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HaiXia Wang, JunTao Luo, WenXia Tian, WenQing Yan, Sheng Ge, YaHui Zhang, WenGuang Sun
Tocotrienols (T3s) are a subgroup of vitamin E and they have been widely tested to inhibit cell growth in various tumor types. Previous studies have shown that T3s inhibit cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of T3s in the regulation of cellular bioenergetic processes remains unclear. In this study, we found that γ-T3 interacts with mitochondrial electron transfer chain NDUFB8 (a subunit of complex I) and SDHB (a subunit of complex II) and inhibits oxidative phosphorylation (OXPHOS), and triggers the production of reactive oxygen species (ROS)...
February 12, 2019: Toxicology
Nathaniel Parsons, Balasubramaniam Annamalai, Elisabeth Obert, Gloriane Schnabolk, Stephen Tomlinson, Bärbel Rohrer
Age-related macular degeneration (AMD) is the leading cause of blindness in the US. Polymorphisms in complement components are associated with increased AMD risk, and it has been hypothesized that an overactive complement system is partially responsible for AMD pathology. Choroidal neovascularization (CNV) has two phases, injury/angiogenesis and repair/fibrosis. Complement activation has been shown to be involved in the angiogenesis phase of murine CNV, but has not been investigated during repair. Anaphylatoxin (C3a and C5a) signaling in particular has been shown to be involved in both tissue injury and repair in other models...
February 11, 2019: Molecular Immunology
Mariana A Ajalla Aleixo, Victor L Rangel, Joane K Rustiguel, Ricardo A P de Pádua, M Cristina Nonato
Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into L-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. They are very important targets both in the study of human metabolic disorders and as potential therapeutic targets in neglected tropical diseases and tuberculosis. In this study, human FH (HsFH) was characterized by using enzyme kinetics, differential scanning fluorimetry (DSF) and X-ray crystallography...
February 14, 2019: FEBS Journal
Ashish Sarraju, Joshua W Knowles
Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor ( LDLR ), apolipoprotein B-100 ( APOB ), and proprotein convertase subtulisin/kexin type 9 genes ( PCSK9 ) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation...
2019: Frontiers in Cardiovascular Medicine
Ivo Petrov, Andreea Dumitrescu, Michaela Snejdrlova, Barak Zafrir, Beata Wożakowska-Kapłon, Lubomira Fabryova, Hrvoje Pintarić, Ian Bridges, Reneta Petkova
INTRODUCTION: A retrospective/prospective observational study was conducted to explore the current management of hyperlipidaemia in high-risk (HR) and very high risk (VHR) patients in central/eastern Europe and Israel. METHODS: The study enrolled adult patients who were receiving lipid-lowering therapy and attending a specialist (cardiologist/diabetologist/lipidologist) or internist for a routine visit at 57 sites (including academic/specialist/internal medicine centres) across Bulgaria, Croatia, Czech Republic, Israel, Poland, Romania and Slovakia...
February 13, 2019: Advances in Therapy
Seohyuk Lee, Leo E Akioyamen, Sumayah Aljenedil, Jean-Baptiste Rivière, Isabelle Ruel, Jacques Genest
AIMS: Familial hypercholesterolemia (FH) is the most common genetic disorder in medicine, with a prevalence of 1/250. Affected individuals have elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and, more recently, genetic testing. We sought to determine the impact of genetic testing on the: 1) diagnosis of 'definite familial hypercholesterolemia', 2) initiation and adherence of lipid-lowering therapy and 3) risk of ASCVD...
February 12, 2019: European Journal of Preventive Cardiology
Sabina Beheshti, Christian M Madsen, Anette Varbo, Børge G Nordestgaard
Context: How best to identify families with premature myocardial infarction is unclear. Objective: We compared approaches to identify familial premature myocardial infarction in the general population using different familial hypercholesterolemia(FH) criteria and low-density lipoprotein(LDL) cholesterol cut points. Design and Setting: Clinical and mutation criteria for FH, and LDL cholesterol cut points were applied for identification of familial premature myocardial infarction in 106,732 individuals from the Copenhagen General Population Study...
