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Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid arthritis: a systematic review and network meta-analysis.
Li, N, Gou, ZP, Du, SQ, Zhu, XH, Lin, H, Liang, XF, Wang, YS, Feng, P
Clinical rheumatology. 2022;(3):677-688
Abstract
OBJECTIVES Janus kinase (JAK) inhibitors are a new class of medication for treatment of rheumatoid arthritis (RA), and such inhibitors alter levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in RA patients. However, the extent of such changes has not been systematically reviewed. METHOD A systematic review and network meta-analysis was performed on randomized trials in RA patients in response to JAKi identified from Pubmed, Medline, Embase, and Cochrane Controlled Trials Register. The primary outcome was mean change of HDL-C and LDL-C from baseline. Mean treatment differences and the rank of the effect of various JAKi on HDL-C and LDL-C were estimated. RESULTS Based on data from 18 unique studies involving five approved JAK inhibitors and 6697 RA patients (JAKi = 3341, placebo = 3356), such inhibitors led to a mean increase of 8.11 mg/dl (95% CI 6.65-9.58, I2 = 82%) in HDL levels from baseline, and a mean increase of 11.37 mg/dl (95% CI 7.84-14.91, I2 = 88%) in LDL levels from baseline. Cardiovascular disease risk did not differ significantly between patients who received JAK inhibitors or those who received placebo or active agents. CONCLUSIONS Our analysis suggests that, at their recommended doses, all five JAK inhibitors lead to an increase in HDL and LDL levels in RA patients. Further long-term research is required to extend these results and understand whether changes in lipid levels in RA patients can affect cardiovascular risk. Key Points • This is the first systematic review and NMA examining the effect of all five clinically approved JAK inhibitors on lipid levels in RA patients. • Recommended doses of JAK inhibitors used for the treatment of RA patients can induce a significant increase in HDL and LDL levels. • Indirect pairwise comparisons suggest that only upadacitinib and peficitinib have significantly different ability to induce LDL change in RA patients.
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Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.
Muso, E, Sakai, S, Ogura, Y, Yukawa, S, Nishizawa, Y, Yorioka, N, Saito, T, Mune, M, Sugiyama, S, Iino, Y, et al
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2022;(1):220-228
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Abstract
Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .
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LDL particle size and antioxidant HDL function improve after sustained virological response in patients with chronic HCV.
Vargas, JI, Rivera, K, Arrese, M, Benitez, C, Barrera, F, Hugo, M, Arab, JP, Pino, K, Barrera, A, Lopez-Lastra, M, et al
Annals of hepatology. 2022;(1):100555
Abstract
HCV infection is associated with an increased incidence of cardiovascular (CV) events. Mechanisms underlying this association remain unknown. In our study, twenty HCV patients (median age 60.5 years, 65% male and 80% with cirrhosis) were evaluated prior, during and after direct-acting antiviral treatment. Ninety percent of patients achieved sustained virological response (SVR). Significant changes were observed in LDL particle size index, measured by LDL-C/apoB ratio, which increased after treatment (p = 0.023). In addition, HDL antioxidant capacity improved gradually from 34.4% at baseline to 42.4% at 4 weeks (p = 0.011), 65.9% at end of treatment EOT (p = 0.002) and remained elevated at 12-week (p = 0.001) after EOT compared to baseline values. Our findings suggest that a shift to a less atherogenic lipid profile may be a possible mechanism associated with CV risk reduction in patients with HCV infection achieving SVR.
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The Beneficial Effects of Astaxanthin on Glucose Metabolism and Modified Low-Density Lipoprotein in Healthy Volunteers and Subjects with Prediabetes.
Urakaze, M, Kobashi, C, Satou, Y, Shigeta, K, Toshima, M, Takagi, M, Takahashi, J, Nishida, H
Nutrients. 2021;(12)
Abstract
UNLABELLED Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. METHODS We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. RESULTS After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. CONCLUSIONS our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.
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Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation.
