Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Atherosclerosis is a chronic,inflammatory disorder characterized by the deposition of excess lipids in the arterial intima.The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis.Lipid homeostasis,especially cho-lesterol homeostasis,plays a crucial role during the formation of foam cells.Recently,lipid droplet-associated proteins,including PAT and CIDE family proteins,have been shown to control the development of athero-sclerosis by regulating the formation,growth,stabiliza-tion and functions of lipid droplets in macrophage-derived foam cells.This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins.Understanding the process of foam cell for-mation will aid in the future discovery of novel thera-peutic interventions for atherosclerosis.

Effects of Andrographolide on the Activation of Mitogen Activated Protein Kinases and Nuclear Factor-κ B in Mouse Peritoneal Macrophage-derived Foam Cells

Objective： To observe the effect of andrographolide on the activation of mitogen-activated protein kinases （MAPKs） and expression of nuclear factor- kB （NF-kB） in macrophage foam cells. Methods： The mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein （ox-LDL）, ox-LDL＋andrographolide, or neither （control）. The phosphorylation of MAPK molecules （p38MAPK, JNK, ERK1/2） and the expressions of NK- kB p65 were examined by Western blot. Results： As compared with cells in the control group, the expressions of phospho-p38 and NF- kB p65 were increased in the cells cultured with either ox-LDL or ox-LDL＋andrographolide （P〈0.01）, but attenuated significantly in the presence of ox-LDL＋ andrographolide when compared with ox-LDL （P〈0.05）. The phospho-JNK increased in the presence of either ox-LDL or ox-LDL＋andrographolide when compared with control cells （P〈0.01）, but no significant difference existed between ox-LDL and ox-LDL＋andrographolide （P〉0.05）. The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells （P〈0.01）, but no significant differences existed between the cells cultured in the presence of ox-LDL＋andrographolide and the control medium （P〉0.05）. Conclusions： Andrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-kB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis.

Differential expression of miRNA in THP-1-derived foam cell model induced by drug-containing serum of Yimaijiangzhi decoction

Objective: To investigate the differential expression of miRNA and related biological functions and signaling pathways after the intervention of the THP-1-derived foam cell model with the drug-containing serum of Yimaijiangzhi Decoction. Methods: The experiment was divided into macrophage group, foam cell model group and Yimaijiangzhi drug-containing serum group. THP-1 cells were induced into macrophages by Fopol ester, and induced differentiated macrophages were given ox-LDL to establish foam cell model, and Yimaijiangzhi decoction rat serum was used to intervene the foam cells. Total RNA was extracted from cells in each group for miRNA sequencing, differential expression of miRNA was screened, and relevant target genes were predicted for GO analysis and KEGG analysis, protein interaction network and miRNA-target gene interaction network were established, and RT-qPCR was used to verify the possible signaling pathways for improving atherosclerosis. Result: The difference miRNA between blank group and model group was hsa-miR-302c-3p, hsa-miR-302d-3p, hsa- mir-30d-3p, hsa-mir-3189-3p, hsa-mir-374b-5p, hsa-mir-423-5p, hsa-mir-423-5p, and hsa- mir-4781-3p, hsa-mir-663a;The miRNAs of model group and Yimaijiangzhi drug-containing serum group were hsa-mir-3150a-3p, hsa-mir-7704, hsa-mir-887-3p, hsa-mir-150-5p, hsa- mir-423-5p, hsa-mir-374c-3p, hsa-mir-374c-3p, hsa-mir-374b-5p;The difference of miRNAs prediction target genes between model group and Yimaijiangzhi drug-containing serum group showed that the miRNA prediction target genes were mainly enriched in MAPK signaling pathway, ErbB signaling pathway, Hippo signaling pathway, Wnt signaling pathway and other signaling pathways. SCN1A, PRKACA, MECP2, EIF4E, SRSF1, MBNL1, PRKCA, PPARGC1A may be the potential key targets for the effect of the drug-containing serum of Yimaijiangzhi Decoction on THP-1-derived foam cells. Conclusion: hsa-mir-374c-3p, hsa- mir-423-5p, and hsa-mir-374b-5p are important miRNAs that the drug-containing serum of Yimaijiangzhi Decoction acts on foam cells. The significantly differentially expressed mirnas and significantly enriched related signaling pathways may provide new ideas for the diagnosis and treatment of atherosclerosis.