February 7, 2019: Journal of Clinical Endocrinology and Metabolism
Arthur Dopler, Leonie Guntau, Markus J Harder, Annette Palmer, Britta Höchsmann, Hubert Schrezenmeier, Thomas Simmet, Markus Huber-Lang, Christoph Q Schmidt
The plasma proteins Factor H (FH) and its alternate splice variant FH-like protein 1 (FHL-1) are the major regulators of the complement alternative pathway. The indiscriminate nature of alternative pathway activation necessitates the regulators to be host selective, but the underlying principles of selectivity remained largely elusive. By analyzing human FH and FHL-1 for protection of different host and foreign cells (rabbit and yeast), we uncovered a 2-fold discriminatory mechanism of FH in favor of self: relative to FHL-1, FH exhibits a regulatory benefit on self but importantly, also, a regulatory penalty on nonself surfaces, yielding a selectivity factor of ∼2...
February 11, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Mika Hori, Eiji Miyauchi, Cheol Son, Mariko Harada-Shiba
BACKGROUND: More than 2500 variants of the low-density lipoprotein receptor (LDLR) gene have been reported in familial hypercholesterolemia (FH). However, the effects of these variants on the pathophysiology of FH have not been fully clarified. OBJECTIVE: Our aim was to examine whether the c.2579C>T (p.A860V) variant of the LDLR gene affects the phenotype of FH. We present 2 index cases harboring biallelic LDLR variants, including the c.2579C>T (p.A860V) variant, which is defined as having uncertain significance in ClinVar...
January 16, 2019: Journal of Clinical Lipidology
Joseph T Rabban, Emily Chan, Julie Mak, Charles Zaloudek, Karuna Garg
Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome...
February 6, 2019: American Journal of Surgical Pathology
Roberto Garcia, Jaime Burkle
Cardiovascular disease (CVD) is the leading cause of death in the world. According to the World Health Organization, an estimated 17.9 million people died from CVD in 2016, representing 31% of all global deaths. Of these deaths, 5% are due to myocardial infarction and stroke. Dyslipidemia is known as the major risk factor of atherosclerotic cardiovascular disease. With current therapies, about 60% of high-risk CVD patients do not achieve LDL-C goals, and in patients with familiar hypercholesterolemia (FH) at maximum intensity statin treatment, only 20% achieve LDL-C goals...
February 7, 2019: Archives of Medical Research
Alexander J Procter, Julia Y Sun, Paul N Malcolm, Andoni P Toms
BACKGROUND: The assessment of liver percentage fat fraction (%FF) using proton density fat fraction sequences is becoming increasingly accessible. Previous studies have tended to use multiple small ROIs that focus on Couinaud segments. In an effort to simplify day-to-day analysis, this study assesses the impact of using larger, elliptical ROIs focused on a single hepatic lobe. Additionally, we assess the impact of sampling fewer transhepatic slices when measuring %FF. METHODS: Retrospective analysis of prospectively obtained images from 34 volunteers using an IDEAL IQ sequence...
February 8, 2019: BMC Medical Imaging
Henry N Ginsberg, Jaakko Tuomilehto, G Kees Hovingh, Bertrand Cariou, Raul D Santos, Alan S Brown, Santosh K Sanganalmath, Andrew Koren, Desmond Thompson, Frederick J Raal
PURPOSE: This post-hoc analysis examined whether age modified the efficacy and safety of alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH). METHODS: Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years)...
February 8, 2019: Cardiovascular Drugs and Therapy
Yuxuan He, Hongyan Li, Yong Zhang, Junjie Hu, Yulong Shen, Jin Feng, Xingxu Zhao
The aim of this study was to reveal the mechanism of enhanced ram sperm motility induced by heavy ion radiation (HIR) after in vitro liquid storage. Ram semen was stored for 24 hours at 5°C and then irradiated with 0.1 Gy carbon ion radiation (CIR). In comparison to nonirradiated (NIR) sperm, the motility, viability, and adenosine triphosphate content were all higher in CIR sperm, and the reactive oxygen species levels were lower. Moreover, 87 differential mitochondrial protein spots were detected in 2-dimensional gels between CIR and NIR sperm and were identified as 52 corresponding proteins...
January 2019: Dose-response: a Publication of International Hormesis Society
Raquel Arroyo-Olivares, Rodrigo Alonso, Gracia Quintana-Navarro, Francisco Fuentes-Jiménez, Nelva Mata, Ovidio Muñiz-Grijalvo, José L Díaz-Díaz, Daniel Zambón, Francisco Arrieta, Jesús García-Cruces, Juan A Garrido-Sanjuan, José R Banegas, Pedro Mata
OBJECTIVE: Healthy lifestyle habits are the cornerstone in the management of familial hypercholesterolaemia (FH). Nevertheless, dietary studies on FH-affected populations are scarce. The present study analyses dietary habits, adherence to a Mediterranean diet pattern and physical activity in an adult population with FH and compares them with their non-affected relatives. DESIGN: Cross-sectional study. SETTING: Data came from SAFEHEART, a nationwide study in Spain...
