, Xiaojuan; Moghaddam, Minoo J.; Sagnella, Sharon M.; Conn, Charlotte E.; Mulet, Xavier; Danon, Stephen J.; Waddington, Lynne J.; Drummond, Calum J.

    2014-09-24

    A series of prodrug analogues based on the established chemotherapy agent, 5-fluorouracil, have been prepared and characterized. C18 alkyl and alkenyl chains with increasing degree of unsaturation were attached to the N4 position of the 5-fluorocytosine (5-FC) base via a carbamate bond. Physicochemical characterization of the prodrug analogues was carried out using a combination of differential scanning calorimetry, cross-polarized optical microscopy, X-ray diffraction and small-angle X-ray scattering. The presence of a monounsaturated oleyl chain was found to promote lyotropic liquid crystalline phase formation in excess water with a fluid lamellar phase observed at room temperature and one or more bicontinuous cubic phases at 37 °C. The bulk phase was successfully dispersed into liposomes or cubosomes at room and physiological temperature respectively. In vitro toxicity of the nanoparticulate 5-FCOle dispersions was evaluated against several normal and cancer cell types over a 48 h period and exhibited an IC50 of -100 μM against all cell types. The in vivo efficacy of 5-FCOle cubosomes was assessed against the highly aggressive mouse 4T1 breast cancer model and compared to Capecitabine (a water-soluble commercially available 5-FU prodrug) delivered at the same dosages. After 21 days of treatment, the 0.5 mmol 5-FCOle treatment group exhibited a significantly smaller average tumour volume than all other treatment groups including Capecitabine at similar dosage. These results exemplify the potential of self-assembled amphiphile prodrugs for delivery of bioactives in vivo.

  3. Lipid Rafts Act as Specialized Domains for Tetanus Toxin Binding and Internalization into Neurons

    PubMed Central

    Herreros, Judit; Ng, Tony; Schiavo, Giampietro

    2001-01-01

    Tetanus (TeNT) is a zinc protease that blocks neurotransmission by cleaving the synaptic protein vesicle-associated membrane protein/synaptobrevin. Although its intracellular catalytic activity is well established, the mechanism by which this neurotoxin interacts with the neuronal surface is not known. In this study, we characterize p15s, the first plasma membrane TeNT binding proteins and we show that they are glycosylphosphatidylinositol-anchored glycoproteins in nerve growth factor (NGF)-differentiated PC12 cells, spinal cord cells, and purified motor neurons. We identify p15 as neuronal Thy-1 in NGF-differentiated PC12 cells. Fluorescence lifetime imaging microscopy measurements confirm the close association of the binding domain of TeNT and Thy-1 at the plasma membrane. We find that TeNT is recruited to detergent-insoluble lipid microdomains on the surface of neuronal cells. Finally, we show that cholesterol depletion affects a raft subpool and blocks the internalization and intracellular activity of the toxin. Our results indicate that TeNT interacts with target cells by binding to lipid rafts and that cholesterol is required for TeNT internalization and/or trafficking in neurons. PMID:11598183

  4. GnRH antagonists: a new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6.

    PubMed

    Jiang, G; Stalewski, J; Galyean, R; Dykert, J; Schteingart, C; Broqua, P; Aebi, A; Aubert, M L; Semple, G; Robson, P; Akinsanya, K; Haigh, R; Riviere, P; Trojnar, J; Junien, J L; Rivier, J E

    2001-02-01

    A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph/4Amf(P)-D4Aph/D4Amf(Q)-Leu-ILys-Pro-DAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA2) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH2 with Atz = 3'-amino-1H-1',2',4'-triazol-5'-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (s.c.) administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (31) and eight other congeners (20, 35, 37, 39, 41, 45-47) were identified that exhibited significantly longer duration of action than acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 microg in 100 microL of phosphate buffer. No correlation was found between retention times on a C18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA2) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg s.c. in 5% mannitol (injection

  5. Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues.

    PubMed

    Conde-Frieboes, Kilian; Thøgersen, Henning; Lau, Jesper F; Sensfuss, Ulrich; Hansen, Thomas K; Christensen, Leif; Spetzler, Jane; Olsen, Helle B; Nilsson, Cecilia; Raun, Kirsten; Dahl, Kirsten; Hansen, Birgit S; Wulff, Birgitte S

    2012-03-08

    We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues. Furthermore, amino acids at the N-terminal of α-MSH (Ser-Tyr-Ser) not considered to be part of the pharmacophore were found to have an influence on the MC4/MC1 receptor selectivity. While the acetyl analogues have an in vivo effect for around 7 h, the long chain fatty acid analogues have an effect up to 48 h in an acute feeding study in male Sprague-Dawley rats after a single subcutaneous administration.

  6. Direct-acting antiviral agents against hepatitis C virus and lipid metabolism

    PubMed Central

    Kanda, Tatsuo; Moriyama, Mitsuhiko

    2017-01-01

    Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia. PMID:28883690

  7. The antioxidant behaviour of melatonin and structural analogues during lipid peroxidation depends not only on their functional groups but also on the assay system.

    PubMed

    Fagali, Natalia; Catalá, Angel

    2012-07-13

    There is no general agreement yet on the antioxidant effect of pineal indoles against lipid peroxidation. Accordingly, the main goal of the present work was to study the antioxidant activity of melatonin (MLT), N-acetylserotonin (NAS), 5-HO-tryptophan (5HO-TRP) and 5-methoxytryptamine (5MTP) in two different lipid systems with high content of polyunsaturated fatty acids (PUFAs): triglycerides (rich in 20:5 n-3, 22:6 n-3) dissolved in chloroform and sonicated liposomes made of retinal lipids (rich in 22:6 n-3). In the triglyceride-chloroform-system the peroxidation reaction was initiated by cumene hydroperoxide (CHP) whereas liposomes were peroxidized with Fe(2+). The techniques employed at the present work were: (1) TBARS production, (2) DPPH assay, (3) determination of conjugated dienes production and (4) analysis of fatty acid profile by GC-MS. Butylated hydroxytoluene (BHT) was employed as a reference because of its well known antioxidant capacity. Our results showed that MLT and 5MTP were unable to protect PUFAs against lipid peroxidation in both systems, whereas NAS and 5HO-TRP were better antioxidants that BHT in the triglyceride-system but ineffective in the liposome-system. We conclude that the antioxidant behaviour of pineal indoles depends not only on their functional groups but also on the assay system and could be explained by the polar paradox theory.

  8. Murine lipid phosphate phosphohydrolase-3 acts as a cell-associated integrin ligand

    SciTech Connect

    Humtsoe, Joseph O.; Bowling, Rodney A.; Feng, Shu; Wary, Kishore K. . E-mail: kwary@ibt.tamhsc.edu

    2005-09-30

    Lipid phosphate phosphohydrolase-3 (LPP3) is a cell surface protein that exhibits ectoenzyme activity. Previously, we identified human LPP3 in a functional assay of angiogenesis and showed that the Arg-Gly-Asp (RGD) motif in the proposed second extracellular domain interacts with a subset of integrins to mediate cell-cell adhesion. In contrast to the RGD domain of human LPP3, murine Lpp3 contains a variant sequence, Arg-Gly-Glu (RGE). Whether the RGE motif of murine Lpp3 mediates cell-cell interaction has not been studied. In this report, we test the hypothesis that the cell adhesion function of the LPP3 protein is conserved across mouse and human. A glutathione S-transferase (GST) fusion protein of the proposed second extracellular loop of the murine Lpp3 sequence (GST-mLpp3-RGE) promoted attachment of cells in a long-term cell adhesion assay. GST-mLpp3-RGE interacted with {alpha}{sub 5}{beta}{sub 1} and {alpha}{sub v}{beta}{sub 3} integrins in a solid-phase ELISA, while a mutant control, GST-hLPP3-RAD, did not. Long-term adhesion of endothelial cells to GST-mLpp3-RGE induced phosphorylation of FAK, SHC, and CAS, whereas adhesion to GST-hLPP3-RAD failed to do so. Upon long-term adhesion both the GST-hLPP3-RGD and GST-mLpp3-RGE substrates bound to the {alpha}{sub 5}{beta}{sub 1} integrin of FRT-{alpha}{sub 5}(+) cells, an interaction that was inhibited by an anti-{alpha}{sub 5} integrin antibody. In addition, a cell aggregation assay showed that the intact mLpp3-RGE protein interacts with {alpha}{sub 5}{beta}{sub 1} and {alpha}{sub v}{beta}{sub 3} integrins expressed by adjacent cells, an interaction that can be blocked by GRGDSP peptides and anti-LPP3-RGD antibodies. These data, together with the known importance of integrins in angiogenesis, provide a mechanism for the function of LPP3 in cell-cell interactions in both human and mouse.

  9. Comparative assessment of the effects of subdermal levonorgestrel implant system and long acting progestogen injection method on lipid metabolism.

    PubMed

    Anwar, M; Soejono, S K; Maruo, T; Abdullah, N

    1994-03-01

    In order to compare the effects of two type of long-acting progestogen contraceptive methods with subdermal levonorgestrel (LNG) implants and depot-medroxyprogesterone acetate (DMPA) injections on lipid metabolism, a clinical cohort study was performed by requiring 25 women in each group adopting either LNG implant or DMPA injection method voluntarily. After 6 months of use, serum levels of triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol were determined and compared between the two groups of acceptors. The mean of total cholesterol in LNG implant acceptors was significantly lower than that in DMPA injection acceptors. The mean values of HDL-cholesterol in LNG implant acceptors (41.7 +/- 7.7 mg/dl) and in DMPA injection acceptors (45.0 +/- 9.0 mg/dl) were in the normal range without significant difference between the two groups. The mean value of triglycerides did not differ significantly between LNG implant acceptors (77.6 +/- 25.1 mg/dl) and DMPA injection acceptors (91.0 +/- 30.3 mg/dl). Serum concentrations of lipid fractions such as HDL-cholesterol and LDL-cholesterol in LNG implant acceptors were relatively low compared to those in DMPA injection acceptors. Since there was a comparable reduction in both total-and HDL-cholesterol levels in the LNG implant group, the ratio of total-to HDL-cholesterol, which is thought to be a factor in determining the risk of coronary artery disease, remained in the normal range (2 +/- 4.5). This suggests that the use of these two contraceptive methods with progestogens does not alter the risk of development of coronary artery disease.

  10. Fields of application of continuous subcutaneous insulin infusion in the treatment of diabetes and implications in the use of rapid-acting insulin analogues.

    PubMed

    Pitocco, D; Rizzi, A; Scavone, G; Tanese, L; Zaccardi, F; Manto, A; Ghirlanda, G

    2013-09-01

    In western countries, diabetes mellitus, because of macrovascular and microvascular complications related to it, is still an important cause of death. Patients with type 1 diabetes mellitus (T1DM) have a six-time higher risk of mortality than healthy patients. Since the Diabetes Control and Complications Trial (DCCT) established how an intensive therapy is necessary to prevent diabetes mellitus complications, many studies have been conducted to understand which method is able to reach an optimal metabolic control. In the past 30 years continuous subcutaneous insulin infusion established/introduced as a validate alternative to multiple daily injections. Several trials demonstrated that, when compared to MDI, CSII brings to a better metabolic control, in terms of a reduction of glycated hemoglobin and blood glucose variability, hypoglycemic episodes and improvement in quality of life. Because of their pharmacokinetic and pharmacodynamic characteristics, rapid-action insulin analogues are imposed as best insulin to be used in CSII. The rapid onset and the fast reached peak make them better mimic the way how pancreas secretes insulin. CSII by pump is not free from issues. Catheter occlusions, blockages, clogs can arrest insulin administration. The consequent higher levels of glycemic values, can easily bring to the onset of ketoacidosis, with an high risk for patients' life. Aspart is a rapid analogue obtained by aminoacidic substitution. It is as effective as lispro and glulisine in gaining a good metabolic control and even better in reducing glucose variability. Some studies tried to compare rapid analogues in terms of stability. Obtained data are controversial. An in vivo study evidenced higher stability or glulisine, while studies in vitro highlighted a higher safety of aspart. Nowadays it is not possible to assess which analogues is safer. When the infusion set is changed every 48 hours equivalent rates of occlusions have been observed.

  11. Type 1 diabetes control and pregnancy outcomes in women treated with continuous subcutaneous insulin infusion (CSII) or with insulin glargine and multiple daily injections of rapid-acting insulin analogues (glargine-MDI).

    PubMed

    Bruttomesso, D; Bonomo, M; Costa, S; Dal Pos, M; Di Cianni, G; Pellicano, F; Vitacolonna, E; Dodesini, A R; Tonutti, L; Lapolla, A; Di Benedetto, A; Torlone, E

    2011-11-01

    The best way to treat pregnant patients who have type 1 diabetes is still unclear. For this reason, the present study compared metabolic control and maternal-fetal outcomes in patients treated with continuous subcutaneous infusions of rapid-acting insulin analogues (CSII) or with insulin glargine and multiple daily injections of rapid-acting insulin analogues (glargine-MDI). This retrospective multicentre study involved 144 women with type 1 diabetes, 100 of whom were using CSII and 44 glargine-MDI. Outcomes analyzed were metabolic control, diabetes complications, pregnancy outcome, perinatal morbidity and mortality, and fetal malformations. The two groups were comparable for age, prepregnancy BMI, primiparous rate and diabetes complications, although patients using CSII had longer duration of diabetes (P=0.03) and higher White classifications (P=0.04). In both groups, metabolic control improved during pregnancy, but good control was reached earlier among patients using CSII. At parturition, patients using CSII had lower HbA(1c) (6.2±0.7% vs 6.5±0.8%; P=0.02) and required less insulin (P<0.01). Weight gain was similar in both groups, and maternal-fetal outcomes did not differ. In pregnant patients with type 1 diabetes, MDI and CSII are equivalent in terms of metabolic control and fetal-maternal outcomes, although patients using CSII achieved good control earlier and with less insulin. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  12. Epinephrine analogues.

    PubMed

    Sneader, W

    2001-11-01

    Tyramine was the first epinephrine analogue to be introduced into medicine, in the early 1900s. It was followed by ephedrine and pseudoephedrine in the 1920s and by the amfetamines a decade later. The popularity of the amfetamines grew throughout the 1930s and 1940s; after that, there was a slowly dawning realization that they were being widely abused. Isoprenaline, introduced in the 1950s, was soon recognized as superior to epinephrine when used as an inhaler by asthmatics, and it remained the drug of choice for the relief of bronchospasm until around 1970. Orciprenaline, which featured an orcinol system, had a long duration of action and was active by mouth; Boehringer marketed it both as an inhaler and as a syrup for the prophylaxis of bronchospasm. The greatly superior bronchodilators salbutamol and terbutaline, launched in 1968 and 1970, respectively, incorporate further variation on the molecular theme that had led to the development of orciprenaline. (c) 2001 Prous Science. All rights reserved.

  13. Lamellar crystalline self-assembly behaviour and solid lipid nanoparticles of a palmityl prodrug analogue of Capecitabine—A chemotherapy agent

    SciTech Connect

    Gong, Xiaojuan; Moghaddam, Minoo J.; Sagnella, Sharon M.; Conn, Charlotte E.; Danon, Stephen J.; Waddington, Lynne J.; Drummond, Calum J.

    2014-09-24

    An amphiphile prodrug, 5'-deoxy-5-fluoro-N4-(palmityloxycarbonyl) cytidine or 5'-deoxy-5-fluoro-N4-(hexadecanaloxycarbonyl) cytidine (5-FCPal), consisting of the same head group as the commercially available chemotherapeutic agent Capecitabine, linked to a palmityl hydrocarbon chain via a carbamate bond is reported. Thermal analysis of this prodrug indicates that it melts at ~115 °C followed quickly by degradation beginning at ~120 °C. The neat solid 5-FCPal amphiphile acquires a lamellar crystalline arrangement with a d-spacing of 28.6 ± 0.3 Å, indicating interdigitation of the hydrocarbon chains. Under aqueous conditions, solid 5-FCPal is non-swelling and no lyotropic liquid crystalline phase formation is observed. In order to assess the in vitro toxicity and in vivo efficacy in colloidal form, solid lipid nanoparticles (SLNs) with an average size of ~700 nm were produced via high pressure homogenization. The in vitro toxicity of the 5-FCPal SLNs against several different cancer and normal cell types was assessed over a 48 h period, and IC50 values were comparable to those observed for Capecitabine. The in vivo efficacy of the 5-FCPal SLNs was then assessed against the highly aggressive mouse 4T1 breast cancer model. To do so, the prodrug SLNs were administered orally at 3 different dosages (0.1, 0.25, 0.5 mmol/mouse/day) and compared to Capecitabine delivered at the same dosages. After 21 days of receiving the treatments, the 0.5 mmol dose of 5-FCPal exhibited the smallest average tumour volume. Since 5-FCPal is activated in a similar manner to Capecitabine via a 3 step enzymatic pathway with the final step occurring preferentially at the tumour site, formulation of the prodrug into SLNs combines the advantage of selective, localized activation with the sustained release properties of nanostructured amphiphile self-assembly and multiple payload materials thereby potentially creating a more effective anticancer agent.

  14. Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A

    PubMed Central

    Simonson, B; Morani, A S; Ewald, A W M; Walker, L; Kumar, N; Simpson, D; Miller, J H; Prisinzano, T E; Kivell, B M

    2015-01-01

    BACKGROUND AND PURPOSE Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile. EXPERIMENTAL APPROACH We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists. KEY RESULTS Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT. CONCLUSIONS AND IMPLICATIONS SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24641310

  15. Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A.

    PubMed

    Simonson, B; Morani, A S; Ewald, A W M; Walker, L; Kumar, N; Simpson, D; Miller, J H; Prisinzano, T E; Kivell, B M

    2015-01-01

    Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile. We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists. Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT. SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  16. Effect of subcutaneous injection of a long-acting analogue of somatostatin (SMS 201-995) on plasma thyroid-stimulating hormone in normal human subjects

    SciTech Connect

    Itoh, S.; Tanaka, K.; Kumagae, M.; Takeda, F.; Morio, K.; Kogure, M.; Hasegawa, M.; Horiuchi, T.; Watabe, T.; Miyabe, S.

    1988-01-01

    SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 ..mu..g of SMS or a placebo to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61 +/- 0.09, 4.91 +/- 0.30 and 8.52 +/- 1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50, and 100 ..mu..g of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110 +/- 3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50, and 100 ..mu..g of SMS, the plasma TSH levels were 43.8 +/- 19.4, 33.9 +/- 9.4 and 24.9 +/- 3.2%, respectively, of the basal values.

  17. The future of somatostatin analogue therapy.

    PubMed

    Stewart, P M; James, R A

    1999-10-01

    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  18. Antinociceptive activity of glycosidic enkephalin analogues.

    PubMed

    Rodríguez, R E; Rodríguez, F D; Sacristán, M P; Torres, J L; Reig, F; García Antón, J M; Valencia, G

    1990-01-01

    The antinociceptive activity of two new enkephalin analogues: N1.5-(beta-D-glucopyranosyl)[D-Met2, Pro5]enkephalinamide and N1.5-(beta-D-galactopyranosyl)[D-Met2, Pro5]enkephalinamide was assessed using the tail immersion and paw pressure behavioural tests. Both enkephalin analogues appear to be more active than morphine when injected either into the fourth ventricle or intrathecally; the galactose analogue is more than 5000 times more active than morphine when injected into the fourth ventricle. The analgesic effects produced by the analogues are partially reversed by SC naloxone (0.1 mg/kg) and totally reversed when the dose of naloxone used was 1 mg/kg, suggesting that the analogues act upon more than one type of opiate receptor (mu/delta).

  19. Rise in RBC aggregability and concomitant decrease in blood pressure 10 days after injection of the long acting erythropoietin analogue methoxy polyethylene glycol-epoetin-β (MIRCERA®).

    PubMed

    Joré, Céline; Brun, Jean-Frédéric; Varlet-Marie, Emmanuelle

    2016-01-01

    Erythropoietin (EPO) is a major regulator of blood viscosity. Its long lasting action analogue methoxy polyethylene glycol-epoetin-β (MIRCERA®) seems to be also employed in modern doping. We took the opportunity of a study aiming at developing a detection of recent MIRCERATM injection in the context of doping detection to assess the effects of this EPO analogue on red blood cells (RBC) aggregation. A single dose 200 μg of MIRCERA® was injected to 10 male volunteers and blood samplings were drawn over 24 days. After injection a decrease in mean corpuscular volume at day 2 (p < 0.01) and day 10 (p < 0.02), a rise in reticulocyte count (p < 0.001) between day 4 and day 17 and a decrease in ferritin a day 5 (p < 0.05) was observed. Hemoglobin decreased at day 4 (p < 0.005). Hematocrit was unchanged. There was a dramatic (+67%) increase in RBC aggregation index "M" (from 9.49±1.01 to 17.66±1.8, p < 0.01). A decrease in systolic blood pressure was observed during the period from day 4 to day 17 (at day 10: -11.90±2.28 mmHg, p < 0.001; at day 17: -15.80±2.83, p < 0.001). There was also a decrease in diastolic blood pressure, mean and pulse pressure. Correlations between this decrease in blood pressure and "M" did not reach significance but pulse pressure was positively correlated to "M" (r = 0.743, p < 0.05).These data show that the long acting erythropoietin analogue MIRCERA® strongly increases RBC aggregation parallel to a decrease in blood pressure, but a possible causative link between the two events is not clearly evidenced.

  20. Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues.

    PubMed

    Yamashita, Ayako; Norton, Emily; Petersen, Peter J; Rasmussen, Beth A; Singh, Guy; Yang, Youjin; Mansour, Tarek S; Ho, Douglas M

    2003-10-06

    A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

  1. Lipid antigens in immunity

    PubMed Central

    Dowds, C. Marie; Kornell, Sabin-Christin

    2014-01-01

    Lipids are not only a central part of human metabolism but also play diverse and critical roles in the immune system. As such, they can act as ligands of lipid-activated nuclear receptors, control inflammatory signaling through bioactive lipids such as prostaglandins, leukotrienes, lipoxins, resolvins, and protectins, and modulate immunity as intracellular phospholipid- or sphingolipid-derived signaling mediators. In addition, lipids can serve as antigens and regulate immunity through the activation of lipid-reactive T cells, which is the topic of this review. We will provide an overview of the mechanisms of lipid antigen presentation, the biology of lipid-reactive T cells, and their contribution to immunity. PMID:23999493

  2. Ascorbate does not act as a pro-oxidant towards lipids and proteins in human plasma exposed to redox-active transition metal ions and hydrogen peroxide.

    PubMed

    Suh, Jung; Zhu, Ben-Zhan; Frei, Balz

    2003-05-15

    The combination of ascorbate, transition metal ions, and hydrogen peroxide (H(2)O(2)) is an efficient hydroxyl radical generating system called "the Udenfriend system." Although the pro-oxidant role of ascorbate in this system has been well characterized in vitro, it is uncertain whether ascorbate also acts as a pro-oxidant under physiological conditions. To address this question, human plasma, used as a representative biological fluid, was either depleted of endogenous ascorbate with ascorbate oxidase, left untreated, or supplemented with 25 microM-1 mM ascorbate. Subsequently, the plasma samples were incubated at 37 degrees C with 50 microM-1 mM iron (from ferrous ammonium sulfate), 60 or 100 microM copper (from cupric sulfate), and/or 200 microM or 1 mM H(2)O(2). Although endogenous and added ascorbate was depleted rapidly in the presence of transition metal ions and H(2)O(2), no cholesterol ester hydroperoxides or malondialdehyde were formed, i.e., ascorbate protected against, rather than promoted, lipid peroxidation. Conversely, depletion of endogenous ascorbate was sufficient to cause lipid peroxidation, the rate and extent of which were enhanced by the addition of metal ions but not H(2)O(2). Ascorbate also did not enhance protein oxidation in plasma exposed to metal ions and H(2)O(2), as assessed by protein carbonyl formation and depletion of reduced thiols. Interestingly, neither the rate nor the extent of endogenous alpha-tocopherol oxidation in plasma was affected by any of the treatments. Our data show that even in the presence of redox-active iron or copper and H(2)O(2), ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in human plasma in vitro.

  3. Changes in serum lipid profiles caused by three regimens of interferon-free direct-acting antivirals for patients infected with hepatitis C virus.

    PubMed

    Inoue, Takako; Goto, Takaaki; Iio, Etsuko; Matsunami, Kayoko; Fujiwara, Kei; Shinkai, Noboru; Matsuura, Kentaro; Matsui, Takeshi; Nojiri, Shunsuke; Tanaka, Yasuhito

    2017-08-19

    As described previously, serum low-density lipoprotein cholesterol (LDL-C) increases during treatment of chronic hepatitis C (CHC) with interferon-free direct-acting antivirals (DAAs). We sought to compare the changes of serum lipid profiles caused by three regimens. A total of 216 CHC patients were enrolled. Among 170 patients infected with HCV genotype 1b, 85 received daclatasvir plus asunaprevir (DCV/ASV) and 85 received sofosbuvir plus ledipasvir (SOF/LDV). Forty-six infected with HCV genotype 2 received sofosbuvir plus ribavirin (SOF/RBV). Serum total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were measured at baseline, 4, 8, 12 (for all regimens) and 24 weeks (for DCV/ASV) during treatment (4w, 8w, 12w and 24w, respectively) and 12 and 24 weeks after treatment (p12w and p24w, respectively). In 69 (81.2%) patients receiving DCV/ASV and achieved a sustained virological response 24 (SVR24), TC and LDL-C increased significantly from baseline to p24w. In 84 (98.8%) receiving SOF/LDV and achieved SVR24, TC and LDL-C increased significantly from baseline to 8w, and TC decreased significantly from 8w to p12w. The 45 (97.8%) receiving SOF/RBV and achieved SVR24 showed no significant changes. At 12w, TC and LDL-C increased to a greater degree in patients receiving SOF/LDV, than those receiving DCV/ASV or SOF/RBV. During treatment with DAAs, the serum lipid profile may reflect not only recovery from the disruption of lipid metabolism induced by HCV, but also the pharmacological effects of DAAs. Further investigations are needed to elucidate the effect of DAAs on serum lipid profiles. This article is protected by copyright. All rights reserved.

  4. Hormonal regulation of lipid metabolism in developing coho salmon, Oncorhynchus kisutch

    SciTech Connect

    Sheridan, M.A.

    1985-01-01

    Lipid metabolism in juvenile coho salmon is characterized, and adaptive changes in lipid mobilization are described in relation to development and hormonal influences. The rates of lipogenesis and lipolysis were determined in selected tissues of juvenile salmon during the period of seawater preadaptive development (smoltification). Neutral lipid (sterol) and fatty acid synthesis in the liver and mesenteric fat was measured by tritium incorporation. Fatty acid synthesis in the liver and mesenteric fat decreased by 88% and 81%, respectively, between late February (parr) and early June (smolt). To assess the role of hormones in smoltification-associated lipid depletion, growth hormone, prolactin, thyroxin and cortisol were administered in vivo early in development (parr) to determine if any of these factors could initiate the metabolic responses normally seen later in development (smolt). Growth hormone stimulated lipid mobilization from coho salmon parr. Prolactin strongly stimulated lipid mobilization in coho parr. Thyroxin and cortisol also stimulated lipid mobilization for coho salmon parr. The direct effect of hormones was studied by in vitro pH-stat incubation of liver slices. These data suggest that norepinephrine stimulates fatty acid release via ..beta..-adrenergic pathways. Somatostatin and its partial analogue from the fish caudal neurosecretory system, urotensin II, also affect lipid mobilization. These results establish the presence of hormone-sensitive lipase in salmon liver and suggest that the regulation of lipid metabolism in salmon involves both long-acting and short-acting hormonal agents.

  5. Methyl salicylate 2-O-β-D-lactoside, a novel salicylic acid analogue, acts as an anti-inflammatory agent on microglia and astrocytes

    PubMed Central

    2011-01-01

    Background Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-O-β-D-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309. Findings Our studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation. Conclusions We demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD. PMID:21831328

  6. Synthesis, biological evaluation and molecular modeling study of thiadiazolo[3,2-a][1,3]diazepine analogues of HIE-124 as a new class of short acting hypnotics.

    PubMed

    El-Subbagh, Hussein I; Hassan, Ghada S; El-Taher, Kamal E H; El-Messery, Shahenda M; Al-Azab, Adel S; Abdelaziz, Alaa A-M; Hefnawy, Mohamed M

    2016-11-29

    A new series of 6,7-dihydro-[1,3,4]thiadiazolo[3,2-a][1,3]diazepine analogues were synthesized, and biological evaluated. Compound GS-62 (33) exhibited potent in vivo short acting hypnotic activity with onset time, duration of sleep and therapeutic index of 6.4 ± 0.2, 94.8 ± 5.3 min, 6.62, respectively), in comparison to thiopental sodium (6). Compounds 33 did not show any sign of acute tolerance reported with the maintenance dose of 6. Meanwhile 33 potentiated the in vivo hypnotic effect of 6 in an equimolar amounts (0.06 mmol) combination showing an onset and duration of 7.5 ± 1.3, 62.5 ± 5.9 min, respectively. This combination allowed the use of lower doses of both drugs to avoid the undesirable side effects. Docking studies revealed favorable interactions and binding to BDZ binding site of the GABAA receptor especially with Arg87, Arg149, and Thr151 amino acid residues. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Template polymerization of nucleotide analogues

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.

    1991-01-01

    Recent work on the template-directed reactions of the natural D-nucleotides has made it clear that l-nucleotides and nucleotide-like derivatives of other sugars would strongly inhibit the formation of long oligonucleotides. Consequently, attention is focusing on molecules simpler than nucleotides that might have acted as monomers of an information transfer system. We have begun a general exploration of the template directed reactions of diverse peptide analogues. I will present work by Dr. Taifeng Wu on oxidative oligomerization of phosphorothioates and of Dr. Mary Tohidi on the cyclic polymerization of nucleoside and related cyclic pyrophosphates.

  8. Intranasal infusion of nanostructured lipid carriers (NLC) containing CNS acting drug and estimation in brain and blood.

    PubMed

    Alam, M Intakhab; Baboota, Sanjula; Ahuja, Alka; Ali, Mushir; Ali, Javed; Sahni, Jasjeet K

    2013-08-01

    The present study was aimed to evaluate the nanostrucured lipid carriers (NLC) containing duloxetine (DLX-NLC) for intranasal infusion through the nasal cavity of rat. The in vivo nasal infusion studies were performed using Wistar rats and the amount of DLX permeated and its amount in brain and blood was estimated. The effects on absorption rate and type of drug delivery systems (nanocarriers and drug solution) for nose to brain/blood permeation were assessed. DLX was found to be permeated from the nasal cavity into the body of rat and the permeated amount was found to be more in case of DLX-NLC. Approximately 2.5-times better permeation was exhibited by DLX-NLC than DLX-solution. Appreciable amount of DLX was estimated in blood and brain and the estimated amount was higher in case of DLX-NLC. Thus the administration of NLC containing DLX through intranasal route was found to be potential method for the delivery of DLX for the treatment of depression.

  9. Survey of Analogue Spacetimes

    NASA Astrophysics Data System (ADS)

    Visser, Matt

    Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  10. Lipid-core nanocapsules restrained the indomethacin ethyl ester hydrolysis in the gastrointestinal lumen and wall acting as mucoadhesive reservoirs.

    PubMed

    Cattani, Vitória Berg; Fiel, Luana Almeida; Jäger, Alessandro; Jäger, Eliézer; Colomé, Letícia Marques; Uchoa, Flavia; Stefani, Valter; Dalla Costa, Teresa; Guterres, Sivia Stanisçuaski; Pohlmann, Adriana Raffin

    2010-01-31

    The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from lipid-core nanocapsules (NC) is converted into indomethacin (IndOH) in the intestine lumen, intestine wall or after the particles reach the blood stream. NC-IndOEt had monomodal size distribution (242 nm; PDI 0.2) and zeta potential of -11 mV. The everted rat gut sac model showed IndOEt passage of 0.16 micromol m(-2) through the serosal fluid (30 min). From 15 to 120 min, the IndOEt concentrations in the tissue increased from 6.13 to 27.47 micromol m(-2). No IndOH was formed ex vivo. A fluorescent-NC formulation was used to determine the copolymer bioadhesion (0.012 micromol m(-2)). After NC-IndOEt oral administration to rats, IndOEt and IndOH were detected in the gastrointestinal tract (contents and tissues). In the tissues, the IndOEt concentrations decreased from 459 to 5 microg g(-1) after scrapping, demonstrating the NC mucoadhesion. In plasma (peripheric and portal vein), in spleen and liver, exclusively IndOH was detected. In conclusion, after oral dosing of NC-IndOEt, IndOEt is converted into IndOH in the intestinal lumen and wall before reaching the blood stream. The complexity of a living system was not predicted by the ex vivo gut sac model. Copyright 2009 Elsevier B.V. All rights reserved.

  11. Differential targeting of glucosylceramide and galactosylceramide analogues after synthesis but not during transcytosis in Madin-Darby canine kidney cells

    PubMed Central

    1995-01-01

    A short-chain analogue of galactosylceramide (6-NBD-amino-hexanoyl- galactosylceramide, C6-NBD-GalCer) was inserted into the apical or the basolateral surface of MDCK cells and transcytosis was monitored by depleting the opposite cell surface of the analogue with serum albumin. In MDCK I cells 32% of the analogue from the apical surface and 9% of the analogue from the basolateral surface transcytosed to the opposite surface per hour. These numbers were very similar to the flow of membrane as calculated from published data on the rate of fluid-phase transcytosis in these cells, demonstrating that C6-NBD-GalCer acted as a marker of bulk membrane flow. It was calculated that in MDCK I cells 155 microns membrane transcytosed per cell per hour in each direction. The fourfold higher percentage transported from the apical surface is explained by the apical to basolateral surface area ratio of 1:4. In MDCK II cells, with an apical to basolateral surface ratio of 1:1, transcytosis of C6-NBD-GalCer was 25% per hour in both directions. Similar numbers were obtained from measuring the fraction of endocytosed C6-NBD-GalCer that subsequently transcytosed. Under these conditions lipid leakage across the tight junction could be excluded, and the vesicular nature of lipid transcytosis was confirmed by the observation that the process was blocked at 17 degrees C. After insertion into one surface of MDCK II cells, the glucosylceramide analogue C6-NBD-GlcCer randomly equilibrated over the two surfaces in 8 h. C6-NBD-GalCer and -GlcCer transcytosed with identical kinetics. Thus no lipid selectivity in transcytosis was observed. Whereas the mechanism by which MDCK cells maintain the different lipid compositions of the two surface domains in the absence of lipid sorting along the transcytotic pathway is unclear, newly synthesized C6-NBD-GlcCer was preferentially delivered to the apical surface of MDCK II cells as compared with C6-NBD-GalCer. PMID:7593186

  12. Fluorescent polyene ceramide analogues as membrane probes.

    PubMed

    Nieves, Ingrid; Artetxe, Ibai; Abad, José Luis; Alonso, Alicia; Busto, Jon V; Fajarí, Lluís; Montes, L Ruth; Sot, Jesús; Delgado, Antonio; Goñi, Félix M

    2015-03-03

    Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.

  13. A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects.

    PubMed

    Talukdar, Saswata; Zhou, Yingjiang; Li, Dongmei; Rossulek, Michelle; Dong, Jennifer; Somayaji, Veena; Weng, Yan; Clark, Ronald; Lanba, Adhiraj; Owen, Bryn M; Brenner, Martin B; Trimmer, Jeffrey K; Gropp, Kathryn E; Chabot, Jeffrey R; Erion, Derek M; Rolph, Timothy P; Goodwin, Bryan; Calle, Roberto A

    2016-03-08

    FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Total body nitrogen and total body carbon as indicators of body protein and body lipids in the melon fly: Effects of methoprene, a juvenile hormone analogue, and of diet supplementation with hydrolyzed yeast

    USDA-ARS?s Scientific Manuscript database

    The application of methoprene and dietary protein enhanced mating success and had no effect on survival in male melon fly Bactrocera cucurbitae Coquillett (Diptera: Tephritidae). .The objective of the present study was to investigate the effect of methoprene and protein on body lipids and protein tu...

  15. Natural Analogue Synthesis Report

    SciTech Connect

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide

  16. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  17. Germananes: Germanium Graphane Analogues

    NASA Astrophysics Data System (ADS)

    Goldberger, Joshua

    2014-03-01

    Graphene's success has shown that it is not only possible to create stable, single-atom thick sheets from a crystalline solid, but that these materials have fundamentally different properties than the parent material. Our interest focuses on the synthesis and properties of Group IV graphane analogues. We have synthesized for the first time, mm-scale crystals of a hydrogen-terminated germanium multilayered graphane analogue (germanane, GeH) from the topochemical deintercalation of CaGe2. This layered van der Waals solid is analogous to multilayered graphane. The surface layer of GeH only slowly oxidizes in air over the span of five months, while the underlying layers are resilient to oxidation. We demonstrate that it is possible to covalently terminate the external surface with organic substituents to tune the electronic structure, and enhance the stability. These materials represent a new class of covalently terminated graphane analogues having great potential for a wide range of optoelectronic and sensing applications, especially since theory predicts a direct band gap of 1.53 eV and an electron mobility of 18,000 cm2/Vs which is five times higher than that of bulk Ge.

  18. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  19. Lipid Profile

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Lipid Profile Share this page: Was this page helpful? Also ... as: Lipid Panel; Coronary Risk Panel Formal name: Lipid Profile Related tests: Cholesterol ; HDL Cholesterol ; LDL Cholesterol ; Triglycerides ; ...

  20. Synthesis and cytotoxicity properties of amiodarone analogues.

    PubMed

    Bigler, Laurent; Spirli, Carlo; Fiorotto, Romina; Pettenazzo, Andrea; Duner, Elena; Baritussio, Aldo; Follath, Ferenc; Ha, Huy Riem

    2007-06-01

    Amiodarone (AMI) is a potent antiarrhythmic agent; however, its clinical use is limited due to numerous side effects. In order to investigate the structure--cytotoxicity relationship, AMI analogues were synthesized, and then, using rabbit alveolar macrophages, were tested for viability and for the ability to interfere with the degradation of surfactant protein A (SP-A) and with the accumulation of an acidotropic dye. Our data revealed that modification of the diethylamino-beta-ethoxy group of the AMI molecule may affect viability, the ability to degrade SP-A and vacuolation differently. In particular, PIPAM (2d), an analogue with a piperidyl moiety, acts toward the cells in a similar manner to AMI, but is less toxic. Thus, it would be possible to reduce the cytotoxicity of AMI by modifying its chemical structure.

  1. Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents

    PubMed Central

    Hyrina, Anastasia; Meng, Fanrui; McArthur, Steven J.; Eivemark, Sharlene; Nabi, Ivan R.; Jean, François

    2017-01-01

    Viral hijacking and manipulation of host-cell biosynthetic pathways by human enveloped viruses are shared molecular events essential for the viral lifecycle. For Flaviviridae members such as hepatitis C virus and dengue virus (DENV), one of the key subsets of cellular pathways that undergo manipulation is the lipid metabolic pathways, underlining the importance of cellular lipids and, in particular, lipid droplets (LDs) in viral infection. Here, we hypothesize that targeting cellular enzymes that act as key regulators of lipid homeostasis and LD formation could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with all DENV serotypes (1–4) circulating around the world. Using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrate that inhibition of SKI-1/S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the LD numbers and LD-positive areas and provides a means of effectively inhibiting infection by DENV (1–4). Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV infection [median inhibitory dose (EC50) = 1.2 microM; median cytotoxic dose (CC50) = 81 microM; selectivity index (SI) = 68)] and a ~3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid, which acts as an inducer of LD formation in PF-429242-treated and non-treated control cells. Collectively, our results demonstrate that human SKI-1/S1P is a potential target for indirect-acting pan-serotypic anti-DENV agents and reveal new therapeutic opportunities associated with the use of lipid-modulating drugs for controlling DENV infection. PMID:28339489

  2. Cationic dialkylarylphosphates: a new family of bio-inspired cationic lipids for gene delivery.

    PubMed

    Le Corre, Stéphanie S; Belmadi, Nawal; Berchel, Mathieu; Le Gall, Tony; Haelters, Jean-Pierre; Lehn, Pierre; Montier, Tristan; Jaffrès, Paul-Alain

    2015-01-28

    In this work that aims to synthesize and evaluate new cationic lipids as vectors for gene delivery, we report the synthesis of a series of cationic lipids in which a phosphate functional group acts as a linker to assemble on a molecular scale, two lipid chains and one cationic polar head. The mono or dicationic moiety is connected to the phosphate group by an aryl spacer. In this work, two synthesis strategies were evaluated. The first used the Atherton-Todd coupling reaction to introduce a phenolic derivative to dioleylphosphite. The second strategy used a sequential addition of lipid alcohol and a phenolic derivative on POCl3. The two methods are efficient, but the latter allows larger yields. Different polar head groups were introduced, thus producing amphiphilic compounds possessing either one permanent (N-methyl-imidazolium, pyridinium, trimethylammonium) or two permanent cationic charges. All these cationic lipids were formulated as liposomal solutions and characterized (size and zeta potential). They formed stable liposomal solutions both in water (at pH 7.0) and in a weakly acidic medium (at pH 5.5). Finally, this new generation of cationic lipids was used to deliver DNA into various human-derived epithelial cells cultured in vitro. Compared with Lipofectamine used as a reference commercial lipofection reagent, some cationic dialkylarylphosphates were able to demonstrate potent gene transfer abilities, and noteworthily, monocationic derivatives were much more efficient than dicationic analogues.

  3. Comparative lipid composition of heterotrophically and autotrophically grown Sulfolobus acidocaldarius.

    PubMed

    Langworthy, T A

    1977-06-01

    Complex lipids from the thermoacidophilic facultative autotroph Sulfolobus acidocaldarius, as well as a strictly autotrophic isolate, were compared between cells grown on yeast extract and elemental sulfur. Lipids from both organisms grown autotrophically were nearly identical. Each contained about 15% neutral lipids, 35% glycolipids, and 50% acidic lipids. Glycolipids and acidic lipids contained C40H82-76-derived glycerol ether residues. Major glycolipids included the glycerol ether analogues of glucosyl galactosyl diglyceride (5%) and glucosyl polyol diglyceride (75%). Acidic lipids were comprised mainly of the glycerol ether analogues of phosphatidyl inositol (7%), inositolphosphoryl glucosyl polyol diglyceride (72%), and a partially characterized sulfate- and phosphate-containing derivative of glucosyl polyol diglyceride (13%). The lipids from cells grown heterotrophically were similar to those from autotrophically grown cells, except that the partially characterized acidic lipid was absent. In addition, the two glycolipids as well as the respective inositolphosphoryl derivatives were each present in nearly equal proportions.

  4. Comparative lipid composition of heterotrophically and autotrophically grown Sulfolobus acidocaldarius.

    PubMed Central

    Langworthy, T A

    1977-01-01

    Complex lipids from the thermoacidophilic facultative autotroph Sulfolobus acidocaldarius, as well as a strictly autotrophic isolate, were compared between cells grown on yeast extract and elemental sulfur. Lipids from both organisms grown autotrophically were nearly identical. Each contained about 15% neutral lipids, 35% glycolipids, and 50% acidic lipids. Glycolipids and acidic lipids contained C40H82-76-derived glycerol ether residues. Major glycolipids included the glycerol ether analogues of glucosyl galactosyl diglyceride (5%) and glucosyl polyol diglyceride (75%). Acidic lipids were comprised mainly of the glycerol ether analogues of phosphatidyl inositol (7%), inositolphosphoryl glucosyl polyol diglyceride (72%), and a partially characterized sulfate- and phosphate-containing derivative of glucosyl polyol diglyceride (13%). The lipids from cells grown heterotrophically were similar to those from autotrophically grown cells, except that the partially characterized acidic lipid was absent. In addition, the two glycolipids as well as the respective inositolphosphoryl derivatives were each present in nearly equal proportions. Images PMID:863856

  5. Cost-effectiveness of insulin analogues for diabetes mellitus.

    PubMed

    Cameron, Chris G; Bennett, Heather A

    2009-02-17

    Insulin analogues may be associated with fewer episodes of hypoglycemia than conventional insulins. However, they are costly alternatives. We compared the cost-effectiveness of insulin analogues and conventional insulins used to treat type 1 and type 2 diabetes mellitus in adults. We conducted a cost-effectiveness evaluation of insulin analogues versus conventional insulins using the Center for Outcomes Research Diabetes Model. We compared rapid-acting analogues (insulin aspart and insulin lispro) with regular human insulin, and long-acting analogues (insulin glargine and insulin detemir) with neutral protamine Hagedorn insulin. We derived clinical information for the comparisons from meta-analyses of randomized controlled trials. We obtained cost and utility estimates from published sources. We performed sensitivity analyses to test the robustness of our results. For type 1 diabetes, insulin aspart was more effective and less costly than regular human insulin. Insulin lispro was associated with an incremental cost of Can$28,996 per quality-adjusted life-year. The incremental cost per quality-adjusted life-year was Can$87,932 for insulin glargine and Can$387,729 for insulin detemir, compared with neutral protamine Hagedorn insulin. For type 2 diabetes, insulin aspart was associated with an incremental cost of Can$22,488 per quality-adjusted life-year compared with regular human insulin. For insulin lispro, the incremental cost was Can$130,865. Compared with neutral protamine Hagedorn insulin, insulin detemir was less effective and more costly. Insulin glargine was associated with an incremental cost of Can$642,994 per quality-adjusted life-year. The model was sensitive to changes in the effect size of hemoglobin A(1c) and to decrements applied to utility scores when fear of hypoglycemia was included as a factor. The cost-effectiveness of insulin analogues depends on the type of insulin analogue and whether the patient receiving the treatment has type 1 or type 2

  6. Total body nitrogen and total body carbon as indicators of body protein and body lipids in the melon fly Bactrocera cucurbitae: effects of methoprene, a juvenile hormone analogue, and of diet supplementation with hydrolyzed yeast.