Thymic Stromal Lmphopoietin Pomotes Macrophage-derived Foam Cell Formation

The effect of thymic stromal lymphopoietin（TSLP） on macrophage-derived foam cell formation and the underlying mechanism were studied. Macrophages isolated from C57BL/6 mice were co-cultured in vitro with different concentrations of TSLP or TSLPR-antibody in the presence of oxidized low density lipoprotein（ox-LDL）. The effects of TSLP on macrophage-derived foam cell formation were observed by using oil red O staining and intracellular lipid determination. The expression levels of foam cell scavenger receptors（CD36 and SRA） as well as ABCA1 and TSLPR were detected by using RT-PCR and Western blotting. As compared with the control group, TSLP treatment significantly promoted lipid accumulation in macrophages, significantly increased protein expression of CD36 and TSLPR in a dose-dependent manner, and significantly reduced the expression of ABCA1 protein in a dose-dependent manner. No significant differences were noted between the TSLPR-antibody group and the control group. TSLP may down-regulate the expression of cholesterol efflux receptor ABCA1 and up-regulate scavenger receptor expression via the TSLPR signaling pathway, thereby promoting macrophage-derived foam cell formation.

MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis

Accumulation of macrophage"foam"cells,laden with cholesterol and cholesteryl ester,within the intima of large arteries,is a hallmark of early"fatty streak"lesions which can progress to complex,multicellular atheromatous plaques,involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response.Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway.Within the arterial intima,however,this mechanism is overwhelmed,leading to distinct changes in macrophage phenotype and inflammatory status.Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function,and in particular the importance of small non-coding micro-RNA(miRNA)sequences in this context.This review identifies some of the miRNA sequences which play a key role in regulating"foam"cell formation and atherogenesis,highlighting sequences involved in cholesterol accumulation,those influencing inflammation in sterol-loaded cells,and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.

Effects of cell wall property on compressive performance of aluminum foams

The effects of cell wall property on the compressive performance of high porosity, closed-cell aluminum foams prepared by gas injection method were investigated. The research was conducted both experimentally and numerically. Foam specimens prepared from conditioned melt were tested under uniaxial compressive loading condition. The cell wall microstructure and fracture were observed through optical microscope（OM） and scanning electron microscope（SEM）, which indicates that the cell wall property is impaired by the defects in cell walls and oxide films on the cell wall surface. Subsequently, finite element（FE） models based on three-dimensional thin shell Kelvin tetrakaidecahedron were developed based on the mechanical properties of the raw material and solid material that are determined by using experimental measurements. The simulation results show that the plateau stress of the nominal stress-strain curve exhibits a linear relationship with the yield strength of the cell wall material. The simulation plateau stress is higher than the experimental data, partly owing to the substitution of solid material for cell wall material in the process of the establishment of FE models.

Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction;however,the effects on skeletal tissue and the underlying mechanisms are still unclear.Here,we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles,leading to a switch in skeletal stem/progenitor cell(SSPC)differentiation between osteoblasts and adipocytes and bone deterioration.Bone marrow macrophage(BMM)-secreted extracellular vesicles(BMM-EVs)from obese mice induced bone deterioration(decreased bone volume,bone microstructural deterioration,and increased adipocyte numbers)when administered to lean mice.Conversely,BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients.We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates,miR-140(with the function of promoting adipogenesis)and miR-378a(with the function of enhancing osteogenesis)coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis.BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration,while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice.BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration.More importantly,we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system,and this approach rescued bone deterioration in obese mice.Thus,our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage

Berberine is identified to lower the serum cholesterol level in human and hamster through the induction of low density lipoproteins （LDL） receptor in hepatic cells. To evaluate its potential in preventing atherosclerosis, the effect of berberine on atherosclerosis development in apolipoprotcin E-deficient （apoE^-/-） mice was investigated. In apoE^-/- mice, berberine induced in rivo foam cell formation and promoted atheroselerosis development. The foam cell formation induced by berberinc was also observed in mouse RAW264.7 cells, as well as in mouse and human primary macrophages. By inducing scavenger receptor A （SR-A） expression in macrophages, berberine increased the uptake of modified LDL （DiO-Ac-LDL）. Bcrberine-induced SR-A expression was also observed in macrophage foam cells in vivo and in the cells at atherosclerotic lesion. Analysis in RAW264.7 cells indicated that berberine induced SR-A expression by suppressing PTEN expression, which led to sustained Akt activation. Our results suggest that to evaluate the potential of a cholesterol-reducing compound in alleviating atherosclerosis, its effect on the ceils involved in atherosclerosis development, such as macrophages, should also be considered. Promotion of foam cell formation could counter-balance the beneficial effect of lowering serum cholesterol.

