Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(9), P. 577 - 592

Published: March 22, 2022

Language: Английский

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The Multifaceted Biology of PCSK9

Endocrine Reviews, Journal Year: 2021, Volume and Issue: 43(3), P. 558 - 582

Published: Oct. 9, 2021

This article reviews the discovery of PCSK9, its structure-function characteristics, and presently known proposed novel biological functions. The major critical function PCSK9 deduced from human mouse studies, as well cellular structural analyses, is role in increasing levels circulating LDL-cholesterol (LDLc), via ability to enhance sorting escort cell surface LDL receptor (LDLR) lysosomes. implicates binding catalytic domain EGF-A LDLR. also requires presence C-terminal Cys/His-rich (CHRD), secreted cytosolic cyclase associated protein 1 (CAP-1), possibly another membrane-bound "protein X". Curiously, PCSK9-deficient mice, an alternative downregulation LDLR by taking place liver female mice a 17β-estradiol-dependent manner still unknown mechanism. Recent studies have extended our understanding functions namely implication septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation cancer regulation T-cell MHC-I, which govern anti-tumoral activity CD8 + T cells. Because inhibition may be advantageous these processes, availability injectable safe inhibitors (PCSK9i) that reduces 50-60% LDLc above effect statins highly valuable. Indeed, mAb siRNA could added current immunotherapies cancer/metastasis.

Language: Английский

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Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(5), P. 1313 - 1313

Published: Feb. 27, 2022

Statins are competitive inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and have been used to treat elevated low-density lipoprotein cholesterol (LDL-C) for almost four decades. Antioxidant anti-inflammatory properties which independent the lipid-lowering effects statins, i.e., their pleiotropic effects, might be beneficial in prevention or treatment many diseases. This review discusses antioxidant statins achieved by modulating nuclear factor erythroid 2 related 2/ heme oxygenase-1 (Nrf2/HO-1) pathway different organs Nrf2 other proteins involved Nrf2/HO-1 signaling a crucial role cellular responses oxidative stress, is risk ASCVD. can significantly increase DNA-binding activity induce expression its target genes, such as HO-1 glutathione peroxidase) GPx, (thus protecting cells against stress. could partly explained modulation pathway.

Language: Английский

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Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Mediators of Inflammation, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 20

Published: Jan. 28, 2022

Background. Several studies have reported that statins anti-inflammatory effects. Nevertheless, results of clinical trials concerning the effect on levels C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) been inconsistent. Therefore, we performed a systematic review meta-analysis randomized (RCTs) evaluating hs-CRP in patients with cardiovascular diseases (CVDs). Methods. Literature search major databases was to find eligible RCTs assessing serum from inception until last week April 2021. The sizes were determined for weighted mean difference (WMD) 95% confidence intervals (CI). Results. 26 identified (3010 2968 controls) 20 (3026 CRP. Statins reduced ( $\text{WMD}=-0.97\text{mg}/\text{L}$ ; CI: -1.26 -0.68 mg/L; id="M2"> P < 0.001 ) id="M3"> 3.05 -4.86 -1.25 id="M4"> CVDs. decreased receiving both high-intensity moderate/low-intensity treatments these drugs. In addition, duration treatment longer than 10 weeks levels. Only statin could marginally decrease CVDs patients. Conclusions. This showed efficacy reduce concentrations different types

Language: Английский

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Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(7), P. 1534 - 1549.e7

Published: June 14, 2024

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists people type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte mouse models, we investigated how long-acting regulate fasted fed functions. In functional assays, enhanced insulin signaling, augmented glucose uptake, increased the conversion of glycerol cooperative manner insulin; however, absence insulin, lipolysis. diet-induced obese mice treated circulating were reduced during oral lipid challenge, lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support model for modulate both function differentially cooperating augment clearance state while enhancing release when are state.