    PubMed

    ul Haq, Ihsan; Mayr, Leopold; Teal, P E A; Hendrichs, Jorge; Robinson, Alan S; Stauffer, Christian; Hood-Nowotny, Rebecca

    2010-12-01

    The application of methoprene, and providing access to diet including hydrolyzed yeast, are treatments known to enhance mating success in the male melon fly Bactrocera cucurbitae Coquillett (Diptera: Tephritidae), supporting their use in mass rearing protocols for sterile males in the context of sterile insect technique (SIT) programmes. The objective of the present laboratory study was to investigate the effect of methoprene application and diet supplementation with hydrolyzed yeast (protein) on the turnover of body lipids and protein to confirm the feasibility of their application in melon fly SIT mass-rearing programmes. While females had access to a diet that included hydrolyzed yeast (protein), males were exposed to one of the following treatments: (1) topical application of methoprene and access to diet including protein (M+P+); (2) only diet including protein (M-P+); (3) only methoprene (M+P-) and (4) untreated, only sugar-fed, control males (M-P-). Total body carbon (TBC) and total body nitrogen (TBN) of flies were measured at regular intervals from emergence to 35 days of age for each of the different treatments. Nitrogen assimilation and turnover in the flies were measured using stable isotope ((15)N) dilution techniques. Hydrolyzed yeast incorporation into the diet significantly increased male body weight, TBC and TBN as compared to sugar-fed males. Females had significantly higher body weight, TBC and TBN as compared to all males. TBC and TBN showed age-dependent changes, increasing until the age of sexual maturity and decreasing afterwards in both sexes. Methoprene treatment did not significantly affect TBC or TBN. The progressive increase with age of TBC suggests that lipogenesis occurs in adult male B. cucurbitae, as is the case in other tephritids. Stable isotope dilution was shown to be an effective method for determining N uptake in B. cucurbitae. This technique was used to show that sugar-fed males rely solely on larval N reserves and that the N

  7. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  8. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    PubMed

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

  9. Sarcoplasmic reticulum calcium ATPase is inhibited by organic vanadium coordination compounds: pyridine-2,6-dicarboxylatodioxovanadium(V), BMOV, and an amavadine analogue.

    PubMed

    Aureliano, Manuel; Henao, Fernando; Tiago, Teresa; Duarte, Rui O; Moura, J J G; Baruah, Bharat; Crans, Debbie C

    2008-07-07

    The general affinity of the sarcoplasmic reticulum (SR) Ca (2+)-ATPase was examined for three different classes of vanadium coordination complexes including a vanadium(V) compound, pyridine-2,6-dicarboxylatodioxovanadium(V) (PDC-V(V)), and two vanadium(IV) compounds, bis(maltolato)oxovanadium(IV) (BMOV), and an analogue of amavadine, bis( N-hydroxylamidoiminodiacetato)vanadium(IV) (HAIDA-V(IV)). The ability of vanadate to act either as a phosphate analogue or as a transition-state analogue with enzymes' catalysis phosphoryl group transfer suggests that vanadium coordination compounds may reveal mechanistic preferences in these classes of enzymes. Two of these compounds investigated, PDC-V(V) and BMOV, were hydrolytically and oxidatively reactive at neutral pH, and one, HAIDA-V(IV), does not hydrolyze, oxidize, or otherwise decompose to a measurable extent during the enzyme assay. The SR Ca (2+)-ATPase was inhibited by all three of these complexes. The relative order of inhibition was PDC-V(V) > BMOV > vanadate > HAIDA-V(IV), and the IC 50 values were 25, 40, 80, and 325 microM, respectively. Because the observed inhibition is more potent for PDC-V(V) and BMOV than that of oxovanadates, the inhibition cannot be explained by oxovanadate formation during enzyme assays. Furthermore, the hydrolytically and redox stable amavadine analogue HAIDA-V(IV) inhibited the Ca (2+)-ATPase less than oxovanadates. To gauge the importance of the lipid environment, studies of oxidized BMOV in microemulsions were performed and showed that this system remained in the aqueous pool even though PDC-V(V) is able to penetrate lipid interfaces. These findings suggest that the hydrolytic properties of these complexes may be important in the inhibition of the calcium pump. Our results show that two simple coordination complexes with known insulin enhancing effects can invoke a response in calcium homeostasis and the regulation of muscle contraction through the SR Ca (2+)-ATPase.

  10. L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities.

    PubMed Central

    Babizhayev, M A; Seguin, M C; Gueyne, J; Evstigneeva, R P; Ageyeva, E A; Zheltukhina, G A

    1994-01-01

    Carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) are natural imidazole-containing compounds found in the non-protein fraction of mammalian tissues. Carcinine was synthesized by an original procedure and characterized. Both carnosine and carcinine (10-25 mM) are capable of inhibiting the catalysis of linoleic acid and phosphatidylcholine liposomal peroxidation (LPO) by the O2(-.)-dependent iron-ascorbate and lipid-peroxyl-radical-generating linoleic acid 13-monohydroperoxide (LOOH)-activated haemoglobin systems, as measured by thiobarbituric-acid-reactive substance. Carcinine and carnosine are good scavengers of OH. radicals, as detected by iron-dependent radical damage to the sugar deoxyribose. This suggests that carnosine and carcinine are able to scavenge free radicals or donate hydrogen ions. The iodometric, conjugated diene and t.l.c. assessments of lipid hydroperoxides (13-monohydroperoxide linoleic acid and phosphatidylcholine hydroperoxide) showed their efficient reduction and deactivation by carnosine and carcinine (10-25 mM) in the liberated and bound-to-artificial-bilayer states. This suggests that the peroxidase activity exceeded that susceptible to direct reduction with glutathione peroxidase. Imidazole, solutions of beta-alanine, or their mixtures with peptide moieties did not show antioxidant potential. Free L-histidine and especially histamine stimulated iron (II) salt-dependent LPO. Due to the combination of weak metal chelating (abolished by EDTA), OH. and lipid peroxyl radicals scavenging, reducing activities to liberated fatty acid and phospholipid hydroperoxides, carnosine and carcinine appear to be physiological antioxidants able to efficiently protect the lipid phase of biological membranes and aqueous environments. PMID:7998987

  11. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

  12. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    DTIC Science & Technology

    2011-07-01

    the effects of DHB analogues to ascertain if they are longer-acting compounds than the parent compound. Although obtaining the first and only drug ...useful in the treatment of PD. Body of Work The goal of this study is to fully assess and compare the potency of compounds that are structurally...SARA 313: Carcinogenicity Classification (components present at 0.1% or more): none, unless listed below TSCA (US Toxic Substances Control Act

  13. The TLR2 agonist in polysaccharide-K is a structurally distinct lipid which acts synergistically with the protein-bound β-glucan.

    PubMed

    Quayle, Kenneth; Coy, Catherine; Standish, Leanna; Lu, Hailing

    2015-04-01

    Protein-bound polysaccharide-K (Krestin; PSK) is a hot-water extract of Trametes versicolor with immune stimulatory activity. It has been used for the past 30 years and has demonstrated anti-tumor efficacy in multiple types of cancer. The ability of PSK to activate dendritic cells and T cells is dependent on its ability to stimulate Toll-like receptor 2 (TLR2), yet it remains unknown which structural component within PSK activates TLR2. The purpose of this study was to identify the TLR2 agonist within PSK and understand its role in the overall mechanism of PSK's immunogenic activity. TLR2 activity was eliminated by treatment with lipoprotein lipase but not by trypsin or lyticase. Rapid centrifugation of PSK can separate the fraction with TLR2 agonist activity from the soluble β-glucan fraction. To study the potential interaction between the β-glucan component and the lipid component, we labeled the soluble β-glucan with fluorescein. Uptake of the labeled β-glucan by J774A macrophages and JAWSII dendritic cells was inhibited by anti-Dectin-1 antibody but not by anti-TLR2 antibody, confirming that Dectin-1 is the receptor for β-glucan. Interestingly, pre-treatment of JAWSII cells with the TLR2-active lipid fraction significantly enhanced the uptake of the soluble β-glucan, indicating the synergy between the TLR2 agonist component and the β-glucan component. Altogether, these results present evidence that PSK has two active components-the well-characterized protein-bound β-glucan and a previously unreported lipid-which work synergistically via the Dectin-1 and TLR2 receptors.

  14. Cardiac specific effects of thyroid hormone analogues.

    PubMed

    Danzi, S; Klein, I

    2011-10-01

    There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) β isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific α-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TRβ and 1 TRα selective agonists as well as 2 putative TR antagonists in our α-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the α-MHC primary transcript in response to administration of drug. The TRα and only 2 of the TRβ agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of α-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete. © Georg Thieme Verlag KG Stuttgart · New York.

  15. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  16. Neuroprotective actions of a histidine analogue in models of ischemic stroke.

    PubMed

    Tang, Sung-Chun; Arumugam, Thiruma V; Cutler, Roy G; Jo, Dong-Gyu; Magnus, Tim; Chan, Sic L; Mughal, Mohamed R; Telljohann, Richard S; Nassar, Matthew; Ouyang, Xin; Calderan, Andrea; Ruzza, Paolo; Guiotto, Andrea; Mattson, Mark P

    2007-05-01

    Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.

  17. Vibrio cholerae thiol peroxidase-glutaredoxin fusion is a 2-Cys TSA/AhpC subfamily acting as a lipid hydroperoxide reductase.

    PubMed

    Cha, Mee-Kyung; Hong, Seung-Keun; Lee, Dong-Suk; Kim, Il-Han

    2004-03-19

    Recently, novel hybrid thiol peroxidase (TPx) proteins fused with a glutaredoxin (Grx) were found from some pathogenic bacteria, cyanobacteria, and anaerobic sulfur-oxidizing phototroph. The phylogenic tree analysis that was constructed from the aligned sequences showed two major branches. Haemophilus influenzae TPx.Grx was grouped in one branch as a 1-Cys subfamily of the thiol-specific antioxident protein/AhpC family. Most TPx.Grx proteins, including Vibrio cholerae TPx.Grx, were grouped in the 2-Cys subfamily. To explain the existence of two subgroups in novel hybrid TPx proteins, we have compared the kinetics given by V. cholerae TPx.Grx, H. influenzae TPx.Grx, their separated TPx domains, and a set of mutants devoid of the redox-active cysteines. The kinetic study described here demonstrates clearly that V. cholerae TPx.Grx is a 2-Cys TPx subfamily. For the first time, we also demonstrate the lipid peroxidase activity of V. cholerae TPx.Grx fusion and suggest the in vivo function of 2-Cys TPx.Grx fusion serving as a lipid peroxidase.

  18. Teduglutide, a glucagon-like peptide 2 analogue: a novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury.

    PubMed

    Arda-Pirincci, Pelin; Oztay, Fusun; Bayrak, Bertan Boran; Yanardag, Refiye; Bolkent, Sehnaz

    2012-12-01

    Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium-potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury.

  19. Four thiol peroxidases contain a conserved GCT catalytic motif and act as a versatile array of lipid peroxidases in Anabaena sp. PCC7120.

    PubMed

    Cha, Mee-Kyung; Hong, Seung-Keun; Kim, Il-Han

    2007-06-01

    The Anabaena sp. (ANASP) genome contains seven open reading frames with homology to thiol peroxidase (TPx), also known as peroxiredoxin (Prx). Based on sequence similarities among putative TPx's derived from various cyanobacteria genomes, we designated the seven putative TPx members as VCP, VCT, TCS, and GCT clusters according to the sequence of their conserved catalytic motif. The GCT cluster consists of four members, named GCT1, GCT2, GCT3, and GCT4. The ANASP GCT-TPx genes were recombinantly expressed in Escherichia coli. The purified proteins were characterized with an emphasis on the ability to destroy various peroxides, the electron donor, and the conserved cysteine structure as a catalytic intermediate. All GCT members, as an atypical 2-Cys TPx family, exerted the highest peroxidase activity toward a lipid hydroperoxide using an electron from thioredoxin. Periplasmic protein analysis revealed that GCT2 and GCT4 are distributed in the cytoplasm, whereas GCT1 and GCT3, homologues of E. coli bacterioferritin comigratory protein/plant PrxQ, are localized in the periplasmic space. Immunoblots of the heterocystic proteins showed that the level of GCT2 in the heterocyst is comparable to that in the vegetative cell, whereas the other GCT members were not significantly detected in the heterocyst. The transcriptional responses of ANASP GCT genes to various oxidative stresses and growth environments were multifarious. Their intrinsic differences in transcriptional responsiveness and cellular localization suggest that this large GCT cluster is designed as an adaptive strategy to efficiently combat lipid hydroperoxide in Anabaena sp. that perform oxygenic photosynthesis and N(2) fixation.

  20. Differential membrane fluidization by active and inactive cannabinoid analogues.

    PubMed

    Mavromoustakos, T; Papahatjis, D; Laggner, P

    2001-06-06

    The effects of the two cannabinomimetic drugs (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl-2-(hexyl)-1,3-dithiolane (AMG-3) and its pharmacologically less active 1-methoxy analogue (AMG-18) on the thermotropic and structural properties of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) liposomes have been studied by X-ray diffraction and differential scanning calorimetry (DSC). DSC data revealed that the incorporation of the drugs affect differently the thermotropic properties of DPPC. The presence of the more active drug distinctly broadened and attenuated both the pretransition and main phase transition of DPPC bilayers, while the inactive analogue had only minor effects. Small and wide angle X-ray diffraction data showed that the two cannabinoids have different effects on the lipid phase structures and on the hydrocarbon chain packing. The pharmacologically active analogue, AMG-3, was found to efficiently fluidize domains of the lipids in the L(beta)' gel phase, and to perturb the regular multibilayer lattice. In the liquid crystalline L(alpha) phase, AMG-3 was also found to cause irregularities in packing, suggesting that the drug induces local curvature. At the same concentration, the inactive AMG-18 had only minor structural effects on the lipids. At about 10-fold or higher concentrations, AMG-18 was found to produce similar but still less pronounced effects in comparison to those observed by AMG-3. The dose-dependent, different thermotropic and structural effects by the two cannabinoid analogues suggest that these may be related to their biological activity.

  1. Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4-Aminocrotonic and 4-Aminotetrolic Acids.

    PubMed

    Johnston, Graham A R

    2016-03-01

    Analogues of the neurotransmitter GABA containing unsaturated bonds are restricted in the conformations they can attain. This review traces three such analogues from their synthesis to their use as neurochemicals. trans-4-Aminocrotonic acid was the first conformationally restricted analogue to be extensively studied. It acts like GABA across a range of macromolecules from receptors to transporters. It acts similarly to GABA on ionotropic receptors. cis-4-Aminocrotonic acid selectively activates bicuculline-insensitive GABAC receptors. 4-Aminotetrolic acid, containing a triple bond, activates bicuculline-sensitive GABAA receptors. These findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations. These and related analogues are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors.

  2. Reducible cationic lipids for gene transfer.

    PubMed Central

    Wetzer, B; Byk, G; Frederic, M; Airiau, M; Blanche, F; Pitard, B; Scherman, D

    2001-01-01

    One of the main challenges of gene therapy remains the increase of gene delivery into eukaryotic cells. We tested whether intracellular DNA release, an essential step for gene transfer, could be facilitated by using reducible cationic DNA-delivery vectors. For this purpose, plasmid DNA was complexed with cationic lipids bearing a disulphide bond. This reduction-sensitive linker is expected to be reduced and cleaved in the reducing milieu of the cytoplasm, thus potentially improving DNA release and consequently transfection. The DNA--disulphide-lipid complexation was monitored by ethidium bromide exclusion, and the size of complexes was determined by dynamic light scattering. It was found that the reduction kinetics of disulphide groups in DNA--lipid complexes depended on the position of the disulphide linker within the lipid molecule. Furthermore, the internal structure of DNA--lipid particles was examined by small-angle X-ray scattering before and after lipid reduction. DNA release from lipid complexes was observed after the reduction of disulphide bonds of several lipids. Cell-transfection experiments suggested that complexes formed with selected reducible lipids resulted in up to 1000-fold higher reporter-gene activity, when compared with their analogues without disulphide bonds. In conclusion, reduction-sensitive groups introduced into cationic lipid backbones potentially allow enhanced DNA release from DNA--lipid complexes after intracellular reduction and represent a tool for improved vectorization. PMID:11389682

  3. Reducible cationic lipids for gene transfer.

    PubMed

    Wetzer, B; Byk, G; Frederic, M; Airiau, M; Blanche, F; Pitard, B; Scherman, D

    2001-06-15

    One of the main challenges of gene therapy remains the increase of gene delivery into eukaryotic cells. We tested whether intracellular DNA release, an essential step for gene transfer, could be facilitated by using reducible cationic DNA-delivery vectors. For this purpose, plasmid DNA was complexed with cationic lipids bearing a disulphide bond. This reduction-sensitive linker is expected to be reduced and cleaved in the reducing milieu of the cytoplasm, thus potentially improving DNA release and consequently transfection. The DNA--disulphide-lipid complexation was monitored by ethidium bromide exclusion, and the size of complexes was determined by dynamic light scattering. It was found that the reduction kinetics of disulphide groups in DNA--lipid complexes depended on the position of the disulphide linker within the lipid molecule. Furthermore, the internal structure of DNA--lipid particles was examined by small-angle X-ray scattering before and after lipid reduction. DNA release from lipid complexes was observed after the reduction of disulphide bonds of several lipids. Cell-transfection experiments suggested that complexes formed with selected reducible lipids resulted in up to 1000-fold higher reporter-gene activity, when compared with their analogues without disulphide bonds. In conclusion, reduction-sensitive groups introduced into cationic lipid backbones potentially allow enhanced DNA release from DNA--lipid complexes after intracellular reduction and represent a tool for improved vectorization.

  4. Review of Insulin and its Analogues in Diabetes Mellitus

    PubMed Central

    Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

    2012-01-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  5. Oral peptide delivery by tetraether lipid liposomes.

    PubMed

    Parmentier, Johannes; Thewes, Bernhard; Gropp, Felix; Fricker, Gert

    2011-08-30

    The aim of this study is to improve of oral peptide delivery by a novel type of liposomes containing tetraether lipids (TELs) derived from archaea bacteria. Liposomes were used for the oral delivery of the somatostatin analogue octreotide. TELs were extracted from Sulfolobus acidocaldarius and subsequently purified to single compounds. Liposomes were prepared by the film method followed by extrusion. Vesicles in size between 130 and 207 nm were obtained as confirmed by photon correlation spectroscopy. The pharmacokinetics of radiolabeled TELs in liposomes was investigated after oral administration to rats. 1.6% of the applied radioactivity in fed and 1.5% in fasted rats was recovered in the blood and inner organs after 2h, while most of the radioactivity remained in the gastro-intestinal tract. After 24h the percentage of radioactivity in inner organs was reduced to 0.6% in fed rats, respectively 1.0% in fasted animals. Several liposomal formulations containing dipalmitoyl phosphatidylcholine (DPPC) and TELs in different ratios were loaded with octreotide and orally administered. Liposomes with 25% TEL could improve the oral bioavailability of octreotide 4.1-fold and one formulation with a cationic TEL derivative 4.6-fold. TEL-liposomes probably act by protecting the peptide in the gastro-intestinal tract.

  6. The membrane lipids of Halobacterium halobium

    PubMed Central

    Marshall, Carolyn L.; Brown, A. D.

    1968-01-01

    The lipid content of the cell membrane of Halobacterium halobium increased from about 15% to 21% during exponential growth of the organism. Total lipid phosphorus more than doubled during the growth cycle. The mixture of membrane lipids from stationary-phase organisms was similar to lipid mixtures from whole cells of other halobacteria inasmuch as 80% of the lipid phosphorus occurred in a diether analogue of phosphatidylglycerophosphate and an additional 7·5% occurred in the ether analogue of phosphatidylglycerol. The lipid mixture was more complex than those reported for other halophils, however, 12 components being recognized in the acetone-insoluble fraction and 17 in the acetone-soluble fraction. There were major changes in the proportions of some minor components of the acetone-insoluble fraction during a growth cycle. Three nitrogenous lipids were recognized in the acetone-insoluble fraction, but all were present in relatively low proportion. One, which was not a phospholipid, contained a bound peptide. Of the 17 acetonesoluble compounds, 15 were pigments. The major carotenoids were α- and β-bacteriorubrin. The carotenoid pigments occurred at maximal concentration after 6–7 days' growth. ImagesFig. 2. PMID:5701674

  7. PTH analogues and osteoporotic fractures.

    PubMed

    Verhaar, Harald J J; Lems, Willem F

    2010-09-01

    At present there are two parathyroid hormone (PTH) analogues (PTH 1 - 34 and PTH 1 - 84) registered for the treatment of established osteoporosis in postmenopausal women (PTH 1 - 34 and PTH 1 - 84) and in men (PTH 1 - 34 only) who are at increased risk of having a fracture. The efficacy and safety of PTH 1 - 34 and PTH 1 - 84 in the management of osteoporosis is evaluated by reviewing published literature and presentations from scientific meetings through to 2010. This review focuses on data on fracture risk reduction and safety endpoints of PTH analogues. The adverse reactions reported most are nausea, pain in the extremities, headache and dizziness. Exogenous PTH analogues, given as daily subcutaneous injections, stimulate bone formation, increase bone mass and bone strength, and improve calcium balance. In postmenopausal women with osteoporosis, PTH analogues reduced the risk of vertebral (PTH 1 - 34 and PTH 1 - 84) and non-vertebral fractures (only PTH 1 - 34). In men and women with glucocorticosteroid-induced osteoporosis, PTH 1 - 34 reduced the risk of vertebral fractures. In general, PTH analogues are well tolerated with an acceptable safety profile: they can be used for the prevention and treatment of fractures in postmenopausal women with severe, established osteoporosis.

  8. Milk lipids

    USDA-ARS?s Scientific Manuscript database

    Milk fat conveys a number of desirable qualities to food, and various lipid components contribute to human nutrition and health. Over 96% of milk lipids consist of triacylglycerols, which contain a variety of fatty acids. Di- and monoacylglycerols, free fatty acids, sterols, and phospho-, glyco-,...

  9. Pressor effects of tryptamine analogues.

    PubMed Central

    Bosin, T R; Hixson, E J; Maickel, R P

    1976-01-01

    1. Methylation of tryptamine in the 1-position had little effect on the potency of the drug as a pressor agent in the intact anaesthetized rat. 2. In contrast, substitution of a benzo[b]thiophene ring system for the indole ring decreased the pressor activity. 3. Pretreatment of the animals with reserpine reduced the pressor effect of tryptamine and its benzo[b]thiophene analogue while increasing the effect of the 1-methylindole analogue. 4. Pretreatment with phenoxybenzamine reduced the pressor effect of all three compounds. PMID:1252662

  10. Synthesis of l-lyxo-phytosphingosine and its 1-phosphonate analogue using a threitol acetal synthon.

    PubMed

    Lu, Xuequan; Byun, Hoe-Sup; Bittman, Robert

    2004-08-06

    The first synthesis of an isosteric phosphonate analogue of the aminotriol lipid phytosphingosine (3), together with an improved synthesis of (2S,3S,4S)-phytosphingosine (2), are described. A key intermediate is 3-pentylidene acetal 9, which was prepared in two steps from dimethyl 2,3-O-benzylidene-d-tartrate (7). Copyright 2004 American Chemical Society

  11. A Modern Analogue for Proterozoic Inverse Carbon Isotope Signatures

    NASA Astrophysics Data System (ADS)

    Close, H. G.; Diefendorf, A. F.; Freeman, K. H.; Pearson, A.

    2008-12-01

    The carbon isotope distribution preserved in sedimentary lipids changes near the Neoproterozoic-Cambrian boundary. In older samples, n-alkyl lipids contain more 13C than both isoprenoid lipids and kerogen [1]. In younger samples, the opposite prevails. Although extreme heterotrophy has been invoked as a mechanism to explain the enrichment in 13C [2], here we suggest another explanation. The switch may reflect a fundamental transition from an oligotrophic ocean dominated by prokaryotic biomass, to an ocean in which carbon fixation is more intensive and burial is dominated by eukaryotic biomass. An analogue for Proterozoic ordering is found in the modern, oligotrophic Pacific Ocean, where n-alkyl lipids of picoplankton (0.2-0.5 μm particulate matter) contain excess 13C relative to the same lipids found in larger size classes (> 0.5 μm). Picoplanktonic lipids are heavier isotopically (-18 ‰) than both the sterols of eukaryotes (-23 ‰ to -26 ‰) and the total organic matter (-20 ‰; TOM). The 0.2-0.5 μm size class also has a distinct chain-length abundance profile. Although large particles must be the vehicle for total carbon export, paradoxically the lipid component of export production appears to be dominated by the 0.2-0.5 μm source. The picoplanktonic chain lengths and isotopic composition dominate lipids of TOM at 670 meters. When the ratio of prokaryotic to eukaryotic production is high, as in the modern central Pacific Ocean, it appears that exported material has an inverse carbon isotope signature similar to that preserved in Precambrian samples. [1] Logan, G. A. et al., Nature 376:53-56 (1995). [2] Rothman, D. H. et al., PNAS 100:8124-8129 (2003).

  12. Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation.

    PubMed

    Bolze, Florian; Bast, Andrea; Mocek, Sabine; Morath, Volker; Yuan, Detian; Rink, Nadine; Schlapschy, Martin; Zimmermann, Anika; Heikenwalder, Mathias; Skerra, Arne; Klingenspor, Martin

    2016-09-01

    Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition. In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.

  13. Synthetic analogues of cyanobacterial alkaloid cylindrospermopsin and their toxicological activity.

    PubMed

    Cartmell, Christopher; Evans, Daniel M; Elwood, Jessica M L; Fituri, Hisham S; Murphy, Patrick J; Caspari, Thomas; Poniedziałek, Barbara; Rzymski, Piotr

    2017-10-01

    Cylindrospermopsin (CYN) is a naturally occurring alkaloid produced by a variety of cyanobacteria and known to induce oxidative stress-mediated toxicity in eukaryotic cells. Despite extensive research on the mechanism of CYN toxicity, an understanding of the structural features responsible for this toxicity and the mechanism by which it can enter the cell are still not clear. It was established that the presence of both the uracil and guanidine groups is essential in biological activity of CYN whilst not much is known in this regard on the role of tether that separates them and the attached hydroxyl group. Therefore, in the present study we have prepared three synthetic analogues possessing uracil and guanidine groups separated by a variable length tether (4-6 carbons) and containing a hydroxyl function in a position orientation to CYN, together with a tetracyclic analogue of CYN lacking the hydroxyl group at C-7. The toxicity of these compounds was then compared with CYN and guanidinoacetate (GAA; the primary substrate in CYN biosynthesis) in an in vitro model using human neutrophils isolated from healthy subjects. The lowest activity measured by means of reactive oxygen species generation, lipid peroxidation and cell death was observed for GAA and the tetracyclic analogue. The greatest toxicity was found in an analogue with a 6-carbon tether, but all three analogues and CYN caused rapid onset of redox imbalance. These results add to the general understanding of CYN toxicity and preliminary findings suggest that the -OH group at C-7 may be significant for the cellular transport of CYN and/or be involved in its toxic activity inside the cell, a hypothesis which requires further testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Synthesis of daidzin analogues as potential agents for alcohol abuse.

    PubMed

    Gao, Guang-Yao; Li, Dian-Jun; Keung, Wing Ming

    2003-09-01

    Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.

  15. Long-Chain Glycerol Diether and Polyol Dialkyl Glycerol Triether Lipids of Sulfolobus acidocaldarius

    PubMed Central

    Langworthy, Thomas A.; Mayberry, William R.; Smith, Paul F.

    1974-01-01

    Cells of Sulfolobus acidocaldarius contain about 2.5% total lipid on a dry-weight basis. Total lipid was found to contain 10.5% neutral lipid, 67.6% glycolipid, and 21.7% polar lipid. The lipids contained C40H80 isopranol glycerol diethers. Almost no fatty acids were present. The glycolipids were composed of about equal amounts of the glycerol diether analogue of glucosyl galactosyl diglyceride and a glucosyl polyol glycerol diether. The latter compound contained an unidentified polyol attached by an ether bond to the glycerol diether. The polar lipids contained a small amount of sulfolipid, which appeared to be the monosulfate derivative of glucosyl polyol glycerol diether. About 40% of the lipid phosphorus was found in the diether analogue of phosphatidyl inositol. The remaining lipid phosphorus was accounted for by approximately equal amounts of two inositol monophosphate-containing phosphoglycolipids, inositolphosphoryl glucosyl galactosyl glycerol diether and inositolphosphoryl glucosyl polyol glycerol diether. Images PMID:4407015

  16. Long-chain glycerol diether and polyol dialkyl glycerol triether lipids of Sulfolobus acidocaldarius.

    PubMed

    Langworthy, T A; Mayberry, W R; Smith, P F

    1974-07-01

    Cells of Sulfolobus acidocaldarius contain about 2.5% total lipid on a dry-weight basis. Total lipid was found to contain 10.5% neutral lipid, 67.6% glycolipid, and 21.7% polar lipid. The lipids contained C(40)H(80) isopranol glycerol diethers. Almost no fatty acids were present. The glycolipids were composed of about equal amounts of the glycerol diether analogue of glucosyl galactosyl diglyceride and a glucosyl polyol glycerol diether. The latter compound contained an unidentified polyol attached by an ether bond to the glycerol diether. The polar lipids contained a small amount of sulfolipid, which appeared to be the monosulfate derivative of glucosyl polyol glycerol diether. About 40% of the lipid phosphorus was found in the diether analogue of phosphatidyl inositol. The remaining lipid phosphorus was accounted for by approximately equal amounts of two inositol monophosphate-containing phosphoglycolipids, inositolphosphoryl glucosyl galactosyl glycerol diether and inositolphosphoryl glucosyl polyol glycerol diether.

  17. Long and Short Lipid Molecules Experience the Same Interleaflet Drag in Lipid Bilayers

    NASA Astrophysics Data System (ADS)

    Horner, Andreas; Akimov, Sergey A.; Pohl, Peter

    2013-06-01

    Membrane interleaflet viscosity ηe affects tether formation, phase separation into domains, cell shape changes, and budding. Contrary to the expected contribution to interleaflet coupling from interdigitation, the slide of lipid patches in opposing monolayers conferred the same value ηe≈3×109Jsm-4 for the friction experienced by the ends of both short and long chain fluorescent lipid analogues. Consistent with the weak dependence of the translational diffusion coefficient on lipid length, the in-layer viscosity was, albeit length dependent, much smaller than ηe.

  18. Interaction of Daptomycin with Lipid Bilayers: A Lipid Extracting Effect

    PubMed Central

    2015-01-01

    Daptomycin is the first approved member of a new structural class of antibiotics, the cyclic lipopeptides. The peptide interacts with the lipid matrix of cell membranes, inducing permeability of the membrane to ions, but its molecular mechanism has been a puzzle. Unlike the ubiquitous membrane-acting host-defense antimicrobial peptides, daptomycin does not induce pores in the cell membranes. Thus, how it affects the permeability of a membrane to ions is not clear. We studied its interaction with giant unilamellar vesicles (GUVs) and discovered a lipid-extracting phenomenon that correlates with the direct action of daptomycin on bacterial membranes observed in a recent fluorescence microscopy study. Lipid extraction occurred only when the GUV lipid composition included phosphatidylglycerol and in the presence of Ca2+ ions, the same condition found to be necessary for daptomycin to be effective against bacteria. Furthermore, it occurred only when the peptide/lipid ratio exceeded a threshold value, which could be the basis of the minimal inhibitory concentration of daptomycin. In this first publication on the lipid extracting effect, we characterize its dependence on ions and lipid compositions. We also discuss possibilities for connecting the lipid extracting effect to the antibacterial activity of daptomycin. PMID:25093761

  19. Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease

    PubMed Central

    Jin, Lihua; Wang, Rui; Zhu, Yanlin; Zheng, Weili; Han, Yaping; Guo, Fusheng; Ye, Frank Bin; Li, Yong

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling. PMID:26620317

  20. Chemical Synthesis and Molecular Recognition of Phosphatase-Resistant Analogues of Phosphatidylinositol-3-phosphate

    PubMed Central

    Xu, Yong; Lee, Stephanie A.; Kutateladze, Tatiana G.; Sbrissa, Diego; Shisheva, Assia; Prestwich, Glenn D.

    2008-01-01

    The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. In order to provide chemical tools to study of the changes in cell physiology mediated by these lipids, three new metabolically-stabilized (ms) analogues of phosphatidylinositol-3-phosphate (PtdIns(3)P were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-monofluoromethylphosphonate and 3-phosphorothioate analogues of PtdIns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of PtdIns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl and dibutyryl chains. In addition, we introduce a new phosphorlyation reagent, monofluoromethylphosphonyl chloride, which has general applications for the preparation of “pKa-matched” monofluorophosphonates. These ms-PtdIns(3)P analogues exhibited reduced binding activities with 15N-labelled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-PtdIns(3)Ps into membrane-mimetic dodecylphosphocholine (DPC) micelles. In addition, the PtdIns(3)P analogues with dioleyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis. PMID:16417379

  1. Neuronal Analogues of Conditioning Paradigms

    DTIC Science & Technology

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  2. Desferrithiocin Analogue Uranium Decorporation Agents

    PubMed Central

    Bergeron, Raymond J.; Wiegand, Jan; Singh, Shailendra

    2010-01-01

    Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue. PMID:19399680

  3. Epidermal lipids.

    PubMed

    Wertz, P W

    1992-06-01

    Epidermal lipids play important roles in cell structure, in control of growth and differentiation, in determining cohesion and desquamation, and in formation and function of a permeability barrier. Knowledge of the structures and composition of the epidermal lipids is important for understanding these functions. The lipids present in epidermis include phospholipids, monohexosylceramides, ceramides, cholesterol, cholesterol esters, cholesterol sulfate, triglycerides, and fatty acids. The phospholipids are major structural components of the plasma membranes and membranous organelles in the viable and differentiating keratinocytes. In addition, phospholipids serve in several transmembranal signaling processes and as a reservoir for arachidonic acid, the precursor of the eicosanoids. Monohexosylceramides are thought to function in the assembly of lamellar bodies, and in the final stage of differentiation are converted to a structurally heterogenous mixture of ceramides in the intercellular space of the stratum corneum and to a unique ceramide covalently attached to the corneocyte surface. The mixture of lipids in the stratum corneum, composed principally of ceramides, cholesterol, cholesterol esters, and fatty acids, prevents desiccation and limits the penetration of a variety of noxious environmental agents. The stratum corneum lipids represent a major product of epidermal differentiation, and free sphingosine liberated from ceramides in this terminally differentiated compartment may provide a feedback mechanism for the regulation of the differentiation process.

  4. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  5. Insulin analogues in pregnancy and specific congenital anomalies: a literature review.

    PubMed

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa; Morgan, Margery; de Jong-van den Berg, Lolkje T W; Wang, Hao

    2016-05-01

    Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies.

  6. Lipid Nanotechnology

    PubMed Central

    Mashaghi, Samaneh; Jadidi, Tayebeh; Koenderink, Gijsje; Mashaghi, Alireza

    2013-01-01

    Nanotechnology is a multidisciplinary field that covers a vast and diverse array of devices and machines derived from engineering, physics, materials science, chemistry and biology. These devices have found applications in biomedical sciences, such as targeted drug delivery, bio-imaging, sensing and diagnosis of pathologies at early stages. In these applications, nano-devices typically interface with the plasma membrane of cells. On the other hand, naturally occurring nanostructures in biology have been a source of inspiration for new nanotechnological designs and hybrid nanostructures made of biological and non-biological, organic and inorganic building blocks. Lipids, with their amphiphilicity, diversity of head and tail chemistry, and antifouling properties that block nonspecific binding to lipid-coated surfaces, provide a powerful toolbox for nanotechnology. This review discusses the progress in the emerging field of lipid nanotechnology. PMID:23429269

  7. Isolation and analysis of membrane lipids and lipid rafts in common carp (Cyprinus carpio L.).

    PubMed

    Brogden, Graham; Propsting, Marcus; Adamek, Mikolaj; Naim, Hassan Y; Steinhagen, Dieter

    2014-03-01

    Cell membranes act as an interface between the interior of the cell and the exterior environment and facilitate a range of essential functions including cell signalling, cell structure, nutrient uptake and protection. It is composed of a lipid bilayer with integrated proteins, and the inner leaflet of the lipid bilayer comprises of liquid ordered (Lo) and liquid disordered (Ld) domains. Lo microdomains, also named as lipid rafts are enriched in cholesterol, sphingomyelin and certain types of proteins, which facilitate cell signalling and nutrient uptake. Lipid rafts have been extensively researched in mammals and the presence of functional lipid rafts was recently demonstrated in goldfish, but there is currently very little knowledge about their composition and function in fish. Therefore a protocol was established for the analysis of lipid rafts and membranous lipids in common carp (Cyprinus carpio L.) tissues. Twelve lipids were identified and analysed in the Ld domain of the membrane with the most predominant lipids found in all tissues being; triglycerides, cholesterol, phosphoethanolamine and phosphatidylcholine. Four lipids were identified in lipid rafts in all tissues analysed, triglycerides (33-62%) always found in the highest concentration followed by cholesterol (24-32%), phosphatidylcholine and sphingomyelin. Isolation of lipid rafts was confirmed by identifying the presence of the lipid raft associated protein flotillin, present at higher concentrations in the detergent resistant fraction. The data provided here build a lipid library of important carp tissues as a baseline for further studies into virus entry, protein trafficking or environmental stress analysis.

  8. 5-Stabilized phosphatidylinositol 3,4,5-trisphosphate analogues bind Grp1 PH, inhibit phosphoinositide phosphatases, and block neutrophil migration.

    PubMed

    Zhang, Honglu; He, Ju; Kutateladze, Tatiana G; Sakai, Takahiro; Sasaki, Takehiko; Markadieu, Nicolas; Erneux, Christophe; Prestwich, Glenn D

    2010-02-15

    Metabolically stabilized analogues of PtdIns(3,4,5)P3 have shown long-lived agonist activity for cellular events and selective inhibition of lipid phosphatase activity. We describe an efficient asymmetric synthesis of two 5-phosphatase-resistant analogues of PtdIns(3,4,5)P3, the 5-methylene phosphonate (MP) and 5-phosphorothioate (PT). Furthermore, we illustrate the biochemical and biological activities of five stabilized PtdIns(3,4,5)P3 analogues in four contexts. First, the relative binding affinities of the 3-MP, 3-PT, 5-MP, 5-PT, and 3,4,5-PT3 analogues to the Grp1 PH domain are shown, as determined by NMR spectroscopy. Second, the enzymology of the five analogues is explored, showing the relative efficiency of inhibition of SHIP1, SHIP2, and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the greatly reduced ability of these phosphatases to process these analogues as substrates as compared to PtdIns(3,4,5)P3. Third, exogenously delivered analogues severely impair complement factor C5a-mediated polarization and migration of murine neutrophils. Finally, the new analogues show long-lived agonist activity in mimicking insulin action in sodium transport in A6 cells.

  9. Coupled TLC and MALDI-TOF/MS Analyses of the Lipid Extract of the Hyperthermophilic Archaeon Pyrococcus furiosus

    PubMed Central

    Lobasso, Simona; Lopalco, Patrizia; Angelini, Roberto; Vitale, Rita; Huber, Harald; Müller, Volker; Corcelli, Angela

    2012-01-01

    The lipidome of the marine hyperthermophilic archaeon Pyrococcus furiosus was studied by means of combined thin-layer chromatography and MALDI-TOF/MS analyses of the total lipid extract. 80–90% of the major polar lipids were represented by archaeol lipids (diethers) and the remaining part by caldarchaeol lipids (tetraethers). The direct analysis of lipids on chromatography plate showed the presence of the diphytanylglycerol analogues of phosphatidylinositol and phosphatidylglycerol, the N-acetylglucosamine-diphytanylglycerol phosphate plus some caldarchaeol lipids different from those previously described. In addition, evidence for the presence of the dimeric ether lipid cardiolipin is reported, suggesting that cardiolipins are ubiquitous in archaea. PMID:23193375

  10. Synthesis and evaluation of a tag-free photoactive phospho-ceramide analogue-1 (PCERA-1) probe to study immunomodulation in macrophages.

    PubMed

    Dandela, Rambabu; Mashiach, Roi; Adepu, Raju; Gregor, Rachel; Athamna, Muhammad; Zecharia, Efrat; Ernst, Orna; Zor, Tsaffrir; Meijler, Michael M

    2017-03-30

    Phospho-ceramide analogue-1 (PCERA-1), a synthetic analogue of ceramide-1-phosphate (C1P), has been previously shown to act as a potent modulator of macrophage activity and inflammation. We have developed an efficient synthesis of PCERA-1 from readily available starting materials, and designed and prepared derivatives of this analogue, including a photoaffinity probe to tag and identify putative proteins that bind PCERA-1.

  11. Choline Analogues in Malaria Chemotherapy

    PubMed Central

    Peyrottes, Suzanne; Caldarelli, Sergio; Wein, Sharon; Périgaud, Christian; Pellet, Alain; Vial, Henri

    2012-01-01

    Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches. PMID:22607139

  12. Ecstasy analogues found in cacti.

    PubMed

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs."

  13. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  14. High-resolution mass spectrometry analysis of tetrodotoxin (TTX) and its analogues in puffer fish and shellfish.

    PubMed

    Bane, Vaishali; Brosnan, Brid; Barnes, Paul; Lehane, Mary; Furey, Ambrose

    2016-09-01

    Tetrodotoxin (TTX) is an emerging toxin in the European marine environment. It has various known structural analogues. It acts as a sodium channel blocker; the ability of each analogue to bind to the sodium channel varies with the particular structure of each analogue. Thus, each analogue will vary in its toxic potential. TTX analogues co-occur in food samples at variable concentrations. An LC-MS method was developed for the identification and quantitation of several analogues of TTX using an LTQ-Orbitrap XL mass spectrometer. The LTQ-Orbitrap XL mass spectrometer facilitates high mass accuracy measurement up to 100,000 full width at half maximum (FWHM). Using high resolution at 100,000 FWHM allows for the identification of TTX and its analogues in various matrices, including puffer fish and molluscan shellfish samples (Δ ppm = 0.28-3.38). The confirmation of characteristic fragment ions of TTX and its analogues was achieved by determining their elemental formulae via high mass accuracy. A quantitative method was then developed and optimised using these characteristic fragment ions. The limit of quantitation (LOQ) of the method was 0.136 µg g(-1) (S/N = 10) and the limit of detection (LOD) was 0.041 µg g(-1) (S/N = 3) spiking TTX standard into TTX-free mackerel fish extracts. The method was applied to naturally contaminated puffer fish and molluscan shellfish samples to confirm the presence of TTX and its analogues.

  15. Composition of Hydrothermal Vent Microbial Communities as Revealed by Analyses of Signature Lipids, Stable Carbon Isotopes and Aquificales Cultures

    NASA Technical Reports Server (NTRS)

    Jahnke, L. L.; Eder, W.; Huber, Robert; Hinrichs, K-U.; Hayes, J. M.; DesMarais, D. J.; Cady, S. L.; Hope, J. M.; Summons, R. E.

    2001-01-01

    This paper describes a study of lipid biomarker composition and carbon isotopic fractionation in cultured Aquificales and natural analogues from Yellowstone National Park. Additional information is contained in the original extended abstract.

  16. Composition of Hydrothermal Vent Microbial Communities as Revealed by Analyses of Signature Lipids, Stable Carbon Isotopes and Aquificales Cultures

    NASA Technical Reports Server (NTRS)

    Jahnke, L. L.; Eder, W.; Huber, Robert; Hinrichs, K-U.; Hayes, J. M.; DesMarais, D. J.; Cady, S. L.; Hope, J. M.; Summons, R. E.

    2001-01-01

    This paper describes a study of lipid biomarker composition and carbon isotopic fractionation in cultured Aquificales and natural analogues from Yellowstone National Park. Additional information is contained in the original extended abstract.

  17. Terrestrial research in Mars analogue environments

    NASA Astrophysics Data System (ADS)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  18. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  19. Heteroatom-Containing Porphyrin Analogues.

    PubMed

    Chatterjee, Tamal; Shetti, Vijayendra S; Sharma, Ritambhara; Ravikanth, Mangalampalli

    2017-02-22

    The heteroatom-containing porphyrin analogues or core-modified porphyrins that resulted from the replacement of one or two pyrrole rings with other five-membered heterocycles such as furan, thiophene, selenophene, tellurophene, indene, phosphole, and silole are highly promising macrocycles and exhibit quite different physicochemical properties compared to regular azaporphyrins. The properties of heteroporphyrins depend on the nature and number of different heterocycle(s) present in place of pyrrole ring(s). The heteroporphyrins provide unique and unprecedented coordination environments for metals. Unlike regular porphyrins, the monoheteroporphyrins are known to stabilize metals in unusual oxidation states such as Cu and Ni in +1 oxidation states. The diheteroporphyrins, which are neutral macrocycles without ionizable protons, also showed interesting coordination chemistry. Thus, significant progress has been made in last few decades on core-modified porphyrins in terms of their synthesis, their use in building multiporphyrin arrays for light-harvesting applications, their use as ligands to form interesting metal complexes, and also their use for several other studies. The synthetic methods available in the literature allow one to prepare mono- and diheteroporphyrins and their functionalized derivatives, which were used extensively to prepare several covalent and noncovalent heteroporphyrin-based multiporphyrin arrays. The methods are also developed to synthesize different hetero analogues of porphyrin derivatives such as heterocorroles, heterochlorins, heterocarbaporphyrinoids, heteroatom-substituted confused porphyrins, and so on. This Review summarizes the key developments that have occurred in heteroporphyrin chemistry over the last four decades.

  20. Studies on the hypolipdemic and estrogenic activities of 2,8-dibenzylcyclooctanone and its analogues.

    PubMed

    Cayen, M N; Dubuc, J; Givner, M L; Greselin, E; Revesz, C

    1976-07-01

    The effects of 2,8-dibenzylcyclooctanone (DBCO) and a series of its analogues on serum lipids and on estrogenic activity in rats were studied. Assays of the estrogenicity of DBCO showed that although the compound is a very weak estrogen, it exhibited estrogenic activity at doses that were hypolipidemic. Among the analogues, only those containing the dibenzylcyclooctanone system were active. All compounds demonstrating hypocholesterolemic activity, except the weakly active compound 15, also reduced the weights of the seminal vesicles and ventral prostate and increased the weight of the adrenal gland. Compounds containing a benzylidene group or reduced ketone group did not exhibit any activity. It is concluded that the hypocholesterolemic activity of the structural analogues of DBCO is correlated with their estrogenicity.

  1. Effects of curcumin and curcumin analogues on TRP channels.

    PubMed

    Nalli, Marianna; Ortar, Giorgio; Schiano Moriello, Aniello; Di Marzo, Vincenzo; De Petrocellis, Luciano

    2017-10-01

    A series of 33 curcumin analogues was synthesized and tested on TRPA1, TRPM8, and TRPV1 channels. Twenty of them acted as good modulators of TRPA1 channels. None was able to significantly activate TRPM8 channels, while curcumin itself and six curcuminoids belonging to the 1,3-dicarbonyl and acyclic series behaved as 'true' antagonists with IC50 values<5μM. Only few curcuminoids were able to modulate TRPV1 channels with EC50 and IC50 values ranging from 3.4 and 6.0μM. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  3. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  4. Macrolactam analogues of macrolide natural products.

    PubMed

    Hügel, Helmut M; Smith, Andrew T; Rizzacasa, Mark A

    2016-12-07

    The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.

