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Mehmet U Bikkul, Craig S Clements, Lauren S Godwin, Martin W Goldberg, Ian R Kill, Joanna M Bridger
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal premature ageing disease in children. HGPS is one of several progeroid syndromes caused by mutations in the LMNA gene encoding the nuclear structural proteins lamins A and C. In classic HGPS the mutation G608G leads to the formation of a toxic lamin A protein called progerin. During post-translational processing progerin remains farnesylated owing to the mutation interfering with a step whereby the farnesyl moiety is removed by the enzyme ZMPSTE24...
June 15, 2018: Biogerontology
Yosuke Hoshino, Eric A Gaucher
Isoprenoids and their derivatives represent the largest group of organic compounds in nature and are distributed universally in the three domains of life. Isoprenoids are biosynthesized from isoprenyl diphosphate units, generated by two distinctive biosynthetic pathways: mevalonate pathway and methylerthritol 4-phosphate pathway. Archaea and eukaryotes exclusively have the former pathway, while most bacteria have the latter. Some bacteria, however, are known to possess the mevalonate pathway genes. Understanding the evolutionary history of these two isoprenoid biosynthesis pathways in each domain of life is critical since isoprenoids are so interweaved in the architecture of life that they would have had indispensable roles in the early evolution of life...
June 14, 2018: Molecular Biology and Evolution
Soo-Jin Yeom, Moonjung Kim, Seong Keun Kim, Dae-Hee Lee, Kil Koang Kwon, Hyewon Lee, Haseong Kim, Dong-Myung Kim, Seung-Goo Lee
BACKGROUND: Isoprene is a five-carbon chemical that is an important starting material for the synthesis of rubber, elastomers, and medicines. Although many plants produce huge amounts of isoprene, it is very difficult to obtain isoprene directly from plants because of its high volatility and increasing environmental regulations. Over the last decade, microorganisms have emerged as a promising alternative host for efficient and sustainable bioisoprene production. Isoprene synthase (IspS) has received much attention for the conversion of isoprene from dimethylallyl diphosphate (DMAPP)...
June 15, 2018: BMC Plant Biology
J Scott Lee, Andrew Roberts, Dennis Juarez, Thanh-Trang T Vo, Shruti Bhatt, Lee-Or Herzog, Sharmila Mallya, Richard J Bellin, Suresh K Agarwal, Ahmed Hamed Salem, Tu Xu, Jia Jia, Lingxiao Li, John R Hanna, Matthew S Davids, Angela G Fleischman, Susan O'Brien, Lloyd T Lam, Joel D Leverson, Anthony Letai, Jonathan H Schatz, David A Fruman
Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells...
June 13, 2018: Science Translational Medicine
Nenggang Chen, Pingrong Wang, Chunmei Li, Qian Wang, Jihong Pan, Fuliang Xiao, Yang Wang, Kuan Zhang, Caixia Li, Bin Yang, Changhui Sun, Xiaojian Deng
Plant isoprenoids are dependent on two independent pathways, the cytosolic mevalonate (MVA) pathway and the plastidic methylerythritol phosphate (MEP) pathway. IspE is one of seven known enzymes in the MEP pathway. Currently, no IspE gene has been identified in rice. In addition, no virescent mutants have been reported to result from a gene mutation affecting the MEP pathway. In this study, we isolated a green-revertible yellow leaf mutant gry340 in rice. The mutant exhibited a reduced level of photosynthetic pigments, and an arrested development of chloroplasts and mitochondria in its yellow leaves...
June 8, 2018: Plant & Cell Physiology
Zehua Qin, Rubing Zhang, Jianping Yu
Perillyl alcohol, [4-isopropylene-1-cyclohexene] methanol, is a monocyclic monoterpene alcohol with special odorous similar to that of linalool and terpineol. It has application potential in pharmaceutical, daily chemical and food industries. In this study, one method for the synthesis of perillyl alcohol through the MVA pathway was studied. First, the MVA metabolic pathway originated from Enterococcus faecalis was constructed in Escherichia coli to synthesize limonene. Limonene was further transformed to perillyl alcohol by the hydroxylation of cytochrome P450 alkane hydroxylase...
May 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Peta Bradbury, Daniela Traini, Alaina J Ammit, Paul M Young, Hui Xin Ong
Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism...
June 8, 2018: Advanced Drug Delivery Reviews
R H Weng, J Yang, Y H Wang
No abstract text is available yet for this article.
