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Mei-Chieh Chen, Yuan-Chin Tsai, Jen-Ho Tseng, Jr-Jiun Liou, Steve Horng, Heng-Ching Wen, Yu-Ching Fan, Wen-Bin Zhong, Sung-Po Hsu
Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0-20 μM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate (MEV) and geranylgeranyl pyrophosphate (GGpp) by simvastatin induced G1 arrest and increased apoptotic cell populations at the sub-G1 phase. Adding MEV and GGpp prevented the simvastatin-inhibited cell proliferation...
December 13, 2017: International Journal of Molecular Sciences
Massimo Mezzavilla, Ronald Rodrigues Moura, Fulvio Celsi, Paola Maura Tricarico, Sergio Crovella
Mevalonate kinase deficiency (MKD) is an autosomal recessive inflammatory disease. Mutations in MVK gene are associated with MKD with modest genotype-phenotype correlation. In spite of recent guidelines indicating specific MVK mutations for the more severe form or the milder one, little is known about MVK variability within and between populations. The aim of this work is to provide supplementary information about MVK variability useful in the molecular diagnosis of MKD, as well as to unravel the presence of novel genes potentially involved as involved in the clinical heterogeneity of MKD phenotype...
December 12, 2017: Rheumatology International
Thomas Krieg, Anne Sydow, Sonja Faust, Ina Huth, Dirk Holtmann
Herein, we demonstrate that CO2 can be converted by an engineered "Knallgas" bacterium (Cupriavidus necator) to the terpene α-humulene. Heterologous expression of the mevalonate pathway and α-humulene synthase resulted in a production of approx. 10 mg α-humulene per gram cell dry mass (CDM) under heterotrophic conditions. This first example of chemolithoautotrophic production of a terpene from carbon dioxide, hydrogen and oxygen is a promising starting point for the production of different high value terpene compounds from abundant and simple raw materials...
December 12, 2017: Angewandte Chemie
Antonietta Santoro, Elena Ciaglia, Vanessa Nicolin, Alessandra Pescatore, Lucia Prota, Mario Capunzo, Matilde V Ursini, Stefania L Nori, Maurizio Bifulco
OBJECTIVE: N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation. MATERIALS AND METHODS: TNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays...
December 11, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Rosemary Yu, Joseph Longo, Jenna E van Leeuwen, Peter J Mullen, Wail Ba-Alawi, Benjamin Haibe-Kains, Linda Z Penn
The statin family of drugs preferentially trigger tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins...
December 11, 2017: Cancer Research
Bradley R Miller, Yan Kung
The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although HMGR inhibition by statin drugs is well understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range in cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data on the enzyme's cofactor preferences...
December 11, 2017: Biochemistry
Sara Landolfo, Giuseppe Ianiri, Salvatore Camiolo, Andrea Porceddu, Giuliana Mulas, Rossella Chessa, Giacomo Zara, Ilaria Mannazzu
A molecular approach was applied to the study of the carotenoid biosynthetic pathway of Rhodotorula mucilaginosa. At first, functional annotation of the genome of R. mucilaginosa C2.5t1 was carried out and gene ontology categories were assigned to 4033 predicted proteins. Then, a set of genes involved in different steps of carotenogenesis was identified and those coding for phytoene desaturase, phytoene synthase/lycopene cyclase and carotenoid dioxygenase (CAR genes) proved to be clustered within a region of ~10 kb...
December 8, 2017: Microbiology
Wenwen Zhang, Xiaoxiao Yang, Yuanli Chen, Wenquan Hu, Lipei Liu, Xiaomeng Zhang, Mengyang Liu, Lei Sun, Ying Liu, Miao Yu, Xiaoju Li, Luyuan Li, Yan Zhu, Qing Robert Miao, Jihong Han, Yajun Duan
Deficiency of hepatic Nogo-B receptor (NgBR) expression activates liver X receptor α (LXRα) in an adenosine monophosphate-activated protein kinase α (AMPKα)-dependent manner, thereby inducing severe hepatic lipid accumulation and hypertriglyceridemia. Statins have been demonstrated non-cholesterol lowering effects including anti-nonalcoholic fatty liver disease (NAFLD). Herein, we investigated if the anti-NAFLD function of statins depends on activation of NgBR expression. In vivo, atorvastatin protected apoE deficient or NgBR floxed, but not hepatic NgBR deficient mice, against Western diet (WD)-increased triglyceride levels in liver and serum...
