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Cholesterol Analogs and Vitamin-Conjugated Ionizable Lipids Enhance Lipid Nanoparticle Delivery for In Vitro and In Vivo Applications.

LNP-mediated mRNA delivery encounters challenges with insufficient efficacy, poor safety, and unstable performance. Moreover, the distinct r … bility for in vitro use only. For the in vivo-oriented strategy, eight vitamin-conjugated ionizable lipids were synthesized. Six of these lipids were selected for animal screening, and two exhibited higher in vivo protein expression levels compared with the commercial LNP control. Accelerated stability studies demonstrated that LNPs containing these vita …

Impact of ionizable lipid type on the pharmacokinetics and biodistribution of mRNA-lipid nanoparticles after intravenous and subcutaneous injection.

Ionizable lipids play a crucial role in mRNA-lipid nanoparticle (LNP) formulations by facilitating mRNA encapsulation, promoting cell uptake, and enhancing endosomal escape of mRNA-LNPs. Despite their importance in mRNA delivery, the specific effects of ionizable lipids on mRNA-LNP in vivo pharmacokinetics (PK) and biodistribution remain underexplored. This study examines the effect of SM-102, ALC-0315, DLin-MC3-DMA (MC3), and 113-O12B ionizable lipids in mRNA-LNP formulations on plasma PK of lipid and mRNA, and biodistribution of expressed protein following subcutaneous (SC) and intravenous (…

mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.

The mechanistic target of rapamycin (mTOR) is a key regulator of lipid homeostasis by controlling processes including lipid uptake and biosynthesis. mTOR dysregulation and consequent altered lipid metabolism are common in various diseases, including cancers, making mTOR a promising therapeutic target. Therefore, it is crucial to understand how mTOR activation and inhibition reprogram lipid homeostasis. In human cancer cell lines, mTOR inhibition induces alternative lipid uptake through translation eukaryotic initiation factor 3D (eIF3D)-mediated low-density lipoprotein receptor (LDLR)-related

Naringenin cationic lipid-modified nanoparticles mitigate MASLD progression by modulating lipid homeostasis and gut microbiota.

Naringenin (NAR) possesses various pharmacological activities including antioxidant, anti-inflammatory, and hepatoprotective effects. However, its therapeutic efficacy is limited by its hydrophobic and crystalline nature. This study aimed to investigate the therapeutic potential and molecular mechanisms of NAR efficiently loaded into cationic nanoparticles (NP-NAR) for treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a mouse model. The results demonstrated that NP-NAR effectively ameliorated lipid metabolism dysbiosis, oxidative stress, insulin resistance, and infla

Benzo[a]pyrene exposure increases inflammation, lipid accumulation, and lipid metabolism disfunction in the clam Ruditapes philippinarum.

Environmental pollution influences human diseases like metabolic dysfunction associated fatty liver disease (MAFLD). Bivalves' digestive glands are confronted with persistent organic pollutants (POPs) pollution, resulting in lipid metabolism disorders, and this process is also similar to the formation of MAFLD. In this study, we chose benzo[a]pyrene (B[a]P), a typical POPs, to investigate the impaired lipid metabolism and inflammatory risk of digestive glands in clam Ruditapes philippinarum towards B[a]P. The results indicated that accumulation of B[a]P in digestive glands was progressively hi

Lipid management for primary and secondary stroke prevention consensus paper of the International Lipid Expert Panel (ILEP).

Ischemic stroke is a significant global health challenge, accounting for approximately 66 % of all strokes worldwide. Recent data indicates that stroke was the third leading cause of death (10.7 % of all deaths), following ischemic heart disease and COVID-19. In 2021, nearly 94 million people were living with the consequences of a stroke, and about 12 million new cases were reported. Major risk factors for stroke include high systolic blood pressure, exposure to ambient particulate matter, smoking, and elevated levels of low-density lipoprotein cholesterol (LDL-C), with LDL-C contributing to n

Polyglycerol-Based Lipids: A Next-Generation Alternative to PEG in Lipid Nanoparticles for Advanced Drug Delivery Systems.

Polyethylene glycol (PEG) is widely used to provide a stealth effect in various therapeutic applications. However, an increased occurrence of anti-PEG antibodies in patients can lead to immunological side effects and accelerated blood clearance, reducing the efficiency of PEG-based delivery vectors. One of these PEG-containing vectors is lipid nanoparticles (LNPs), which effectively deliver nucleic acids. Their high potential for treating a great number of diseases in the future was already showcased in the mRNA vaccines developed during the COVID-19 pandemic. Thus, the aim of our study was to

Tuning the polyethylene glycol-lipid anchor length of lipid nanoparticles to enhance brain-targeted siRNA delivery.

The blood-brain barrier (BBB) remains a major challenge in the treatment of central nervous system (CNS) diseases. Lipid nanoparticles (LNPs) have emerged as promising carriers for small interfering RNA (siRNA) delivery to the brain. However, their ability to penetrate the BBB remains limited, with typically <1 % of the injected dose reaching the brain. Among various design strategies, PEGylation of lipids has been widely used to improve nanoparticle stability, prolong circulation time, and modulate tissue distribution. Notably, the length of the Polyethylene Glycol-lipid (PEG-lipid) anchor ha…

Inflammation-Driven Lipid Suppression in Hospitalized Patients: Insights Into the Inflammatory Lipid Paradox From a Retrospective Study.