  5. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-03

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  6. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  7. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  8. Conserved Molecular Superlattices in a Series of Homologous Synthetic Mycobacterial Cell-Wall Lipids Forming Interdigitated Bilayers.

    PubMed

    Martin-Bertelsen, Birte; Yaghmur, Anan; Franzyk, Henrik; Justesen, Sarah; Kirkensgaard, Jacob J K; Foged, Camilla

    2016-12-06

    Synthetic analogues of the cell-wall lipid monomycoloyl glycerol (MMG) are promising as next-generation vaccine adjuvants. In the present study, the thermotropic phase behavior of an array of synthetic MMG analogues was examined by using simultaneous small- and wide-angle X-ray scattering under excess water conditions. The MMG analogues differed in the alkyl chain lengths and in the stereochemistry of the polar glycerol headgroup or of the lipid tails (native-like versus alternative compounds). All MMG analogues formed poorly hydrated lamellar phases at low temperatures and inverse hexagonal (H2) phases at higher temperatures prior to melting. MMG analogues with a native-like lipid acid configuration self-assembled into noninterdigitated bilayers whereas the analogues displaying an alternative lipid acid configuration formed interdigitated bilayers in a subgel (Lc') state. This is in contrast to previously described interdigitated phases for other lipids, which are usually in a gel (Lβ) state. All investigated MMG analogues displayed an abrupt direct temperature-induced phase transition from Lc' to H2. This transition is ultimately driven by the lipid chain melting and the accompanying change in molecular shape. No intermediate structures were found, but the entire array of MMG analogues displayed phase coexistence during the lamellar to H2 transition. The structural data also showed that the headgroups of the MMG analogues adopting the alternative lipid acid configuration were ordered and formed a two-dimensional molecular superlattice, which was conserved regardless of the lipid tail length. To our knowledge, the MMG analogues with an alternative lipid acid configuration represent the first example of a lipid system showing both interdigitation and superlattice formation, and as such could serve as an interesting model system for future studies. The MMG analogues are also relevant from a subunit vaccine perspective because they are well-tolerated and display

  9. The role of the substrate lipid in processive glycan polymerization by the peptidoglycan glycosyltransferases.

    PubMed

    Perlstein, Deborah L; Wang, Tsung-Shing Andrew; Doud, Emma H; Kahne, Daniel; Walker, Suzanne

    2010-01-13

    The peptidoglycan glycosyltransferases (PGTs) catalyze the processive polymerization of a C55 lipid-linked disaccharide (Lipid II) to form peptidoglycan, the main component of the bacterial cell wall. Our ability to understand this reaction has been limited due to challenges identifying the appropriate substrate analogues to selectively interrogate the donor (the elongating strand) and acceptor (Lipid II) sites. To address this problem, we have developed an assay using synthetic substrates that can discriminate between the donor and acceptor sites of the PGTs. We have shown that each site has a distinct lipid length preference. We have also established that processive polymerization depends on the length of the lipid attached to the donor.

  10. Partitioning of amino-acid analogues in a five-slab membrane model

    SciTech Connect

    Sengupta, D; Smith, Jeremy C; Ullmann, G. Matthias

    2008-09-01

    The positional preferences of the twenty amino-acid residues in a phospholipid bilayer are investigated by calculating the solvation free energy of the corresponding side chain analogues using a five-slab continuum electrostatic model. The side-chain analogues of the aromatic residues tryptophan and tyrosine are found to partition in the head-group region, due to compensation between the increase of the non-polar component of the solvation free energy at the boundary with the aqueous region and the decrease in the electrostatic component. The side chain analogue of phenylalanine differs from the other aromatic molecules by being able to partition in both the head-group region and the membrane core. This finding is consistent with experimental findings of the position of phenylalanine in membrane helices. Interestingly, the charged side-chain analogues of arginine and lysine are shown to prefer the head-group region in an orientation that allows the charged moiety to interact with the aqueous layer. The orientation adopted is similar to the 'snorkelling' effect seen in lysine and arginine residues in membrane helices. In contrast, the preference of the charged side-chain analogues of histidine (protonated) and aspartate (deprotonated) for the aqueous layer is shown to be due to a steep decrease in the electrostatic component of the solvation free energy at the boundary to the aqueous region. The calculations allow an understanding of the origins of side chain positioning in membranes and are thus useful in understanding membrane-protein:lipid thermodynamics.

  11. Surfactin analogues produced by Bacillus subtilis strains grown on rapeseed cake

    NASA Astrophysics Data System (ADS)

    Jajor, Paweł; Piłakowska-Pietras, Dorota; Krasowska, Anna; Łukaszewicz, Marcin

    2016-12-01

    Microbiologically produced surface acting compounds (biosurfactants) have very interesting properties with many potential industrial applications. Lipopeptides is a particularly promising group of biosurfactants in respect to the potentially huge number of various chemical structures. The chemical diversity results from fatty acid moiety (e.g. length, saturation, branching or hydroxylation) and type and sequence of the amino acids in the peptide chain. The limiting factor for the design and analysis of various lipopeptides is the ability of the targeted biosynthesis. Biosynthesis of particular lipopeptides may be potentially achieved by strain selection, culture conditions, or molecular engineering. The well-known lipopeptedes (surfactins, iturins, and fengycins) producer is B. subtilis. The aim of this study was to study targeted surfactin structural analogues biosynthesis in response to culture conditions in view of the design and production of tailor-made lipopeptides. Two B. subtilis strains (KB1 and #309) were tested for surfactin production. Both strains produced a mixture of five major surfactin analogues with the number of carbons in an alkyl chain ranging from 12 to 16. The two strains differed with respect to their oxygen demand for optimal surfactin biosynthesis (lower oxygen demand for KB1). The amount of air influenced the relative ratios of surfactin analogues. Lower oxygen amount decreased the share of C15 analogues while it increased the share of C12 analogues. Thus, the biosynthesis of a desired surfactin analogue may controlled by both strain and culture conditions.

  12. Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors.

    PubMed

    Valdés, James J; Butterill, Philip T; Růžek, Daniel

    2017-03-18

    The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues. The mechanism how this single mutation causes Flaviviridae viruses to escape nucleoside analogues is not yet known. Given the pivotal position of the serine residue in motif B that supports motif F, we hypothesized the threonine mutation causes alterations in nucleoside exploration within the entry tunnel. Implementing a stochastic molecular software showed the all-atom 2'-C-methylated analogue reaction within the active sites of wild type and serine-threonine mutant polymerases from Hepacivirus and Flavivirus. Compared with the wild type, the serine-threonine mutant polymerases caused a significant decrease of analogue contacts with conserved interrogating residues in motif F and a displacement of metal ion cofactors. The simulations significantly showed that during the analogue exploration of the active site the hydrophobic methyl group in the serine-threonine mutant repels water-mediated hydrogen bonds with the 2'-C-methylated analogue, causing a concentration of water-mediated bonds at the substrate-interacting sites. Collectively, the data are an insight into a molecular escape mechanism by Flaviviridae viruses from 2'-C-methylated nucleoside analogue inhibitors.

  13. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of β-ionone and benzaldehyde. The stabilities of β-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than β-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than β-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  14. Privacy Act

    EPA Pesticide Factsheets

    Learn about the Privacy Act of 1974, the Electronic Government Act of 2002, the Federal Information Security Management Act, and other information about the Environmental Protection Agency maintains its records.

  15. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  16. Space analogue studies in Antarctica.

    PubMed

    Lugg, D; Shepanek, M

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  17. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  18. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  19. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  20. Conformationally Constrained Analogues of Diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C

    PubMed Central

    Kang, Ji-Hye; Peach, Megan L.; Pu, Yongmei; Lewin, Nancy E.; Nicklaus, Marc C.; Blumberg, Peter M.; Marquez, Victor E.

    2008-01-01

    A group of DAG-lactones with altered functionality (C=O → CH2 or C=O → C=S) at the sn-1 and sn-2 carbonyl pharmacophores was synthesized and used as probes to dissect the individual role of each carbonyl in binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to insure the correct orientation and disposition of pharmacophores at the binding site. PMID:16134942

  1. Lipid-lipid and lipid-drug interactions in biological membranes

    NASA Astrophysics Data System (ADS)

    Martynowycz, Michael W.

    Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the air-liquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray reflectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the in-plane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances. Circumventing deficiencies in small, hydrophobic drugs is approached by using biologically mimetic oligomers. Peptoids, mimetic of host

  2. Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity.

    PubMed

    Rodriguez, Cristian R; Alvarez, Lautaro D; Dansey, M Virginia; Paolo, Luciano S; Veleiro, Adriana S; Pecci, Adali; Burton, Gerardo

    2017-01-01

    Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the

  3. Lipid Neuroprotectants and Traumatic Glaucomatous Neurodegeneration

    DTIC Science & Technology

    2016-05-01

    without pain or obvious symptoms. Specific lipids naturally present in the clear fluid of the anterior chamber of the eye in healthy individuals but...normal human eyes and determine their effect on lowering the IOP in the eyes of animal models (mouse, normotensive monkeys). Scope of Research: To...uniquely present in the normal aqueous humor act as regulators of intraocular pressure. Methods, topical application of lipids, IOP measurements by

  4. Rapid modification of retroviruses using lipid conjugates

    NASA Astrophysics Data System (ADS)

    Mukherjee, Nimisha G.; Lyon, L. Andrew; LeDoux, Joseph M.

    2009-02-01

    Methods are needed to manipulate natural nanoparticles. Viruses are particularly interesting because they can act as therapeutic cellular delivery agents. Here we examine a new method for rapidly modifying retroviruses that uses lipid conjugates composed of a lipid anchor (1,2-distearoyl-sn-glycero-3-phosphoethanolamine), a polyethylene glycol chain, and biotin. The conjugates rapidly and stably modified retroviruses and enabled them to bind streptavidin. The implication of this work for modifying viruses for gene therapy and vaccination protocols is discussed.

  5. Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

    PubMed Central

    Dennis, Edward A.

    2016-01-01

    In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also “encode” specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of “surface dilution kinetics” for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A2 (PLA2) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral information-containing signaling molecules; for example, PLA2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal “reflection” on these scientific advances. PMID:27555328

  6. Analogue gravity models from conformal rescaling

    NASA Astrophysics Data System (ADS)

    Hossenfelder, Sabine; Zingg, Tobias

    2017-08-01

    Analogue gravity is based on a mathematical identity between quantum field theory in curved space-time and the propagation of perturbations in certain condensed matter systems. But not every curved space-time can be simulated in such a way. For analogue gravity to work, one needs not only a condensed matter system that generates the desired metric tensor, but this system then also has to obey its own equations of motion. However, the relation to the metric tensor usually overdetermines the equations of the underlying condensed matter system, such that they in general cannot be fulfilled. In this case the desired metric does not have an analogue. Here, we show that the class of metrics that have an analogue is larger than previously thought. The reason is that the analogue metric is only defined up to a choice of parametrization of the perturbation in the underlying condensed matter system. In this way, the class of analogue gravity models can be vastly expanded.

  7. Loratadine analogues as MAGL inhibitors.

    PubMed

    Patel, Jayendra Z; Ahenkorah, Stephen; Vaara, Miia; Staszewski, Marek; Adams, Yahaya; Laitinen, Tuomo; Navia-Paldanius, Dina; Parkkari, Teija; Savinainen, Juha R; Walczyński, Krzysztof; Laitinen, Jarmo T; Nevalainen, Tapio J

    2015-04-01

    Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50=1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

  8. Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

    PubMed Central

    van Heijenoort, Jean

    2007-01-01

    Summary: This review is an attempt to bring together and critically evaluate the now-abundant but dispersed data concerning the lipid intermediates of the biosynthesis of bacterial peptidoglycan. Lipid I, lipid II, and their modified forms play a key role not only as the specific link between the intracellular synthesis of the peptidoglycan monomer unit and the extracytoplasmic polymerization reactions but also in the attachment of proteins to the bacterial cell wall and in the mechanisms of action of antibiotics with which they form specific complexes. The survey deals first with their detection, purification, structure, and preparation by chemical and enzymatic methods. The recent important advances in the study of transferases MraY and MurG, responsible for the formation of lipids I and II, are reported. Various modifications undergone by lipids I and II are described, especially those occurring in gram-positive organisms. The following section concerns the cellular location of the lipid intermediates and the translocation of lipid II across the cytoplasmic membrane. The great efforts made since 2000 in the study of the glycosyltransferases catalyzing the glycan chain formation with lipid II or analogues are analyzed in detail. Finally, examples of antibiotics forming complexes with the lipid intermediates are presented. PMID:18063720

  9. Lipid intermediates in the biosynthesis of bacterial peptidoglycan.

    PubMed

    van Heijenoort, Jean

    2007-12-01

    This review is an attempt to bring together and critically evaluate the now-abundant but dispersed data concerning the lipid intermediates of the biosynthesis of bacterial peptidoglycan. Lipid I, lipid II, and their modified forms play a key role not only as the specific link between the intracellular synthesis of the peptidoglycan monomer unit and the extracytoplasmic polymerization reactions but also in the attachment of proteins to the bacterial cell wall and in the mechanisms of action of antibiotics with which they form specific complexes. The survey deals first with their detection, purification, structure, and preparation by chemical and enzymatic methods. The recent important advances in the study of transferases MraY and MurG, responsible for the formation of lipids I and II, are reported. Various modifications undergone by lipids I and II are described, especially those occurring in gram-positive organisms. The following section concerns the cellular location of the lipid intermediates and the translocation of lipid II across the cytoplasmic membrane. The great efforts made since 2000 in the study of the glycosyltransferases catalyzing the glycan chain formation with lipid II or analogues are analyzed in detail. Finally, examples of antibiotics forming complexes with the lipid intermediates are presented.

  10. The emerging roles of lipids in circadian control.

    PubMed

    Adamovich, Yaarit; Aviram, Rona; Asher, Gad

    2015-08-01

    Lipids play vital roles in a wide variety of cellular functions. They act as structural components in cell membranes, serve as a major form of energy storage, and function as key signaling molecules. Mounting evidence points towards a tight interplay between lipids and circadian clocks. In mammals, circadian clocks regulate the daily physiology and metabolism, and disruption of circadian rhythmicity is associated with altered lipid homeostasis and pathologies such as fatty liver and obesity. Concomitantly, emerging evidence suggest that lipids are embedded within the core clock circuitry and participate in circadian control. Recent advances in lipidomics methodologies and their application in chronobiology studies have shed new light on the cross talk between circadian clocks and lipid homeostasis. We review herein the latest literature related to the involvement of lipids in circadian clock's function and highlight the contribution of circadian lipidomics studies to our understanding of circadian rhythmicity and lipid homeostasis. This article is part of a Special Issue entitled Brain Lipids.

  11. Planetary habitability: lessons learned from terrestrial analogues

    NASA Astrophysics Data System (ADS)

    Preston, Louisa J.; Dartnell, Lewis R.

    2014-01-01

    Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which

  12. Spontaneous charged lipid transfer between lipid vesicles.

    PubMed

    Richens, Joanna L; Tyler, Arwen I I; Barriga, Hanna M G; Bramble, Jonathan P; Law, Robert V; Brooks, Nicholas J; Seddon, John M; Ces, Oscar; O'Shea, Paul

    2017-10-03

    An assay to study the spontaneous charged lipid transfer between lipid vesicles is described. A donor/acceptor vesicle system is employed, where neutrally charged acceptor vesicles are fluorescently labelled with the electrostatic membrane probe Fluoresceinphosphatidylethanolamine (FPE). Upon addition of charged donor vesicles, transfer of negatively charged lipid occurs, resulting in a fluorescently detectable change in the membrane potential of the acceptor vesicles. Using this approach we have studied the transfer properties of a range of lipids, varying both the headgroup and the chain length. At the low vesicle concentrations chosen, the transfer follows a first-order process where lipid monomers are transferred presumably through the aqueous solution phase from donor to acceptor vesicle. The rate of transfer decreases with increasing chain length which is consistent with energy models previously reported for lipid monomer vesicle interactions. Our assay improves on existing methods allowing the study of a range of unmodified lipids, continuous monitoring of transfer and simplified experimental procedures.

  13. Multiscale modeling of lipids and lipid bilayers.

    PubMed

    Lyubartsev, Alexander P

    2005-12-01

    A multiscale modeling approach is applied for simulations of lipids and lipid assemblies on mesoscale. First, molecular dynamics simulation of initially disordered system of lipid molecules in water within all-atomic model was carried out. On the next stage, structural data obtained from the molecular dynamics (MD) simulation were used to build a coarse-grained (ten sites) lipid model, with effective interaction potentials computed by the inverse Monte Carlo method. Finally, several simulations of the coarse-grained model on longer length- and time-scale were performed, both within Monte Carlo and molecular dynamics simulations: a periodical sample of lipid molecules ordered in bilayer, a free sheet of such bilayer without periodic boundary conditions, formation of vesicle from a plain membrane, process of self-assembly of lipids randomly dispersed in volume. It was shown that the coarse-grained model, developed exclusively from all-atomic simulation data, reproduces well all the basic features of lipids in water solution.

  14. Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

    PubMed Central

    Vora, J. P.; Owens, D. R.; Dolben, J.; Atiea, J. A.; Dean, J. D.; Kang, S.; Burch, A.; Brange, J.

    1988-01-01

    OBJECTIVE--To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN--Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING--Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS--Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS--After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT--To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U

  15. Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation*

    PubMed Central

    Bate, Clive; Tayebi, Mourad; Williams, Alun

    2010-01-01

    A hallmark of prion diseases is the conversion of the host-encoded prion protein (PrPC where C is cellular) into an alternatively folded, disease-related isoform (PrPSc, where Sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. The formation of PrPSc is dependent upon the presence of PrPC in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. PrPC is targeted to these lipid rafts because it is attached to membranes via a glycosylphosphatidylinositol anchor. Here, we show that treatment of prion-infected neuronal cell lines (ScN2a, ScGT1, or SMB cells) with synthetic glycosylphosphatidylinositol analogues, glucosamine-phosphatidylinositol (glucosamine-PI) or glucosamine 2-O-methyl inositol octadecyl phosphate, reduced the PrPSc content of these cells in a dose-dependent manner. In addition, ScGT1 cells treated with glucosamine-PI did not transmit infection following intracerebral injection to mice. Treatment with glucosamine-PI increased the cholesterol content of ScGT1 cell membranes and reduced activation of cytoplasmic phospholipase A2 (PLA2), consistent with the hypothesis that the composition of cell membranes affects key PLA2-dependent signaling pathways involved in PrPSc formation. The effect of glucosamine-PI on PrPSc formation was also reversed by the addition of platelet-activating factor. Glucosamine-PI caused the displacement of PrPC from lipid rafts and reduced expression of PrPC at the cell surface, putative sites for PrPSc formation. We propose that treatment with glucosamine-PI modifies local micro-environments that control PrPC expression and activation of PLA2 and subsequently inhibits PrPSc formation. PMID:20427265

  16. Membrane effects of dihydropyrimidine analogues with larvicidal activity.

    PubMed

    Sánchez-Borzone, Mariela E; Mariani, Maria E; Miguel, Virginia; Gleiser, Raquel M; Odhav, Bharti; Venugopala, Katharigatta N; García, Daniel A

    2017-02-01

    Two recently synthesized dihydropyrimidines (DHPMs) analogues have demonstrated larvicide and repellent activity against Anopheles arabiensis. DHPMs high lipophilicity suggests that these compounds may interact directly with the membrane and modify their biophysical properties. The purpose of the present study was to characterize the interaction of both compounds with artificial membranes. Changes on the properties of DPPC films were studied using Langmuir monolayers. The presence of DHPMs in the subphase modified the interfacial characteristics of DPPC compression isotherms, causing the expansion of the monolayer, inducing the disappearance of DPPC phase transition and increasing the molecular packing of the film. Moreover, both compounds showed ability to penetrate into the lipid monolayers at molecular pressures comparable to those in biological membranes. The effects of both DHPMs on the molecular organization of DPPC liposomes were measured by fluorescence anisotropy. The results indicate that their presence between lipid molecules would induce an increasing intermolecular interaction, diminishing the bilayer fluidity mainly at the polar region. Finally, we performed free diffusion MD simulations and obtained spatially resolved free energy profiles of DHPMs partition into a DPPC bilayer through Potential of Mean Force (PMF) calculations. In agreement with the experimental assays, PMF profiles and MD simulations showed that DHPMs are able to partition into DPPC bilayers, penetrating into the membrane and stablishing hydrogen bonds with the carbonyl moiety. Our results suggest that DHPMs bioactivity could involve their interaction with the lipid molecules that modulate the supramolecular organization of the biological membranes and consequently the membrane proteins functionality. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Structures of a DNA Polymerase Inserting Therapeutic Nucleotide Analogues.

    PubMed

    Schaich, Matthew A; Smith, Mallory R; Cloud, Ashley S; Holloran, Sean M; Freudenthal, Bret D

    2017-09-01

    Members of the nucleoside analogue class of cancer therapeutics compete with canonical nucleotides to disrupt numerous cellular processes, including nucleotide homeostasis, DNA and RNA synthesis, and nucleotide metabolism. Nucleoside analogues are triphosphorylated and subsequently inserted into genomic DNA, contributing to the efficacy of therapeutic nucleosides in multiple ways. In some cases, the altered base acts as a mutagen, altering the DNA sequence to promote cellular death; in others, insertion of the altered nucleotide triggers DNA repair pathways, which produce lethal levels of cytotoxic intermediates such as single and double stranded DNA breaks. As a prerequisite to many of these biological outcomes, the modified nucleotide must be accommodated in the DNA polymerase active site during nucleotide insertion. Currently, the molecular contacts that mediate DNA polymerase insertion of modified nucleotides remain unknown for multiple therapeutic compounds, despite decades of clinical use. To determine how modified bases are inserted into duplex DNA, we used mammalian DNA polymerase β (pol β) to visualize the structural conformations of four therapeutically relevant modified nucleotides, 6-thio-2'-deoxyguanosine-5'-triphosphate (6-TdGTP), 5-fluoro-2'-deoxyuridine-5'-triphosphate (5-FdUTP), 5-formyl-deoxycytosine-5'-triphosphate (5-FodCTP), and 5-formyl-deoxyuridine-5'-triphosphate (5-FodUTP). Together, the structures reveal a pattern in which the modified nucleotides utilize Watson-Crick base pairing interactions similar to that of unmodified nucleotides. The nucleotide modifications were consistently positioned in the major groove of duplex DNA, accommodated by an open cavity in pol β. These results provide novel information for the rational design of new therapeutic nucleoside analogues and a greater understanding of how modified nucleotides are tolerated by polymerases.

  18. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

    IMPORTANCE Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE Cells were exposed to teduglutide or vehicle control. MAINOUTCOMESAND MEASURES We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription–polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD

  19. Lipid14: The Amber Lipid Force Field

    PubMed Central

    2015-01-01

    The AMBER lipid force field has been updated to create Lipid14, allowing tensionless simulation of a number of lipid types with the AMBER MD package. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The Lennard-Jones and torsion parameters of both the head and tail groups have been revised and updated partial charges calculated. The force field has been validated by simulating bilayers of six different lipid types for a total of 0.5 μs each without applying a surface tension; with favorable comparison to experiment for properties such as area per lipid, volume per lipid, bilayer thickness, NMR order parameters, scattering data, and lipid lateral diffusion. As the derivation of this force field is consistent with the AMBER development philosophy, Lipid14 is compatible with the AMBER protein, nucleic acid, carbohydrate, and small molecule force fields. PMID:24803855

  20. Do lipids influence the allergic sensitization process?

    PubMed Central

    Bublin, Merima; Eiwegger, Thomas; Breiteneder, Heimo

    2014-01-01

    Allergic sensitization is a multifactorial process that is not only influenced by the allergen and its biological function per se but also by other small molecular compounds, such as lipids, that are directly bound as ligands by the allergen or are present in the allergen source. Several members of major allergen families bind lipid ligands through hydrophobic cavities or electrostatic or hydrophobic interactions. These allergens include certain seed storage proteins, Bet v 1–like and nonspecific lipid transfer proteins from pollens and fruits, certain inhalant allergens from house dust mites and cockroaches, and lipocalins. Lipids from the pollen coat and furry animals and the so-called pollen-associated lipid mediators are codelivered with the allergens and can modulate the immune responses of predisposed subjects by interacting with the innate immune system and invariant natural killer T cells. In addition, lipids originating from bacterial members of the pollen microbiome contribute to the outcome of the sensitization process. Dietary lipids act as adjuvants and might skew the immune response toward a TH2-dominated phenotype. In addition, the association with lipids protects food allergens from gastrointestinal degradation and facilitates their uptake by intestinal cells. These findings will have a major influence on how allergic sensitization will be viewed and studied in the future. PMID:24880633

  1. Do lipids influence the allergic sensitization process?

    PubMed

    Bublin, Merima; Eiwegger, Thomas; Breiteneder, Heimo

    2014-09-01

    Allergic sensitization is a multifactorial process that is not only influenced by the allergen and its biological function per se but also by other small molecular compounds, such as lipids, that are directly bound as ligands by the allergen or are present in the allergen source. Several members of major allergen families bind lipid ligands through hydrophobic cavities or electrostatic or hydrophobic interactions. These allergens include certain seed storage proteins, Bet v 1-like and nonspecific lipid transfer proteins from pollens and fruits, certain inhalant allergens from house dust mites and cockroaches, and lipocalins. Lipids from the pollen coat and furry animals and the so-called pollen-associated lipid mediators are codelivered with the allergens and can modulate the immune responses of predisposed subjects by interacting with the innate immune system and invariant natural killer T cells. In addition, lipids originating from bacterial members of the pollen microbiome contribute to the outcome of the sensitization process. Dietary lipids act as adjuvants and might skew the immune response toward a TH2-dominated phenotype. In addition, the association with lipids protects food allergens from gastrointestinal degradation and facilitates their uptake by intestinal cells. These findings will have a major influence on how allergic sensitization will be viewed and studied in the future.

  2. Clinical uses of gonadotropin-releasing hormone analogues.

    PubMed Central

    Casper, R F

    1991-01-01

    Gonadotropin-releasing hormone (Gn-RH) analogues are synthetic derivatives of the native hypothalamic peptide with alterations in their chemical structure that result in changes in biologic activity. Several Gn-RH agonists are available for clinical use, and all act through the same mechanism: first to stimulate and then to inhibit gonadotropin and gonadal steroid secretion by downregulating the pituitary Gn-RN receptors. This review should provide clinicians with a working knowledge of the physiologic and pharmacokinetic features of Gn-RH agonists. Although over 2000 articles concerning Gn-RH analogues have been published I chose to review only those that were the first to report a novel clinical application. Gn-RH agonists have proved to be extremely efficacious in treating gonadal steroid-dependent problems such as endometriosis, uterine leiomyoma, precocious puberty and prostate and breast cancers, and they have resulted in very few side effects. Long-term use may, however, lead to skeletal calcium loss in women as a consequence of hypoestrogenism. Further research is needed to prevent this and maintain clinical efficacy. PMID:1986827

  3. Reduced peptide bond pseudopeptide analogues of neurotensin.

    PubMed

    Doulut, S; Rodriguez, M; Lugrin, D; Vecchini, F; Kitabgi, P; Aumelas, A; Martinez, J

    1992-01-01

    Pseudopeptide analogues of the C-terminal hexapeptide of neurotensin (H-Arg-Arg-Pro-Tyr-Ile-Leu-OH) were obtained by replacing each peptide bond by the reduced peptide bond CH2NH. The resulting analogues were then examined for their ability to inhibit binding of labeled neurotensin to new-born mouse brain membranes and for stimulation of guinea pig ileum contraction. Replacement of the Ile12-Leu13, Tyr11-Ile12, Pro10-Tyr11 and Lys9-Pro10 peptide bonds resulted in about 2000-, 3400-, 200- and 3400-fold losses, respectively, in binding affinity and 400-, 750-, 250- and 300-fold losses, respectively, in biological activity. Replacement of both Arg8 and Arg9 by lysine led to an analogue exhibiting the same pharmacological profile as the C-terminal hexapeptide of neurotensin. Interestingly, replacement of the Lys8-Lys9 peptide bond by the CH2NH bond produced an analogue exhibiting the same affinity for neurotensin receptors, but 10 times more potent in stimulating guinea pig ileum contraction. N-terminal protected analogues (by the Boc group) showed decreased potency as compared with their amino-free corresponding compounds.

  4. Analogue Downscaling of Seasonal Rainfall Forecasts

    NASA Astrophysics Data System (ADS)

    Charles, A. N.; Timbal, B.; Hendon, H.

    2010-12-01

    We have taken an existing statistical downscaling model (SDM), based on meteorological analogues that was developed for downscaling climate change projections (Timbal et al 2009), and applied it in the seasonal forecasting context to produce downscaled rainfall hindcasts from a coupled model seasonal forecast system (POAMA). Downscaling of POAMA forecasts is required to provide seasonal climate information at local scales of interest. Analogue downscaling is a simple technique to generate rainfall forecasts appropriate to the local scale by conditioning on the large scale predicted GCM circulation and the local topography and climate. Analogue methods are flexible and have been shown to produce good results when downscaling 20th century South Eastern Australian rainfall output from climate models. A set of re-forecasts for three month rainfall at 170 observing stations in the South Murray Darling region of Australia were generated using predictors from the POAMA re-forecasts as input for the analogue SDM. The predictors were optimised over a number of different GCMS in previous climate change downscaling studies. Downscaling with the analogue SDM results in predicted rainfall with realistic variance while maintaining the modest predictive skill of the dynamical model. Evaluation of the consistency between the large scale mean of downscaled and direct GCM output precipitation is encouraging.

  5. On the mechanical analogue of DNA.

    PubMed

    Yakushevich, Ludmila

    2017-03-01

    The creation of mechanical analogues of biological systems is known as a useful instrument that helps to understand better the dynamical mechanisms of the functioning of living organisms. Mechanical analogues of biomolecules are usually constructed for imitation of their internal mobility, which is one of the most important properties of the molecules. Among the different types of internal motions, angular oscillations of nitrous bases are of special interest because they make a substantial contribution to the base pairs opening that in turn is an important element of the process of the DNA-protein recognition. In this paper, we investigate the possibility to construct a mechanical analogue for imitation of angular oscillations of nitrous bases in inhomogeneous DNA. It is shown that the analogue has the form of a mechanical chain of non-identical pendulums that oscillate in the gravitational field of the Earth and coupled by identical springs. The masses and lengths of pendulums, as well as the distances between neighboring pendulums and the rigidity of springs are calculated. To illustrate the approach, we present the result of construction of the mechanical analogue of the fragment of the sequence of bacteriophage T7D.

  6. A novel benzonitrile analogue inhibits rhinovirus replication.

    PubMed

    Lacroix, Céline; Querol-Audí, Jordi; Roche, Manon; Franco, David; Froeyen, Mathy; Guerra, Pablo; Terme, Thierry; Vanelle, Patrice; Verdaguer, Núria; Neyts, Johan; Leyssen, Pieter

    2014-10-01

    To study the characteristics and the mode of action of the anti-rhinovirus compound 4-[1-hydroxy-2-(4,5-dimethoxy-2-nitrophenyl)ethyl]benzonitrile (LPCRW_0005). The antiviral activity of LPCRW_0005 was evaluated in a cytopathic effect reduction assay against a panel of human rhinovirus (HRV) strains. To unravel its precise molecular mechanism of action, a time-of-drug-addition study, resistance selection and thermostability assays were performed. The crystal structure of the HRV14/LPCRW_0005 complex was elucidated as well. LPCRW_0005 proved to be a selective inhibitor of the replication of HRV14 (EC(50) of 2 ± 1 μM). Time-of-drug-addition studies revealed that LPCRW_0005 interferes with the earliest stages of virus replication. Phenotypic drug-resistant virus variants were obtained (≥30-fold decrease in susceptibility to the inhibitory effect of LPCRW_0005), which carried either an A150T or A150V amino acid substitution in the VP1 capsid protein. The link between the mutant genotype and drug-resistant phenotype was confirmed by reverse genetics. Cross-resistance studies and thermostability assays revealed that LPCRW_0005 has a similar mechanism of action to the capsid binder pleconaril. Elucidation of the crystal structure of the HRV14/LPCRW_0005 complex revealed the existence of multiple hydrophobic and polar interactions between the VP1 pocket and LPCRW_0005. LPCRW_0005 is a novel inhibitor of HRV14 replication that acts as a capsid binder. The compound has a chemical structure that is markedly smaller than that of other capsid binders. Structural studies show that LPCRW_0005, in contrast to pleconaril, leaves the toe end of the pocket in VP1 empty. This suggests that extended analogues of LPCRW_0005 that fill the full cavity could be more potent inhibitors of rhinovirus replication. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e

  7. DMSO Induces Dehydration near Lipid Membrane Surfaces

    PubMed Central

    Cheng, Chi-Yuan; Song, Jinsuk; Pas, Jolien; Meijer, Lenny H.H.; Han, Songi

    2015-01-01

    Dimethyl sulfoxide (DMSO) has been broadly used in biology as a cosolvent, a cryoprotectant, and an enhancer of membrane permeability, leading to the general assumption that DMSO-induced structural changes in cell membranes and their hydration water play important functional roles. Although the effects of DMSO on the membrane structure and the headgroup dehydration have been extensively studied, the mechanism by which DMSO invokes its effect on lipid membranes and the direct role of water in this process are unresolved. By directly probing the translational water diffusivity near unconfined lipid vesicle surfaces, the lipid headgroup mobility, and the repeat distances in multilamellar vesicles, we found that DMSO exclusively weakens the surface water network near the lipid membrane at a bulk DMSO mole fraction (XDMSO) of <0.1, regardless of the lipid composition and the lipid phase. Specifically, DMSO was found to effectively destabilize the hydration water structure at the lipid membrane surface at XDMSO <0.1, lower the energetic barrier to dehydrate this surface water, whose displacement otherwise requires a higher activation energy, consequently yielding compressed interbilayer distances in multilamellar vesicles at equilibrium with unaltered bilayer thicknesses. At XDMSO >0.1, DMSO enters the lipid interface and restricts the lipid headgroup motion. We postulate that DMSO acts as an efficient cryoprotectant even at low concentrations by exclusively disrupting the water network near the lipid membrane surface, weakening the cohesion between water and adhesion of water to the lipid headgroups, and so mitigating the stress induced by the volume change of water during freeze-thaw. PMID:26200868

  8. DMSO induces dehydration near lipid membrane surfaces.

    PubMed

    Cheng, Chi-Yuan; Song, Jinsuk; Pas, Jolien; Meijer, Lenny H H; Han, Songi

    2015-07-21

    Dimethyl sulfoxide (DMSO) has been broadly used in biology as a cosolvent, a cryoprotectant, and an enhancer of membrane permeability, leading to the general assumption that DMSO-induced structural changes in cell membranes and their hydration water play important functional roles. Although the effects of DMSO on the membrane structure and the headgroup dehydration have been extensively studied, the mechanism by which DMSO invokes its effect on lipid membranes and the direct role of water in this process are unresolved. By directly probing the translational water diffusivity near unconfined lipid vesicle surfaces, the lipid headgroup mobility, and the repeat distances in multilamellar vesicles, we found that DMSO exclusively weakens the surface water network near the lipid membrane at a bulk DMSO mole fraction (XDMSO) of <0.1, regardless of the lipid composition and the lipid phase. Specifically, DMSO was found to effectively destabilize the hydration water structure at the lipid membrane surface at XDMSO <0.1, lower the energetic barrier to dehydrate this surface water, whose displacement otherwise requires a higher activation energy, consequently yielding compressed interbilayer distances in multilamellar vesicles at equilibrium with unaltered bilayer thicknesses. At XDMSO >0.1, DMSO enters the lipid interface and restricts the lipid headgroup motion. We postulate that DMSO acts as an efficient cryoprotectant even at low concentrations by exclusively disrupting the water network near the lipid membrane surface, weakening the cohesion between water and adhesion of water to the lipid headgroups, and so mitigating the stress induced by the volume change of water during freeze-thaw.

  9. Lipid flopping in the liver.

    PubMed

    Linton, Kenneth J

    2015-10-01

    Bile is synthesized in the liver and is essential for the emulsification of dietary lipids and lipid-soluble vitamins. It is a complex mixture of amphiphilic bile acids (BAs; which act as detergent molecules), the membrane phospholipid phosphatidylcholine (PC), cholesterol and a variety of endogenous metabolites and waste products. Over the last 20 years, the combined effort of clinicians, geneticists, physiologists and biochemists has shown that each of these bile components is transported across the canalicular membrane of the hepatocyte by its own specific ATP-binding cassette (ABC) transporter. The bile salt export pump (BSEP) ABCB11 transports the BAs and drives bile flow from the liver, but it is now clear that two lipid transporters, ABCB4 (which flops PC into the bile) and the P-type ATPase ATP8B1/CDC50 (which flips a different phospholipid in the opposite direction) play equally critical roles that protect the biliary tree from the detergent activity of the bile acids. Understanding the interdependency of these lipid floppases and flippases has allowed the development of an assay to measure ABCB4 function. ABCB4 harbours numerous mis-sense mutations which probably reflects the spectrum of liver disease rooted in ABCB4 aetiology. Characterization of the effect of these mutations at the protein level opens the possibility for the development of personalized prognosis and treatment.

  10. Interaction of lipids with the neurotensin receptor 1.

    PubMed

    Bolivar, Juan H; Muñoz-García, Juan C; Castro-Dopico, Tomas; Dijkman, Patricia M; Stansfeld, Phillip J; Watts, Anthony

    2016-06-01

    Information about lipid-protein interactions for G protein-coupled receptors (GPCRs) is scarce. Here, we use electron spin resonance (ESR) and spin-labelled lipids to study lipid interactions with the rat neurotensin receptor 1 (NTS1). A fusion protein containing rat NTS1 fully able to bind its ligand neurotensin was reconstituted into phosphatidylcholine (PC) bilayers at specific lipid:protein molar ratios. The fraction of motionally restricted lipids in the range of 40:1 to 80:1 lipids per receptor suggested an oligomeric state of the protein, and the result was unaffected by increasing the hydrophobic thickness of the lipid bilayer from C-18 to C-20 or C-22 chain length PC membranes. Comparison of the ESR spectra of different spin-labelled lipids allowed direct measurement of lipid binding constants relative to PC (Kr), with spin-labelled phosphatidylethanolamine (PESL), phosphatidylserine (PSSL), stearic acid (SASL), and a spin labelled cholesterol analogue (CSL) Kr values of 1.05±0.05, 1.92±0.08, 5.20±0.51 and 0.91±0.19, respectively. The results contrast with those from rhodopsin, the only other GPCR studied this way, which has no selectivity for the lipids analysed here. Molecular dynamics simulations of NTS1 in bilayers are in agreement with the ESR data, and point to sites in the receptor where PS could interact with higher affinity. Lipid selectivity could be necessary for regulation of ligand binding, oligomerisation and/or G protein activation processes. Our results provide insight into the potential modulatory mechanisms that lipids can exert on GPCRs. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Genetic engineering to produce polyketide analogues.

    PubMed

    Reeves, Christopher D; Rodriguez, Eduardo

    2009-01-01

    Polyketides are pharmaceutically important and structurally diverse natural products. Creating analogues for drug development can be done with chemistry, but this is generally restricted to a few accessible functional groups. Analogues can also be made by genetic engineering, which is particularly effective for polyketides synthesized by a modular polyketide synthase (PKS). Such a PKS displays colinearity, which means that the structural features along the polyketide chain are determined by the catalytic specificities in corresponding modules along a molecular assembly line. The assembly line can be genetically engineered through addition, deletion, or mutation of catalytic domains or the reorganization of whole modules. Chemically synthesized precursors also can be fed to engineered assembly lines to further expand the repertoire of analogues. These various methods are discussed with an aim of providing a guide to the strategies most likely to succeed in a given circumstance. Recent information that could be relevant to future polyketide engineering projects is also discussed.

  12. Synthesis and anticancer evaluation of spermatinamine analogues.

    PubMed

    Moosa, Basem A; Sagar, Sunil; Li, Song; Esau, Luke; Kaur, Mandeep; Khashab, Niveen M

    2016-03-15

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcysteine carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines, that is, cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5-10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Antimalarial Properties of Simplified Kalihinol Analogues.

    PubMed

    Daub, Mary Elisabeth; Prudhomme, Jacques; Ben Mamoun, Choukri; Le Roch, Karine G; Vanderwal, Christopher D

    2017-03-09

    Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.

  14. Global analogue of the Aharonov-Bohm effect

    SciTech Connect

    Navin, R.L.

    1993-12-31

    This thesis deals with a global analogue of the Aharonov-Bohm effect previously pointed out by other authors. The effect was not well understood because the pure Aharonov-Bohm cross section was thought to be merely an approximate low energy limit. This thesis provides a detailed analysis and reveals that in the particular model considered, there is an exact Aharonov-Bohm cross section over the energy range that a mass splitting occurs. At energies slightly above the mass splitting, the effect has completely disappeared and there is effectively no scattering at large distances. This is a curious observation as it was previously thought that a global theory would not act exactly like a local one over an extended range of energies. It begs the heretical speculation that experimentally observed forces modelled with Lagrangians possessing local symmetries may have an underlying global theory.

  15. GABAA Receptor Modulation by Etomidate Analogues

    PubMed Central

    Pejo, Ervin; Santer, Peter; Wang, Lei; Dershwitz, Philip; Husain, S. Shaukat; Raines, Douglas E.

    2015-01-01

    Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. We characterized the GABAA receptor and hypnotic potencies of etomidate analogues. We then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogues to their structures in order to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage-clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1(L264T)) that enhances anesthetic sensitivity (n = 36 – 60 measurements per concentration-response curve). The hypnotic potencies of etomidate analogues were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 – 21 measurements per dose-response curve). Three-dimensional quantitative structure-activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogues ranged by 91-fold and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated and a pharmacophore model was built that revealed both the structural elements in etomidate analogues associated with high potency and the interactions that these elements make with the etomidate binding site. Conclusion There are multiple specific structural elements in etomidate and etomidate analogues that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more. PMID:26691905

  16. Insulin analogues: action profiles beyond glycaemic control.

    PubMed

    Eckardt, Kristin; Eckel, Jürgen

    2008-02-01

    A variety of studies have documented significant improvements in the treatment of type 1 and 2 diabetes after the introduction of artificial insulins. This review gives an overview of insulin analogues which are currently approved for therapeutical use. Clinical data regarding the efficiency to control blood glucose level as well as improving HbA1c level in comparison to conventional insulin preparations in type 1 and 2 diabetic patients are summarized. Furthermore, special features of insulin analogues regarding their signalling properties are discussed with focus on the proliferative effects of insulin glargine as well as some recent data of insulin detemir.

  17. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  18. Intrinsic lipid preferences and kinetic mechanism of Escherichia coli MurG.

    PubMed

    Chen, Lan; Men, Hongbin; Ha, Sha; Ye, Xiang-Yang; Brunner, Livia; Hu, Yanan; Walker, Suzanne

    2002-05-28

    MurG, the last enzyme involved in the intracellular phase of peptidoglycan synthesis, is a membrane-associated glycosyltransferase that couples N-acetyl glucosamine to the C4 hydroxyl of a lipid-linked N-acetyl muramic acid derivative (lipid I) to form the beta-linked disaccharide (lipid II) that is the minimal subunit of peptidoglycan. Lipid I is anchored to the bacterial membrane by a 55 carbon undecaprenyl chain. Because this long lipid chain impedes kinetic analysis of MurG, we have been investigating alternative substrates containing shortened lipid chains. We now describe the intrinsic lipid preferences of MurG and show that the optimal substrate for MurG in the absence of membranes is not the natural substrate. Thus, while the undecaprenyl carrier lipid may be critical for certain steps in the biosynthetic pathway to peptidoglycan, it is not required-in fact, is not preferred-by MurG. Using synthetic substrate analogues and products containing different length lipid chains, as well as a synthetic dead-end acceptor analogue, we have also shown that MurG follows a compulsory ordered Bi Bi mechanism in which the donor sugar binds first. This information should facilitate obtaining crystals of MurG with substrates bound, an important goal because MurG belongs to a major superfamily of NDP-glycosyltransferases for which no structures containing intact substrates have yet been solved.

  19. Iminosugar C-Glycoside Analogues of α-d-GlcNAc-1-Phosphate: Synthesis and Bacterial Transglycosylase Inhibition

    PubMed Central

    2015-01-01

    We herein describe the first synthesis of iminosugar C-glycosides of α-d-GlcNAc-1-phosphate in 10 steps starting from unprotected d-GlcNAc. A diastereoselective intramolecular iodoamination–cyclization as the key step was employed to construct the central piperidine ring of the iminosugar and the C-glycosidic structure of α-d-GlcNAc. Finally, the iminosugar phosphonate and its elongated phosphate analogue were accessed. These phosphorus-containing iminosugars were coupled efficiently with lipophilic monophosphates to give lipid-linked pyrophosphate derivatives, which are lipid II mimetics endowed with potent inhibitory properties toward bacterial transglycosylases (TGase). PMID:25137529

  20. Synthesis of modified peptidoglycan precursor analogues for the inhibition of glycosyltransferase.

    PubMed

    Dumbre, Shrinivas; Derouaux, Adeline; Lescrinier, Eveline; Piette, André; Joris, Bernard; Terrak, Mohammed; Herdewijn, Piet

    2012-06-06

    The peptidoglycan glycosyltransferases (GTs) are essential enzymes that catalyze the polymerization of glycan chains of the bacterial cell wall from lipid II and thus constitute a validated antibacterial target. Their enzymatic cavity is composed of a donor site for the growing glycan chain (where the inhibitor moenomycin binds) and an acceptor site for lipid II substrate. In order to find lead inhibitors able to fill this large active site, we have synthesized a series of substrate analogues of lipid I and lipid II with variations in the lipid, the pyrophosphate, and the peptide moieties and evaluated their biological effect on the GT activity of E. coli PBP1b and their antibacterial potential. We found several compounds able to inhibit the GT activity in vitro and cause growth defect in Bacillus subtilis . The more active was C16-phosphoglycerate-MurNAc-(L-Ala-D-Glu)-GlcNAc, which also showed antibacterial activity. These molecules are promising leads for the design of new antibacterial GT inhibitors.

  1. Why homogeneous boundary conditions lead to heterogeneous internal strain in analogue simple shear experiments - explained by numerical modeling

    NASA Astrophysics Data System (ADS)

    Exner, Ulrike; Frehner, Marcel; Mancktelow, Neil S.; Grujic, Djordje

    2010-05-01

    deformed during an experiment and represent boundary conditions in the third dimension (i.e the z-direction). In the two-dimensional numerical simulation, this viscous shear boundary condition is represented by a velocity-dependent traction force that acts on the analogue material. The numerical simple shear experiments including this traction force precisely reproduce the heterogeneous strain observed in analogue experiments. Therefore, we conclude that boundary effects in the third dimension of simple shear rigs (i.e. weak viscous layers) are the primary reason for the observed heterogeneous strain field. As the viscous stresses arising from deforming the weak boundary layers are velocity dependent, the deviation from a homogeneous strain pattern in the analogue material depends on the applied shear strain rate. We thus recommend to run analogue models in shear boxes at preferably low strain rates.

