70 results on '"Krimbou L"'
Search Results
2. Upregulation of rate-limiting enzymes in cholesterol metabolism by PKCδ mediates endothelial apoptosis in diabetic wound healing.
- Author
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Qin, Peiliang, Zhou, Peng, Huang, Yating, Long, Binbin, Gao, Ruikang, Zhang, Shan, Zhu, Bingjie, Li, Yi-Qing, and Li, Qin
- Published
- 2024
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3. Significance of the Wnt signaling pathway in coronary artery atherosclerosis.
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Khan, Kashif, Bin Yu, Tardif, Jean-Claude, Rhéaume, Eric, Al-Kindi, Hamood, Filimon, Sabin, Pop, Cristina, Genest, Jacques, Cecere, Renzo, and Schwertani, Adel
- Published
- 2024
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4. Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease.
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Servín Muñoz, Iris Valeria, Ortuño-Sahagún, Daniel, Griñán-Ferré, Christian, Pallàs, Mercè, and González-Castillo, Celia
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LYSOSOMAL storage diseases ,HISTONE deacetylase inhibitors ,MUTANT proteins ,PROTEIN folding ,ALZHEIMER'S disease - Abstract
Niemann–Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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5. Closing the gaps in patient management of dyslipidemia: stepping into cardiovascular precision diagnostics with apolipoprotein profiling.
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Reijnders, Esther, van der Laarse, Arnoud, Ruhaak, L. Renee, and Cobbaert, Christa M.
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APOLIPOPROTEIN B ,LIPID metabolism ,APOLIPOPROTEIN E4 ,LDL cholesterol ,LOW density lipoproteins ,LIPOPROTEIN A ,APOLIPOPROTEINS ,DYSLIPIDEMIA - Abstract
In persons with dyslipidemia, a high residual risk of cardiovascular disease remains despite lipid lowering therapy. Current cardiovascular risk prediction mainly focuses on low-density lipoprotein cholesterol (LDL-c) levels, neglecting other contributing risk factors. Moreover, the efficacy of LDL-c lowering by statins resulting in reduced cardiovascular risk is only partially effective. Secondly, from a metrological viewpoint LDL-c falls short as a reliable measurand. Both direct and calculated LDL-c tests produce inaccurate test results at the low end under aggressive lipid lowering therapy. As LDL-c tests underperform both clinically and metrologically, there is an urging need for molecularly defined biomarkers. Over the years, apolipoproteins have emerged as promising biomarkers in the context of cardiovascular disease as they are the functional workhorses in lipid metabolism. Among these, apolipoprotein B (ApoB), present on all atherogenic lipoprotein particles, has demonstrated to clinically outperform LDL-c. Other apolipoproteins, such as Apo(a) - the characteristic apolipoprotein of the emerging risk factor lipoprotein(a) -, and ApoC-III - an inhibitor of triglyceride-rich lipoprotein clearance -, have attracted attention as well. To support personalized medicine, we need to move to molecularly defined risk markers, like the apolipoproteins. Molecularly defined diagnosis and molecularly targeted therapy require molecularly measured biomarkers. This review provides a summary of the scientific validity and (patho)physiological role of nine serum apolipoproteins, Apo(a), ApoB, ApoC-I, ApoC-II, ApoC-III, ApoE and its phenotypes, ApoA-I, ApoA-II, and ApoA-IV, in lipid metabolism, their association with cardiovascular disease, and their potential as cardiovascular risk markers when measured in a multiplex apolipoprotein panel. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. High-Density Lipoprotein Metabolism and Function in Cardiovascular Diseases: What about Aging and Diet Effects?
- Author
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Morvaridzadeh, Mojgan, Zoubdane, Nada, Heshmati, Javad, Alami, Mehdi, Berrougui, Hicham, and Khalil, Abdelouahed
- Abstract
Cardiovascular diseases (CVDs) have become the leading global cause of mortality, prompting a heightened focus on identifying precise indicators for their assessment and treatment. In this perspective, the plasma levels of HDL have emerged as a pivotal focus, given the demonstrable correlation between plasma levels and cardiovascular events, rendering them a noteworthy biomarker. However, it is crucial to acknowledge that HDLs, while intricate, are not presently a direct therapeutic target, necessitating a more nuanced understanding of their dynamic remodeling throughout their life cycle. HDLs exhibit several anti-atherosclerotic properties that define their functionality. This functionality of HDLs, which is independent of their concentration, may be impaired in certain risk factors for CVD. Moreover, because HDLs are dynamic parameters, in which HDL particles present different atheroprotective properties, it remains difficult to interpret the association between HDL level and CVD risk. Besides the antioxidant and anti-inflammatory activities of HDLs, their capacity to mediate cholesterol efflux, a key metric of HDL functionality, represents the main anti-atherosclerotic property of HDL. In this review, we will discuss the HDL components and HDL structure that may affect their functionality and we will review the mechanism by which HDL mediates cholesterol efflux. We will give a brief examination of the effects of aging and diet on HDL structure and function. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function.
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Rueter J, Rimbach G, and Huebbe P
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- Apolipoproteins E, Humans, Mitochondria, Protein Isoforms, Alzheimer Disease, Biological Phenomena
- Abstract
Human apolipoprotein E (APOE), originally known for its role in lipid metabolism, is polymorphic with three major allele forms, namely, APOEε2, APOEε3, and APOEε4, leading to three different human APOE isoforms. The ε4 allele is a genetic risk factor for Alzheimer's disease (AD); therefore, the vast majority of APOE research focuses on its role in AD pathology. However, there is increasing evidence for other functions of APOE through the involvement in other biological processes such as transcriptional regulation, mitochondrial metabolism, immune response, and responsiveness to dietary factors. Therefore, the aim of this review is to provide an overview of the potential novel functions of APOE and their characterization. The detection of APOE in various cell organelles points to previously unrecognized roles in mitochondria and others, although it is actually considered a secretory protein. Furthermore, numerous interactions of APOE with other proteins have been detected, providing indications for new metabolic pathways involving APOE. The present review summarizes the current evidence on APOE beyond its original role in lipid metabolism, to change the perspective and encourage novel approaches to future research on APOE and its isoform-dependent role in the cellular metabolism., (© 2022. The Author(s).)
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- 2022
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8. Development of a Microminipig Model of Atherosclerosis for the Evaluation of a HMGCR Inhibitor.
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TOMONOBU YAMADA, HIROKI KAWAGUCHI, AKI MATSUOKA, KOHEI AKIOKA, NAOKI MIURA, HIROYUKI IZUMI, and AKIHIDE TANIMOTO
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ATHEROSCLEROSIS ,REDUCTASE inhibitors ,CARDIOVASCULAR diseases risk factors ,HYPERCHOLESTEREMIA ,ANIMAL models in research - Abstract
Background/Aim: Atherosclerosis is known as a major risk factor for cardiovascular disease, and development of an animal model of atherosclerosis is required to investigate its clinical pathogenesis. We studied the optimal amount of cholesterol in the diet and the optimal experimental period for development of a Microminipig model of atherosclerosis for the evaluation of a hydroxymethylglutaryl-CoA reductase (HMGCR) inhibitor (atorvastatin). Materials and Methods: Eighteen male animals (3-4 months old) were divided into 3 groups. Group 1 consisted of control animals receiving a normal chow diet, Group 2 animals received a high fat (12% w/w) and low cholesterol (0.1% w/w) diet (HFLCD), and Group 3 animals received HFLCD+statin for 12 weeks. Animals received statin at 3 mg/kg body weight per day. HFLCD did not down-regulate the hepatic expression of HMGCR mRNA. Results: HFLCD increased body, omentum, and mesenteric adipose tissue weight, and induced hypercholesterolemia and atherosclerotic lesions in the abdominal aorta. HFLCD+statin inhibited hypercholesterolemia and atherosclerotic lesions, but not obesity. Conclusion: A microminipig atherosclerosis model induced by HFLCD can be used in the evaluation of HMGCR inhibitors for the treatment of hypercholesterolemia and atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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9. ANGPTL3 (Angiopoietin-Like 3) Preferentially Resides on High-Density Lipoprotein in the Human Circulation, Affecting Its Activity.
