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Find video protocols related to scientific articles indexed in Pubmed.
Possible antioxidant mechanism of melanoidins extract from Shanxi aged vinegar in mitophagy-dependent and mitophagy-independent pathways.
J. Agric. Food Chem.
PUBLISHED: 08-14-2014
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Melanoidins are widely reported to have antioxidant activity; however, their mechanism has not been frequently studied. In this study, we found that melanoidins from Shanxi aged vinegar induced mitopahgy, the specific autophagic elimination of mitochondria, as assessed by up-regulation of the autophagy markers LC3-II and Beclin1 as well as degradation of the autophagy substrate p62 and mitochondrial proteins. Melanoidins reduced reactive oxygen species (ROS) in normal human liver cells and mouse livers through a mitophagy-dependent pathway, by the observation that the reducing ROS effect of melanoidins was partially lost when mitophagy was inhibited by chloroquine. Impaired Akt signaling was found in cells treated with melanoidins, which might explain the activation of autophagy induced by melanoidins. These results suggest that in addition to direct free radical scavenging activity, melanoidins decreased ROS levels through mitophagy in which damaged mitochondria, the source of ROS, were degraded.
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A two-stage approach for medical supplies intermodal transportation in large-scale disaster responses.
Int J Environ Res Public Health
PUBLISHED: 06-30-2014
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We present a two-stage approach for the "helicopters and vehicles" intermodal transportation of medical supplies in large-scale disaster responses. In the first stage, a fuzzy-based method and its heuristic algorithm are developed to select the locations of temporary distribution centers (TDCs) and assign medial aid points (MAPs) to each TDC. In the second stage, an integer-programming model is developed to determine the delivery routes. Numerical experiments verified the effectiveness of the approach, and observed several findings: (i) More TDCs often increase the efficiency and utility of medical supplies; (ii) It is not definitely true that vehicles should load more and more medical supplies in emergency responses; (iii) The more contrasting the traveling speeds of helicopters and vehicles are, the more advantageous the intermodal transportation is.
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Irisin has no effect on lipolysis in 3T3-L1 adipocytes or fatty acid metabolism in HepG2 hepatocytes.
Endocrine
PUBLISHED: 05-22-2014
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Irisin, a newly identified myokine responsible for browning of white or beige adipocytes, has been reported to be present at reduced levels in diabetic patients and associated with obesity, serum triglyceride (TG) levels, and intrahepatic TG levels. We wondered whether irisin could directly affect fatty acid and TG metabolism in adipocytes and hepatocytes. We examined the effects of various concentrations of irisin on lipolysis (according to Oil Red O staining, free fatty acid release, and glycerol release), protein expression of HSL and ATGL, and mRNA expression of other lipid-related genes (UCP-1, PPAR?, FABP-4, HSL, ATGL, PPAR?, and CPT-1) in mature 3T3-L1 adipocytes, as well as mRNA levels of genes involved in the synthesis (SREBP-1C and FAS) and ?-oxidation (PPAR? and CPT-1) of fatty acids in HepG2 hepatocytes under physiological or hyperglycemic conditions. Our results revealed that although irisin significantly increased the mRNA levels of UCP-1 and PPAR?, it failed to show detectable effects on lipolysis, HSL or ATGL protein levels, or the mRNA expression of other lipid-related genes in mature 3T3-L1 adipocytes. In HepG2 hepatocytes, high glucose induced the upregulation of SREBP-1C and FAS and the downregulation of PPAR?; however, no significant effect of irisin on gene expression was observed under either physiological or hyperglycemic conditions. We therefore conclude that irisin has no significant direct effect on lipolysis in 3T3-L1 adipocytes or on fatty acid metabolism in HepG2 hepatocytes.
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Deficiency of CCAAT/enhancer binding protein-epsilon reduces atherosclerotic lesions in LDLR-/- mice.
