CD36 facilitates oxidized low density lipoprotein uptake and is implicated in development of atherosclerotic lesions. CD36 also binds unmodified high and very low density lipoproteins (HDL, VLDL) but Show more
CD36 facilitates oxidized low density lipoprotein uptake and is implicated in development of atherosclerotic lesions. CD36 also binds unmodified high and very low density lipoproteins (HDL, VLDL) but its role in the metabolism of these particles is unclear. Several polymorphisms in the CD36 gene were recently shown to associate with serum HDL cholesterol. To gain insight into potential mechanisms for these associations we examined HDL metabolism in CD36 null (CD36(-/-)) mice. Feeding CD36(-/-) mice a high cholesterol diet significantly increased serum HDL, cholesterol and phospholipids, as compared to wild type mice. HDL apolipoproteins apoA-I and apoA-IV were increased and shifted to higher density HDL fractions suggesting altered particle maturation. Clearance of dual-labeled HDL was unchanged in CD36(-/-) mice and cholesterol uptake from HDL or LDL by isolated CD36(-/-) hepatocytes was unaltered. However, CD36(-/-) hepatocytes had higher cholesterol and phospholipid efflux rates. In addition, expression and secretion of apoA-I and apoA-IV were increased reflecting enhanced PXR. Similar to hepatocytes, cholesterol and phospholipid efflux were enhanced in CD36(-/-) macrophages without changes in protein levels of ABCA1, ABCG1 or SR-B1. However, biotinylation assays showed increased surface ABCA1 localization in CD36(-/-) cells. In conclusion, CD36 influences reverse cholesterol transport and hepatic ApoA-I production. Both pathways are enhanced in CD36 deficiency, increasing HDL concentrations, which suggests the potential benefit of CD36 inhibition. Show less
The neighboring position of apolipoprotein A-I (apoA-I) and apolipoprotein A-V (apoA-V) gene and the modulation of apoA-V on the concentrations, size and maturation of high density lipoprotein (HDL) m Show more
The neighboring position of apolipoprotein A-I (apoA-I) and apolipoprotein A-V (apoA-V) gene and the modulation of apoA-V on the concentrations, size and maturation of high density lipoprotein (HDL) may indicate a special relationship between apoA-V and HDL. To assess the effects of apoA-V on HDL structure and related functions in vitro, a series of recombinant HDL (rHDL) were synthesized in vitro with various mass ratios of recombinant apoA-I: apoA-V. An increase in apoA-V in rHDL resulted in enhanced lipid-binding ability, increased phospholipid content and larger particle size. Furthermore, the lipid-free and lipid-bound apoA-V in rHDL showed antioxidant capacity against low density lipoprotein (LDL) in vitro. In THP-1 derived macrophages, apoA-V of rHDL was shown to have no influence on the uptake of oxidized LDL (oxLDL) and intracellular lipid accumulation. Thus, the addition of apoA-V to rHDL resulted in changes in several rHDL properties, including increased lipid-binding ability, phospholipid content, particle size and antioxidant capacity. These alterations may explain the modulation of apoA-V on HDL in vivo and the beneficial functions of apoA-V on atherosclerosis. Show less
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic Show more
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk. Show less
Genetic variations in the APOA1/C3/A4/A5 gene cluster have been studied and proposed to be the leading key for susceptibility to cardiovascular diseases and age-associated disorders. We aimed to inves Show more
Genetic variations in the APOA1/C3/A4/A5 gene cluster have been studied and proposed to be the leading key for susceptibility to cardiovascular diseases and age-associated disorders. We aimed to investigate the associations of rs12721026 (APOA1) and rs1729408 (APOA5) polymorphisms and their haplotypes with some age-related diseases, as well as with lipids and proteins serum levels in a cohort from a Brazilian Elderly Longitudinal Study (EPIDOSO). Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Statistical analyses were carried out using logistic regression analysis, Student's t-test, and linkage disequilibrium (LD) analysis. Polymorphic allele frequencies were 0.095 and 0.449 for rs12721026 and rs1729408, respectively. The C-allele of rs1729408 was associated with higher high-density lipoprotein (HDL) (P = 0.022) and glycated hemoglobin levels (P = 0.020). We also showed that rs12721026 and rs1729408 were in LD. The GC haplotype, which is composed of the G-allele of rs12721026 and the C-allele of rs1729408, was significantly associated with obesity (P = 0.028), with higher glycated hemoglobin (P = 0.006), and fasting glucose (P = 0.0003) compared to the TT haplotype, which includes the wild-type alleles of both polymorphisms. Moreover, we found an association between the TC haplotype and higher HDL levels (P = 0.0039). This is the first time that haplotypes involving these polymorphisms were evaluated. Our results showed that these polymorphisms were involved in the development of obesity and in alterations of lipids and proteins serum levels in a Brazilian population. The present findings might also clarify the role of these polymorphisms and their haplotypes in lipids and proteins metabolism. Show less
The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-re Show more
The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community. Show less
Debbie Y Dao, Xue Yang, Lisa M Flick+3 more · 2010 · Journal of orthopaedic research : official publication of the Orthopaedic Research Society · Wiley · added 2026-04-24
Axis inhibition proteins 1 and 2 (Axin1 and Axin2) are scaffolding proteins that modulate at least two signaling pathways that are crucial in skeletogenesis: the Wnt/beta-catenin and TGF-beta signalin Show more
Axis inhibition proteins 1 and 2 (Axin1 and Axin2) are scaffolding proteins that modulate at least two signaling pathways that are crucial in skeletogenesis: the Wnt/beta-catenin and TGF-beta signaling pathways. To determine whether Axin2 is important in skeletogenesis, we examined the skeletal phenotype of Axin2-null mice in a wild-type or Axin1(+/-) background. Animals with disrupted Axin2 expression displayed a runt phenotype when compared to heterozygous littermates. Whole-mount and tissue beta-galactosidase staining of Axin2(LacZ/LacZ) mice revealed that Axin2 is expressed in cartilage tissue, and histological sections from knockout animals showed shorter hypertrophic zones in the growth plate. Primary chondrocytes were isolated from Axin2-null and wild-type mice, cultured, and assayed for type X collagen gene expression. While type II collagen levels were depressed in cells from Axin2-deficient animals, type X collagen gene expression was enhanced. There was no difference in BrdU incorporation between null and heterozygous mice, suggesting that loss of Axin2 does not alter chondrocyte proliferation. Taken together, these findings reveal that disruption of Axin2 expression results in accelerated chondrocyte maturation. In the presence of a heterozygous deficiency of Axin1, Axin2 was also shown to play a critical role in craniofacial and axial skeleton development. Show less
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, Show more
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less
Platelet function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in this process. We tested association of 2.5 million SNPs with pla Show more
Platelet function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in this process. We tested association of 2.5 million SNPs with platelet aggregation responses to three agonists (ADP, epinephrine and collagen) in two cohorts of European ancestry (NShow less
The x protein of HBV (HBx) has been involved in the development of hepatocellular carcinoma (HCC), with a possible link to individual genotypes. Nevertheless, the underlying mechanism remains obscure. Show more
The x protein of HBV (HBx) has been involved in the development of hepatocellular carcinoma (HCC), with a possible link to individual genotypes. Nevertheless, the underlying mechanism remains obscure. In this study, we aim to identify the HBx-induced protein profile in HepG2 cells by LC-MS/MS proteomics analysis. Our results indicated that proteins were differentially expressed in HepG2 cells transfected by HBx of various genotypes. Proteins associated with cytoskeleton were found to be either up-regulated (MACF1, HMGB1, Annexin A2) or down-regulated (Lamin A/C). These may in turn result in the decrease of focal adhesion and increase of cell migration in response to HBx. Levels of other cellular proteins with reported impact on the function of extracellular matrix (ECM) proteins and cell migration, including Ca(2+)-binding proteins (S100A11, S100A6, and S100A4) and proteasome protein (PSMA3), were affected by HBx. The differential protein profile identified in this study was also supported by our functional assay which indicated that cell migration was enhanced by HBx. Our preliminary study provided a new platform to establish a comprehensive cellular protein profile by LC-MS/MS proteomics analysis. Further downstream functional assays, including our reported cell migration assay, should provide new insights in the association between HCC and HBx. Show less