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Kraaijenhof, Jordan M., Tromp, Tycho R., Nurmohamed, Nick S., Reeskamp, Laurens F., Langenkamp, Marije, Levels, Johannes H. M., Boekholdt, S. Matthijs, Wareham, Nicholas J., Hoekstra, Menno, Stroes, Erik S. G., Hovingh, G. Kees, and Grefhorst, Aldo
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- 2023
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10. Searching for Atherosclerosis Biomarkers by Proteomics: A Focus on Lesion Pathogenesis and Vulnerability.
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Nieddu, Gabriele, Formato, Marilena, and Lepedda, Antonio Junior
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PERIPHERAL vascular diseases ,ATHEROSCLEROSIS ,ATHEROSCLEROTIC plaque ,BIOMARKERS ,PROTEOMICS ,HUMAN origins - Abstract
Plaque rupture and thrombosis are the most important clinical complications in the pathogenesis of stroke, coronary arteries, and peripheral vascular diseases. The identification of early biomarkers of plaque presence and susceptibility to ulceration could be of primary importance in preventing such life-threatening events. With the improvement of proteomic tools, large-scale technologies have been proven valuable in attempting to unravel pathways of atherosclerotic degeneration and identifying new circulating markers to be utilized either as early diagnostic traits or as targets for new drug therapies. To address these issues, different matrices of human origin, such as vascular cells, arterial tissues, plasma, and urine, have been investigated. Besides, proteomics was also applied to experimental atherosclerosis in order to unveil significant insights into the mechanisms influencing atherogenesis. This narrative review provides an overview of the last twenty years of omics applications to the study of atherogenesis and lesion vulnerability, with particular emphasis on lipoproteomics and vascular tissue proteomics. Major issues of tissue analyses, such as plaque complexity, sampling, availability, choice of proper controls, and lipoproteins purification, will be raised, and future directions will be addressed. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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11. Apolipoprotein-CIII O -Glycosylation, a Link between GALNT2 and Plasma Lipids.
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Naber, Annemieke, Demus, Daniel, Slieker, Roderick, Nicolardi, Simone, Beulens, Joline W. J., Elders, Petra J. M., Lieverse, Aloysius G., Sijbrands, Eric J. G., 't Hart, Leen M., Wuhrer, Manfred, and van Hoek, Mandy
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BLOOD lipids ,GENOME-wide association studies ,HDL cholesterol ,TYPE 2 diabetes ,LIPID metabolism ,APOLIPOPROTEIN E4 - Abstract
Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII
0a ), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c , apo-CIII1 and apo-CIII2 ). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a . This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease. [ABSTRACT FROM AUTHOR]- Published
- 2023
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12. The Impact of MiR-33a-5p Inhibition in Pro-Inflammatory Endothelial Cells.
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Huang, Kun, Pitman, Mark, Oladosu, Olanrewaju, Echesabal-Chen, Jing, Vojtech, Lucia, Esobi, Ikechukwu, Larsen, Jessica, Jo, Hanjoong, and Stamatikos, Alexis
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ENDOTHELIAL cells ,PROTEIN expression ,POLYMERSOMES ,CHOLESTEROL ,ENDOTHELIUM - Abstract
Evidence suggests cholesterol accumulation in pro-inflammatory endothelial cells (EC) contributes to triggering atherogenesis and driving atherosclerosis progression. Therefore, inhibiting miR-33a-5p within inflamed endothelium may prevent and treat atherosclerosis by enhancing apoAI-mediated cholesterol efflux by upregulating ABCA1. However, it is not entirely elucidated whether inhibition of miR-33a-5p in pro-inflammatory EC is capable of increasing ABCA1-dependent cholesterol efflux. In our study, we initially transfected LPS-challenged, immortalized mouse aortic EC (iMAEC) with either pAntimiR33a5p plasmid DNA or the control plasmid, pScr. We detected significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux in iMAEC transfected with pAntimiR33a5p when compared to iMAEC transfected with pScr. We subsequently used polymersomes targeting inflamed endothelium to deliver either pAntimiR33a5p or pScr to cultured iMAEC and showed that the polymersomes were selective in targeting pro-inflammatory iMAEC. Moreover, when we exposed LPS-challenged iMAEC to these polymersomes, we observed a significant decrease in miR-33a-5p expression in iMAEC incubated with polymersomes containing pAntimR33a5p versus control iMAEC. We also detected non-significant increases in both ABCA1 protein and apoAI-mediated cholesterol in iMAEC exposed to polymersomes containing pAntimR33a5p when compared to control iMAEC. Based on our results, inhibiting miR-33a-5p in pro-inflammatory EC exhibits atheroprotective effects, and so precisely delivering anti-miR-33a-5p to these cells is a promising anti-atherogenic strategy. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease.
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Guillas, Isabelle, Lhomme, Marie, Pionneau, Cédric, Matheron, Lucrèce, Ponnaiah, Maharajah, Galier, Sophie, Lebreton, Sandrine, Delbos, Marie, Ma, Feng, Darabi, Maryam, Khoury, Petra El, Abifadel, Marianne, Couvert, Philippe, Giral, Philippe, Lesnik, Philippe, Guerin, Maryse, Le Goff, Wilfried, and Kontush, Anatol
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CHOLESTERYL ester transfer protein ,CARDIOVASCULAR diseases ,CARDIOVASCULAR diseases risk factors ,DYSLIPIDEMIA ,LIPID metabolism ,CLUSTERIN ,IMMUNOREGULATION - Abstract
While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. Lysophosphatidylglucoside/GPR55 signaling promotes foam cell formation in human M2c macrophages.
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Shimai, Ryosuke, Hanafusa, Kei, Nakayama, Hitoshi, Oshima, Eriko, Kato, Masaki, Kano, Koki, Matsuo, Ichiro, Miyazaki, Tetsuro, Tokano, Takashi, Hirabayashi, Yoshio, Iwabuchi, Kazuhisa, and Minamino, Tohru
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FOAM cells ,MACROPHAGES ,FOAM ,CELL membranes ,CARDIOVASCULAR diseases ,MONOCYTES ,LOW density lipoprotein receptors - Abstract
Atherosclerosis is a major cause of cerebral and cardiovascular diseases. Intravascular plaques, a well-known pathological finding of atherosclerosis, have a necrotic core composed of macrophages and dead cells. Intraplaque macrophages, which are classified into various subtypes, play key roles in maintenance of normal cellular microenvironment. Excessive uptake of oxidized low-density lipoprotein causes conversion of macrophages to foam cells, and consequent progression/exacerbation of atherosclerosis. G-protein-coupled receptor 55 (GPR55) signaling has been reported to associate with atherosclerosis progression. We demonstrated recently that lysophosphatidylglucoside (lysoPtdGlc) is a specific ligand of GPR55, although in general physiological ligands of GPR55 are poorly understood. Phosphatidylglucoside is expressed on human monocytes and can be converted to lysoPtdGlc. In the present study, we examined possible involvement of lysoPtdGlc/GPR55 signaling in foam cell formation. In monocyte-derived M2c macrophages, lysoPtdGlc/GPR55 signaling inhibited translocation of ATP binding cassette subfamily A member 1 to plasma membrane, and cholesterol efflux. Such inhibitory effect was reversed by GPR55 antagonist ML193. LysoPtdGlc/GPR55 signaling in M2c macrophages was involved in excessive lipid accumulation, thereby promoting foam cell formation. Our findings suggest that lysoPtdGlc/GPR55 signaling is a potential therapeutic target for inhibition of atherosclerosis progression. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Decreased Serum Apolipoprotein CIII in the Acute Phase of Kawasaki Disease.
