Exosome-Based Treatment for Atherosclerosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Heo J
PROVIDER: S-EPMC8778342 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rationale: Tailored inflammation control is badly needed for the treatment of kinds of inflammatory diseases, such as atherosclerosis. IL-10 is a potent anti-inflammatory cytokine, while systemic and repeated delivery could cause detrimental side-effects due to immune repression. In this study, we have developed a nano-system to deliver inflammation-responsive Il-10 mRNA preferentially into macrophages for tailored inflammation control. Methods: Il-10 was engineered to harbor a modified HCV-IRES (hepatitis C virus internal ribosome entry site), in which the two miR-122 recognition sites were replaced by two miR-155 recognition sites. The translational responsiveness of the engineered mRNA to miR-155 was tested by Western blot or ELISA. Moreover, the engineered Il-10 mRNA was passively encapsulated into exosomes by forced expression in donor cells. Therapeutic effects on atherosclerosis and the systemic leaky expression effects in vivo of the functionalized exosomes were analyzed in ApoE-/- (Apolipoprotein E-deficient) mice. Results: The engineered IRES-Il-10 mRNA could be translationally activated in cells when miR-155 was forced expressed or in M1 polarized macrophages with endogenous miR-155 induced. In addition, the engineered IRES-Il-10 mRNA, when encapsulated into the exosomes, could be efficiently delivered into macrophages and some other cell types in the plaque in ApoE-/- mice. In the recipient cells of the plaque, the encapsulated Il-10 mRNA was functionally translated into protein, with relatively low leaky in other tissues/organs without obvious inflammation. Consistent with the robust Il-10 induction in the plaque, exosome-based delivery of the engineered Il-10 could alleviate the atherosclerosis in ApoE-/- mice. Conclusion: Our study established a potent platform for controlled inflammation control via exosome-based systemic and repeated delivery of engineered Il-10 mRNA, which could be a promising strategy for atherosclerosis treatment.
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Project description:In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.
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Project description:Atherosclerosis, being an inflammation-associated disease, represents a considerable healthcare problem. Its origin remains poorly understood, and at the same time, it is associated with extensive morbidity and mortality worldwide due to myocardial infarctions and strokes. Unfortunately, drugs are unable to effectively prevent plaque formation. Systemic administration of pharmaceuticals for the inhibition of plaque destabilization bears the risk of adverse effects. At present, nanoscience and, in particular, nanomedicine has made significant progress in both imaging and treatment of atherosclerosis. In this review, we focus on recent advances in this area, discussing subjects such as nanocarriers-based drug targeting principles, approaches towards the treatment of atherosclerosis, utilization of theranostic agents, and future prospects of nanoformulated therapeutics against atherosclerosis and inflammatory diseases. The focus is placed on articles published since 2015 with additional attention to research completed in 2019-2020.
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Project description:Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe-/-) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe-/- mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm-/-) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.
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Project description:BackgroundGlucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system.ResultsThe size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was - 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility.ConclusionThe present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.
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Project description:In the study, a biomimetic platform for anti-inflammatory-based treatment of atherosclerotic plaque was developed. Gliclazide (GL) as an anti-inflammasome agent was encapsulated in PLGA nanoparticles (NP), which were coated by monocyte membrane using an extrusion procedure. The size and zeta potential of the nanoghost (NG) changed to 292 and - 10 nm from 189.5 to -34.1 in the core NP. In addition, the actual size of 62.5 nm with a coating layer of 5 nm was measured using TEM. The NG was also showed a sustained release profile with the drug loading content of about 4.7%. Beside to attenuated TNFα, decrease in gene expression levels of NLRP3, MyD88, NOS, IL-1β, IL-18 and caspases 1/3/8/9 in LPS-primed monocytes exposed to NG strongly indicated remarkable inflammation control. After systemic toxicity evaluation and pharmacokinetic analysis of NP and NG, intravenous NG treatment of rabbits with experimentally induced atherosclerosis revealed remarkably less plaque lesions, foam cells, lipid-laden macrophages, and pathological issues in tunica media of aorta sections. Higher expression of CD163 than CD68 in aorta of NG-treated rabbits strongly reveals higher M2/M1 macrophage polarization. The bio/hemocompatible, biomimetic and anti-inflammatory NG can be considered as a potential platform for immunotherapy of particularly atherosclerosis in the field of personalized medicine.
