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Shinwan Kany, Mathias Woschek, Niels Kneip, Ramona Sturm, Miriam Kalbitz, Marc Hanschen, Borna Relja
Osteosarcoma is the leading primary bone cancer in young adults and exhibits high chemoresistance rates. Therefore, characterization of both alternative treatment options and the underlying mechanisms is essential. Simvastatin, a cholesterol-lowering drug, has among its pleiotropic effects anticancer potential. Characterizing this potential and the underlying mechanisms in osteosarcoma is the subject of the present study. Human osteosarcoma cells (SaOS-2 and U2OS) were treated with simvastatin (4-66 µM) for 48 or 72 h...
April 2018: International Journal of Oncology
Guangkai Bian, Anwei Hou, Yujie Yuan, Ben Hu, Shu Cheng, Ziling Ye, Yingtong Di, Zixin Deng, Tiangang Liu
The potential power of sesquiterpene synthase FgJ03939 from Fusarium graminearum was fully exploited in a farnesyl diphosphate-overexpressing Saccharomyces cerevisiae chassis to produce the novel sesquiterpenes fusariumdiene (1), epi-fusagramineol (2), and fusagramineol (3) with 5/7 bicyclic and 5/6/3 tricyclic ring systems, respectively, as well as five known sesquiterpenes (4-8). The structure of the unusual skeletons was characterized, and an absolute configuration was proposed. A mechanism for the biosynthesis of 1-8 was also proposed...
March 7, 2018: Organic Letters
Marcia Ortega-Ramos, Daniel P Canniffe, Matthew Radle, C Neil Hunter, Donald A Bryant, John H Golbeck
Engineering photosynthetic bacteria to utilize a heterologous reaction center that contains a different (bacterio) chlorophyll could improve solar energy conversion efficiency by allowing cells to absorb a broader range of the solar spectrum. One promising candidate is the homodimeric type I reaction center from Heliobacterium modesticaldum. It is the simplest known reaction center and uses bacteriochlorophyll (BChl) g, which absorbs in the near-infrared region of the spectrum. Like the more common BChls a and b, BChl g is a true bacteriochlorin...
February 26, 2018: Biochimica et Biophysica Acta
Georgina C Girt, Amit Mahindra, Zaaima J H Al Jabri, Megan De Ste Croix, Marco R Oggioni, Andrew G Jamieson
A series of lipopeptidomimetics derived from teixobactin have been prepared that probe the role of residues (1-6) as a membrane anchor and the function of enduracididine. The most active compounds, with a farnesyl tail and End10 to Lys10 or Orn10 substitution have potent activity (MIC 8 μg mL-1 ) against S. aureus. These results pave the way for the synthesis of simple, cost-effective yet potent lipopeptidomimetic antimicrobials.
February 27, 2018: Chemical Communications: Chem Comm
Sandra Pelleieux, Cynthia Picard, Louise Lamarre-Théroux, Doris Dea, Valérie Leduc, Youla S Tsantrizos, Judes Poirier
The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP) ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i...
February 2, 2018: Neurobiology of Aging
Tamer M Sakr, Mohammed A Khedr, Hassan M Rashed, Maged E Mohamed
l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug...
February 23, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mario Rizzetto
New therapeutic strategies to treat chronic hepatitis D are directed to deprive the hepatitis D virus (HDV) of functions necessary to complete its life cycle that are provided by the hepatitis B virus (HBV) and by the host. Current options are (1) the block by the synthetic peptide Myrcludex B of HBV surface antigen (HBsAg) entry into cells through the inhibition of the sodium taurocholate cotransporting receptor; (2) the inhibition with lonafarnib of the farnesylation of the large HD antigen, required for virion assembly; (3) the presumed reduction by the nucleic acid polymer REP 2139 of the release of the HBsAg and subviral HBV particles necessary for HD virion morphogenesis...
February 2018: Seminars in Liver Disease
Bingyin Peng, Lars K Nielsen, Sotirios C Kampranis, Claudia E Vickers
Monoterpene production in Saccharomyces cerevisae requires the introduction of heterologous monoterpene synthases (MTSs). The endogenous farnesyl pyrosphosphate synthase (FPPS; Erg20p) competes with MTSs for the precursor geranyl pyrophosphate (GPP), which limits the production of monoterpenes. ERG20 is an essential gene that cannot be deleted and transcriptional down-regulation of ERG20 has failed to improve monoterpene production. Here, we investigated an N-degron-dependent protein degradation strategy to down-regulate Erg20p activity...