- Author
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Kanai T, Ito T, and Tajima T
- Abstract
Plasma exchange is an effective treatment for Kawasaki disease (KD), suggesting that plasma from patients with KD bears its causative agents. The aim of this study was to use mass spectrometry to identify candidate agents in patient sera. Serum samples were obtained from 17 KD patients. In six patients, samples were collected in each of three phases: the acute phase prior to acetylsalicylic acid (ASA) and intravenous immunoglobulin administration (Phase A1), the remission phase with ASA (Phase A2), and the remission phase without any medication (Phase A3). Sera from the remaining 11 patients were collected during Phases A1 and A2. The study also included two age- and gender-matched control groups, one with eight afebrile children and one with eight febrile children diagnosed with infectious disease. Patients in Phase A1 and febrile controls did not differ in body temperature, white blood cell counts, or C-reactive protein levels. Mass spectrometry analysis revealed that the intensity levels of m/z 9416, identified as apolipoprotein CIII (Apo CIII), were lower in Phase A1 samples compared with samples from patients in Phases A2 and A3, and from febrile controls (all comparisons, p < 0.01). Serum Apo CIII levels were also lower in Phase A1 samples compared with samples from Phase A2 patients and afebrile controls (both p < 0.01), but samples from patients in Phase A2 did not differ significantly from those of the afebrile controls (p = 0.55). This study demonstrated that serum Apo CIII level was decreased in the acute phase of KD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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16. Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease.
- Author
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Kononov, Stanislav, Azarova, Iuliia, Klyosova, Elena, Bykanova, Marina, Churnosov, Mikhail, Solodilova, Maria, and Polonikov, Alexey
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CORONARY artery disease ,CAROTID intima-media thickness ,LDL cholesterol ,GENOME-wide association studies ,ROSUVASTATIN - Abstract
We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and p-values were calculated through adaptive permutation tests by the PLINK software, v1.9. Over one-year rosuvastatin therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm < 0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm < 0.05). In conclusion, polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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17. Association of a Novel Homozygous Variant in ABCA1 Gene with Tangier Disease.
- Author
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Barbosa-Gouveia, Sofía, Fernández-Crespo, Silvia, Lazaré-Iglesias, Héctor, González-Quintela, Arturo, Vázquez-Agra, Néstor, and Hermida-Ameijeiras, Álvaro
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RECESSIVE genes ,GENETIC variation ,HDL cholesterol ,PROTEIN structure ,CORONARY disease ,PROTEIN models - Abstract
Tangier disease (TD) is a rare autosomal recessive disorder caused by a variant in the ABCA1 gene, characterized by significantly reduced levels of plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (ApoA-I). TD typically leads to accumulation of cholesterol in the peripheral tissues and early coronary disease but with highly variable clinical expression. Herein, we describe a case study of a 59-year-old male patient with features typical of TD, in whom a likely pathogenic variant in the ABCA1 gene was identified by whole-exome sequencing (WES), identified for the first time as homozygous (NM_005502.4: c.4799A>G (p. His1600Arg)). In silico analysis including MutationTaster and DANN score were used to predict the pathogenicity of the variant and a protein model generated by SWISS-MODEL was built to determine how the homozygous variant detected in our patient may change the protein structure and impact on its function. This case study describes a homozygous variant of the ABCA1 gene, which is responsible for a severe form of TD and underlines the importance of using bioinformatics and genomics for linking genotype to phenotype and better understanding and accounting for the functional impact of genetic variations. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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18. SMN Deficiency Destabilizes ABCA1 Expression in Human Fibroblasts: Novel Insights in Pathophysiology of Spinal Muscular Atrophy.
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Gabanella, Francesca, Onori, Annalisa, Pisani, Cinzia, Fiore, Marco, Ferraguti, Giampiero, Colizza, Andrea, de Vincentiis, Marco, Ceccanti, Marco, Inghilleri, Maurizio, Corbi, Nicoletta, Passananti, Claudio, and Di Certo, Maria Grazia
- Subjects
SPINAL muscular atrophy ,ATP-binding cassette transporters ,RNA metabolism ,PATHOLOGICAL physiology ,FIBROBLASTS ,HOMEOSTASIS ,HYPERTROPHIC scars - Abstract
The deficiency of survival motor neuron protein (SMN) causes spinal muscular atrophy (SMA), a rare neuromuscular disease that affects different organs. SMN is a key player in RNA metabolism regulation. An intriguing aspect of SMN function is its relationship with plasma membrane-associated proteins. Here, we provide a first demonstration that SMN affects the ATP-binding cassette transporter A1, (ABCA1), a membrane protein critically involved in cholesterol homeostasis. In human fibroblasts, we showed that SMN associates to ABCA1 mRNA, and impacts its subcellular distribution. Consistent with the central role of ABCA1 in the efflux of free cholesterol from cells, we observed a cholesterol accumulation in SMN-depleted human fibroblasts. These results were also confirmed in SMA type I patient-derived fibroblasts. These findings not only validate the intimate connection between SMN and plasma membrane-associated proteins, but also highlight a contribution of dysregulated cholesterol efflux in SMA pathophysiology. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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19. Expression Pattern and Molecular Mechanism of Oxidative Stress-Related Genes in Myocardial Ischemia–Reperfusion Injury.
- Author
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Wu, Jiahe, Luo, Jingyi, Cai, Huanhuan, Li, Chenze, Lei, Zhe, Lu, Yi, Ni, Lihua, Cao, Jianlei, Cheng, Bo, and Hu, Xiaorong
- Published
- 2023
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20. Systematic Assessment of Protein C-Termini Mutated in Human Disorders.
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FitzHugh, Zachary T. and Schiller, Martin R.
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SUBSTITUENTS (Chemistry) ,POST-translational modification ,AMINO acid sequence ,BINDING sites ,PROTEINS - Abstract
All proteins have a carboxyl terminus, and we previously summarized eight mutations in binding and trafficking sequence determinants in the C-terminus that, when disrupted, cause human diseases. These sequence elements for binding and trafficking sites, as well as post-translational modifications (PTMs), are called minimotifs or short linear motifs. We wanted to determine how frequently mutations in minimotifs in the C-terminus cause disease. We searched specifically for PTMs because mutation of a modified amino acid almost always changes the chemistry of the side chain and can be interpreted as loss-of-function. We analyzed data from ClinVar for disease variants, Minimotif Miner and the C-terminome for PTMs, and RefSeq for protein sequences, yielding 20 such potential disease-causing variants. After additional screening, they include six with a previously reported PTM disruption mechanism and nine with new hypotheses for mutated minimotifs in C-termini that may cause disease. These mutations were generally for different genes, with four different PTM types and several different diseases. Our study helps to identify new molecular mechanisms for nine separate variants that cause disease, and this type of analysis could be extended as databases grow and to binding and trafficking motifs. We conclude that mutated motifs in C-termini are an infrequent cause of disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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21. Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Phosphate Accelerates Cellular Cholesterol Efflux in THP-1 Cells.
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Komatsu, Tomohiro, Abe, Satomi, Nakashima, Shihoko, Sasaki, Kei, Higaki, Yasuki, Saku, Keijiro, Miura, Shin-ichiro, and Uehara, Yoshinari
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RETINOID X receptors ,CD26 antigen ,ATP-binding cassette transporters ,SITAGLIPTIN ,CHOLESTEROL ,PROTEIN kinase inhibitors ,HIGH density lipoproteins - Abstract
Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with
3 H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (p < 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux. [ABSTRACT FROM AUTHOR]- Published
- 2023
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22. A Multi-Trait Association Analysis of Brain Disorders and Platelet Traits Identifies Novel Susceptibility Loci for Major Depression, Alzheimer's and Parkinson's Disease.