PLoS ONE
PUBLISHED: 01-01-2014
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The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBP? is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr-/-) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBP? is involved in systemic lipid metabolism and that silencing of C/EBP? could decrease the development of atherosclerosis.
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Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice.
FASEB J.
PUBLISHED: 06-10-2013
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We examined the effects of a natural secondary bile acid, hyodeoxycholic acid (HDCA), on lipid metabolism and atherosclerosis in LDL receptor-null (LDLRKO) mice. Female LDLRKO mice were maintained on a Western diet for 8 wk and then divided into 2 groups that received chow, or chow + 1.25% HDCA, diets for 15 wk. We observed that mice fed the HDCA diet were leaner and exhibited a 37% (P<0.05) decrease in fasting plasma glucose level. HDCA supplementation significantly decreased atherosclerotic lesion size at the aortic root region, the entire aorta, and the innominate artery by 44% (P<0.0001), 48% (P<0.01), and 94% (P<0.01), respectively, as compared with the chow group. Plasma VLDL/IDL/LDL cholesterol levels were significantly decreased, by 61% (P<0.05), in the HDCA group as compared with the chow diet group. HDCA supplementation decreased intestinal cholesterol absorption by 76% (P<0.0001) as compared with the chow group. Furthermore, HDL isolated from the HDCA group exhibited significantly increased ability to mediate cholesterol efflux ex vivo as compared with HDL of the chow diet group. In addition, HDCA significantly increased the expression of genes involved in cholesterol efflux, such as Abca1, Abcg1, and Apoe, in a macrophage cell line. Thus, HDCA is a candidate for antiatherosclerotic drug therapy.
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Testing the iron hypothesis in a mouse model of atherosclerosis.
Cell Rep
PUBLISHED: 05-23-2013
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Hepcidin, the iron-regulatory hormone and acute phase reactant, is proposed to contribute to the pathogenesis of atherosclerosis by promoting iron accumulation in plaque macrophages, leading to increased oxidative stress and inflammation in the plaque (the "iron hypothesis"). Hepcidin and iron may thus represent modifiable risk factors in atherosclerosis. We measured hepcidin expression in Apoe(-/-) mice with varying diets and ages. To assess the role of macrophage iron in atherosclerosis, we generated Apoe(-/-) mice with macrophage-specific iron accumulation by introducing the ferroportin ffe mutation. Macrophage iron loading was also enhanced by intravenous iron injection. Contrary to the iron hypothesis, we found that hepatic hepcidin expression was not increased at any stage of the atherosclerosis progression in Apoe(-/-) or Apoe/ffe mice and that the atherosclerotic plaque size was not increased in mice with elevated macrophage iron. Our results strongly argue against any significant role of macrophage iron in atherosclerosis progression in mice.
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Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells.
Exp Ther Med
PUBLISHED: 02-16-2013
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Studies have indicated that the immune system plays a pivotal role in hepatitis. Substance P (SP) has been shown to modulate the immune response. In order to investigate the role of SP in liver injury and to determine whether it leads to pro-inflammatory signaling, we established a mouse model of hepatic injury induced by concanavalin A (ConA). We also exposed mouse Kupffer cells (KCs) to SP in vitro. Cytokine and SP levels in liver homogenates were detected using enzyme-linked immunosorbent assay (ELISA) and the protective effects of L-703,606 were evaluated through serological and histological assessments. Neurokinin-1 receptor (NK-1R) expression was evaluated by immunofluorescence and quantitative polymerase chain reaction (PCR). The levels of SP, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased in the ConA-treated mice and the levels of ALT and AST were markedly reduced by L-703,606-pretreatment. Liver injury was significantly reduced by treatment with L-703,606. The mouse KCs expressed NK-1R and SP increased NK-1R mRNA expression. Furthermore, NK-1R blockade eliminated the effect of SP on NK-1R mRNA expression. The cytokine levels exhibited a substantial increase in the SP-pretreated KCs compared with the KCs that were cultured in control medium. The inter-leukin (IL)-6 and tumor necrosis factor (TNF)-? levels in the L-703,606-pretreated KCs were significantly lower compared with those in the SP-pretreated KCs. Our study suggests that neurogenic inflammation induced by SP plays an important role in hepatitis. Mouse KCs express NK-1R and SP increases NK-1R mRNA expression. SP enhances IL-6 and TNF-? secretion and an NK-1R antagonist inhibits this secretion.
