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Naoki Makino, Toyoki Maeda, Nobuyuki Abe
Telomere shortening is well known to be associated with the aging process and aging-associated diseases, including diabetes. The telomere length and subtelomeric methylation status in peripheral leucocytes (LTL) were compared in elderly type 2 diabetes patients (T2D) and diabetes free controls (C). The methylation status was analyzed the between of MspI-TRF lengths and HpaII-TRF lengths by using methylation-sensitive and -insensitive restriction enzyme isoschizomers, MspI and HpaII, respectively. Although the mean telomere lengths, MspI-TRF or HpaII-TRF, were no difference in patients between C and T2D...
February 20, 2019: Canadian Journal of Physiology and Pharmacology
Xi-Xiang Tang, Xia Yan, Wen-Hao Fu, Lu-Qi Yi, Bo-Wen Tang, Li-Bo Yu, Meijuan Fang, Zhen Wu, Ying-Kun Qiu
Fusarium solani H915 (MCCC3A00957), a fungus originating from mangrove sediment, showed potent inhibitory activity against tea pathogenic fungus Pestalotiopsis theae. Successive chromatographic separation on an ethyl acetate (EtOAc) extract of F. solani H915 resulted in the isolation of five new alkenoic diacid derivatives, fusarilactones A-C (1-3), fusaridioic acids B (4) and C (5), in addition to seven known compounds (6-12). The chemical structures of these metabolites were elucidated on the basis of UV, IR, HR-ESI-MS and NMR spectroscopic data...
February 20, 2019: Journal of Agricultural and Food Chemistry
Youngah Jo, Jason S Hamilton, Seonghwan Hwang, Kristina Garland, Gennipher A Smith, Shan Su, Iris Fuentes, Sudha Neelam, Bonne M Thompson, Jeffrey G McDonald, Russell A DeBose-Boyd
Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2 . Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1...
February 20, 2019: ELife
Ivan Gout
Coenzyme A (CoA) is an indispensable cofactor in all living organisms. It is synthesized in an evolutionarily conserved pathway by enzymatic conjugation of cysteine, pantothenate (Vitamin B5), and ATP. This unique chemical structure allows CoA to employ its highly reactive thiol group for diverse biochemical reactions. The involvement of the CoA thiol group in the production of metabolically active CoA thioesters (e.g. acetyl CoA, malonyl CoA, and HMG CoA) and activation of carbonyl-containing compounds has been extensively studied since the discovery of this cofactor in the middle of the last century...
February 19, 2019: Biochemical Society Transactions
Yuyu Song, Kartik Subramanian, Matthew J Berberich, Steven Rodriguez, Isabel J Latorre, Catherine M Luria, Robert Everley, Mark W Albers, Timothy J Mitchison, Peter K Sorger
The immortalized human ReNcell VM cell line represents a reproducible and easy-to-propagate cell culture system for studying the differentiation of neural progenitors. To better characterize the starting line and its subsequent differentiation, we assessed protein and phospho-protein levels and cell morphology over a 15-day period during which ReNcell progenitors differentiated into neurons, astrocytes and oligodendrocytes. Five of the resulting datasets measured protein levels or states of phosphorylation based on tandem-mass-tag (TMT) mass spectrometry and four datasets characterized cellular phenotypes using high-content microscopy...
February 19, 2019: Scientific Data
QianQian Han, QianQian Liu, Hui Zhang, Meili Lu, Hongxin Wang, Futian Tang, Yingjie Zhang
BACKGROUND Simvastatin, an HMG-CoA reductase inhibitor, has been reported to exert multiple protective effects on the cardiovascular system. However, the molecular mechanism remains to be examined. The present study was designed to study the effects of simvastatin on cardiac hypertrophy in diabetic rats and to explore its potential mechanism. MATERIAL AND METHODS Sprague-Dawley rats were assigned into a control (Con) group, a streptozotocin (STZ) group, and a STZ+simvastatin (STZ+SIM) group. The level of reactive oxygen species (ROS) was measured by using dihydroethidium (DHE) staining...
February 15, 2019: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Mithila Tennakoon, Dinesh Kankanamge, Kanishka Senarath, Zehra Fasih, Ajith Karunarathne
Guanine nucleotide-binding proteins (G proteins) facilitate transduction of external signals to the cell interior, regulate a majority of eukaryotic signaling, and thus have become crucial disease drivers. G proteins largely function at the inner leaflet of the plasma membrane (PM) using covalently attached lipid anchors. Both small monomeric and heterotrimeric G proteins are primarily prenylated, either with a 15-carbon farnesyl or a 20-carbon geranylgeranyl polyunsaturated lipid. The mevalonate (HMG-CoA reductase) pathway synthesizes lipids for G protein prenylation...