Upregulation of endothelin 1 (ET-1) causing blood flow alteration and increased extracellular matrix production are characteristic features of diabetic angiopathy. Several glucose-induced signaling me Show more
Upregulation of endothelin 1 (ET-1) causing blood flow alteration and increased extracellular matrix production are characteristic features of diabetic angiopathy. Several glucose-induced signaling mechanisms cause ET-1 upregulation in diabetic angiopathy. Extracellular signal-regulated kinase 5 (ERK5) is a member of the MAPK family, which plays a key role in cardiovascular development. ERK kinase (MEK) 5 is the specific MEK for ERK5 activation. In this study we examined the role of glucose-induced ERK5 signaling in mediating ET-1 expression in diabetic angiopathy. We investigated retinas from 1-month STZ-induced diabetic rats and human macro- and microvascular endothelial cells to study ERK5-dependent ET-1 alterations. Glucose (25 mmol/L) caused significant upregulation of ET-1 mRNA and downregulation of ERK5 and Kruppel-like factor 2 (KLF2) after 24 h treatment in the endothelial cells. Simultaneously, phospho-ERK5 proteins were reduced. Activation of ERK5 by constitutively active MEK5 (caMEK5) upregulated KLF2 and suppressed ET-1 expression in both cell lines, whereas ERK5 siRNA transfection resulted in decreased ERK5 and KLF2 and increased ET-1 mRNA expression. In addition, caMEK5 prevented glucose-induced upregulation of ET-1. Furthermore, 1 month of diabetes caused a significant increase in retinal ET-1 mRNA and decrease in ERK5 mRNA expression. These data indicate that ERK5 signaling regulates glucose-induced ET-1 expression in diabetes. The ERK5/ET-1 pathway may provide a potential novel target for the treatment of diabetic angiopathy. Show less
Adult human bone marrow-derived multipotent progenitor cells (MPCs) are able to differentiate into a variety of specialized cell types, including chondrocytes, and are considered a promising candidate Show more
Adult human bone marrow-derived multipotent progenitor cells (MPCs) are able to differentiate into a variety of specialized cell types, including chondrocytes, and are considered a promising candidate cell source for use in cartilage tissue engineering. In this study, we examined the regulation of MPC chondrogenesis by mitogen-activated protein kinases in an attempt to better understand how to generate hyaline cartilage in the laboratory that more closely resembles native tissue. Specifically, we employed the high-density pellet culture model system to assess the roles of ERK5 and ERK1/2 pathway signaling in MPC chondrogenesis. Western blotting revealed that high levels of ERK5 phosphorylation correlate with low levels of MPC chondrogenesis and that as TGF-beta 3-enhanced MPC chondrogenesis proceeds, phospho-ERK5 levels steadily decline. Conversely, levels of phospho-ERK1/2 paralleled the progression of MPC chondrogenesis. siRNA-mediated knockdown of ERK5 pathway components MEK5 and ERK5 resulted in increased MPC pellet mRNA transcript levels of the cartilage-characteristic marker genes SOX9, COL2A1, AGC, L-SOX5, and SOX6, as well as enhanced accumulation of SOX9 protein, collagen type II protein, and Alcian blue-stainable proteoglycan. In contrast, knockdown of ERK1/2 pathway members MEK1 and ERK1 decreased expression of all chondrogenic markers tested. Finally, overexpression of MEK5 and ERK5 also depressed MPC chondrogenesis, as indicated by diminished activity of a co-transfected collagen II promoter-luciferase reporter construct. In conclusion, our results suggest a novel role for the ERK5 pathway as an important negative regulator of adult human MPC chondrogenesis and illustrate that the ERK5 and ERK1/2 kinase cascades play opposing roles regulating MPC cartilage formation. Show less
We report a case of a 6-month-old boy with a mixed phenotype acute leukemia (MPAL), bilineal and biphenotypic immunophenotype (B-lymphoid lineage and combined B-lymphoid and monocytic lineage) with t( Show more
