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Natsumi Ideno, Shikou Umeyama, Takashi Watanabe, Mami Nakajima, Tsutomu Sato, Tsutomu Hoshino
The acyclic molecule squalene (1) is cyclized into a 6,6,6,6,5-fused pentacyclic hopene (2) and hopanol (3) (ca. 5:1) by Alicyclobacillus acidocaldarius squalene-hopene cyclase (AaSHC). The polycyclization reaction proceeds with regio- and stereochemical specificity under precise enzymatic control. This pentacyclic hopane skeleton is generated by folding 1 into an all-chair conformation. The Ala306 in AaSHC is conserved in known SHCs; however, increases in steric bulk (A306T and A306V) led to the accumulation of 6,6,6,5-fused tetracyclic scaffolds possessing 20R stereochemistry in high yield (94% for A306V)...
June 17, 2018: Chembiochem: a European Journal of Chemical Biology
David Coman, Lisenka E L M Vissers, Lisa G Riley, Michael P Kwint, Roxanna Hauck, Janet Koster, Sinje Geuer, Sarah Hopkins, Barbra Hallinan, Larry Sweetman, Udo F H Engelke, T Andrew Burrow, John Cardinal, James McGill, Anita Inwood, Christine Gurnsey, Hans R Waterham, John Christodoulou, Ron A Wevers, James Pitt
Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect...
June 1, 2018: American Journal of Human Genetics
Naoki Shimizu, Junya Ito, Shunji Kato, Yurika Otoki, Masashi Goto, Takahiro Eitsuka, Teruo Miyazawa, Kiyotaka Nakagawa
Oxidation of squalene (SQ) causes a decline in the nutritional value of SQ in foods, as well as an accumulation of SQ oxidation products in skin lipids which lead to adverse skin conditions. However, mechanistic insights as to how SQ is oxidized by different oxidation mechanisms have been limited, and thus effective measures towards the prevention of SQ oxidation have not been identified. In this study, we oxidized SQ by either singlet oxygen oxidation or free radical oxidation, and monitored the formation of the six SQ monohydroperoxide (SQOOH) isomers, the primary oxidation products of SQ, at the isomeric level...
June 14, 2018: Scientific Reports
Theresa M Catania, Caroline A Branigan, Natalia Stawniak, Jennifer Hodson, David Harvey, Tony R Larson, Tomasz Czechowski, Ian A Graham
Artemisia annua is established as an efficient crop for the production of the anti-malarial compound artemisinin, a sesquiterpene lactone synthesized and stored in Glandular Secretory Trichomes (GSTs) located on the leaves and inflorescences. Amorpha-4,11-diene synthase (AMS) catalyzes the conversion of farnesyl pyrophosphate (FPP) to amorpha-4,11-diene and diphosphate, which is the first committed step in the synthesis of artemisinin. FPP is the precursor for sesquiterpene and sterol biosynthesis in the plant...
2018: Frontiers in Plant Science
D Fagot, D M Pham, J Laboureau, E Planel, L Guerin, C Nègre, M Donovan, B A Bernard
OBJECTIVE: Oxidative stress and low grade chronic inflammation stand out as key features of physiological skin aging. The aim of this study was to examine in normal human epidermal keratinocytes (NHEK) and human dermal fibroblasts (HDF) grown in vitro, the antioxidant and anti-inflammatory properties of crocin, a carotenoid glycoside responsible for the color of saffron. Moreover, considering the newly emerging field of skin glycobiology and the presence of two gentiobiosyl moieties in crocin, the effect of crocin on NHEK glycosylation pathways was for the first time investigated...
June 12, 2018: International Journal of Cosmetic Science
Lan Anh Thi Hoang, Ha Cam Nguyen, Thom Thi Le, Thi Huong Quynh Hoang, Van Nhat Pham, Minh Hien Thi Hoang, Hoai Thu Thi Ngo, Dang Diem Hong
Schizochytrium mangrovei strain PQ6 was investigated for co-production of docosahexaenoic acid (C22: 6ω-3, DHA) and squalene using a 30 L bioreactor with a working volume of 15 L under various batch and fed-batch fermentation process regimes. The fed-batch process was a more efficient cultivation strategy for achieving higher biomass production rich in DHA and squalene. The final biomass, total lipid, unsaponifiable lipid content and DHA productivity were 105.25 g · L-1 , 43.40% of dry cell weight, 8.58% total lipid and 61...
June 11, 2018: Journal of Phycology
Yangjie Wei, Jian Xiong, Nicholas R Larson, Vidyashankara Iyer, Gautam Sanyal, Sangeeta B Joshi, David B Volkin, C Russell Middaugh
The effects of two squalene based emulsion adjuvant systems (ME.0 and SE) on the structure and stability of the recombinant protein antigen alpha-toxin (AT), a potential vaccine candidate for Staphylococcus aureus infection, were investigated using Fourier Transform Infrared (FTIR) and both steady-state and time-resolved intrinsic fluorescence spectroscopy as well as differential scanning calorimetry (DSC). A component study, performed to identify the effects of the individual emulsion's components, showed negligible interactions between AT and ME...