February 19, 2018: Metabolic Engineering
Shuang Liu, Muhammad N A Sahid, Erika Takemasa, Kazutaka Maeyama, Masaki Mogi
Nitrogen-containing bisphosphonates (NBPs) have been widely used as bone anti-resorptive drugs for the treatment of osteoclast-dependent bone disorders. Zoledronate is currently the most potent NBP, and has potential as an inhibitor of farnesyl pyrophosphate synthase. The present study was undertaken to elucidate the possible effects of zoledronate on FcεRI-dependent mast cell activity in vitro, which is essential for in maintaining homeostasis of the gastrointestinal mucosa. Treatment with zoledronate significantly diminished exocytosis of mast cells, which was reflected by a decrease of FcεRI-dependent histamine release compared to that in vehicle-treated mast cells...
February 15, 2018: Biochemical Pharmacology
E Kobayashi, M Aga, S Kondo, C Whitehurst, T Yoshizaki, J S Pagano, J Shackelford
Increasing evidence shows that exosomes are key regulators in cancer cell-to-cell communication. Several reports on Epstein-Barr virus (EBV)-related malignancies demonstrate that latent membrane protein 1 (LMP1) secreted by exosomes derived from EBV- or LMP1-positive cells can promote cancer progression and metastasis. However, the mechanism by which LMP1 is loaded into exosomes is still poorly understood. Here, we examined whether the process of LMP1 loading into exosomes is linked to the multifunctional molecule of the ubiquitin system-ubiquitin C-terminal hydrolase-L1 (UCH-L1)...
January 2018: MSphere
Jianjun Qiao, Yi Sun, Lujuan Gao, Chengyan He, Wenqian Zheng
Farnesylation, which is catalyzed by farnesyltransferase, promotes membrane association of the modified protein and protein-protein interactions, and plays an important role in a number of physiological processes of pathogenic fungi, including stress response, environmental adaption and virulence. Lonafarnib is an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor with excellent pharmacokinetic and safety profile. In the present study, we investigated the in vitro activities of lonafarnib alone or combined with azoles, including itraconazole, voriconazole, and posaconazole, against 22 strains of Aspergillus spp...
October 9, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Celine Brooks, Joseph Murphy, Marycharmain Belcastro, Daniel Heller, Saravanan Kolandaivelu, Oleg Kisselev, Maxim Sokolov
Primary cilia are microtubule-based organelles, which protrude from the plasma membrane and receive a wide range of extracellular signals. Various cilia use G protein-coupled receptors (GPCRs) for the detection of these signals. For instance, vertebrate rod photoreceptors use their cilia (also called outer segments) as antennae detecting photons by GPCR rhodopsin. Rhodopsin recognizes incoming light and activates its G protein, transducin, which is composed of three subunits α, β, and γ. Similar to all G protein γ subunits, the transducin Gγ1 subunit undergoes C-terminal prenylation resulting in the addition of an isoprenoid farnesyl; however, the significance of this posttranslational modification is unclear...
2018: Frontiers in Molecular Neuroscience
David Hottman, Shaowu Cheng, Andrea Gram, Kyle LeBlanc, Li-Lian Yuan, Ling Li
Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-β deposition and neuroinflammation but only reduction in FT rescues cognitive function...
February 2, 2018: Neuroscience
Jong Yun Han, Sung Hwa Seo, Jae Myeong Song, Hongweon Lee, Eui-Sung Choi
For recombinant production of squalene, which is a triterpenoid compound with increasing industrial applications, in microorganisms generally recognized as safe, we screened Saccharomyces cerevisiae strains to determine their suitability. A strong strain dependence was observed in squalene productivity among Saccharomyces cerevisiae strains upon overexpression of genes important for isoprenoid biosynthesis. In particular, a high level of squalene production (400 ± 45 mg/L) was obtained in shake flasks with the Y2805 strain overexpressing genes encoding a bacterial farnesyl diphosphate synthase (ispA) and a truncated form of hydroxyl-3-methylglutaryl-CoA reductase (tHMG1)...
February 2, 2018: Journal of Industrial Microbiology & Biotechnology
Roman Petrovsky, Georg Krohne, Jörg Großhans
The nuclear envelope has a stereotypic morphology consisting of a flat double layer of the inner and outer nuclear membrane, with interspersed nuclear pores. Underlying and tightly linked to the inner nuclear membrane is the nuclear lamina, a proteinous layer of intermediate filament proteins and associated proteins. Physiological, experimental or pathological alterations in the constitution of the lamina lead to changes in nuclear morphology, such as blebs and lobulations. It has so far remained unclear whether the morphological changes depend on the differentiation state and the specific lamina protein...