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Tirozzi, Alfonsina, Quiccione, Miriam Shasa, Cerletti, Chiara, Donati, Maria Benedetta, de Gaetano, Giovanni, Iacoviello, Licia, and Gialluisi, Alessandro
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ALZHEIMER'S disease ,PARKINSON'S disease ,TELOMERES ,MENTAL depression ,LOCUS (Genetics) ,MEAN platelet volume ,GENOME-wide association studies ,CELLULAR aging ,BLOOD platelet aggregation - Abstract
Among candidate neurodegenerative/neuropsychiatric risk-predictive biomarkers, platelet count, mean platelet volume and platelet distribution width have been associated with the risk of major depressive disorder (MDD), Alzheimer's disease (AD) and Parkinson's disease (PD) through epidemiological and genomic studies, suggesting partial co-heritability. We exploited these relationships for a multi-trait association analysis, using publicly available summary statistics of genome-wide association studies (GWASs) of all traits reported above. Gene-based enrichment tests were carried out, as well as a network analysis of significantly enriched genes. We analyzed 4,540,326 single nucleotide polymorphisms shared among the analyzed GWASs, observing 149 genome-wide significant multi-trait LD-independent associations (p < 5 × 10
−8 ) for AD, 70 for PD and 139 for MDD. Among these, 27 novel associations were detected for AD, 34 for PD and 40 for MDD. Out of 18,781 genes with annotated variants within ±10 kb, 62 genes were enriched for associations with AD, 70 with PD and 125 with MDD (p < 2.7 × 10−6 ). Of these, seven genes were novel susceptibility loci for AD (EPPK1, TTLL1, PACSIN2, TPM4, PIF1, ZNF689, AZGP1P1), two for PD (SLC26A1, EFNA3) and two for MDD (HSPH1, TRMT61A). The resulting network showed a significant excess of interactions (enrichment p = 1.0 × 10−16 ). The novel genes that were identified are involved in the organization of cytoskeletal architecture (EPPK1, TTLL1, PACSIN2, TPM4), telomere shortening (PIF1), the regulation of cellular aging (ZNF689, AZGP1P1) and neurodevelopment (EFNA3), thus, providing novel insights into the shared underlying biology of brain disorders and platelet parameters. [ABSTRACT FROM AUTHOR]- Published
- 2023
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23. HDL Functions—Current Status and Future Perspectives.
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Endo, Yasuhiro, Fujita, Masanori, and Ikewaki, Katsunori
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HDL cholesterol ,WESTERN countries ,CAUSES of death ,CLINICAL trials ,NIACIN - Abstract
Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials. [ABSTRACT FROM AUTHOR]
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- 2023
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24. Effect of Linoleic Acid on Cholesterol Levels in a High-Fat Diet-Induced Hypercholesterolemia Rat Model.
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Azemi, Nurul Adila, Azemi, Ahmad Khusairi, Abu-Bakar, Luqman, Sevakumaran, Vigneswari, Muhammad, Tengku Sifzizul Tengku, and Ismail, Noraznawati
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HYPERCHOLESTEREMIA ,SPRAGUE Dawley rats ,ANIMAL disease models ,BLOOD cholesterol ,BLOOD lipids ,LINOLEIC acid ,ASPARTATE aminotransferase - Abstract
Cardiovascular disease is the leading cause of morbidity and mortality worldwide, accounting for almost one-third of all deaths. The risk factors for developing this disease include high levels of serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), alongside low levels of high-density lipoprotein (HDL). Dietary linoleic acid has been suggested to reduce these risk factors. This study aims to determine the effects of linoleic acid on cholesterol levels, liver function tests, and structural changes in liver tissue in comparison with fenofibrate in a hypercholesterolemic rat model. Thirty-six male Sprague Dawley rats (150–180 g) were divided into non-hypercholesterolemic and hypercholesterolemic groups. Hypercholesterolemia was induced in the rats by feeding them with a high-fat diet for two weeks. After two weeks, the non-hypercholesterolemic and hypercholesterolemic rats were equally divided into six groups (n = 6): control non-hypercholesterolemic rats, non-hypercholesterolemic rats treated with fenofibrate (60 mg/kg), non-hypercholesterolemic rats treated with linoleic acid (5 mg/kg), control hypercholesterolemic rats, hypercholesterolemic rats treated with fenofibrate (60 mg/kg), and hypercholesterolemic rats treated with linoleic acid (5 mg/kg). The changes in the rats' body weight, serum lipid profiles, atherogenic indices, and liver function test results were obtained. The rats' liver tissues were stained for histopathological analysis. The linoleic acid-treated hypercholesterolemic rats exhibited significantly reduced serum TC, TG, LDL, aspartate aminotransferase, and alanine aminotransferase levels, as well as increased HDL levels compared with the control hypercholesterolemic rats. These linoleic acid effects were comparable to those in the fenofibrate-treated hypercholesterolemic rats. In conclusion, linoleic acid possesses early anti-hypercholesterolemic properties, which may be due to the reductions in serum cholesterol levels and mild early structural changes in the liver tissues of hypercholesterolemic rats. Therefore, continued studies on linoleic acid in atherosclerotic and/or obese animal models are suggested. [ABSTRACT FROM AUTHOR]
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- 2023
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25. A Label-Free Proteomic Approach for the Identification of Biomarkers in the Exosome of Endometrial Cancer Serum.
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Sommella, Eduardo, Capaci, Valeria, Aloisio, Michelangelo, Salviati, Emanuela, Campiglia, Pietro, Molinario, Giuseppe, Licastro, Danilo, Di Lorenzo, Giovanni, Romano, Federico, Ricci, Giuseppe, Monasta, Lorenzo, and Ura, Blendi
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BIOMARKERS ,EXOSOMES ,WESTERN immunoblotting ,MULTIVARIATE analysis ,PROTEOMICS ,BIOINFORMATICS ,ENDOMETRIAL tumors ,MASS spectrometry ,DESCRIPTIVE statistics ,RESEARCH funding ,LOGISTIC regression analysis ,RECEIVER operating characteristic curves - Abstract
Simple Summary: Endometrial cancers (ECs) are mostly adenocarcinomas arising from the inner part of the uterus. The identification of serum biomarkers may be useful for an early diagnosis. This study compared the exosome serum proteins of 12 patients with EC with those of 12 non-cancer subjects, and identified 33 proteins with diagnostic potential. Quantification analysis in 36 patients with endometrial cancer compared to 36 healthy individuals confirmed the upregulation of APOA1, HBB, CA1, HBD, LPA, SAA4, PF4V1, and APOE. We developed a statistical model based on this set of proteins that detects cancer samples with excellent sensitivity and specificity levels, particularly for stage 1 ECs. In our opinion, the combined levels of PF4V1, CA1, HBD, and APOE have great potential to reach the clinical stage, after a validation phase. Endometrial cancers (ECs) are mostly adenocarcinomas arising from the inner part of the uterus. The identification of serum biomarkers, either soluble or carried in the exosome, may be useful in making an early diagnosis. We used label-free quantification mass spectrometry (LFQ-MS)-based proteomics to investigate the proteome of exosomes in the albumin-depleted serum from 12 patients with EC, as compared to 12 healthy controls. After quantification and statistical analysis, we found significant changes in the abundance (p < 0.05) of 33 proteins in EC vs. control samples, with a fold change of ≥1.5 or ≤0.6. Validation using Western blotting analysis in 36 patients with EC as compared to 36 healthy individuals confirmed the upregulation of APOA1, HBB, CA1, HBD, LPA, SAA4, PF4V1, and APOE. A multivariate logistic regression model based on the abundance of these proteins was able to separate the controls from the EC patients with excellent sensitivity levels, particularly for stage 1 ECs. The results show that using LFQ-MS to explore the specific proteome of serum exosomes allows for the identification of biomarkers in EC. These observations suggest that PF4V1, CA1, HBD, and APOE represent biomarkers that are able to reach the clinical stage, after a validation phase. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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26. Compound Heterozygote Mutation in the SMPD1 Gene Leading to Nieman-Pick Disease Type A.
