Apolipoprotein Mimetic Peptide Inhibits Neutrophil-Driven Inflammatory Damage via Membrane Remodeling and Suppression of Cell Lysis.
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ABSTRACT:
SUBMITTER: Lee MW
PROVIDER: S-EPMC8720511 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The apolipoprotein A-I (apoA-I) mimetic peptide 4F displays prominent anti-inflammatory properties, including the ability to reduce vascular macrophage content. Macrophages are a heterogenous group of cells, represented by two principal phenotypes, the classically activated M1 macrophage and an alternatively activated M2 phenotype. We recently reported that 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype similar to that displayed by M2 macrophages. In the current study, microarray analysis of gene expression in monocyte-derived macrophages (MDMs) was carried out to identify inflammatory pathways modulated by 4F treatment. ApoA-I treatment of MDMs served as a control. Transcriptional profiling revealed that 4F and apoA-I modulated expression of 113 and 135 genes that regulate inflammatory responses, respectively. Cluster heat maps revealed that 4F and apoA-I induced similar changes in expression for 69 common genes. Modulation of other gene products, including STAT1 and PPARG, were unique for 4F treatment. Besides modulating inflammatory responses, 4F was found to alter gene expression in cell-to-cell signaling, cell growth/proliferation, lipid metabolism and cardiovascular system development. These data suggest that the protective effects of 4F in a number of disease states may be due to underlying changes in monocyte/macrophage gene expression. 16 samples analyzed (four 4F+LPS, four 4F, four Controls+LPS, four Controls).
2012-09-30 | E-GEOD-36933 | biostudies-arrayexpress
Project description:Apolipoprotein E (apoE) is well known as an antiatherogenic protein via regulating lipid metabolism and inflammation. We previously reported that a human apoE mimetic peptide, EpK, reduced atherosclerosis in apoE null (apoE(-/-)) mice through reducing inflammation without affecting plasma lipid levels. Here, we construct another human apoE mimetic peptide, named hEp, and investigate whether expression of hEp can reduce atherosclerotic lesion development in aged female apoE(-/-) mice with pre-existing lesions. We found that chemically synthesized hEp significantly decreased cholesterol accumulation induced by oxidized low density lipoprotein and the expression of inflammatory cytokines TNF? and IL-6 induced by lipopolysaccharide in macrophages. In an in vivo study, Lv-hEp-GFP lentiviruses were intravenously injected into 9 month-old apoE(-/-) mice. Mice were then fed a chow diet for 18 weeks. Results showed that in comparison to the Lv-GFP lentivirus injection (Lv-GFP) group, Lv-hEp-GFP lentivirus injection achieved hepatic hEp expression and secretion in apoE(-/-) mice. It was observed that hEp expression significantly reduced plasma VLDL and LDL cholesterol levels and decreased aortic atherosclerotic lesions. This was accompanied by an increase of LDL receptor expression and a reduction of TNF? and IL-6 mRNA levels in the liver. Moreover, expression of hEp increased plasma paraoxonase-1 activity and decreased plasma myeloperoxidase activity and serum amyloid A levels. Our study provides evidence that hEp may be developed as a promising therapeutic apoE mimetic peptide for atherosclerosis-related cardiovascular diseases through its induction of plasma VLDL/LDL cholesterol clearance as well as its anti-oxidative and anti-inflammatory activities.
| S-EPMC5009400 | biostudies-literature
Project description:Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II-deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr-/- ) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl-/- ) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.
| S-EPMC8359806 | biostudies-literature
Project description:The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant Acinetobacter baumannii, even eliminating large inocula (108 CFU/ml) within 30 min. LC99.9 in PBS and 50% pooled human plasma was 2 μg/ml (1.4 μM) and 8 μg/ml (5.6 μM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation–reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. C. elegans infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant A. baumannii.
