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https://www.readbyqxmd.com/read/28206704/lipid-lowering-efficacy-and-safety-of-alirocumab-in-patients-with-or-without-diabetes-a-sub-analysis-of-odyssey-combo-ii
#1
Lawrence A Leiter, Jose Luis Zamorano, Maja Bujas-Bobanovic, Michael J Louie, Guillaume Lecorps, Christopher P Cannon, Yehuda Handelsman
AIM: This sub-analysis of the ODYSSEY COMBO II study compared the effects of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in high cardiovascular risk patients with or without diabetes mellitus (DM) receiving maximally tolerated statin therapy. MATERIALS AND METHODS: COMBO II was a 104-week, double-blind study (n = 720) enrolling patients with documented atherosclerotic cardiovascular disease (ASCVD) and baseline LDL-C ≥70 mg/dL (1...
February 16, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28204827/hepatic-hnf1-transcription-factors-control-the-induction-of-pcsk9-mediated-by-rosuvastatin-in-normolipidemic-hamsters
#2
Bin Dong, Amar Bahadur Singh, Vikram Ravindra Shende, Jingwen Liu
Proprotein convertase subtilisin/kexin type 9 (PCSK9) impedes low‑density lipoprotein (LDL) receptor (LDLR)-mediated LDL-cholesterol uptake and has hence emerged as a critical regulator of serum cholesterol levels and a new therapeutic target for the treatment of hypercholesterolemia. Statins have been shown to elevate circulating PCSK9 levels by stimulating PCSK9 gene transcription, which reduces the clinical efficacy of statin in LDL‑cholesterol reduction. The transcription of PCSK9 is partially controlled by the hepatocyte nuclear factor 1 (HNF1) binding site embedded in the proximal region of its promoter...
March 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28203441/lipoprotein-a-and-inhibitors-of-proprotein-convertase-subtilisin-kexin-type-9
#3
COMMENT
Kazuhiko Kotani, Maciej Banach
Lipoprotein(a) [Lp(a)] has been identified as a risk factor for cardiovascular disease. Lp(a) levels are also high under certain clinical conditions, including familial hypercholesterolemia and high blood low-density lipoprotein (LDL) cholesterol levels. Few effective generic therapies for modulating Lp(a) have been developed. However, new therapies involving inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) using monoclonal antibodies have markedly reduced the blood LDL levels-and the Lp(a) levels as well...
January 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28199412/modulation-of-cholesterol-transport-by-maternal-hypercholesterolemia-in-human-full-term-placenta
#4
Ran Zhang, Shan Dong, Wei-Wei Ma, Xue-Ping Cai, Zhi-Yin Le, Rong Xiao, Qi Zhou, Huan-Ling Yu
The significance of maternal cholesterol transporting to the fetus under normal as well as pathological circumstances is less understood. The objective of this study was to observe the effects of maternal hypercholesterolemia on placental cholesterol transportation. Human full-time placenta, maternal and venous cord blood were sampled at delivery from the pregnant women with serum total cholesterol (TC) concentrations at third trimester higher than 7.25 mM (n = 19) and the pregnant women with normal TC concentrations (n = 19)...
2017: PloS One
https://www.readbyqxmd.com/read/28196290/curcumin-protects-against-intestinal-origin-endotoxemia-in-rat-liver-cirrhosis-by-targeting-pcsk9
#5
Yu Cai, Di Lu, Yanting Zou, Chaohui Zhou, Hongchun Liu, Chuantao Tu, Feng Li, Lili Liu, Shuncai Zhang
Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl4 )-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl4 subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl4 -induced cirrhosis rats...
February 14, 2017: Journal of Food Science
https://www.readbyqxmd.com/read/28193639/an-endorsement-of-pcsk9-inhibitors-funded-by-%C3%A2-their-manufacturers
#6
Nigel Hawkes
No abstract text is available yet for this article.
