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Takeshi Funakoshi, Toshihiko Aki, Masateru Tajiri, Kana Unuma, Koichi Uemura
Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure...
October 18, 2016: Journal of Biological Chemistry
Young Youp Koh, Dong Yoon Lim
OBJECTIVE: The present study was aimed to investigate the characteristics of simvastatin, one of statins, on the catecholamine (CA) secretion from the perfused model of the isolated rat adrenal gland, and also to clarify its mechanism of action. DESIGN AND METHOD: The adrenal gland was isolated and perfused with Krebs-bicarbonate. CA was measured directly by using the fluorospectrophotometer. RESULTS: Simvastatin inhibited ACh-evoked CA secretory response in a dose- and time-dependent fashion...
September 2016: Journal of Hypertension
Jessica Brandi, Ilaria Dando, Elisa Dalla Pozza, Giulia Biondani, Rosalind Jenkins, Victoria Elliott, Kevin Park, Giuseppina Fanelli, Lello Zolla, Eithne Costello, Aldo Scarpa, Daniela Cecconi, Marta Palmieri
: Recently, we have shown that the secretome of pancreatic cancer stem cells (CSCs) is characterized by proteins that participate in cancer differentiation, invasion, and metastasis. However, the differentially expressed intracellular proteins that lead to the specific characteristics of pancreatic CSCs have not yet been identified, and as a consequence the deranged metabolic pathways are yet to be elucidated. To identify the modulated proteins of pancreatic CSCs, iTRAQ-based proteomic analysis was performed to compare the proteome of Panc1 CSCs and Panc1 parental cells, identifying 230 modulated proteins...
October 13, 2016: Journal of Proteomics
Yi Rang Na, Gyo Jung Gu, Daun Jung, Young Won Kim, Juri Na, Jin Sun Woo, Joo Youn Cho, Hyewon Youn, Seung Hyeok Seok
GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow-derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF-mediated increase of TNF-α, IL-1β, IL-6, and IL-12p70 synthesis upon LPS stimulation...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jilong Wang, Suthamat Niyompanich, Yi-Shu Tai, Jingyu Wang, Wenqin Bai, Prithviraj Mahida, Tuo Gao, Kechun Zhang
: Chromosomal integration of heterologous metabolic pathways is optimal for industrially relevant fermentation, as plasmid-based fermentation causes extra metabolic burden and genetic instabilities. In this work, chromosomal integration was adapted for the production of mevalonate which can be readily converted into β-methyl-δ-valerolactone, a monomer for the production of mechanically tunable polyesters. The mevalonate pathway driven by a constitutive promoter was integrated into the chromosome of Escherichia coli to replace the native fermentation gene adhE or ldhA The engineered strains (CMEV-1 and CMEV-2) did not require inducer or antibiotic, and showed slightly higher maximal productivities (0...
October 7, 2016: Applied and Environmental Microbiology
Takaaki Higashi, Hiromitsu Hayashi, Yuki Kitano, Kensuke Yamamura, Takayoshi Kaida, Kota Arima, Katsunobu Taki, Shigeki Nakagawa, Hirohisa Okabe, Hidetoshi Nitta, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba
Diabetes and obesity are associated with non-alcoholic steatohepatitis and an increased incidence of hepatocellular carcinoma (HCC). TAZ and YAP are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. Statins are commonly used to patients with metabolic problems as hypercholesterolemia. Statins also have anti-cancer properties, and the cross-talk between mevalonate pathway and Hippo pathway was known. The aim of this study is to confirm the statin's anti-cancer effects on HCC cells and its survival benefits in HCC patients with curative surgery...
November 2016: Medical Oncology
M Cuccioloni, L Bonfili, M Mozzicafreddo, V Cecarini, S Scuri, M Cocchioni, M Nabissi, G Santoni, A M Eleuteri, M Angeletti
Mangiferin is a natural xanthone glycoside with therapeutic potential. Herein, its cytotoxic properties were explored in a human cell model of breast adenocarcinoma. The results supported the multi-target nature of mangiferin action, as the inhibition of three enzymatic systems, namely HMG-CoA reductase, the proteasome and plasmin, respectively in charge of regulating cholesterol homeostasis, protein turnover and cell adhesion, was documented for the first time. Globally, mangiferin was able to selectively block breast cancer cell growth by inducing apoptosis and by arresting cell proliferation through a combined action on cholesterol and proteasome pathways, as well as to inhibit plasmin-mediated mechanisms of cell migration...