  2. Polyamine metabolism in a member of the phylum Microspora (Encephalitozoon cuniculi): effects of polyamine analogues

    PubMed Central

    Bacchi, Cyrus J.; Rattendi, Donna; Faciane, Evangeline; Yarlett, Nigel; Weiss, Louis M.; Frydman, Benjamin; Woster, Patrick; Wei, Benjamin; Marton, Laurence J.; Wittner, Murray

    2011-01-01

    The uptake, biosynthesis and catabolism of polyamines in the microsporidian parasite Encephalitozoon cuniculi are detailed with reference to the effects of oligoamine and arylamine analogues of polyamines. Enc. cuniculi, an intracellular parasite of mammalian cells, has both biosynthetic and catabolic enzymes of polyamine metabolism, as demonstrated in cell-free extracts of mature spores. The uptake of polyamines was measured in immature, pre-emergent spores isolated from host cells by Percoll gradient. Spermine was rapidly taken up and metabolized to spermidine and an unknown, possibly acetamidopropanal, by spermidine/spermine N1-acetyltransferase (SSAT) and polyamine oxidase (PAO). Most of the spermidine and the unknown product were found in the cell incubation medium, indicating they were released from the cell. bis(Ethyl) oligoamine analogues of polyamines, such as SL-11144 and SL-11158, as well as arylamine analogues [BW-1, a bis(phenylbenzyl) 3-7-3 analogue] blocked uptake and interconversion of spermine at micromolar levels and, in the case of BW-1, acted as substrate for PAO. The Enc. cuniculi PAO activity differed from that found in mammalian cells with respect to pH optimum, substrate specificity and sensitivity to known PAO inhibitors. SL-11158 inhibited SSAT activity with a mixed type of inhibition in which the analogue had a 70-fold higher affinity for the enzyme than the natural substrate, spermine. The interest in Enc. cuniculi polyamine metabolism and the biochemical effects of these polyamine analogues is warranted since they cure model infections of Enc. cuniculi in mice and are potential candidates for human clinical trials. PMID:15133083

  3. Substrate selectivity of Dengue and Zika virus NS5 polymerase towards 2'-modified nucleotide analogues.

    PubMed

    Potisopon, Supanee; Ferron, François; Fattorini, Véronique; Selisko, Barbara; Canard, Bruno

    2017-04-01

    In targeting the essential viral RNA-dependent RNA-polymerase (RdRp), nucleotide analogues play a major role in antiviral therapies. In the Flaviviridae family, the hepatitis C virus (HCV) can be eradicated from chronically infected patients using a combination of drugs which generally include the 2'-modified uridine analogue Sofosbuvir, delivered as nucleotide prodrug. Dengue and Zika viruses are emerging flaviviruses whose RdRp is closely related to that of HCV, yet no nucleoside drug has been clinically approved for these acute infections. We have purified dengue and Zika virus full-length NS5, the viral RdRps, and used them to assemble a stable binary complex made of NS5 and virus-specific RNA primer/templates. The complex was used to assess the selectivity of NS5 towards nucleotide analogues bearing modifications at the 2'-position. We show that dengue and Zika virus RdRps exhibit the same discrimination pattern: 2'-O-Me > 2'-C-Me-2'-F > 2'-C-Me nucleoside analogues, unlike HCV RdRp for which the presence of the 2'-F is beneficial rendering the discrimination pattern 2'-O-Me > 2'-C-Me ≥ 2'-C-Me-2'-F. Both 2'-C-Me and 2'-C-Me-2'-F analogues act as non-obligate RNA chain terminators. The dengue and Zika NS5 nucleotide selectivity towards 2'-modified NTPs mirrors potency of the corresponding analogues in infected cell cultures.

  4. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  5. Differential Client Attractiveness in a Counseling Analogue

    ERIC Educational Resources Information Center

    Davis, Carl S.; And Others

    1977-01-01

    Investigated variations in conceptual complexity level of counselor and client on counselor attraction to the client. Counselor trainees rated attractiveness of clients following two counseling analogue tasks in which the client was depicted as exhibiting high or low conceptual level. More complex clients are more attractive across both levels.…

  6. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-03-01

    Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

  7. Solanapyrone analogues from a Hawaiian fungicolous fungus

    USDA-ARS?s Scientific Manuscript database

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  8. Analoguing Creativity & Culture: A Method for Metaphors.

    ERIC Educational Resources Information Center

    Thompson, Timothy N.

    Adding to the benefits of using metaphors as tools, "analoguing" (a method of analysis that focuses on metaphors for meanings in use and meanings of metaphors in use) helps avoid excessive categorization and separation by looking for unities and patterns in phenomena rather than for divisions. Six months of observation of patterns of…

  9. Lipid Storage Diseases

    MedlinePlus

    ... developing effective enzyme replacement therapies for Gaucher and Fabry diseases. NINDS-funded scientists continue to study how lipids ... developing effective enzyme replacement therapies for Gaucher and Fabry diseases. NINDS-funded scientists continue to study how lipids ...

  10. Irinotecan Lipid Complex Injection

    MedlinePlus

    Irinotecan lipid complex is used in combination with other medications to treat pancreatic cancer that has spread to other ... worsened after treatment with other chemotherapy medications. Irinotecan lipid complex is in a class of antineoplastic medications ...

  11. Vincristine Lipid Complex Injection

    MedlinePlus

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer ... least two different treatments with other medications. Vincristine lipid complex is in a class of medications called ...

  12. Daunorubicin Lipid Complex Injection

    MedlinePlus

    Daunorubicin lipid complex is used to treat advanced Kaposi's sarcoma (a type of cancer that causes abnormal tissue to ... body) related to acquired immunodeficiency syndrome (AIDS). Daunorubicin lipid complex is in a class of medications called ...

  13. Parenteral Nutrition and Lipids.

    PubMed

    Raman, Maitreyi; Almutairdi, Abdulelah; Mulesa, Leanne; Alberda, Cathy; Beattie, Colleen; Gramlich, Leah

    2017-04-14

    Lipids have multiple physiological roles that are biologically vital. Soybean oil lipid emulsions have been the mainstay of parenteral nutrition lipid formulations for decades in North America. Utilizing intravenous lipid emulsions in parenteral nutrition has minimized the dependence on dextrose as a major source of nonprotein calories and prevents the clinical consequences of essential fatty acid deficiency. Emerging literature has indicated that there are benefits to utilizing alternative lipids such as olive/soy-based formulations, and combination lipids such as soy/MCT/olive/fish oil, compared with soybean based lipids, as they have less inflammatory properties, are immune modulating, have higher antioxidant content, decrease risk of cholestasis, and improve clinical outcomes in certain subgroups of patients. The objective of this article is to review the history of IVLE, their composition, the different generations of widely available IVLE, the variables to consider when selecting lipids, and the complications of IVLE and how to minimize them.

  14. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Dicarba analogues of α-conotoxin RgIA. Structure, stability, and activity at potential pain targets.

    PubMed

    Chhabra, Sandeep; Belgi, Alessia; Bartels, Peter; van Lierop, Bianca J; Robinson, Samuel D; Kompella, Shiva N; Hung, Andrew; Callaghan, Brid P; Adams, David J; Robinson, Andrea J; Norton, Raymond S

    2014-12-11

    α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.

  16. A novel lunar bed rest analogue.

    PubMed

    Cavanagh, Peter R; Rice, Andrea J; Licata, Angelo A; Kuklis, Matthew M; Novotny, Sara C; Genc, Kerim O; Englehaupt, Ricki K; Hanson, Andrea M

    2013-11-01

    Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system. We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated. A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%. The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

  17. MR-Visible Lipids and the Tumor Microenvironment

    PubMed Central

    Delikatny, E. James; Chawla, Sanjeev; Leung, Daniel-Joseph; Poptani, Harish

    2013-01-01

    MR-visible lipids or mobile lipids are defined as lipids that are observable using proton magnetic resonance spectroscopy in cells and in tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in intracellular neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review will discuss factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo and radiotherapy, and to human tumors where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment will be discussed including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in detoxification of the cell or act as an alternate energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and assessment of treatment response both in animal models of cancer as well as human brain tumors will also be discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be used as a potential biomarker for assessing treatment response in cancer. PMID:21538631

  18. Analogue VLSI for probabilistic networks and spike-time computation.

    PubMed

    Murray, A

    2001-02-01

    The history and some of the methods of analogue neural VLSI are described. The strengths of analogue techniques are described, along with residual problems to be solved. The nature of hardware-friendly and hardware-appropriate algorithms is reviewed and suggestions are offered as to where analogue neural VLSI's future lies.

  19. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    PubMed

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  20. Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes.

    PubMed

    Scott, Sarah A; Spencer, Cierra T; O'Reilly, Matthew C; Brown, Kyle A; Lavieri, Robert R; Cho, Chul-Hee; Jung, Dai-Il; Larock, Richard C; Brown, H Alex; Lindsley, Craig W

    2015-02-20

    Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection, and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes, small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues, additional parallel synthesis, and evaluation in multiple PLD assays, we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field.

  1. [Reflections of a clinician on the switch from human to analogue insulin treatment].

    PubMed

    Deák, László

    2012-10-07

    The development of insulin therapy has not been stopped since the manufacturing of human insulin, because better mimic of physiological insulin response made it necessary to modify the human insulin molecule in order to create rapidly absorbing insulin analogues and 24-hour acting basal insulin analogues. Clinical observations indicate that the complete switch from human basal-bolus therapy to insulin analogues means not only "unit-for-unit" switch but it represents a transfer to an insulin therapy with different basal/bolus ratio as a result of different pharmacokinetic and pharmacodynamic properties of insulin and the level of insulin resistance of the patient. With reference to a case-history, the author presents his experience on a switch from human insulin to insulin analogue. Furthermore, the author summarizes data obtained from a few cases reported in international literature which draw the attention to the fact that the basal/bolus ratio should be adjusted individually, which may be the key for the success in the therapy in these cases.

  2. Inhibition of serine and proline racemases by substrate-product analogues.

    PubMed

    Harty, Matthew; Nagar, Mitesh; Atkinson, Logan; Legay, Christina M; Derksen, Darren J; Bearne, Stephen L

    2014-01-01

    d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (Ki=167±21mM, Ki'=661±81mM, cf. Km=19±2mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki=111±15mM, cf. Km=5.7±0.5mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.

  3. Nutrients and neurodevelopment: lipids.

    PubMed

    González, Horacio F; Visentin, Silvana

    2016-10-01

    Nutrients, lipids in particular, make up the central nervous system structure and play major functional roles: they stimulate development, migration, and nerve cell differentiation. They are part of gray matter, white matter, nerve nuclei, and synaptogenesis. Breast milk contains lipids which are crucial for infant brain development. The lipid profile of breast milk was used as a guideline for the development of breast milk substitutes. However, to date, no substitute has matched it. Complementary feeding should include docosahexaenoic acid, arachidonic acid, other polyunsaturated fatty acids, saturated fatty acids, and complex lipids found in milk fat. The lipid composition of breast milk depends on maternal intake and nutritional status during pregnancy and breast-feeding. It has a great impact on development. Our goal is to review scientific literature regarding the role of lipids on infant brain development and the importance of breast milk lipid composition, maternal diet, and complementary feeding.

  4. Lipids and Prostate Cancer

    PubMed Central

    Suburu, Janel; Chen, Yong Q.

    2012-01-01

    The role of lipid metabolism has gained particular interest in prostate cancer research. A large body of literature has outlined the unique upregulation of de novo lipid synthesis in prostate cancer. Concordant with this lipogenic phenotype is a metabolic shift, in which cancer cells use alternative enzymes and pathways to facilitate the production of fatty acids. These newly synthesized lipids may support a number of cellular processes to promote cancer cell proliferation and survival. Hence, de novo lipogenesis is under intense investigation as a therapeutic target. Epidemiologic studies suggest dietary fat may also contribute to prostate cancer; however, whether dietary lipids and de novo synthesized lipids are differentially metabolized remains unclear. Here, we highlight the lipogenic nature of prostate cancer, especially the promotion of de novo lipid synthesis, and the significance of various dietary lipids in prostate cancer development and progression. PMID:22503963

  5. Efficacy of the small molecule inhibitor of Lipid II BAS00127538 against Acinetobacter baumannii

    PubMed Central

    de Leeuw, Erik PH

    2014-01-01

    Objective To test the activity of a small molecule compound that targets Lipid II against Acinetobacter baumannii. Methods Susceptibility to small molecule Lipid II inhibitor BAS00127538 was assessed using carbapenem- and colistin-resistant clinical isolates of A. baumannii. In addition, synergy between colisitin and this compound was assessed. Results Small molecule Lipid II inhibitor BAS00127538 potently acts against A. baumannii and acts synergistically with colistin. Conclusion For the first time, a compound that targets Lipid II is described that acts against multi-drug resistant isolates of A. baumannii. The synergy with colistin warrants further lead development of BAS00127538. PMID:25143710

  6. The CD1 size problem: lipid antigens, ligands, and scaffolds

    PubMed Central

    Ly, Dalam

    2014-01-01

    Whereas research on CD1d has emphasized a few glycosyl ceramides, the broader family of four human CD1 antigen-presenting molecules binds hundreds of distinct self-lipids. Individual lipid types bind within CD1 grooves in different ways, such that they partially fill the groove, match the groove volume, or protrude substantially from the groove. These differing modes of binding can now be connected to differing immunological functions, as individual lipids can act as stimulatory antigens, inhibitory ligands, or space-filling scaffolds. Because each type of CD1 protein folds to produce antigen-binding grooves with differing sizes and shapes, CD1a, CD1b, CD1c, CD1d, and CD1e have distinct mechanisms of capturing self-lipids and exchanging them for foreign lipids. The size discrepancy between endogeneous lipids and groove volume is most pronounced for CD1b. Recent studies show that the large CD1b cavity can simultaneously bind two self-lipids, the antigen, and its scaffold lipid, which can be exchanged for one large bacterial lipid. In this review, we will highlight recent studies showing how cells regulate lipid antigen loading and the roles CD1 groove structures have in control of the presentation of chemically diverse lipids to T cells. PMID:24658584

  7. Mechanics of Lipid Bilayer Membranes

    NASA Astrophysics Data System (ADS)

    Powers, Thomas R.

    All cells have membranes. The plasma membrane encapsulates the cell's interior, acting as a barrier against the outside world. In cells with nuclei (eukaryotic cells), membranes also form internal compartments (organelles) which carry out specialized tasks, such as protein modification and sorting in the case of the Golgi apparatus, and ATP production in the case of mitochondria. The main components of membranes are lipids and proteins. The proteins can be channels, carriers, receptors, catalysts, signaling molecules, or structural elements, and typically contribute a substantial fraction of the total membrane dry weight. The equilibrium properties of pure lipid membranes are relatively well-understood, and will be the main focus of this article. The framework of elasticity theory and statistical mechanics that we will develop will serve as the foundation for understanding biological phenomena such as the nonequilibrium behavior of membranes laden with ion pumps, the role of membrane elasticity in ion channel gating, and the dynamics of vesicle fission and fusion. Understanding the mechanics of lipid membranes is also important for drug encapsulation and delivery.

  8. The role of retinal in the long-range protein-lipid interactions in bacteriorhodopsin-phosphatidylcholine vesicles.

    PubMed

    Bryl, K; Yoshihara, K

    2001-01-01

    The effects of bacteriorhodopsin analogues and the analogues of a bacteriorhodopsin mutant (D96N) on the lateral organization of lipids have been investigated with lipid species with a variety of acyl chain lengths. The analogues, obtained by regeneration of bacterioopsin or mutant opsin with 14-, 12-, 10-, or 8-fluororetinal, were reconstituted with 1,2-didodecanoyl-sn-glycero-3-phosphocholine, 1,2-ditetradecanoyl-sn-glycero-3-phosphocholine, 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine, and 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine. The phase behavior of the protein-lipid systems was investigated at different temperatures and different protein/lipid molar ratios by analyzing the fluorescence and phase properties of the 1-acyl-2-[8-(2-anthroyl)octanol]-sn-glycero-3-phosphocholine probe. The (8,10,12)-bacteriorhodopsins had a similar effect on the lipid phase transition to that induced by native bacteriorhodopsin: a rigidifying effect on the three shorter lipid species and a fluidifying effect on the longest-chain lipids used. The substitution of retinal with 14-fluororetinal resulted in much stronger effects of the protein on the lipids: a more pronounced up-shift of the lipid phase transition temperature, a rigidifying effect on all the lipids used, and an elongation of the distance over which the hydrophobic thickness of the lipid bilayer was perturbed by the protein. Evidence was provided that retinal contributed to the long-range protein-lipid interactions in bacteriorhodopsin-phosphatidylcholine vesicles. The extent of this contribution was dependent on the retinal structure in close vicinity to the Shiff base and on the compactness of the protein structure.

  9. Optimization of propafenone analogues as antimalarial leads.

    PubMed

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  10. Properties of phosphatidylcholine in the presence of its monofluorinated analogue.

    PubMed

    Smith, Eric A; van Gorkum, Christiaan M; Dea, Phoebe K

    2010-03-01

    In aqueous solution, the monofluorinated phospholipid 1-palmitoyl-2-[16-fluoropalmitoyl]sn-glycero-3-phosphocholine (F-DPPC) interdigitates without the use of inducing agents. To understand the thermal and physical properties of this unique lipid, F-DPPC was combined with the non-fluorinated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC). Differential scanning calorimetry (DSC) was used to determine the miscibility and thermotropic phase behavior of these binary lipid mixtures. In addition, the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) and a DPH-labeled analogue of DPPC, 2-(3-(diphenylhexatrienyl) propanoyl)-1-hexadecanoyl-sn-glycero-3-phosphocholine (beta-DPH HPC, aka DPH-PC or DPHpPC), were used to detect interdigitation. In F-DPPC, the fluorescence intensity of both probes decreased a similar amount and to a degree that is consistent with an interdigitated system. We also determined that there are two separate effects of increasing the ratio of F-DPPC in the DPPC/F-DPPC system. With low amounts of F-DPPC, there is little evidence that the system is heavily interdigitated. Instead, we hypothesize that the introduction of F-DPPC provides nucleation sites that alter the kinetics, reversibility, and temperature of the main transition (T(m)). At higher mol% of F-DPPC, we propose that interdigitated F-DPPC-rich domains form to create a phase-segregated system. While DPPC/F-DPPC was highly miscible, the DAPC/F-DPPC system was significantly less miscible. Additionally, we observed that DAPC/F-DPPC samples have reduced solubility in water, which affected the acquisition of fluorescence data. However, our DSC results indicate the existence of DAPC-rich and F-DPPC-rich components. Furthermore, this data support that the mixing was disruptive to lipid packing and that the presence of DAPC hinders the interdigitation of F-DPPC.

  11. Magnetic fabric analyses in analogue models of clays

    NASA Astrophysics Data System (ADS)

    García-Lasanta, Cristina; Román-Berdiel, Teresa; Izquierdo-Llavall, Esther; Casas-Sainz, Antonio

    2017-04-01

    Anisotropy of magnetic susceptibility (AMS) studies in sedimentary rocks subjected to deformation indicate that magnetic fabrics orientation can be conditioned by multiple factors: sedimentary conditions, magnetic mineralogy, successive tectonic events, etc. All of them difficult the interpretation of the AMS as a marker of the deformation conditions. Analogue modeling allows to isolate the variables that act in a geological process and to determine the factors and in which extent they influence in the process. This study shows the magnetic fabric analyses applied to several analogue models developed with common commercial red clays. This material resembles natural clay materials that, despite their greater degree of impurities and heterogeneity, have been proved to record a robust magnetic signal carried by a mixture of para- and ferromagnetic minerals. The magnetic behavior of the modeled clay has been characterized by temperature dependent magnetic susceptibility curves (from 40 to 700°C). The measurements were performed combining a KLY-3S Kappabridge susceptometer with a CS3 furnace (AGICO Inc., Czech Republic). The obtained results indicate the presence of an important content of hematite as ferromagnetic phase, as well as a remarkable paramagnetic fraction, probably constituted by phyllosilicates. This mineralogy is common in natural materials such as Permo-Triassic red facies, and magnetic fabric analyses in these natural examples have given consistent results in different tectonic contexts. In this study, sedimentary conditions and magnetic mineralogy are kept constant and the influence of the tectonic regime in the magnetic fabrics is analyzed. Our main objective is to reproduce several tectonic contexts (strike-slip and compression) in a sedimentary environment where material is not yet compacted, in order to determine how tectonic conditions influence the magnetic fabric registered in each case. By dispersing the clays in water and after allowing their

  12. Antitumoral cyclic peptide analogues of chlamydocin.

    PubMed

    Bernardi, E; Fauchere, J L; Atassi, G; Viallefont, P; Lazaro, R

    1993-01-01

    A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

  13. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  14. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  15. Benchmarking analogue models of brittle thrust wedges

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido; Buiter, Susanne J. H.; Boutelier, Jennifer; Burberry, Caroline; Callot, Jean-Paul; Cavozzi, Cristian; Cerca, Mariano; Chen, Jian-Hong; Cristallini, Ernesto; Cruden, Alexander R.; Cruz, Leonardo; Daniel, Jean-Marc; Da Poian, Gabriela; Garcia, Victor H.; Gomes, Caroline J. S.; Grall, Céline; Guillot, Yannick; Guzmán, Cecilia; Hidayah, Triyani Nur; Hilley, George; Klinkmüller, Matthias; Koyi, Hemin A.; Lu, Chia-Yu; Maillot, Bertrand; Meriaux, Catherine; Nilfouroushan, Faramarz; Pan, Chang-Chih; Pillot, Daniel; Portillo, Rodrigo; Rosenau, Matthias; Schellart, Wouter P.; Schlische, Roy W.; Take, Andy; Vendeville, Bruno; Vergnaud, Marine; Vettori, Matteo; Wang, Shih-Hsien; Withjack, Martha O.; Yagupsky, Daniel; Yamada, Yasuhiro

    2016-11-01

    We performed a quantitative comparison of brittle thrust wedge experiments to evaluate the variability among analogue models and to appraise the reproducibility and limits of model interpretation. Fifteen analogue modeling laboratories participated in this benchmark initiative. Each laboratory received a shipment of the same type of quartz and corundum sand and all laboratories adhered to a stringent model building protocol and used the same type of foil to cover base and sidewalls of the sandbox. Sieve structure, sifting height, filling rate, and details on off-scraping of excess sand followed prescribed procedures. Our analogue benchmark shows that even for simple plane-strain experiments with prescribed stringent model construction techniques, quantitative model results show variability, most notably for surface slope, thrust spacing and number of forward and backthrusts. One of the sources of the variability in model results is related to slight variations in how sand is deposited in the sandbox. Small changes in sifting height, sifting rate, and scraping will result in slightly heterogeneous material bulk densities, which will affect the mechanical properties of the sand, and will result in lateral and vertical differences in peak and boundary friction angles, as well as cohesion values once the model is constructed. Initial variations in basal friction are inferred to play the most important role in causing model variability. Our comparison shows that the human factor plays a decisive role, and even when one modeler repeats the same experiment, quantitative model results still show variability. Our observations highlight the limits of up-scaling quantitative analogue model results to nature or for making comparisons with numerical models. The frictional behavior of sand is highly sensitive to small variations in material state or experimental set-up, and hence, it will remain difficult to scale quantitative results such as number of thrusts, thrust spacing

  16. Synthesis of constrained analogues of tryptophan

    PubMed Central

    Negrato, Marco; Abbiati, Giorgio; Dell’Acqua, Monica

    2015-01-01

    Summary A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues. PMID:26664620

  17. Polyamine analogues targeting epigenetic gene regulation.

    PubMed

    Huang, Yi; Marton, Laurence J; Woster, Patrick M; Casero, Robert A

    2009-11-04

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of

  18. Sterculic Acid and Its Analogues Are Potent Inhibitors of Toxoplasma gondii.

    PubMed

    Hao, Pan; Alaraj, Intisar Q M; Dulayymi, Juma'a R Al; Baird, Mark S; Liu, Jing; Liu, Qun

    2016-04-01

    Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC50 value of 36.2 μM, compared with EC50 values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis.

  19. Effect of thyroid hormones and their analogues on the mitochondrial calcium transport activity.

    PubMed

    De Giovanni, R; Asta, L; Covello, C; Marotta, M; Mazzulla, S; Parrilla, R; Pitrelli, G; Spena, A; Martino, G

    1992-01-01

    In this paper the authors studied the effects of thyroid hormones and their structural analogues on the mitochondrial calcium transport activities. The thyroid hormones, 3,5,3' L-triiodothyronine (LT3) and 3,5,3'5' L-tetraiodothyronine (LT4) at physiological intracellular concentrations between 7.2 and 9 nM, decouple total Ca++ transport, as well as inhibit the passive transport of Ca++, either due to oxidation of pyruvate, malate or succinate or after inhibition with rotenone. The optical isomers 3,5,3' D-triiodothyronine (DT3) and 3,5,3',5' D-tetraiodothyronine (DT4) are less effective at all the used concentrations. Furthermore the structural analogues 3,3',5' L-triiodothyronine (LrT3), 3,5-dicloro, 3',5' L-diiodothyronine (LDiClT2) and 3,5 L-diiodothyronine (LT2) furnished even less effects on the same activities. The effect of the thyroid hormones and of their structural analogues has revealed that the mitochondrial calcium transport may be influenced both by a stereospecific interaction between hormones and protein ligands and by a lipophilic chaotropic action on the mitochondrial membranes lipids. In this context it is interesting to consider that both thyroid hormones and Ca++ transport activity are interacting with the energetic metabolism by means of phosphorylation and substrate oxidation mechanism.

  20. Sterculic Acid and Its Analogues Are Potent Inhibitors of Toxoplasma gondii

    PubMed Central

    Hao, Pan; Alaraj, Intisar Q. M.; Dulayymi, Juma’a R. Al; Baird, Mark S.; Liu, Jing; Liu, Qun

    2016-01-01

    Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC50 value of 36.2 μM, compared with EC50 values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis. PMID:27180571

  1. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss. PMID:27626017

  2. Thymidine analogues for tracking DNA synthesis.

    PubMed

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-09-15

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  3. Epidermal surface lipids.

    PubMed

    Pappas, Apostolos

    2009-03-01

    A layer of lipids, which are of both sebaceous and keratinocyte origin, covers the surface of the skin. The apparent composition of surface lipids varies depending on the selected method of sampling. Lipids produced by the epidermal cells are an insignificant fraction of the total extractable surface lipid on areas rich in sebaceous glands. Due to the holocrine activity of the sebaceous gland, its product of secretion (sebum) is eventually released to the surface of the skin and coats the fur as well. Lipids of epidermal origin fill the spaces between the cells, like mortar or cement. The sebaceous lipids are primarily non polar lipids as triglycerides, wax esters and squalene, while epidermal lipids are a mixture of ceramides, free fatty acids and cholesterol. The composition of the sebaceous lipids is unique and intriguing and elevated sebum excretion is a major factor involved in the pathophysiology of acne. Recent studies have elucidated the roles that epidermal surface lipids have on normal skin functions and acne.

  4. Epidermal surface lipids

    PubMed Central

    2009-01-01

    A layer of lipids, which are of both sebaceous and keratinocyte origin, covers the surface of the skin. The apparent composition of surface lipids varies depending on the selected method of sampling. Lipids produced by the epidermal cells are an insignificant fraction of the total extractable surface lipid on areas rich in sebaceous glands. Due to the holocrine activity of the sebaceous gland, its product of secretion (sebum) is eventually released to the surface of the skin and coats the fur as well. Lipids of epidermal origin fill the spaces between the cells, like mortar or cement. The sebaceous lipids are primarily non polar lipids as triglycerides, wax esters and squalene, while epidermal lipids are a mixture of ceramides, free fatty acids and cholesterol. The composition of the sebaceous lipids is unique and intriguing and elevated sebum excretion is a major factor involved in the pathophysiology of acne. Recent studies have elucidated the roles that epidermal surface lipids have on normal skin functions and acne. PMID:20224687

  5. Phosphoinositides alter lipid bilayer properties

    PubMed Central

    Hobart, E. Ashley; Koeppe, Roger E.; Andersen, Olaf S.

    2013-01-01

    to alter lipid bilayer properties, in addition to any other effects they may have. The results further show that exogenous PIP2, as well as structural analogues that differ in acyl chain length or phosphorylation state, alters lipid bilayer properties at the concentrations used in many cell physiological experiments. PMID:23712549

  6. ACTION OF A HISTIDINE ANALOGUE, 1,2,4-TRIAZOLE-3-ALANINE, IN SALMONELLA TYPHIMURIUM

    PubMed Central

    Levin, Alfred P.; Hartman, Philip E.

    1963-01-01

    Levin, Alfred P. (The Johns Hopkins University, Baltimore, Md.), and Philip E. Hartman. Action of a histidine analogue, 1,2,4-triazole-3-alanine, in Salmonella typhimurium. J. Bacteriol. 86:820–828. 1963.—The effect of the histidine analogue, 1,2,4-triazole-3-alanine (TRA), on growth and enzyme synthesis in histidine auxotrophs of Salmonella typhimurium has been studied. TRA allows an increase of approximately 50% in the amount of protein in a culture but does not allow concomitant synthesis of ribonucleic acid and deoxyribonucleic acid. Although the analogue prevents the formation of active bacteriophage and of enzymatically active inosine 5′-phosphate dehydrogenase, it does not prevent the formation of enzymatically active l-histidinol phosphate phosphatase or of imidazoleacetol phosphate transaminase, two enzymes involved in the biosynthesis of histidine. Of the three known functions of histidine in the cell, TRA mimics two: it is incorporated into protein, and it acts as a repressor material for synthesis of enzymes involved in the formation of histidine. TRA fails to act as a feedback inhibitor of the first step in the formation of histidine. Images PMID:14066480

  7. Structure-activity relationship studies of flavonol analogues on pollen germination.

    PubMed

    Forbes, Alaina M; Meier, G Patrick; Haendiges, Stacey; Taylor, Loverine P

    2014-03-12

    Flavonoids are polyphenolic compounds required in the fertilization process in many, if not all, plants. However, the exact biological mechanism(s) and the interacting proteins are unknown. To determine the characteristics important in activating or inhibiting the pollination sequence, a structure-activity relationship analysis of natural and synthetic flavonols was conducted. Flavonol analogues were synthesized through a modified "one-pot" procedure that utilized a Baker-Venkataraman type rearrangement and a Suzuki-Miyaura cross-coupling of a halo-flavonol with an organotrifluoroborate. Of the flavonols tested, kaempferol was the only compound to act as a full agonist. The other smaller, less sterically hindered flavonols (galangin, kaempferide, and 4'-methyl flavonol) acted as partial agonists. Larger more hydrophobic flavonol analogues (3'- and 4'-benzoyl, 3'- and 4'-phenyl, and 3'- and 4'-iodo flavonols) had minimal or no agonist activity. Competition assays between kaempferol and these minimally activating flavonols showed that these analogues inhibited the action of kaempferol in a manner consistent with noncompetitive antagonism. The results suggest that steric hindrance is the most important factor in determining a good agonist. Hydrogen bonding also had a positive effect as long as the substituent did not cause any steric hindrance.

  8. Novel probes for visualizing reactive oxygen species in lipid membranes

    NASA Astrophysics Data System (ADS)

    Krumova, Katerina; Cosa, Gonzalo

    2010-04-01

    This work describes the rationale behind the preparation of fluorescent probes for imaging lipid peroxyl radicals within membranes of living cells (fluorescent lipophilic antioxidants). The new probes are based on BODIPY dyes tethered to phenol moieties. We discuss the spectroscopic properties of these novel probes, specifically the BODIPY-α-tocopherol analogue B-TOH, and present a molecular level explanation, based on photoinduced electron transfer, that accounts for the significant emission enhancement that the probe BTOH experiences upon reaction with peroxyl free radicals. In addition to the spectroscopy results in homogeneous media, we also describe studies performed in model lipid membranes which show that the sensitivity of BTOH towards lipid peroxyl radicals is somewhat reduced when the probe is membrane embedded. Solutions to increase the sensitivity of the free radical probes are discussed based on the redox potential of BODIPY dyes.

  9. Functional organization of the HIV lipid envelope

    PubMed Central

    Huarte, Nerea; Carravilla, Pablo; Cruz, Antonio; Lorizate, Maier; Nieto-Garai, Jon A.; Kräusslich, Hans-Georg; Pérez-Gil, Jesús; Requejo-Isidro, Jose; Nieva, José L.

    2016-01-01

    The chemical composition of the human immunodeficiency virus type 1 (HIV-1) membrane is critical for fusion and entry into target cells, suggesting that preservation of a functional lipid bilayer organization may be required for efficient infection. HIV-1 acquires its envelope from the host cell plasma membrane at sites enriched in raft-type lipids. Furthermore, infectious particles display aminophospholipids on their surface, indicative of dissipation of the inter-leaflet lipid asymmetry metabolically generated at cellular membranes. By combining two-photon excited Laurdan fluorescence imaging and atomic force microscopy, we have obtained unprecedented insights into the phase state of membranes reconstituted from viral lipids (i.e., extracted from infectious HIV-1 particles), established the role played by the different specimens in the mixtures, and characterized the effects of membrane-active virucidal agents on membrane organization. In determining the molecular basis underlying lipid packing and lateral heterogeneity of the HIV-1 membrane, our results may help develop compounds with antiviral activity acting by perturbing the functional organization of the lipid envelope. PMID:27678107

  10. Acting Atoms.

    ERIC Educational Resources Information Center

    Farin, Susan Archie

    1997-01-01

    Describes a fun game in which students act as electrons, protons, and neutrons. This activity is designed to help students develop a concrete understanding of the abstract concept of atomic structure. (DKM)

  11. Acting Atoms.

    ERIC Educational Resources Information Center

    Farin, Susan Archie

    1997-01-01

    Describes a fun game in which students act as electrons, protons, and neutrons. This activity is designed to help students develop a concrete understanding of the abstract concept of atomic structure. (DKM)

  12. Anionic lipids and the maintenance of membrane electrostatics in eukaryotes

    PubMed Central

    Platre, Matthieu Pierre

    2017-01-01

    ABSTRACT A wide range of signaling processes occurs at the cell surface through the reversible association of proteins from the cytosol to the plasma membrane. Some low abundant lipids are enriched at the membrane of specific compartments and thereby contribute to the identity of cell organelles by acting as biochemical landmarks. Lipids also influence membrane biophysical properties, which emerge as an important feature in specifying cellular territories. Such parameters are crucial for signal transduction and include lipid packing, membrane curvature and electrostatics. In particular, membrane electrostatics specifies the identity of the plasma membrane inner leaflet. Membrane surface charges are carried by anionic phospholipids, however the exact nature of the lipid(s) that powers the plasma membrane electrostatic field varies among eukaryotes and has been hotly debated during the last decade. Herein, we discuss the role of anionic lipids in setting up plasma membrane electrostatics and we compare similarities and differences that were found in different eukaryotic cells. PMID:28102755

  13. Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance.

    PubMed

    González-García, Ismael; Fernø, Johan; Diéguez, Carlos; Nogueiras, Rubén; López, Miguel

    2017-01-01

    Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase and AMP-activated protein kinase, impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues not suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases such as insulin resistance, cardiomyopathy, atherosclerosis, and steatohepatitis. Current data have reported that, similar to what is observed in peripheral tissues, complex lipids such as ceramides and sphingolipids act as lipotoxic species at the hypothalamic level to impact metabolism. Here, we will review what is currently known about hypothalamic lipid metabolism and the modulation of energy homeostasis. © 2016 S. Karger AG, Basel.

  14. Artificial surfactants based on analogues of SP-B and SP-C.

    PubMed

    Johansson, J; Curstedt, T; Robertson, B

    2001-01-01

    The hydrophobic proteins SP-B and SP-C are important components of natural surfactant preparations currently used in clinical practice, and physiologically active surfactants can be made from isolated SP-B and/or SP-C reconstituted with synthetic lipids. Efforts have been made to produce these polypeptides, or analogues with similarfunction, by organic synthesis or expression in heterologous systems. It is important to obtain proper folding of the synthetic peptides, as required for optimal interaction with the surfactant lipids. Another issue is to avoid loss of SP-C activity due to alpha-helix to beta-sheet transition. This latter problem can be circumvented by replacing the polyvaline stretch of SP-C with a polyleucine stretch containing a few lysines. Palmitoylation of cysteines or serines at positions 5 and 6 also seems important for the properties of SP-C. SP-B, which is too big a molecule to be easily produced by organic synthesis. apparently can be replaced in an artificial surfactant by a peptide capable of cross-linking phospholipid bilayers. The development of synthetic analogues of the surfacant proteins might make it possible to tailor artificial surfactants for specific therapeutic missions, for instance by enhancing resistance to inactivation by meconium, plasma proteins, or oxygen radicals or maximizing bacteriostatic effects.

  15. Vitamin E Analogue Improves Rabbit Sperm Quality during the Process of Cryopreservation through Its Antioxidative Action

    PubMed Central

    Zhu, Zhendong; Fan, Xiaoteng; Lv, Yinghua; Zhang, Nan; Fan, Chuning; Zhang, Pengfei; Zeng, Wenxian

    2015-01-01

    The process of cryopreservation results in high concentration of reactive oxygen species which is detrimental to spermatozoa. The aim of this study was to investigate whether addition of vitamin E analogue to freezing extender can facilitate the cryosurvival of spermatozoa in rabbits, and how vitamin E protects spermatozoa against damages during the process of preservation. Freshly ejaculated semen was diluted with Tris-citrate-glucose extender supplemented with different concentrations of Trolox (a vitamin E analogue). The level of radical oxygen species (ROS) in spermatozoa that was exposed to Trolox was significantly lower than that of the control during each step of the process of preservation. The percentage of frozen-thawed spermatozoa with lipid peroxidation in the Trolox treatments was significantly lower than that of the control. The motility, intact acrosome, membrane integrity and mitochondrial potentials of the frozen-thawed spermatozoa in the treatment of 200 μM Trolox were significantly higher than those of the control. These observations suggest that addition of vitamin E to a freezing extender leads to higher integrity of acrosome, plasma membrane and mitochondrial membrane potential as well as higher motility. Vitamin E protects spermatozoa through its capacity to quench ROS accumulation and lipid peroxidation during the process of preservation. Addition of Trolox is recommended to facilitate the improvement of semen preservation for the rabbit breeding industry. PMID:26700473

  16. Structures, dynamics, and water permeation free energy across bilayers of Lipid A and its analog studied with molecular dynamics simulation.

    PubMed

    Wei, Tao; Huang, Tiefan; Qiao, Baofu; Zhang, Mo; Ma, Heng; Zhang, Lin

    2014-11-20

    Fundamental studies of the supramolecular layer structures, dynamics and water permeation free energy of hexa-acyl-chain Lipid A and its analogue of tetra-acyl chains would be useful for polymer membranes design for endotoxin removal in water treatment, drug delivery and other biotechnologies. In this work, we studied their supramolecular bilayer by using molecular dynamics simulations and efficient free energy computations. Our simulation accuracy was verified by the agreement between the bilayer structural properties (structure factor, bilayer thickness, and the area per lipid) and lateral diffusion coefficient in our simulation and experimental measurements. More importantly, our simulation for the first time illustrated hexagonal compact packing of the hydrocarbon acyl chains within a leaflet of Lipid A membrane (at 298 K and water content of 40 wt %), which is consistent with experiments. In contrast, Lipid A analogue is found with less ordered ripple structures at the same condition. Our study also demonstrated slower dynamics and larger and broader free energy barrier (∼23 kJ/mol) for water permeation for Lipid A, compared with that of Lipid A analogue. Moreover, the analysis of dynamics showed that highly hydrated hydrophilic diglucosamine backbone is structurally stable, whereas the interdigitated hydrophobic acyl chain tails inside the membrane with faster dynamics screen the aqueous environment from the lipid interior and also reinforce the membrane's structural stability.

  17. Covalent binding of an NAD+ analogue to horse liver alcohol dehydrogenase in a ternary complex with pyrazole.

    PubMed

    Goulas, P

    1987-10-15

    Examination of the model of the fixation site of the adenosine phosphate part of NAD+ on horse liver alcohol dehydrogenase led us to synthesize a NAD+ analogue N6-[N-(8-amino-3,6-dioxaoctyl)carbamoylmethyl]-NAD+ in order to alkylate the carboxylic acid group of Asp-273 and to convert the normally dissociable coenzyme into a permanently bound prosthetic group. This NAD+ analogue is coupled to the horse liver alcohol dehydrogenase in the ternary complex formed with pyrazole. In these conditions the degree of fixation varies between 0.4 and 0.58 coenzyme molecule/enzyme subunit molecule. The N6-[N-(8-amino-3,6-dioxaoctyl)carbamoylmethyl]NAD+ acts as a true prosthetic group which can be reduced and reoxidized by a coupled substrate reaction and the internal activity of this holoenzyme corresponds to the amount of analogue incorporated.

  18. Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis.

    PubMed

    Gevers, Tom J G; Nevens, Frederik; Torres, Vicente E; Hogan, Marie C; Drenth, Joost P H

    2016-04-01

    Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. [Treatment effects analysis of preoperative long-acting somatostatin analogs combined trans-sphenoidal endoscopic surgery for patients with growth hormone secreting pituitary macroadenomas].

    PubMed

    Zhang, L Y; Deng, K; Zhang, Y; Yao, Y; Zhu, H J; Jin, Z M; Pan, H

    2017-02-07

    Objective: To evaluate the treatment effects of preoperative long-acting somatostatin analogue (SSA) combined trans-sphenoidal endoscopic surgery for patients with growth hormone (GH)-secreting pituitary macroadenomas. Methods: Retrospective analysis was carried out on 20 patients with GH-secreting pituitary macroadenomas who were treated with preoperative SSA and trans-sphenoidal endoscopic surgery in our apartment from January 2010 to January 2016. We also selected 20 patients with only trans-sphenoidal endoscopic surgery treatment and 20 patients with preoperative SSA and non-trans-sphenoidal endoscopic surgery treatment. The changes of tumor imaging, endocrine and blood pressure before and after treatment were analysed. Results: The Gross total resection (GTR) rate of invasive GH-secreting pituitary macroadenomas of preoperative SSA combined trans-sphenoidal endoscopic surgery group (8/13) were higher than that if only trans-sphenoidal endoscopic surgery group (4/16) and preoperative SSA combined non endoscopic surgery group (1/8) (P<0.05). Meanwhile, preoperative SSA combined trans-sphenoidal endoscopic surgery group had significantly improved the GH levels, blood glucose, lipid metabolism and blood pressure levels (P<0.05). Conclusion: The trans-sphenoidal endoscopic surgery on patients with GH-secreting pituitary macroadenomas has a significant improvement on GH levels, blood glucose, lipid metabolism and blood pressure levels. Through the treatment of preoperative long-acting SSA, the gross total resection rate is higher than other two groups.

  20. Synthesis and biological assay of erlotinib analogues and BSA-conjugated erlotinib analogue.

    PubMed

    Boobalan, Ramalingam; Liu, Kuang-Kai; Chao, Jui-I; Chen, Chinpiao

    2017-04-15

    A series of erlotinib analogues that have structural modification at 6,7-alkoxyl positions is efficiently synthesized. The in vitro anti-tumor activity of synthesized compounds is studied in two non-small cell lung cancer (NSCLC) cell lines (A549 and H1975). Among the synthesized compounds, the iodo compound 6 (ETN-6) exhibits higher anti-cancer activity compared to erlotinib. An efficient method is developed for the conjugation of erlotinib analogue-4, alcohol compound, with protein, bovine serum albumin (BSA), via succinic acid linker. The in vitro anti-tumor activity of the protein attached erlotinib analogue, 8 (ETN-4-Suc-BSA), showed stronger inhibitory activity in both A549 and H1975 NSCLC cell lines. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Synthetic analogues of the natural compound cryphonectric acid interfere with photosynthetic machinery through two different mechanisms.

    PubMed

    Teixeira, Róbson Ricardo; Pereira, Wagner Luiz; Tomaz, Deborah Campos; de Oliveira, Fabrício Marques; Giberti, Samuele; Forlani, Giuseppe

    2013-06-12

    A series of isobenzofuran-1(3H)-ones (phthalides), analogues of the naturally occurring phytotoxin cryphonectric acid, were designed, synthesized, and fully characterized by NMR, IR, and MS analyses. Their synthesis was achieved via condensation, aromatization, and acetylation reactions. The measurement of the electron transport chain in spinach chloroplasts showed that several derivatives are capable of interfering with the photosynthetic apparatus. Few of them were found to inhibit the basal rate, but a significant inhibition was brought about only at concentrations exceeding 50 μM. Some other analogues acted as uncouplers or energy transfer inhibitors, with a remarkably higher effectiveness. Isobenzofuranone addition to the culture medium inhibited the growth of the cyanobacterium Synechococcus elongatus , with patterns consistent with the effects measured in vitro upon isolated chloroplasts. The most active derivatives, being able to completely suppress algal growth at 20 μM, may represent structures to be exploited for the design of new active ingredients for weed control.

  2. Aluminofluorides and beryllofluorides as inhibitors of sulphatases. Analogues of hydrogen sulphate?

    PubMed Central

    Roy, A B

    1991-01-01

    The inhibition of fluoride of sulphatase A from ox liver and of the sulphatases of Helix pomatia and Aspergillus oryzae is decreased by EDTA and increased by Al3+ or Be2+, implicating aluminofluorides and beryllofluorides in the reaction. The inhibition, which is reversible, takes several minutes to develop fully and, at least for the sulphatase of H. pomatia, is of a non-linear mixed competitive-non-competitive type. It is suggested that the aluminofluorides and beryllofluorides are acting as analogues of HSO4-. If so, then this behaviour must be considered, as well as their role as analogues of phosphate, in interpreting the effects of these compounds in intact cells. PMID:1953634

  3. Amygdalin analogues inhibit IFN-γ signalling and reduce the inflammatory response in human epidermal keratinocytes.

    PubMed

    Paoletti, Iole; De Gregorio, Vincenza; Baroni, Adone; Tufano, Maria Antonietta; Donnarumma, Giovanna; Perez, Juan Jesus

    2013-12-01

    Peptide T (PT), an octapeptide fragment located in the V2 region of the HIV-1 gp120-coating protein, appears to be beneficial in the treatment of psoriasis. Our previous investigations suggest that keratinocytes play a key role in conditioning the therapeutic effects of PT in psoriasis. The aim of this study was to explore the effects of PT and the peptidomimetic natural products, Dhurrin and Prunasin, on the expression of the IL-6, IL-8, IL-23, HSP70 and ICAM-1 on IFN-γ and TNF-α-NHEK activated cells. Moreover, we analysed the interference of PT and its analogues through STAT-3 activation. Our results show that the analogues tested exhibit the beneficial biological effects of PT, suggesting the primary role of keratinocytes upon which PT and the peptidomimetics act directly, by reducing proinflammatory responses. Its reduction appears to be important for therapeutic approach in psoriasis pathogenesis.