Zhang, B, Hao, Z, Zhou, W, Zhang, S, Sun, M, Li, H, Hou, N, Jing, C, Zhao, M
Bioengineered. 2021;(1):4887-4898
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Abstract
Formononetin (FMNT), a flavonoid identified from the Chinese herb Astragalus membranaceus, possesses anti-inflammatory or anti-oxidative properties in different human diseases. This study aims to comprehensively elucidate the function of FMNT in atherosclerosis and its underlying mechanisms. Online public databases were used to identify the drug-disease targets. Protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were applied to explore the potential targets and signaling pathways involved in FMNT against atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (ox-LDL) to construct an atherosclerosis cell model in vitro. Endothelial cell function was assessed via examining cell proliferation, inflammatory factors, oxidative markers, reactive oxygen species (ROS), and apoptosis. Western blot was performed to detect the expression of cyclooxygenase-2 (COX-2), endothelial nitric oxide synthase (eNOS), cleaved caspase-3, and peroxisome proliferator-activated receptor-γ (PPAR-γ). A total of 39 overlapping target genes of FMNT and atherosclerosis were identified. Through the PPI network analysis, 14 hub genes were screened and found to be closely relevant to inflammation, oxidative stress, and apoptosis. Results of KEGG pathway assays indicated that lots of targets were enriched in PPAR signaling. Functionally, FMNT could protect against ox-LDL-induced inflammatory reaction, oxidative stress, and apoptosis in HUVECs. Moreover, FMNT attenuated ox-LDL-mediated inactivation of PPAR-γ signaling. GW9662, a PPAR-γ antagonist, reversed the inhibitory effect of FMNT on ox-LDL-induced endothelial injury. In conclusion, FMNT alleviates ox-LDL-induced endothelial injury in HUVECs by stimulating PPAR-γ signaling, providing a theoretical basis for employing FMNT as a potential drug to combat atherosclerosis.Abbreviations: FMNT formononetin; PPI: protein-protein interaction; GO: Gene Ontology; KEGG Kyoto Encyclopedia of Genes and Genomes; HUVECs: human umbilical vein endothelial cells; ox-LDL: oxidized low-density lipoprotein; COX-2: cyclooxygenase-2; eNOS: endothelial nitric oxide synthase; PPAR-γ: peroxisome proliferator-activated receptor-γ; CVD: cardiovascular disease; TCM: traditional Chinese medicines; OGDR oxygen-glucose deprivation/reoxygenation; ROS: reactive oxygen species; FBS: fetal bovine serum; CCK-8: cell counting kit-8; EdU: 5-Ethynyl-2'-deoxyuridine; SOD: antioxidant enzymes superoxide dismutase; MDA: malondialdehyde; DCFH-DA: 2',7'-dichlorofluorescein-diacetate; PVDF polyvinylidene fluoride; ANOVA one-way analysis of variance; PPARs: peroxisome proliferation-activated receptors.
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Regulation of Apolipoprotein A-I Gene Expression in Human Macrophages by Oxidized Low-Density Lipoprotein.
Nekrasova, EV, Larionova, EE, Danko, K, Kuzmina, DO, Shavva, VS, Kudriavtsev, IV, Orlov, SV
Biochemistry. Biokhimiia. 2021;(10):1201-1213
Abstract
Apolipoprotein A-I (ApoA-I) is a key component of reverse cholesterol transport in humans. In the previous studies, we demonstrated expression of the apoA-I gene in human monocytes and macrophages; however, little is known on the regulation of the apoA-I expression in macrophages during the uptake of modified low-density lipoprotein (LDL), which is one of the key processes in the early stages of atherogenesis leading to formation of foam cells. Here, we demonstrate a complex nature of the apoA-I regulation in human macrophages during the uptake of oxidized LDL (oxLDL). Incubation of macrophages with oxLDL induced expression of the apoA-I gene within the first 24 hours, but suppressed it after 48 h. Both effects depended on the interaction of oxLDL with the TLR4 receptor, rather than on the oxLDL uptake by the macrophages. The oxLDL-mediated downregulation of the apoA-I gene depended on the ERK1/2 and JNK cascades, as well as on the NF-κB cascade.