We report a case of a 6-month-old boy with a mixed phenotype acute leukemia (MPAL), bilineal and biphenotypic immunophenotype (B-lymphoid lineage and combined B-lymphoid and monocytic lineage) with t(10;11)(p12;q23);MLL-MLLT10. He was treated with acute myeloid leukemia protocol and in complete remission at 7-month follow-up. To the best of our knowledge, this is the first reported MLL-MLLT10 rearranged case presenting as MPAL in an infant. From a clinical practice standpoint, this case illustrates the importance of detection of MLL rearrangement due to its prognostic implication and the effectiveness of flow cytometry immunophenotyping in diagnosing MPAL and monitoring minimal residual disease. Show less
Carbohydrate response element binding protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have prev Show more
Carbohydrate response element binding protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have previously reported that high glucose can activate the transcriptional activity of ChREBP independent of the protein phosphatase 2A (PP2A)-mediated increase in nuclear entry and DNA binding. Here, we found that formation of glucose-6-phosphate (G-6-P) is essential for glucose activation of ChREBP. The glucose response of GAL4-ChREBP is attenuated by D-mannoheptulose, a potent hexokinase inhibitor, as well as over-expression of glucose-6-phosphatase (G6Pase); kinetics of activation of GAL4-ChREBP can be modified by exogenously expressed GCK. Further metabolism of G-6-P through the two major glucose metabolic pathways, glycolysis and pentose-phosphate pathway, is not required for activation of ChREBP; over-expression of glucose-6-phosphate dehydrogenase (G6PD) diminishes, whereas RNAi knockdown of the enzyme enhances, the glucose response of GAL4-ChREBP, respectively. Moreover, the glucose analogue 2-deoxyglucose (2-DG), which is phosphorylated by hexokinase, but not further metabolized, effectively upregulates the transcription activity of ChREBP. In addition, over-expression of phosphofructokinase (PFK) 1 and 2, synergistically diminishes the glucose response of GAL4-ChREBP. These multiple lines of evidence support the conclusion that G-6-P mediates the activation of ChREBP. Show less
To investigate the genotype-phenotype correlation in Chinese familial and sporadic hypertrophic cardiomyopathy, specific exons of the myosin binding protein-c gene (MYBPC3) were screened in six famili Show more
To investigate the genotype-phenotype correlation in Chinese familial and sporadic hypertrophic cardiomyopathy, specific exons of the myosin binding protein-c gene (MYBPC3) were screened in six families with hypertrophic cardiomyopathy (HCM; FHCM) and in 20 patients with sporadic HCM (SHCM) from the Anhui Province region of China. The V896M mutation was detected for the first time in China in two families with FHCM. The mutation was not found in 100 healthy control subjects. No mutations of MYBPC3 were detected in any of the SHCM patients. In contrast to previous reports, the V896M mutation may be a disease-causing mutation in China, and exon 27 of MYBPC3 may be a mutational hotspot in FHCM patients. However, mutations of MYBPC3 were not prevalent among SHCM patients. Show less
The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a Show more
The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context. We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks. Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported. Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation. Show less
To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human Show more
To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway. Show less
In order to understand the molecular mechanisms underlying effects of feeding rice protein on lipid and glucose homeostasis, weanling rats were fed AIN-93G diets made with casein or rice protein isola Show more