| S-EPMC9445589 | biostudies-literature
Project description:The apolipoprotein A-I (apoA-I) mimetic peptide 4F displays prominent anti-inflammatory properties, including the ability to reduce vascular macrophage content. Macrophages are a heterogenous group of cells, represented by two principal phenotypes, the classically activated M1 macrophage and an alternatively activated M2 phenotype. We recently reported that 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype similar to that displayed by M2 macrophages. In the current study, microarray analysis of gene expression in monocyte-derived macrophages (MDMs) was carried out to identify inflammatory pathways modulated by 4F treatment. ApoA-I treatment of MDMs served as a control. Transcriptional profiling revealed that 4F and apoA-I modulated expression of 113 and 135 genes that regulate inflammatory responses, respectively. Cluster heat maps revealed that 4F and apoA-I induced similar changes in expression for 69 common genes. Modulation of other gene products, including STAT1 and PPARG, were unique for 4F treatment. Besides modulating inflammatory responses, 4F was found to alter gene expression in cell-to-cell signaling, cell growth/proliferation, lipid metabolism and cardiovascular system development. These data suggest that the protective effects of 4F in a number of disease states may be due to underlying changes in monocyte/macrophage gene expression.
2012-09-30 | GSE36933 | GEO
Project description:OBJECTIVE:At present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti-inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN-105, in a microglial cell line and murine model of ischemic stroke. METHODS:Ten to 13-week-old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN-105 (0.1 mg/kg) in 100 ?L volume or vehicle via tail vein injection at various time points. Survival, motor-sensory functional outcomes using rotarod test and 4-limb wire hanging test, infarct volume assessment using 2,3,5-Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor-alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN-105 in ischemic stroke. RESULTS:Mice receiving CN-105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN-105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN-105 reduces proinflammatory pathways and lower oxidative stress. INTERPRETATION:CN-105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN-105 represents an attractive candidate for clinical translation.
| S-EPMC5376751 | biostudies-literature
Project description:Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20:1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20:1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modified LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention.
| S-EPMC4442877 | biostudies-literature
Project description:Apolipoprotein A-I mimetic peptides are amphipathic alpha helix peptides that display similar functions to apolipoprotein A-I, and preclinical studies have evaluated . In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration by decreasing the expression of IFNα. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed fifteen days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.
2020-12-08 | GSE162764 | GEO
Project description:The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPAR? (peroxisome-proliferator-activated receptor ?) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen-consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in ??m (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPAR? antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism.
| S-EPMC4432873 | biostudies-literature
Project description:Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a source of substantial morbidity and remains difficult to treat. New strategies for beneficial anti-inflammatory therapies would be highly desirable. Apolipoprotein (apo) E has immunomodulatory effects and synthetically derived apoE-mimetic peptides are beneficial in models of sepsis and neuroinflammation. We have reported that the antennapedia-linked apoE-mimetic peptide COG112 inhibits the inflammatory response to the colitis-inducing pathogen Citrobacter rodentium in vitro by inhibiting NF-?B activation. We now determined the effect of COG112 in mouse models of colitis. Using C. rodentium as an infection model, and dextran sulfate sodium (DSS) as an injury model, mice were treated with COG112 by intraperitoneal injection. With C. rodentium, COG112 improved the clinical parameters of survival, body weight, colon weight, and histologic injury. With DSS, COG112 ameliorated the loss of body weight, reduction in colon length, and histologic injury, whether administered concurrently with induction of colitis, during induction plus recovery, or only during the recovery phase of disease. In both colitis models, COG112 inhibited colon tissue inducible nitric-oxide synthase (iNOS), KC, TNF-?, IFN-?, and IL-17 mRNA expression, and reduced nuclear translocation of NF-?B, as determined by immunoblot and immunofluorescence confocal microscopy. I?B kinase (IKK) activity was also reduced, which is necessary for activation of the canonical NF-?B pathway. Isolated colonic epithelial cells exhibited marked attenuation of expression of iNOS and the CXC chemokines KC and MIP-2. These studies indicate that apoE-mimetic peptides such as COG112 are novel potential therapies for IBD.
| S-EPMC3030385 | biostudies-literature