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Kavčič, Alja, Homan, Matjaž, Živanović, Milanka, Debeljak, Maruša, Butenko, Tita, Torkar, Ana Drole, Tanšek, Mojca Žerjav, Bertok, Sara, Battelino, Tadej, and Groselj, Urh
- Subjects
FAILURE to thrive syndrome ,AUDITORY neuropathy ,AUDITORY evoked response ,LIPIDOSES ,NIEMANN-Pick diseases ,GENETIC mutation ,SYMPTOMS - Abstract
Patient: Male, 11-month-old Final Diagnosis: Niemann-Pick disease type A Symptoms: Hepatosplenomegaly • failure to thrive • neurodegenerative disorder Medication: -- Clinical Procedure: -- Specialty: Endocrinology and Metabolic Objective: Rare disease Background: Niemann-Pick disease (NPD) type A is an autosomal recessive lipid storage disorder caused by acid sphingomyelinase deficiency due to a mutation in the SMPD1 gene. Type A is the most severe phenotype of NPD, with early onset in infancy and unfavorable outcome in early childhood. Case Report: An 11-month-old boy with hepatosplenomegaly, elevated liver transaminases, and faltering growth was admitted to our hospital for further assessment of potential liver disease. He had severe generalized muscular hypotonia, muscular hypotrophy, reduced muscular strenght, joint laxity, weak deep tendon reflexes, and severe motor developmental delay. Leukodystrophy was seen on the brain MRI, and brainstem auditory evoked potentials were characteristic for auditory neuropathy. A chest X-ray showed signs of interstitial lung disease, which was not further evaluated due to absence of respiratory distress. Liver biopsy histopathologic findings were indicative for lipid storage disease. Genetic analysis showed that the patient is a compound heterozygote in the SMPD1 gene -- (NM_000543.5): c.573delT p.(Ser192Alafs*65), which was inherited from the mother and c.1267C>T p.(His423Tyr) was inherited from the father. Both variants were previously individually reported in NPD type A and B. The clinical phenotype in our patient was characteristic of NPD type A, with an early onset and a rapidly progresive neurodegeneration. The patient was included in multidisciplinary follow-up, providing him symptomatic treatment and support. Conclusions: We present a case of NPD type A caused by a rare compound heterozygote mutation in the SMPD1 gene. Most clinical findings and the disease course were typical for NPD type A, except for bilateral auditory neuropathy, which seems to be an uncommon finding in this phenotype and could be underestimated due to infrequent testing for auditory dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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27. Clinical Significance of Lipid Transport Function of ABC Transporters in the Innate Immune System.
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Kotlyarov, Stanislav and Kotlyarova, Anna
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- 2022
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28. Obstructive Sleep Apnoea and Lipid Metabolism: The Summary of Evidence and Future Perspectives in the Pathophysiology of OSA-Associated Dyslipidaemia.
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Meszaros, Martina and Bikov, Andras
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SLEEP apnea syndromes ,LIPID metabolism ,DYSLIPIDEMIA ,PATHOLOGICAL physiology ,HIGH density lipoproteins - Abstract
Obstructive sleep apnoea (OSA) is associated with cardiovascular and metabolic comorbidities, including hypertension, dyslipidaemia, insulin resistance and atherosclerosis. Strong evidence suggests that OSA is associated with an altered lipid profile including elevated levels of triglyceride-rich lipoproteins and decreased levels of high-density lipoprotein (HDL). Intermittent hypoxia; sleep fragmentation; and consequential surges in the sympathetic activity, enhanced oxidative stress and systemic inflammation are the postulated mechanisms leading to metabolic alterations in OSA. Although the exact mechanisms of OSA-associated dyslipidaemia have not been fully elucidated, three main points have been found to be impaired: activated lipolysis in the adipose tissue, decreased lipid clearance from the circulation and accelerated de novo lipid synthesis. This is further complicated by the oxidisation of atherogenic lipoproteins, adipose tissue dysfunction, hormonal changes, and the reduced function of HDL particles in OSA. In this comprehensive review, we summarise and critically evaluate the current evidence about the possible mechanisms involved in OSA-associated dyslipidaemia. [ABSTRACT FROM AUTHOR]
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- 2022
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29. PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer's Disease.
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Papotti, Bianca, Adorni, Maria Pia, Marchi, Cinzia, Zimetti, Francesca, Ronda, Nicoletta, Panighel, Giovanni, Lupo, Maria Giovanna, Vilella, Antonietta, Giuliani, Daniela, Ferri, Nicola, and Bernini, Franco
- Subjects
CHOLESTEROL metabolism ,ALZHEIMER'S disease ,AMYLOID beta-protein ,CHOLESTEROL ,ENTORHINAL cortex ,LOW density lipoprotein receptors ,ASTROCYTES - Abstract
The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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30. Plasma high‐density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume.
- Author
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Pedrini, Steve, Doecke, James D., Hone, Eugene, Wang, Penghao, Thota, Rohith, Bush, Ashley I., Rowe, Christopher C., Dore, Vincent, Villemagne, Victor L., Ames, David, Rainey‐Smith, Stephanie, Verdile, Giuseppe, Sohrabi, Hamid R., Raida, Manfred R., Taddei, Kevin, Gandy, Sam, Masters, Colin L., Chatterjee, Pratishtha, and Martins, Ralph N.
- Subjects
ALZHEIMER'S disease ,HIGH density lipoproteins ,FREIGHT & freightage ,CARRIERS ,APOLIPOPROTEIN E ,CHOLESTEROL metabolism - Abstract
Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low‐Density Lipoprotein (LDL) cholesterol. On the other hand, High‐Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL‐functionality, which depends upon the HDL‐cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL‐cargo (Cholesterol, ApoA‐I, ApoA‐II, ApoC‐I, ApoC‐III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC‐Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA‐I ratio in AD and HC‐Conv, as well as an increased ApoD/ApoA‐I ratio and a decreased ApoA‐II/ApoA‐I ratio in AD. Higher cholesterol/ApoA‐I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA‐II/ApoA‐I and ApoJ/ApoA‐I ratios were associated with greater cortical grey matter volume (and for ApoA‐II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status‐independent manner, the ApoE/ApoA‐I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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31. Association of MARC1 , ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men.
- Author
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Rivera-Paredez, Berenice, Aparicio-Bautista, Diana I., Argoty-Pantoja, Anna D., Patiño, Nelly, Flores Morales, Jeny, Salmerón, Jorge, León-Reyes, Guadalupe, and Velázquez-Cruz, Rafael
- Subjects
MEXICANS ,HYPERTRIGLYCERIDEMIA ,DISEASE risk factors ,SINGLE nucleotide polymorphisms ,GENETIC variation ,HIGH density lipoproteins - Abstract
Epidemiological studies have reported that the Mexican population is highly susceptible to dyslipidemia. The MARC1, ADCY5, and BCO1 genes have recently been involved in lipidic abnormalities. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) rs2642438, rs56371916, and rs6564851 on MARC1, ADCY5, and BCO1 genes, respectively, with the lipid profile in a cohort of Mexican adults. We included 1900 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were collected through a structured questionnaire and standardized procedures. Genotyping was performed using a predesigned TaqMan assay. A genetic risk score (GRS) was created on the basis of the three genetic variants. Associations analysis was estimated using linear and logistic regression. Our results showed that rs2642438-A and rs6564851-A alleles had a risk association for hypertriglyceridemia (OR = 1.57, p = 0.013; and OR = 1.33, p = 0.031, respectively), and rs56371916-C allele a trend for low HDL-c (OR = 1.27, p = 0.060) only in men. The GRS revealed a significant association for hypertriglyceridemia (OR = 2.23, p = 0.022). These findings provide evidence of an aggregate effect of the MARC1, ADCY5, and BCO1 variants on the risk of hypertriglyceridemia in Mexican men. This knowledge could represent a tool for identifying at-risk males who might benefit from early interventions and avoid secondary metabolic traits. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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32. HDL metabolism and functions impacting on cell cholesterol homeostasis are specifically altered in patients with abdominal aortic aneurysm.
