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Journal of Diabetes Investigation Dec 2023Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C... (Randomized Controlled Trial)
Randomized Controlled Trial
Prospective randomized comparative study of the effect of pemafibrate add-on or double statin dose on small dense low-density lipoprotein-cholesterol in patients with type 2 diabetes and hypertriglyceridemia on statin therapy.
AIMS/INTRODUCTION
Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C levels, pemafibrate and statins can reduce sdLDL-C levels. However, it remains unclear whether adding pemafibrate or increasing statin doses would more effectively reduce sdLDL-C levels in patients receiving statin therapy.
MATERIALS AND METHODS
A total of 97 patients with type 2 diabetes and hypertriglyceridemia who were treated with statins were randomly assigned to the pemafibrate 0.2 mg/day addition or statin dose doubled, and followed for 12 weeks. sdLDL-C was measured by our established homogenous assay.
RESULTS
The percentage and absolute reductions of sdLDL-C levels were significantly greater in the pemafibrate add-on group than the statin doubling group (-32.8 vs -8.1%; -16 vs -3 mg/dL, respectively). Triglyceride levels were reduced only in the pemafibrate add-on group (-44%), and LDL-C levels were reduced only in the statin doubling group (-8%), whereas levels of non-high-density lipoprotein-C and apolipoprotein B were similarly decreased (7-9%) in both groups. The absolute reductions of sdLDL-C levels were closely associated with decreased triglyceride, LDL-C, non-high-density lipoprotein-C and apolipoprotein B. In the subgroup analysis, the effect of pemafibrate add-on on sdLDL-C reductions was observed irrespective of baseline lipid parameters or statin type. No serious adverse effects were observed in both groups.
CONCLUSIONS
In patients with type 2 diabetes and hypertriglyceridemia, the addition of pemafibrate to a statin is superior to doubling a statin in reducing sdLDL-C without increasing adverse effects.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus, Type 2; Cholesterol, LDL; Prospective Studies; Hypertriglyceridemia; Triglycerides; Lipoproteins; Apolipoproteins
PubMed: 37647503
DOI: 10.1111/jdi.14076 -
Indian Heart Journal Mar 2024Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density... (Review)
Review
Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Cholesterol, LDL; Anticholesteremic Agents; Acute Disease; Pancreatitis; Hypolipidemic Agents; Oligonucleotides, Antisense; Dyslipidemias; Chemical and Drug Induced Liver Injury
PubMed: 37979722
DOI: 10.1016/j.ihj.2023.11.003 -
Cell Biology and Toxicology Dec 2023To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in...
OBJECTIVES
To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD).
BACKGROUND
The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.
METHODS
In vivo, we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression.
RESULTS
Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis.
CONCLUSIONS
These findings identify a previously unknown mechanism of Herpud1 upregulation in Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.
HIGHLIGHTS
• Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD. • In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy. • 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice.
Topics: Humans; Mice; Animals; Aortic Valve; Osteogenesis; Aortic Valve Stenosis; Transcription Factors; Lipoproteins, LDL; Cells, Cultured; Membrane Proteins
PubMed: 36746840
DOI: 10.1007/s10565-023-09794-w -
Immunology Letters Feb 2024The membrane protein CD36 is a lipid transporter, scavenger receptor, and receptor for the antiangiogenic protein thrombospondin 1 (TSP1). CD36 is expressed by cancer... (Review)
Review
The membrane protein CD36 is a lipid transporter, scavenger receptor, and receptor for the antiangiogenic protein thrombospondin 1 (TSP1). CD36 is expressed by cancer cells and by many associated cells including various cancer-infiltrating immune cell types. Thereby, CD36 plays critical roles in cancer, and it has been reported to affect cancer growth, metastasis, angiogenesis, and drug resistance. However, these roles are partly contradictory, as CD36 has been both reported to promote and inhibit cancer progression. Moreover, the mechanisms are also partly contradictory, because CD36 has been shown to exert opposite cellular effects such as cell division, senescence and cell death. This review provides an overview of the diverse effects of CD36 on tumor progression, aiming to shed light on its diverse pro- and anti-cancer roles, and the implications for therapeutic targeting.