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Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity.
Injury
PUBLISHED: 02-16-2013
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Th17 lymphocytes have important roles in inflammation and autoimmune disease. Research on relationship between Th17 lymphocytes and pain associated with lumbar disc herniation (LDH) is limited. The purpose of this study was to examine the association of pain and Th17 lymphocyte and interleukin (IL)-17 levels in patients with herniated and non-herniated lumbar discs.
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The effects of qindan-capsule-containing serum on the TGF-?1/ERK signaling pathway, matrix metalloproteinase synthesis and cell function in adventitial fibroblasts.
Pharm Biol
PUBLISHED: 02-04-2013
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Qindan capsule (QC), a compound used in traditional Chinese medicine, has been used as an anti-hypertensive agent in clinical settings for years. Our previous studies have shown that QC can improve the morphological index of the artery, down-regulate the collagen volume fraction in the media and inhibit the transformation of smooth muscle cells. However, the detailed mechanisms underlying its effects require further investigation, which might provide more scientific evidence for the clinical treatment of hypertensive vascular remodeling (VR).
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Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes.
Int. J. Mol. Med.
PUBLISHED: 01-28-2013
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Glucagon-like peptide 1 (GLP-1), a gut-derived peptide, has been reported to have profound effects on metabolism and to reduce insulin resistance. Adipocyte hyperplasia stimulated by preadipocyte differentiation has a positive effect on adipose tissue insulin sensitivity. However, it remains less clear whether GLP-1 plays a role in adipogenesis. In this study, we examined the effect of GLP-1 on preadipocyte differentiation and investigated the mechanisms that may be involved in this effect. In our 3T3-L1 cell study, we tested the levels of adipocyte-specific markers and signaling pathways during preadipocyte differentiation. In addition, Oil Red O staining was used to examine lipid accumulation. Image Pro Plus 5.02 was used to analyze the size and number of lipid droplets. We found that GLP-1 elevated the protein expression levels of free fatty acid-binding protein 4 (aP2) and the transcription factor peroxisome proliferator-activated receptor-? (PPAR??) in a dose-dependent manner during 3T3?L1 preadipocyte differentiation. Furthermore, RT?PCR results showed that GLP-1 promoted CCAAT/enhancer-binding protein ? (C/EBP?) and lipoprotein lipase (LPL) expression at the transcriptional level. These data suggest that GLP-1 promotes preadipocyte differentiation. Our study also found that treatment of the cells with 100 nM GLP-1 enhanced the phosphorylation of Akt signaling during the first 24 h of differentiation. Although Oil Red O staining showed that GLP?1 had no significant effect on lipid accumulation, there were increased numbers of small adipocytes in the cells treated with 100 nM GLP?1. Taken together, these results indicate that GLP-1 regulates 3T3?L1 adipogenesis and the Akt signaling pathway may be involved in this process. The differentiated small adipocytes may have a positive effect against insulin resistance and obesity.
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Cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated acute epileptic neuronal death in vitro.
Brain Res.
PUBLISHED: 01-07-2013
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Intense poly(ADP-ribose) polymerase-1 (PARP-1) activation was implicated as a major cause of caspase-independent cell death in the hippocampal neuronal culture (HNC) model of acute acquired epilepsy (AE). The molecular mechanisms are quite complicated. The linkage among neuronal death, cellular nicotinamide adenine dinucleotide (NAD) levels, apoptosis-inducing factor (AIF) translocation, SIRT1 expression and activity were investigated here. The results showed that PARP-1 over-activation caused by Mg²?-free stimuli led to cellular NAD depletion which could block AIF translocation from mitochondria to nucleus and attenuate neuronal death. Also, SIRT1 deacetylase activity was reduced by Mg²?-free treatment, accompanied by elevated ratio of neuronal death, which could be rescued by NAD repletion. These data demonstrated that cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated epileptic neuronal death in the HNC model of acute AE.