February 14, 2019: Molecular Pharmacology
Vanessa Gerber, Lixin Yang, Masanari Takamiya, Vanessa Ribes, Victor Gourain, Ravindra Peravali, Johannes Stegmaier, Ralf Mikut, Markus Reischl, Marco Ferg, Sepand Rastegar, Uwe Strähle
Specification of neurons in the spinal cord relies on extrinsic and intrinsic signals, which in turn are interpreted by expression of transcription factors. V2 interneurons develop from the ventral aspects of the spinal cord. We report here a novel neuronal V2 subtype, named V2s, in zebrafish embryos. Formation of these neurons depends on the transcription factors sox1a and sox1b. They develop from common gata2a/gata3 dependent precursors co-expressing markers of V2b and V2s interneurons. Chemical blockage of Notch signaling causes a decrease of V2s and an increase of V2b cells...
February 13, 2019: Development
Marie France Bouchard, Francis Bergeron, Jasmine Grenier Delaney, Louis-Mathieu Harvey, Robert S Viger
GATA4 is an essential transcriptional regulator required for gonadal development, differentiation, and function. In the developing testis, proposed GATA4-regulated genes include steroidogenic factor 1 (Nr5a1), SRY-related HMG box 9 (Sox9), and anti-Müllerian hormone (Amh). While some of these genes have been validated as genuine GATA4 targets, it remains unclear whether GATA4 is a direct regulator of endogenous Amh transcription. We used a CRISPR/Cas9-based approach to specifically inactivate or delete the sole GATA binding motif of the proximal mouse Amh promoter...
February 13, 2019: Endocrinology
Stephanie G Harshman, M Kyla Shea, Xueyan Fu, Michael A Grusak, Donald Smith, Stefania Lamon-Fava, Athan Kuliopulos, Andrew Greenberg, Sarah L Booth
Background: Menaquinone-4 (MK4), a vitamin K metabolite, is converted from phylloquinone through a process that requires intermediates of endogenous cholesterol production. Recent evidence suggests that MK4 is involved in kidney function. Objective: The purpose of this study was to determine the effect of atorvastatin treatment on MK4 formation in young and old male mice. Methods: C57BL/6 male mice (4-mo-old and 20-mo-old) were randomly assigned to either a diet containing 300 mg atorvastatin/kg with 3 mg phylloquinone/kg or a control diet containing 3 mg phylloquinone/kg for 8 wk...
February 8, 2019: Journal of Nutrition
Pooja Acharya, Ramaprasad R Talahalli
In this study, the effect of n-3 fatty acids (FA) [α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] on the intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic bile acid transporters (BAT) was assessed in young and aged dyslipidemic rats. Dyslipidemia was induced in young and aged rats by feeding a high-fat (HF) diet. Experimental groups received diets containing canola oil (HF + CNO) and fish oil (HF + FO) as a source of ALA and EPA + DHA, respectively...
February 10, 2019: Lipids
Anne Tournadre
Statin-associated muscle symptoms (SAMSs) vary considerably in frequency and severity, with a spectrum extending from myalgia with normal creatine kinase (CK) levels or asymptomatic hyperCKemia to potentially life-threatening rhabdomyolysis and necrotizing autoimmune myopathy. Myalgia with CK elevation is the most common presentation. Onset is usually within 1 month after statin initiation or dosage intensification, and the symptoms can be expected to resolve within a few weeks after treatment discontinuation...
February 5, 2019: Joint, Bone, Spine: Revue du Rhumatisme
Na Xu, Hongmei Gan, Chao Qin, Xin-Long Wang, Zhongmin Su
Design and synthesis of metal-organic polyhedra (MOPs) with targeted geometries from predetermined secondary building units (SBUs) is a long-standing challenge in chemistry and material science. The theoretical prediction shows that there are 6 possible polyhedra from (3,4)-c octahedron to (3,5)-c icosahedron with minimal transitivity (simplest possible). Except missing one polyhedron (mtr) due to the unfavorable angles, we report five MOPs based on these structures, including an octahedral (3,4)-c VMOP-21 (rdo), an icosahedral (3,5)-c VMOP-25 (trc), and three intermediate derived trinodal (3,4,5)-c VMOP-22~24 (ghm, hmg, xum)...