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Project description:Atherosclerosis is a common metabolic disease characterized by lipid metabolic disorder. The processes of atherosclerosis include endothelial dysfunction, new endothelial layer formation, lipid sediment, foam cell formation, plaque formation, and plaque burst. Owing to the adverse effects of first-line medications, it is urgent to discover new medications to deal with atherosclerosis. Berberine is one of the most promising natural products derived from traditional Chinese medicine. However, the panoramic mechanism of berberine against atherosclerosis has not been discovered clearly. In this study, we used network pharmacology to investigate the interaction between berberine and atherosclerosis. We identified potential targets related to berberine and atherosclerosis from several databases. A total of 31 and 331 putative targets for berberine and atherosclerosis were identified, respectively. Then, we constructed berberine and atherosclerosis targets with PPI data. Berberine targets network with PPI data had 3204 nodes and 79437 edges. Atherosclerosis targets network with PPI data had 5451 nodes and 130891 edges. Furthermore, we merged the two PPI networks and obtained the core PPI network from the merged PPI network. The core PPI network had 132 nodes and 3339 edges. At last, we performed functional enrichment analyses including GO and KEGG pathway analysis in David database. GO analysis indicated that the biological processes were correlated with G1/S transition of mitotic cells cycle. KEGG pathway analysis found that the pathways directly associated with berberine against atherosclerosis were cell cycle, ubiquitin mediated proteolysis, MAPK signaling pathway, and PI3K-Akt signaling pathway. After combining the results in context with the available treatments for atherosclerosis, we considered that berberine inhibited inflammation and cell proliferation in the treatment of atherosclerosis. Our study provided a valid theoretical foundation for future research.
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Project description:Exosomes, nano-sized extracellular vesicles for intercellular communications, are gaining rapid momentum as a novel strategy for the diagnosis and therapeutics of a spectrum of diseases including cancers. Secreted by various cell sources, exosomes pertain numerous functionalities from their parental cells and have enhanced stability that enable them with many features favorable for clinical use and commercialization. This paper focuses on the possible roles of exosomes in cancer therapeutics and reviews current exosome-based innovations toward enhanced cancer management and challenges that limit their clinical translation. Importantly, this paper casts insights on how cold atmospheric plasma, an emerging anticancer strategy, may aid in innovations on exosome-based onco-therapeutics toward improved control over cancers.
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Project description:Exosomes are reported to mediate several disease-related microRNAs (miRNAs) to affect the progression of diseases, including atherosclerosis. Here, we aimed to screen the atherosclerosis-associated miRNAs and preliminarily investigate the potential regulatory mechanism of atherosclerosis. First, the lesion model for human umbilical vein endothelial cells (HUVECs) was favorably constructed. Later, through RNA-sequencing and bioinformatics analyses, miR-342-5p was identified in lesion model for HUVECs. MiR-342-5p overexpression or knockdown evidently promoted or inhibited the apoptosis of HUVECs impaired by H2O2. Mechanistically, PPP1R12B was found to have great potential as a target of miR-342-5p in HUVECs impaired by H2O2, supported by RNA-sequencing and a series of bioinformatics analyses. Meanwhile, the effect of miR-342-5p on PPP1R12B expression in HUVECs' lesion model was explored, revealing that miR-342-5p had an inhibitory role in PPP1R12B expression. Additionally, adipose-derived mesenchymal stem cells (ADSCs) in spindle-like shape and their derived exosomes with 30 to 150 nm diameter were characterized. Furthermore, results showed miR-342-5p was evidently decreased in the presence of ADSCs-derived exosomes. These findings indicated ADSCs-derived exosomes restrained the expression of miR-324-5p in lesion model. Collectively, this work demonstrates an atherosclerosis-associated miR-342-5p and reveals a preliminary possible mechanism in which miR-342-5p mediated by ADSCs-derived exosomes protects endothelial cells against atherosclerosis.
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Project description:Stroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long-term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell-based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. Stem Cells Translational Medicine 2018;7:451-455.
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