In order to understand the molecular mechanisms underlying effects of feeding rice protein on lipid and glucose homeostasis, weanling rats were fed AIN-93G diets made with casein or rice protein isolate (RPI) for 14 d. Peroxisome proliferator-activated receptor (PPAR)alpha genes and proteins involved in fatty acid degradation were upregulated by feeding RPI (P < 0.05), accompanied by increased promoter binding and nuclear expression of PPARalpha and its heterodimerization partner retinoid X receptor (P < 0.05). Effects of RPI feeding on hepatic PPARgamma signaling were significant but less robust. Feeding RPI also increased hepatic genes involved in cholesterol metabolism and transport. However, feeding RPI had no effect on binding of liver X-receptor (LXR)alpha to the cytochrome P450 (CYP)7A1 promoter. The effect of RPI feeding on PPARalpha signaling appeared to be direct and was reversed when RPI diets were switched to casein. In another experiment, male Sprague-Dawley rats were fed casein diets from postnatal day (PND) 24 to PND64 or were fed high fat 'Western' diets containing 0.5% cholesterol made with either casein or RPI. Increased liver triglyceride content, hypercholesterolemia and insulin resistance in the 'Western' diet-fed rats were partially prevented by feeding RPI (P < 0.05). mRNA and protein expression of hepatic enzymes involved in fatty acid synthesis were suppressed by feeding 'Western diets' containing RPI (P < 0.05), despite a lack of effects on nuclear concentrations of sterol regulatory element binding protein-1c. These data suggest that attenuation of metabolic syndrome observed in RPI-fed rats after consumption of diets high in fat and cholesterol occur as a result of improved lipid and glucose homeostasis partly as a result of activation of PPARs. Show less
Berberine, a botanical alkaloid purified from Cortidis rhizoma, has effects in cardiovascular diseases, yet the mechanism is not fully understood. Foam cells play a critical role in the progression of Show more
Berberine, a botanical alkaloid purified from Cortidis rhizoma, has effects in cardiovascular diseases, yet the mechanism is not fully understood. Foam cells play a critical role in the progression of atherosclerosis. This study aimed to investigate the effect of berberine on the formation of foam cells by macrophages and the underlying mechanism. Treatment with berberine markedly suppressed oxidized low-density lipoprotein (oxLDL)-mediated lipid accumulation, which was due to an increase in cholesterol efflux. Berberine enhanced the mRNA and protein expression of ATP-binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Additionally, functional inhibition of ABCA1 with a pharmacological inhibitor or neutralizing antibody abrogated the effects of berberine on cholesterol efflux and lipid accumulation. Moreover, berberine induced the nuclear translocation and activation of liver X receptor alpha (LXRalpha) but not its protein expression. Knockdown of LXRalpha mRNA expression by small interfering RNA abolished the berberine-mediated protective effects on ABCA1 protein expression and oxLDL-induced lipid accumulation in macrophages. These data suggest that berberine abrogates the formation of foam cells by macrophages by enhancing LXRalpha-ABCA1-dependent cholesterol efflux. Show less
The mechanisms of action of vitamin A deficiency (VAD) on lipid metabolism in the rat kidney were investigated in adult female rats and their offspring. The rats were randomized into three groups: (1) Show more
The mechanisms of action of vitamin A deficiency (VAD) on lipid metabolism in the rat kidney were investigated in adult female rats and their offspring. The rats were randomized into three groups: (1) control, in which the mother and offspring received a normal diet (4000 retinol IU/kg diet) for 8 weeks; (2) VAD group, in which the mothers and offspring received a VAD diet (400 retinol IU/kg diet) for 8 weeks; (3) vitamin A-refed group, in which a group of pups on a VAD diet for 8 weeks received a complete diet (6500 retinol IU/kg diet) for 15 days. The lipid metabolism of the offsprings' kidneys and its relation to the expression of apolipoprotein B100 (Apo-B100), liver X receptor alpha (LXRalpha), and retinoid X receptor-alpha/beta (RXRalpha/beta) mRNA was analyzed. VAD was found to alter renal lipid metabolism and its immune environment due to the expression of Apo-B100. Compared with the control, VAD rats had significantly higher levels of transforming growth factor-beta 1 and lower levels of ABCA1, a key gene involved in cholesterol efflux and tissue lipid homeostasis. The expression of LXRalpha and RXRalpha/beta mRNA also decreased in the VAD rat kidney. Vitamin A refeeding reversed all of the changes. Lipid metabolism involved in renal reverse cholesterol transport may be mediated by decreasing the signaling through the ABCA1 cholesterol efflux pathway, which is significantly modified in kidneys of vitamin A-deficient rats. Show less