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Resveratrol inhibits the growth of gastric cancer by inducing g1 phase arrest and senescence in a sirt1-dependent manner.
PLoS ONE
PUBLISHED: 01-01-2013
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Resveratrol, a naturally occurring polyphenolic compound, has been reported to exert anticancer activity by affecting diverse molecular targets. In this study, we examined the effects and the underlying mechanisms of resveratrol on gastric cancer. We found that resveratrol inhibited the proliferation of gastric cancer cells in a dose-dependent manner. At the concentration of 25 and 50 µM, resveratrol inhibited the cell viability and diminished the clonogenic potential of gastric cancer cells. Resveratrol treatment arrested gastric cancer cells in the G1 phase and led to senescence instead of apoptosis. Regulators of the cell cycle and senescence pathways, including cyclin D1, cyclin-dependent kinase (CDK4 and 6), p21 and p16, were dysregulated by resveratrol treatment. The inhibitory effects of resveratrol on gastric cancer were also verified in vivo using a nude mice xenograft model. Resveratrol (40 mg/kg/d) exerted inhibitory activities on gastric cancer development and significantly decreased the fractions of Ki67-positive cells in the tumor specimens from the nude mice. After resveratrol treatment, the induction of senescence and the changes in the expression of the regulators involved in the cell cycle and senescence pathways were similar to what we observed in vitro. However, the depletion of Sirtuin (Sirt)1 reversed the above-described effects of resveratrol both in vitro and in vivo. Our data suggest that resveratrol inhibits gastric cancer in a Sirt1-dependent manner and provide detailed evidence for the possibility of applying resveratrol in gastric cancer prevention and therapy.
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A peptide-mediated targeting gene delivery system for malignant glioma cells.
Int J Nanomedicine
PUBLISHED: 01-01-2013
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Glioblastoma multiforme (GBM) is the most common and malignant glioma. Although there has been considerable progress in treatment strategies, the prognosis of many patients with GBM remains poor. In this work, polyethylenimine (PEI) and the VTWTPQAWFQWV (VTW) peptide were modified and synthesized into GBM-targeting nanoparticles. The transfection efficiency of U-87 (human glioblastoma) cells was evaluated using fluorescence microscopy and flow cytometry. Cell internalization was investigated to verify the nanoparticle delivery into the cytoplasm. Results showed that the methods of polymer conjugation and the amount of VTW peptide were important factors to polymer synthesis and transfection. The PEI-VTW20 nanoparticles increased the transfection efficiency significantly. This report describes the use of VTW peptide-based PEI nanoparticles for intracellular gene delivery in a GBM cell-specific manner.
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Pathway of Toll-like receptor 7/B cell activating factor/B cell activating factor receptor plays a role in immune thrombocytopenia in vivo.
PLoS ONE
PUBLISHED: 03-24-2011
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Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP.
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TLR7 promotes Th1 polarization in immune thrombocytopenia.
Thromb. Res.
PUBLISHED: 02-11-2011
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T helper 1 cell (Th1) polarization persists in the autoimmune response found in immune thrombocytopenia (ITP). Toll-like receptor 7 (TLR7) expression, which also plays an important role in autoimmune diseases, was verified to increase in ITP. However, the exact role of TLR7 in ITP is not well elucidated. Here, we explored the hypothesis that TLR7 participates in the pathophysiology of ITP by affecting Th1 polarization.
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The imbalance of Th17/Treg in patients with uterine cervical cancer.
Clin. Chim. Acta
PUBLISHED: 01-07-2011
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Th17/Treg was reported to play critical roles in immunoregulation, and its imbalance may lead to autoimmune diseases and allergic reactions. Information on Th17/Treg in cancer bearing hosts is still limited.