December 4, 2017: Biochimica et Biophysica Acta
Atteyet F Yassin, Stefan Langenberg, Marcel Huntemann, Alicia Clum, Manoj Pillay, Krishnaveni Palaniappan, Neha Varghese, Natalia Mikhailova, Supratim Mukherjee, T B K Reddy, Chris Daum, Nicole Shapiro, Natalia Ivanova, Tanja Woyke, Nikos C Kyrpides
The permanent draft genome sequence of Actinotignum schaalii DSM 15541T is presented. The annotated genome includes 2,130,987 bp, with 1777 protein-coding and 58 rRNA-coding genes. Genome sequence analysis revealed absence of genes encoding for: components of the PTS systems, enzymes of the TCA cycle, glyoxylate shunt and gluconeogensis. Genomic data revealed that A. schaalii is able to oxidize carbohydrates via glycolysis, the nonoxidative pentose phosphate and the Entner-Doudoroff pathways. Besides, the genome harbors genes encoding for enzymes involved in the conversion of pyruvate to lactate, acetate and ethanol, which are found to be the end products of carbohydrate fermentation...
2017: PloS One
Sholeem Griffin, Giulio Preta, Iain Martin Sheldon
Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO...
December 6, 2017: Scientific Reports
Mohit P Dalwadi, Marco Garavaglia, Joseph P Webb, John R King, Nigel P Minton
The mevalonate pathway is normally found in eukaryotes, and allows for the production of isoprenoids, a useful class of organic compounds. This pathway has been successfully introduced to Escherichia coli, enabling a biosynthetic production route for many isoprenoids. In this paper, we develop and solve a mathematical model for the concentration of metabolites in the mevalonate pathway over time, accounting for the loss of acetyl-CoA to other metabolic pathways. Additionally, we successfully test our theoretical predictions experimentally by introducing part of the pathway into Cupriavidus necator...
November 30, 2017: Journal of Theoretical Biology
Yanlong Wei, Ali Mohsin, Qi Hong, Meijin Guo, Hongqing Fang
The multiple plasmid system, mostly relied, for heterogeneous gene expression, results in genetic instability and low mean productivity. To address this, an integration method was employed for investigating expression of heterogenous pathway in E. coli cells; where mevalonate upper pathway was found efficiently expressed. Subsequently, to improve lycopene production, chromosomal multiple position integration strategy was used to strengthen mevalonate upper pathway. Meanwhile, the plasmid system was employed for mevalonate lower pathway and lycopene pathway expression to finally generate the mutant D711 strain...
November 14, 2017: Bioresource Technology
Yoshifumi Hayashi, Tomokazu Ito, Tohru Yoshimura, Hisashi Hemmi
(E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) is an intermediate of the methylerythritol phosphate pathway. Utilization of HMBPP by lycopene elongase from Corynebacterium glutamicum, which is a UbiA-family prenyltransferase responsible for C50 carotenoid biosynthesis, was investigated using an Escherichia coli strain that contained the exogenous mevalonate pathway as well as the carotenoid biosynthetic pathway. Inhibition of the endogenous methylerythritol phosphate pathway resulted in loss of the production of C50 carotenoid flavuxanthin, while C40 lycopene formation was retained...
December 1, 2017: Bioscience, Biotechnology, and Biochemistry
Federica Iannelli, Rita Lombardi, Maria Rita Milone, Biagio Pucci, Simona De Rienzo, Alfredo Budillon, Francesca Bruzzese
BACKGROUND: Modifications of lipid metabolism have been progressively accepted as a hallmark of tumor cells and in particular, an elevated lipogenesis has been described in various types of cancers. OBJECTIVE: Important or deregulated activity of the mevalonate pathway has been demonstrated in different tumors and a wide range of studies have suggested that tumor cells are more dependent on the unceasing availability of mevalonate pathway metabolites than their non-malignant complements...