Language: Английский

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The cardioprotective actions of statins in targeting mitochondrial dysfunction associated with myocardial ischaemia-reperfusion injury

Pharmacological Research, Journal Year: 2021, Volume and Issue: 175, P. 105986 - 105986

Published: Nov. 17, 2021

Language: Английский

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Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(4), P. 943 - 943

Published: Feb. 7, 2024

The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth blue–green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented milestone for treatment atherosclerotic cardiovascular disease. A new therapy hypercholesterolemia since discovery is ezetimibe, first and only agent inhibiting intestinal absorption. Ezetimibe was approved by FDA October 2002. year later, association between gain-of-function PCSK9 genetic mutations reported, this opened a era lipid-lowering therapies. Monoclonal antibodies small-interfering RNA approaches to reduce were developed clinical use 2015 2022, respectively. Finally, newly bempedoic acid, oral adenosine triphosphate citrate lyase inhibitor lowers LDL-C, able major adverse events both primary secondary prevention. In present narrative review, we summarize pharmacological properties efficacy all these agents currently used tailored patients with

Language: Английский

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The chemical composition analysis of Yixin Tongmai Granules using UHPLC-MS/MS and exploration of its potential mechanism in treatment of coronary artery disease based on network pharmacology and molecular docking

Medicine, Journal Year: 2025, Volume and Issue: 104(8), P. e41620 - e41620

Published: Feb. 21, 2025

Yixin Tongmai Granules (YTG) is a popular Chinese herbal granules for the treatment of coronary artery disease (CAD), but its molecular pharmacological mechanism still unclear. This article explores CAD from perspective network pharmacology. We analyzed chemical composition YTG using UHPLC-MS/MS and identified 131 ingredients. The relative drug content 33 ingredients exceeded 0.5%. These were further screened SwissADME platform with ADME criteria. Using HIT database SwissTargetPrediction platform, high probability targets these generated. Venn Diagram, 96 effective associated identified, involving 14 core study imported into STRING obtained through topology analysis: TP53, STAT3, transcription factor Jun, MAPK3, MAPK1, AKT1, SRC, MYC, BCL2, p65, TNF, ESR2. Then enrichment analysis Metascape indicated that, in system anti-CAD, principal pathways are “Lipid Atherosclerosis”, “Pathways cancer”, “AGE-RAGE signaling pathway diabetic complications.” Next, affinities between their examined individually docking. Finally, based on deep mining PubMed literature, this investigated relationship each target CAD, ingredients, inferred main YTG, namely Tanshinone IIA, Cryptotanshinone, Caffeic acid, Denshensu, Ononin, Formononetin.

Language: Английский

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PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Current Atherosclerosis Reports, Journal Year: 2022, Volume and Issue: 24(12), P. 995 - 1004

Published: Nov. 16, 2022

Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes interest investigate possible adverse effects pertaining risk new-onset diabetes (NOD).While safety results reported either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY alirocumab) did not rise incidence NOD, Mendelian randomization analyses were almost concordant showing an increased NOD. This evidence was line with post-marketing reports highlighting that evolocumab alirocumab primarily related mild hyperglycaemia rather than diabetes, most hyperglycaemic events occurring during first 6 months treatment. Considering different nature genetic studies randomized controlled trials, careful monitoring patients, particularly earlier phases treatment, identification those more susceptible develop treatment PCSK9 should be minimal concern.

Language: Английский

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Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities

MedComm, Journal Year: 2024, Volume and Issue: 5(6)

Published: May 24, 2024

Abstract White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, stem and progenitor immune but also an endocrine that important for regulating metabolic homeostasis. In individuals with obesity, dynamic cellular changes in result phenotypic switching dysfunction, including pathological expansion, WAT fibrosis, cell infiltration, endoplasmic reticulum stress, ectopic lipid accumulation, ultimately leading to chronic low‐grade inflammation insulin resistance. Recently, many distinct subpopulations of have been identified, providing new insights into the potential mechanisms dysfunction obesity. Therefore, targeting white therapeutic agent treating obesity obesity‐related diseases great scientific interest. Here, we provide overview remodeling discuss underlying regulatory dysfunction. Currently, studies uncovered promising targets strategies treatment. We outline signaling pathways summarize existing antiobesity treatment pharmacological approaches, lifestyle interventions, novel therapies.

Language: Английский

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