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Biodegradable microfibers deliver the antitumor drug temozolomide to glioma C6 cells in vitro.
Pharmazie
PUBLISHED: 12-16-2010
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To develop effective implants for delivery of 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide (temozolomide; TM) with low initial burst and less neurotoxicity, TM-loaded poly-propylene carbonate (PPC) fiber was fabricated by electrospinning. Some of the fiber sheets were then covered with alginate (ALG). Influences of several preparation parameters on drug delivery behavior were investigated. The micro-morphology of these fibers was studied using scanning electron microscopy and differential scanning calorimetry. In vitro release properties of two forms of samples were observed and their cytotoxicity against C6 glioma cells was assessed. Using strict preparation parameters, smooth and uniform fiber could only be obtained when the PPC concentration was 8 % by weight, at 20cm and a voltage of 15 kV between the nozzle and the collection instrument. Fiber diameter was about 3 microm. The initial burst of drug-fiber sheets was reduced after the fiber sheets were covered with ALG. Cytotoxicity test results suggested that both forms of drug fibers inhibit the C6 glioma cells continuously; the pure drug-fiber sheets were strongly cytotoxic. We conclude that (a) electrospinning is a reliable fabrication method for M-loaded PPC fibers; and (b) an ALG coating reduces the initial burst of the fiber sheets.
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Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models.
Stem Cells Dev.
PUBLISHED: 11-08-2010
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Hyperkinetic pulmonary arterial hypertension (PAH) severely influences the success of operation for congenital heart disease and deteriorates the prognosis of disease. Adipose-derived stromal cell (ADSC) is a good alternative multipotent stem cell for regeneration medicine. PAH rat models were established by arteriovenous shunt and ADSCs were isolated, cultured, and labeled in vitro. Twelve weeks after shunt operation, rats received an injection of 5 × 10(7) ADSCs. Two weeks after transplantation, hemodynamic abnormality induced by the shunt flow and the hypertrophy of right ventricle were reversed, which was confirmed by invasive measurement and echocardiography examination. The PAH rats receiving cell transplantation demonstrated decreased remodeling of small arteries in the lung; immunohistochemistry analysis showed augmented expression of hepatocyte growth factor (HGF) and increased number of pulmonary small arteries. Western blot and real-time reverse transcriptase-polymerase chain reaction indicated that the protein and mRNA levels of HGF and endothelial nitric oxide synthase increased, respectively, in the lung after cell transplantation. Our results suggested that ADSC transplantation can ameliorate PAH induced by shunt flow by enhancing the expression of HGF and subsequently promoting angiogenesis in the injured lung tissue.
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NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 10-14-2010
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To test the hypothesis that NF-E2-related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties.
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Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.
Circ. Res.
PUBLISHED: 06-24-2010
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The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall.
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Tissue-specific expression of TIPE2 provides insights into its function.
Mol. Immunol.
PUBLISHED: 05-16-2010
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Tumor necrosis factor-alpha-induced protein-8 like-2 (TNFAIP8L2, TIPE2) is a newly discovered negative regulator of innate immunity and cellular immunity. TIPE2 deficiency in mice causes fetal inflammatory diseases and TIPE2 downregulation in humans is associated with systemic autoimmunity. However, TIPE2 deficiency leads to a selective defect in humoral immunity. Due to the lack of a suitable antibody, the nature of cells and tissues that express TIPE2 protein has not been determined. In this study, we generated a highly specific antibody to TIPE2 and examined TIPE2 expression in various murine tissues by immunohistochemistry and RT-PCR. We found that TIPE2 was a cytoplasmic protein expressed preferentially in lymphoid tissues and a small group of non-lymphoid tissues. Within the lymphoid compartment, T cells appear to express high level of TIPE2 protein, while B cells and B cell zones of lymphoid organs were devoid of TIPE2. Within most of the non-lymphoid tissues, TIPE2 was not detected. However, several endocrine tissues and skeletal muscle expressed detectable TIPE2 protein and mRNA. Furthermore, high levels of TIPE2 were detected in monocyte/macrophage derived cell lines and ovarian adenocarcinoma cells, but not detectable or weakly expressed in most human carcinoma cell lines. These results indicate that TIPE2 may perform tissue-specific functions in both lymphoid and non-lymphoid compartments. They may also explain why TIPE2 deficiency enhanced cellular but not humoral immunity.