June 2, 2018: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Susana Barros, Rosa Montes, José Benito Quintana, Rosario Rodil, Ana André, Ana Capitão, Joana Soares, Miguel M Santos, Teresa Neuparth
Simvastatin (SIM), a hypocholesterolaemic compound, is among the most prescribed pharmaceuticals for cardiovascular disease prevention worldwide. Several studies have shown that acute exposure to SIM causes multiple adverse effects in aquatic organisms. However, uncertainties still remain regarding the chronic effects of SIM in aquatic ecosystems. Therefore, the present study aimed to investigate the effects of SIM in the model freshwater teleost zebrafish (Danio rerio) following a chronic exposure (90 days) to environmentally relevant concentrations ranging from 8 ng/L to 1000 ng/L...
May 25, 2018: Aquatic Toxicology
Daniela Heilos, Clemens Röhrl, Christine Pirker, Bernhard Englinger, Dina Baier, Thomas Mohr, Michaela Schwaiger, Shahid Muhammad Iqbal, Sushilla van Schoonhoven, Kristaps Klavins, Tanja Eberhart, Ursula Windberger, Judith Taibon, Sonja Sturm, Hermann Stuppner, Gunda Koellensperger, Rita Dornetshuber-Fleiss, Walter Jäger, Rosa Lemmens-Gruber, Walter Berger
Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have established destruxin-resistant sublines of HCT116 colon carcinoma cells by selection with the most prevalent derivatives, destruxin (dtx)A, dtxB and dtxE. Various cell biological and molecular techniques were applied to elucidate the regulatory mechanisms underlying these acquired and highly stable destruxin resistance phenotypes...
May 22, 2018: Oncotarget
David Bartee, Michael J Wheadon, Caren L Freel Meyers
Targeting essential bacterial processes beyond cell wall, protein, nucleotide, and folate syntheses holds promise to reveal new antimicrobial agents and expand the potential drugs available for combination therapies. The synthesis of isoprenoid precursors, isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), is vital for all organisms; however, humans use the mevalonate pathway for production of IDP/DMADP while many pathogens, including Plasmodium falciparum and Mycobacterium tuberculosis, use the orthogonal methylerythritol phosphate (MEP) pathway...
June 5, 2018: Journal of Organic Chemistry
Juan A Lara, Alma Burciaga-Monge, Angel Chávez, Marc Revés, Rodolfo Lavilla, Monserrat Arró, Albert Boronat, Teresa Altabella, Albert Ferrer
Steryl esters (SEs) serve as a storage pool of sterols that helps to maintain proper levels of free sterols (FSs) in cell membranes throughout plant growth and development, and participates in the recycling of FSs and fatty acids released from cell membranes in aging tissues. SEs are synthesized by sterol acyltransferases, a family of enzymes that catalyze the transfer of fatty acil groups to the hydroxyl group at C-3 position of the sterol backbone. Sterol acyltransferases are categorized into acyl-CoA:sterol acyltransferases (ASAT) and phospholipid:sterol acyltransferases (PSAT) depending on whether the fatty acyl donor substrate is a long-chain acyl-CoA or a phospolipid...
2018: Frontiers in Plant Science
Dongpu Dai, Xiaotong Sun, Jie Ding, Yuxiao Chen, Shenjiang Hu
Farnesyl pyrophosphate synthase (FPPS) is a vital enzyme in the mevalonate pathway. Our previous study has indicated that overexpression of FPPS increases hypoxia/reoxygenation (HR) injury in Heart-derived H9c2 Cells. Hence, we designed this experiment to further investigate the effect of FPPS on myocardial ischemia/reperfusion (MIR) injury using a transgenic (Tg) model, and explore the relevant mechanisms. The results showed that when mouse hearts were subjected to ex vivo I/R, Tg mice have a higher CK and LDH, a larger myocardial infarct size and lower heart function recovery...
June 1, 2018: Gene
Sumie Kato, María Francisca Liberona, Javier Cerda-Infante, Marianela Sanchez, Jenny F Henriquez, Carolina Bizama, Maria Loreto Bravo, Pamela Gonzalez, Roger Gejman, Jorge Branes, Karen García, Carolina Ibañez, Gareth Ivor Owen, Juan Carlos Roa, Viviana Montecinos, Mauricio Arturo Cuello
Cell plasticity of 'stem-like' cancer-initiating cells (CICs) is a hallmark of cancer, allowing metastasis and cancer progression. Here, we studied whether simvastatin, a lipophilic statin, could impair the metastatic potential of CICs in high-grade serous ovarian cancer (HGS-ovC), the most lethal among the gynecologic malignancies. qPCR, immunoblotting, and immunohistochemistry were used to assess simvastatin effects on proteins involved in stemness and epithelial-mesenchymal cell plasticity (EMT). Its effects on tumor growth and metastasis were evaluated using different models (e...