In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoie Show more
In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood. Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages. Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1. Show less
Toll-like receptors (TLRs) are related to foam cell formation (FCF), key event in the establishment/progression of atherosclerosis. The activation of TLR2 and TLR4 can increase FCF. The aim of this st Show more
Toll-like receptors (TLRs) are related to foam cell formation (FCF), key event in the establishment/progression of atherosclerosis. The activation of TLR2 and TLR4 can increase FCF. The aim of this study was to evaluate the role of TLR9 in FCF. Murine macrophages were treated with CpG-ODN, TLR9 agonist, and oxidized particles of LDL (Paz-PC) and FCF was analyzed by means of Oil Red O staining. The administration of CpG-ODN plus Paz-PC onto macrophages increased the amount of lipid droplets, correlated to increased levels of tumor necrosis factor (TNF)-alpha, IFNbeta, and IP-10. The underlying mechanism by which TLR9 ligation influenced Paz-PC in the FCF was NF-kappaB- and IRF7-dependent, as observed by higher levels of phosphorylated IkappaBalpha, increased nuclear translocation of the p65 subunit, lower levels of the total IKKalpha protein and higher release of interferon-dependent cytokines, such as IP-10. Liver X receptors (LXRs) regulate lipid cellular transport and negatively modulate TLR-dependent signaling pathways. Indeed, the addition of GW3965, synthetic LXRs agonist, significantly reduced FCF after CpG-ODN plus Paz-PC stimulation. In this condition, we observed decreased levels of the nuclear translocation of the p65 subunit, related to the higher presence of LXRalpha into the nucleus. TNF-alpha, IP-10, and IFNbeta levels were reduced by the administration of GW3965 following CpG-ODN and Paz-PC treatment. In conclusion, the activation of TLR9 facilitates the formation of foam cells in an NF-kappaB- and IRF7-dependent manner, countered by the activation of LXRs. This study further support LXRs as potential anti-atherosclerotic target. Show less
Cell polarity proteins regulate tight junction formation and directional migration in epithelial cells. To date, the mechanism by which these polarity proteins assemble at the leading edge of migratin Show more
Cell polarity proteins regulate tight junction formation and directional migration in epithelial cells. To date, the mechanism by which these polarity proteins assemble at the leading edge of migrating epithelial cells remains unclear. We report that occludin, a transmembrane protein, is localized at the leading edge of migrating cells and regulates directional cell migration. During migration, occludin knockdown disrupted accumulation of aPKC-Par3 and PATJ at the leading edge, and led to a disorganized microtubule network and defective reorientation of the microtubule organization center (MTOC). Phosphorylation of occludin at tyrosine 473 residue allowed recruitment of p85 alpha to the leading edge via association with its C-terminal SH2 domain. Loss of occludin attenuated activation of PI3K, leading to disorganization of the actin cytoskeleton and reduced cell protrusions. Our data indicate that occludin is required for the leading-edge localization of polarity proteins aPKC-Par3 and PATJ and promotes cell protrusion by regulating membrane-localized activation of PI3K. Show less
Lung cancer is one of the most devastating diseases worldwide. RGS17 is previously shown to be over-expressed in human lung adenocarcinomas and plays an important role in lung tumor growth. Here we ha Show more
Lung cancer is one of the most devastating diseases worldwide. RGS17 is previously shown to be over-expressed in human lung adenocarcinomas and plays an important role in lung tumor growth. Here we have identified a miRNA, has-mir-182, involved in the regulation of RGS17 expression through two conserved sites located in its 3' UTR region. Consistently, endogenous RGS17 expression level is regulated by hsa-mir-182 in human lung cancer cell lines. Similar to the knockdown of RGS17, ectopic expression of hsa-mir-182 significantly inhibits lung cancer cell proliferation and anchorage-independent cell growth, which can be rescued by re-expression of RGS17. Taken together, these data have provided the first evidence of miRNA regulation of RGS17 expression in lung cancer. Show less