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Impaired development of atherosclerosis in Abcg1-/- Apoe-/- mice: identification of specific oxysterols that both accumulate in Abcg1-/- Apoe-/- tissues and induce apoptosis.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 03-18-2010
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To generate Abcg1(-/-) Apoe(-/-) mice to understand the mechanism and cell types involved in changes in atherosclerosis after loss of ABCG1.
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Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis.
J. Lipid Res.
PUBLISHED: 02-28-2010
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Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice. In this report we investigate this mechanism and explore a therapeutic avenue based on inhibition of CSF-1 signaling. Lesions from macrophage colony stimulating factor-1 (Csf1)+/- mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and inflammation. In vitro studies indicated that CSF-1 is chemotactic for monocytes. Bone marrow transplantation studies suggested that vascular cell-derived, rather than macrophage-derived, CSF-1 is responsible for the effect on atherosclerosis. Consistent with previous studies, CSF-1 affected lesion development in a dose-dependent manner, suggesting that pharmacological inhibition of CSF-1 might achieve similar results. Indeed, we observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. This observation was accompanied by a reduction in the expression of adhesion factors (ICAM-1), macrophage markers (F4/80), inflammatory cytokines (Il-6, Il-1beta), and macrophage matrix degradation enzymes (MMP-9). We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention.
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Identification and validation of genes affecting aortic lesions in mice.
J. Clin. Invest.
PUBLISHED: 02-22-2010
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Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.
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Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis.
Arthritis Res. Ther.
PUBLISHED: 01-26-2010
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The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.
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Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.
Circ Cardiovasc Genet
PUBLISHED: 12-30-2009
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We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.
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Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice.
Circ Cardiovasc Genet
PUBLISHED: 10-19-2009
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Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans.
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Chylomicronemia elicits atherosclerosis in mice--brief report.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 10-08-2009
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The risk of atherosclerosis in the setting of chylomicronemia has been a topic of debate. In this study, we examined susceptibility to atherosclerosis in Gpihbp1-deficient mice (Gpihbp1(-/-)), which manifest severe chylomicronemia as a result of defective lipolysis.
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The synergistic inhibition of atherogenesis in apoE-/- mice between pravastatin and the sPLA2 inhibitor varespladib (A-002).
J. Lipid Res.
PUBLISHED: 06-23-2009
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Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE(-/-) mice were investigated. Male apoE(-/-) mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-alpha actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by approximately 75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.
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Genetic regulation of atherosclerotic plaque size and morphology in the innominate artery of hyperlipidemic mice.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 01-02-2009
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We sought to determine the genetic factors contributing to atherosclerotic plaque size and cellular composition in the innominate artery, a murine model of advanced atherosclerosis.
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Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate.
Cardiovasc Diabetol
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All of the components of metabolic syndrome (MetS) have been regarded as risk factors for coronary artery disease (CAD). Early detection of CAD in asymptomatic patients with MetS remains a challenge. Cystatin C,which has been proposed as a novel marker of renal dysfunction,is correlated with mortality in CAD, The purpose of the study was to evaluate whether cystatin C is a potential marker of asymptomatic CAD in MetS patients with normal kidney function.
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Effect of 9p21.3 coronary artery disease locus neighboring genes on atherosclerosis in mice.
Circulation
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The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap, the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b, in atherosclerosis using knockout mice models.
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Functional interaction of TRPV4 channel protein with annexin A2 in DRG.
Neurol. Res.