February 8, 2019: Public Health Nutrition
Rhushikesh A Kulkarni, Daniel W Bak, Darmood Wei, Sarah E Bergholtz, Chloe A Briney, Jonathan H Shrimp, Aktan Alpsoy, Abigail L Thorpe, Arissa E Bavari, Daniel R Crooks, Michaella Levy, Laurence Florens, Michael P Washburn, Norma Frizzell, Emily C Dykhuizen, Eranthie Weerapana, W Marston Linehan, Jordan L Meier
Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We applied a fumarate-competitive chemoproteomic probe in concert with LC-MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models...
February 4, 2019: Nature Chemical Biology
Rachele M Hendricks-Sturrup, Christine Y Lu
Cardiovascular disease (CVD) is the leading cause of death in the United States (US), with familial hypercholesterolemia (FH) being a major inherited and genetic risk factor for premature CVD and atherosclerosis. Genetic testing has helped patients and providers confirm the presence of known pathogenic and likely pathogenic variations in FH-associated genes. Key organizations, such as the Centers for Disease Control and Prevention (CDC), American Heart Association (AHA), FH Foundation, and National Lipid Association (NLA), have recognized the clinical utility of FH genetic testing...
February 1, 2019: Journal of Personalized Medicine
Jinming Guo, Houjuan Xing, Menghao Chen, Wei Wang, Hongfu Zhang, Shiwen Xu
Hydrogen sulfide (H2 S) is a toxic gas and one of the air pollutants of great concern. High-concentrated H2 S can induce energy metabolism disturbance and apoptosis. However, the mechanism of H2 S-induced liver injuries is unknown. Lipopolysaccharide (LPS), the main component of endotoxin, can cause fulminant hepatitis. Here, we evaluated the effects of H2 S combined with LPS on the energy metabolism and apoptosis pathway in the liver using a one-day-old chicken as a model. Our results showed that the expression levels of energy metabolism-related genes (AMP-activated protein kinase (AMPK), Hypoxia-inducible factor-1 (HIF-1), aconitase 2 (ACO2), hexokinase1 (HK1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), lactate dehydrogenase B (LDHB), phosphofructokinase (PFK), pyruvate kinase (PK) and succinate dehydrogenase B (SDHB)) tended to decrease, that the status of apoptosis increased, and that the expression levels of apoptosis-related genes (caspase3, BCL2, and bax) increased in H2 S group, suggesting that H2 S exposure disturbed the energy metabolism in the liver and induced hepatocyte apoptosis through the mitochondrial pathway...
January 28, 2019: Science of the Total Environment
Segolene Hescot, Maria Curras-Freixes, Timo Deutschbein, Anouk van Berkel, Delphine Vezzosi, Laurence Amar, Christelle de la Fouchardière, Nuria Valdes, Nando Riccardi, Christine Do Cao, Jerome Bertherat, Bernard Goichot, Felix Beuschlein, Delphine Drui, Letizia Canu, Patricia Niccoli, Sandrine Laboureau, Antoine Tabarin, Sophie Leboulleux, Bruna Calsina, Rossella Libé, Antongiulio Faggiano, Martin Schlumberger, Francoise Borson-Chazot, Massimo Mannelli, Anne-Paule Gimenez-Roqueplo, Philippe Caron, Henri J L M Timmers, Martin Fassnacht, Mercedes Robledo, Isabelle Borget, Eric Baudin
Background: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival in MPP patients. Patients and Methods: Retrospective multicentric study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. Results: We included 169 patients from 18 European centers...
February 1, 2019: Journal of Clinical Endocrinology and Metabolism
Delu Song, Yoshiyasu Ueda, Rupak Bhuyan, Imran Mohammed, Takashi Miwa, Damodar Gullipali, Hangsoo Kim, Lin Zhou, Ying Song, Hannah Schultz, Albert Bargoud, Joshua L Dunaief, Wen-Chao Song
Single nucleotide polymorphisms and rare mutations in Factor H (FH; official name CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FHR/R ) share features with human atypical hemolytic uremic syndrome. Here, we report that FHR/R mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FHR/R mice. Optical coherence tomography imaging of FHR/R mice showed retinal degeneration, edema, and detachment...
January 31, 2019: American Journal of Pathology
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