November 29, 2017: Recent Patents on Anti-cancer Drug Discovery
Claudia Rita Corso, Daniel Fernandes Martins, Stephanie Carvalho Borges, Olair Carlos Beltrame, José Ederaldo Queiroz Telles, Nilza Cristina Buttow, Maria Fernanda de Paula Werner
The present study compares the effects of a low and high doses of simvastatin in a model of peripheral neuropathy by evaluating sensorial, motor, and morphological parameters. First, male Wistar rats were orally treated with vehicle (saline, 1 mL/kg), simvastatin (2 and 80 mg/kg) or morphine (2 mg/kg, s.c.), 1 h before 2.5% formalin injection. Neuropathic pain was induced by crushing the sciatic nerve, and mechanical and cold allodynia, nerve function, histology, MPO and NAG concentrations, as well as mevalonate induced-nociception were evaluated...
November 29, 2017: Inflammopharmacology
Wanna Zhang, Long Ma, Haijun Xiao, Chen Liu, Lin Chen, Shaolong Wu, Gemei Liang
Juvenile hormones (JHs) are crucial regulators for multiple physiological processes in insects. In the current study, 10 genes in mevalonate pathway involved in JH biosynthesis were identified from Helicoverpa armigera. Tissue-specific expression analysis showed that six genes were highly expressed in the head which contained the JH biosynthetic gland (corpora allata). Temporal expression pattern showed that 10 of 12 genes were highly transcribed in the late 2nd-instar when the in vivo JH titer reached the peak, indicating a tight correlation between JH titer and the transcription of JH synthetic pathway genes...
November 29, 2017: Scientific Reports
Sébastien Pellaud, Laurent Mène-Saffrané
Tocochromanols are organic compounds mostly produced by photosynthetic organisms that exhibit vitamin E activity in animals. They result from the condensation of homogentisate with four different polyprenyl side chains derived all from geranylgeranyl pyrophosphate. The core tocochromanol biosynthesis has been investigated in several photosynthetic organisms and is now well-characterized. In contrast, our current knowledge of the biosynthesis and transport of tocochromanol biosynthetic precursors is much more limited...
2017: Frontiers in Plant Science
Chunlan Xu, Sally Ghali, Jiani Wang, David Q Shih, Christina Ortiz, Caroline C Mussatto, Elaine C Lee, Diana H Tran, Jonathan P Jacobs, Venu Lagishetty, Phillip Fleshner, Lori Robbins, Michelle Vu, Tressia C Hing, Dermot P B McGovern, Hon Wai Koon
Many Crohn's disease (CD) patients develop intestinal strictures, which are difficult to prevent and treat. Cationic steroid antimicrobial 13 (CSA13) shares cationic nature and antimicrobial function with antimicrobial peptide cathelicidin. As many functions of cathelicidin are mediated through formyl peptide receptor-like 1 (FPRL1), we hypothesize that CSA13 mediates anti-fibrogenic effects via FPRL1. Human intestinal biopsies were used in clinical data analysis. Chronic trinitrobenzene sulfonic acid (TNBS) colitis-associated intestinal fibrosis mouse model with the administration of CSA13 was used...
November 27, 2017: Scientific Reports
Umair Ilyas, Reem Altaf, Syed Aun Muhammad, Muhammad Imran Qadir, Humaira Nadeem, Safia Ahmed
Methicillin resistant Staphylococcus aureus (MRSA) is resistant to known antibiotics and has become a great challenge for healthcare professionals, therefore new molecules are needed to manage this situation. In this study, new lead molecules 4-Amino-5-(2-Hydroxyphenyl)-1,2,4-Triazol-3-Thione (U1) and4-(2-hydroxybenzalidine) amine-5-(2-hydroxy) phenyl-1,2,4-triazole-3-thiol(U1A Schiff base) were synthesized by fusion method that showed promising antibacterial activity (U1A: 26mm and U1: 14mm) against MRSA.FT-IR and NMR were used for structural characterization of these derivatives and their toxicity properties were assessed by Lipinski's rule of 5...
November 2017: Pakistan Journal of Pharmaceutical Sciences
Louis Patrick Conway, Fang Fang Liu, Qian Li, Josef Voglmeir
Galactokinases are a class of enzymes which belong to the GHMP (galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase) superfamily and catalyse the phosphorylation of galactose in the first step of the Leloir pathway. Here we report the discovery of three enzymes from Shewanella woodyi which have been classified as galactokinases based on sequence similarity. However, each of these enzymes show little to no significant activity towards galactose and instead exhibit a strong preference for glucose...
October 31, 2017: Carbohydrate Research
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