Cell structure of microcellular combustible object foamed by supercritical carbon dioxide

In order to solve the issue that the combustible objects for cased telescoped ammunition (CTA) didn't burn completely during the combustion process, the microcellular combustible objects were foamed with numerous cells in the micron order to improve the combustion performance by the supercritical carbon dioxide (SCeCO2) foaming technology. As the cell structure determined the combustion properties of microcellular combustible objects, the solubility of SCeCO2 dissolved into the combustible objects was obtained from the gravimetric method, and scanning electron microscope (SEM) was applied to characterize the cell structure under various process conditions of solubility, foaming temperature and foaming time. SEM images indicate that the cell diameter of microcellular combustible objects is in the level of 1 mm and the cell density is about 1011 cell,cm^-3. The microcellular combustible objects fabricated by the SCeCO2 foaming technology are smooth and uniform, and the high specific surface area of cell structure can lead to the significant combustion performance of microcellular combustible object for CTA in the future.

Role of VLDL Receptor in the Process of Foam Cell Formation

The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low density lipoprotein (LDL), respectively for 24 h and 48 h, foam cells formation was identified by oil red O staining and cellular contents of triglyceride (TG) and total cholesterol (TC) were determined. The mRNA levels of LDLR, LDLR related protein (LRP) and VLDLR were detected by semi quantitative RT PCR. The results demonstrated that VLDL, β VLDL and LDL could increase the contents of TG and TC in macrophages. Cells treated with VLDL or β VLDL showed markedly increased expression of VLDLR and decreased expression of LDLR, whereas LRP was up regulated slightly. For identifying the effect of VLDL receptor on cellular lipid accumulation, ldl A7 VR cells, which expresses VLDLR and trace amount of LRP without functional LDLR, was used to incubate with lipoproteins for further examination. The results elucidated that the uptake of triglyceride rich lipoprotein mediated by VLDLR plays an important role in accumulation of lipid and the formation of foam cells.

Liraglutide reduces oxidized LDL-induced oxidative stress and fatty degen- eration in Raw 264.7 cells involving the AMPK/SREBP1 pathway

Baekgound Recent studies have suggested a potential role for liraglutide in the prevention and stabilization ofatherosclerotic vascular disease. However, the molecular mechanisms underlying the effect of liraglutide on atherosclerosis have not been well elucidated. The pur- pose of this study was to examine whether liraglutide protects against oxidative stress and fatty degeneration via modulation of AMP-activated protein kinase （AMPK）/sterol regulatory element binding transcription factor 1 （SREBP1） signaling pathway in foam ceils. Methods Mouse macrophages Raw264.7 cells were exposed to oxidized low density lipoprotein （oxLDL） to induce the formation of foam cells. The cells were incubated with oxLDL （50 μg/mL）, liraglutide （0.1, 0.5, 1 and 2 nmol/L） or exendin-3 （9-39） （1, 10 and 100 nmol/L） alone, or in combination. Oil Red O staining was used to detect intracellular lipid droplets. The levels of TG and cholesterol were measured using the commercial kits. Oxidative stress was determined by measuring intracellular reactive oxygen species （ROS）, malondialdehyde （MDA） and superoxide dismutase 1 （SOD）. Western blot analysis was used to examine the expression of AMPKal, SREBP1, phosphory- lated AMPKal, phosphorylated SREBP1, glucagon-like peptide-1 （GLP-1） and GLP-1 receptor （GLP-1R）. Results Oil Red O staining showed that the cytoplasmic lipid droplet accumulation was visibly decreased in foam cells by treatment with liraglutide. The TG and cholesterol content in the liraglutide-treated foam cells was significantly decreased. In addition, foam ceils manifested an impaired oxidative stress following liraglutide treatment, as evidenced by increased SOD, and decreased ROS and MDA. However, these effects of liraglutide on foam cells were attenuated by the use of GLP-IR antagonist exendin-3 （9-39）. Furthermore, we found that the expression level of AMPKa 1 and phosphorylated AMPKct 1 was significantly increased while the expression level of SREBP 1 and phosphorylated SREBP 1 was significantly decreased in foam cells following treatment with liraglutide. Conclusions This study for the first time demonstrated that the effect of liraglutide on reducing oxidative stress and fatty degeneration in oxLDL-induced Raw264.7 cells is accompanied by the alteration of AMPK/SREBP1 pathway. This study provided a potential molecular mechanism for the effect of liraglutide on reducing oxidative stress and fatty degeneration.

