DOI•
Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia.
16 Nov 2021-Vol. 2, Iss: 11, pp 100446
TL;DR: In this paper, three epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in Cg-Lepob/J (ob/ob) mice.
Abstract: Summary Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lepob/J (ob/ob) mice. Vaccination with the E3 (32EPKSRFAMLD41) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoeshl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.
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TL;DR: In this paper , the development of vaccines in broad fields ranging from conventional prophylactic vaccines against infectious diseases to therapeutic vaccines against chronic diseases and cancer providing a comprehensive overview of recent advances in eight different vaccine forms.
Abstract: Vaccines are essential public health tools and play an important role in reducing the burden of infectious diseases in the population. Emerging infectious diseases and outbreaks pose new challenges for vaccine development, requiring the rapid design and production of safe and effective vaccines against diseases with limited resources. Here, we focus on the development of vaccines in broad fields ranging from conventional prophylactic vaccines against infectious diseases to therapeutic vaccines against chronic diseases and cancer providing a comprehensive overview of recent advances in eight different vaccine forms (live attenuated vaccines, inactivated vaccines, polysaccharide and polysaccharide conjugate vaccines, recombinant subunit vaccines, virus-like particle and nanoparticle vaccines, polypeptide vaccines, DNA vaccines, and mRNA vaccines) and the therapeutic vaccines against five solid tumors (lung cancer breast cancer colorectal cancer liver cancer and gastric cancer), three infectious diseases (human immunodeficiency virus, hepatitis B virus and human papillomavirus-induced diseases) and three common chronic diseases (hypertension, diabetes mellitus and dyslipidemia). We aim to provide new insights into vaccine technologies, platforms, applications and understanding of potential next-generation preventive and therapeutic vaccine technologies paving the way for the vaccines design in the future.
5 citations
TL;DR: In this article , the angiopoietin-like-3 (ANGPTL3) inhibitors were used to target LDL-C and triglyceride-rich lipoproteins.
Abstract: Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors. ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid–based therapies will shape the future of the lipid arena. ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction.
5 citations
TL;DR: A review of the development of anti-ANGPTL3 anti-drugs can be found in this article , which highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.
3 citations
TL;DR: The potential of traditional and emerging lipid-lowering approaches for cardiovascular prevention by targeting small dense LDL particles (sdLDL) seem to have the most significant potential for therapeutic modulation.
Abstract: Compelling evidence supports the causative link between increased levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (CVD) development. For that reason, the principal aim of primary and secondary cardiovascular prevention is to reach and sustain recommended LDL-C goals. Although there is a considerable body of evidence that shows that lowering LDL-C levels is directly associated with CVD risk reduction, recent data shows that the majority of patients across Europe cannot achieve their LDL-C targets. In attempting to address this matter, a new overarching concept of a lipid-lowering approach, comprising of even more intensive, much earlier and longer intervention to reduce LDL-C level, was recently proposed for high-risk patients. Another important concern is the residual risk for recurrent cardiovascular events despite optimal LDL-C reduction, suggesting that novel lipid biomarkers should also be considered as potential therapeutic targets. Among them, small dense LDL particles (sdLDL) seem to have the most significant potential for therapeutic modulation. This paper discusses the potential of traditional and emerging lipid-lowering approaches for cardiovascular prevention by targeting sdLDL particles.
2 citations
TL;DR: In this paper , the role and responsibility of natural resistance factors, protein and lipid metabolism in the formation of piglets post-vaccination immunity against circovirus is researched, and it was revealed that before vaccination, 31.46% of the studied samples have a positive reaction in ELISA; their number increases to 67.80-71.16% on the 40th and 70th days after vaccination.
Abstract: The role and responsibility of natural resistance factors, protein and lipid metabolism in the formation of piglets post-vaccination immunity against circovirus is researched. Blood was taken for tests before and on the 15th, 40th and 70th day after the vaccination. The sampled blood was analyzed to determine immunological and biochemical parameters. It was revealed that before vaccination, 31.46% of the studied samples have a positive reaction in ELISA; their number increases to 67.80–71.16% on the 40th and 70th days after vaccination.In the blood of piglets, especially on the 40th and 70th day after the vaccination, the total count of leukocytes, monocytes and lymphocytes increases by 1.21; 2.28 times and 1.48 times, but neutrophils reduced by 1.74 times along with the phagocytic properties activation. The anabolic directivity of protein metabolism is defined by the synthesis of globulin proteins. At the same time albumin-synthesizing activity in a liver decreased and “cytolysis reaction” of hepatocytes was detected. In the lipid profile of piglets’ blood, the content of LDL‑cholesterol increased by 1.44 times, while that of triglycerides decreased by 2.64 times. X‑ray spectral analysis revealed the correlation between the formation of post-vaccination immunity and two factors: the factor of the principal component (PC) 1, which is predominantly associated with indicators of natural resistance, and PC2, which is associated with metabolism indicators. The research results show that in order to increase the efficiency of formation of post-vaccination immunity in piglets, it is necessary to combine vaccination with hepatoprotective drugs.
1 citations
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TL;DR: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth.
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TL;DR: In this trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events.
Abstract: BackgroundEvolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. MethodsWe conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. ResultsAt 48 weeks, the ...
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