  4. Two persistent organic pollutants which act through different xenosensors (alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin) interact in a mixture and downregulate multiple genes involved in human hepatocyte lipid and glucose metabolism.

    PubMed

    Ambolet-Camoit, Ariane; Ottolenghi, Chris; Leblanc, Alix; Kim, Min Ji; Letourneur, Franck; Jacques, Sébastien; Cagnard, Nicolas; Guguen-Guillouzo, Christiane; Barouki, Robert; Aggerbeck, Martine

    2015-09-01

    Individuals, typically, are exposed to mixtures of environmental xenobiotics affecting multiple organs and acting through different xenosensors and pathways in species and cell-type specific manners. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are Persistent Organic Pollutants (POPs) and endocrine disruptors which act through different xenosensors and accumulate in the liver. Our objective in this HEALS study was to investigate the effects of the mixture of these POPs on gene expression in a human-derived hepatocyte cell line, HepaRG. We found that, in spite of having largely uncorrelated effects, TCDD and α-endosulfan, when mixed, alter the expression of genes. The combined effects of the mixture of the POPs significantly altered the expression of 100 genes (42 up- and 58 down-regulated) whereas the same concentration of either POP alone did not alter significantly the expression of these genes. For 32 other genes, selective inhibitory crosstalk between TCDD and α-endosulfan was observed. One of the POPs inhibited the effect, on gene expression, of the other in the mixture although, when used alone, that POP did not affect expression. The expression of another 82 genes was significantly altered (up- or down-regulated) by a single POP. The addition of the second POP either increased, in the same direction, the effect on gene expression or had no further effect. At low concentrations (0.2 nM TCDD and 1 μM α-endosulfan), the POPs still had significant effects and the levels of expression of the corresponding proteins were found to be affected for some genes. Particularly striking was the 80-90% inhibition, by the mixture, of the expression of a number of genes of several hepatic intermediary metabolic pathways (glycerolipid metabolism, FXR/RXR activation, glycolysis/gluconeogenesis, retinoid and bile acid biosynthesis), whereas each pollutant alone had only a moderate effect. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie

  5. Microalgae lipid characterization.

    PubMed

    Yao, Linxing; Gerde, Jose A; Lee, Show-Ling; Wang, Tong; Harrata, Kamel A

    2015-02-18

    To meet the growing interest of utilizing microalgae biomass in the production of biofuels and nutraceutical and pharmaceutical lipids, we need suitable analytical methods and a comprehensive database for their lipid components. The objective of the present work was to demonstrate methodology and provide data on fatty acid composition, lipid class content and composition, characteristics of the unsaponifiables, and type of chlorophylls of five microalgae. Microalgae lipids were fractionated into TAG, FFA, and polar lipids using TLC, and the composition of fatty acids in total lipids and in each lipid class, hydrocarbons, and sterols were determined by GC-MS. Glyco- and phospholipids were profiled by LC/ESI-MS. Chlorophylls and their related metabolites were qualified by LC/APCI-MS. The melting and crystallization profiles of microalgae total lipids and their esters were analyzed by DSC to evaluate their potential biofuel applications. Significant differences and complexities of lipid composition among the algae tested were observed. The compositional information is valuable for strain selection, downstream biomass fractionation, and utilization.

  6. Lipid Quality in Infant Nutrition: Current Knowledge and Future Opportunities

    PubMed Central

    Delplanque, Bernadette; Gibson, Robert; Koletzko, Berthold; Lapillonne, Alexandre; Strandvik, Birgitta

    2015-01-01

    Abstract Dietary lipids are key for infants to not only meet their high energy needs but also fulfill numerous metabolic and physiological functions critical to their growth, development, and health. The lipid composition of breast milk varies during lactation and according to the mother's diet, whereas the lipid composition of infant formulae varies according to the blend of different fat sources. This report compares the compositions of lipids in breast milk and infant formulae, and highlights the roles of dietary lipids in term and preterm infants and their potential biological and health effects. The major differences between breast milk and formulae lie in a variety of saturated fatty acids (such as palmitic acid, including its structural position) and unsaturated fatty acids (including arachidonic acid and docosahexaenoic acid), cholesterol, and complex lipids. The functional outcomes of these differences during infancy and for later child and adult life are still largely unknown, and some of them are discussed, but there is consensus that opportunities exist for improvements in the qualitative lipid supply to infants through the mother's diet or infant formulae. Furthermore, research is required in several areas, including the needs of term and preterm infants for long-chain polyunsaturated fatty acids, the sites of action and clinical effects of lipid mediators on immunity and inflammation, the role of lipids on metabolic, neurological, and immunological outcomes, and the mechanisms by which lipids act on short- and long-term health. PMID:25883056

  7. Identification and occurrence of analogues of dechlorane 604 in Lake Ontario sediment and their accumulation in fish.

    PubMed

    Shen, Li; Jobst, Karl J; Reiner, Eric J; Helm, Paul A; McCrindle, Robert; Taguchi, Vince Y; Marvin, Chris H; Backus, Sean; MacPherson, Karen A; Brindle, Ian D

    2014-10-07

    The dechlorane family of flame retardants, which includes Mirex (also known as Dechlorane), Dechlorane Plus (DP), and Dechloranes (Dec) 602, 603, and 604, were manufactured at a facility along the Niagara River, upstream of Lake Ontario. Some of these compounds remain in use. In a previous study, we found Mirex and Dec602 to have greater bioaccumulation potentials than Dec604 and DP based on calculated biota-sediment accumulation factors (BSAFs). In this study, analogues of Dec604, containing fewer bromines and mixed substitutions of bromine and chlorine, were identified in Lake Ontario sediment and fish using high and ultrahigh resolution mass spectrometric techniques. The tribromo-Dec604 (Br3Dec604) analogue, known as Dechlorane 604 Component B (Dec604 CB), was present in lake trout and whitefish at concentrations of 10-60 ng/g lipid weight, approximately 50-200 times greater than concentrations measured for Dec604. In addition, BrDec604 and Br2Dec604 analogues, and mixed Br2Cl2Dec604, Br3ClDec604, Br2ClDec604, and BrCl2Dec604 analogues were also present. We have shown that solutions of Dec604 and Dec604 CB exposed to UV-light undergo photodebromination and give rise to the analogues found in sediment and fish. Dec604 CB and other lesser halogenated analogues of Dec604 show greater bioaccumulation potentials than Dec604, Dec602 and DP, based on BSAFs, which highlight the need to consider likely impurities and degradation products in the assessment of persistent, bioaccumulative, and toxic compounds.

  8. Langmuir-Blodgett films of fluorinated glycolipids and polymerizable lipids and their phase separating behavior.

    PubMed

    Scheibe, Patrick; Schoenhentz, Jerome; Platen, Tobias; Hoffmann-Röder, Anja; Zentel, Rudolf

    2010-12-07

    This paper describes the phase separating behavior of Langmuir monolayers from mixtures of different lipids that (i) either carry already a glycopeptide recognition site or can be easily modified to carry one and (ii) polymerizable lipids. To ensure demixing during compression, we used fluorinated lipids for the biological headgroups and hydrocarbon based lipids as polymerizable lipids. As a representative for a lipid monomer, which can be polymerized in the hydrophilic headgroup, a methacrylic monomer was used. As a monomer, which can be polymerized in the hydrophobic tail, a lipid with a diacetylene unit was used (pentacosadiynoic acid, PDA). The fluorinated lipids were on the one hand a perfluorinated lipid with three chains and on the other hand a partially fluorinated lipid with a T(N)-antigen headgroup. The macroscopic phase separation was observed by Brewster angle microscopy, whereas the phase separation on the nanoscale level was observed by atomic force microscopy. It turned out that all lipid mixtures showed (at least) a partial miscibility of the hydrocarbon compounds in the fluorinated compounds. This is positive for pattern formation, as it allows the formation of small demixed 2D patterned structures during crystallization from the homogeneous phase. For miscibility especially a liquid analogue phase proved to be advantageous. As lipid 3 with three fluorinated lipid chains (very stable monolayer) is miscible with the polymerizable lipids 1 and 2, it was mostly used for further investigations. For all three lipid mixtures, a phase separation on both the micrometer and the nanometer level was observed. The size of the crystalline domains could be controlled not only by varying the surface pressure but also by varying the molar composition of the mixtures. Furthermore, we showed that the binary mixture can be stabilized via UV polymerization. After polymerization and subsequent expansion of the barriers, the locked-in polymerized structures are stable

  9. Lipid substrate specificity of phosphatidylethanolamine N-methyltransferase of Tetrahymena

    SciTech Connect

    Smith, J.D.

    1986-05-01

    The ciliate protozoan Tetrahymena thermophila forms about 60% of its phosphatidylcholine by methylation of phosphatidylethanolamine with S-adenosylmethionine using the enzyme phosphatidylethanolamine N-methyltransferase. Analogues of ethanolamine or of ethanolamine phosphate are incorporated into the phospholipids of Tetrahymena when cells are cultured in their presence. These compounds, 3-amino-1-propanol, 2-aminoethylphosphonate, 3-aminopropylphosphonate and N,N-dimethylaminoethylphosphonate replace from 50 to 75% of the ethanolamine phosphate in phosphatidylethanolamine. However, analysis of the phospholipids of lipid-altered Tetrahymena showed that none of the phosphatidylethanolamine analogues had been converted to the corresponding phosphatidylcholine analogue. No incorration of (/sup 14/C-CH/sub 3/)methionine into the phosphatidylcholine analogues could be demonstrated in vivo, nor was label from (/sup 3/H-CH/sub 3/)S-adenosylmethionine incorporated in virto. Thus, only phosphatidylethanolamine and its monomethyl and dimethyl derivatives have been found to be substrates for the phosphatidylethanoiamine N-methyltransferase. The enzyme therefore requires a phospholipid substrate containing an ester linkage between the alkylamine and phosphorus, with the amino group required to be ..beta.. to the alcohol.

  10. Analogues of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) as potential anti-platelet-aggregation agents.

    PubMed Central

    Zamecnik, P C; Kim, B; Gao, M J; Taylor, G; Blackburn, G M

    1992-01-01

    Dense granules of platelets contain a high content of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A). We have previously demonstrated an antithrombotic effect of this compound in a live rabbit model. In the present study we find that certain synthetic Ap4A analogues are superior to Ap4A in inhibiting ADP-induced aggregation of human platelets. Analogues having a P--C--P bridge located in the P2,P3 position of Ap4A are the most potent inhibitors. These analogues are also resistant to hydrolytic enzymes. Analogues having the above characteristics exhibit competitive inhibition with ADP in the ADP-induced platelet aggregation reaction. These compounds, such as AppCHFppA, may be useful as antithrombotic agents. The analogues ApSppSpA and ApSpCHFpSpA also showed good inhibitory effects on ADP-induced platelet aggregation. In addition, this action of Ap4A and its analogues provides an example of a dinucleotide inducing an antagonistic effect by occupying an extracellular mononucleotide binding site on platelets. It calls attention to the possibility that Ap4A and its analogues may act in a similar way in whole organisms, triggering effector or inhibitory responses in any one of a variety of cells. PMID:1549600

  11. Lipid Droplets And Cellular Lipid Metabolism

    PubMed Central

    Walther, Tobias C.; Farese, Robert V.

    2013-01-01

    Among organelles, lipid droplets (LDs) uniquely constitute a hydrophobic phase in the aqueous environment of the cytosol. Their hydrophobic core of neutral lipids stores metabolic energy and membrane components, making LDs hubs for lipid metabolism. In addition, LDs are implicated in a number of other cellular functions, ranging from protein storage and degradation to viral replication. These processes are functionally linked to many physiological and pathological conditions, including obesity and related metabolic diseases. Despite their important functions and nearly ubiquitous presence in cells, many aspects of LD biology are unknown. In the past few years, the pace of LD investigation has increased, providing new insights. Here, we review the current knowledge of LD cell biology and its translation to physiology. PMID:22524315

  12. Lipids and lipid metabolism in eukaryotic algae.

    PubMed

    Guschina, Irina A; Harwood, John L

    2006-03-01

    Eukaryotic algae are a very diverse group of organisms which inhabit a huge range of ecosystems from the Antarctic to deserts. They account for over half the primary productivity at the base of the food chain. In recent years studies on the lipid biochemistry of algae has shifted from experiments with a few model organisms to encompass a much larger number of, often unusual, algae. This has led to the discovery of new compounds, including major membrane components, as well as the elucidation of lipid signalling pathways. A major drive in recent research have been attempts to discover genes that code for expression of the various proteins involved in the production of very long-chain polyunsaturated fatty acids such as arachidonic, eicosapentaenoic and docosahexaenoic acids. Such work is described here together with information about how environmental factors, such as light, temperature or minerals, can change algal lipid metabolism and how adaptation may take place.

  13. Polyamine analogues bind human serum albumin.

    PubMed

    Beauchemin, R; N'soukpoé-Kossi, C N; Thomas, T J; Thomas, T; Carpentier, R; Tajmir-Riahi, H A

    2007-10-01

    Polyamine analogues show antitumor activity in experimental models, and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues, such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333), in aqueous solution at physiological conditions using a constant protein concentration and various polyamine contents (microM to mM). FTIR, UV-visible, and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind nonspecifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 x 10(3) M(-1), KBE-333 = 5.63 x 10(2) M(-1), and KBE-3333 = 3.66 x 10(2) M(-1). The protein secondary structure showed major alterations with a reduction of alpha-helix from 55% (free protein) to 43-50% and an increase of beta-sheet from 17% (free protein) to 29-36% in the 333, BE-333, and BE-3333 complexes, indicating partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues compared to those of the biogenic polyamines.

  14. The Lehmer Matrix and Its Recursive Analogue

    DTIC Science & Technology

    2010-01-01

    for failing to comply with a collection of information if it does not display a currently valid OMB control number . 1. REPORT DATE 2010 2. REPORT...TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE The Lehmer matrix and its recursive analogue 5a. CONTRACT NUMBER 5b...GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND

  15. New synthetic approaches towards analogues of bedaquiline.

    PubMed

    Priebbenow, Daniel L; Barbaro, Lisa; Baell, Jonathan B

    2016-10-12

    Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

  16. Conformationally constrained analogues of L-prolyl-l-leucylglycinamide

    SciTech Connect

    Yu, K.L.

    1986-01-01

    The tripeptide, L-prolyl-L-leucylglycinamide (PLG), has been shown to modulate the pharmacological response of the neurotransmitter, dopamine, in the central nervous system. Many physical studies have suggested that PLG can exist in a type II ..beta..-bend conformation. In this study several types of conformationally constrained analogues capable of mimicking different types of conformations of PLG have been designed to answer two questions: (1) Is the type II ..beta..-bend the bioactive conformation of PLG. (2) Does the Leu-Gly amide bond of PLG need to be in a cis or trans configuration in order for it to bind to its receptor. The analogues of PLG that have been synthesized include the following: (1) Lactam analogues, (2) Cyclic peptides, (3) Olefinic analogue, and (4) Tetazole analogues. The analogues synthesized were tested in a (/sup 3/H)-ADTN binding assay to determine their ability to enhance the binding of this dopamine agonist to dopamine receptors.

  17. Lipids in DDGS

    USDA-ARS?s Scientific Manuscript database

    Distillers dried grains with soluble (DDGS) are one of the main coproducts of ethanol production from using the dry-grinding process. The lipids from corn or sorghum are not utilized in ethanol production, and are thus concentrated in DDGS. The main lipid components in corn and sorghum DDGS are tr...

  18. Lipids: Absorption and transport

    USDA-ARS?s Scientific Manuscript database

    Lipid has long been recognized as an important dietary component. Dietary lipid (fat) is a critical source of metabolic energy and a substrate for the synthesis of metabolically active compounds (essential fatty acids), and serves as a carrier for other nutrients such as the fat-soluble vitamins A, ...

  19. Introduction to membrane lipids.

    PubMed

    Epand, Richard M

    2015-01-01

    Biological membranes are composed largely of lipids and proteins. The most common arrangement of lipids in biological membranes is as a bilayer. This arrangement spontaneously forms a barrier for the passage of polar materials. The bilayer is thin but can have a large area in the dimension perpendicular to its thickness. The physical nature of the bilayer membrane will vary according to the conditions of the environment as well as the chemical structure of the lipid constituents of the bilayer. These physical properties determine the function of the membrane together with specific structural features of the lipids that allow them to have signaling properties. The lipids of the membrane are not uniformly distributed. There is an intrinsic asymmetry between the two monolayers that constitute the bilayer. In addition, some lipids tend to be enriched in particular regions of the membrane, termed domains. There is evidence that certain domains recruit specific proteins into that domain. This has been suggested to be important for allowing interaction among different proteins involved in certain signal transduction pathways. Membrane lipids have important roles in determining the physical properties of the membrane, in modulating the activity of membrane-bound proteins and in certain cases being specific secondary messengers that can interact with specific proteins. A large variety of lipids present in biological membranes result in them possessing many functions.

  20. Critical amino acid residues of maurocalcine involved in pharmacology, lipid interaction and cell penetration.

    PubMed

    Mabrouk, Kamel; Ram, Narendra; Boisseau, Sylvie; Strappazzon, Flavie; Rehaim, Amel; Sadoul, Rémy; Darbon, Hervé; Ronjat, Michel; De Waard, Michel

    2007-10-01

    Maurocalcine (MCa) is a 33-amino acid residue peptide that was initially identified in the Tunisian scorpion Scorpio maurus palmatus. This peptide triggers interest for three main reasons. First, it helps unravelling the mechanistic basis of Ca(2+) mobilization from the sarcoplasmic reticulum because of its sequence homology with a calcium channel domain involved in excitation-contraction coupling. Second, it shows potent pharmacological properties because of its ability to activate the ryanodine receptor. Finally, it is of technological value because of its ability to carry cell-impermeable compounds across the plasma membrane. Herein, we characterized the molecular determinants that underlie the pharmacological and cell-penetrating properties of maurocalcine. We identify several key amino acid residues of the peptide that will help the design of cell-penetrating analogues devoid of pharmacological activity and cell toxicity. Close examination of the determinants underlying cell penetration of maurocalcine reveals that basic amino acid residues are required for an interaction with negatively charged lipids of the plasma membrane. Maurocalcine analogues that penetrate better have also stronger interaction with negatively charged lipids. Conversely, less effective analogues present a diminished ability to interact with these lipids. These findings will also help the design of still more potent cell penetrating analogues of maurocalcine.

  1. Charge Isomers of Myelin Basic Protein: Structure and Interactions with Membranes, Nucleotide Analogues, and Calmodulin

    PubMed Central

    Wang, Chaozhan; Neugebauer, Ute; Bürck, Jochen; Myllykoski, Matti; Baumgärtel, Peter; Popp, Jürgen; Kursula, Petri

    2011-01-01

    As an essential structural protein required for tight compaction of the central nervous system myelin sheath, myelin basic protein (MBP) is one of the candidate autoantigens of the human inflammatory demyelinating disease multiple sclerosis, which is characterized by the active degradation of the myelin sheath. In this work, recombinant murine analogues of the natural C1 and C8 charge components (rmC1 and rmC8), two isoforms of the classic 18.5-kDa MBP, were used as model proteins to get insights into the structure and function of the charge isomers. Various biochemical and biophysical methods such as size exclusion chromatography, calorimetry, surface plasmon resonance, small angle X-ray and neutron scattering, Raman and fluorescence spectroscopy, and conventional as well as synchrotron radiation circular dichroism were used to investigate differences between these two isoforms, both from the structural point of view, and regarding interactions with ligands, including calmodulin (CaM), various detergents, nucleotide analogues, and lipids. Overall, our results provide further proof that rmC8 is deficient both in structure and especially in function, when compared to rmC1. While the CaM binding properties of the two forms are very similar, their interactions with membrane mimics are different. CaM can be used to remove MBP from immobilized lipid monolayers made of synthetic lipids - a phenomenon, which may be of relevance for MBP function and its regulation. Furthermore, using fluorescently labelled nucleotides, we observed binding of ATP and GTP, but not AMP, by MBP; the binding of nucleoside triphosphates was inhibited by the presence of CaM. Together, our results provide important further data on the interactions between MBP and its ligands, and on the differences in the structure and function between MBP charge isomers. PMID:21647440

  2. Mitochondrial lipids in neurodegeneration.

    PubMed

    Aufschnaiter, Andreas; Kohler, Verena; Diessl, Jutta; Peselj, Carlotta; Carmona-Gutierrez, Didac; Keller, Walter; Büttner, Sabrina

    2017-01-01

    Mitochondrial dysfunction is a common feature of many neurodegenerative diseases, including proteinopathies such as Alzheimer's or Parkinson's disease, which are characterized by the deposition of aggregated proteins in the form of insoluble fibrils or plaques. The distinct molecular processes that eventually result in mitochondrial dysfunction during neurodegeneration are well studied but still not fully understood. However, defects in mitochondrial fission and fusion, mitophagy, oxidative phosphorylation and mitochondrial bioenergetics have been linked to cellular demise. These processes are influenced by the lipid environment within mitochondrial membranes as, besides membrane structure and curvature, recruitment and activity of different proteins also largely depend on the respective lipid composition. Hence, the interaction of neurotoxic proteins with certain lipids and the modification of lipid composition in different cell compartments, in particular mitochondria, decisively impact cell death associated with neurodegeneration. Here, we discuss the relevance of mitochondrial lipids in the pathological alterations that result in neuronal demise, focussing on proteinopathies.

  3. Idiopathic bilateral lipid keratopathy.

    PubMed Central

    Alfonso, E.; Arrellanes, L.; Boruchoff, S. A.; Ormerod, L. D.; Albert, D. M.

    1988-01-01

    A 52-year-old Mexican man presented with asymptomatic, bilaterally symmetrical lipid infiltrates of the cornea and adjacent limbus. No evidence of previous ocular disease or systemic disorder of lipid metabolism could be detected. Penetrating keratoplasty of the right eye was required. The cornea was rigid and thick, with posterior bulging into the anterior chamber. Light microscopy revealed deep corneal lipid granules, foamy histiocytes, vascularisation, and chronic non-granulomatous inflammation. Transmission electron microscopy showed extracellular lipid spaces and numerous intracytoplasmic lipid vacuoles in histiocytes, keratocytes, conjunctival epithelium, and the endothelium of blood vessels in the corneal stroma and adjacent limbal conjunctiva. Histochemical analysis revealed the presence of neutral fats, free fatty acids, cholesterol, and phospholipids. Images PMID:3395592

  4. Membranes: a meeting point for lipids, proteins and therapies.

    PubMed

    Escribá, Pablo V; González-Ros, José M; Goñi, Félix M; Kinnunen, Paavo K J; Vigh, Lászlo; Sánchez-Magraner, Lissete; Fernández, Asia M; Busquets, Xavier; Horváth, Ibolya; Barceló-Coblijn, Gwendolyn

    2008-06-01

    Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio-temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co-/post-translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.

  5. Membranes: a meeting point for lipids, proteins and therapies

    PubMed Central

    Escribá, Pablo V; González-Ros, José M; Goñi, Félix M; Kinnunen, Paavo K J; Vigh, Lászlo; Sánchez-Magraner, Lissete; Fernández, Asia M; Busquets, Xavier; Horváth, Ibolya; Barceló-Coblijn, Gwendolyn

    2008-01-01

    Abstract Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio-temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co-/post-translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy. PMID:18266954

  6. The role of interfacial lipids in stabilizing membrane protein oligomers.

    PubMed

    Gupta, Kallol; Donlan, Joseph A C; Hopper, Jonathan T S; Uzdavinys, Povilas; Landreh, Michael; Struwe, Weston B; Drew, David; Baldwin, Andrew J; Stansfeld, Phillip J; Robinson, Carol V

    2017-01-19

    Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways but is often difficult to define or predict. Here we report the development of a mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125 α-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT, one of the proteins with the lowest oligomeric stability), we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na(+)/H(+) antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of α-helical membrane proteins, including G-protein-coupled receptors.

  7. The role of interfacial lipids in stabilising membrane protein oligomers

    PubMed Central

    Uzdavinys, Povilas; Landreh, Michael; Struwe, Weston B.; Drew, David; Baldwin, Andrew J.; Stansfeld, Phillip J.; Robinson, Carol V.

    2017-01-01

    Oligomerisation of membrane proteins in response to lipid binding plays a critical role in many cell-signaling pathways 1 but is often difficult to define 2 or predict 3. Here we develop a mass spectrometry platform to determine simultaneously presence of interfacial lipids and oligomeric stability and discover how lipids act as key regulators of membrane protein association. Evaluation of oligomeric strength for a dataset of 125 α-helical oligomeric membrane proteins revealed an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT) 4 one of the proteins with the lowest oligomeric stability, we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid binding sites or expression in cardiolipin (CDL) deficient Escherichia coli, abrogated dimer formation. Molecular dynamics simulation revealed that CDL acts as a bidentate ligand bridging across subunits. Subsequently, we show that for the sugar transporter SemiSWEET from Vibrio splendidus 5, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesised that lipids would be essential for dimerisation of the Na+/H+ antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for substantially more stable, homologous NapA from Thermus thermophilus. We found that lipid binding is obligatory for dimerisation of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of α-helical membrane proteins, including GPCRs. PMID:28077870

  8. U.S. Nuclear Regulatory Commission natural analogue research program

    SciTech Connect

    Kovach, L.A.; Ott, W.R.

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  9. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Cordatos, Harry

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  10. Balancing Act

    ERIC Educational Resources Information Center

    Kennedy, Mike

    2007-01-01

    For some administrators and planners, designing and building education facilities may sometimes seem like a circus act--trying to project a persona of competence and confidence while juggling dozens of issues. Meanwhile, the audience--students, staff members and taxpayers--watch and wait with anticipation in hopes of getting what they paid for and…

  11. Balancing Act

    ERIC Educational Resources Information Center

    Kennedy, Mike

    2007-01-01

    For some administrators and planners, designing and building education facilities may sometimes seem like a circus act--trying to project a persona of competence and confidence while juggling dozens of issues. Meanwhile, the audience--students, staff members and taxpayers--watch and wait with anticipation in hopes of getting what they paid for and…

  12. Synthesis of a cyanopeptide-analogue with trypsin activating properties.

    PubMed

    Radau, G; Rauh, D

    2000-04-17

    An efficient synthesis of a peptidic analogue of cyanobacterial metabolites with proposed serine protease inhibitory activity has been developed. Surprisingly, one trypsin activating compound was obtained.

  13. Intracellular accumulation of potent amiloride analogues by human neutrophils

    SciTech Connect

    Simchowitz, L.; Woltersdorf, O.W. Jr.; Cragoe, E.J. Jr.

    1987-11-25

    The mechanism of uptake of a series of amiloride derivatives by human neutrophils was investigated using (/sup 14/C)amiloride and the /sup 14/C-labeled 5-(1-hexahydroazepinyl)-6-bromo analogue (BrMM) which is approximately 500-fold more potent than the parent compound at inhibiting Na+/H+ exchange. At an external concentration of 2 microM, the influx of BrMM at 37 degrees C was rapid, reaching a steady state by approximately 20 min. The rate of BrMM uptake (approximately 25 mumol/liter.min) was approximately 90-fold faster than for the same concentration of amiloride, a finding which correlates with differences in lipid partitioning of the two compounds. Uptake was unrelated to specific binding to Na+/H+ exchange transport sites: influx of either drug was nonsaturable whereas amiloride- and BrMM-mediated inhibition of Na+/H+ countertransport obeyed Michaelis-Menten kinetics with apparent Ki values of approximately 75 and approximately 0.2 microM. Entry occurred exclusively via the neutral (uncharged) forms (pK'a 8.40-8.55). Influx was markedly pH-dependent: it was enhanced by extracellular alkalinization and reduced by acidification. Influx was, however, insensitive to large changes in membrane voltage, thereby implying the protonated (charged) species to be impermeant. About 75% of the total intracellular pool of amiloride, but only approximately 25% of BrMM, is contained within the lysosomes, an expected consequence of the partitioning and subsequent trapping of a weak base within this strongly acidic subcellular compartment. With BrMM, there was a relative approximately 60-fold enrichment in the internal/external water concentration ratio of the drug; the value for amiloride was much less, approximately 4. This disparity is consistent with substantial binding of BrMM to internal constituents, presumably to proteins and/or nucleic acids.

  14. Self-Powered Analogue Smart Skin.

    PubMed

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity.

  15. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  16. Role of Cosmic Dust Analogues in prebiotic chemistry

    NASA Astrophysics Data System (ADS)

    Brucato, J. R.; Strazzulla, G.; Baratta, G. A.; Saladino, R.; di Mauro, E.

    Dust grains could have played an important role in driving the formation of complex molecular compounds relevant for the prebiotic chemistry occurred in the early Earth. Dust and molecular compounds present in space experienced very different environments, with temperatures ranging from few to thousands of Kelvins, and with very harsh conditions due to particle and UV irradiations. Astronomical observations of the interstellar medium, coupled with direct in-situ investigations of solar system bodies performed by space missions and laboratory analyses of extraterrestrial material have shown the presence of large amount of organic molecules. The detection of more than one hundred molecules demonstrates that chemical reactions can proceed successfully in space. However, due to low efficiency, formation of complex molecules in gas phase is not feasible, then an active chemistry has been suggested to take place at cryogenic temperatures (~10 K) on cosmic dust grains acting as catalysts. We will present laboratory results on catalytic effects of Cosmic Dust Analogues (CDAs) with olivine composition, in the synthesis of organic molecules under different physical conditions by using formamide (NH2COH). We will show the important role of CDAs in prebiotic chemistry experiments simulating processes occurring in astronomical environments relevant for the origin of life in the Solar System.

  17. Molecular mechanisms underlying a cellular analogue of operant reward learning

    PubMed Central

    Lorenzetti, Fred D.; Baxter, Douglas A.; Byrne, John H.

    2008-01-01

    SUMMARY Operant conditioning is a ubiquitous but mechanistically poorly understood form of associative learning in which an animal learns the consequences of its behavior. Using a single-cell analogue of operant conditioning in neuron B51 of Aplysia, we examined second-messenger pathways engaged by activity and reward and how they may provide a biochemical association underlying operant learning. Conditioning was blocked by Rp-cAMP, a peptide inhibitor of PKA, a PKC inhibitor and by expressing a dominant negative isoform of Ca2+-dependent PKC (apl-I). Thus, both PKA and PKC were necessary for operant conditioning. Injection of cAMP into B51 mimicked the effects of operant conditioning. Activation of PKC also mimicked conditioning, but was dependent on both cAMP and PKA, suggesting that PKC acted at some point upstream of PKA activation. Our results demonstrate how these molecules can interact to mediate operant conditioning in an individual neuron important for the expression of the conditioned behavior. PMID:18786364

  18. Curvature-induced lipid segregation

    NASA Astrophysics Data System (ADS)

    Zheng, Bin; Meng, Qing-Tian; B. Selinger Robin, L.; V. Selinger, Jonathan; Ye, Fang-Fu

    2015-06-01

    We investigate how an externally imposed curvature influences lipid segregation on two-phase-coexistent membranes. We show that the bending-modulus contrast of the two phases and the curvature act together to yield a reduced effective line tension. On largely curved membranes, a state of multiple domains (or rafts) forms due to a mechanism analogous to that causing magnetic-vortex formation in type-II superconductors. We determine the criterion for such a multi-domain state to occur; we then calculate respectively the size of the domains formed on cylindrically and spherically curved membranes. Project supported by the Hundred-Talent Program of the Chinese Academy of Sciences (FY) and the National Science Foundation of USA via Grant DMR-1106014 (RLBS, JVS).

  19. Imaging of blood plasma coagulation at supported lipid membranes.

    PubMed

    Faxälv, Lars; Hume, Jasmin; Kasemo, Bengt; Svedhem, Sofia

    2011-12-15

    The blood coagulation system relies on lipid membrane constituents to act as regulators of the coagulation process upon vascular trauma, and in particular the 2D configuration of the lipid membranes is known to efficiently catalyze enzymatic activity of blood coagulation factors. This work demonstrates a new application of a recently developed methodology to study blood coagulation at lipid membrane interfaces with the use of imaging technology. Lipid membranes with varied net charges were formed on silica supports by systematically using different combinations of lipids where neutral phosphocholine (PC) lipids were mixed with phospholipids having either positively charged ethylphosphocholine (EPC), or negatively charged phosphatidylserine (PS) headgroups. Coagulation imaging demonstrated that negatively charged SiO(2) and membrane surfaces exposing PS (obtained from liposomes containing 30% of PS) had coagulation times which were significantly shorter than those for plain PC membranes and EPC exposing membrane surfaces (obtained from liposomes containing 30% of EPC). Coagulation times decreased non-linearly with increasing negative surface charge for lipid membranes. A threshold value for shorter coagulation times was observed below a PS content of ∼6%. We conclude that the lipid membranes on solid support studied with the imaging setup as presented in this study offers a flexible and non-expensive solution for coagulation studies at biological membranes. It will be interesting to extend the present study towards examining coagulation on more complex lipid-based model systems. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Peripheral gating of pain signals by endogenous analgesic lipids

    PubMed Central

    Piomelli, Daniele; Sasso, Oscar

    2014-01-01

    Primary sensory afferents and their neighboring host-defense cells are a rich source of lipid-derived mediators that contribute to the sensation of pain caused by tissue damage and inflammation. But an increasing number of lipid molecules have been shown to act in an opposite way, to suppress the inflammatory process, restore homeostasis in damaged tissues and attenuate pain sensitivity by regulating neural pathways that transmit nociceptive signals from the periphery of the body to the central nervous system. PMID:24473264

  1. Regulation of lipid droplet turnover by ubiquitin ligases.

    PubMed

    Alberts, Philipp; Rotin, Daniela

    2010-07-19

    Mutation of the protein spartin is a cause of one form of spastic paraplegia. Spartin interacts with ubiquitin ligases of the Nedd4 family, and a recent report in BMC Biology now shows that it acts as an adaptor to recruit and activate the ubiquitin ligase AIP4 onto lipid droplets, leading to the ubiquitination and degradation of droplet-associated proteins. A deficiency of spartin apparently causes lipid droplets to accumulate.

  2. Synthesis of Lipidated Proteins.

    PubMed

    Mejuch, Tom; Waldmann, Herbert

    2016-08-17

    Protein lipidation is one of the major post-translational modifications (PTM) of proteins. The attachment of the lipid moiety frequently determines the localization and the function of the lipoproteins. Lipidated proteins participate in many essential biological processes in eukaryotic cells, including vesicular trafficking, signal transduction, and regulation of the immune response. Malfunction of these cellular processes usually leads to various diseases such as cancer. Understanding the mechanism of cellular signaling and identifying the protein-protein and protein-lipid interactions in which the lipoproteins are involved is a crucial task. To achieve these goals, fully functional lipidated proteins are required. However, access to lipoproteins by means of standard expression is often rather limited. Therefore, semisynthetic methods, involving the synthesis of lipidated peptides and their subsequent chemoselective ligation to yield full-length lipoproteins, were developed. In this Review we summarize the commonly used methods for lipoprotein synthesis and the development of the corresponding chemoselective ligation techniques. Several key studies involving full-length semisynthetic lipidated Ras, Rheb, and LC3 proteins are presented.

  3. Lipids of Debaryomyces hansenii

    PubMed Central

    Merdinger, Emanuel; Devine, Edward M.

    1965-01-01

    Merdinger, Emanuel (Roosevelt University, Chicago, Ill.), and Edward M. Devine, Jr. Lipids of Debaryomyces hansenii. J. Bacteriol. 89:1488–1493. 1965.—The separation of neutral lipids and phospholipids from the lipid extract of Debaryomyces hansenii NRRL Y-1448 was accomplished by using a single column packed with silicic acid. The neutral lipids comprised 67%, and the phospholipids 33%, of the total lipid extract. Qualitative and quantitative characterization of the lipids was effected by various analytical procedures. Gas chromatography of the fatty acid methyl esters showed 11 acids, of which 59.7% were unsaturated. The most abundant among the unsaturated acids was the monounsaturated C18 acid (50.1%). Among the saturated acids, palmitic acid (23.5%) prevailed. Ratios of fatty acid to glycerol, phosphorus to glycerol, and phosphorus to fatty acid were ascertained for combined cuts from the neutral lipids and the phospholipids. The presence of ergosterol, stigmasterol, and an unidentified sterol was established by gas chromatography. Also present were saturated hydrocarbons containing 16 to 39 carbon atoms, C22 being the most prevalent. PMID:14291585

  4. Lipid-absorbing Polymers

    NASA Technical Reports Server (NTRS)

    Marsh, H. E., Jr.; Wallace, C. J.

    1973-01-01

    The removal of bile acids and cholesterol by polymeric absorption is discussed in terms of micelle-polymer interaction. The results obtained with a polymer composed of 75 parts PEO and 25 parts PB plus curing ingredients show an absorption of 305 to 309%, based on original polymer weight. Particle size effects on absorption rate are analyzed. It is concluded that crosslinked polyethylene oxide polymers will absorb water, crosslinked polybutadiene polymers will absorb lipids; neither polymer will absorb appreciable amounts of lipids from micellar solutions of lipids in water.

  5. [Lipid formulations of amphotericin].

    PubMed

    Botero, Martha C; Puentes-Herrera, Marcela; Cortés, Jorge A

    2014-10-01

    Amphotericin B deoxycholate use has increased during the past years in parallel with the increase in the number of immunosuppressed patients suffering invasive fungal infections. This drug is associated with a high rate of side effects, especially renal toxicity. Lipid formulations (liposomal, lipid complex, colloidal suspension and the Indian liposomal formulation) have been developed, which share the same antifungal spectrum but differ in efficacy and toxicity. A review of amphotericin lipid formulations is presented, focusing on differences in efficacy and, especially renal toxicity. The main problem for use of these formulations in Latin America is their highcost.

  6. Lake Superior lipids

    EPA Pesticide Factsheets

    Fish chemistry data (d13C, d15N, C:N, lipid content) published in Rapid Commun. Mass Spectrom. 2015, 29, 2069??2077 DOI: 10.1002/rcm.7367This dataset is associated with the following publication:Hoffman , J., M. Sierszen , and A. Cotter. Fish tissue lipid-C:N relationships for correcting ä13C values and estimating lipid content in aquatic food web studies. Rapid Communications in Mass Spectrometry. Wiley InterScience, Silver Spring, MD, USA, 29(21): 2069–2077, (2015).

  7. Effects of insulin and other antihyperglycaemic agents on lipid profiles of patients with diabetes.

    PubMed

    Chaudhuri, A; Dandona, P

    2011-10-01

    Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases is partly associated with hyperglycaemia as well as dyslipidaemia. Pharmacological treatment of diabetic hyperglycaemia involves the use of the older oral antidiabetic drugs [OADs: biguanides, sulphonylureas (SUs), α-glucosidase inhibitors and thiazolidinediones], insulin (human and analogues) and/or incretin-based therapies (glucagon-like peptide-1 analogues and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to improve lipid profiles in patients with diabetes. These effects may have benefits on cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of OADs, insulins and incretin-based therapies on lipid variables along with the possible mechanisms and clinical implications of these findings. The effects of intensive versus conventional antihyperglycaemic therapy on cardiovascular outcomes and lipid profiles are also discussed. A major conclusion of this review is that agents within the same class of OADs can have different effects on lipid variables and that contrary to the findings in experimental models, insulin has been shown to have beneficial effects on lipid variables in clinical trials. Further studies are needed to understand the precise effect and the mechanisms of these effects of insulin on lipids.

  8. Lipid binding and membrane penetration of polymyxin B derivatives studied in a biomimetic vesicle system.

    PubMed Central

    Katz, Marina; Tsubery, Haim; Kolusheva, Sofiya; Shames, Alex; Fridkin, Mati; Jelinek, Raz

    2003-01-01

    Understanding membrane interactions and cell-wall permeation of Gram-negative bacteria is of great importance, owing to increasing bacterial resistance to existing drugs and therapeutic treatments. Here we use biomimetic lipid vesicles to analyse membrane association and penetration by synthetic derivatives of polymyxin B (PMB), a potent naturally occurring antibacterial cyclic peptide. The PMB analogues studied were PMB nonapeptide (PMBN), in which the hydrophobic alkyl residue was cleaved, PMBN diastereomer containing D-instead of L-amino acids within the cyclic ring (dPMBN) and PMBN where the hydrophobic alkyl chain was replaced with an Ala6 repeat (Ala6-PMBN). Peptide binding measurements, colorimetric transitions induced within the vesicles, fluorescence quenching experiments and ESR spectroscopy were applied to investigate the structural parameters underlying the different membrane-permeation profiles and biological activities of the analogues. The experiments point to the role of negatively charged lipids in membrane binding and confirm the prominence of lipopolisaccharide (LPS) in promoting membrane association and penetration by the peptides. Examination of the lipid interactions of the PMB derivatives shows that the cyclic moiety of PMB is not only implicated in lipid attachment and LPS binding, but also affects penetration into the inner bilayer core. The addition of the Ala6 peptide moiety, however, does not significantly promote peptide insertion into the hydrophobic lipid environment. The data also indicate that the extent of penetration into the lipid bilayer is not related to the overall affinity of the peptides to the membrane. PMID:12848621

  9. A Lipid Gate for the Peripheral Control of Pain

    PubMed Central

    Hohmann, Andrea G.; Seybold, Virginia; Hammock, Bruce D.

    2014-01-01

    Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P450 and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain. PMID:25392487

  10. Role of the extractable lipids and polymeric lipids in sorption of organic contaminants onto plant cuticles.

    PubMed

    Chen, Baoliang; Li, Yungui; Guo, Yiting; Zhu, Lizhong; Schnoor, Jerald L

    2008-03-01

    The distinct role of extractable and polymeric lipids in plant cuticle, precursors of SOM, has received scarce attention to elucidate plant uptake and soil affinity with organic contaminants. Sorption of naphthalene and 1-naphthol to fruit cuticular fractions isolated from two species were investigated. The polarity index, physical conformation, and glass transition temperature (Tg) of these cuticular fractions were characterized by elemental analysis, Fourier transform infrared spectroscopy, and differential scanning calorimetry, respectively. Cutin, a polymeric lipid, is the major sorption medium of the cuticle due to its large mass fraction and liquid-like nature (Tg approximately -30 degrees C). Sorption of cutin is suppressed by the extractable lipids (wax, Tg approximately 44 degrees C) acting as an antiplasticizer (enhance cutin's Tg) over nonpolar contributor. Whereas polysaccharide, as a plasticizer (lower Tg value) and polar contributor, regulates affinity of polymeric lipids (cutin and cutan). The contribution of cutin to sorption by bulk cuticle overshadows the role of waxes, and the sorption capability (K(oc)) of cutin overwhelms the octanol-water partition coefficient (K(ow)). Therefore, uptake of organic contaminants by these plants would be seriously under-predicted by their extractable lipid content and compound's K(ow) values. Along with the observed linear relationships of K(oc) with cutin content in these cuticular fractions, we suggest for the first time that the depolymerizable lipid fraction (cutin) is required to accurately predict plant accumulation of organic contaminants.

  11. Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties.

    PubMed

    Baldisserotto, Anna; Vertuani, Silvia; Bino, Alessia; De Lucia, Daniela; Lampronti, Ilaria; Milani, Roberta; Gambari, Roberto; Manfredini, Stefano

    2015-01-01

    Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis.

  12. Formation of arenicin-1 microdomains in bilayers and their specific lipid interaction revealed by Z-scan FCS.

    PubMed

    Macháň, Radek; Hof, Martin; Chernovets, Tatsiana; Zhmak, Maxim N; Ovchinnikova, Tatiana V; Sýkora, Jan

    2011-04-01

    Z-scan fluorescence correlation spectroscopy (FCS) is employed to characterize the interaction between arenicin-1 and supported lipid bilayers (SLBs) of different compositions. Lipid analogue C8-BODIPY 500/510C5-HPC and ATTO 465 labelled arenicin-1 are used to detect changes in lipid and peptide diffusion upon addition of unlabelled arenicin-1 to SLBs. Arenicin-1 decreases lipid mobility in negatively charged SLBs. According to diffusion law analysis, microdomains of significantly lower lipid mobility are formed. The analysis of peptide FCS data confirms the presence of microdomains for anionic SLBs. No indications of microdomain formation are detected in SLBs composed purely of zwitterionic lipids. Additionally, our FCS results imply that arenicin-1 exists in the form of oligomers and/or aggregates when interacting with membranes of both compositions.

  13. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  14. Slip dynamics in an analogue faultzone

    NASA Astrophysics Data System (ADS)

    Rudolf, Michael; Rosenau, Matthias; Oncken, Onno

    2017-04-01

    Elastic stress in the lithosphere releases through slip along pre-existing planes of weakness (fault zones). Slip events may occur on many spatial and temporal scales. They range from short-term localised seismic slip (earthquakes) to aseismic slip transients and long-term distributed slip in cataclastic or ductile shear zones. The interplay of seismic and aseismic fault slip is poorly understood, potentially complex and very costly to model numerically. Therefore, we designed an analogue experiment using a rate-and-state frictional material (fused glass beads), that shows unstable (seismic) and stable (aseismic) slip. This is embedded in an elastic material (ballistic gelatin) that models upper crustal elastic rebound. In the analogue model presented here, we examine the influence of multiple parameters on the slip dynamics and overall statistics of ruptures within a glass bead shear zone. We use a customised rotary shear apparatus (Schulze ring-shear tester) to monitor shear stress during shear. The apparatus allows a direct control of shear rate and normal stress. Its transparent lid enables concurrent monitoring of the frictional contact surface. Digital image correlation is used to measure on-fault deformation. Because of the rate-and-state frictional properties of glass beads (a-b = -0.0138), the used setup produces regular stick-slip events under certain normal loading and strain rate conditions. Preliminary analysis shows the following: The events feature statistics similar to natural slip systems, i.e. a magnitude distribution similar to single faults. Estimated moment magnitudes of the laboratory earthquakes range from MW = -7 to -6. A Gutenberg-Richter like decay up to a certain corner magnitude followed by a characteristic peak is observable. With decreasing loading rate the recurrence time and size of events increase exponentially with exponents similar to natural events. Rupture dynamics are characterised by a transition from two-dimensional crack

  15. A nonlinear dynamic analogue model of substorms

    NASA Astrophysics Data System (ADS)

    Klimas, A. J.; Baker, D. N.; Roberts, D. A.; Fairfield, D. H.; Büchner, J.