The Effect of Neferine on Foam Cell Formation by Anti-low Density Liporotein Oxidation

Oxidatively modified low density lipoprtein (LDL) plays an important role in atheroslerosis (AS) development. To investigate the role of neferine (Nef) in anti-LDL oxidation and foam cell formation, the lipoprotein was derived and subjected to three different treatments: N-LDL (normal LDL), Cu(2+) +LDL and Cu(2+)+Nef+LDL. The LDLs were put at 25℃ for 24 h and the thiobarbituric acid reactive substance (TBARS) values were determined. They were 0. 57 ±0. 02, 6.01±0. 22 and 2. 26±0. 13 nmol/mg protein, respectively. The difference was very significant (P<0.01) for each two groups by t test. Mouse peritoneal macrophage (MΦ) were exposed to 50 μg protein/ml of Cu(2+) + LDL and Cu(2+)+Nef+LDL at 37℃ for 60 h. The tryglyceride (TG) and total cholesterol (TC) content in Mad were assayed. The results showed that Cu(2+) + LDL was more efficient than Cu(2+)+Nef+LDL in stimulating lipid accumulation in MΦ(P <0. 001). The study demonstrated that Nef could inhibit Cu(2+)-mediated LDL oxidation and thereby inhibiting macrophage-derived foam cell formation.

Tensile property of Al-Si closed-cell aluminum foam

Al-Si closed-cell aluminum foams of different densities were prepared by molten body transitional foaming process.The tensile behavior of Al-Si closed-cell aluminum foam was studied and the influence of relative densities on the tensile strength and elastic modulus was also researched.The results show that the fracture surfaces of Al-Si closed-cell aluminum foam display quasi-cleavage fracture consisting of brittle cleavages and ductile dimples.The tensile strength and elastic modulus are strictly affected by the relative density of Al-Si closed-cell aluminum foam.With increasing relative density,the tensile strength increases and the strain at which the peak strength is measured also increases;in addition,the elastic modulus increases with increasing relative density.

Numerical Modeling of the Compression Process of Elastic Open-cell Foams

The random models of open-cell foams that can reflect the actual cell geometrical properties are constructed with the Voronoi technique. The compression process of elastic open-cell foams is simulated with the nonlinear calculation module of finite element analysis program. In order to get the general results applicable to this kind of materials, the dimensionless compressive stress is used and the stress-strain curves of foam models with different geometrical properties are obtained. Then, the influences of open-cell geometrical properties, including the shape of strut cross section, relative density and cell shape irregularity, on the compressive nonlinear mechani- cal performance are analyzed. In addition, the numerical results are compared with the predicted results of cubic staggering model. Nu- merical results indicate that the simulated results reflect the compressive process of foams quite well and the geometrical properties of cell have significant influences on the nonlinear mechanical behavior of foams.

Relationship between Microcellular Foaming Injection Molding Process Parameters and Cell Size

In order to study the relationship between the main process parameters and the cell size, the mathematical model of cell growth of microcellular foaming injection process is built. Then numeric simulation is employed as experimental method, and the Taguchi method is used to analyze significance of effect of process parameters on the cell size. At last the process parameters are focused on melt temperature, injection time, mold temperature and pretidied volume. The significance order from big to small of the effect of each process parameters on cell size is melt temperature, pre-filled volume, injection time, and mold temperature. On the basis of above research, the effect of each process parameter on cell size is further researched. Appropriate reduction of the melt temperature and increase of the pre-filled volume can optimize the cell size effectively, while the effects of injection time and mold temperature on cell size are less significant.