June 5, 2018: Journal of Pharmaceutical Sciences
Rushit N Lodaya, Luis A Brito, Tom Y H Wu, Andrew T Miller, Gillis R Otten, Manmohan Singh, Derek T O'Hagan
Adjuvants are required to enhance immune responses to typically poorly immunogenic recombinant antigens. Toll like receptor agonists (TLRa) have been widely evaluated as adjuvants, since they activate the innate immune system. Currently, licensed vaccines adjuvanted with TLRa include the TLR4 agonist Monophosphoryl Lipid (MPL), while additional TLRa are in clinical development. Unfortunately, naturally derived TLRa are often complex and heterogeneous entities, which brings formulation challenges. Consequently, the use of synthetic small molecule TLRa has significant advantages, since they are well-defined discreet molecules, which can be chemically modified to modulate their physicochemical properties...
June 5, 2018: Journal of Pharmaceutical Sciences
José M Lou-Bonafonte, Roberto Martínez-Beamonte, Teresa Sanclemente, Joaquín C Surra, Luis V Herrera-Marcos, Javier Sanchez-Marco, Carmen Arnal, Jesús Osada
Squalene is a triterpenic compound found in a large number of plants and other sources with a long tradition of research since it was first reported in 1926. Herein we present a systematic review of studies concerning squalene published in the last eight years. These studies have provided further support for its antioxidant, anti-inflammatory and anti-atherosclerotic properties in vivo and in vitro. Moreover, an anti-neoplastic effect in nutrigenetic-type treatments, which depend on the failing metabolic pathway of tumors, has also been reported...
June 8, 2018: Molecular Nutrition & Food Research
Nadja Heine, Caleb Arata, Allen H Goldstein, Frances A Houle, Kevin R Wilson
Here we report a new multiphase reaction mechanism by which Criegee Intermediates (CI), formed by ozone reactions at an alkene surface, convert SO2 to SO3 to produce sulfuric acid; a precursor for new particle formation (NPF). During the heterogeneous ozone reaction, in the presence of 220 ppb SO2, an unsaturated aerosol (squalene) undergoes rapid chemical erosion, which is accompanied by NPF. A kinetic model predicts that mechanism for chemical erosion and NPF originate from a common elementary step (CI + SO2) that produces both gas phase SO3 and small ketones...
June 8, 2018: Journal of Physical Chemistry Letters
Andrej Babic, Laurent Vinet, Vineetha Chellakudam, Karolina Janikowska, Eric Allemann, Norbert Lange
Novel drug delivery systems targeting native, transplanted or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes display low nM affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1...
June 5, 2018: Bioconjugate Chemistry
Georgios Koutrotsios, Nick Kalogeropoulos, Andriana C Kaliora, Georgios Zervakis
Pleurotus ostreatus, P. eryngii and P. nebrodensis were cultivated on non-conventional substrates containing grape marc (GMC) or olive mill by-products (OMB); wheat straw (WHS) served as control. GMC-based media demonstrated equal/better mushroom productivity than WHS for P. eryngii and P. nebrodensis, while the cultivation performance of P. eryngii was improved in OMB-based media. Both GMC and OMB substrates led to large increase of fruit-bodies content in phenolic acids, resveratrol, triterpenic compounds and ergosterol; in particular, P...
June 5, 2018: Journal of Agricultural and Food Chemistry
Ruchi Singh, Pankhuri Gupta, Furqan Khan, Susheel Kumar Singh, Sanchita, Tripti Mishra, Anil Kumar, Sunita Singh Dhawan, Pramod Arvind Shirke
In general medicinal plants grown under water limiting conditions show much higher concentrations of secondary metabolites in comparison to control plants. In the present study, Withania somnifera plants were subjected to water stress and data related to drought tolerance phenomenon was collected and a putative mechanistic concept considering growth responses, physiological behaviour, and metabolite content and gene expression aspects is presented. Drought induced metabolic and physiological responses as well as drastic decrease in CO2 uptake due to stomatal limitations...
July 2018: Plant Science: An International Journal of Experimental Plant Biology
Nicola Cicero, Ambrogina Albergamo, Andrea Salvo, Giuseppe Daniel Bua, Giovanni Bartolomeo, Valentina Mangano, Archimede Rotondo, Vita Di Stefano, Giuseppa Di Bella, Giacomo Dugo
Different specialty extra virgin oils, produced by cold-pressing fruits/nuts (olive, pequi, palm, avocado, coconut, macadamia and Brazil nut) and seeds (grapeseed and canola), and retailed in the Brazilian region of Minas Gerais, were chemically characterized. Specifically, for each type of oil, the fatty acid composition was elucidated by GC-FID, the contents of selected polyphenols and squalene were determined respectively by UHPLC-MS and UHPLC-PDA, whereas minerals were explored by means of ICP-MS. Olive oil was confirmed to have the highest MUFA content due to a valuable level of oleic acid, while oils from grapeseed, Brazil nut and canola were marked by nutritionally important PUFA levels...