    Linear prediction filter studies have shown that the magnetospheric response to energy transfer from the solar wind contains both directly driven and unloading components. These studies have also shown that the magnetospheric response is significantly nonlinear and, thus, the linear prediction filtering technique and other correlative techniques which assume a linear magnetospheric response cannot give a complete deacription of that response. Here, the solar wind-magnetosphere interaction is discussed within the framework of deterministic nonlinear dynamics. An earlier dripping faucet mechanical analogue to the magnetosphere is first reviewed and then the plasma physical counterpart to the mechanical model is constructed. A Faraday loop in the magnetotail is considered and the relationship of electric potentials on the loop to changes in the magnetic flux threading the loop is developed. This approach leads to a model of geomagnetic activity which is similar to the earlier mechanical model but described in terms of the geometry and plasma contents of the magnetotail. This Faraday loop response model contains analogues to both the directly driven and the storage-release magnetospheric responses and it includes, in a fundamental way, the inherent nonlinearity of the solar wind-magnetosphere system. It can be chancterized as a nonlinear, damped harmonic oscillator that is driven by the loading-unloading substorm cycle. The model is able to explain many of the features of the linear prediction filter results. In particular, at low geomagnetic activity levels the model exbibits the "regular dripping" response which provides an explanation for the unloading component at 1 hour lag in the linear prediction filters. Further, the model suggests that the disappearance of the unloading component in the linear prediction filters at high geomagnetic activity levels is due to a chaotic transition beyond which the loading-unloading mechanism becomes aperiodic. The model predicts

  16. Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain.

    PubMed

    Melo, Tânia; Videira, Romeu A; André, Sónia; Maciel, Elisabete; Francisco, Carla S; Oliveira-Campos, Ana M; Rodrigues, Lígia M; Domingues, Maria R M; Peixoto, Francisco; Manuel Oliveira, M

    2012-03-01

    phosphatidylcholine (PC), PE, phosphatidylinositol (PI) and CL and by the presence of oxidized phosphatidylserines. Additionally, in both the T1 and T2 groups, the lipid content and molecular composition of brain mitochondria PL are perturbed to a lesser extent than in the tacrine group. Abnormalities in CL content and the amount of oxidized phosphatidylserines were associated with significant reductions in mitochondrial enzymes activities, mainly complex I. These results indicate that tacrine and its analogues impair mitochondrial function and bioenergetics, thus compromising the activity of brain cells. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  17. Blood Test: Lipid Panel

    MedlinePlus

    ... HDL) and bad (LDL) cholesterol, as well as triglycerides (a certain type of fat). A lipid panel ... results for your good and bad cholesterol and triglycerides.Good (HDL) cholesterol: Your body needs good cholesterol ...

  18. Lipid-Mediated Endocytosis

    PubMed Central

    Ewers, Helge; Helenius, Ari

    2011-01-01

    Receptor-mediated endocytosis is used by a number of viruses and toxins to gain entry into cells. Some have evolved to use specific lipids in the plasma membrane as their receptors. They include bacterial toxins such as Shiga and Cholera toxin and viruses such as mouse polyoma virus and simian virus 40. Through multivalent binding to glycosphingolipids, they induce lipid clustering and changes in membrane properties. Internalization occurs by unusual endocytic mechanisms involving lipid rafts, induction of membrane curvature, trans-bilayer coupling, and activation of signaling pathways. Once delivered to early endosomes, they follow diverse intracellular routes to the lumen of the ER, from which they penetrate into the cytosol. The role of the lipid receptors is central in these well-studied processes. PMID:21576253

  19. Doxorubicin Lipid Complex Injection

    MedlinePlus

    ... in combination with another chemotherapy drug to treat multiple myeloma (a type of cancer of the bone marrow) ... When doxorubicin lipid complex is used to treat multiple myeloma, it is given on certain days every 3 ...

  20. Metabolism. Part III: Lipids.

    ERIC Educational Resources Information Center

    Bodner, George M.

    1986-01-01

    Describes the metabolic processes of complex lipids, including saponification, activation and transport, and the beta-oxidation spiral. Discusses fatty acid degradation in regard to biochemical energy and ketone bodies. (TW)

  1. Metabolism. Part III: Lipids.

    ERIC Educational Resources Information Center

    Bodner, George M.

    1986-01-01

    Describes the metabolic processes of complex lipids, including saponification, activation and transport, and the beta-oxidation spiral. Discusses fatty acid degradation in regard to biochemical energy and ketone bodies. (TW)

  2. Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets

    PubMed Central

    Schauberger, Eric; Peinhaupt, Miriam; Cazares, Tareian

    2017-01-01

    Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy. Lipids are critical participants in cell signaling events which influence key physiologic (bronchoconstriction) and immune phenomena (degranulation, chemotaxis, sensitization). Lipid-mediated cellular mechanisms including: (1) formation of structural support platforms (lipid rafts) for receptor signaling complexes, (2) activation of a diverse family of G-protein coupled receptors, and (3) mediating intracellular signaling cascades by acting as second messengers. Here, we review four classes of bioactive lipids (platelet activating factor, the leukotrienes, the prostanoids, and the sphingolipids) with special emphasis on lipid synthesis pathways and signaling, atopic disease pathology, and the ongoing development of atopy treatments targeting lipid mediator pathways. PMID:27333777

  3. Immobilization and activity assay of cytochrome P450 on patterned lipid membranes

    SciTech Connect

    Ueda, Yoshihiro; Morigaki, Kenichi . E-mail: morigaki-kenichi@aist.go.jp; Tatsu, Yoshiro; Yumoto, Noboru; Imaishi, Hiromasa . E-mail: himaish@kobe-u.ac.jp

    2007-04-20

    We report on a methodology for immobilizing cytochrome P450 on the surface of micropatterned lipid bilayer membranes and measuring the enzymatic activity. The patterned bilayer comprised a matrix of polymeric lipid bilayers and embedded fluid lipid bilayers. The polymeric lipid bilayer domains act as a barrier to confine fluid lipid bilayers in defined areas and as a framework to stabilize embedded membranes. The fluid bilayer domains, on the other hand, can contain lipid compositions that facilitate the fusion between lipid membranes, and are intended to be used as the binding agent of microsomes containing rat CYP1A1. By optimizing the membrane compositions of the fluid bilayers, we could selectively immobilize microsomal membranes on these domains. The enzymatic activity was significantly higher on lipid bilayer substrates compared with direct adsorption on glass. Furthermore, competitive assay experiment between two fluorogenic substrates demonstrated the feasibility of bioassays based on immobilized P450s.

  4. Analogue Divider by Averaging a Triangular Wave

    NASA Astrophysics Data System (ADS)

    Selvam, Krishnagiri Chinnathambi

    2017-03-01

    A new analogue divider circuit by averaging a triangular wave using operational amplifiers is explained in this paper. The triangle wave averaging analog divider using operational amplifiers is explained here. The reference triangular waveform is shifted from zero voltage level up towards positive power supply voltage level. Its positive portion is obtained by a positive rectifier and its average value is obtained by a low pass filter. The same triangular waveform is shifted from zero voltage level to down towards negative power supply voltage level. Its negative portion is obtained by a negative rectifier and its average value is obtained by another low pass filter. Both the averaged voltages are combined in a summing amplifier and the summed voltage is given to an op-amp as negative input. This op-amp is configured to work in a negative closed environment. The op-amp output is the divider output.

  5. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

    PubMed Central

    Oueis, Emilia; Adamson, Catherine; Mann, Greg; Ludewig, Hannes; Redpath, Philip; Migaud, Marie

    2015-01-01

    Abstract Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID:26507241

  6. A simple analogue of lung mechanics.

    PubMed

    Sherman, T F

    1993-12-01

    A model of the chest and lungs can be easily constructed from a bottle of water, a balloon, a syringe, a rubber stopper, glass and rubber tubing, and clamps. The model is a more exact analogue of the body than the classic apparatus of Hering in two respects: 1) the pleurae and intrapleural fluid are represented by water rather than air, and 2) the subatmospheric "intrapleural" pressure is created by the elasticity of the "lung" (balloon) rather than by a vacuum pump. With this model, students can readily see how the lung is inflated and deflated by movements of the "diaphragm and chest" (syringe plunger) and how intrapleural pressures change as this is accomplished.

  7. Naturalness in an emergent analogue spacetime.

    PubMed

    Liberati, Stefano; Visser, Matt; Weinfurtner, Silke

    2006-04-21

    Effective field theories (EFTs) have been widely used as a framework in order to place constraints on the Planck suppressed Lorentz violations predicted by various models of quantum gravity. There are, however, technical problems in the EFT framework when it comes to ensuring that small Lorentz violations remain small--this is the essence of the "naturalness" problem. Herein we present an "emergent" spacetime model, based on the "analogue gravity" program, by investigating a specific condensed-matter system. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore, our model explicitly avoids the naturalness problem, and makes specific suggestions regarding how to construct a physically reasonable quantum gravity phenomenology.

  8. Analogue Divider by Averaging a Triangular Wave

    NASA Astrophysics Data System (ADS)

    Selvam, Krishnagiri Chinnathambi

    2017-08-01

    A new analogue divider circuit by averaging a triangular wave using operational amplifiers is explained in this paper. The triangle wave averaging analog divider using operational amplifiers is explained here. The reference triangular waveform is shifted from zero voltage level up towards positive power supply voltage level. Its positive portion is obtained by a positive rectifier and its average value is obtained by a low pass filter. The same triangular waveform is shifted from zero voltage level to down towards negative power supply voltage level. Its negative portion is obtained by a negative rectifier and its average value is obtained by another low pass filter. Both the averaged voltages are combined in a summing amplifier and the summed voltage is given to an op-amp as negative input. This op-amp is configured to work in a negative closed environment. The op-amp output is the divider output.

  9. A hypnotic analogue of clinical confabulation.

    PubMed

    Cox, Rochelle E; Barnier, Amanda J

    2015-01-01

    Confabulation-fabricated or distorted memories about oneself-occurs in many disorders, but there is no reliable technique for investigating it in the laboratory. The authors used hypnosis to model clinical confabulation by giving subjects a suggestion for either (a) amnesia for everything that had happened since they started university, (b) amnesia for university plus an instruction to fill in memory gaps, or (c) confusion about the temporal order of university events. They then indexed different types of memory on a confabulation battery. The amnesia suggestion produced the most confabulation, especially for personal semantic information. Notably, subjects confabulated by making temporal confusions. The authors discuss the theoretical implications of this first attempt to model clinical confabulation and the potential utility of such analogues.

  10. Jupiter analogues and planets of active stars

    NASA Astrophysics Data System (ADS)

    Kürster, M.; Zechmeister, M.; Endl, M.; Lo Curto, G.; Hartman, H.; Nilsson, H.; Henning, T.; Hatzes, A. P.; Cochran, W. D.

    2013-04-01

    Combined results are now available from a 15 year long search for Jupiter analogues around solar-type stars using the ESO CAT + CES, ESO 3.6 m + CES, and ESO 3.6 m + HARPS instruments. They comprise planet (co-)discoveries (ι Hor and HR 506) and confirmations (three planets in HR 3259) as well as non-confirmations of planets (HR 4523 and ɛ Eri) announced elsewhere. A long-term trend in ɛ Ind found by our survey is probably attributable to a Jovian planet with a period >30 yr, but we cannot fully exclude stellar activity effects as the cause. A 3.8 year periodic variation in HR 8323 can be attributed to stellar activity.

  11. Lipid droplet dynamics during Schizosaccharomyces pombe sporulation and their role in spore survival

    PubMed Central

    Yang, Hui-Ju; Osakada, Hiroko; Kojidani, Tomoko; Haraguchi, Tokuko

    2017-01-01

    ABSTRACT Upon nitrogen starvation, the fission yeast Schizosaccharomyces pombe forms dormant spores; however, the mechanisms by which a spore sustains life without access to exogenous nutrients remain unclear. Lipid droplets are reservoirs of neutral lipids that act as important cellular energy resources. Using live-cell imaging analysis, we found that the lipid droplets of mother cells redistribute to their nascent spores. Notably, this process was actin polymerization-dependent and facilitated by the leading edge proteins of the forespore membrane. Spores lacking triacylglycerol synthesis, which is essential for lipid droplet formation, failed to germinate. Our results suggest that the lipid droplets are important for the sustenance of life in spores. PMID:28011631

  12. Phloem Proteomics Reveals New Lipid-Binding Proteins with a Putative Role in Lipid-Mediated Signaling

    PubMed Central

    Barbaglia, Allison M.; Tamot, Banita; Greve, Veronica; Hoffmann-Benning, Susanne

    2016-01-01

    Global climate changes inversely affect our ability to grow the food required for an increasing world population. To combat future crop loss due to abiotic stress, we need to understand the signals responsible for changes in plant development and the resulting adaptations, especially the signaling molecules traveling long-distance through the plant phloem. Using a proteomics approach, we had identified several putative lipid-binding proteins in the phloem exudates. Simultaneously, we identified several complex lipids as well as jasmonates. These findings prompted us to propose that phloem (phospho-) lipids could act as long-distance developmental signals in response to abiotic stress, and that they are released, sensed, and moved by phloem lipid-binding proteins (Benning et al., 2012). Indeed, the proteins we identified include lipases that could release a signaling lipid into the phloem, putative receptor components, and proteins that could mediate lipid-movement. To test this possible protein-based lipid-signaling pathway, three of the proteins, which could potentially act in a relay, are characterized here: (I) a putative GDSL-motif lipase (II) a PIG-P-like protein, with a possible receptor-like function; (III) and PLAFP (phloem lipid-associated family protein), a predicted lipid-binding protein of unknown function. Here we show that all three proteins bind lipids, in particular phosphatidic acid (PtdOH), which is known to participate in intracellular stress signaling. Genes encoding these proteins are expressed in the vasculature, a prerequisite for phloem transport. Cellular localization studies show that the proteins are not retained in the endoplasmic reticulum but surround the cell in a spotted pattern that has been previously observed with receptors and plasmodesmatal proteins. Abiotic signals that induce the production of PtdOH also regulate the expression of GDSL-lipase and PLAFP, albeit in opposite patterns. Our findings suggest that while all three

  13. Phloem proteomics reveals new lipid-binding proteins with a putative role in lipid-mediated signaling

    DOE PAGES

    Barbaglia, Allison M.; Tamot, Banita; Greve, Veronica; ...

    2016-04-28

    Global climate changes inversely affect our ability to grow the food required for an increasing world population. To combat future crop loss due to abiotic stress, we need to understand the signals responsible for changes in plant development and the resulting adaptations, especially the signaling molecules traveling long-distance through the plant phloem. Using a proteomics approach, we had identified several putative lipid-binding proteins in the phloem exudates. Simultaneously, we identified several complex lipids as well as jasmonates. These findings prompted us to propose that phloem (phospho-) lipids could act as long-distance developmental signals in response to abiotic stress, and thatmore » they are released, sensed, and moved by phloem lipid-binding proteins (Benning et al., 2012). Indeed, the proteins we identified include lipases that could release a signaling lipid into the phloem, putative receptor components, and proteins that could mediate lipid-movement. To test this possible protein-based lipid-signaling pathway, three of the proteins, which could potentially act in a relay, are characterized here: (I) a putative GDSL-motif lipase (II) a PIG-P-like protein, with a possible receptor-like function; (III) and PLAFP (phloem lipid-associated family protein), a predicted lipid-binding protein of unknown function. Here we show that all three proteins bind lipids, in particular phosphatidic acid (PtdOH), which is known to participate in intracellular stress signaling. Genes encoding these proteins are expressed in the vasculature, a prerequisite for phloem transport. Cellular localization studies show that the proteins are not retained in the endoplasmic reticulum but surround the cell in a spotted pattern that has been previously observed with receptors and plasmodesmatal proteins. Abiotic signals that induce the production of PtdOH also regulate the expression of GDSL-lipase and PLAFP, albeit in opposite patterns. Our findings suggest that while all

  14. Phloem proteomics reveals new lipid-binding proteins with a putative role in lipid-mediated signaling

    SciTech Connect

    Barbaglia, Allison M.; Tamot, Banita; Greve, Veronica; Hoffmann-Benning, Susanne

    2016-04-28

    Global climate changes inversely affect our ability to grow the food required for an increasing world population. To combat future crop loss due to abiotic stress, we need to understand the signals responsible for changes in plant development and the resulting adaptations, especially the signaling molecules traveling long-distance through the plant phloem. Using a proteomics approach, we had identified several putative lipid-binding proteins in the phloem exudates. Simultaneously, we identified several complex lipids as well as jasmonates. These findings prompted us to propose that phloem (phospho-) lipids could act as long-distance developmental signals in response to abiotic stress, and that they are released, sensed, and moved by phloem lipid-binding proteins (Benning et al., 2012). Indeed, the proteins we identified include lipases that could release a signaling lipid into the phloem, putative receptor components, and proteins that could mediate lipid-movement. To test this possible protein-based lipid-signaling pathway, three of the proteins, which could potentially act in a relay, are characterized here: (I) a putative GDSL-motif lipase (II) a PIG-P-like protein, with a possible receptor-like function; (III) and PLAFP (phloem lipid-associated family protein), a predicted lipid-binding protein of unknown function. Here we show that all three proteins bind lipids, in particular phosphatidic acid (PtdOH), which is known to participate in intracellular stress signaling. Genes encoding these proteins are expressed in the vasculature, a prerequisite for phloem transport. Cellular localization studies show that the proteins are not retained in the endoplasmic reticulum but surround the cell in a spotted pattern that has been previously observed with receptors and plasmodesmatal proteins. Abiotic signals that induce the production of PtdOH also regulate the expression of GDSL-lipase and PLAFP, albeit in opposite patterns. Our findings suggest that while all three

  15. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; hide

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  16. Current european regulatory perspectives on insulin analogues

    PubMed Central

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  17. Terrestrial analogues for lunar impact melt flows

    NASA Astrophysics Data System (ADS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2017-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pāhoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pāhoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  18. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  19. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  20. Induction of abortion by different prostaglandin analogues.

    PubMed

    Bygdeman, M; Wiqvist, N

    1974-01-01

    The clinical advantages and disadvantages of intra amniotic administration of PGF2alpha in comparison with hypertonic saline has recently been summarized by the Prostaglandin Task Force within the World Health Organization Expanded program. The investigation comprised approximately 1,500 patients treated randomly with the two methods. The main advantage of the PG method was a significantly shorter induction-abortion interval and a lesser risk for serious complications and the significant disadvantage a slight increase in the mean frequency of minor complaints in terms of diarrhoea and vomiting. With PGF2alpha it seems difficult to obtain a "one shot" method to terminate second trimester pregnancy even with the intra-amniotic route of administration. The 15-methyl analogues seem more promising in this respect. The uterine response following administration of this compound is characterized by a more gradual initiation of uterine stimulation and a sustained effect, One intraamniotic injection of 2.5 mg 15-methyl-PGF2alpha induced abortion in nearly 100% of the cases and the incidence of side effects was low. Promising results with this compound have also been obtained following a single extra-amniotic instillation or by repeated intramuscular injections. Vaginal administration of 15-methyl PGF2alpha or its methyl ester can also be used for termination of pregnancy. Recently orally active PG analogues have become available for clinical testing. One of these compounds, 16,16-dimethyl-PGE2 may in some cases stimulate uterine contractility sufficiently to induce a second trimester abortion following repeated oral administration.

  1. Tren-based analogues of bacillibactin: structure and stability.

    PubMed

    Dertz, Emily A; Xu, Jide; Raymond, Kenneth N

    2006-07-10

    Synthetic analogues were designed to highlight the effect of the glycine moiety of bacillibactin on the overall stability of the ferric complex as compared to synthetic analogues of enterobactin. Insertion of a variety of amino acids to catecholamide analogues based on a Tren (tris(2-aminoethyl)amine) backbone increased the overall acidity of the ligands, causing an enhancement of the stability of the resulting ferric complex as compared to TRENCAM. Solution thermodynamic behavior of these siderophores and their synthetic analogues was investigated through potentiometric and spectrophotometric titrations. X-ray crystallography, circular dichroism, and molecular modeling were used to determine the chirality and geometry of the ferric complexes of bacillibactin and its analogues. In contrast to the Tren scaffold, addition of a glycine to the catechol chelating arms causes an inversion of the trilactone backbone, resulting in opposite chiralities of the two siderophores and a destabilization of the ferric complex of bacillibactin compared to ferric enterobactin.

  2. A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure.

    PubMed

    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye; Smillie, Sarah-Jane; Schnelle, Moritz; Srivastava, Salil; Alawi, Khadija M; Wilde, Elena; Mitchell, Jennifer; Farrell-Dillon, Keith; Richards, Daniel A; Maltese, Giuseppe; Siow, Richard C; Nandi, Manasi; Clark, James E; Shah, Ajay M; Sams, Anette; Brain, Susan D

    2017-07-25

    Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting (t½ ≥7 hours) acylated α-CGRP analogueAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo. The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology. The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg(-1)·d(-1), SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes. These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3) increasing

  3. Acyl-Lipid Metabolism

    PubMed Central

    Li-Beisson, Yonghua; Shorrosh, Basil; Beisson, Fred; Andersson, Mats X.; Arondel, Vincent; Bates, Philip D.; Baud, Sébastien; Bird, David; DeBono, Allan; Durrett, Timothy P.; Franke, Rochus B.; Graham, Ian A.; Katayama, Kenta; Kelly, Amélie A.; Larson, Tony; Markham, Jonathan E.; Miquel, Martine; Molina, Isabel; Nishida, Ikuo; Rowland, Owen; Samuels, Lacey; Schmid, Katherine M.; Wada, Hajime; Welti, Ruth; Xu, Changcheng; Zallot, Rémi; Ohlrogge, John

    2013-01-01

    Acyl lipids in Arabidopsis and all other plants have a myriad of diverse functions. These include providing the core diffusion barrier of the membranes that separates cells and subcellular organelles. This function alone involves more than 10 membrane lipid classes, including the phospholipids, galactolipids, and sphingolipids, and within each class the variations in acyl chain composition expand the number of structures to several hundred possible molecular species. Acyl lipids in the form of triacylglycerol account for 35% of the weight of Arabidopsis seeds and represent their major form of carbon and energy storage. A layer of cutin and cuticular waxes that restricts the loss of water and provides protection from invasions by pathogens and other stresses covers the entire aerial surface of Arabidopsis. Similar functions are provided by suberin and its associated waxes that are localized in roots, seed coats, and abscission zones and are produced in response to wounding. This chapter focuses on the metabolic pathways that are associated with the biosynthesis and degradation of the acyl lipids mentioned above. These pathways, enzymes, and genes are also presented in detail in an associated website (ARALIP: http://aralip.plantbiology.msu.edu/). Protocols and methods used for analysis of Arabidopsis lipids are provided. Finally, a detailed summary of the composition of Arabidopsis lipids is provided in three figures and 15 tables. PMID:23505340

  4. Lipids in preventive dentistry.

    PubMed

    Kensche, A; Reich, M; Kümmerer, K; Hannig, M; Hannig, C

    2013-04-01

    There is still a great demand for the improvement of oral prophylaxis methods. One repeatedly described approach is rinsing with edible oils. The aim of the present review paper was to analyze the role of lipids in bioadhesion and preventive dentistry. Despite limited sound scientific data, extensive literature search was performed to illustrate possible effects of lipids in the oral cavity. It is to be assumed that lipophilic components modulate the process of bioadhesion to the oral hard tissues as well as the composition and ultrastructure of the initial oral biofilm or the pellicle, respectively. Thereby, lipids could add hydrophobic characteristics to the tooth surface hampering bacterial colonization and eventually decreasing caries susceptibility. Also, a lipid-enriched pellicle might be more resistant in case of acid exposure and could therefore reduce the erosive mineral loss. Furthermore, anti-inflammatory effects on the oral soft tissues were described. However, there is only limited evidence for these beneficial impacts. Neither the lipid composition of saliva and pellicle nor the interactions of lipids with the initial oral biofilm and the pellicle layer have been investigated adequately until now. Edible oils might qualify as mild supplements to conventional strategies for the prevention of caries, erosion, and periodontal diseases but further research is necessary. Against the background of current scientific and empirical knowledge, edible oils might be used as oral hygiene supplements but a decisive benefit for the oral health status is questionable.

  5. Lipids of mitochondria.

    PubMed

    Horvath, Susanne E; Daum, Günther

    2013-10-01

    A unique organelle for studying membrane biochemistry is the mitochondrion whose functionality depends on a coordinated supply of proteins and lipids. Mitochondria are capable of synthesizing several lipids autonomously such as phosphatidylglycerol, cardiolipin and in part phosphatidylethanolamine, phosphatidic acid and CDP-diacylglycerol. Other mitochondrial membrane lipids such as phosphatidylcholine, phosphatidylserine, phosphatidylinositol, sterols and sphingolipids have to be imported. The mitochondrial lipid composition, the biosynthesis and the import of mitochondrial lipids as well as the regulation of these processes will be main issues of this review article. Furthermore, interactions of lipids and mitochondrial proteins which are highly important for various mitochondrial processes will be discussed. Malfunction or loss of enzymes involved in mitochondrial phospholipid biosynthesis lead to dysfunction of cell respiration, affect the assembly and stability of the mitochondrial protein import machinery and cause abnormal mitochondrial morphology or even lethality. Molecular aspects of these processes as well as diseases related to defects in the formation of mitochondrial membranes will be described. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Measuring brain lipids.

    PubMed

    Dawson, Glyn

    2015-08-01

    The rapid development of analytical technology has made lipidomics an exciting new area and this review will focus more on modern approaches to lipidomics than on earlier technology. Although not fully comprehensive for all possible brain lipids, the intent is to at least provide a reference for the analysis of classes of lipids found in brain and nervous tissue. We will discuss problems posed by the brain because of its structural and functional heterogeneity, the development changes it undergoes (myelination, aging, pathology etc.) and its cellular heterogeneity (neurons, glia etc.). Section 2 will discuss the various ways in which brain tissue can be extracted to yield lipids for analysis and section 3 will cover a wide range of techniques used to analyze brain lipids such as chromatography and mass-spectrometry. In Section 4 we will discuss ways of analyzing some of the specific biologically active brain lipids found in very small amounts except in pathological conditions and section 5 looks to the future of experimental lipidomic modification in the brain. This article is part of a Special Issue entitled Brain Lipids.

  7. Acyl-Lipid Metabolism

    PubMed Central

    Li-Beisson, Yonghua; Shorrosh, Basil; Beisson, Fred; Andersson, Mats X.; Arondel, Vincent; Bates, Philip D.; Baud, Sébastien; Bird, David; DeBono, Allan; Durrett, Timothy P.; Franke, Rochus B.; Graham, Ian A.; Katayama, Kenta; Kelly, Amélie A.; Larson, Tony; Markham, Jonathan E.; Miquel, Martine; Molina, Isabel; Nishida, Ikuo; Rowland, Owen; Samuels, Lacey; Schmid, Katherine M.; Wada, Hajime; Welti, Ruth; Xu, Changcheng; Zallot, Rémi; Ohlrogge, John

    2010-01-01

    Acyl lipids in Arabidopsis and all other plants have a myriad of diverse functions. These include providing the core diffusion barrier of the membranes that separates cells and subcellular organelles. This function alone involves more than 10 membrane lipid classes, including the phospholipids, galactolipids, and sphingolipids, and within each class the variations in acyl chain composition expand the number of structures to several hundred possible molecular species. Acyl lipids in the form of triacylglycerol account for 35% of the weight of Arabidopsis seeds and represent their major form of carbon and energy storage. A layer of cutin and cuticular waxes that restricts the loss of water and provides protection from invasions by pathogens and other stresses covers the entire aerial surface of Arabidopsis. Similar functions are provided by suberin and its associated waxes that are localized in roots, seed coats, and abscission zones and are produced in response to wounding. This chapter focuses on the metabolic pathways that are associated with the biosynthesis and degradation of the acyl lipids mentioned above. These pathways, enzymes, and genes are also presented in detail in an associated website (ARALIP: http://aralip.plantbiology.msu.edu/). Protocols and methods used for analysis of Arabidopsis lipids are provided. Finally, a detailed summary of the composition of Arabidopsis lipids is provided in three figures and 15 tables. PMID:22303259

  8. Ribosome-Mediated Incorporation of Dipeptides and Dipeptide Analogues into Proteins in Vitro.

    PubMed

    Maini, Rumit; Dedkova, Larisa M; Paul, Rakesh; Madathil, Manikandadas M; Chowdhury, Sandipan Roy; Chen, Shengxi; Hecht, Sidney M

    2015-09-09

    Plasmids containing 23S rRNA randomized at positions 2057-2063 and 2502-2507 were introduced into Escherichia coli, affording a library of clones which produced modified ribosomes in addition to the pre-existing wild-type ribosomes. These clones were screened with a derivative of puromycin, a natural product which acts as an analogue of the 3'-end of aminoacyl-tRNA and terminates protein synthesis by accepting the growing polypeptide chain, thereby killing bacterial cells. The puromycin derivative in this study contained the dipeptide p-methoxyphenylalanylglycine, implying the ability of the modified ribosomes in clones sensitive to this puromycin analogue to recognize dipeptides. Several clones inhibited by the puromycin derivative were used to make S-30 preparations, and some of these were shown to support the incorporation of dipeptides into proteins. The four incorporated species included two dipeptides (Gly-Phe (2) and Phe-Gly (3)), as well as a thiolated dipeptide analogue (4) and a fluorescent oxazole (5) having amine and carboxyl groups approximately the same distance apart as in a normal dipeptide. A protein containing both thiolated dipeptide 4 and a 7-methoxycoumarin fluorophore was found to undergo fluorescence quenching. Introduction of the oxazole fluorophore 5 into dihydrofolate reductase or green fluorescent protein resulted in quite strong enhancement of its fluorescence emission, and the basis for this enhancement was studied. The aggregate results demonstrate the feasibility of incorporating dipeptides as a single ribosomal event, and illustrate the lack of recognition of the central peptide bond in the dipeptide, potentially enabling the incorporation of a broad variety of structural analogues.

  9. Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldehyde scavenger histidyl-containing analogues of carnosine.

    PubMed

    Guiotto, Andrea; Calderan, Andrea; Ruzza, Paolo; Osler, Alessio; Rubini, Chiara; Jo, Dong-Gyu; Mattson, Mark P; Borin, Gianfranco

    2005-09-22

    The synthesis, scavenging activity, and cytoprotective profiles of histidyl-containing carnosine analogues bearing hydrazide or 1,2-diol moieties is reported. Some compounds have demonstrated higher aldehyde-sequestering efficiency than carnosine and were also efficient in protecting SH-SY5Y neuroblastoma cells and rat hippocampal neurons from 4-hydroxy-trans-2,3-nonenal (HNE)-mediated death. The cytoprotective efficacy of these compounds suggests their potential use as therapeutic agents for disorders that involve excessive membrane lipids peroxidation and HNE-mediated neuronal toxicity.

  10. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    PubMed

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  11. Mannosylerythritol lipids: production and applications.

    PubMed

    Morita, Tomotake; Fukuoka, Tokuma; Imura, Tomohiro; Kitamoto, Dai

    2015-01-01

    Mannosylerythritol lipids (MELs) are a glycolipid class of biosurfactants produced by a variety yeast and fungal strains that exhibit excellent interfacial and biochemical properties. MEL-producing fungi were identified using an efficient screening method for the glycolipid production and taxonomical classification on the basis of ribosomal RNA sequences. MEL production is limited primarily to the genus Pseudozyma, with significant variability among the MEL structures produced by each species. Outside of Pseudozyma, one recently isolated strain, Ustilago scitaminea, has been shown to exhibit abundant MEL-B production from sugarcane juice. Structural analyses of these compounds suggest a role for MELs in numerous cosmetic applications. MELs act as effective topical moisturizers and can repair damaged hair. Furthermore, these compounds have been shown to exhibit both protective and healing activities, to activate fibroblasts and papilla cells, and to act as natural antioxidants. In this review, we provide a brief summary of MEL research over the past few decades, focusing on the identification of MEL-producing fungi, the structural characterization of MELs, the use of alternative compounds as a primary carbon source, and the use of these compounds in cosmetic applications.

  12. The inhibitor effect of probencid and structural analogues on organic anions and chloride permeabilities in ox erythrocytes.

    PubMed

    Motais, R; Cousin, J L

    1976-01-21

    Probenecid inhibits anion movements (organic anions and chloride) in ox erythrocytes. The I50 is 4. 10(-5) M. Structural analogues such as carinamide, p-carboxybenzene sulfonamide and p-carboxy N,N-diethyl benzene sulfonamide, which are drugs of the sulfonamide class, were also found to inhibit anion transport. These results reinforce the previously discussed view based on structural considerations, that sulfonamides act on the red cell membrane as competitors of anion transport. It is possible that probenecid and carinamide act in a similar way in the kidney.

  13. Novel analogues of degarelix incorporating hydroxy-, methoxy- and pegylated-urea moieties at positions 3, 5, 6 and the N-terminus

    PubMed Central

    Samant, Manoj P.; Hong, Doley J.; Croston, Glenn; Rivier, Catherine; Rivier, Jean

    2008-01-01

    Novel degarelix (Fe200486) analogues were screened for antagonism of GnRH-induced response (IC50) in a reporter gene assay. Inhibition of luteinizing hormone release over time was measured in the castrated male rat. Nω-hydroxy- and Nω-methoxy-carbamoylation of Dab and Dap at position 3 (3-6), and Nω-hydroxy-, Nω-methoxy-carbamoylation and pegylation of 4Aph at positions 5 and 6 (7-10, 15-17, 22-25) were carried out. Modulation of hydrophobicity was achieved using different acylating groups at the N-terminus (11-14, 18-21, 26-28). Analogues 8, 15-17, 22 and 23 were equipotent to acyline (IC50 = 0.69 nM) and degarelix (IC50 = 0.58 nM) in vitro. Analogues 7, 17 and 23 were shorter acting than acyline, when 9, 11, 13, 15, 16 and 22 were longer acting. Only 9 and 14 were inactive at releasing histamine. No analogue exhibited a duration of action comparable to that of degarelix. Analogues with shorter and longer retention times on HPLC (a measure of hydrophilicity) than degarelix were identified. PMID:16759096

  14. A photoactivable phospholipid analogue that specifically labels membrane cytoskeletal proteins of intact erythrocytes

    SciTech Connect

    Pradhan, D.; Williamson, P.; Schlegel, R.A. )

    1989-08-22

    A radioactive photoactivable analogue of phosphatidylethanolamine, 2-(2-azido-4-nitrobenzoyl)-1-acyl-sn-glycero-3-phospho({sup 14}C)ethanolamine(({sup 14}C)AzPE), was synthesized. Upon incubation with erythrocytes in the dark, about 90% of ({sup 14}C)AzPE spontaneously incorporated into the cells; of this fraction, about 90% associated with the membrane, all of it noncovalently. Upon photoactivation, 3-4% of the membrane-associated probe was incorporated into protein. Analysis of this fraction by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, as well as extraction of labeled membranes with alkali or detergent, showed that the probe preferentially labeled cytoskeletal proteins. ({sup 14}C)AzPE appears to be a useful tool for the study of lipid-protein interactions at the cytoplasmic face of the plasma membrane of intact cells.

  15. Interaction pathways between soft lipid nanodiscs and plasma membranes: A molecular modeling study.

    PubMed

    Li, Shixin; Luo, Zhen; Xu, Yan; Ren, Hao; Deng, Li; Zhang, Xianren; Huang, Fang; Yue, Tongtao

    2017-10-01

    Lipid nanodisc, a model membrane platform originally synthesized for study of membrane proteins, has recently been used as the carrier to deliver amphiphilic drugs into target tumor cells. However, the central question of how cells interact with such emerging nanomaterials remains unclear and deserves our research for both improving the delivery efficiency and reducing the side effect. In this work, a binary lipid nanodisc is designed as the minimum model to investigate its interactions with plasma membranes by using the dissipative particle dynamics method. Three typical interaction pathways, including the membrane attachment with lipid domain exchange of nanodiscs, the partial membrane wrapping with nanodisc vesiculation, and the receptor-mediated endocytosis, are discovered. For the first pathway, the boundary normal lipids acting as ligands diffuse along the nanodisc rim to gather at the membrane interface, repelling the central bola lipids to reach a stable membrane attachment. If bola lipids are positioned at the periphery and act as ligands, they diffuse to form a large aggregate being wrapped by the membrane, leaving the normal lipids exposed on the membrane exterior by assembling into a vesicle. Finally, by setting both central normal lipids and boundary bola lipids as ligands, the receptor-mediated endocytosis occurs via both deformation and self-rotation of the nanodiscs. All above pathways for soft lipid nanodiscs are quite different from those for rigid nanoparticles, which may provide useful guidelines for design of soft lipid nanodiscs in widespread biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Diverse relations between ABC transporters and lipids: An overview.

    PubMed

    Neumann, Jennifer; Rose-Sperling, Dania; Hellmich, Ute A

    2017-04-01

    It was first discovered in 1992 that P-glycoprotein (Pgp, ABCB1), an ATP binding cassette (ABC) transporter, can transport phospholipids such as phosphatidylcholine, -ethanolamine and -serine as well as glucosylceramide and glycosphingolipids. Subsequently, many other ABC transporters were identified to act as lipid transporters. For substrate transport by ABC transporters, typically a classic, alternating access model with an ATP-dependent conformational switch between a high and a low affinity substrate binding site is evoked. Transport of small hydrophilic substrates can easily be imagined this way, as the molecule can in principle enter and exit the transporter in the same orientation. Lipids on the other hand need to undergo a 180° degree turn as they translocate from one membrane leaflet to the other. Lipids and lipidated molecules are highly diverse, so there may be various ways how to achieve their flipping and flopping. Nonetheless, an increase in biophysical, biochemical and structural data is beginning to shed some light on specific aspects of lipid transport by ABC transporters. In addition, there is now abundant evidence that lipids affect ABC transporter conformation, dynamics as well as transport and ATPase activity in general. In this review, we will discuss different ways in which lipids and ABC transporters interact and how lipid translocation may be achieved with a focus on the techniques used to investigate these processes. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Maltose Neopentyl Glycol-3 (MNG-3) Analogues for Membrane Protein Study

    PubMed Central

    Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J.; Guan, Lan; Byrne, Bernadette

    2015-01-01

    Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayer and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs behaved superior to a conventional detergent, n–dodecyl–β–D–maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation. PMID:25813698

  18. A lysophosphatidic acid analogue is revealed as a potent inhibitor of phosphatidylcholine synthesis, inducing apoptosis.

    PubMed Central

    Gueguen, Geneviéve; Granci, Virginie; Rogalle, Pierre; Briand-Mésange, Fabienne; Wilson, Michéle; Klaébé, Alain; Tercé, François; Chap, Hugues; Salles, Jean-Pierre; Simon, Marie-Françoise; Gaits, Frédérique

    2002-01-01

    A previous study demonstrated that cross-desensitization experiments performed with the lysophosphatidic acid (LPA) analogues (R)- and (S)-N-palmitoyl-norleucinol 1-phosphate (PNPAs) inhibited LPA-induced platelet aggregation without any stereospecificity. Here we report opposite biological effects of the two enantiomers on mitogenesis of IMR-90 fibroblasts in relation to their respective metabolism. (R)PNPA was proliferative, while (S)PNPA induced apoptosis by specifically inhibiting phosphatidylcholine biosynthesis at the last step of the CDP-choline pathway controlled by cholinephosphotransferase. This effect was not direct but required dephosphorylation of PNPAs by ecto-lipid phosphate phosphatase before cellular uptake of the generated N-palmitoyl-norleucinols (PNOHs). Inhibition of cholinephosphotransferase by the derivative (S)PNOH was confirmed by an in vitro assay. (S)PNPA proapoptotic effects led us to clarify the mechanism linking cholinephosphotransferase inhibition to apoptosis. Three proapoptotic responses were observed: the activation of caspase-3, the production of ceramides from newly synthesized pools (as demonstrated by the inhibitor Fumonisin B1) and finally the activation of stress-activated protein kinase, p38 and c-Jun N-terminal kinases 1/2, as a result of ceramide increase. Thus our data demonstrate that synthetic analogues of LPA might display stereospecific effects leading to apoptosis independently of classical LPA-activated pathways. PMID:12197836

  19. Antidiabetic activity of benzopyrone analogues in nicotinamide-streptozotocin induced type 2 diabetes in rats.

    PubMed

    Nayak, Yogendra; Hillemane, Venkatachalam; Daroji, Vijay Kumar; Jayashree, B S; Unnikrishnan, M K

    2014-01-01

    Benzopyrones are proven antidiabetic drug candidate in diabetic drug discovery. In this view novel synthetic benzopyrone analogues were selected for testing in experimental diabetes. Type 2 diabetes (T2D) was induced in Wistar rats by streptozotocin (60 mg/kg, i.p.) followed by nicotinamide (120 mg/kg i.p.). Rats having fasting blood glucose (FBG)>200 mg/dL, 7 days after T2D-induction, are selected for the study. Test compounds and standard treatment were continued for 15 days. FBG, oral glucose tolerance test (OGTT), and insulin tolerance test (ITT) were determined on 21st day after induction of T2D. Plasma lipids and serum insulin were estimated. Homeostatic model assessment (HOMA-IR) was then calculated from serum insulin. Rats were sacrificed and pancreas was isolated for histopathological observations. Oxidative stress markers were estimated in liver homogenate. Quercetin, a natural product with benzopyrone ring, showed significant hypoglycemic activity comparable to glibenclamide. Treatment with test compounds lowered the FBG and insulin resistance was significant alleviated as determined by OGTT, HOMA-IR, and ITT. There was significant normalisation of liver antioxidant enzymes compared to diabetic rats indicating that all the synthesised benzopyrone analogues are beneficial in reducing oxidative stress and are on par with the standard quercetin and glibenclamide in experimental T2D.

  20. Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study.

    PubMed

    Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J; Guan, Lan; Byrne, Bernadette; Chae, Pil Seok

    2015-05-07

    Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, n-dodecyl-β-D-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation.

  1. The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes.

    PubMed

    Ali, Eunüs S; Hua, Jin; Wilson, Claire H; Tallis, George A; Zhou, Fiona H; Rychkov, Grigori Y; Barritt, Greg J

    2016-09-01

    The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Neoglycolipid analogues of ganglioside G sub M1 as functional receptors of cholera toxin

    SciTech Connect

    Pacuszka, T.; Bradley, R.M.; Fishman, P.H. )

    1991-03-12

    The authors synthesized several lipid analogues of ganglioside G{sub M1} by attaching its oligosaccharide moiety (G{sub M1}OS) to aminophospholipids, aliphatic amines, and cholesteryl hemisuccinate. They incubated G{sub M1}-deficient rat glioma C6 cells with each of the derivatives as well as native G{sub M1} and assayed the cells for their ability to bind and respond to cholera toxin. On the basis of the observed increase in binding of {sup 125}I-labeled cholera toxin, it was apparent that the cells took up and initially incorporated most of the derivatives into the plasma membrane. In the case of the aliphatic amine derivatives, the ability to generate new toxin binding sites was dependent on chain length; whereas the C{sub 10} derivative was ineffective, C{sub 12} and higher analogues were effective. Increased binding was dependent on both the concentration of the neoglycolipid in the medium and the time of exposure. Cells pretreated with the various derivatives accumulated cyclic AMP in response to cholera toxin, but there were differences in their effectiveness. The cholesterol and long-chain aliphatic amine derivatives were more effective than native G{sub M1}, whereas the phospholipid derivatives were less effective. The distance between G{sub M1}OS and the phospholipid also appeared to influence its functional activity. The results indicate that although G{sub M1}OS provides the recognition site for the binding of cholera toxin, the nature of the lipid moiety plays an important role in the action of the toxin.

  3. Study of structure and orientation of mesentericin Y105, a bacteriocin from Gram-positive Leuconostoc mesenteroides, and its Trp-substituted analogues in phospholipid environments.

    PubMed

    Castano, Sabine; Desbat, Bernard; Delfour, Antoine; Dumas, Jean Marie; da Silva, Alexandra; Dufourcq, Jean

    2005-02-01

    Mesentericin Y105 (Mes-Y105) is a bacteriocin secreted by Leuconostoc mesenteroides which is particularly active on Listeria. It is constituted by 37 residues and reticulated by one disulfide bridge. It has two W residues, W18 and W37, which can be studied by fluorescence. Two single substituted W/F analogues were synthesized (Mes-Y105/W18 and Mes-Y105/W37) to differentiate the local environment around each W and to study their changes in the presence of lipid vesicles. Fluorescence experiments show that, for the pure Trp-analogues, W18 and W37 are fully exposed to solvent whatever pH and buffer conditions. In the presence of lipid vesicles, both became buried. Lipid affinities were estimated: they are weak for zwitterionic phospholipids but an order of magnitude higher for negatively charged phosphatidylserine (PS) and phosphatidylglycerol (PG) lipids. On negatively charged PG lipids, Mes-Y105 and Mes-Y105/W37 display comparable lipid affinities. A decrease in lipid affinity is observed for Mes-Y105/W18 compared to Mes-Y105, which means that W37 would seem to be required for increased lipid selectivity. In the lipid-bound state W18 is strongly dehydrated, probably embedded into the acyl chains, while W37 stands more at the interface. Mes-Y105 was also studied by polarization modulation infrared reflection absorption spectroscopy (PMIRRAS), alone and in various phospholipid environments, to obtain structural information and to assess lipid perturbations. At nanomolar concentrations close to those required for anti-Listeria activity, Mes-Y105 forms films at the air/water interface and inserts into negatively charged lipid monolayers. In situ infrared data show that Mes-Y105 binding only affects the polar head group vibrations while the lipid order of the acyl chains remains unaffected. The PMIRRAS show that Mes-Y105 folds into an N-terminal antiparallel beta-sheet followed by an alpha-helix, both structures being tilted (40 degrees) compared to the normal at the

  4. Structure-activity relationship of tryptamine analogues on the heart of Venus mercenaria.

    PubMed

    GREENBERG, M J

    1960-09-01

    A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor.

  5. Studies of inositol 1-phosphate analogues as inhibitors of the phosphatidylinositol phosphate synthase in mycobacteria.

