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12:04 EDT 30th March 2020 | BioPortfolio

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Showing "PCSK9 Inhibitors From Nature Lessons Clinical Utility" PubMed Articles 1–25 of 38,000+

PCSK9 Inhibitors: From Nature's Lessons to Clinical Utility.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL.


PCSK9 and inflammation: Role of shear stress, pro-inflammatory cytokines and LOX-1 4.

PCSK9 degrades LDL receptors and subsequently increases serum LDL-cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL-cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates TLR4 expres...

Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes.

PCSK9 is an endogenous inhibitor of the LDL receptor pathway. Recently, Mendelian randomization studies have raised a doubt about the diabetogenic risk of PCSK9 inhibitors. Here, we assessed the relationship between plasma PCSK9 levels and the risk of new onset diabetes (NOD).


Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Targeting PCSK9: Implications for basic science and upcoming challenges.

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the progression of atherosclerosis. Statin therapy for lowering LDL-C reduces the risk of atherosclerotic cardiovascular disease and is the recommended first-line treatment for patients with high LDL-C levels. However, some patients are unable to achieve an adequate reduction in LDL-C with statins or are statin intolerant; thus, PCSK9 inhibitors were developed to reduce LDL-C beyond statin therapy. PCSK9 monoclonal antibodies dramatically r...

A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that down-regulates hepatic low-density lipoprotein receptor (LDLR) by binding and shuttling LDLR to lysosomes for degradation. The development of therapy that inhibits PCSK9 has attracted considerable attention for the management of cardiovascular disease risk. However, only monoclonal antibodies of PCSK9 have reached the clinic use. Oral administration of small-molecule transcriptional inhibitors has the potential to become a ther...

PCSK9 inhibitors in clinical practice: novel directions and new experiences.

In randomized clinical trials, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively reduce low-density lipoprotein-cholesterol (LDL-C) with a favorable tolerability and safety profile. Our purpose is to provide real-world data regarding the indications, efficacy and safety of PCSK9i.

Meta-analysis of Randomized Controlled Trials Assessing the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies on Mortality and Cardiovascular Outcomes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by monoclonal antibodies has been shown to reduce low density lipoprotein (LDL-C) but its effects on cardiovascular (CV) outcomes have not been fully described. The aim of this study is to assess the impact of PCSK9 inhibition on mortality and CV outcomes by pooling data from all available randomized clinical trials (RCT) of PCSK9 inhibitors. We conducted a comprehensive search of electronic databases, up to December 1, 2018, for all RCTs comp...

Design of organo-peptides as bipartite PCSK9 antagonists.

Proprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates LDL-c levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered a cryptic groove that is situated adjacent to the main LDLR binding site and is accessible to compounds. Here, we designed potent bipartite inhib...

Inhibitors of Organic Anion-Transporting Polypeptides 1B1 and 1B3: Clinical Relevance and Regulatory Perspective.

Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical st...

Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in PCSK9 and mTORC1.

The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients.

Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis.

In parallel to the increasing prevalence of metabolic syndrome, the prevalence of hepatic steatosis has also increased dramatically worldwide. Hepatic steatosis is a major risk factor of hepatic cirrhosis, cardiovascular disease and type 2 diabetes. Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been positively associated with the metabolic syndrome. However, the association between PCSK9 and the liver function is still controversial.

Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii...

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.

More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH.

CDK4/6 inhibitors prolong OS.

PCSK9 and atherosclerosis burden in the coronary arteries of patients undergoing coronary angiography.

To investigate the association between plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations, current acute coronary syndrome (ACS), coronary artery disease (CAD) presence, severity and extension and the burden of coronary calcifications in patients with suspected CAD.

Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations.

PCSK9 is a protein secreted by the liver that binds to the low-density lipoprotein receptor (LDLR), causing LDLR internalization, decreasing the clearance of circulating LDL particles. Mutations in PCSK9 that strengthen its interactions with LDLR result in familial hypercholesterolemia (FH) and early onset atherosclerosis, while nonsense mutations of PCSK9 result in cardio-protective hypocholesterolemia. These observations led to PCSK9 inhibition for cholesterol lowering becoming a high-interest therapeutic...

A Genetic Approach to the Association Between PCSK9 and Sepsis.

Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date.

Coagulation mixing studies: utility, algorithmic strategies and limitations for lupus anticoagulant testing or follow up of abnormal coagulation tests.

Coagulation testing underpins the investigation of hemostasis and/or monitoring of anticoagulation therapy for prevention and/or treatment of thrombosis related pathology. Assessment of coagulation results requires comparison against a normal reference range or interval (NRR/NRI). Results flagged as 'abnormal' (i.e., above the NRR/NRI for patients not on anticoagulant therapy), typically require further evaluation, for example by follow up or reflexive testing, to identify the reason for prolongation, espec...

Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis.

PCSK9 (Proprotein convertase Subtilisin/Kexin Type 9), an important regulator of lipid metabolism, has been shown to play a role in hepatocellular carcinoma by promoting metastasis. PCSK9 interferes with LDL metabolism and causes dyslipidemias in hematological malignancies particularly acute lymphoblastic leukemia. Nutraceuticals like berberine, curcumin and polydatin have been found effective in modulating PCSK9 expression by lowering LDL levels. Eugenol, a nutraceutical has shown a promising role in cance...

Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor).

PCSK9 (proprotein convertase subtilisin-kexin 9) enhances the degradation of the LDLR (low-density lipoprotein receptor) in endosomes/lysosomes. This study aimed to determine the sites of PCSK9 phosphorylation at Ser-residues and the consequences of such posttranslational modification on the secretion and activity of PCSK9 on the LDLR. Approach and Results: Fam20C (family with sequence similarity 20, member C) phosphorylates serines in secretory proteins containing the motif S-X-E/phospho-Ser, including the...

Clinical study on factor Ⅷ inhibitor in children with hemophilia A.

To reveal the related factors of inhibitors and differences ofhemorrhage and joint disease before and after the production of inhibitors in children with hemophilia A (HA) . Retrospective analyses of the clinical data of 381 children with HA under the age of 16 registered in the Registration Management Center of Hemophilia in Henan Provincial from January 2015 to August 2018. A total of the 381 children were enrolled with 116 (30.4%) mild, 196 (51.4%) moderate, and 69 (18.1%) severe cases; 54 patients (14...

The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH pati...

A new index of clinical utility for diagnostic tests.

Clinical utility of a diagnostic test depends on its diagnostic accuracy, the pretest probability of disease and the clinical consequences of the test results. Tools for evaluating clinical utility are scarce. We propose a new clinical utility index (CUI), which is the expected gain in utility (EGU) of the test divided by the EGU of an ideal test, both adjusted for EGU of the optimal clinical action without testing. The index expresses the relative benefit of using the test compared to using an optimal test...

Is Takayasu arteritis the result of a Mycobacterium tuberculosis infection? The use of TNF inhibitors may be the proof-of-concept to demonstrate that this association is epiphenomenal.

Although the association between Takayasu arteritis (TA) and latent or active Mycobacterium tuberculosis infection has been suggested for a long time, studies conducted in recent years are challenging this notion. Until recently, the possibility of a pathogenic relationship between TA and tuberculosis (TB) was considered a medical curiosity, but the advent of tumor necrosis factor (TNF) inhibitors as therapy for recalcitrant TA cases, as well as the widespread use of Bacille Calmette-Guérin (BCG) for vacci...


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