Introduction Systemic inflammation alters lipid metabolism by suppressing hepatic lipoprotein synthesis, increasing catabolism, and impairing reverse cholesterol transport. These changes result in reduced levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol (TC), despite elevated cardiovascular risk, which is a phenomenon termed the "inflammatory lipid paradox." While well-characterized in chronic inflammatory diseases, such as rheumatoid arthritis, its prevalence and clinical impact in hospitalized adults with systemic inflammation remain underexplore

Zearalenone exacerbates lipid metabolism disorders by promoting liver lipid droplet formation and disrupting gut microbiota.

Zearalenone (ZEA), produced by Fusarium, is a fungal toxin commonly found in maize, wheat, and other cereals. ZEA has the ability to bind to … inal microbiota. This study highlights the synergistic effects of long-term low-dose ZEA and excess lipids, providing a theoretical basis for elucidating the mechanism of chronic toxicity of ZEA and its negative impact on metabolic diseases.

Statin drugs and lipid modulation: Mechanistic basis considering lipid rafts, kinase signaling, myopathy, and cancer.

Statins are drugs that have been widely used to decrease the levels of cholesterol and are usually well tolerated. Increasing evidence suggests that these lipid-lowering drugs can impact the structural and functional integrity of lipid rafts, which are regulators for cellular signaling, protein trafficking, and membrane dynamics. This review discusses the dual actions of statins, encompassing both enzymatic inhibition and direct biophysical interactions with lipid membranes. The hydrophobicity of statins may drive the selective disruption of the raft components, potentially influencing major p

The immunomodulatory p43 secreted protein of Trichuris whipworm parasites is a lipid carrier that binds signalling lipids and precursors.

Trichuris whipworms cause disease and morbidity in humans and other animals. Their prolonged intestinal infections persist despite intact immune systems of their hosts and are attributed to immunomodulatory activities of their secretions. The p43 (Tm-DLP-1) protein of Trichuris muris of mice comprises 95% of the protein secreted by adult parasites, binds matrix proteoglycans, and has immune cytokine (IL-13)-neutralising activity. Using fluorescence-based methods we show that p43 binds fatty acids and retinol, including signalling lipids or precursors thereof. The orthologue of p43 from the hum…

Анионические липиды модифицируют наночастицы mRNA-липидную иммуногенность и обеспечивают защиту в мышиной модели множественного склероза.

Модульность платформ mRNA-липидных наночастиц (mRNA-LNP) позволила им быстро адаптироваться от вакцин против инфекционных заболеваний к новым видам применения для лечения иммунных расстройств. Вместе с тем распространение МРНА-ЛНП на аутоиммунные и подстрекательские заболевания требует точного контроля над адресацией иммунных клеток и иммуногенностью. Здесь мы систематически исследуем, как включение анионических липидов в ЛНП модифицирует как тропизм иммунных клеток, так и врожденную иммунную активацию. Используя библиотеку, состоящую из 40 различных составов LNP, мы показываем, что анионные л

Совпадение в аннотации оригинала
The modularity of mRNA-lipid nanoparticle (mRNA-LNP) platforms has enabled their rapid adaptation from infectious disease vaccines to emergi … ne cell targeting and immunogenicity. Here, we systematically investigate how incorporating anionic lipids into LNPs modulates both immune cell tropism and innate immune activation. Using a library of 40 distinct LNP formulations, we demonstrate that anionic lipids enhance mRNA delivery to splenic dendritic cells, reduce early cellular markers of adjuvan …

Associations of lipids and lipid-modifying drug target genes with atrial fibrillation risk based on genomic data.

BACKGROUND: The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence. METHODS: Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cho…

Progesterone increases hepatic lipid content and plasma lipid levels through PR- B-mediated lipogenesis.

Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction by binding to progesterone receptors (PR). However, the physiological role of P4 in the liver is understudied. P4-mediated lipid metabolism in the liver was investigated in this study, as P4 facilitates insulin resistance and influences energy metabolism. While exogenous lipids are mainly obtained from food, the liver synthesizes endogenous triglycerides and cholesterol from a carbohydrate diet. Hepatic de novo lipogenesis (DN…

Causal effects of circulating lipids and lipid-lowering drugs on the risk of atopic dermatitis: a mendelian randomization study.

Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD. Statistically, the random-effects inverse-v…

Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design.

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-ba

Lipid Level, Lipid Variability, and Risk of Multiple Myeloma: A Nationwide Population-Based Study of 3,527,776 Subjects.

(1) Background: There is evidence that abnormality in lipid metabolism promotes cancer development. This study investigated whether lipid level and its variability are associated with the development of MM at a population level. (2) Methods: A retrospective cohort study included a total of 3,527,776 subjects aged 40 and above who participated in ≥3 health examinations within the previous five years, including the index year (2012-2013). Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) were measured, and visi

Comparison of MRI features in lipid-rich and lipid-poor adrenal adenomas using subjective and quantitative analysis.

OBJECTIVE: To compare MR-imaging features in benign lipid-rich and lipid-poor adrenal adenomas. MATERIALS AND METHODS: With institutional review board approval, we compared 23 consecutive lipid-poor adenomas (chemical shift [CS] signal intensity [SI] index < 16.5%) imaged with MRI to 29 consecutive lipid-rich adenomas (CS-SI index ≥ 16.5%) imaged during the same time period. A blinded radiologist measured T2-weighted (T2W) SI ratio (adrenal adenoma/psoas muscle), dynamic enhancement wash-in (WI) and wash-out (WO) indices, and T2W texture features. Two blinded Radiologists (R1/R2) assessed T2W

CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation.

Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44-/- mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44-/- AMs had increased expression of CD36, a lipid scaveng…