February 13, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28181408/epigallocatechin-gallate-induces-an-up-regulation-of-ldl-receptor-accompanied-by-a-reduction-of-pcsk9-via-the-annexin-a2-independent-pathway-in-hepg2-cells
#7
Kohei Kitamura, Yudai Okada, Kenji Okada, Yuya Kawaguchi, Satoshi Nagaoka
SCOPE: In animal studies, epigallocatechin gallate (EGCG), the dominant catechin in green tea, has been shown to improve cholesterol metabolism. However, the molecular mechanisms of EGCG underlying these functions have not been fully understood. In this study, we aimed to clarify the molecular mechanisms of the effect of EGCG on cholesterol metabolism mainly in HepG2 cells. METHODS AND RESULTS: We found that EGCG induced a reduction of the extracellular proprotein convertase subtilisin/kexin 9 (PCSK9) level accompanied by an up-regulation of the LDL receptor (LDLR) in HepG2 cells...
February 9, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28181260/a-mechanism-based-pharmacokinetic-pharmacodynamic-model-for-bococizumab-a-humanized-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-and-its-application-in-early-clinical-development
#8
Chandrasekhar Udata, Pamela D Garzone, Barry Gumbiner, Tenshang Joh, Hong Liang, Kai-Hsin Liao, Jason H Williams, Xu Meng
Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28179607/half-a-century-tales-of-familial-hypercholesterolemia-fh-in-japan
#9
Hiroshi Mabuchi
Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly...
February 8, 2017: Journal of Atherosclerosis and Thrombosis
https://www.readbyqxmd.com/read/28179493/nutritional-and-lipid-modulation-of-pcsk9-effects-on-cardiometabolic-risk-factors
#10
REVIEW
Jacqueline A Krysa, Teik Chye Ooi, Spencer D Proctor, Donna F Vine
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease involved in the regulation of LDL receptor (LDLR) expression and apolipoprotein B lipoprotein cholesterol metabolism. Hepatic PCSK9 protein expression, activity, and secretion have been shown to affect cholesterol homeostasis. An upregulation of hepatic PSCK9 protein leads to increased LDLR degradation, resulting in decreased uptake of apoB lipoproteins and a consequent increase in the plasma concentration of these lipoproteins, including LDL and chylomicron remnants...
February 8, 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28178673/actinidia-chinensis-planch-root-extract-inhibits-cholesterol-metabolism-in-hepatocellular-carcinoma-through-upregulation-of-pcsk9
#11
Mingyan He, Jiayun Hou, Lingyan Wang, Minghuan Zheng, Tingting Fang, Xiangdong Wang, Jinglin Xia
Actinidia chinensis Planch root extract (acRoots) is a traditional Chinese medicine with anti-tumor efficacy. To investigate the mechanisms responsible for this activity, we examined the effects of acRoots on cholesterol metabolism in hepatocellular carcinoma (HCC). mRNA chip analysis was used to identify the metabolic genes regulated by acRoots. The effects of acRoots on cholesterol synthesis and uptake were evaluated by measuring intracellular cholesterol levels and 3,3'-dioctadecylindocarbocyanine-labeled low-density lipoprotein (Dil-LDL) uptake...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28176216/pcsk9-targets-important-for-lipid-metabolism
#12
Rainer Schulz, Klaus-Dieter Schlüter
Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48...
February 7, 2017: Clinical Research in Cardiology Supplements
https://www.readbyqxmd.com/read/28169949/molecular-basis-of-familial-hypercholesterolemia
#13
Caroline S Bruikman, Gerard K Hovingh, John J P Kastelein
PURPOSE OF REVIEW: To provide an overview about the molecular basis of familial hypercholesterolemia. RECENT FINDINGS: Familial hypercholesterolemia is a common hereditary cause of premature coronary heart disease. It has been estimated that 1 in every 250 individuals has heterozygous familial hypercholesterolemia and that fewer than 1% of patients with familial hypercholesterolemia have been identified across the globe. If heterozygous familial hypercholesterolemia is left untreated, it is likely that coronary heart disease will manifest clinically prior to the age of 55 years and that half of all patients will prematurely die from the consequences of myocardial infarction...
February 4, 2017: Current Opinion in Cardiology
https://www.readbyqxmd.com/read/28167353/genetic-risk-analysis-of-coronary-artery-disease-in-pakistani-subjects-using-a-genetic-risk-score-of-21-variants
#14
Saleem Ullah Shahid, Shabana, Jackie A Cooper, Katherine E Beaney, Kawah Li, Abdul Rehman, Steve E Humphries
BACKGROUND AND AIMS: Conventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels...