- Author
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Adorni, Maria Pia, Palumbo, Marcella, Marchi, Cinzia, Zimetti, Francesca, Ossoli, Alice, Turri, Marta, Bernini, Franco, Hollan, Ivana, Moláček, Jiří, Treska, Vladislav, and Ronda, Nicoletta
- Subjects
ABDOMINAL aortic aneurysms ,CHOLESTERYL ester transfer protein ,CAROTID intima-media thickness ,ANKLE brachial index ,CARDIOVASCULAR diseases risk factors ,CHOLESTEROL ,BLOOD cholesterol - Abstract
Background: The etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities. Methods: We measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively. Results: We found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (-16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA. Conclusions: We demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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33. Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases.
- Author
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Alagarsamy, Jeyashree, Jaeschke, Anja, and Hui, David Y.
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APOLIPOPROTEIN E ,CELL receptors ,BLOOD lipoproteins ,NEUROLOGICAL disorders ,HEPARAN sulfate proteoglycans ,VASCULAR smooth muscle - Abstract
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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34. Metabolomics Profiling of Vitamin D Status in Relation to Dyslipidemia.
- Author
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Mousa, Hanaa, Elrayess, Mohamed A., Diboun, Ilhame, Jackson, Simon K., and Zughaier, Susu M.
- Subjects
VITAMIN D ,METABOLOMICS ,DYSLIPIDEMIA ,VITAMIN D deficiency ,METABOLIC syndrome - Abstract
Vitamin D deficiency is a global disorder associated with several chronic illnesses including dyslipidemia and metabolic syndrome. The impact of this association with both dyslipidemia and vitamin D deficiency on metabolomics profile is not yet fully understood. This study analyses the metabolomics and lipidomic signatures in relation to vitamin D status and dyslipidemia. Metabolomics data were collected from Qatar Biobank database and categorized into four groups based on vitamin D and dyslipidemia status. Metabolomics multivariate analysis was performed using the orthogonal partial least square discriminate analysis (OPLS-DA) whilst linear models were used to assess the per-metabolite association with each of the four dyslipidemia/vitamin D combination groups. Our results indicate a high prevalence of vitamin D deficiency among the younger age group, while dyslipidemia was more prominent in the older group. A significant alteration of metabolomics profile was observed among the dyslipidemic and vitamin D deficient individuals in comparison with control groups. These modifications reflected changes in some key pathways including ceramides, diacylglycerols, hemosylceramides, lysophospholipids, phosphatidylcholines, phosphatidylethanol amines, and sphingomyelins. Vitamin D deficiency and dyslipidemia have a deep impact on sphingomyelins profile. The modifications were noted at the level of ceramides and are likely to propagate through downstream pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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35. Selective BET inhibitor RVX-208 ameliorates periodontal inflammation and bone loss.
- Author
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Sun M, Clayton N, Alam S, Asmussen N, Wong A, Kim JH, Luong G, Mokhtari S, Pellei D, Carrico CK, Schwartz Z, Boyan BD, Giannobile WV, Sahingur SE, and Lin Z
- Subjects
- Rats, Humans, Animals, X-Ray Microtomography, Inflammation drug therapy, Osteoclasts, Cytokines, Alveolar Bone Loss drug therapy, Alveolar Bone Loss prevention & control, Alveolar Bone Loss pathology, Periodontitis drug therapy, Periodontitis prevention & control, Periodontitis pathology
- Abstract
Aim: To determine the effects of RVX-208, a selective bromodomain and extra-terminal domain (BET) inhibitor targeting bromodomain 2 (BD2), on periodontal inflammation and bone loss., Materials and Methods: Macrophage-like cells (RAW264.7) and human gingival epithelial cells were challenged by Porphyromonas gingivalis (Pg) with or without RVX-208. Inflammatory gene expression and cytokine production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RAW264.7 cells were induced to osteoclast differentiation. After RVX-208 treatment, osteoclast differentiation was evaluated by histology, tartrate-resistant-acid-phosphatase (TRAP) activity and the expression of osteoclast-specific genes. The effect of RVX-208 on osteoclast transcriptome was studied by RNA sequencing. Periodontitis was induced in rats by ligature and local RVX-208 treatment was administered every other day. Alveolar bone loss was measured by micro-computed tomography., Results: RVX-208 inhibited inflammatory gene expression and cytokine production in Pg-infected cells. Osteoclast differentiation was inhibited by RVX-208, as evidenced by reduced osteoclast number, TRAP activity and osteoclast-specific gene expression. RVX-208 displayed a more selective and less profound suppressive impact on transcriptome compared with pan-BET inhibitor, JQ1. RVX-208 administration prevented the alveolar bone loss in vivo., Conclusions: RVX-208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi-drug' for the prevention of periodontitis., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2023
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36. Expression of the Stem Cell Marker ABCB5 in Normal and Tumor Tissues.
- Author
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SAEED, MOHAMED E. M., BOULOS, JOELLE C., MACHEL, KEVIN, ANDABILI, NASIM, MAROUNI, THAMAIL, ROTH, WILFRIED, and EFFERTH, THOMAS
- Subjects
STEM cells ,PROGENITOR cells ,MELANOCYTES ,MICE ,LIVER cells ,CANCER treatment - Abstract
Background/Aim: The ATP-binding cassette subfamily B member 5 (ABCB5) transporter plays a pivotal role in melanocyte progenitor cell fusion and has been identified as a tumor-initiating cell marker. In this study, we determined ABCB5 expression in normal tissues among various species, i.e., Homo sapiens, Mus musculus (mouse), Rattus norvegicus (rat), Sus scrofa domesticus (pig), Gallus gallus (chicken), Anser anser (goose), Poecilia reticulata (Guppy fish), and Lumbricus terrestris (earthworm), as well as 426 biopsies of different human tumor types (colorectal, cervical, endometrium, vaginal, nasopharyngeal, kidney, breast, colon, prostate, pancreas, lung, gallbladder, bladder, brain, liver, skin, small intestine, testis, tonsil, uterus, thyroid, stomach, esophagus, fallopian, parotid, and ovary). Materials and Methods: Using immunohistochemical staining, ABCB5 expression was detected and evaluated in formalin-fixed, paraffin-embedded sections. Results: High ABCB5 expression was found in normal tissues in specialized cells with secretory and excretory functions, chorionic villi of the placenta, hepatocytes, and blood-tissue barrier sites in the brain and testis. Besides, heterogeneous expression of ABCB5 was also observed in many different tumor types derived from breast, endometrium, ovary, uterus, cervix, prostate, lung, brain, colon, liver, nasopharynx, and others. Conclusion: The localization of ABCB5 in different normal tissues suggests that this protein has an excretory pumping role for physiological metabolites and xenobiotics. This physiological role highlighted its possible impact on the development of multidrug resistance in tumors. Further studies are required to establish the possible clinical significance of ABCB5 as a predictive marker for drug resistance and as a prognostic marker for patient survival. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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37. Role of ABCA1 in Cardiovascular Disease.
- Author
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Wang, Jing, Xiao, Qianqian, Wang, Luyun, Wang, Yan, Wang, Daowen, and Ding, Hu
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ATP-binding cassette transporters ,CARDIOVASCULAR diseases ,HDL cholesterol ,APOLIPOPROTEIN A ,HIGH density lipoproteins ,CORONARY disease - Abstract
Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, ABCA1 facilitates the efflux of excess intracellular cholesterol and phospholipids and controls the rate-limiting step of reverse cholesterol transport. In addition, ABCA1 interacts with the apolipoprotein receptor and suppresses inflammation through a series of signaling pathways. Thus, ABCA1 may prevent cardiovascular disease by inhibiting inflammation and maintaining lipid homeostasis. Several studies have indicated that post-transcriptional modifications play a critical role in the regulation of ABCA1 transportation and plasma membrane localization, which affects its biological function. Meanwhile, carriers of the loss-of-function ABCA1 gene are often accompanied by decreased expression of ABCA1 and an increased risk of cardiovascular diseases. We summarized the ABCA1 transcription regulation mechanism, mutations, post-translational modifications, and their roles in the development of dyslipidemia, atherosclerosis, ischemia/reperfusion, myocardial infarction, and coronary heart disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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38. Functional Characterization of Endothelial Cells Differentiated from Porcine Epiblast Stem Cells.