    PubMed

    Morii, Hiroyuki; Okauchi, Tatsuo; Nomiya, Hiroki; Ogawa, Midori; Fukuda, Kazumasa; Taniguchi, Hatsumi

    2013-03-01

    We previously reported a novel pathway for the biosynthesis of phosphatidylinositol in mycobacteria via phosphatidylinositol phosphate (PIP) [Morii H., Ogawa, M., Fukuda, K., Taniguchi, H., and Koga, Y (2010) J. Biochem. 148, 593-602]. PIP synthase in the pathway is a promising target for the development of new anti-mycobacterium drugs. In the present study, we evaluated the characteristics of the PIP synthase of Mycobacterium tuberculosis. Four types of compounds were chemically synthesized based on the assumption that structural homologues of inositol 1-phosphate, a PIP synthase substrate, would act as PIP synthase inhibitors, and the results confirmed that all synthesized compounds inhibited PIP synthase activity. The phosphonate analogue of inositol 1-phosphate (Ino-C-P) had the greatest inhibitory effect among the synthesized compounds examined. Kinetic analysis indicated that Ino-C-P acted as a competitive inhibitor of inositol 1-phosphate. The IC(50) value for Ino-C-P inhibition of the PIP synthase activity was estimated to be 2.0 mM. Interestingly, Ino-C-P was utilized in the same manner as the normal PIP synthase substrate, leading to the synthesis of a phosphonate analogue of PIP (PI-C-P), which had a structure similar to that of the natural product, PIP. In addition, PI-C-P had high inhibitory activity against PIP synthase.

  6. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  7. Design of multi-epitope, analogue-based cancer vaccines.

    PubMed

    Fikes, John D; Sette, Alessandro

    2003-09-01

    The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.

  8. Analogues of erectile dysfunction drugs: an under-recognised threat.

    PubMed

    Poon, W T; Lam, Y H; Lai, C K; Chan, Albert Y W; Mak, Tony W L

    2007-10-01

    To investigate the problem of drug analogue adulteration in male erectile dysfunction health products. Survey of over-the-counter male erectile dysfunction health products available in convenience stores and pharmacies in Hong Kong. Tertiary referral centre for clinical toxicology analysis in Hong Kong. The pattern and extent of adulteration of male erectile dysfunction health products with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues. Of 26 products studied, one (4%) was found to contain undeclared sildenafil, while 14 (54%) contained drug analogues of different kinds. The latter included acetildenafil, hydroxyacetildenafil, hydroxyhomosildenafil, and piperidenafil. The first three were analogues of sildenafil and the last was an analogue of vardenafil. One young patient presented with ataxia after taking an acetildenafil-containing product. The positive rate of concealed drug analogues in male erectile dysfunction health products is alarmingly high. Such analogues are difficult to detect by ordinary laboratory methods, and might be used in an attempt to evade regulatory inspection. Without going through the stringent drug testing process, the adverse effects of these chemicals remain largely unknown and unpredictable. Effective surveillance system and control measures are needed urgently. The medical profession and the public should be alerted to this under-recognised threat.

  9. Sebaceous gland lipids

    PubMed Central

    Ottaviani, Monica; Camera, Emanuela; Mastrofrancesco, Arianna

    2009-01-01

    The principal activity of mature sebaceous glands is producing and secreting sebum, which is a complex mixture of lipids. Sebum composition is different among species and this difference is probably due to the function that sebum has to absolve. In human sebum there are unique lipids, such as squalene and wax esters not found anywhere else in the body nor among the epidermal surface lipids. Moreover, they correspond to major components supplying the skin with protection. However, the ultimate role of human sebum, as well the metabolic pathways regulating its composition and secretion rate, are far from a complete understanding. Increased sebum secretion is considered, among all features, the major one involved in the pathophysiology of acne. Along with increased sebum secretion rate, quali- and quantitative modifications of sebum are likely to occur in this pathology. Understanding the factors and mechanisms that regulate sebum production is needed in order to identify new targets that can be addressed to achieve a selective modulation of lipid biosynthesis as a novel therapeutic strategy to correct lipid disregulations in acne and other disorders of the pilosebaceous unit. PMID:20224686

  10. The 2-Methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats

    PubMed Central

    Morani, Aashish S.; Ewald, Amy; Prevatt-Smith, Katherine M.; Prisinzano, Thomas E.; Kivell, Bronwyn

    2014-01-01

    κ opioid receptor activation by traditional arylacetamide agonists and the novel neoclerodane diterpene κ opioid receptor agonist Salvinorin A (Sal A) results in attenuation of cocaine-seeking behavior in pre-clinical models of addiction. However, adverse effects such as sedation, depression and aversion limit their clinical utility. The Sal A analogue, 2-methoxymethyl salvinorin B (MOM Sal B) is a longer acting Sal A analogue with high affinity for κ opioid receptors. In this study, we tested MOM Sal B for its ability to modulate cocaine-seeking behavior in rats. MOM Sal B (0.3 mg/kg) successfully attenuated cocaine-seeking but also attenuated sucrose reinforcement. No change in activity was observed in either cocaine-induced hyperactivity or spontaneous open field activity tests but increased immobility and decreased swimming times in the forced swim test were observed. This study indicates that κ opioid receptor activation by more potent Sal A analogues modulates cocaine-seeking behavior non-selectively without causing sedation, suggesting an improved side effects profile. However, pro-depressive effects are seen, which may limit the therapeutic potential of this compound. Future studies with Sal A analogues having affinities at other opioid receptors are warranted as they have the potential to identify compounds having effective anti-addiction properties. PMID:24201308

  11. The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats.

    PubMed

    Morani, Aashish S; Ewald, Amy; Prevatt-Smith, Katherine M; Prisinzano, Thomas E; Kivell, Bronwyn M

    2013-11-15

    κ Opioid receptor activation by traditional arylacetamide agonists and the novel neoclerodane diterpene κ opioid receptor agonist Salvinorin A (Sal A) results in attenuation of cocaine-seeking behavior in pre-clinical models of addiction. However, adverse effects such as sedation, depression and aversion limit their clinical utility. The Sal A analogue, 2-methoxy-methyl salvinorin B (MOM Sal B) is a longer acting Sal A analogue with high affinity for κ opioid receptors. In this study, we tested MOM Sal B for its ability to modulate cocaine-seeking behavior in rats. MOM Sal B (0.3mg/kg) successfully attenuated cocaine-seeking but also attenuated sucrose reinforcement. No change in activity was observed in either cocaine-induced hyperactivity or spontaneous open field activity tests but increased immobility and decreased swimming times in the forced swim test were observed. This study indicates that κ opioid receptor activation by more potent Sal A analogues modulates cocaine-seeking behavior non-selectively without causing sedation, suggesting an improved side effects profile. However, pro-depressive effects are seen, which may limit the therapeutic potential of this compound. Future studies with Sal A analogues having affinities at other opioid receptors are warranted as they have the potential to identify compounds having effective anti-addiction properties.

  12. Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues.

    PubMed Central

    Lasnitzki, I.

    1976-01-01

    The influence of vitamin A-related compounds on hyperplasia and metaplasia induced by methylcholanthrene was studied in mouse prostate glands in organ culture. Methylcholanthrene was found to cause extensive hyperplasia and squamous metaplasia of the prostatic epithelium which persisted after withdrawal of the carcinogen. The retinoids included retinoic acid and 6 of its structural analogues synthesized in an attempt to enhance the anticarcinogenic action and reduce the toxicity of the parent compound. These where the cyclopentenyl analogus 7699, A2-retinoic acid, 13-cis-alpha-retinoic acid and 3 aromatic analogues. Administration of the compounds following the carcinogen reduced the extent and incidence of hyperplasia significantly and with the exception of one compound reversed the squamous metaplasia. Two of the aromatic analogues, one with a terminal ethylamide group (1430), and the other with a terminal ethylester group (9369), proved to be the most potent inhibitors, followed by compound 7699 and (9369), proved to be the most potent inhibitors, followed by compound 7699 and retinoic acid. A2-retinoic acid and 13-cis-alpha-retinoic acid showed the lowest activity. The inhibition of hyperplasia appeared to be mediated via a reduction of DNA synthesis. It seemed unrelated to either the biological growth-promoting activity of the compounds or their surface-active properties. It is tentatively suggested that vitamin A and its analogues may act as hormones. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:987794

  13. Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

    PubMed Central

    Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

    2017-01-01

    Background The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. Materials and methods In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. Results The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. Discussion The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening. PMID:28053504

  14. Inhibition by amiloride analogues of Na sup + -dependent hexose uptake in LLC-PK sub 1 /Cl sub 4 cells

    SciTech Connect

    Cook, J.S.; Shaffer, C.; Cragoe, E.J. Jr. Merck Sharp and Dohme Research Laboratories, West Point, PA )

    1987-08-01

    Amiloride and four analogues of amiloride were shown to inhibit Na{sup +}-dependent, phlorizin-sensitive hexose uptake by a clone of pig kidney cells, LLC-PK{sub 1}/Cl{sub 4}. The analogues tested were: 5-(N-ethyl-N-isopropyl)amiloride (EIPA), 5-(N-methyl-N-isobutyl)amiloride (MIBA), 3{prime},4{prime}-dichlorobenzamil, and phenamil. The transport substrate was the nonmetabolizable glucose analogue {alpha}-methyl-D-glucoside. Blockade of Na{sup +}-K{sup +} transport at the basolateral membranes or removal of divalent cations from the assay medium had little effect on the initial rate of hexose uptake, whereas MIBA remained an effective inhibitor under both conditions. The inhibitions by EIPA of Na{sup +}-H{sup +} exchange and hexose-dependent Na{sup +} uptake could be distinguished by appropriate choice of concentrations of the inhibitor. Hexose transport inhibition does not appear to be secondary to other known effects of the amilorides. Inhibition by all analogues is enhanced when they are tested in low (2 mM) Na{sup +} medium, where they show half-maximal inhibition in the range of 100-300 {mu}M. More detailed kinetic analysis of inhibition by EIPA shows it to be competitive with Na{sup +} with a K{sub i} of 73-107 {mu}M. It is concluded that the amilorides are acting directly on the hexose transporter.

  15. Intracellular Metabolism of Nucleoside/Nucleotide Analogues: a Bottleneck to Reach Active Drugs on HIV Reverse Transcriptase.

    PubMed

    Varga, Andrea; Lionne, Corinne; Roy, Béatrice

    2016-01-01

    To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3'-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

  16. Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation.

    PubMed

    Jubeli, Emile; Maginty, Amanda B; Abdul Khalique, Nada; Raju, Liji; Abdulhai, Mohamad; Nicholson, David G; Larsen, Helge; Pungente, Michael D; Goldring, William P D

    2015-10-01

    Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid-DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those

  17. LM cell growth and membrane lipid adaptation to sterol structure.

    PubMed

    Rujanavech, C; Silbert, D F

    1986-06-05

    Using a sterol auxotroph of the LM cell mouse fibroblast, we demonstrate that relatively few cholesterol analogues can substitute for cholesterol as a growth factor. The auxotroph grows normally on desmosterol and trans-22-dehydrocholesterol and at reduced rates on dihydrocholesterol, campesterol, and 22,23-dihydrobrassicasterol. It does not grow with beta-sitosterol, stigmasterol, ergosterol, or cis-22-dehydrocholesterol when the sterol is present as sole supplement but does grow at normal rates when the analogue is supplied with suboptimal amounts of cholesterol. Two contrasting types of membrane lipid changes are observed in cells grown on cholesterol analogues. In cells grown with dihydrocholesterol, a marked increase in desaturation and elongation of fatty acids is noted. Conversely, when cells are grown with cis-22-dehydrocholesterol, desaturation and elongation of fatty acids are severely curtailed. Cells grown on alkyl sterols respond like cells grown on cis-22-dehydrocholesterol but in a less pronounced fashion. The effects of sterol substitution in mammalian cells versus in lower eukaryotes are compared, and an explanation for the secondary changes in fatty acid composition in terms of phospholipid phase behavior is suggested.

  18. Lipid trafficking in plant cells.

    PubMed

    Hurlock, Anna K; Roston, Rebecca L; Wang, Kun; Benning, Christoph

    2014-09-01

    Plant cells contain unique organelles such as chloroplasts with an extensive photosynthetic membrane. In addition, specialized epidermal cells produce an extracellular cuticle composed primarily of lipids, and storage cells accumulate large amounts of storage lipids. As lipid assembly is associated only with discrete membranes or organelles, there is a need for extensive lipid trafficking within plant cells, more so in specialized cells and sometimes also in response to changing environmental conditions such as phosphate deprivation. Because of the complexity of plant lipid metabolism and the inherent recalcitrance of membrane lipid transporters, the mechanisms of lipid transport within plant cells are not yet fully understood. Recently, several new proteins have been implicated in different aspects of plant lipid trafficking. While these proteins provide only first insights into limited aspects of lipid transport phenomena in plant cells, they represent exciting opportunities for further studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Synthesis of pacidamycin analogues via an Ugi-multicomponent reaction.

    PubMed

    Okamoto, Kazuya; Sakagami, Masahiro; Feng, Fei; Takahashi, Fumiyo; Uotani, Kouichi; Togame, Hiroko; Takemoto, Hiroshi; Ichikawa, Satoshi; Matsuda, Akira

    2012-07-15

    The second-generation synthesis of 3'-hydroxypacidamycin D (2) has been accomplished via an Ugi-four component reaction at a late stage of the synthesis. This approach provided ready access to a range of analogues including diastereomers of the diaminobutylic acid residue and hybrid-type analogues of mureidomycins. Biological evaluations of these analogues indicated that the stereochemistry at the diaminobutylic acid residue has a crucial impact on both the MraY biochemical inhibition and whole-cell antibacterial activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Mars on Earth: soil analogues for future Mars missions

    NASA Astrophysics Data System (ADS)

    Marlow, Jeffrey J.; Martins, Zita; Sephton, Mark A.

    2008-04-01

    Preparations for missions to Mars are a major concern for scientists. Predicting how equipment and experiments will perform on the planet is difficult because tests are restricted to Earth. Mars soil analogues are being used to solve this problem. These terrestrial materials are chemically and physically similar to martian soils and, because they contain unusual minerals and trace amounts of organic matter, are scientifically interesting in their own right. However, no current analogue is appropriate for all necessary tests. Here we describe Mars soil analogues, identify limitations and suggest the need for new Mars simulants.

  1. Synthesis of chalcone analogues with increased antileishmanial activity.

    PubMed

    Boeck, Paula; Bandeira Falcão, Camila Alves; Leal, Paulo César; Yunes, Rosendo Augusto; Filho, Valdir Cechinel; Torres-Santos, Eduardo Caio; Rossi-Bergmann, Bartira

    2006-03-01

    Eighteen analogues of an active natural chalcone were synthesized using xanthoxyline and some derivatives, and these analogues were tested for selective activity against both promastigotes and intracellular amastigotes of Leishmania amazonensis in vitro. Three analogues (10, 12, and 19) containing nitro, fluorine or bromine groups, respectively, displayed increased selective activity against the parasites as compared with the natural chalcone. The nitrosylated chalcone 10 was also tested intralesionally in infected mice and was found to be as effective as Pentostan reference drug at a dose 100 times higher than that of the chalcone in controlling both the lesion growth and the parasite burden.

  2. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    PubMed Central

    Verlee, Arno; Heugebaert, Thomas; van der Meer, Tom; Kerchev, Pavel I; Van Breusegem, Frank

    2017-01-01

    For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl)benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues. PMID:28326139

  3. Lipid Production from Nannochloropsis

    PubMed Central

    Ma, Xiao-Nian; Chen, Tian-Peng; Yang, Bo; Liu, Jin; Chen, Feng

    2016-01-01

    Microalgae are sunlight-driven green cell factories for the production of potential bioactive products and biofuels. Nannochloropsis represents a genus of marine microalgae with high photosynthetic efficiency and can convert carbon dioxide to storage lipids mainly in the form of triacylglycerols and to the ω-3 long-chain polyunsaturated fatty acid eicosapentaenoic acid (EPA). Recently, Nannochloropsis has received ever-increasing interests of both research and public communities. This review aims to provide an overview of biology and biotechnological potential of Nannochloropsis, with the emphasis on lipid production. The path forward for the further exploration of Nannochloropsis for lipid production with respect to both challenges and opportunities is also discussed. PMID:27023568

  4. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    PubMed

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  5. X-rays from Green Pea analogues

    NASA Astrophysics Data System (ADS)

    Brorby, M.; Kaaret, P.

    2017-09-01

    X-ray observations of two metal-deficient luminous compact galaxies (LCG; SHOC 486 and SDSS J084220.94+115000.2) with properties similar to the so-called Green Pea galaxies were obtained using the Chandra X-ray Observatory. Green Pea galaxies are relatively small, compact (a few kpc across) galaxies that get their green colour from strong [O iii] λ5007 Å emission, an indicator of intense, recent star formation. These two galaxies were predicted to have the highest observed count rates, using the X-ray luminosity-star formation rate (LX-SFR) relation for X-ray binaries, from a statistically complete sample drawn from optical criteria. We determine the X-ray luminosity relative to SFR and metallicity for these two galaxies. Neither exhibits any evidence of active galactic nuclei, and we suspect that the X-ray emission originates from unresolved populations of high-mass X-ray binaries. We discuss the LX-SFR-metallicity plane for star-forming galaxies and show that the two LCGs are consistent with the prediction of this relation. This is the first detection of Green Pea analogues in X-rays.

  6. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  7. Isomer-shift analogue in neutron resonances

    NASA Astrophysics Data System (ADS)

    Meister, A.; Pabst, D.; Pikelner, L. B.; Seidel, K.

    1981-06-01

    For the first time, the recently predicted chemical shift of neutron resonances, to be regarded as an analogue to the Mössbauer isomer shift, has been experimentally observed studying the 6.67 eV resonance of 238U. The experimental shifts were determined by a chi-square fitting technique from the time-of-flight transmission spectra of metallic uranium and four uranium compounds measured at the Dubna IBR-30 pulsed reactor. A computational method has been applied to estimate, and compensate for, the influence of the crystal-lattice vibrations on the experimental values thus obtained. The electron density differences at the nucleus have been calculated for the various sample pairs using available data on chemical X-ray shifts in uranium compounds, on Mössbauer isomer shifts in isovalent neptunium compounds and on free-ion electron densities. The resonance shift results lead to the conclusion that the mean-square charge radius of 238U diminishes by 1.7 -0.8+1.2 fm 2 upon capturing the resonance neutron.

  8. [Lipids, depression and suicide].

    PubMed

    Colin, A; Reggers, J; Castronovo, V; Ansseau, M

    2003-01-01

    Polyunsatured fatty acids are made out of a hydrocarbonated chain of variable length with several double bonds. The position of the first double bond (omega) differentiates polyunsatured omega 3 fatty acids (for example: alpha-linolenic acid or alpha-LNA) and polyunsatured omega 6 fatty acids (for example: linoleic acid or LA). These two classes of fatty acids are said to be essential because they cannot be synthetised by the organism and have to be taken from alimentation. The omega 3 are present in linseed oil, nuts, soya beans, wheat and cold water fish whereas omega 6 are present in maize, sunflower and sesame oil. Fatty acids are part of phospholipids and, consequently, of all biological membranes. The membrane fluidity, of crucial importance for its functioning, depends on its lipidic components. Phospholipids composed of chains of polyunsatured fatty acids increase the membrane fluidity because, by bending some chains, double bonds prevent them from compacting themselves perfectly. Membrane fluidity is also determined by the phospholipids/free cholesterol ratio, as cholesterol increases membrane viscosity. A diet based on a high proportion of essential polyunsatured fatty acids (fluid) would allow a higher incorporation of cholesterol (rigid) in the membranes to balance their fluidity, which would contribute to lower blood cholesterol levels. Brain membranes have a very high content in essential polyunsatured fatty acids for which they depend on alimentation. Any dietary lack of essential polyunsatured fatty acids has consequences on cerebral development, modifying the activity of enzymes of the cerebral membranes and decreasing efficiency in learning tasks. The prevalence of depression seems to increase continuously since the beginning of the century. Though different factors most probably contribute to this evolution, it has been suggested that it could be related to an evolution of alimentary patterns in the Western world, in which polyunsatured omega 3

  9. Lipids of Ankistrodesmus braunii.

    PubMed

    WILLIAMS, V R; McMILLAN, R

    1961-02-17

    Ankistrodesmus braunii wasgrown to stationary phase on a chemically defined medium and its cellular lipids were analyzed. The lipid content was found to vary from 18 to 73 percent of dry weight for cultures of different age and method of analysis. The pigments of the nonsaponifiable fraction were separated by adsorption chromatography and counter-current extraction and tentatively identified. The fatty acid fraction was converted to the corresponding methyl esters and analyzed by gas chromatography. The principal fatty acids present were: palmitic, oleic, and linolenic acids. Traces were detected of caprylic, capric, lauric, and palmitoleic acids.

  10. About lipids and toxins.

    PubMed

    Reig, Núria; van der Goot, F Gisou

    2006-10-09

    Many mono or multicellular organisms secrete soluble proteins, referred to as protein toxins, which alter the behavior of foreign, or target cells, possibly leading to their death. These toxins affect either the cell membrane by forming pores or modifying lipids, or some intracellular target. To reach this target, they must cross one of the cellular membranes, generally that of an intracellular organelle. As described in this minireview, lipids play crucial roles in the intoxication process of most if not all toxins, by allowing/promoting binding, endocytosis, trafficking and/or translocation into the cytoplasm.

  11. Immobilized lipid-bilayer materials

    DOEpatents

    Sasaki, Darryl Y.; Loy, Douglas A.; Yamanaka, Stacey A.

    2000-01-01

    A method for preparing encapsulated lipid-bilayer materials in a silica matrix comprising preparing a silica sol, mixing a lipid-bilayer material in the silica sol and allowing the mixture to gel to form the encapsulated lipid-bilayer material. The mild processing conditions allow quantitative entrapment of pre-formed lipid-bilayer materials without modification to the material's spectral characteristics. The method allows for the immobilization of lipid membranes to surfaces. The encapsulated lipid-bilayer materials perform as sensitive optical sensors for the detection of analytes such as heavy metal ions and can be used as drug delivery systems and as separation devices.

  12. Act resilient.

    PubMed

    Joseph, Genie; Bice-Stephens, Wynona

    2014-01-01

    Attendees have reported changing from being fearful to serene, from listless to energized, from disengaged to connected, and becoming markedly less anxious in a few weeks. Anecdotally, self-reported stress levels have been reduced by over 50% after just one class. Attendees learn not to be afraid of their feelings by working with emotions in a playful manner. When a person can act angry, but separate himself from his personal story, the emotional energy exists in a separate form that is not attached to specific events, and can be more easily dealt with and neutralized. Attendees are taught to "take out the emotional trash" through expressive comedy. They become less intimated by their own emotional intensity and triggers as they learn how even metaphorical buckets of anger, shame, guilt and hurt can be emotionally emptied. The added benefit is that this is accomplished without the disclosure of personal information of the requirement to reexperience past pain which can trigger its own cascade of stress.

  13. Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.

    PubMed

    Pathak, N M; Pathak, V; Lynch, A M; Irwin, N; Gault, V A; Flatt, P R

    2015-09-05

    The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3β. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.

  14. Chemically-activatable alkyne-tagged probe for imaging microdomains in lipid bilayer membranes

    PubMed Central

    Yamaguchi, Satoshi; Matsushita, Taku; Izuta, Shin; Katada, Sumika; Ura, Manami; Ikeda, Taro; Hayashi, Gosuke; Suzuki, Yuta; Kobayashi, Koya; Tokunaga, Kyoya; Ozeki, Yasuyuki; Okamoto, Akimitsu

    2017-01-01

    A chemically-activatable alkynyl steroid analogue probe has been synthesized for visualizing the lipid raft membrane domains by Raman microscopy. The Raman probe, in which ring A of its steroid backbone is replaced with an alkynyl group, was designed to enable activation of the alkyne signal through the Eschenmoser-Tanabe fragmentation reaction of the oxidized cholesterol precursor in lipid bilayer membranes. The alkynyl steroid analogue was observed to form liquid-ordered raft-like domains on a model giant-liposome system in a similar manner as cholesterol, and the large alkyne signal of the accumulated probe at 2120 cm−1 was mapped on the microdomains with a Raman microscope. The alkyne moiety of the probe was confirmed to be converted from the α,β-epoxy ketone group of its precursor by reaction with p-toluensulfonyl hydrazine under a mild condition. Through the reaction, the alkyne signal of the probe was activated on the lipid bilayer membrane of liposomes. Furthermore, the signal activation of the probe was also detected on living cells by stimulated Raman scattering microscopy. The ring-A-opened alkyne steroid analogue, thus, provides a first chemically-activatable Raman probe as a promising tool for potentially unravelling the intracellular formation and trafficking of cholesterol-rich microdomains. PMID:28117375

  15. Nuclear Lipids in the Nervous System: What they do in Health and Disease.

    PubMed

    Garcia-Gil, Mercedes; Albi, Elisabetta

    2017-02-01

    In the last 20 years it has been widely demonstrated that cell nucleus contains neutral and polar lipids localized in nuclear membranes, nucleoli, nuclear matrix and chromatin. Nuclear lipids may show specific organization forming nuclear lipid microdomains and have both structural and functional roles. Depending on their localization, nuclear lipids play different roles such as the regulation of nuclear membrane and nuclear matrix fluidity but they also can act as platforms for vitamin and hormone function, for active chromatin anchoring, and for the regulation of gene expression, DNA duplication and transcription. Crosstalk among different kinds of lipid signalling pathways influence the physiopathology of numerous cell types. In neural cells the nuclear lipids are involved in cell proliferation, differentiation, inflammation, migration and apoptosis. Abnormal metabolism of nuclear lipids might be closely associated with tumorigenesis and neurodegenerative diseases such as Alzheimer disease and Parkinson disease among others.

  16. Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery.

    PubMed

    Date, Abhijit A; Vador, Nimish; Jagtap, Aarti; Nagarsenker, Mangal S

    2011-07-08

    To evaluate the ability of Gelucire 50/13 (an amphiphilic lipid excipient) to act as a stabilizer for lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and to establish the ability of Gelucire 50/13 based lipid nanocarriers to improve oral delivery of hydrophobic drugs using repaglinide (RPG) as a model drug. The ability of Gelucire 50/13 to nanosize various solid lipids was evaluated. The ability of Gelucire 50/13 to yield NLC was evaluated by using Precirol ATO 5 as a model solid lipid and various liquid lipids (oils). Gelucire 50/13 based NLC (GeluPearl) were evaluated for their ability to improve the efficacy of RPG on oral administration in comparison to RPG tablets. The short term stability of RPG-GeluPearl was evaluated at 25 °C/60% RH. Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month.

  17. Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery

    NASA Astrophysics Data System (ADS)

    Date, Abhijit A.; Vador, Nimish; Jagtap, Aarti; Nagarsenker, Mangal S.

    2011-07-01

    Purpose. To evaluate the ability of Gelucire 50/13 (an amphiphilic lipid excipient) to act as a stabilizer for lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and to establish the ability of Gelucire 50/13 based lipid nanocarriers to improve oral delivery of hydrophobic drugs using repaglinide (RPG) as a model drug. Methods. The ability of Gelucire 50/13 to nanosize various solid lipids was evaluated. The ability of Gelucire 50/13 to yield NLC was evaluated by using Precirol ATO 5 as a model solid lipid and various liquid lipids (oils). Gelucire 50/13 based NLC (GeluPearl) were evaluated for their ability to improve the efficacy of RPG on oral administration in comparison to RPG tablets. The short term stability of RPG-GeluPearl was evaluated at 25 °C/60% RH. Results. Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month. Indian patent application number 2167/MUM/2008.

  18. A Non-Verbal Analogue to the Verbal Transformation Effect

    ERIC Educational Resources Information Center

    Lass, Norman J.; And Others

    1973-01-01

    Investigates the effectiveness of non-speech auditory stimuli in eliciting transformations analogous to those reported for speech stimuli to determine if a non-verbal analogue to the verbal transformation effect exists. (DD)

  19. Trustworthiness and Influence: A Reexamination in an Extended Counseling Analogue.

    ERIC Educational Resources Information Center

    Rothmeier, Rosemarie C.; Dixon, David N.

    1980-01-01

    The study demonstrated that: (1) interviewer trustworthiness can be manipulated in an analogue interview setting; and (2) interviewer trustworthiness is related to interpersonal influence in the interview setting. Findings follow a pattern of outcomes predicted by cognitive dissonance theory. (Author)

  20. Generalised insulin oedema after intensification of treatment with insulin analogues.

    PubMed

    Adamo, Luigi; Thoelke, Mark

    2013-02-20

    We report a case of generalised insulin oedema after intensification of treatment with genetically modified insulin. This is the first case of generalised oedema in response to treatment with insulin analogues in a patient not insulin naive.

  1. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful?

  2. Effect of glutamate analogues on brain tumor cell lines.

    PubMed

    Campbell, G L; Bartel, R; Freidman, H S; Bigner, D D

    1985-10-01

    Glutamate analogues have been used in many different experimental approaches in neurobiology. A small number of these analogues have been classified as gliotoxic. We have examined the effect of seven glutamate analogues (five gliotoxic and two neurotoxic) on the growth and viability of four human glioma cell lines, one human medulloblastoma cell line, and one human sarcoma cell line. Aminoadipic acid and homocysteic acid predominantly affected the growth of two glioma cell lines in the presence of 4 mM glutamine. Phosphonobutyric acid predominantly affected the other two glioma cell lines and the medulloblastoma cell line in the presence of 4 mM glutamine. In medium containing no glutamine, all three analogues had marked effects on all the cell lines except the sarcoma cell line. These effects were dose dependent. We postulate that these results can in part be explained on the basis of metabolic compartmentalization.

  3. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

  4. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

  5. Weather and event generators based on analogues of atmospheric circulation

    NASA Astrophysics Data System (ADS)

    Yiou, Pascal

    2015-04-01

    Analogues of atmospheric circulation have had numerous applications on weather prediction, climate reconstructions and detection/attribution analyses. A stochastic weather generator based on circulation analogues was recently proposed by Yiou (2014) to simulate sequences of European temperatures. One of the features of this weather generator is that it preserves the spatial and temporal structures of the climate variables to be simulated. This method is flexible enough to be combined efficiently with a storm detection algorithm in order to generate large catalogues of high impact extra-tropical storms that hit Europe. I will present the gist of the method of circulation analogues and some performances. Two promising applications for weather generators based on this method (ensemble climate prediction and extra-tropical storms) will be tested. References Yiou, P.: AnaWEGE: a weather generator based on analogues of atmospheric circulation, Geosci. Model Dev., 7, 531-543, doi:10.5194/gmd-7-531-2014, 2014.

  6. Cell-cycle analyses using thymidine analogues in fission yeast.

    PubMed

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

    Thymidine analogues are powerful tools when studying DNA synthesis including DNA replication, repair and recombination. However, these analogues have been reported to have severe effects on cell-cycle progression and growth, the very processes being investigated in most of these studies. Here, we have analyzed the effects of 5-ethynyl-2'-deoxyuridine (EdU) and 5-Chloro-2'-deoxyuridine (CldU) using fission yeast cells and optimized the labelling procedure. We find that both analogues affect the cell cycle, but that the effects can be mitigated by using the appropriate analogue, short pulses of labelling and low concentrations. In addition, we report sequential labelling of two consecutive S phases using EdU and 5-bromo-2'-deoxyuridine (BrdU). Furthermore, we show that detection of replicative DNA synthesis is much more sensitive than DNA-measurements by flow cytometry.

  7. Analogues for Wild2: Carbonaceous Chondrites Shot into Aerogel

    NASA Astrophysics Data System (ADS)

    Hicks, L. J.; Bridges, J. C.; MacArthur, J. L.; Wickham-Eade, J. E.; Price, M. C.; Burchell, M. J.; Butterworth, A. L.; Baker, S. H.

    2016-08-01

    Comet Wild2 particles show similarities to carbonaceous chondrites. We compare Wild2 grains to analogue shots of CV3 and CR2 powders in aerogel tracks, using the same techniques, to make accurate comparisons.

  8. Expanding roles for lipid droplets

    PubMed Central

    Welte, Michael A.

    2015-01-01

    Summary Lipid droplets are the intracellular sites for neutral lipid storage. They are critical for lipid metabolism and energy homeostasis, and their dysfunction has been linked to many diseases. Accumulating evidence suggests that the roles lipid droplets play in biology are significantly broader than previously anticipated. Lipid droplets are the source of molecules important in the nucleus: they can sequester transcription factors and chromatin components and generate the lipid ligands for certain nuclear receptors. Lipid droplets have also emerged as important nodes for fatty acid trafficking, both inside the cell and between cells. In immunity, new roles for droplets, not directly linked to lipid metabolism, have been uncovered, as assembly platforms for specific viruses and as reservoirs for proteins that fight intracellular pathogens. Until recently, knowledge about droplets in the nervous system has been minimal, but now there are multiple links between lipid droplets and neurodegeneration: Many candidate genes for Hereditary Spastic Paraplegia also have central roles in lipid-droplet formation and maintenance, and mitochondrial dysfunction in neurons can lead to transient accumulating of lipid droplets in neighboring glial cells, an event that may, in turn, contribute to neuronal damage. As the cell biology and biochemistry of lipid droplets are increasingly well understood, the next few years should yield many new mechanistic insights into these novel functions of lipid droplets. PMID:26035793

  9. Asymmetric heat transfer from nanoparticles in lipid bilayers

    NASA Astrophysics Data System (ADS)

    Potdar, Dipti; Sammalkorpi, Maria

    2015-12-01

    Here, we use molecular dynamics simulations to characterize the heat transfer properties of lipid bilayer - gold nanoparticle systems in which the nanoparticle acts as a heat source. The focus is on dipalmitoylphosphatidylcholine (DPPC) lipid bilayers and thiolated alcohol and alkyl functionalized nanoparticles as prototype hydrophilic and hydrophobic nanoparticles. We find hydrophilic nanoparticles which are partly in contact with the surrounding water environment are more efficient in transferring heat to the system than hydrophobic ones which reside surrounded by the membrane. This is because of the hydrogen bonding capability of the hydroxy pentanethiol and the more efficient heat conductivity through water than the lipid bilayer. Additionally, we find the heat conductance is strongly asymmetric and has a discontinuity between the bilayer leaflets. In total, the findings provide understanding on heat transport from localized heat sources in lipid bilayers and could bear significance, e.g., in engineering and controlling photoactivated triggering of liposomal systems.

  10. Cytarabine Lipid Complex Injection

    MedlinePlus

    ... used to treat lymphomatous meningitis (a type of cancer in the covering of the spinal cord and brain). Cytarabine lipid complex is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in your body.

  11. Lipid composition of cyanidium.

    PubMed

    Allen, C F; Good, P; Holton, R W

    1970-11-01

    The major lipids in Cyanidium caldarium Geitler are monogalactosyl diglyceride, digalactosyl diglyceride, plant sulfolipid, lecithin, phosphatidyl glycerol, phosphatidyl inositol, and phosphatidyl ethanolamine. Fatty acid composition varies appreciably among the lipids, but the major ones are palmitic acid, oleic acid, linoleic acid, and moderate amounts of stearic acid. Trace amounts of other acids in the C(14) to C(20) range were also present. Moderate amounts of linolenic acid were found in two strains, but not in a third. The proportion of saturated acid is relatively high in all lipids ranging from about a third in monogalactosyl diglyceride to three-fourths in sulfolipid. This may be a result of the high growth temperature. Lipases forming lysosulfolipid, and lysophosphatidyl glycerol are active in ruptured cells; galactolipid is degraded with loss of both acyl residues. Thus the lipid and fatty acid composition of Cyanidium more closely resembles that of green algae than that of the blue-green algae, although there are differences of possible phylogenetic interest.

  12. Planar bilayer lipid memebranes

    NASA Astrophysics Data System (ADS)

    Tien, H. Ti

    The planar bilayer lipid membrane, also known as lipid bilayer membrane, black lipid membrane or simply BLM(s), for short, has been investigated since its inception in 1960, the details of which have been described in a monograph published in 1974. This review is a report on the advances in the BLM research since that time. After a brief introduction, the first five sections consider various aspects of experimental methods, optical properties, thermodynamics of lipid bilayers, permeability, and electrical properties of BLMs. Section 7 deals with the use of BLM as energy transducer, particularly the transduction of light into electrical energy. Section 8, the longest portion of the paper, is devoted to modelling of biomembranes, such as the plasma membrane of cells, the thylakoid membrane of chloroplasts, the cristae membrane of mitochondria, the visual receptor membrane of the eye, and the nerve membrane. The concluding section points out that studies of BLMs facilitate the initial testing of working hypothses and may lead to a better choice of appropriate in vivo and reconstituted membrane experiments.

  13. Lipids in cheese

    USDA-ARS?s Scientific Manuscript database

    Lipids are present in cheese at levels above 20 percent and are analyzed by several techniques. Scanning electron microscopy and confocal laser scanning microscopy are used to examine the microstructure, gas chromatography is employed to look at fatty acid composition, and differential scanning cal...

  14. Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

    PubMed

    Aoyagi, Yutaka; Fujiwara, Koji; Yamazaki, Akira; Sugawara, Naoko; Yano, Reiko; Fukaya, Haruhiko; Hitotsuyanagi, Yukio; Takeya, Koichi; Ishiyama, Aki; Iwatsuki, Masato; Otoguro, Kazuhiko; Yamada, Haruki; Ōmura, Satoshi

    2014-01-15

    A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.

  15. Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics.

    PubMed

    Ichikawa, Satoshi; Yamaguchi, Mayumi; Hsuan, Lee Shang; Kato, Yuta; Matsuda, Akira

    2015-04-10

    Carbacaprazamycins, which are chemically stable analogues of caprazamycins, were designed and synthesized. These analogues were active against drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and their activities were comparable to those of the parent caprazamycins. The effect of treatment with carbacaprazamycin on morphological changes in S. aureus indicated that the mode of action was completely different from those of existing peptidoglycan inhibitors.

  16. Adjuvant properties of a simplified C32 monomycolyl glycerol analogue.

    PubMed

    Bhowruth, Veemal; Minnikin, David E; Agger, Else Marie; Andersen, Peter; Bramwell, Vincent W; Perrie, Yvonne; Besra, Gurdyal S

    2009-04-01

    A simplified C(32) monomycolyl glycerol (MMG) analogue demonstrated enhanced immunostimulatory activity in a dioctadecyl ammonium bromide (DDA)/Ag85B-ESAT-6 formulation. Elevated levels of IFN-gamma and IL-6 were produced in spleen cells from mice immunised with a C(32) MMG analogue comparable activity to the potent Th1 adjuvant, trehalose 6,6'-di-behenate (TDB).

  17. Analogue and digital linear modulation techniques for mobile satellite

    NASA Technical Reports Server (NTRS)

    Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

    1990-01-01

    The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

  18. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  19. Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

    PubMed

    Singh, Vijay P; Poon, Jia-fei; Engman, Lars

    2013-12-20

    In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

  20. Iterative Approach to the Discovery of Novel Degarelix Analogues: Substitutions at Positions 3, 7 and 8. Part II

    PubMed Central

    Samant, Manoj P.; Gulyas, Jozsef; Hong, Doley J.; Croston, Glenn; Rivier, Catherine; Rivier, Jean

    2008-01-01

    Degarelix, (FE200486, Ac-d-2Nal1-d-4Cpa2-d-3Pal3-Ser4-4Aph(l-Hor)5-d-4Aph(Cbm)6-Leu7-Ilys8-Pro9-d-Ala10-NH2) is a potent and very long acting antagonist of gonadotropin-releasing hormone (GnRH) after subcutaneous administration in mammals including humans. Analogues of degarelix were synthesized, characterized and screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. The duration of action was also determined in the castrated male rat assay in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone (LH) release. Structurally, this series of analogues has novel substitutions at positions 3, 7, 8 and Nα-methylation at positions 6, 7 and 8 in the structure of degarelix. These substitutions were designed to probe the spatial limitations of the receptors cavity and to map the steric and ionic boundaries. Some functional groups were introduced that were hypothesized to influence the phamacokinetic properties of the analogues like bioavailability, solubility, intra- or inter-molecular hydrogen bond forming capacity and ability to bind carrier proteins. Substitutions at positions 3 ([Nβ-(2-pyridyl-methyl)d-Dap3]degarelix, IC50 = 2.71 nM) (5), 7 ([Pra7]degarelix, IC50 = 2.11 nM) (16), 8 ([Nδ-(IGly)Orn8]degarelix, IC50 = 1.38 nM) (20), and N-methylation ([Nα-methyl-Leu7]degarelix, IC50 = 1.47 nM) (32) yielded analogues that were equipotent to degarelix (2) in vitro (IC50 = 1.64 nM) but shorter acting in vivo. Out of the 33 novel analogues tested for the duration of action in this series, two analogues ([Nε-cyclohexyl-Lys8]degarelix, IC50 = 1.50 nM) (23) and ([Nβ-(IβAla)Dap8]degarelix, IC50 = 1.98 nM) (26) had antagonist potencies and duration of action similar to that of azaline B {inhibited LH (>80%) release for >72 h after sc injection to castrated male rats at a standard dose of 50 µg/rat in 5% mannitol}. Under similar conditions analogues ([N

  1. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers

    PubMed Central

    2017-01-01

    Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition

  2. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers.

    PubMed

    Liu, Yun; Lehn, Jean-Marie; Hirsch, Anna K H

    2017-02-21

    Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular

  3. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  4. Analogue gravitational phenomena in Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2012-08-01

    Analogue gravity is based on the simple observation that perturbations propagating in several physical systems can be described by a quantum field theory in a curved spacetime. While phenomena like Hawking radiation are hardly detectable in astrophysical black holes, these effects may be experimentally tested in analogue systems. In this Thesis, focusing on Bose-Einstein condensates, we present our recent results about analogue models of gravity from three main perspectives: as laboratory tests of quantum field theory in curved spacetime, for the techniques that they provide to address various issues in general relativity, and as toy models of quantum gravity. The robustness of Hawking-like particle creation is investigated in flows with a single black hole horizon. Furthermore, we find that condensates with two (white and black) horizons develop a dynamical instability known in general relativity as black hole laser effect. Using techniques borrowed from analogue gravity, we also show that warp drives, which are general relativistic spacetimes allowing faster-than-light travel, are unstable. Finally, the cosmological constant issue is investigated from an analogue gravity perspective and relativistic Bose-Einstein condensates are proposed as new analogue systems with novel interesting properties.

  5. The relevance of analogue studies for understanding obsessions and compulsions.

    PubMed

    Abramowitz, Jonathan S; Fabricant, Laura E; Taylor, Steven; Deacon, Brett J; McKay, Dean; Storch, Eric A

    2014-04-01

    Analogue samples are often used to study obsessive-compulsive (OC) symptoms and related phenomena. This approach is based on the hypothesis that results derived from such samples are relevant to understanding OC symptoms in individuals with a diagnosis of obsessive-compulsive disorder (OCD). Two decades ago, Gibbs (1996) reviewed the available literature and found initial support for this hypothesis. Since then there have been many important advances addressing this issue. The purpose of the present review was to synthesize various lines of research examining the assumptions of using analogue samples to draw inferences about people with OCD. We reviewed research on the prevalence of OC symptoms in non-clinical populations, the dimensional (vs. categorical) nature of these symptoms, phenomenology, etiology, and studies on developmental and maintenance factors in clinical and analogue samples. We also considered the relevance of analogue samples in OCD treatment research. The available evidence suggests research with analogue samples is highly relevant for understanding OC symptoms. Guidelines for the appropriate use of analogue designs and samples are suggested.

  6. Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

    PubMed

    Satishkumar, Sakilam; Vuram, Prasanna K; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J; Montemayor, Michelle M Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K

    2015-10-09

    Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  7. Amphotericin B Lipid Complex Injection

    MedlinePlus

    Amphotericin B lipid complex injection is used to treat serious, possibly life-threatening fungal infections in people who did not respond ... to tolerate conventional amphotericin B therapy. Amphotericin B lipid complex injection is in a class of medications ...

  8. Prostaglandin analogues in the treatment of glaucoma.

    PubMed

    Lindén, C; Alm, A

    1999-05-01

    Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available. Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 microg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including beta-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes. Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published.

  9. Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

    PubMed Central

    Kaščáková, Slávka; Hofland, Leo J.; De Bruijn, Henriette S.; Ye, Yunpeng; Achilefu, Samuel; van der Wansem, Katy; van der Ploeg-van den Heuvel, Angelique; van Koetsveld, Peter M.; Brugts, Michael P.; van der Lelij, Aart-Jan; Sterenborg, Henricus J. C. M.; ten Hagen, Timo L. M.; Robinson, Dominic J.; van Hagen, Martin P.

    2014-01-01

    Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate. PMID:25111655

  10. Lipid partitioning at the nuclear envelope controls membrane biogenesis

    PubMed Central

    Barbosa, Antonio Daniel; Sembongi, Hiroshi; Su, Wen-Min; Abreu, Susana; Reggiori, Fulvio; Carman, George M.; Siniossoglou, Symeon

    2015-01-01

    Partitioning of lipid precursors between membranes and storage is crucial for cell growth, and its disruption underlies pathologies such as cancer, obesity, and type 2 diabetes. However, the mechanisms and signals that regulate this process are largely unknown. In yeast, lipid precursors are mainly used for phospholipid synthesis in nutrient-rich conditions in order to sustain rapid proliferation but are redirected to triacylglycerol (TAG) stored in lipid droplets during starvation. Here we investigate how cells reprogram lipid metabolism in the endoplasmic reticulum. We show that the conserved phosphatidate (PA) phosphatase Pah1, which generates diacylglycerol from PA, targets a nuclear membrane subdomain that is in contact with growing lipid droplets and mediates TAG synthesis. We find that cytosol acidification activates the master regulator of Pah1, the Nem1-Spo7 complex, thus linking Pah1 activity to cellular metabolic status. In the absence of TAG storage capacity, Pah1 still binds the nuclear membrane, but lipid precursors are redirected toward phospholipids, resulting in nuclear deformation and a proliferation of endoplasmic reticulum membrane. We propose that, in response to growth signals, activation of Pah1 at the nuclear envelope acts as a switch to control the balance between membrane biogenesis and lipid storage. PMID:26269581

  11. Lipid modulation of thermal transient receptor potential channels.

    PubMed

    Hernández-García, Enrique; Rosenbaum, Tamara

    2014-01-01

    There is a subgroup of transient receptor potential (TRP) ion channels that are responsive to temperature (thermo-TRP channels). These are important to a variety of sensory and physiological phenomena such as pain and taste perception. All thermo-TRP channels known to date are subject to modulation by lipidic molecules of many kinds, from the ubiquitous cholesterol to more specialized molecules such as prostaglandins. Although the mechanisms and sites of binding of lipids on thermo-TRPs are largely unknown, the explosion on research of lipids and ion channels has revealed previously unsuspected roles for them. Diacyl glycerol is a lipid produced by phospholipase C (PLC) and it was discovered to modulate TRP channels in the eye of the fly, and many mammal TRP channels have been found to interact with lipids. While most of the lipids acting on thermo-TRP channels have been found to activate them, there are a few capable of inhibition. Phosphatidylinositol 4,5-bisphosphate is even capable of both inhibition and activation on a couple of thermo-TRPs, depending on the cellular context. More data is required to assess the mechanism through which lipids affect thermo-TRP channel activity and the physiological importance of this interaction.