January 22, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28166668/annals-express-association-between-plasma-proprotein-convertase-subtilisin-kexin-type-9-level-and-coronary-artery-calcification
#15
Xi Zhao, Hui-Wen Zhang, Sha Li, Yan Zhang, Rui-Xia Xu, Cheng-Gang Zhu, Na-Qiong Wu, Yuan-Lin Guo, Ping Qing, Xiao-Lin Li, Geng Liu, Qian Dong, Jing Sun, Jianjun Li
BACKGROUND: Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be related to several risk factors and diseases such as inflammatory markers and coronary artery disease (CAD). The aim of present study was to investigate whether plasma PCSK9 level was associated with coronary artery calcification (CAC). METHODS: A total of 403 consecutive untreated patients with angina-like chest pain who received electron beam computed tomography (EBCT) were enrolled and a CAC score (CACS) was also measured...
January 1, 2017: Annals of Clinical Biochemistry
https://www.readbyqxmd.com/read/28163543/proprotein-convertase-subtilisin-kexin-type-9-enzyme-inhibitors-an-emerging-new-therapeutic-option-for-the-treatment-of-dyslipidemia
#16
Faizan Mazhar, Nafis Haider
The treatment of hypercholesterolemia entered in a new phase of development with the introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the market. The Food and Drug Administration and European Medicines Agency recently approved the alirocumab and evolocumab, subcutaneously injectable monoclonal antibody every 2 or 4 weeks against PCSK9, for the treatment of hypercholesterolemia in patients with intolerance or inadequate response to statins, especially for the secondary prevention or in the case of familial hypercholesterolemia...
October 2016: Journal of Pharmacology & Pharmacotherapeutics
https://www.readbyqxmd.com/read/28161202/analysis-of-children-and-adolescents-with-familial-hypercholesterolemia
#17
Ilenia Minicocci, Simone Pozzessere, Cristina Prisco, Anna Montali, Alessia di Costanzo, Eliana Martino, Francesco Martino, Marcello Arca
OBJECTIVE: To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia (FH)-causative mutations in unselected children with hypercholesterolemia. STUDY DESIGN: LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3.7 years) with clinically diagnosed FH. The presence of polygenic hypercholesterolemia was further evaluated by genotyping 6 low-density lipoprotein cholesterol (LDL-C)-raising single-nucleotide polymorphisms...
February 1, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/28157721/complexity-of-mechanisms-among-human-proprotein-convertase-subtilisin-kexin-type-9-variants
#18
Jacqueline S Dron, Robert A Hegele
PURPOSE OF REVIEW: There are many reports of human variants in proprotein convertase subtilisin-kexin type 9 (PCSK9) that are either gain-of-function (GOF) or loss-of-function (LOF), with downstream effects on LDL cholesterol and cardiovascular disease (CVD) risk. However, data on particular mechanisms have only been minimally curated. RECENT FINDINGS: GOF variants are individually ultrarare, affect all domains of the protein, act to reduce LDL receptor expression through several mechanisms, are a minor cause of familial hypercholesterolemia, have been reported mainly within families, have variable LDL cholesterol-raising effects, and are associated with increased CVD risk mainly through observational studies in families and small cohorts...
February 2, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28155622/the-role-of-proprotein-convertase-subtilisin-kexin-type-9-inhibitors-in-the-management-of-dyslipidemia
#19
Konstantinos Tziomalos
BACKGROUND: Treatment with statins substantially reduces cardiovascular morbidity and mortality both in patients with and without established cardiovascular disease. Accordingly, statins represent the cornerstone of lipid-lowering treatment. However, there are still unmet clinical needs in the management of dyslipidemia. Indeed, it is difficult to achieve low-density lipoprotein cholesterol (LDL-C) targets in many patients, particularly in those at very high cardiovascular risk or in those with very high baseline LDL-C levels [e...
February 1, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28145001/treatment-with-the-natural-fxr-agonist-chenodeoxycholic-acid-reduces-clearance-of-plasma-ldl-whilst-decreasing-circulating-pcsk9-lipoprotein-a-and-apolipoprotein-c-iii
#20
M Ghosh Laskar, M Eriksson, M Rudling, B Angelin
BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous (125) I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg(-1) day(-1) )...
February 1, 2017: Journal of Internal Medicine
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