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https://www.readbyqxmd.com/read/27771416/candidate-gene-analysis-of-the-fibrinogen-phenotype-reveals-the-importance-of-polygenic-co-regulation
#1
H Toinét Cronjé, Cornelie Nienaber-Rousseau, Lizelle Zandberg, Tinashe Chikowore, Zelda de Lange, Tertia van Zyl, Marlien Pieters
Fibrinogen and its functional aspects have been linked to cardiovascular disease. There is vast discrepancy between the heritability of fibrinogen concentrations observed in twin studies and the heritability uncovered by genome wide association studies. We postulate that some of the missing heritability might be explained by the pleiotropic and polygenic co-regulation of fibrinogen through multiple targeted genes, apart from the fibrinogen genes themselves. To this end we investigated single nucleotide polymorphisms (SNPs) in genes coding for phenotypes associated with total and γ' fibrinogen concentrations and clot properties...
October 19, 2016: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/27747489/current-consensus-and-controversies-in-guidelines-for-lipid-and-hypertension-management-in-diabetes
#2
Om P Ganda, Joanna Mitri
Despite major advances, many patients with diabetes are currently achieving suboptimal control of lipids and blood pressure. The new cholesterol guidelines by the ACC/AHA have reignited the emphasis on more intensive treatment with statins in the population at high risk of CVD, including those with diabetes. While these guidelines do not include specific lipid goals, several other guidelines have retained previously defined risk-based LDL-C and non-HDL-C goals. More recent data indicate potential benefits in CVD outcomes with non-statin therapy added to statin therapy...
November 2016: Current Cardiology Reports
https://www.readbyqxmd.com/read/27662822/the-anti-adipogenic-effect-of-peripheral-blood-mononuclear-cells-is-absent-with-pcsk9-loss-of-function-variants
#3
AnneMarie Gagnon, Teik C Ooi, Marion Cousins, Colette Favreau, Kathy Henry, Anne Landry, Alexander Sorisky
OBJECTIVE: To determine the effect of (1) an oral fat load and (2) pro-protein convertase subtilisin/kexin type (PCSK) 9 loss-of-function (LOF) variant status on the ability of peripheral blood mononuclear cells (PBMC) to inhibit human adipogenesis. METHODS: PBMC from subjects with one or more PCSK9 LOF variants versus non-variant controls were compared in the fasting state and after an oral fat load. RESULTS: Fasting triglyceride (TG) levels were lower in the LOF variant versus non-variant group but rose to the same level after the oral fat load...
September 24, 2016: Obesity
https://www.readbyqxmd.com/read/27424187/evaluation-of-a-new-genetic-epidemiology-resource-the-intermountain-genealogy-registry
#4
Stacey Knight, Arthur T Maness, Sue M Dintelman, Benjamin D Horne
BACKGROUND: Many landmark genetic breakthroughs, including the recent discovery of PCSK-9 inhibitor drugs, were accomplished with substantial contributions from evaluation of pedigrees. Finding and ascertaining high-value pedigrees is not trivial and requires considerable time and cost. Here, we describe the creation of the Intermountain Genealogy Registry for use in studying the genetics of cardiovascular and other diseases. METHODS: Using publicly available pedigree records and probabilistic linkage techniques, we created a genealogy of ≈23 million records that we linked to 3...
July 16, 2016: Human Heredity
https://www.readbyqxmd.com/read/27096698/the-new-face-of-hyperlipidemia-management-proprotein-convertase-subtilisin-kexin-inhibitors-pcsk-9-and-their-emergent-role-as-an-alternative-to-statin-therapy
#5
Lillian Smith, Juan Mosley, Jarah Yates, Luke Caswell
This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha)...
2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/26976708/xanthohumol-improves-dysfunctional-glucose-and-lipid-metabolism-in-diet-induced-obese-c57bl-6j-mice
#6
Cristobal L Miranda, Valerie D Elias, Joshua J Hay, Jaewoo Choi, Ralph L Reed, Jan F Stevens
Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The dose-dependent effects of XN on glucose and lipid metabolism in a preclinical model of metabolic syndrome were the focus of our study. Forty-eight male C57BL/6J mice, 9 weeks of age, were randomly divided into three XN dose groups of 16 animals. The mice were fed a high-fat diet (60% kcal as fat) supplemented with XN at dose levels of 0, 30, or 60 mg/kg body weight/day, for 12 weeks. Dietary XN caused a dose-dependent decrease in body weight gain...