January 24, 2018: European Journal of Cell Biology
Sen Liu, Mingzhi Su, Shao-Jiang Song, Jongki Hong, Hae Young Chung, Jee H Jung
An investigation of the jellyfish-derived fungus Penicillium chrysogenum J08NF-4 led to the isolation of two new meroterpene derivatives, chrysogenester (1) and 5-farnesyl-2-methyl-1-O-methylhydroquinone (2), and four known farnesyl meroterpenes. Docking analysis of 1 showed that it binds to PPAR-γ in the same manner as the natural PPAR-γ agonist amorfrutin B (7). Compound 1 activated PPAR-γ in murine Ac2F liver cells and increased nuclear PPAR-γ protein levels in murine RAW 264.7 macrophages. Because one of the main biological functions of PPAR-γ agonists is to suppress inflammatory response, an in vitro study was performed to explore the anti-inflammatory potency of 1 and the mechanism involved...
February 1, 2018: Journal of Natural Products
Bin Zhang, Yan Liu, Mengmeng Chen, Juntao Feng, Zhiqing Ma, Xing Zhang, Chuanshu Zhu
Celastrol is an active triterpenoid compound derived from Tripterygium wilfordii which is well-known as a traditional Chinese medicinal plant. Squalene synthase has a vital role in condensing two molecules of farnesyl diphosphate to form squalene, a key precursor of triterpenoid biosynthesis. In the present study, T. wilfordii squalene synthase (TwSQS) was cloned followed by prokaryotic expression and functional verification. The open reading frame cDNA of TwSQS was 1242 bp encoding 413 amino acids. Bioinformatic and phylogenetic analysis showed that TwSQS had high homology with other plant SQSs...
January 29, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Dianyong Jia, Shiqing Gao, Pengfei Duan, Jibao Chen, Fengxia Tian, Xiudao Yu
Aphids are major agricultural pests that cause significant yield losses of crops each year. (E)-β-farnesene (EβF), as the main component of the aphid alarm pheromones, can interrupt aphid feeding and cause other conspecies in the vicinity to become agitated or disperse from their host plant. Furthermore, EβF can function as a kairomone in attracting aphid predators. EβF synthase genes, which encode enzymes that convert farnesyl diphosphate (FPP) to the acyclic sesquiterpene EβF, have been isolated and characterized from peppermint (Mentha × piperita and Mentha asiatica), Yuzu (Citrus junos), Douglas fir (Pseudotsuga menziesii), sweet wormwood (Artemisia annua) and chamomile (Matricaria recutita), respectively...
January 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Ying Jin, Wenquan Hu, Tong Liu, Ujala Rana, Irene Aguilera-Barrantes, Amanda Kong, Suresh N Kumar, Bei Wang, Pin Gao, Xiang Wang, Yajun Duan, Aiping Shi, Dong Song, Ming Yang, Sijie Li, Bing Han, Gang Zhao, Zhimin Fan, Qing Robert Miao
Intrinsic or acquired chemoresistance is a hurdle in oncology. Only 7%-16% of estrogen receptor α (ERα) positive breast cancer cases achieve a pathological complete response (pCR) after neo-adjuvant chemotherapy. Nogo-B receptor (NgBR) is a cell surface receptor that binds farnesylated Ras and promotes Ras translocation to the plasma membrane. Here, we demonstrate NgBR as a potential therapeutic target for ERα positive breast cancer patients to attenuate paclitaxel resistance. NgBR knockdown enhanced paclitaxel-induced cell apoptosis by modulating expression of p53 and survivin in ERα positive breast cancer cells via NgBR-mediated PI3K/AKT and MAPK/ERK signaling pathways...
January 23, 2018: Cancer Letters
Paola Andrade, David Manzano, Karla Ramirez-Estrada, Daniel Caudepon, Montserrat Arro, Albert Ferrer, Michael A Phillips
The sesquiterpene alcohol nerolidol, synthesized from farnesyl diphosphate (FDP), mediates plant-insect interactions across multiple trophic levels with major implications for pest management in agriculture. We compared nerolidol engineering strategies in tobacco using agroinfiltration to transiently express strawberry (Fragraria ananassa) linalool/nerolidol synthase (FaNES1) either at the endoplasmic reticulum (ER) or in the cytosol as a soluble protein. Using solid phase microextraction and gas chromatography-mass spectrometry (SPME-GCMS), we have determined that FaNES1 directed to the ER via fusion to the transmembrane domain of squalene synthase or hydroxymethylglutaryl - CoA reductase displayed significant improvements in terms of transcript levels, protein accumulation, and volatile production when compared to its cytosolic form...
February 2018: Plant Science: An International Journal of Experimental Plant Biology
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