July 2018: Food Research International
Gaia Fumagalli, Giulia Giorgi, Máté Vágvölgyi, Eleonora Colombo, Michael S Christodoulou, Veronica Collico, Davide Prosperi, Franco Dosio, Attila Hunyadi, Monica Montopoli, Mariafrancesca Hyeraci, Alessandra Silvani, Giordano Lesma, Lisa Dalla Via, Daniele Passarella
Heteronanoparticles (H-NPs) consisting of conjugates characterized by a squalene tail linked to doxorubicin and ecdysteroid derivatives are presented. Biological evaluation on A2780ADR cell line confirms not only the maintenance of the activity of the parental drug but also the ability to overcome cancer resistance. The in vitro cell uptake was demonstrated, and the involvement of an endosomal-mediated pathway was suggested.
May 10, 2018: ACS Medicinal Chemistry Letters
Seiya Tanaka, Motohiro Tani
In the yeast Saccharomyces cerevisiae, complex sphingolipids have three types of polar head group, and breakdown of the normal composition causes several cellular dysfunctions. Previously we found that loss of biosynthesis of mannosylinositol phosphorylceramide (MIPC) causes a defect in cell wall integrity. In this study, we screened for multicopy suppressor genes that rescue the defect in cell wall integrity in cells lacking MIPC synthases (Sur1 and Csh1), and found that the defect is partly suppressed by upregulation of ergosterol biosynthesis...
May 18, 2018: FEBS Journal
Emilie Seydoux, Hong Liang, Natasha Dubois Cauwelaert, Michelle Archer, Nicholas D Rintala, Ryan Kramer, Darrick Carter, Christopher B Fox, Mark T Orr
The involvement of innate receptors that recognize pathogen- and danger-associated molecular patterns is critical to programming an effective adaptive immune response to vaccination. The synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA) synergizes with the squalene oil-in-water emulsion (SE) formulation to induce strong adaptive responses. Although TLR4 signaling through MyD88 and TIR domain-containing adapter inducing IFN-β are essential for GLA-SE activity, the mechanisms underlying the synergistic activity of GLA and SE are not fully understood...
May 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Maria Polycarpou-Schwarz, Matthias Groß, Pieter Mestdagh, Johanna Schott, Stefanie E Grund, Catherina Hildenbrand, Joachim Rom, Sebastian Aulmann, Hans-Peter Sinn, Jo Vandesompele, Sven Diederichs
Breast cancer is a leading cause of cancer-related death in women. Small open reading frame (sORF)-encoded proteins or microproteins constitute a new class of molecules often transcribed from presumed long non-coding RNA transcripts (lncRNAs). The translation of some of these sORFs has been confirmed, but their cellular function and importance remains largely unknown. Here, we report the identification and characterization of a novel microprotein of 10 kDa, which we named Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1)...
May 16, 2018: Oncogene
Dong Hao Wang, Rinat Ran-Ressler, Judy St Leger, Erika Nilson, Lauren Palmer, Richard Collins, J Thomas Brenna
Vernix caseosa, the white waxy coating found on newborn human skin, is thought to be a uniquely human substance. Its signature characteristic is exceptional richness in saturated branched chain fatty acids (BCFA) and squalene. Vernix particles sloughed from the skin suspended in amniotic fluid are swallowed by the human fetus, depositing BCFA/squalene throughout the gastrointestinal (GI) tract, thereby establishing a unique microbial niche that influences development of nascent microbiota. Here we show that late-term California sea lion (Zalophus californianus) fetuses have true vernix caseosa, delivering BCFA and squalene to the fetal GI tract thereby recapitulating the human fetal gut microbial niche...
May 10, 2018: Scientific Reports
Avani B Chokshi, Mahesh T Chhabria, Pritesh R Desai
INTRODUCTION: In the present research work, a pharmacophore based virtual screening was performed using Discovery Studio 2.1 for the discovery of some novel molecules as inhibitors of Squalene Synthase Enzyme, a key enzyme in cholesterol biosynthetic pathway. Methos: A quantitative pharmacophore HypoGen was generated and the best HypoGen, had two ring aromatic and one hydrogen bond acceptor lipid features. The best HypoGen showed a very good correlation coefficient (r = 0.901) with satisfactory cost analysis...
May 7, 2018: Current Computer-aided Drug Design
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