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The effect of vitamin D supplementation on flow-mediated dilatation, oxidized LDL and intracellular adhesion molecule 1 on type 2 diabetic patients with hypertension: A randomized, placebo-controlled, double-blind trial.
Qasemi, R, Ghavamzadeh, S, Faghfouri, AH, Valizadeh, N, Mohammadi, A, Sayyadi, H
Diabetes & metabolic syndrome. 2021;(4):102200
Abstract
AIMS: Current study aimed to evaluate the effect of vitamin D supplementation on flow-mediated dilatation (FMD), oxidized LDL (oxLDL) and intracellular adhesion molecule 1 (ICAM1) in type 2 diabetic patients with hypertension. METHODS In a double-blinded, placebo-controlled trial, 44 patients were randomly divided into vitamin D group (2000 IU/d, n = 23) and placebo group (control, n = 21) for 12 weeks. Vascular function with FMD, Serum 25-OH vitamin D, oxLDL and ICAM1 were assessed at the baseline and after the intervention. This clinical trial was registered at Iranian Registry of Clinical Trials (IRCT20191223045861N1). RESULTS In intervention group serum level of vitamin D increased from 32.42 ± 10.56 to 40.45 ± 12.94 (p < 0.001). In the vitamin D group, oxLDL and ICAM1 significantly decreased and FMD increased significantly in both groups (p < 0.001). The level of oxLDL (p = 0.017) and ICAM1 (p < 0.001) were significantly lower in the vitamin D group than the placebo group and FMD (p < 0.001) was significantly higher in the vitamin D group. CONCLUSIONS Vitamin D supplementation of 2000 IU/d for 12 weeks can improve endothelial function and decrease ICAM1 and oxLDL in type 2 diabetic patients with hypertension.
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Natural products: The role and mechanism in low-density lipoprotein oxidation and atherosclerosis.
Zhang, S, Li, L, Chen, W, Xu, S, Feng, X, Zhang, L
Phytotherapy research : PTR. 2021;(6):2945-2967
Abstract
Atherosclerosis is a chronic inflammatory, metabolic, and epigenetic disease, which leads to the life-threatening coronary artery disease. Emerging studies from bench to bedside have demonstrated the pivotal role of low-density lipoprotein (LDL) oxidation in the initiation and progression of atherosclerosis. This article hereby reviews oxidation mechanism of LDL, and the pro-atherogenic and biomarker role of oxidized LDL in atherosclerosis. We also review the pharmacological effects of several representative natural products (vitamin E, resveratrol, quercetin, probucol, tanshinone IIA, epigallocatechin gallate, and Lycopene) in protecting against LDL oxidation and atherosclerosis. Clinical and basic research supports the beneficial effects of these natural products in inhibiting LDL oxidation and preventing atherosclerosis, but the data are still controversial. This may be related to factors such as the population and the dosage and time of taking natural products involved in different studies. Understanding the mechanism of LDL oxidation and effect of oxidized LDL help researchers to find novel therapies against atherosclerosis.
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Umbrella Review on Non-Statin Lipid-Lowering Therapy.
Beshir, SA, Hussain, N, Elnor, AA, Said, ASA
Journal of cardiovascular pharmacology and therapeutics. 2021;(5):437-452
Abstract
OBJECTIVES The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. METHODS AND MATERIALS Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. RESULTS AND DISCUSSION In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. CONCLUSION Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.
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The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Jamialahmadi, T, Baratzadeh, F, Reiner, Ž, Simental-Mendía, LE, Xu, S, Susekov, AV, Santos, RD, Sahebkar, A
Mediators of inflammation. 2021;:9661752
Abstract
BACKGROUND Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes. OBJECTIVE The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL. METHODS PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias. RESULTS Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, p < 0.001; I 2: 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, p = 0.206; I 2: 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, p = 0.004; I 2: 0%). CONCLUSION High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.