Topics: Humans; CD36 Antigens; Neoplasms; Membrane Proteins; Lipoproteins, LDL
PubMed: 38122906
DOI: 10.1016/j.imlet.2023.12.002 -
Ophthalmic Plastic and Reconstructive... Dec 2023Graves orbitopathy (GO) is the most common extrathyroidal manifestation of Graves disease. Although its pathogenesis is not fully elucidated, GO is commonly considered... (Review)
Review
PURPOSE
Graves orbitopathy (GO) is the most common extrathyroidal manifestation of Graves disease. Although its pathogenesis is not fully elucidated, GO is commonly considered an autoimmune disease due to loss of self-tolerance against autoantigens shared by thyroid epithelial cells and orbital fibroblasts. High-dose intravenous glucocorticoids (ivGCs) are the most used treatment for moderate-to-severe, active GO, but the addition of other immunomodulating treatments can improve the efficacy of ivGCs. Among the various risk factors that can affect the occurrence of GO, cholesterol may be worthy of interest. Since 2015 the role of cholesterol and cholesterol-lowering medications has been investigated. The purpose of this review is to discuss this topic, thereby offering new therapeutic opportunities for patients with GO.
METHODS
We searched PubMed for studies published between January 1, 1980 and June 1, 2023, using the search terms "Graves orbitopathy," "thyroid eye disease," "Graves ophthalmopathy," "thyroid ophthalmopathy," "thyroid-associated ophthalmopathy," "endocrine ophthalmopathy," "cholesterol," "lipids," "statins," "low-density lipoprotein," "atorvastatin," and "cholesterol-lowering drugs." Only English-language articles were included.
RESULTS
A correlation between low-density lipoprotein cholesterol and the risk of GO development has been reported. Furthermore, low-density lipoprotein cholesterol has been proposed as a risk factor that can affect the course of GO and the response to ivGCs. The protective role of cholesterol-lowering medications in preventing GO has been also investigated. Statin treatment was found to have potential benefits in reducing the risk of GO in patients with Graves disease. Given these findings, measurement of low-density lipoprotein cholesterol and treatment of hypercholesterolemia in patients with moderate-to-severe, active GO may be considered before starting ivGCs administration. Recently, a randomized clinical trial aimed at investigating the effects of statins in GO suggested that the addition of oral atorvastatin to ivGCs improves the overall outcome of moderate-to-severe, active GO in hypercholesterolemic patients given ivGCs.
CONCLUSIONS
Overall, statins seem to have a preventive and therapeutic role in moderate-to-severe active GO. Their efficacy can be related to cholesterol-lowering activity, pleiotropic actions, and interaction with methylprednisolone.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Graves Ophthalmopathy; Atorvastatin; Graves Disease; Glucocorticoids; Lipoproteins, LDL; Cholesterol; Randomized Controlled Trials as Topic
PubMed: 38054983
DOI: 10.1097/IOP.0000000000002525 -
Clinical and Experimental Hypertension... Dec 2023Endothelial pyroptosis is a pathological mechanism of atherosclerosis (AS). Circular RNAs (circRNAs) are vital in AS progression by regulating endothelial cell...
