scholarly journals Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259353
Author(s):  
Rhogerry Deshycka ◽  
Valentino Sudaryo ◽  
Nai-Jia Huang ◽  
Yushu Xie ◽  
Liyan Y. Smeding ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chimeric Protein ◽  
Mouse Bone Marrow ◽  
Glycophorin A ◽  
Low Density ◽  
Hematopoietic Stem

Low plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor–related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi—based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high-cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N- terminus of red blood cells (RBCs) specific glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced RBCs with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA- GPA mice remained lean for life and maintained normal body weight under a high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA—glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.

scholarly journals Engineered Red Blood Cells Carrying PCSK9 Inhibitors Persistently Lower LDL and Prevent Obesity

2020 ◽  
Author(s):  
Rhogerry Deshycka ◽  
Valentino Sudaryo ◽  
Nai-Jia Huang ◽  
Yushu Xie ◽  
Liyan Y. Smeding ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chimeric Protein ◽  
Mouse Bone Marrow ◽  
Glycophorin A ◽  
Low Density ◽  
Hematopoietic Stem

AbstractLow plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor–related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi - based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N-terminus of glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced red blood cells (RBCs) with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA-GPA mice remained lean for life and maintained normal body weight under high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA - glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.

scholarly journals Effect of moringa leaf meal and season on blood and hormonal profile of the pearl guinea fowl (Numida meleagris)

2021 ◽  
Vol 11 (3) ◽  
pp. 078-092
Author(s):  
Poku Jnr PA ◽  
Kagya-Agyemang JK ◽  
Kwenin WKJ ◽  
Bonsu FRK ◽  
Kyere CG
Keyword(s):  
High Density Lipoprotein ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Rainy Season ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Hormonal Profile ◽  
Leaf Meal ◽  
Numida Meleagris

This study was undertaken to determine the effect of moringa leaf meal and season on blood and hormonal profile of the Pearl Guinea fowl (Numida meleagris) in the Middle belt of Ghana. Thirty-two (32) males and one hundred and twenty-eight (128) female Pearl Guinea fowls aged one-day-old were used for the study. A 3 x 4 factorial experimental design was used for the experiment. Data collected were analyzed using General Linear Model (GLM) procedure of Statistical Analysis System (SAS for Windows, version 7) and means were separated by the probability of difference (PDIFF) procedure of SAS (2008). Mean cell volume was highest (175.39 fl) among Guinea fowls fed with diet containing 12 % moringa leaf meal level. Guinea fowls fed with diet containing 15 % moringa leaf meal had the highest (3.44 x1012/L) red blood cells production. Eosinophil level was highest (3.95 x1012/L) among Guinea fowls fed with diet containing 9 % moringa leaf meal. Birds fed with the moringa diets recorded the highest (P= 0.022) WBC values as compared to the control diet. Triglycerides, high density lipoprotein and low-density lipoprotein levels increased (P<0.05) with increasing levels of dietary moringa leaf meal in the diet. The highest (P= 0.0025) level of progesterone was observed among birds fed with diet containing 12 and 15 % moringa leaf meal inclusion levels. The level of sodium was highest (166.69 nmol/l) among Guinea fowls fed with diet containing 12 % moringa leaf meal. The major and minor rainy seasons recorded the highest (P<0.05) mean cell hemoglobin, red blood cells, albumin and oestrogen levels. Platelets, follicle stimulating hormone, luteinizing hormone, prolactin and chlorine levels were highest (P<0.05) in the dry season while basophil level was highest in the major rainy season. Cholesterol, triglycerides, high density lipoprotein, low density lipoprotein and potassium levels were highest (P<0.05) in the major rainy season. This study concludes that feeding Guinea fowls with moringa leaf meal had positive effect on some haematological, biochemical and hormonal parameters.

scholarly journals Long-term fasting improves lipoprotein-associated atherogenic risk in humans

2021 ◽  
Author(s):  
Franziska Grundler ◽  
Dietmar Plonné ◽  
Robin Mesnage ◽  
Diethard Müller ◽  
Cesare R. Sirtori ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Apolipoprotein A1 ◽  
Health Concern ◽  
Low Density ◽  
Lipoprotein Subclasses ◽  
Ldl Particles ◽  
Increased Risk

Abstract Purpose Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition. Methods This observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days. Results The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged. Conclusion Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia. Trial Registration Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

Oxidized low-density lipoprotein induces hematopoietic stem cell senescence

2013 ◽  
Vol 37 (9) ◽  
pp. 940-948 ◽  
Author(s):  
Xian-Ping Zhang ◽  
Gui-Hai Zhang ◽  
Yu-Ying Wang ◽  
Jun Liu ◽  
Qiang Wei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cell Senescence ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Hematopoietic Stem

Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades

2013 ◽  
Vol 24 (3) ◽  
pp. 437-441 ◽  
Author(s):  
Avishay Elis ◽  
Rong Zhou ◽  
Evan A. Stein
Keyword(s):  
Children And Adolescents ◽  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Cholesterol Levels ◽  
Heterozygous Familial Hypercholesterolaemia

AbstractBackground:This study evaluated the effectiveness of long-term intensive lipid-lowering therapy in children and adolescents with familial hypercholesterolaemia.Methods:The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ∼1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia.Results:Of the 89 patients, 51% were male; the mean age at diagnosis was 8 ± 4 years, and the mean follow-up was 13 ± 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 ± 50 and 142 ± 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation.Conclusions:Long-term statin-based therapy can reduce low-density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly.

scholarly journals Long-term prognostic utility of low-density lipoprotein (LDL) triglyceride in real-world patients with coronary artery disease and diabetes or prediabetes

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Jing-Lu Jin ◽  
Hui-Wen Zhang ◽  
Ye-Xuan Cao ◽  
Hui-Hui Liu ◽  
Qi Hua ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Real World ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
C Statistic ◽  
Prognostic Utility ◽  
Artery Disease ◽  
Stable Cad

Abstract Background Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status. Methods A total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs. Results During a median of 5.1 (interquartile range 3.9 to 5.9) years’ follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149–2.955), 1.828 (1.165–2.867), 2.212 (1.396–3.507), all p < 0.05]. Moreover, adding LDL-TG into the original model increased the C-statistic from 0.687 to 0.704 (∆C-statistic = 0.016, p = 0.028) and from 0.734 to 0.749 (∆C-statistic = 0.014, p = 0.002) in Pre-DM and DM, respectively. Conclusions In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

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