- Author
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Shin, Joon-Hong, Seo, Bo-Gyeong, Lee, In-Won, Kim, Hyo-Jin, Seo, Eun-Chan, Lee, Kwang-Min, Jeon, Soo-Been, Baek, Sang-Ki, Kim, Tae-Suk, Lee, Jeong-Hyung, Choi, Jung-Woo, Hwangbo, Cheol, and Lee, Joon-Hee
- Subjects
STEM cells ,ENDOTHELIAL cells ,EPIBLAST ,PLURIPOTENT stem cells ,VASCULAR diseases - Abstract
Endothelial cells (ECs), lining blood vessels' lumen, play an essential role in regulating vascular functions. As multifunctional components of vascular structures, pluripotent stem cells (PSCs) are the promising source for potential therapeutic applications in various vascular diseases. Our laboratory has previously established an approach for differentiating porcine epiblast stem cells (pEpiSCs) into ECs, representing an alternative and potentially superior cell source. However, the condition of pEpiSCs-derived ECs growth has yet to be determined, and whether pEpiSCs differentiate into functional ECs remained unclear. Changes in morphology, proliferation and functional endothelial marker were assessed in pEpiSCs-derived ECs in vitro. pEpiSCs-derived ECs were subjected to magnetic-activated cell sorting (MACS) to collect CD-31+ of ECs. We found that sorted ECs showed the highest proliferation rate in differentiation media in primary culture and M199 media in the subculture. Next, sorted ECs were examined for their ability to act as typical vascular ECs through capillary-like structure formation assay, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and three-dimensional spheroid sprouting. Consequently, pEpiSCs-derived ECs function as typical vascular ECs, indicating that pEpiSC-derived ECs might be used to develop cell therapeutics for vascular disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
39. HDL as Bidirectional Lipid Vectors: Time for New Paradigms.
- Author
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Luna-Luna, María, Niesor, Eric, and Pérez-Méndez, Óscar
- Subjects
HDL cholesterol ,HIGH density lipoproteins ,LIPIDS ,LIPOPROTEINS ,CORONARY artery disease - Abstract
The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
40. Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1.
- Author
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Hafiane, Anouar, Gianopoulos, Ioanna, Sorci-Thomas, Mary G., and Daskalopoulou, Stella S.
- Published
- 2022
- Full Text
- View/download PDF
41. ABCA7, a Genetic Risk Factor Associated with Alzheimer's Disease Risk in African Americans.
- Author
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Stepler, Kaitlyn E., Gillyard, Taneisha R., Reed, Calla B., Avery, Tyra M., Davis, Jamaine S., and Robinson, Renã A.S.
- Subjects
DISEASE risk factors ,APOLIPOPROTEIN E ,AFRICAN Americans ,PHAGOCYTOSIS ,ATP-binding cassette transporters ,MEMBRANE proteins ,ALZHEIMER'S disease ,RESEARCH funding ,PEPTIDES ,CARRIER proteins - Abstract
African American/Black adults are twice as likely to have Alzheimer's disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and 'omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
42. Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease.
- Author
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Furtado, Jeremy D., Ruotolo, Giacomo, Nicholls, Stephen J., Dullea, Robert, Carvajal-Gonzalez, Santos, and Sacks, Frank M.
- Published
- 2022
- Full Text
- View/download PDF
43. Anti-inflammatory HDL effects are impaired in atrial fibrillation.
- Author
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Holzwirth, Erik, Fischer-Schaepmann, Tina, Obradovic, Danilo, von Lucadou, Mirjam, Schwedhelm, Edzard, Daum, Günter, Hindricks, Gerhard, Marsche, Gunther, Trieb, Markus, Thiele, Holger, Kornej, Jelena, and Büttner, Petra
- Subjects
MYOCARDIAL depressants ,ATRIAL fibrillation ,CD54 antigen ,ANGIOTENSIN converting enzyme ,CELL adhesion molecules ,ACE inhibitors - Abstract
High-density lipoprotein (HDL), best known for cholesterol transport, also has anti-inflammatory effects. Previous studies suggest involvement of myeloperoxidase (MPO) in modification of HDL. HDL bound Sphingosine-1-phosphate (S1P) has been implied to be an essential protein regarding beneficial HDL effects. In this study, we analyzed anti-inflammatory HDL properties in patients with atrial fibrillation (AF), a disease involving atrial inflammation, compared to non-AF controls and whether anti-inflammatory properties improve upon catheter ablation. Additionally, association with serum concentrations of MPO and S1P were assessed. We isolated HDL from 25 AF patients, 13 non-AF individuals and 14 AF patients at follow-up (FU) after catheter ablation. S1P was measured in a cohort of 141 AF and 21 FU patients. Following preincubation with HDL from either group, bovine aortic endothelial cells were stimulated using tumor necrosis factor α and expression of pro-inflammatory genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE) and P-selectin (SELP) was assessed using qPCR. Concentrations of circulating protein of these genes as well as MPO and S1P were measured in serum samples. Compared to non-AF individuals HDL from AF patients suppressed gene expression of the pro-inflammatory adhesion molecules ICAM1, VCAM1, SELE and SELP 27%, 18%, 21% and 57% less, respectively (p < 0.05 for all except SELE p = 0.06). In FU patients, the anti-inflammatory HDL activity was improved (suppression of ICAM1 + 22%, VCAM1 + 10%, SELE + 38% and SELP + 75%, p < 0.05 for all except VCAM1 p = 0.08). AF patients using angiotensin converting enzyme inhibitors or angiotensin receptor blockers had better anti-inflammatory HDL properties than non-users (gene expression suppression at least 28% more, p < 0.05 for all except ICAM1 p = 0.051). Circulating protein concentrations were not correlated with in vitro gene-expression, but circulating P-selectin was generally elevated in AF and FU patients compared to non-AF patients. MPO plasma concentration was positively associated with gene-expression of ICAM1, VCAM1 and SELP (r
2 > 0.4, p < 0.05). Serum concentrations of S1P were increased in FU patients {1.201 µM [1.077–1.543]} compared to AF patients {0.953 µM [0.807–1.135], p < 0.01} but not correlated with ICAM1, VCAM1 and SELP gene expression. We conclude that the anti-inflammatory activity of HDL is impaired in AF patients, which might promote AF progression and AF-associated complications. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
44. Identification and development of a novel 5-gene diagnostic model based on immune infiltration analysis of osteoarthritis.
- Author
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Han, YaGuang, Wu, Jun, Gong, ZhenYu, Zhou, YiQin, Li, HaoBo, Wang, Bo, and Qian, QiRong
- Subjects
CARTILAGE ,HUMORAL immunity ,GENE regulatory networks ,SUPPORT vector machines ,ARTICULAR cartilage ,OSTEOARTHRITIS - Abstract
Background: Osteoarthritis (OA), which is due to the progressive loss and degeneration of articular cartilage, is the leading cause of disability worldwide. Therefore, it is of great significance to explore OA biomarkers for the prevention, diagnosis, and treatment of OA.Methods and Materials: The GSE129147, GSE57218, GSE51588, GSE117999, and GSE98918 datasets with normal and OA samples were downloaded from the Gene Expression Omnibus (GEO) database. The GSE117999 and GSE98918 datasets were integrated, and immune infiltration was evaluated. The differentially expressed genes (DEGs) were analyzed using the limma package in R, and weighted gene co-expression network analysis (WGCNA) was used to explore the co-expression genes and co-expression modules. The co-expression module genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and hub genes were identified by the degree, MNC, closeness, and MCC algorithms. The hub genes were used to construct a diagnostic model based on support vector machines.Results: The Immune Score in the OA samples was significantly higher than in the normal samples, and a total of 2313 DEGs were identified. Through WGCNA, we found that the yellow module was significantly positively correlated with the OA samples and Immune Score and negatively correlated with the normal samples. The 142 DEGs of the yellow module were related to biological processes such as regulation of inflammatory response, positive regulation of inflammatory response, blood vessel morphogenesis, endothelial cell migration, and humoral immune response. The intersections of the genes obtained by the 4 algorithms resulted in 5 final hub genes, and the diagnostic model constructed with these 5 genes showed good performance in the training and validation cohorts.Conclusions: The 5-gene diagnostic model can be used to diagnose OA and guide clinical decision-making. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