Endothelial pyroptosis is a pathological mechanism of atherosclerosis (AS). Circular RNAs (circRNAs) are vital in AS progression by regulating endothelial cell functions. The study aimed to explore whether circ-USP9× regulated pyroptosis of endothelial cell to involve in AS development and the molecular mechanism. Pyroptosis was determined using lactate dehydrogenase (LDH) assay, enzyme linked immunosorbent assay (ELISA), flow cytometry, propidium iodide (PI) staining assay, and western blot. The mechanism of circ-USP9× was determined using RNA pull-down and RNA binding protein immunoprecipitation (RIP) assays. Results showed that circ-USP9× was upregulated in AS and oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of circ-USP9× suppressed ox-LDL induced pyroptosis of HUVECs. Mechanically, circ-USP9× could bind to EIF4A3 in the cytoplasm. Moreover, EIF4A3 was bound to GSDMD and further affects GSDMD stability. Overexpression of EIF4A3 rescued cell pyroptosis induced by circ-USP9× depletion. In short, circ-USP9× interacted with EIF4A3 to enhance GSDMD stability, thus further promoting ox-LDL-induced pyroptosis of HUVECs. These findings suggested that circ-USP9× participates in AS progression and may be a potential therapeutic target for AS.
Topics: Humans; Apoptosis; Atherosclerosis; Cell Proliferation; DEAD-box RNA Helicases; Enzyme-Linked Immunosorbent Assay; Eukaryotic Initiation Factor-4A; Human Umbilical Vein Endothelial Cells; L-Lactate Dehydrogenase; Lipoproteins, LDL; MicroRNAs; Phosphate-Binding Proteins; Pore Forming Cytotoxic Proteins; Pyroptosis
PubMed: 36890708
DOI: 10.1080/10641963.2023.2186319 -
Clinical and Experimental Hypertension... Dec 2023Circular RNAs (circRNAs) regulate the function of vascular smooth muscle cells (VSMCs) in atherosclerosis (AS) progression. We aimed to explore the role of circUSP9X in... (Review)
Review
Circular RNAs (circRNAs) regulate the function of vascular smooth muscle cells (VSMCs) in atherosclerosis (AS) progression. We aimed to explore the role of circUSP9X in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs. Cell proliferation was assessed using cell counting kit-8 and EDU assays. Cell migration was evaluated using Transwell and wound healing assays. The interaction between circUSP9X or STIM1 and miR-599 was analyzed using dual-luciferase reporter and RNA pull-down assays. Their levels were examined using quantitative real-time PCR. CircUSP9X and STIM1 expression was increased, whereas miR-599 expression was reduced in the serum of patients with AS and ox-LDL-stimulated VSMCs. Overexpression of circUSP9X facilitated the proliferation and migration of VSMCs induced by ox-LDL. CircUSP9X sponged miR-599, which targeted STIM1. MiR-599 reversed the effects induced by circUSP9X, and STIM1 reversed the effects induced by miR-599. Taken together, CircUSP9X promoted proliferation and migration in ox-LDL-treated VSMCs via the miR-599/STIM1 axis, providing a theoretical basis for the role of circUSP9X/miR-599/STIM1 axis in AS.
Topics: Humans; Muscle, Smooth, Vascular; Atherosclerosis; Cell Proliferation; Lipoproteins, LDL; MicroRNAs
PubMed: 37963203
DOI: 10.1080/10641963.2023.2280758 -
Advanced Healthcare Materials Nov 2023Low-density lipoprotein (LDL), especially oxidative modified LDL (Ox-LDL), is the key risk factor for plaque accumulation and the development of cardiovascular disease....
Low-density lipoprotein (LDL), especially oxidative modified LDL (Ox-LDL), is the key risk factor for plaque accumulation and the development of cardiovascular disease. Herein, a highly specific Ox-LDL-triggered fluorogenic-colorimetric probe Pro-P1 is developed for visualizing the oxidation and aggregation progress of lipoproteins and plaque. A series of green fluorescent protein chromophores with modified donor-acceptor structures, containing carbazole as an electron donor and various substituents including pyridine-vinyl (P1), phenol-vinyl (P2), N, N-dimethylaniline-vinyl (P3), and thiophene-vinyl (P4), have been synthesized and evaluated. Emission spectroscopy and theoretical calculations of P1-P4 indicate that P1 shows enhanced green fluorescence (λ = 560 nm) by inhibiting its twisted intramolecular charge transfer in the presence of Ox-LDL. This feature allows the selection of P1 as a sensitive probe to directly visualize ferroptosis and Cu -mediated LDL oxidative aggregation via in situ formation of fluorophore-bound Ox-LDL in living cells. The red-emissive probe Pro-P1 (λ = 660 nm) is prepared via borate protection of P1, which can be cleaved into P1 under high expression of HOCl and Ox-LDL condition at the lesion site, resulting in enhanced green emission. The plaque area and size with clear boundaries can be delineated by colorimetric fluorescence imaging and fluorescence lifetime imaging with precise differentiation.