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Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable, non-selective cation channel that is involved in the transmission of pain signals mediated by dorsal root ganglion (DRG). Annexin A2 belongs to a class of membrane-binding proteins that plays an important role in the regulation of ion channels. Nevertheless, little is known about the interaction between them in DRG. In this paper, we evaluated the functional interaction of TRPV4 with annexin A2 in DRG.
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High-resolution association mapping of atherosclerosis loci in mice.
Arterioscler. Thromb. Vasc. Biol.
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The purpose of this study was to fine map previously identified quantitative trait loci affecting atherosclerosis in mice using association analysis.
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The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma.
Oncol. Rep.
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Lung adenocarcinoma, with increased incidence in the world, exhibits poor prognosis and is usually resistant to conventional chemotherapy due to drug resistance. The enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in tumorigenesis and cancer development through chromatin remodeling in various types of cancer. However, its potential role in lung adenocarcinoma has not been well defined. In this study, the expression of EZH2 was examined in lung adenocarcinoma tissues and cell lines. Most interestingly, EZH2 overexpression was detected in tumor tissue and significantly correlated with histological differentiation, pathological tumor-node-metastasis stage and smoking history, but not with gender or age. Furthermore, EZH2 overexpression was also detected in cisplatin-resistant cancer cells rather than cisplatin-sensitive cells. Short hairpin RNA targeted against EZH2 inhibited cell proliferation and migration, and led to G(2)/M cell cycle arrest and apoptosis in both cisplatin-resistant and cisplatin-sensitive cell lines. Moreover, EZH2 knockdown enhanced cisplatin sensitivity of cisplatin-resistant cells and reduced the expression levels of multidrug resistance-related protein 1. Our study suggests that EZH2 contributes to the progression of lung adenocarcinoma, and the deletion of EZH2 inhibits cancer and resensitizes cells to cisplatin in lung adenocarcinoma.
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LXR? is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice.
J. Lipid Res.
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The liver X receptor (LXR) signaling pathway is an important modulator of atherosclerosis, but the relative importance of the two LXRs in atheroprotection is incompletely understood. We show here that LXR?, the dominant LXR isotype expressed in liver, plays a particularly important role in whole-body sterol homeostasis. In the context of the ApoE(-/-) background, deletion of LXR?, but not LXR?, led to prominent increases in atherosclerosis and peripheral cholesterol accumulation. However, combined loss of LXR? and LXR? on the ApoE(-/-) background led to an even more severe cholesterol accumulation phenotype compared to LXR?(-/-)ApoE(-/-) mice, indicating that LXR? does contribute to reverse cholesterol transport (RCT) but that this contribution is quantitatively less important than that of LXR?. Unexpectedly, macrophages did not appear to underlie the differential phenotype of LXR?(-/-)ApoE(-/-) and LXR?(-/-)ApoE(-/-) mice, as in vitro assays revealed no difference in the efficiency of cholesterol efflux from isolated macrophages. By contrast, in vivo assays of RCT using exogenously labeled macrophages revealed a marked defect in fecal sterol efflux in LXR?(-/-)ApoE(-/-) mice. Mechanistically, this defect was linked to a specific requirement for LXR?(-/-) in the expression of hepatic LXR target genes involved in sterol transport and metabolism. These studies reveal a previously unrecognized requirement for hepatic LXR? for optimal reverse cholesterol transport in mice.
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In vitro and in vivo antioxidant and antimutagenic activities of polyphenols extracted from hops (Humulus lupulus L.).
J. Sci. Food Agric.
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Hops (Humulus lupulus L.) contain 40 to 140?mg?g(-1) polyphenols. The objective of this study was to determine the phenolic composition of a high-purity (total phenolic content?=?887?mg?g(-1) ) hop polyphenol extract (HPE) and evaluate its antioxidant activities in vivo and in vitro and antimutagenic activity. The antioxidant activity of HPE was compared with the activity of green tea polyphenols.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.