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the Show more
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. Show less
Investigate the effect of hydrostatic pressure (HP) on 3', 5'-cyclic adenosine monophosphate (cAMP) levels and downstream signaling in cultures of normal optic nerve head (ONH) astrocytes from Caucasi Show more
Investigate the effect of hydrostatic pressure (HP) on 3', 5'-cyclic adenosine monophosphate (cAMP) levels and downstream signaling in cultures of normal optic nerve head (ONH) astrocytes from Caucasian American (CA) and African American (AA) donors. Intracellular cAMP levels were assayed after exposing ONH astrocytes to HP for varying times. Quantitative RT-PCR was used to determine the expression levels of selected cAMP pathway genes in human ONH astrocytes after HP treatment. Western blots were used to measure changes in the phosphorylation state of cAMP response element binding protein (CREB) in astrocytes subjected to HP, ATP, and phosphodiesterase or kinase inhibitors. The basal intracellular cAMP level is similar among AA and CA astrocytes. After exposure to HP for 15 min and 30 min in the presence of a phosphodiesterase inhibitor a further increase of intracellular cAMP was observed in AA astrocytes, but not in CA astrocytes. Consistent with activation of the cAMP-dependent protein kinase pathway, CREB phosphorylation (Ser-133) was increased to a greater extent in AA than in CA astrocytes after 3 h of HP. Exposure to elevated HP for 3-6 h differentially altered the expression levels of selected cAMP pathway genes (ADCY3, ADCY9, PTHLH, PDE7B) in AA compared to CA astrocytes. Treatment with ATP increased more CREB phosphorylation in CA than in AA astrocytes, suggesting differential Ca(2+) signaling in these populations. Activation of the cAMP-dependent signaling pathway by pressure may be an important contributor to increased susceptibility to elevated intraocular pressure and glaucoma in AA, a population at higher risk for the disease. Show less
Ying Gao, Ke Wu, Yi Xu+9 more · 2009 · Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · Springer · added 2026-04-24
To identify acute renal allograft rejection biomarkers in human serum, two-dimensional differential in-gel electrophoresis (2-D DIGE) and reversed phase high-performance liquid chromatography (RP-HPLC Show more
To identify acute renal allograft rejection biomarkers in human serum, two-dimensional differential in-gel electrophoresis (2-D DIGE) and reversed phase high-performance liquid chromatography (RP-HPLC) followed by electrospray ionization mass spectrometry (ESI-MS) were used. Serum samples from renal allograft patients and normal volunteers were divided into three groups: acute rejection (AR), stable renal function (SRF) and normal volunteer (N). Serum samples were firstly processed using Multiple Affinity Removal Column to selectively remove the highest abundance proteins. Differentially expressed proteins were analyzed using 2-D DIGE. These differential protein spots were excised, digested by trypsin, and identified by RP-HPLC-ESI/MS. Twenty-two differentially expressed proteins were identified in serum from AR group. These proteins included complement C9 precursor, apolipoprotein A-IV precursor, vitamin D-binding protein precursor, beta-2-glycoprotein 1 precursor, etc. Vitamin D-binding protein, one of these proteins, was confirmed by ELISA in the independent set of serum samples. In conclusion, the differentially expressed proteins as serum biomarker candidates may provide the basis of acute rejection noninvasive diagnosis. Confirmed vitamin D-binding protein may be one of serum biomarkers of acute rejection. Furthermore, it may provide great insights into understanding the mechanisms and potential treatment strategy of acute rejection. Show less
Chinese medicine has been proposed as a novel strategy for the prevention of metabolic disorders such as obesity. The present study tested 17 Chinese medicinal herbs were tested for their potential an Show more