Topics: Humans; Plaque, Atherosclerotic; Lipoproteins, LDL; Lipoproteins; Oxidation-Reduction
PubMed: 37557912
DOI: 10.1002/adhm.202301595 -
Journal of Translational Medicine Nov 2023Tumor cells with stemness in breast cancer might facilitate the immune microenvironment's suppression process and led to anti-tumor immune effects. The primary objective...
BACKGROUND
Tumor cells with stemness in breast cancer might facilitate the immune microenvironment's suppression process and led to anti-tumor immune effects. The primary objective of this study was to identify potential targets to disrupt the communication between cancer cell stemness and the immune microenvironment.
METHODS
In this study, we initially isolated tumor cells with varying degrees of stemness using a spheroid formation assay. Subsequently, we employed RNA-seq and proteomic analyses to identify genes associated with stemness through gene trend analysis. These stemness-related genes were then subjected to pan-cancer analysis to elucidate their functional roles in a broader spectrum of cancer types. RNA-seq data of 3132 patients with breast cancer with clinical data were obtained from public databases. Using the identified stemness genes, we constructed two distinct stemness subtypes, denoted as C1 and C2. We subsequently conducted a comprehensive analysis of the differences between these subtypes using pathway enrichment methodology and immune infiltration algorithms. Furthermore, we identified key immune-related stemness genes by employing lasso regression analysis and a Cox survival regression model. We conducted in vitro experiments to ascertain the regulatory impact of the key gene on cell stemness. Additionally, we utilized immune infiltration analysis and pan-cancer analysis to delineate the functions attributed to this key gene. Lastly, single-cell RNA sequencing (scRNA-seq) was employed to conduct a more comprehensive examination of the key gene's role within the microenvironment.
RESULTS
In our study, we initially identified a set of 65 stemness-related genes in breast cancer cells displaying varying stemness capabilities. Subsequently, through survival analysis, we pinpointed 41 of these stemness genes that held prognostic significance. We observed that the C2 subtype exhibited a higher stemness capacity compared to the C1 subtype and displayed a more aggressive malignancy profile. Further analysis using Lasso-Cox algorithm identified LDLR as a pivotal immune-related stemness gene. It became evident that LDLR played a crucial role in shaping the immune microenvironment. In vitro experiments demonstrated that LDLR regulated the cell stemness of breast cancer. Immune infiltration analysis and pan-cancer analysis determined that LDLR inhibited the proliferation of immune cells and might promote tumor cell progression. Lastly, in our scRNA-seq analysis, we discovered that LDLR exhibited associations with stemness marker genes within breast cancer tissues. Moreover, LDLR demonstrated higher expression levels in tumor cells compared to immune cells, further emphasizing its relevance in the context of breast cancer.
CONCLUSION
LDLR is an important immune stemness gene that regulates cell stemness and enhances the crosstalk between breast cancer cancer cell stemness and tumor immune microenvironment.
Topics: Humans; Female; Breast Neoplasms; Multiomics; Proteomics; Algorithms; Lipoproteins, LDL; Tumor Microenvironment
PubMed: 38037058
DOI: 10.1186/s12967-023-04699-y -
Nature Cell Biology Jul 2023
Topics: Lipoproteins, LDL; Mitochondria
PubMed: 37277482
DOI: 10.1038/s41556-023-01166-0