Niobium carbide MXenzyme-Driven comprehensive cholesterol regulation for photoacoustic image-guided and anti-inflammatory photothermal ablation in atherosclerosis

Foam cells play a pivotal role in the progression of atherosclerosis progression by triggering inflammation within arterial walls.They release inflammatory molecules that attract additional immune cells,leading to further macrophage recruitment and plaque development.In this study,we develop an osteopontin(OPN)antibody-conjugated niobium carbide(Nb_(2)C-aOPN)MXenzyme designed to selectively target and mildly ablate foam cells while reducing inflammation in the plaque microenvironment.This approach utilizes photonic hyperthermia to decrease plaque size by enhancing cholesterol regulation through both passive cholesterol outflow and positive cholesterol efflux.Nb_(2)C-aOPN MXenzyme exhibits multiple enzyme-mimicking properties,including catalase,superoxide dismutase,peroxidase and glutathione peroxidase,and acts as a scavenger for reactive oxygen and nitrogen species.The inhibition of reactive oxygen and nitrogen species synergizes with photothermal ablation to promote positive cholesterol efflux,leading to reduced macrophage recruitment and a shift in macrophage phenotype from M1 to M2.This integrative strategy on cholesterol regulation and anti-inflammation highlights the potential of multifunctional 2D MXenzyme-based nanomedicine in advancing atherosclerotic regression.

Paeonol attenuates progression of atherosclerotic lesion formation through lipid regulation, anti-inflammatory and antioxidant activities

As an active component extracted from Chinese herb moutan cortex and roots of paeonia lactiflora pallas, paeonol possesses many biological activities, including anti-inflammatory and vascular protection activities. In this study, athero-protective effects of paeonol were investigated in apoliprotein E deficient（Apo E^–/–） mice through the entire course of atherosclerotic development. Apo E^–/– mice were divided into five groups and fed a high-cholesterol diet（HCD） for 5, 15 and 25 weeks. Then they were fed either paeonol or atorvastatin for 6 weeks. The methods, such as ELISA for serum lipid and cytokine analyses, Western blotting for protein expressions, and HE and oil-red o-staining method, were used for evaluation of thoracic aorta lesion area. The results showed that paeonol could significantly reduce body weight, blood lipid, total cholesterol（TC）, triglyceride（TG） and low density lipoprotein（LDL-C） in Apo E^–/– mice at all stages of the atherosclerosis process. Paeonol also reduced the levels of anti-inflammation factors, such as tumor necrosis factor-α（TNF-α）, interleukin（IL）-6, oxidized LDL cholesterol（ox-LDL）, in serum. In paeonol groups, SOD was significantly increased, whereas MDA was decreased compared with the HCD group（P0.01）. Paeonol markedly attenuated the thickness of the lipid-rich plaque and down-regulated the expressions of VCAM-1 and MMP-9 in aorta of mice, suggesting that paeonol could inhibit formation of plaque and stabilize plaques. Taken together, paeonol appeared to have anti-dyslipidemia and anti-atherosclerotic effects by lipid regulation, and it could inhibit the effects of inflammation and oxidative stress on HCD-fed Apo E^–/– mice through the entire course of atherosclerotic development.

Transcriptional Regulation of Lipid Catabolism during Seedling Establishment

Lipid catabolism in germinating seeds provides energy and substrates for initial seedling growth,but how this process is regulated is not well understood.Here,we show that an AT-hook motif-containing nuclear localized(AHL)protein regulates lipid mobilization and fatty acid p-oxidation during seed germination and seedling establishment.AHL4 was identified to directly interact with the lipid mediator phosphatidic acid(PA).Knockout(KO)of AHL4 enhanced,but overexpression(OE)of AHL4 attenuated,triacylglycerol(TAG)degradation and seedling growth.Normal seedling growth of the OE lines was restored by sucrose supplementation to the growth medium.AHL4-OE seedlings displayed decreased expression of genes involved in TAG hydrolysis and fatty acid oxidation,whereas the opposite was observed in AHL4-KOs.These genes contained AHL4-binding cis elements,and AHL4 was shown to bind to the promoter regions of genes encoding the TAG lipases SDP1 and DALL5 and acyl-thioesterase KAT5.These AHL4-DNA interactions were suppressed by PA species that bound to AHL4.These results indicate that AHL4 suppresses lipid catabolism by repressing the expression of specific genes involved in TAG hydrolysis and fatty acid oxidation,and that PA relieves AHL4-mediated suppression and promotes TAG degradation.Thus,AHL4 and PA together regulate lipid degradation during seed germination and seedling establishment.

A study of the lipid-mediated dimerization of the RAGE TM+JM domains by molecular dynamic simulations

Receptor for Advanced Glycation End-products(RAGE) binds to a number of ligand families to display important roles in hyperglycemia, senescence, inflammation, neurodegeneration and cancer. It is reported that RAGE regulates the related biological processes via homo-dimerization by the transmembrane(TM) domain, and evidence further shows that the intracellular domain of RAGE has an influence on the dimerization activity of RAGE. In this study, we explored the underlying interaction mechanism of RAGE TM domains by multiscale coarse-grained(CG) dynamic simulations. Two switching packing modes of the TM dimeric conformations were observed. Through a series of site-directed mutations, we further emphasized the key roles of the A342xxxG346xxG349xxxT353xxL356xxxV360motif in the left-handed configuration and the L345xxxG349xxG352xxxL356motif in the right-handed configuration. In addition, we revealed that the juxtamembrane(JM) domain within JM-A375 can determine the RAGE TM dimeric structure. Overall, we provide the molecular insights into the switching dimerization of RAGE TM domains, as well as the regulation from the JM domains mediated by the anionic lipids.

Regulation of Neutral Lipid Retention by Rab GTPases and Mono-ADP-Ribosylation of CtBP1/BARS

Aberration of lipid storage in lipid droplets (LD) has been linked with the development and progression of several common metabolic diseases including obesity, type II diabetes,