May 30, 2018: Endocrine-related Cancer
Cassandra R Harapas, Annemarie Steiner, Sophia Davidson, Seth L Masters
PURPOSE OF REVIEW: Autoinflammatory diseases are driven by abnormal innate immune activation. In the case of inflammasomopathies, these are all attributable to activation of an inflammasome complex, nucleated by an innate immune sensor such as NLRP3. This review will focus on recent advances that have helped to elucidate the role of three other sensors (NLRP1, NLRC4 and pyrin) which can also cause inflammasomopathies. RECENT FINDINGS: Mutations in pyrin (S242R or E244K) destroy an inhibitory 14-3-3 binding site and result in the newly characterised disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND)...
May 30, 2018: Current Rheumatology Reports
Yoann Millerioux, Muriel Mazet, Guillaume Bouyssou, Stefan Allmann, Tiila-Riikka Kiema, Eloïse Bertiaux, Laetitia Fouillen, Chandan Thapa, Marc Biran, Nicolas Plazolles, Franziska Dittrich-Domergue, Aline Crouzols, Rik K Wierenga, Brice Rotureau, Patrick Moreau, Frédéric Bringaud
De novo biosynthesis of lipids is essential for Trypanosoma brucei, a protist responsible for the sleeping sickness. Here, we demonstrate that the ketogenic carbon sources, threonine, acetate and glucose, are precursors for both fatty acid and sterol synthesis, while leucine only contributes to sterol production in the tsetse fly midgut stage of the parasite. Degradation of these carbon sources into lipids was investigated using a combination of reverse genetics and analysis of radio-labelled precursors incorporation into lipids...
May 29, 2018: PLoS Pathogens
Jannik Helweg-Larsen, Ann-Brit Eg Hansen, Sussi Bagge Mortensen, Isik Somuncu Johansen
Periodic fever syndromes (PFS) are characterised by recurrent fever and excessive systemic inflammation. These rare and hereditary syndromes include familial Mediterranean fever, tumour necrosis factor receptor-1 associated periodic syndrome, mevalonate kinase deficiency and cryopyrin-associated periodic syndrome. Each PFS has distinct clinical and genetic features. Availability of improved genetic methods has improved the understanding of the syndromes and diagnostic testing. The main complication is systemic amyloidosis...
May 28, 2018: Ugeskrift for Laeger
Annalisa Marcuzzi, Claudia Loganes, Erica Valencic, Elisa Piscianz, Lorenzo Monasta, Sabrine Bilel, Roberta Bortul, Claudio Celeghini, Marina Zweyer, Alberto Tommasini
Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith⁻Lemli⁻Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects...
May 19, 2018: International Journal of Molecular Sciences
M S Sujith Kumar, Ibandalin Mawlong, Kishwar Ali, Aruna Tyagi
Plants respond to drought stress in the form of various physio-biochemical and molecular changes at both cellular and molecular levels. Drought stress causes the destruction of cell membranes by disintegration of membrane lipids. One of the major groups of membrane lipids that plays important role in preserving the integrity of cell membranes is phytosterols. HMG-CoA reductase (HMGR) is the principal enzyme in the biosynthesis of plant sterols, synthesized via mevalonic acid pathway. Phospholipid: sterol acyltransferase (PSAT) is another important enzyme that plays an important role in turnover of phytosterols into steryl esters and helps maintain homeostasis of membrane lipids...
May 15, 2018: Plant Physiology and Biochemistry: PPB
Maria Gabriella Matera, Luigino Calzetta, Giulia Gritti, Laura Gallo, Brunella Perfetto, Giovanna Donnarumma, Mario Cazzola, Paola Rogliani, Maria Donniacuo, Barbara Rinaldi
In patients with chronic obstructive pulmonary disease (COPD) the inflammatory response is often steroid-resistant, likely since oxidative stress and cigarette smoking impair histone deacetylase 2 (HDAC2) activity. Since it has been demonstrated that statins may restore the HDAC2 activity in cultured human endothelial cells, the aim of this study was to investigate the effects of statins in reversing the steroid-resistance induced by oxidative stress. We evaluated the effects of simvastatin and dexamethasone on HDAC2 expression and activity, and the role of mevalonate and Rho/ROCK pathways in A549 cells, a human lung type II epithelial cell line stressed with H2 O2 ...
May 18, 2018: European Journal of Pharmacology
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