February 7, 2019: Angewandte Chemie
Simbo M Chiadika, Fisayomi O Shobayo, Syed H Naqvi, Smita S Saraykar, Catherine G Ambrose, Nahid J Rianon
Coronary artery disease (CAD) and osteoporosis, the two most frequently occurring chronic diseases of aging populations, share many risk factors including lack of estrogen, smoking, and low physical activity. CAD and low bone mineral density (BMD) are strongly associated. Statins, (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), are used to prevent and treat CAD and have been associated with high BMD. This cross-sectional study examined associations of BMD with statin use and nonuse in elderly women with or without CAD...
February 5, 2019: Women & Health
Xiaofang Li, Xiaoling Wu, Yun Li, Yumeng Cui, Run Tian, Namita Singh, Muyang Ding, Yang Yang, Yan'e Gao
The development of cervical cancer (CC) is a multi‑gene, multi‑step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY‑related HMG‑box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation‑specific polymerase chain reaction...
February 1, 2019: Oncology Reports
Ryohei Umeda, Hiroki Takanari, Kazue Ogata, Shigekiyo Matsumoto, Takaaki Kitano, Katsushige Ono, Osamu Tokumaru
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used for preventing cardiovascular and cerebrovascular diseases by controlling blood cholesterol level. Additionally, previous studies revealed the scavenging effects of statins on free radicals. We assessed direct scavenging activities of two water-soluble statins, fluvastatin and pravastatin, on multiple free radicals using electron spin resonance spectrometry with spin trapping method. We estimated reaction rate constants ( k fv for fluvastatin, and k pv for pravastatin)...
January 2019: Journal of Clinical Biochemistry and Nutrition
Heng-Yuan Chang, Jia-Ru Wu, Wan-Yun Gao, Huei-Ru Lin, Pei-Yi Chen, Chen-I Chen, Ming-Jiuan Wu, Jui-Hung Yen
Pigeon pea ( Cajanus cajan (L.) Millsp.) is a legume crop consumed as an indigenous vegetable in the human diet and a traditional medicinal plant with therapeutic properties. The current study highlights the cholesterol-modulating effect and underlying mechanisms of the methanol extract of Cajanus cajan L. leaves (MECC) in HepG2 cells. We found that MECC increased the LDLR expression, the cell-surface LDLR levels and the LDL uptake activity in HepG2 cells. We further demonstrated that MECC suppressed the proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and protein expression, but not affected the expression of other cholesterol or lipid metabolism-related genes including inducible degrader of LDLR (IDOL), HMG-CoA reductase (HMGCR), fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC1), and liver X receptor-α (LXR-α) in HepG2 cells...
January 30, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kenneth G-J Ooi, Pauline Khoo, Veronika Vaclavik, Stephanie L Watson
3-Hydroxy-3-methyl-gutaryl coenzyme A (HMG-CoA) reductase inhibitors or 'statins' are a class of lipid lowering drugs with anti-inflammatory, immunomodulatory, and vascular effects. Statins are increasingly being used in the treatment of a variety of medical conditions. We examine the actions of statins on the eye and its associated ophthalmic disorders. Statins can be synthetic or non-synthetic, and their differentiating derivations may contribute to their varying cholesterol-lowering and pleiotropic effects...
January 28, 2019: Survey of Ophthalmology
Bastian Vögeli, Seigo Shima, Tobias Erb, Tristan Wagner
3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyses the last step in mevalonate biosynthesis. HMGR is the target of statin inhibitors that regulate cholesterol concentration in human blood. Here, we report the properties and structures of HMGR from the archaeon Methanothermococcus thermolithotrophicus (mHMGR). The structures of the apoenzyme and the NADPH-complex are highly similar to those of human HMGR. A notable exception is C-terminal helix (Lα10-11) that is straight in both mHMGR structures. This helix is kinked and closes the active site in the human enzyme ternary complex, pointing to a substrate-induced structural rearrangement of C-terminal in class-I HMGRs during the catalytic cycle...
January 31, 2019: FEBS Letters
Un-Jung Yun, Ji-Hye Lee, Jaegal Shim, Kyungsil Yoon, Sung-Ho Goh, Eun Hee Yi, Sang-Kyu Ye, Jae-Seon Lee, Hyunji Lee, Jongsun Park, In Hye Lee, Yong-Nyun Kim
Doxorubicin is a widely used DNA damage-inducing anti-cancer drug. However, its use is limited by its dose-dependent side effects, such as cardiac toxicity. Cholesterol-lowering statin drugs increase the efficacy of some anti-cancer drugs. Cholesterol is important for cell growth and a critical component of lipid rafts, which are plasma membrane microdomains important for cell signaling. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMG-CR) is a critical enzyme in cholesterol synthesis. Here, we show that doxorubicin downregulated HMG-CR protein levels and thus reduced levels of cholesterol and lipid rafts...
January 30, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
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