Carbon Foam Anode Modified by Urea and Its Higher Electrochemical Performance in Marine Benthic Microbial Fuel Cell

Electrode materials have an important effect on the property of microbial fuel cell(MFC). Carbon foam is utilized as an anode and further modified by urea to improve its performance in marine benthic microbial fuel cell(BMFC) with higher voltage and output power. The electrochemical properties of plain carbon foam(PC) and urea-modified carbon foam(UC) are measured respectively. Results show that the UC obtains better wettability after its modification and higher anti-polarization ability than the PC. A novel phenomenon has been found that the electrical potential of the modified UC anode is nearly 100 m V lower than that of the PC, reaching-570 ±10 m V(vs. SCE), and that it also has a much higher electron transfer kinetic activity, reaching 9399.4 m W m-2, which is 566.2-fold higher than that from plain graphite anode(PG). The fuel cell containing the UC anode has the maximum power density(256.0 m W m-2) among the three different BMFCs. Urea would enhance the bacteria biofilm formation with a more diverse microbial community and maintain more electrons, leading to a lower anodic redox potential and higher power output. The paper primarily analyzes why the electrical potential of the modified anode becomes much lower than that of others after urea modification. These results can be utilized to construct a novel BMFC with higher output power and to design the conditioner of voltage booster with a higher conversion ratio. Finally, the carbon foam with a bigger pore size would be a potential anodic material in conventional MFC.

Cell-structure and mechanical properties of closed-cell aluminum foam

The density, cell size and structure of closed-cell aluminum foam were measured by optical microscopy and image analysis. The properties and the mechanism of compressive deformation that occur in closed-cell aluminum foam were measured and discussed. The results show that the cell size of foam with density of 0.37 mg/m^3 is distributed in the range of 0.5 4.0 mm. The cell size of foam with density of 0.33 mg/m^3 is distributed in the range of 0.55.0 mm. The cell wall thickness of both types is 0.10.3 mm. The closed-cell aluminum foam almost belongs to isotropic one, with a variation of ±15% in elastic modulus and yield strength in longitudinal and transverse direction. Under compressive loading, foam materials show inhomogeneous macroscopic deformation. The site of the onset of local plastic deformation depends on the cell structure. The shape of cell is more important than size in determining the yielding susceptibility of the cells. At early stage of deformation,the deformation is localized in narrow bands having width of one cells diameter, and outside the bands the cell still remains the original shape. The cells within bands experience large permanent deformation. The band normals are usually within 20° of the loading axis.

Compressive and energy absorption properties of closed-cell magnesium foams

The quasi-static compressive mechanical behavior and deformation mechanism of closed-cell magnesium foams were studied, and the ef- fects of the density of magnesium foams on the compressive and energy absorption properties were also discussed. The results show that the compressive process of closed-cell magnesium foams is characterized by three deformation stages： linear elastic stage, collapsing stage and densification stage. At the linear elastic stage, the peak compressive strength （t70） and Young＇s modulus （E0） increase as the density increases Magnesium foams can absorb energy at the collapsing stage. In a certain strain range, the energy absorption capacity also increases as the density of magnesium foams increases.

Effects of cell size on compressive properties of aluminum foam

The effects of cell size on the quasi-static and dynamic compressive properties of open cell aluminum foams produced by infiltrating process were studied experimentally. The quasi-static and dynamic compressive tests were carried out on MTS 810 system and SHPB(split Hopkinson pressure bar) respectively. It is found that the elastic moduli and compressive strengths of the studied aluminum foam are not only dependent on the relative density but also dependent on the cell size of the foam under both quasi-static loading and dynamic loading. The foams studied show a significant strain rate sensitivity, the flow strength can be improved as much as 112%, and the cell size also has a sound influence on the strain rate sensitivity of the foams. The foams of middle cell size exhibit the highest elastic modulus, the highest flow strength and the most significant strain rate sensitivity.

Effects of microstructure on uniaxial strength asymmetry of open-cell foams

Based on the elongated Kelvin model, the effect of microstructure on the uniaxial strength asymmetry of open-cell foams is investigated. The results indicate that this asymmetry depends on the relative density, the solid material, the cell morphology, and the strut geometry of open-cell foams. Even though the solid material has the same tensile and compressive strength, the tensile and compressive strength of open-cell foams with asymmetrical sectional struts are still different. In addition, with the increasing degree of anisotropy, the uniaxial strength as well as the strength asymmetry increases in the rise direction but reduces in the transverse direction. Moreover, the plastic collapse ratio between two directions is verified to depend mainly on the cell morphology. The predicted results are compared with Gibson and Ashby＇s theoretical results as well as the experimental data reported in the literature, which validates that the elongated Kelvin model is accurate in explaining the strength asymmetry presented in realistic open-cell foams.