October 12, 2016: Food & Function
Teemu P Miettinen, Mikael Björklund
Eukaryotic cells attempt to maintain an optimal size, resulting in size homeostasis. While cellular content scales isometrically with cell size, allometric laws indicate that metabolism per mass unit should decline with increasing size. Here we use elutriation and single-cell flow cytometry to analyze mitochondrial scaling with cell size. While mitochondrial content increases linearly, mitochondrial membrane potential and oxidative phosphorylation are highest at intermediate cell sizes. Thus, mitochondrial content and functional scaling are uncoupled...
October 4, 2016: Developmental Cell
Jie Sun, Yun Qian, Yue Jiang, Jiaping Chen, Juncheng Dai, Guangfu Jin, Jianming Wang, Zhibin Hu, Sijun Liu, Chong Shen, Hongbing Shen
BACKGROUND: Several genome-wide association studies have discovered novel loci at chromosome 12q24, which includes mevalonate kinase (MVK), methylmalonic aciduria (cobalamin deficiency) cbIB type (MMAB), and potassium channel tetramerization domain-containing 10 (KCTD10), all of which influence HDL-cholesterol concentrations. However, there are few reports on the associations between these polymorphisms and HDL-C concentrations in Chinese population. This study aimed to evaluate the associations between functional polymorphisms in three genes (MVK, MMAB and KCTD10) and HDL-C concentrations, as well as coronary heart disease (CHD) susceptibility in Chinese individuals...
October 4, 2016: Lipids in Health and Disease
Anna Di Benedetto, Marcella Mottolese, Francesca Sperati, Cristiana Ercolani, Luigi Di Lauro, Laura Pizzuti, Patrizia Vici, Irene Terrenato, Abeer M Shaaban, Sreekumar Sundara-Rajan, Matthew P Humphries, Maddalena Barba, Valerie Speirs, Ruggero De Maria, Marcello Maugeri-Saccà
Male breast cancer (MBC) is a rare hormone-driven disease often associated with obesity. HMG-CoAR is the central enzyme of the mevalonate pathway, a molecular route deputed to produce cholesterol and steroid-based hormones. HMG-CoAR regulates the oncogenic Hippo transducers TAZ/YAP whose expression was previously associated with shorter survival in MBC. 225 MBC samples were immunostained for HMG-CoAR and 124 were considered eligible for exploring its relationship with hormone receptors (ER, PgR, AR), Hippo transducers and survival outcomes...
October 7, 2016: Scientific Reports
Ana M Misic, Christine L Cain, Daniel O Morris, Shelley C Rankin, Daniel P Beiting
Staphylococcus species are a leading cause of skin and soft tissue infections in humans and animals, and the antibiotics used to treat these infections are often the same. Methicillin- and multidrug-resistant staphylococcal infections are becoming more common in human and veterinary medicine. From a "One Health" perspective, this overlap in antibiotic use and resistance raises concerns over the potential spread of antibiotic resistance genes. Whole-genome sequencing and comparative genomics analysis revealed that Staphylococcus species use divergent pathways to synthesize isoprenoids...
September 2016: MSphere
Michael B Fessler
Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon (IFN) response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, 'professional' role for sterols and oxysterols in macrophage and T-cell immunity...
September 27, 2016: Trends in Immunology
Meilan Huang, Kexin Wei, Xiao Li, James McClory, Guixiang Hu, Jian-Wei Zou, David Timson
The mevalonate pathway is of important clinical, pharmaceutical, and biotechnological relevance. However, lack of the understanding of the phosphorylation mechanism of the kinases in this pathway has limited rationally engineering the kinases in industry. Here the phosphorylation reaction mechanism of a representative kinase in the mevalonate pathway, phosphomevalonate kinase, was studied by using molecular dynamics and hybrid QM/MM methods. We find that a conserved residue (Ser106) is reorientated to anchor ATP via a stable H-bond interaction...