June 1, 2016: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/26857454/barrier-protection-via-toll-like-receptor-2-signaling-in-porcine-intestinal-epithelial-cells-damaged-by-deoxynivalnol
#7
Min Jeong Gu, Sun Kwang Song, In Kyu Lee, Seongyeol Ko, Seung Eun Han, Suhan Bae, Sang Yun Ji, Byung-Chul Park, Ki-Duk Song, Hak-Kyo Lee, Seung Hyun Han, Cheol-Heui Yun
Intestinal barrier is the first line of defense inside the body and comprises intercellular tight junction (TJ) proteins that regulate paracellular permeability. Deoxynivalenol (DON), a fungal metabolite often found in the contaminated food of domestic animals, is known to impair intestinal barrier function and may be involved in intestinal inflammation. Unlike in humans and mice, the importance of Toll-like receptor (TLR) 2 expressed in porcine intestinal epithelial cells is largely unclear. Therefore, the aim of the present study was to investigate whether TLR2 stimulation enhances intestinal barrier function and protects against DON exposure...
2016: Veterinary Research
https://www.readbyqxmd.com/read/26652782/-pcsk9-inhibition-as-the-new-hope-for-patients-with-familial-hypercholesterolemia-statin-intolerance-and-eventually-for-those-at-the-highest-cardiovascular-risk-focused-on-alirocumab-praluent%C3%A2
#8
REVIEW
Richard Češka
At the present time there are novel hypolipidemics registered globally (alirocumab was the first drug of this group in the world registered by an American drug agency FDA) and in Europe, which in many ways differ from the medicines administered until now. They are bringing another advancement in the treatment of disorders of lipid metabolism and in preventive cardiology. Alirocumab is a fully human monoclonal antibody to PCSK-9 enzyme (proprotein convertase subtilisin kexin-9). PCSK-9 enzyme plays an important role in the metabolism of LDL-cholesterol through affecting the breakdown and eventually the amount and activity of LDL-receptors...
November 2015: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/26547456/predicting-the-overuse-of-pcsk-9-inhibitors
#9
Rene Rodriguez-Gutierrez, Nilay D Shah, Victor M Montori
No abstract text is available yet for this article.
November 10, 2015: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/26545013/atherosclerosis-stabilization-with-pcsk-9-inhibition-an-evolving-concept-for-cardiovascular-prevention
#10
Jennifer G Robinson, Donald D Heistad, Keith A A Fox
Monoclonal antibodies (mAbs) to proprotein convertase subtilisin/kexin type 9 (PCSK-9) can further lower LDL-C by ≥60% in statin-treated patients. Preliminary data suggest they may reduce cardiovascular (CVD) events. Ongoing PCSK-9 mAb cardiovascular outcomes trials could provide the opportunity to determine whether a "legacy effect" similar to that observed for statins will occur over the post-trial observation period. We hypothesize these trials could demonstrate that (1) very aggressive LDL-C lowering with PCSK-9 mAbs added to background statin therapy will induce extensive atherosclerosis stabilization and regression in the large majority of treated patients, and (2) continued maintenance therapy with high intensity statin therapy (with or without ezetimibe) should then inhibit new plaque formation, with a long-term prevention of CVD events...
December 2015: Atherosclerosis
https://www.readbyqxmd.com/read/26492546/emerging-innovative-therapeutic-approaches-targeting-pcsk9-to-lower-lipids
#11
REVIEW
G P S Shantha, J G Robinson
Statins are established therapies for cardiovascular disease prevention and ezetimibe has recently been shown to modestly reduce cardiovascular events when added to background statin therapy. Yet here remains a clear unmet need for additional therapies aimed at lowering low density lipoprotein cholesterol (LDL-C) to further reduce cardiovascular risk. Multiple strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have emerged as effective modalities for LDL-C lowering. PCSK9 monoclonal antibodies are the farthest along in clinical development and alirocumab and evolocumab were approved for clinical use by regulatory agencies in 2015...
January 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/26363575/-importance-of-dyslipidaemia-in-cardiovascular-disease-a-point-of-view
#12
Juan F Ascaso, Rafael Carmena
The authors present their view on the prevention of cardiovascular diseases, accepting the European ESC/EAS guidelines. They consider that the aim of the lipid control, based on LDL-C goals, is essential for the prevention and treatment of cardiovascular diseases. In subjects with metabolic syndrome (mainly, abdominal obesity, pre-diabetes and diabetes), the primary objective should be apoB or Non-HDL-C, which are better associated with cardiovascular risk. The treatment must be lifestyle changes and control of other risk factors...
November 2015: Clínica e Investigación en Arteriosclerosis
https://www.readbyqxmd.com/read/26259032/pcsk6-mediated-corin-activation-is-essential-for-normal-blood-pressure
#13
Shenghan Chen, Pengxiu Cao, Ningzheng Dong, Jianhao Peng, Chunyi Zhang, Hao Wang, Tiantian Zhou, Junhua Yang, Yue Zhang, Elizabeth E Martelli, Sathyamangla V Naga Prasad, Rachel E Miller, Anne-Marie Malfait, Yiqing Zhou, Qingyu Wu
Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia...