Chinese medicine has been proposed as a novel strategy for the prevention of metabolic disorders such as obesity. The present study tested 17 Chinese medicinal herbs were tested for their potential anti-obesity effects. The herbs were evaluated in terms of their abilities to stimulate the transcription of Apolipoprotein A-IV (ApoA-IV) in cultured Caco-2/TC7 enterocytes. The herbs that showed stimulating effects on ApoA-IV transcription were further evaluated in terms of their abilities to reduce the formation of triglyceride in differentiated 3T3-L1 adipocytes. ApoA-IV transcription was stimulated by Rhizoma Alismatis and Radix Angelica Sinensis in a dose- and time-dependent manner in cultured Caco-2/TC7 cells. Moreover, these two herbs reduced the amount of triglyceride in differentiated 3T3-L1 adipocytes. The results suggest that Rhizoma Alistmatis and Radix Angelica Sinensis may have potential anti-obesity effects as they stimulate ApoA-IV transcription and reduce triglyceride formation. Show less
Liver is unique in its capability to regenerate after an injury. Liver regeneration after a 2/3 partial hepatectomy served as a classical model and is adopted frequently to study the mechanism of live Show more
Liver is unique in its capability to regenerate after an injury. Liver regeneration after a 2/3 partial hepatectomy served as a classical model and is adopted frequently to study the mechanism of liver regeneration. In the present study, semiquantitative analysis of protein expression in mouse liver regeneration following partial hepatectomy was performed using an iTRAQ technique. Proteins from pre-PHx control livers and livers regenerating for 24, 48 and 72 h were extracted and inspected using 4-plex isotope labeling, followed by liquid chromatography fractionation, mass spectrometry and statistical differential analysis. A total of 827 proteins were identified in this study. There were 270 proteins for which quantitative information was available at all the time points in both biologically duplicate experiments. Among the 270 proteins, Car3, Mif, Adh1, Lactb2, Fabp5, Es31, Acaa1b and LOC100044783 were consistently down-regulated, and Mat1a, Dnpep, Pabpc1, Apoa4, Oat, Hpx, Hp and Mt1 were up-regulated by a factor of at least 1.5 from that of the controls at one time point or more. The regulation of each differential protein was also demonstrated by monitoring its time-dependent expression changes during the regenerating process. We believe this is the first report to profile the protein changes in liver regeneration utilizing the iTRAQ proteomic technique. Show less
Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polym Show more
Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q Show less
Common polymorphism of the apolipoprotein A5 gene (APOA5, c.553G>T) related to metabolic syndrome components, insulin resistance, and carotid atherosclerosis remains unclear. We investigated the assoc Show more
Common polymorphism of the apolipoprotein A5 gene (APOA5, c.553G>T) related to metabolic syndrome components, insulin resistance, and carotid atherosclerosis remains unclear. We investigated the associations of the APOA5 c.553G>T gene with various metabolic syndrome components and carotid artery atherosclerosis among family members. A total of 661 participants who provided complete genotyping and carotid artery measures were included in this study. Participants with APOA5 c.553T carrier (GT and TT) were more likely to have higher levels of triglycerides and apolipoprotein B, as well as lower levels of high-density lipoprotein (HDL) cholesterol, than participants with the GG genotype. Individuals who carried T alleles had an increased risk of a high level of triglycerides (multivariate odds ratio [OR], 3.86; 95% confidence interval [CI], 1.98-7.55; P<0.0001) and low levels of HDL cholesterol (OR, 2.32; 95% CI, 1.40-3.86; P=0.0012) compared with those without T alleles. The age was an effect modifier for the association between APOA5 genotype and smoking, alcohol drinking, obesity, and lipid profiles, including total, HDL, and low-density lipoprotein (LDL) cholesterol; triglycerides; and apolipoproteins. In addition, the association between APOA5 genotype and hypertriglyceridemia was significant only in adult groups (OR, 3.53; 95% CI, 1.79-6.94), and the association between APOA5 genotype and low HDL cholesterol was stable in young adolescents (OR, 2.39; 95% CI, 1.19-4.78) and adults (OR, 2.20; 95% CI, 1.17-4.15). Our findings indicated that the APOA5 c.553G>T polymorphism is associated with high triglycerides and low HDL cholesterol but not with other metabolic syndrome components or carotid atherosclerosis in this ethnic Chinese population. Show less