October 11, 2016: Journal of Physical Chemistry. B
Kok-Yong Chin, Kok-Lun Pang, Ima-Nirwana Soelaiman
Tocotrienol is a member of vitamin E family and is well-known for its antioxidant and anti-inflammatory properties. It is also a suppressor of mevalonate pathway responsible for cholesterol and prenylated protein synthesis. This review aimed to discuss the health beneficial effects of tocotrienol, specifically in preventing or treating hyperlipidaemia, diabetes mellitus, osteoporosis and cancer with respect to these properties. Evidence from in vitro, in vivo and human studies has been examined. It is revealed that tocotrienol shows promising effects in preventing or treating the health conditions previously mentioned in in vivo and in vitro models...
2016: Advances in Experimental Medicine and Biology
C Galeotti, S Georgin-Lavialle, G Sarrabay, I Touitou, I Koné-Paut
Mevalonate kinase deficiency is a rare, autosomal recessive, auto-inflammatory disease. This results from mutations in the gene MVK coding for the enzyme mevalonate kinase. This enzyme is involved in cholesterol and isoprenoids synthesis. Depending partially of the residual activity of the mevalonate kinase, the clinical spectrum realizes a continuum which extends from the mild phenotype of the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to a lethal form of mevalonic aciduria. The HIDS is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, abdominal pain, diarrhea, arthralgia, hepatomegaly, splenomegaly and skin rash...
September 19, 2016: La Revue de Médecine Interne
Hisataka Sabe, Ari Hashimoto, Shigeru Hashimoto, Tsukasa Oikawa
The mevalonate pathway results in the prenylation of small GTPases, which are pivotal for oncogenesis and cancer malignancies. However, inhibitors of this pathway, such as statins, have not necessarily produced favorable results in clinical trials. We recently identified properties of statin responders, together with the underlying molecular mechanisms and simple biomarkers to predict these responders.
July 2016: Molecular & Cellular Oncology
Nobutaka Suzuki, Tatsuo Ito, Hisanori Matsui, Masayuki Takizawa
TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases...
2016: SpringerPlus
Santosh Kumar, Chase Kempinski, Xun Zhuang, Ayla Norris, Sibongile Mafu, Jiachen Zi, Stephen A Bell, S Eric Nybo, Scott E Kinison, Zuodong Jiang, Sheba Goklany, Kristin B Linscott, Xinlu Chen, Qidong Jia, Shoshana D Brown, John L Bowman, Patricia C Babbitt, Reuben J Peters, Feng Chen, Joe Chappell
Marchantia polymorpha is a basal terrestrial land plant, which like most liverworts accumulates structurally diverse terpenes believed to serve in deterring disease and herbivory. Previous studies have suggested that the mevalonate and methylerythritol phosphate pathways, present in evolutionarily diverged plants, are also operative in liverworts. However, the genes and enzymes responsible for the chemical diversity of terpenes have yet to be described. In the current study, we resorted to a HMMER search tool to identify 17 putative terpene synthase genes from M...
September 20, 2016: Plant Cell
Songyuan Li, Christian Bille Jendresen, Alexander Grünberger, Carlotta Ronda, Sheila Ingemann Jensen, Stephan Noack, Alex Toftgaard Nielsen
Production of proteins and biochemicals in microbial cell factories is often limited by carbon and energy spent on excess biomass formation. To address this issue, we developed several genetic growth switches based on CRISPR interference technology. We demonstrate that growth of Escherichia coli can be controlled by repressing the DNA replication machinery, by targeting dnaA and oriC, or by blocking nucleotide synthesis through pyrF or thyA. This way, total GFP-protein production could be increased by up to 2...
September 16, 2016: Metabolic Engineering
Young Youp Koh, Dong Yoon Lim
OBJECTIVE: The present study was aimed to investigate the characteristics of simvastatin, one of statins, on the catecholamine (CA) secretion from the perfused model of the isolated rat adrenal gland, and also to clarify its mechanism of action. DESIGN AND METHOD: The adrenal gland was isolated and perfused with Krebs-bicarbonate. CA was measured directly by using the fluorospectrophotometer. RESULTS: Simvastatin inhibited ACh-evoked CA secretory response in a dose- and time-dependent fashion...
September 2016: Journal of Hypertension
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