  12. Lipid rafts in immune signalling: current progress and future perspective.

    PubMed

    Varshney, Pallavi; Yadav, Vikas; Saini, Neeru

    2016-09-01

    Lipid rafts are dynamic assemblies of proteins and lipids that harbour many receptors and regulatory molecules and so act as a platform for signal transduction. They float freely within the liquid-disordered bilayer of cellular membranes and can cluster to form larger ordered domains. Alterations in lipid rafts are commonly found to be associated with the pathogenesis of several human diseases and recent reports have shown that the raft domains can also be perturbed by targeting raft proteins through microRNAs. Over the last few years, the importance of lipid rafts in modulating both innate and acquired immune responses has been elucidated. Various receptors present on immune cells like B cells, T cells, basophils and mast cells associate with lipid rafts on ligand binding and initiate signalling cascades leading to inflammation. Furthermore, disrupting lipid raft integrity alters lipopolysaccharide-induced cytokine secretion, IgE signalling, and B-cell and T-cell activation. The objective of this review is to summarize the recent progress in understanding the role of lipid rafts in the modulation of immune signalling and its related therapeutic potential for autoimmune diseases and inflammatory disorders.

  13. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  14. Lipid deacylating enzymes in plants: old activities, new genes.

    PubMed

    Matos, Ana Rita; Pham-Thi, Anh-Thu

    2009-06-01

    Because lipids are major components of cellular membranes, their degradation under stress conditions compromises compartmentalization. However, in addition to having structural roles, membrane lipids are also implicated in signalling processes involving the activity of lipolytic enzymes. Phospholipases D and C, acting on the polar heads of phospholipids, have been relatively well characterized in plants. In contrast, knowledge of lipid deacylating enzymes remains limited. Lipid acyl hydrolases (LAH) are able to hydrolyse both fatty acid moieties of polar lipids. They differ from phospholipases A(1) or A(2) (PLA) acting on sn-1 or sn-2 positions of phospholipids, respectively, as well as from lipases which de-esterify triacylglycerols. The free polyunsaturated fatty acids generated by deacylating enzymes can be used in the biosynthesis of oxylipins and the lysophospholipids, provided by PLAs, are also bioactive molecules. In the four decades that have passed since the first description of LAH activities in plants some enzymes have been purified. In recent years, the widespread use of molecular approaches together with the attention paid to lipid signalling has contributed to a renewed interest in LAH and has led to the identification of different gene families and the characterization of new enzymes. Additionally, several proteins with putative lipase/esterase signatures have been identified. In the present paper we review currently available data on LAHs, PLAs, triacylglycerol lipases and other putative deacylating enzymes. The roles of lipid deacylating enzymes in plant growth, development and stress responses are discussed in the context of their involvement in membrane deterioration, lipid turnover and cellular signalling.

  15. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

    PubMed

    Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

    2013-01-01

    We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

  16. Cytostatic versus Cytocidal Activities of Chloroquine Analogues and Inhibition of Hemozoin Crystal Growth

    PubMed Central

    Gorka, Alexander P.; Alumasa, John N.; Sherlach, Katy S.; Jacobs, Lauren M.; Nickley, Katherine B.; Brower, Jonathan P.; de Dios, Angel C.

    2013-01-01

    We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365–374, 2013). PMID:23114783

  17. Lipid tubule growth by osmotic pressure

    NASA Astrophysics Data System (ADS)

    Rangamani, Padmini; Zhang, Di; Orster, George; Shen, Amy

    2013-11-01

    We present here a procedure for growing lipid tubules in vitro. This method allows us to grow tubules of consistent shape and structure and thus can be a useful tool for nano-engineering applications. There are three stages during the tubule growth process: initiation, elongation and termination. Balancing the forces that act on the tubule head shows that the growth of tubules during the elongation phase depends on the balance between osmotic pressure and the viscous drag exerted on the membrane from the substrate and the external fluid. Using a combination of mathematical modeling and experiment, we identify the key forces that control tubule growth during the elongation phase.

  18. Imaging the Effects of Prostaglandin Analogues on Cultured Trabecular Meshwork Cells by Coherent Anti-Stokes Raman Scattering

    PubMed Central

    Lei, Tim C.; Masihzadeh, Omid; Kahook, Malik Y.; Ammar, David A.

    2013-01-01

    Purpose. The aim of this study was to nondestructively monitor morphological changes to the lipid membranes of primary cultures of living human trabecular meshwork cells (hTMC) without the application of exogenous label. Methods. Live hTMC were imaged using two nonlinear optical techniques: coherent anti-Stokes Raman scattering (CARS) and two-photon autofluorescence (TPAF). The hTMC were treated with a commercial formulation of latanoprost (0.5 μg/mL) for 24 hours before imaging. Untreated cells and cells treated with vehicle containing the preservative benzalkonium chloride (BAK; 2 μg/mL) were imaged as controls. After CARS/TPAF imaging, hTMC were fixed, stained with the fluorescent lipid dye Nile Red, and imaged by conventional confocal microscopy to verify lipid membrane structures. Results. Analysis of CARS/TPAF images of hTMC treated with latanoprost revealed multiple intracellular lipid membranes absent from untreated or BAK-treated hTMC. Treatment of hTMC with sodium fluoride or ouabain, agents shown to cause morphological changes to hTMC, also did not induce formation of intracellular lipid membranes. Conclusions. CARS microscopy detected changes in living hTMC morphology that were validated by subsequent histological stain. Prostaglandin-induced changes to hTMC involved rearrangement of lipid membranes within these cells. These in vitro results identify a novel biological response to a class of antiglaucoma drugs, and further experiments are needed to establish how this effect is involved in the hypotensive action of prostaglandin analogues in vivo. PMID:23900606

  19. Lipid nanotube or nanowire sensor

    DOEpatents

    Noy, Aleksandr [Belmont, CA; Bakajin, Olgica [San Leandro, CA; Letant, Sonia [Livermore, CA; Stadermann, Michael [Dublin, CA; Artyukhin, Alexander B [Menlo Park, CA

    2009-06-09

    A sensor apparatus comprising a nanotube or nanowire, a lipid bilayer around the nanotube or nanowire, and a sensing element connected to the lipid bilayer. Also a biosensor apparatus comprising a gate electrode; a source electrode; a drain electrode; a nanotube or nanowire operatively connected to the gate electrode, the source electrode, and the drain electrode; a lipid bilayer around the nanotube or nanowire, and a sensing element connected to the lipid bilayer.

  20. Lipid nanotube or nanowire sensor

    DOEpatents

    Noy, Aleksandr [Belmont, CA; Bakajin, Olgica [San Leandro, CA; Letant, Sonia [Livermore, CA; Stadermann, Michael [Dublin, CA; Artyukhin, Alexander B [Menlo Park, CA

    2010-06-29

    A sensor apparatus comprising a nanotube or nanowire, a lipid bilayer around the nanotube or nanowire, and a sensing element connected to the lipid bilayer. Also a biosensor apparatus comprising a gate electrode; a source electrode; a drain electrode; a nanotube or nanowire operatively connected to the gate electrode, the source electrode, and the drain electrode; a lipid bilayer around the nanotube or nanowire, and a sensing element connected to the lipid bilayer.

  1. Analogues to features and processes of a high-level radioactive waste repository proposed for Yucca Mountain, Nevada

    USGS Publications Warehouse

    Simmons, Ardyth M.; Stuckless, John S.; with a Foreword by Abraham Van Luik, U.S. Department of Energy

    2010-01-01

    Natural analogues are defined for this report as naturally occurring or anthropogenic systems in which processes similar to those expected to occur in a nuclear waste repository are thought to have taken place over time periods of decades to millennia and on spatial scales as much as tens of kilometers. Analogues provide an important temporal and spatial dimension that cannot be tested by laboratory or field-scale experiments. Analogues provide one of the multiple lines of evidence intended to increase confidence in the safe geologic disposal of high-level radioactive waste. Although the work in this report was completed specifically for Yucca Mountain, Nevada, as the proposed geologic repository for high-level radioactive waste under the U.S. Nuclear Waste Policy Act, the applicability of the science, analyses, and interpretations is not limited to a specific site. Natural and anthropogenic analogues have provided and can continue to provide value in understanding features and processes of importance across a wide variety of topics in addressing the challenges of geologic isolation of radioactive waste and also as a contribution to scientific investigations unrelated to waste disposal. Isolation of radioactive waste at a mined geologic repository would be through a combination of natural features and engineered barriers. In this report we examine analogues to many of the various components of the Yucca Mountain system, including the preservation of materials in unsaturated environments, flow of water through unsaturated volcanic tuff, seepage into repository drifts, repository drift stability, stability and alteration of waste forms and components of the engineered barrier system, and transport of radionuclides through unsaturated and saturated rock zones.

  2. Lanolin-derived lipid mixtures mimic closely the lipid composition and organization of vernix caseosa lipids.

    PubMed

    Rissmann, Robert; Oudshoorn, Marion H M; Kocks, Elise; Hennink, Wim E; Ponec, Maria; Bouwstra, Joke A

    2008-10-01

    The aim of the present study was to use semi-synthetic lipid mixtures to mimic the complex lipid composition, organization and thermotropic behaviour of vernix caseosa (VC) lipids. As VC shows multiple protecting and barrier supporting properties before and after birth, it is suggested that a VC substitute could be an innovative barrier cream for barrier deficient skin. Lanolin was selected as the source of the branched chain sterol esters and wax esters--the main lipid classes of VC. Different lipid fractions were isolated from lanolin and subsequently mixed with squalene, triglycerides, cholesterol, ceramides and fatty acids to generate semi-synthetic lipid mixtures that mimic the lipid composition of VC, as established by high-performance thin-layer chromatography. Differential scanning calorimetry and Fourier transform infrared spectroscopy investigations revealed that triglycerides play an important role in the (lateral) lipid organization and thermotropic behaviour of the synthetic lipid mixtures. Excellent resemblance of VC lipids was obtained when adding unsaturated triglycerides. Moreover, these lipid mixtures showed similar long range ordering as VC. The optimal lipid mixture was evaluated on tape-stripped hairless mouse skin in vivo. The rate of barrier recovery was increased and comparable to VC lipid treatment.

  3. Isolation and characterization of propoxyphenyl linked sildenafil and thiosildenafil analogues in health supplements.

    PubMed

    Kee, Chee-Leong; Ge, Xiaowei; Koh, Hwee-Ling; Low, Min-Yong

    2012-11-01

    Two new phosphodiesterase-5 inhibitors (PDE-5) which consist of one sildenafil analogue and one thiosildenafil analogue have been found in heath supplements. The structural properties of these analogues have been elucidated by NMR, high resolution MS, MS(2), UV and IR spectroscopy. The sildenafil analogue is very similar to aildenafil and the thiosildenafil analogue is similar to thioaildenafil, except the ethoxy group bonded to phenyl ring is replaced by a propoxy group. Hence, the sildenafil analogue is named as propoxyphenyl aildenafil or propoxyphenyl methisosildenafil and the thiosildenafil analogue as propoxyphenyl thioaildenafil or propoxyphenyl thiomethisosildenafil. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Lipids, fatty acids, and more

    USDA-ARS?s Scientific Manuscript database

    Energy is the most expensive component in livestock diets. Lipids are concentrated energy sources and are known to affect growth, feed efficiency, feed dust, and diet palatability. A large majority of research evaluating lipids in livestock has utilized lipids of high quality, dealt mainly with anim...

  5. Lipid topogenesis--35years on.

    PubMed

    Chauhan, Neha; Farine, Luce; Pandey, Kalpana; Menon, Anant K; Bütikofer, Peter

    2016-08-01

    Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed 'lipid topogenesis', were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. "lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes", in the 35 years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. LMSD: LIPID MAPS structure database

    PubMed Central

    Sud, Manish; Fahy, Eoin; Cotter, Dawn; Brown, Alex; Dennis, Edward A.; Glass, Christopher K.; Merrill, Alfred H.; Murphy, Robert C.; Raetz, Christian R. H.; Russell, David W.; Subramaniam, Shankar

    2007-01-01

    The LIPID MAPS Structure Database (LMSD) is a relational database encompassing structures and annotations of biologically relevant lipids. Structures of lipids in the database come from four sources: (i) LIPID MAPS Consortium's core laboratories and partners; (ii) lipids identified by LIPID MAPS experiments; (iii) computationally generated structures for appropriate lipid classes; (iv) biologically relevant lipids manually curated from LIPID BANK, LIPIDAT and other public sources. All the lipid structures in LMSD are drawn in a consistent fashion. In addition to a classification-based retrieval of lipids, users can search LMSD using either text-based or structure-based search options. The text-based search implementation supports data retrieval by any combination of these data fields: LIPID MAPS ID, systematic or common name, mass, formula, category, main class, and subclass data fields. The structure-based search, in conjunction with optional data fields, provides the capability to perform a substructure search or exact match for the structure drawn by the user. Search results, in addition to structure and annotations, also include relevant links to external databases. The LMSD is publicly available at PMID:17098933

  7. First cohomology of 𝔞𝔣𝔣(1) and 𝔞𝔣𝔣(1|1) acting on linear differential operators

    NASA Astrophysics Data System (ADS)

    Basdouri, Imed; Boujelben, Maha; Derbali, Ammar

    2016-10-01

    We consider the 𝔞𝔣𝔣(1)-module structure on the spaces of differential operators acting on the spaces of weighted densities. We compute the first differential cohomology of the Lie superalgebra 𝔞𝔣𝔣(1) with coefficients in differential operators acting on the spaces of weighted densities. We study also the super analogue of this problem getting the same results.

  8. Cyclohexanol analogues are positive modulators of GABAA receptor currents and act as general anaesthetics in vivo

    USDA-ARS?s Scientific Manuscript database

    GABAA receptors meet all the pharmacological criteria required to be considered important general anaesthetic targets. In the following study, the modulatory effects of various commercially available and novel cyclohexanol were investigated on recombinant human '-aminobutyric acid (GABAA, a1ß2'2s) r...

  9. Alteration of cellular lipids and lipid metabolism markers in RTL-W1 cells exposed to model endocrine disrupters.

    PubMed

    Dimastrogiovanni, Giorgio; Córdoba, Marlon; Navarro, Isabel; Jáuregui, Olga; Porte, Cinta

    2015-08-01

    This work investigates the suitability of the rainbow trout liver cell line (RTL-W1) as an in-vitro model to study the ability of model endocrine disrupters, namely TBT, TPT, 4-NP, BPA and DEHP, to act as metabolic disrupters by altering cellular lipids and markers of lipid metabolism. Among the tested compounds, BPA and DEHP significantly increased the intracellular accumulation of triacylglycerols (TAGs), while all the compounds -apart from TPT-, altered membrane lipids - phosphatidylcholines (PCs) and plasmalogen PCs - indicating a strong interaction of the toxicants with cell membranes and cell signaling. RTL-W1 expressed a number of genes involved in lipid metabolism that were modulated by exposure to BPA, TBT and TPT (up-regulation of FATP1 and FAS) and 4-NP and DEHP (down-regulation of FAS and LPL). Multiple and complex modes of action of these chemicals were observed in RTL-W1 cells, both in terms of expression of genes related to lipid metabolism and alteration of cellular lipids. Although further characterization is needed, this might be a useful model for the detection of chemicals leading to steatosis or other diseases associated with lipid metabolism in fish.

  10. Terpenes and lipids of the endocannabinoid and transient-receptor-potential-channel biosignaling systems.

    PubMed

    Janero, David R; Makriyannis, Alexandros

    2014-11-19

    Endocananbnoid-system G-protein coupled receptors (GPCRs) and transient receptor potential (TRP) cation channels are critical components of cellular biosignaling networks. These plasma-membrane proteins are pleiotropic in their ability to interact with and engage structurally diverse ligands. The endocannabinoid and TRP signaling systems overlap in their recognition properties with respect to select naturally occurring plant-derived ligands that belong to the terpene and lipid chemical classes, the overlap establishing a physiological connectivity between these two ubiquitous cell-signaling systems. Identification and pharmacological profiling of phytochemicals engaged by cannabinoid GPCRs and/or TRP channels has inspired the synthesis of novel designer ligands that interact with cannabinoid receptors and/or TRP channels as xenobiotics. Functional interplay between the endocannabinoid and TRP-channel signaling systems is responsible for the antinocifensive action of some synthetic cananbinoids (WIN55,212-2 and AM1241), vasorelaxation by the endocannabinoid N-arachidonylethanolamide (anandamide), and the pain-relief afforded by the synthetic anandamide analogue N-arachidonoylaminophenol (AM404), the active metabolite of the widely used nonprescription analgesic and antipyretic acetaminophen (paracetamol). The biological actions of some plant-derived cannabinoid-receptor (e.g., Δ(9)-tetrahydrocannabinol) or TRP-channel (e.g,, menthol) ligands either carry abuse potential themselves or promote the use of other addictive substances, suggesting the therapeutic potential for modulating these signaling systems for abuse-related disorders. The pleiotropic nature of and therapeutically relevant interactions between cananbinergic and TRP-channel signaling suggest the possibility of dual-acting ligands as drugs.

  11. Lipid domains in bicelles containing unsaturated lipids and cholesterol.

    PubMed

    Cho, Hyo Soon; Dominick, Johnna L; Spence, Megan M

    2010-07-22

    We have created a stable bicelle system capable of forming micrometer-scale lipid domains that orient in a magnetic field, suitable for structural biology determination in solid-state NMR. The bicelles consisted of a mixture of cholesterol, saturated lipid (DMPC), and unsaturated lipid (POPC), a mixture commonly used to create domains in model membranes, along with a short chain lipid (DHPC) that allows formation of the bicelle phase. While maintaining a constant molar ratio of long to short chain lipids, q = ([POPC]+[DMPC])/[DHPC] = 3, we varied the concentrations of the unsaturated lipid, POPC, and cholesterol to observe the effects of the components on bicelle stability. Using (31)P solid-state NMR, we observed that unsaturated lipids (POPC) greatly destabilized the alignment of the membranes in the magnetic field, while cholesterol stabilized their alignment. By combining cholesterol and unsaturated lipids in the bicelles, we created membranes aligning uniformly in the magnetic field, despite very high concentrations of unsaturated lipids. These bicelles, with high concentrations of both cholesterol and unsaturated lipid, showed similar phase behavior to bicelles commonly used in structural biology, but aligned over a wider temperature range (291-314 K). Domains were observed by measuring time-dependent diffusion constants reflecting restricted diffusion of the lipids within micrometer-scale regions of the bicelles. Micron-scale domains have never been observed in POPC/DMPC/cholesterol vesicles, implying that bilayers in bicelles show different phase behavior than their counterparts in vesicles, and that bilayers in bicelles favor domain formation.

  12. D-Ala2-GIP-glu-PAL is neuroprotective in a chronic Parkinson's disease mouse model and increases BNDF expression while reducing neuroinflammation and lipid peroxidation.

    PubMed

    Li, Yanwei; Liu, WeiZhen; Li, Lin; Hölscher, Christian

    2017-02-15

    Type 2 diabetes mellitus (T2DM) is a risk factor for Parkinson's disease (PD). Therefore, treatment to improve insulin resistance in T2DM may be useful for PD patients. Glucose dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family that can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. We had shown previously that D-Ala2-GIP-glu-PAL, a novel long-acting GIP analogue, can play a neuroprotective role in the PD mouse model induced by acute MPTP injection. The drug reduced damage to the dopaminergic neurons and increased CREB-mediated Bcl-2 expression to prevent apoptosis and reduced chronic inflammation in the brain. In the present study, we further tested the effects of chronic treatment by D-Ala2-GIP-glu-PAL in a chronic PD mouse model induced by MPTP (25mg/kg ip.) combination with probenecid (250mg/kg ip.) injection for 5 weeks. The results demonstrated that chronic treatment with D-Ala2-GIP-glu-PAL inhibits MPTP -induced Parkinsonism-like motor disorders in mice, and that the drug prevents dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). Moreover, D-Ala2-GIP-glu-PAL also inhibited the increased levels of expression of α-synuclein in the SNpc and striatum induced by MPTP. Furthermore, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of BDNF. These findings show that GIP signaling is neuroprotective and holds promise as a novel treatment of PD.

  13. Scanning STED-FCS reveals spatiotemporal heterogeneity of lipid interaction in the plasma membrane of living cells

    NASA Astrophysics Data System (ADS)

    Honigmann, Alf; Mueller, Veronika; Ta, Haisen; Schoenle, Andreas; Sezgin, Erdinc; Hell, Stefan W.; Eggeling, Christian

    2014-11-01

    The interaction of lipids and proteins plays an important role in plasma membrane bioactivity, and much can be learned from their diffusion characteristics. Here we present the combination of super-resolution STED microscopy with scanning fluorescence correlation spectroscopy (scanning STED-FCS, sSTED-FCS) to characterize the spatial and temporal heterogeneity of lipid interactions. sSTED-FCS reveals transient molecular interaction hotspots for a fluorescent sphingolipid analogue. The interaction sites are smaller than 80 nm in diameter and lipids are transiently trapped for several milliseconds in these areas. In comparison, newly developed fluorescent phospholipid and cholesterol analogues with improved phase-partitioning properties show more homogenous diffusion, independent of the preference for liquid-ordered or disordered membrane environments. Our results do not support the presence of nanodomains based on lipid-phase separation in the basal membrane of our cultured nonstimulated cells, and show that alternative interactions are responsible for the strong local trapping of our sphingolipid analogue.

  14. The SwissLipids knowledgebase for lipid biology.

    PubMed

    Aimo, Lucila; Liechti, Robin; Hyka-Nouspikel, Nevila; Niknejad, Anne; Gleizes, Anne; Götz, Lou; Kuznetsov, Dmitry; David, Fabrice P A; van der Goot, F Gisou; Riezman, Howard; Bougueleret, Lydie; Xenarios, Ioannis; Bridge, Alan

    2015-09-01

    Lipids are a large and diverse group of biological molecules with roles in membrane formation, energy storage and signaling. Cellular lipidomes may contain tens of thousands of structures, a staggering degree of complexity whose significance is not yet fully understood. High-throughput mass spectrometry-based platforms provide a means to study this complexity, but the interpretation of lipidomic data and its integration with prior knowledge of lipid biology suffers from a lack of appropriate tools to manage the data and extract knowledge from it. To facilitate the description and exploration of lipidomic data and its integration with prior biological knowledge, we have developed a knowledge resource for lipids and their biology-SwissLipids. SwissLipids provides curated knowledge of lipid structures and metabolism which is used to generate an in silico library of feasible lipid structures. These are arranged in a hierarchical classification that links mass spectrometry analytical outputs to all possible lipid structures, metabolic reactions and enzymes. SwissLipids provides a reference namespace for lipidomic data publication, data exploration and hypothesis generation. The current version of SwissLipids includes over 244 000 known and theoretically possible lipid structures, over 800 proteins, and curated links to published knowledge from over 620 peer-reviewed publications. We are continually updating the SwissLipids hierarchy with new lipid categories and new expert curated knowledge. SwissLipids is freely available at http://www.swisslipids.org/. alan.bridge@isb-sib.ch Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

  15. Synthesis and evaluation of analogues of HYNIC as bifunctional chelators for technetium.

    PubMed

    Meszaros, Levente K; Dose, Anica; Biagini, Stefano C G; Blower, Philip J

    2011-06-21

    6-Hydrazinonicotinic acid (HYNIC, 1) is a well-established bifunctional technetium-binding ligand often used to synthesise bioconjugates for radiolabelling with Tc-99m. It is capable of efficient capture of technetium at extremely low concentrations, but the structure of the labelled complexes is heterogeneous and incompletely understood. In particular, it is of interest to determine whether, at the no-carrier-added level, it acts in a chelating or non-chelating mode. Here we report two new isomers of HYNIC: 2-hydrazinonicotinic acid (2-HYNIC, 2), which (like 1) is capable of chelation through the mutually ortho hydrazine and pyridine nitrogens and 4-hydrazinonicotinic acid (4-HYNIC, 3), which is not (due to the para-relationship of the hydrazine and pyridine nitrogens). LC-MS shows that the coordination chemistry of 2 with technetium closely parallels that of conventional 1, and no advantages of one over the other in terms of potential labelling efficiency or isomerism were discernable. Both 1 and 2 formed complexes with the loss of 5 protons from the ligand set, whether the co-ligand was tricine or EDDA. Ligand 3, however, failed to complex technetium except at very high ligand concentration: the marked contrast with 1 and 2 suggests that chelation, rather than nonchelating coordination, is a key feature of technetium coordination by HYNIC. Two further new HYNIC analogues, 2-chloro-6-hydrazinonicotinic acid (2-chloro-HYNIC, 4a) and 2,6-dihydrazinonicotinic acid (diHYNIC, 5) were also synthesised. The coordination chemistry of 4a with technetium was broadly parallel to that of 1 and 2 although it was a less efficient chelator, while 5 also behaved as an efficient chelator of technetium, but its coordination chemistry remains poorly defined and requires further investigation before it can sensibly be adopted for (99m)Tc-labelling. The new analogues 4a and 5 present an opportunity to develop trifunctional HYNIC analogues for more complex bioconjugate synthesis.

  16. Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A.

    PubMed

    Zhang, Yanmin; Chevalier, Arnaud; Khdour, Omar M; Soto, Larisa Morales; Hecht, Sidney M

    2017-06-08

    In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2-O-methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds (1, 4, and 6) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2-4. Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these (4 and 6) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results. Georg Thieme Verlag KG Stuttgart · New York.

  17. Determination of the Hypnotic Potency in Rats of the Novel Ketamine Ester Analogue SN 35210.

    PubMed

    Harvey, Martyn; Sleigh, James; Voss, Logan; Pruijn, Frederik; Jose, Jiney; Gamage, Swarma; Denny, William

    2015-01-01

    Ketamine is a rapidly acting dissociative anaesthetic drug with additional sympathomimetic, analgesic, and antidepressant properties. Despite these advantages, clinical use is curtailed by prolonged psychomimetic effects apparent over the entire dose spectrum. In this study, we report on the hypnotic potency of SN 35210, the first ketamine ester-analogue designed for rapid offset via esterase-mediated hydrolysis. Thirty-three adult Sprague Dawley rats received intravenous racemic ketamine (n = 14), racemic SN 35210 (n = 19), S-enantiomer SN 35210 (n = 17), or R-enantiomer SN 35210 (n = 15), in crossover design. The ability to induce loss of righting reflex (LORR) at a given dose, the duration of righting reflex loss, and the time to return of normal behaviours were recorded. The ED50 for LORR was determined for all agents. The ED50 for righting reflex loss was racemic ketamine 9.6 (95% CI 8.5-10.9) mg/kg, racemic SN 35210 10.4 (95% CI 9.5-11.5) mg/kg, S-enantiomer SN 35210 10.6 (95% CI 9.1-11.8), and R-enantiomer SN 35210 10.3 (95% CI 9.1-11.4) mg/kg. The duration of righting reflex loss and time to return to normal behaviours were approximately 5 times greater for racemic ketamine than all 3 SN 35210 ester analogues. Racemic, and R and S-enantiomer SN 35210, produced LORR in rats at similar doses to the parent compound ketamine. The duration of righting reflex loss, and duration of behavioural aberration, was significantly reduced for all SN 35210 analogues. © 2015 S. Karger AG, Basel.

  18. Analogue modelling of the rupture process of vulnerable stalagmites in an earthquake simulator

    NASA Astrophysics Data System (ADS)

    Gribovszki, Katalin; Bokelmann, Götz; Kovács, Károly; Hegymegi, Erika; Esterhazy, Sofi; Mónus, Péter

    2017-04-01

    the material and the time series of acting horizontal acceleration. Comparing the results from analogue to numerical modelling could improve the accuracy of long-term seismic hazard assessment.

  19. Lipid mediators of insulin resistance.

    PubMed

    Holland, William L; Knotts, Trina A; Chavez, Jose A; Wang, Li-Ping; Hoehn, Kyle L; Summers, Scott A

    2007-06-01

    Lipid abnormalities such as obesity, increased circulating free fatty acid levels, and excess intramyocellular lipid accumulation are frequently associated with insulin resistance. These observations have prompted investigators to speculate that the accumulation of lipids in tissues not suited for fat storage (e.g., skeletal muscle and liver) is an underlying component of insulin resistance and the metabolic syndrome. We review the metabolic fates of lipids in insulin-responsive tissues and discuss the roles of specific lipid metabolites (e.g., ceramides, GM3 ganglioside, and diacylglycerol) as antagonists of insulin signaling and action.

  20. Spectral analysis of lunar analogue samples

    NASA Astrophysics Data System (ADS)

    Offringa, Marloes; Foing, Bernard

    2016-04-01

    Analyses of samples derived from terrestrial analogue sites are used to study lunar processes in their geological context (Foing, Stoker, Ehrenfreund, 2011). For this study samples from the volcanic region of the Eifel, Germany collected during field campaigns (Foing et al., 2010), are analyzed with a variety of spectrometers. The aim is to obtain a database of analyzed samples that could be used as a reference for future in situ measurements. Equipment used in the laboratory consists of a Fourier Transform Infrared (FTIR) spectrometer, an X-Ray Fluorescence (XRF) spectrometer, a Raman laser spectrometer, as well as UV-VIS and NIR reflectance spectrometers. The Raman, UV-VIS and NIR are also used in combination with the EXoGeoLab mock-up lander during field campaigns (Foing, Stoker, Ehrenfreund, 2011). Calibration of the UV-VIS and NIR reflectance spectrometers is the main focus of this research in order to obtain the clearest spectra. The calibration of the UV-VIS and NIR reflectance spectrometers requires the use of a good light source as well as suitable optical fibers to create a signal that covers the widest range in wavelengths available. To eliminate noise towards the edges of this range, multiple measurements are averaged and data is processed by dividing the signal by reference spectra. Calibration of the devices by creating a new dark and reference spectra has to take place after every sample measurement. In this way we take into account changes that occur in the signal due to the eating of the devices during the measurements. Moreover, the integration time is adjusted to obtain a clear signal without leading to oversaturation in the reflectance spectrum. The typical integration times for the UV-VIS reflectance spectrometer vary between 1 - 18 s, depending on the amount of daylight during experiments. For the NIR reflectance spectrometer the integration time resulting in the best signals is approximately 150 ms in combination with a broad spectrum light

  1. Iron isotopes in an Archean ocean analogue

    NASA Astrophysics Data System (ADS)

    Busigny, Vincent; Planavsky, Noah J.; Jézéquel, Didier; Crowe, Sean; Louvat, Pascale; Moureau, Julien; Viollier, Eric; Lyons, Timothy W.

    2014-05-01

    Iron isotopes have been extensively used to trace the history of microbial metabolisms and the redox evolution of the oceans. Archean sedimentary rocks display greater variability in iron isotope ratios and more markedly negative values than those deposited in the Proterozoic and Phanerozoic. This increased variability has been linked to changes in either water column iron cycling or the extent of benthic microbial iron reduction through time. We tested these contrasting scenarios through a detailed study of anoxic and ferruginous Lac Pavin (France), which can serve as a modern analogue of the Archean ocean. A depth-profile in the water column of Lac Pavin shows a remarkable increase in dissolved Fe concentration (0.1-1200 μM) and δ56Fe values (-2.14‰ to +0.31‰) across the oxic-anoxic boundary to the lake bottom. The largest Fe isotope variability is found at the redox boundary and is related to partial oxidation of dissolved ferrous iron, leaving the residual Fe enriched in light isotopes. The analysis of four sediment cores collected along a lateral profile (one in the oxic layer, one at the redox boundary, one in the anoxic zone, and one at the bottom of the lake) indicates that bulk sediments, porewaters, and reactive Fe mostly have δ56Fe values near 0.0 ± 0.2‰, similar to detrital iron. In contrast, pyrite δ56Fe values in sub-chemocline cores (60, 65, and 92 m) are highly variable and show significant deviations from the detrital iron isotope composition (δ56Fepyrite between -1.51‰ and +0.09‰; average -0.93‰). Importantly, the pyrite δ56Fe values mirror the δ56Fe of dissolved iron at the redox boundary—where near quantitative sulfate and sulfide drawdown occurs—suggesting limited iron isotope fractionation during iron sulfide formation. This finding has important implications for the Archean environment. Specifically, this work suggests that in a ferruginous system, most of the Fe isotope variability observed in sedimentary pyrites can

  2. Regulating the Size and Stabilization of Lipid Raft-Like Domains and Using Calcium Ions as Their Probe

    NASA Astrophysics Data System (ADS)

    Raviv, Uri; Szekely, Or

    2012-02-01

    In this paper, we apply means to probe, stabilize and control the size of lipid raft-like domains in vitro. In biomembranes the size of lipid rafts is ca. 10 - 30 nm. In vitro, mixing saturated and unsaturated lipids results in micro-domains, which are unstable and coalesce. Using solution X-ray scattering, we studied the structure of binary and ternary lipid mixtures in the presence of calcium ions. Three lipids were used: saturated, unsaturated and a hybrid (1-saturated-2-unsaturated) lipid that is predominant in the phospholipids of cellular membranes. Only membranes composed of the saturated lipid can adsorb calcium ions, become charged and therefore considerably swell. The selective calcium affinity was used to show that binary mixtures, containing the saturated lipid, phase separated into large-scale domains. Our data suggests that by introducing the hybrid lipid to a mixture of the saturated and unsaturated lipids, the size of the domains decreased with the concentration of the hybrid lipid, until the three lipids could completely mix. We attribute this behavior to the tendency of the hybrid lipid to act as a line-active co-surfactant that can easily reside at the interface between the saturated and the unsaturated lipids and reduce the line-tension between them.

  3. Alcohol and lipid metabolism

    PubMed Central

    Sozio, Margaret; Crabb, David W.

    2008-01-01

    Many new mechanisms for alcoholic steatosis have been suggested by work reported in the last five years. These include alterations of transcriptional controls of lipid metabolism, better understanding of the effects of abnormal methionine metabolism on the endoplasmic reticulum stress response, unraveling of the basis for sensitization of the Kupffer cell to lipopolysaccharide, a better understanding of the role of cytokines and adipokines in alcoholic liver disease, and implication of the innate immune and complement systems in responses to alcohol. Much of this work has been facilitated by work with knockout mice. Undoubtedly, there are interrelationships among these various pathogenic mechanisms that ultimately will provide a more cohesive picture of how heavy alcohol use deranges hepatic lipid metabolism. PMID:18349117

  4. Human Milk Lipids.

    PubMed

    Koletzko, Berthold

    2016-01-01

    Human milk lipids provide the infant with energy and essential vitamins, polyunsaturated fatty acids, and bioactive components. Adding complex lipids and milk fat globule membranes to vegetable oil-based infant formula has the potential to enhance infant development and reduce infections. Cholesterol provision with breastfeeding modulates infant sterol metabolism and may induce long-term benefits. Some 98-99% of milk lipids are comprised by triacylglycerols, whose properties depend on incorporated fatty acids. Attention has been devoted to the roles of the long-chain polyunsaturated fatty acids docosahexaenoic (DHA) and arachidonic (ARA) acids. Recent studies on gene-diet interaction (Mendelian randomization) show that breastfeeding providing DHA and ARA improves cognitive development and reduces asthma risk at school age particularly in those children with a genetically determined lower activity of DHA and ARA synthesis. It appears prudent to follow the biological model of human milk in the design of infant formula as far as feasible, unless conclusive evidence for the suitability and safety of other choices is available. The recent European Union legislative stipulation of a high formula DHA content without required ARA deviates from this concept, and such a novel formula composition has not been adequately evaluated. Great future opportunities arise with significant methodological progress for example in lipidomic analyses and their bioinformatic evaluation, which should enhance understanding of the biology of human milk lipids. Such knowledge might lead to improved dietary advice to lactating mothers as well as to further opportunities to enhance infant formula composition. © 2017 S. Karger AG, Basel.

  5. Stratum Corneum Lipids: Their Role for the Skin Barrier Function in Healthy Subjects and Atopic Dermatitis Patients.

    PubMed

    van Smeden, Jeroen; Bouwstra, Joke A

    2016-01-01

    Human skin acts as a primary barrier between the body and its environment. Crucial for this skin barrier function is the lipid matrix in the outermost layer of the skin, the stratum corneum (SC). Two of its functions are (1) to prevent excessive water loss through the epidermis and (2) to avoid that compounds from the environment permeate into the viable epidermal and dermal layers and thereby provoke an immune response. The composition of the SC lipid matrix is dominated by three lipid classes: cholesterol, free fatty acids and ceramides. These lipids adopt a highly ordered, 3-dimensional structure of stacked densely packed lipid layers (lipid lamellae): the lateral and lamellar lipid organization. The way in which these lipids are ordered depends on the composition of the lipids. One very common skin disease in which the SC lipid barrier is affected is atopic dermatitis (AD). This review addresses the SC lipid composition and organization in healthy skin, and elaborates on how these parameters are changed in lesional and nonlesional skin of AD patients. Concerning the lipid composition, the changes in the three main lipid classes and the importance of the carbon chain lengths of the lipids are discussed. In addition, this review addresses how these changes in lipid composition induce changes in lipid organization and subsequently correlate with an impaired skin barrier function in both lesional and nonlesional skin of these patients. Furthermore, the effect of filaggrin and mutations in the filaggrin gene on the SC lipid composition is critically discussed. Also, the breakdown products of filaggrin, the natural moisturizing factor molecules and its relation to SC-pH is described. Finally, the paper discusses some major changes in epidermal lipid biosynthesis in patients with AD and other related skin diseases, and how inflammation has a deteriorating effect on the SC lipids and SC biosynthesis. The review ends with perspectives on future studies in relation to

  6. Tear Film Lipids

    PubMed Central

    Butovich, Igor A.

    2013-01-01

    Human meibomian gland secretions (MGS, or meibum) are formed from a complex mixture of lipids of different classes such as wax esters, cholesteryl esters, (O-acyl)-ω-hydroxy fatty acids (OAHFA) and their esters, acylglycerols, diacylated diols, free fatty acids, cholesterol, and a smaller amount of other polar and nonpolar lipids, whose chemical nature and the very presence in MGS have been a matter of intense debates. The purpose of this review is to discuss recent results that were obtained using different experimental techniques, estimate limitations of their usability, and discuss their biochemical, biophysical, and physiological implications. To create a lipid map of MGS and tears, the results obtained in the author’s laboratory were integrated with available information on chemical composition of MGS and tears. The most informative approaches that are available today to researchers, such as HPLC-MS, GC-MS, and proton NMR, are discussed in details. A map of the meibomian lipidome (as it is seen in reverse phase liquid chromatography/mass spectrometry experiments) is presented. Directions of future efforts in the area are outlined. PMID:23769846

  7. Lipids and immune function.

    PubMed

    Vitale, J J; Broitman, S A

    1981-09-01

    There is in vitro and in vivo evidence to suggest that dietary lipids play a role in modulating immune function. A review of the current literature on the interrelationships among dietary lipids, blood cholesterol levels, immunosuppression, and tumorigenesis makes for a very strong argument that (a) immunosuppression may be causally related to lymphoproliferative disorders, as well as to tumorigenesis and (b) diets high in polyunsaturated fat, relative to diets high in saturated fat, are more immunosuppressive and are better promotors of tumorigenesis. The effects of dietary fat on immune function seem to be mediated though its component parts, the unsaturated fatty acids, specially linoleic, linolenic, and arachidonic. It is not clear how these components affect immune function. Several studies suggest that one effect is mediated by altering the lipid component of the cell membrane and thus its fluidity; the more fluid the membrane, the less responsive it is. Thus, fluidity of both immune cells and those to be destroyed or protected may be affected. The effects of saturated as well as unsaturated fatty acids may be mediated by modulating serum lipoprotein levels, prostaglandin metabolism, and cholesterol concentrations and metabolism.

  8. Simplified lipid guidelines

    PubMed Central

    Allan, G. Michael; Lindblad, Adrienne J.; Comeau, Ann; Coppola, John; Hudson, Brianne; Mannarino, Marco; McMinis, Cindy; Padwal, Raj; Schelstraete, Christine; Zarnke, Kelly; Garrison, Scott; Cotton, Candra; Korownyk, Christina; McCormack, James; Nickel, Sharon; Kolber, Michael R.

    2015-01-01

    Abstract Objective To develop clinical practice guidelines for a simplified approach to primary prevention of cardiovascular disease (CVD), concentrating on CVD risk estimation and lipid management for primary care clinicians and their teams; we sought increased contribution from primary care professionals with little or no conflict of interest and focused on the highest level of evidence available. Methods Nine health professionals (4 family physicians, 2 internal medicine specialists, 1 nurse practitioner, 1 registered nurse, and 1 pharmacist) and 1 nonvoting member (pharmacist project manager) comprised the overarching Lipid Pathway Committee (LPC). Member selection was based on profession, practice setting, and location, and members disclosed any actual or potential conflicts of interest. The guideline process was iterative through online posting, detailed evidence review, and telephone and online meetings. The LPC identified 12 priority questions to be addressed. The Evidence Review Group answered these questions. After review of the answers, key recommendations were derived through consensus of the LPC. The guidelines were drafted, refined, and distributed to a group of clinicians (family physicians, other specialists, pharmacists, nurses, and nurse practitioners) and patients for feedback, then refined again and finalized by the LPC. Recommendations Recommendations are provided on screening and testing, risk assessments, interventions, follow-up, and the role of acetylsalicylic acid in primary prevention. Conclusion These simplified lipid guidelines provide practical recommendations for prevention and treatment of CVD for primary care practitioners. All recommendations are intended to assist with, not dictate, decision making in conjunction with patients. PMID:26472792

  9. Membrane Organization and Lipid Rafts

    PubMed Central

    Simons, Kai; Sampaio, Julio L.

    2011-01-01

    Cell membranes are composed of a lipid bilayer, containing proteins that span the bilayer and/or interact with the lipids on either side of the two leaflets. Although recent advances in lipid analytics show that membranes in eukaryotic cells contain hundreds of different lipid species, the function of this lipid diversity remains enigmatic. The basic structure of cell membranes is the lipid bilayer, composed of two apposing leaflets, forming a two-dimensional liquid with fascinating properties designed to perform the functions cells require. To coordinate these functions, the bilayer has evolved the propensity to segregate its constituents laterally. This capability is based on dynamic liquid–liquid immiscibility and underlies the raft concept of membrane subcompartmentalization. This principle combines the potential for sphingolipid-cholesterol self-assembly with protein specificity to focus and regulate membrane bioactivity. Here we will review the emerging principles of membrane architecture with special emphasis on lipid organization and domain formation. PMID:21628426

  10. Direct affinity of dopamine to lipid membranes investigated by Nuclear Magnetic Resonance spectroscopy.

    PubMed

    Matam, Yashasvi; Ray, Bruce D; Petrache, Horia I

    2016-04-08

    Dopamine, a naturally occurring neurotransmitter, plays an important role in the brain's reward system and acts on sensory receptors in the brain. Neurotransmitters are contained in lipid membraned vesicles and are released by exocytosis. All neurotransmitters interact with transport and receptor proteins in glial cells, on neuronal dendrites, and at the axonal button, and also must interact with membrane lipids. However, the extent of direct interaction between lipid membranes in the absence of receptors and transport proteins has not been extensively investigated. In this report, we use UV and NMR spectroscopy to determine the affinity and the orientation of dopamine interacting with lipid vesicles made of either phosphatidylcholine (PC) or phosphatidylserine (PS) lipids which are primary lipid components of synaptic vesicles. We quantify the interaction of dopamine's aromatic ring with lipid membranes using our newly developed method that involves reference spectra in hydrophobic environments. Our measurements show that dopamine interacts with lipid membranes primarily through the aromatic side opposite to the hydroxyl groups, with this aromatic side penetrating deeper into the hydrophobic region of the membrane. Since dopamine's activity involves its release into extracellular space, we have used our method to also investigate dopamine's release from lipid vesicles. We find that dopamine trapped inside PC and PS vesicles is released into the external solution despite its affinity to membranes. This result suggests that dopamine's interaction with lipid membranes is complex and involves both binding as well as permeation through lipid bilayers, a combination that could be an effective trigger for apoptosis of dopamine-generating cells.

  11. Phytic acid inhibits lipid peroxidation in vitro.

    PubMed

    Zajdel, Alicja; Wilczok, Adam; Węglarz, Ludmiła; Dzierżewicz, Zofia

    2013-01-01

    Phytic acid (PA) has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II)/ascorbate-induced peroxidation, as well as Fe(II)/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II)/ascorbate. The observed inhibitory effect of PA on Fe(II)/ascorbate-induced lipid peroxidation was lower (10-20%) compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II)/ascorbate-induced peroxidation. In the absence of Fe(II)/ascorbate, PA at 100 μM and 500 μM significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100 μM and 500 μM) significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products.

  12. Phytic Acid Inhibits Lipid Peroxidation In Vitro

    PubMed Central

    Węglarz, Ludmiła; Dzierżewicz, Zofia

    2013-01-01

    Phytic acid (PA) has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II)/ascorbate-induced peroxidation, as well as Fe(II)/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II)/ascorbate. The observed inhibitory effect of PA on Fe(II)/ascorbate-induced lipid peroxidation was lower (10–20%) compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II)/ascorbate-induced peroxidation. In the absence of Fe(II)/ascorbate, PA at 100 μM and 500 μM significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100 μM and 500 μM) significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products. PMID:24260736

  13. Topological regulation of lipid balance in cells.

    PubMed

    Drin, Guillaume

    2014-01-01

    Lipids are unevenly distributed within and between cell membranes, thus defining organelle identity. Such distribution relies on local metabolic branches and mechanisms that move lipids. These processes are regulated by feedback mechanisms that decipher topographical information in organelle membranes and then regulate lipid levels or flows. In the endoplasmic reticulum, the major lipid source, transcriptional regulators and enzymes sense changes in membrane features to modulate lipid production. At the Golgi apparatus, lipid-synthesizing, lipid-flippase, and lipid-transport proteins (LTPs) collaborate to control lipid balance and distribution within the membrane to guarantee remodeling processes crucial for vesicular trafficking. Open questions exist regarding LTPs, which are thought to be lipid sensors that regulate lipid synthesis or carriers that transfer lipids between organelles across long distances or in contact sites. A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient.

  14. Engineering of Insulin Receptor Isoform-Selective Insulin Analogues

    PubMed Central

    Glendorf, Tine; Stidsen, Carsten E.; Norrman, Mathias; Nishimura, Erica; Sørensen, Anders R.; Kjeldsen, Thomas

    2011-01-01

    Background The insulin receptor (IR) exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. Methodology/Principal Findings Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference) even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. Conclusions/Significance We have discovered a new class of IR isoform-selective insulin analogues with 2–4-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits. PMID:21625452

  15. Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps

    PubMed Central

    Valla, Vasiliki

    2010-01-01

    Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insu