45. Association between the ABCA1 (R219K) polymorphism and lipid profiles: a meta-analysis.
- Author
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Shi, Zhangyan, Tian, Yajie, Zhao, Ze, Wu, Yufei, Hu, Xiuxia, Li, Junlin, Chen, Qianliang, Wang, Yan, An, Caiyan, and Zhang, Kejin
- Subjects
HDL cholesterol ,LDL cholesterol ,GENETIC models ,LIPIDS ,ATP-binding cassette transporters - Abstract
Conflicting evidence was found about the relationship between lipid profiles and R219K polymorphism in adenosine triphosphate-binding cassette exporter A1 (ABCA1) gene. In this study, four meta-analyses were conducted to assess the effect of R219K on lipid levels, including high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, total cholesterol, and triglycerides (TG). A total of 125 samples of 87 studies (about 60,262 subjects) were included. The effect of each study was expressed using the standard mean difference (SMD) and 95% confidence interval (95% CI) and pooled by meta-analysis in the random-effects model. Subgroup and meta-regression analyses were conducted to explore potential heterogeneity sources. The overall pooled effect showed the following results. (1) The R219K was significantly associated with HDLC level (SMD = − 0.25 mmol/L, 95%CI − 0.32 to − 0.18, z = − 6.96, P < 0.01, recessive genetic model). People with different genotypes had significantly different HDLC levels under the recessive, codominant and dominant genetic models (all Ps < 0.01). (2) A weak and indeterminate relationship between R219K and TG level was observed (SMD = 0.18 mmol/L, 95%CI 0.06–0.30, z = 3.01, P < 0.01, recessive genetic model). These findings suggested that R219K was associated with HDLC and TG levels, which might implicate a promising clinical application for lipid-related disorders, though the influences of race, health status, BMI, and other heterogeneity sources should be considered when interpreting current findings. The protocol was registered at PROSPERO (registration number: CRD42021231178). [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
46. Reverse Cholesterol Transport Pathway and Cholesterol Efflux in Diabetic Retinopathy.
- Author
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Zhang, Xinyuan, Wang, Kaiyue, Zhu, Ling, and Wang, Qiyun
- Subjects
DIABETIC retinopathy ,CHOLESTEROL ,CHOLESTEROL metabolism ,BLOOD lipoproteins ,DRUG target ,ATP-binding cassette transporters - Abstract
Cholesterol esters, synthesized from cholesterol with long-chain fatty acids, are essential components of plasma lipoproteins and cell membranes that participate in various metabolic processes in the body. Cholesterol can be excreted through the cholesterol reverse transport (RCT) pathway when excessive cholesterol is produced in the extrahepatic cells, which is regulated by the liver X receptor (LXR) and its downstream regulators ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1) genes. Abnormal cholesterol metabolism is closely associated with the development of diabetic retinopathy (DR). However, the precise underlying mechanism of the RCT pathway in the pathogenesis of DR is still not fully understood. This review focused on cholesterol metabolism, with a particular emphasis on the RCT pathway and its correlation with the development of DR. Particular attention has been paid to the key regulators of the RCT pathway: LXR, ABCA1, and ABCG1 genes and their potential therapeutic targets in the management of DR. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
47. Cholesterol Regulates Exosome Release in Cultured Astrocytes.
- Author
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Abdullah, Mohammad, Nakamura, Tomohisa, Ferdous, Taslima, Gao, Yuan, Chen, Yuxin, Zou, Kun, and Michikawa, Makoto
- Subjects
EXOSOMES ,ASTROCYTES ,CHOLESTEROL ,PI3K/AKT pathway ,WESTERN diet ,CELL anatomy - Abstract
Exosomes are vesicles secreted by various kinds of cells, and they are rich in cholesterol, sphingomyelin (SM), phosphatidylcholine, and phosphatidylserine. Although cellular sphingolipid-mediated exosome release has been reported, the involvement of other lipid components of cell membranes in the regulation of exosome release is poorly understood. Here, we show that the level of exosome release into conditioned media is significantly reduced in cultured astrocytes prepared from apolipoprotein E (ApoE) knock-out mice when compared to those prepared from wild-type (WT) mice. The reduced level of exosome release was accompanied by elevated levels of cellular cholesterol. The addition of cholesterol to WT astrocytes significantly increased the cellular cholesterol levels and reduced exosome release. PI3K/Akt phosphorylation was enhanced in ApoE-deficient and cholesterol-treated WT astrocytes. In contrast, the depletion of cholesterol in ApoE-deficient astrocytes due to treatment with β-cyclodextrin recovered the exosome release level to a level similar to that in WT astrocytes. In addition, the reduced levels of exosome release due to the addition of cholesterol recovered to the control levels after treatment with a PI3K inhibitor (LY294002). The cholesterol-dependent regulation of exosome release was also confirmed by in vivo experiments; that is, exosome levels were significantly reduced in the CSF and blood serum of WT mice that were fed a high-fat diet and had increased cholesterol levels when compared to those in WT mice that were fed a normal diet. These results suggest that exosome release is regulated by cellular cholesterol via stimulation of the PI3K/Akt signal pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
48. LilrB3 is a putative cell surface receptor of APOE4.
- Author
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Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, and Shi Y
- Subjects
- Humans, Apolipoprotein E2, Apolipoprotein E3, Protein Isoforms metabolism, Antigens, CD, Apolipoprotein E4 genetics, Receptors, Immunologic
- Abstract
The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms., (© 2022. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)
- Published
- 2023
- Full Text
- View/download PDF
49. Gel-Based Proteomic Identification of Suprabasin as a Potential New Candidate Biomarker in Endometrial Cancer.
- Author
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Celsi, Fulvio, Monasta, Lorenzo, Arrigoni, Giorgio, Battisti, Ilaria, Licastro, Danilo, Aloisio, Michelangelo, Di Lorenzo, Giovanni, Romano, Federico, Ricci, Giuseppe, and Ura, Blendi
- Subjects
ENDOMETRIAL cancer ,BIOMARKERS ,PROTEOMICS ,WESTERN immunoblotting ,ONCOGENES ,BLOOD proteins ,BLOOD serum analysis - Abstract
Endometrial cancer (EC) is the most frequent gynaecologic cancer in postmenopausal women. We used 2D-DIGE and mass spectrometry to identify candidate biomarkers in endometrial cancer, analysing the serum protein contents of 10 patients versus 10 control subjects. Using gel-based proteomics, we identified 24 candidate biomarkers, considering only spots with a fold change in volume percentage ≥ 1.5 or intensity change ≤ 0.6, which were significantly different between cases and controls (p < 0.05). We used Western blotting analysis both in the serum and tissue of 43 patients for data validation. Among the identified proteins, we selected Suprabasin (SBSN), an oncogene previously associated with poor prognosis in different cancers. SBSN principal isoforms were subjected to Western blotting analysis in serum and surgery-excised tissue: both isoforms were downregulated in the tissue. However, in serum, isoform 1 was upregulated, while isoform 2 was downregulated. Data-mining on the TCGA and GTEx projects, using the GEPIA2.0 interface, indicated a diminished SBSN expression in the Uterine Corpus Endometrial Cancer (UCEC) database compared to normal tissue, confirming proteomic results. These results suggest that SBSN, specifically isoform 2, in tissue or serum, could be a potential novel biomarker in endometrial cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
50. Homo Sapiens (Hsa)-microRNA (miR)-6727-5p Contributes to the Impact of High-Density Lipoproteins on Fibroblast Wound Healing In Vitro.
- Author
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Bastaki, Khaled Mahmoud, Tarlton, Jamie Maurice Roy, Lightbody, Richard James, Graham, Annette, and Martin, Patricia Esther
- Published
- 2022
- Full Text
- View/download PDF
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