September 2015: Nature Medicine
https://www.readbyqxmd.com/read/26135857/discovery-approaches-for-novel-dyslipidemia-drugs
#14
REVIEW
Faheem Maqbool, Malihe Safavi, Haji Bahadar, Mahban Rahimifard, Kamal Niaz, Mohammad Abdollahi
INTRODUCTION: Dyslipidemia is increased fasting level of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG), along with decreased levels of HDL cholesterol (HDL-C). Owing to effect on the cardiovascular system and increased chances of metabolic diseases, it is needed to review novel under development drugs and new approaches in drug discovery for dyslipidemia. AREAS COVERED: This article reviews all phases I to IV clinical trials and preclinical trials with results associated with novel treatment of dyslipidemia...
2015: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/25926688/proprotein-convertase-furin-regulates-t-cell-receptor-induced-transactivation
#15
Zsuzsanna Ortutay, Anna Oksanen, Saara Aittomäki, Csaba Ortutay, Marko Pesu
Antigen emergence rapidly stimulates T cells, which leads to changes in cytokine production, cell proliferation, and differentiation. Some of the key molecules involved in these events, such as TGF-β1 and NOTCH1, are synthesized initially as inactive precursors and are proteolytically activated during T cell activation. PCSKs regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK FURIN is induced upon TCR activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance...
July 2015: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/25881830/enediynyl-peptides-and-iso-coumarinyl-methyl-sulfones-as-inhibitors-of-proprotein-convertases-pcsk8-ski-1-s1p-and-pcsk4-pc4-design-synthesis-and-biological-evaluations
#16
Ajoy Basak, Mukunda Goswami, Abishankari Rajkumar, Tapobrata Mitra, Swapan Majumdar, Paul O'Reilly, Hussam M Bdour, Vance L Trudeau, Amit Basak
The proprotein convertases PCSK8 and PCSK4 are, respectively, the 8th and 4th members of Ca(+2)-dependent serine endoprotease of Proprotein Convertase Subtilisin Kexin (PCSK) super family structurally related to the bacterial subtilisin and yeast kexin. The membrane bound PCSK8 (also called SKI-1 or S1P) is implicated in sterol regulation and lipid synthesis via its role in the maturation of human (h) SREBP-2. It also plays role in cartilage formation, bone mineralization, as well as viral pathogenesis. On the other hand, PCSK4 has been linked to mammalian fertilization and placenta growth...
2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/25813623/a-genome-wide-expression-quantitative-trait-loci-analysis-of-proprotein-convertase-subtilisin-kexin-enzymes-identifies-a-novel-regulatory-gene-variant-for-furin-expression-and-blood-pressure
#17
MULTICENTER STUDY
Hannu Turpeinen, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Emma Raitoharju, Nina Hutri-Kähönen, Mari Levula, Niku Oksala, Melanie Waldenberger, Norman Klopp, Thomas Illig, Nina Mononen, Reijo Laaksonen, Olli Raitakari, Mika Kähönen, Terho Lehtimäki, Marko Pesu
Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized...
June 2015: Human Genetics
https://www.readbyqxmd.com/read/25728474/development-and-characterization-of-a-free-therapeutic-ligand-binding-assay-with-assistance-from-kinetics-modeling
#18
LaKenya Williams, Michael Sank, Anjaneya Chimalakonda, Yan Ni, Mark Saewert, Binodh DeSilva, Renuka Pillutla
Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species...
April 2015: Journal of Immunological Methods
https://www.readbyqxmd.com/read/25707773/pro-protein-convertase-subtilisin-kexin-9-concentrations-correlate-with-coronary-artery-disease-atheroma-burden-in-a-pakistani-cohort-with-chronic-chest-pain
#19
T A Walton, S Nishtar, P J Lumb, M A Crook, M S Marber, J Gill, A S Wierzbicki
OBJECTIVE: To determine the relationship between proprotein convertase subtilisin kexin 9 (PCSK9) levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective matched case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and PCSK-9 levels...
July 2015: International Journal of Clinical Practice
https://www.readbyqxmd.com/read/25624351/the-proprotein-convertase-subtilisin-kexin-furina-regulates-zebrafish-host-response-against-mycobacterium-marinum
#20
Markus J T Ojanen, Hannu Turpeinen, Zuzet M Cordova, Milka M Hammarén, Sanna-Kaisa E Harjula, Mataleena Parikka, Mika Rämet, Marko Pesu
Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria...
April 2015: Infection and Immunity
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