We have previously found that CHF1/Hey2 prevents the development of phenylephrine-induced cardiac hypertrophy. To determine the role of CHF1/Hey2 in pressure overload hypertrophy, we performed ascendi Show more
We have previously found that CHF1/Hey2 prevents the development of phenylephrine-induced cardiac hypertrophy. To determine the role of CHF1/Hey2 in pressure overload hypertrophy, we performed ascending aortic banding on wild-type and transgenic mice overexpressing CHF1/Hey2 in the myocardium. We found that both wild-type and transgenic mice developed increased ventricular weight to body weight ratios 1 week after aortic banding. Wild-type mice also developed decreased fractional shortening after 1 week when compared to preoperative echocardiograms and sham-operated controls. Transgenic mice, in comparison, demonstrated preserved fractional shortening. Histological examination of explanted heart tissue demonstrated extensive fibrosis in wild-type hearts, but minimal fibrosis in transgenic hearts. TUNEL staining demonstrated increased apoptosis in the wild-type hearts but not in the transgenic hearts. Exposure of cultured neonatal myocytes from wild-type and transgenic animals to hydrogen peroxide, a potent inducer of apoptosis, demonstrated increased apoptosis in the wild-type cells. Gene Set Analysis of microarray data from wild-type and transgenic hearts 1 week after banding revealed suppression and activation of multiple pathways involving apoptosis, cell signaling, and biosynthesis. These findings demonstrate that CHF1/Hey2 promotes physiological over pathological hypertrophy through suppression of apoptosis and regulation of multiple transcriptional pathways. These findings also suggest that CHF1/Hey2 and its downstream pathways provide a variety of targets for novel heart failure drug discovery, and that genetic polymorphisms in CHF1/Hey2 may affect susceptibility to hypertrophy and heart failure. Show less
Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We Show more
Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1+/-), SMC-specific Notch1 heterozygous deficient (smN1+/-), and general Notch3 homozygous deficient (N3-/-) mice. Compared with wild-type or control mice, N1+/- and smN1+/- mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3-/- mice. Indeed, SMCs derived from explanted aortas of either N1(+/-)- or smN1+/- mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3-/- mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1(+/-)- or smN1+/- mice. In SMCs derived from CHF1/Hey2-/- mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases. Show less
In vertebrates, molecular mechanisms dictate angioblasts' migration and subsequent differentiation into arteries and veins. In this study, we used a microarray screen to identify a novel member of the Show more
In vertebrates, molecular mechanisms dictate angioblasts' migration and subsequent differentiation into arteries and veins. In this study, we used a microarray screen to identify a novel member of the sucrose nonfermenting related kinase (snrk-1) family of serine/threonine kinases expressed specifically in the embryonic zebrafish vasculature and investigated its function in vivo. Using gain- and loss-of-function studies in vivo, we show that Snrk-1 plays an essential role in the migration, maintenance, and differentiation of angioblasts. The kinase function of Snrk-1 is critical for migration and maintenance, but not for the differentiation of angioblasts. In vitro, snrk-1 knockdown endothelial cells show only defects in migration. The snrk-1 gene acts downstream or parallel to notch and upstream of gridlock during artery-vein specification, and the human gene compensates for zebrafish snrk-1 knockdown, suggesting evolutionary conservation of function. Show less
Androgen deprivation is commonly used in the treatment of metastatic prostate cancer. The (-)-gossypol enantiomer has been demonstrated as an effective inhibitor of Bcl-2 in the treatment of prostate Show more
Androgen deprivation is commonly used in the treatment of metastatic prostate cancer. The (-)-gossypol enantiomer has been demonstrated as an effective inhibitor of Bcl-2 in the treatment of prostate cancer. However, the mechanism of gossypol as an inhibitor of androgen biosynthesis is not clear. The present study compared (+)- and (-)-gossypols in the inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-HSD isoform 3 (17beta-HSD3) in human and rat testes. Gossypol enantiomers were more potent inhibitors of rat 3beta-HSD with IC(50)s of approximately 0.2microM compared to 3-5microM in human testes. However, human 17beta-HSD3 was more sensitive to inhibition by gossypol enantiomers, with IC(50)s of 0.36+/-0.09 and 1.13+/-0.12 for (-)- and (+)-gossypols, respectively, compared to 3.43+/-0.46 and 10.93+/-2.27 in rat testes. There were species- and enantiomer-specific differences in the sensitivity of the inhibition of 17beta-HSD3. Gossypol enantiomers competitively inhibited both 3beta-HSD and 17beta-HSD3 by competing for the cofactor binding sites of these enzymes. Gossypol enantiomers, fed orally to rats (20mg/kg), inhibited 3beta-HSD but not 17beta-HSD3. This finding was consistent with the in vitro data, in which rat 3beta-HSD was more sensitive to gossypol inhibition than rat 17beta-HSD3. As the reverse was true for the human enzymes, gossypol might be useful for treating metastatic prostate cancer. Show less
It is well documented that human breast is actively involved in the local formation of estrogens. To determine the site(s) of action of enzymes involved in synthesis and metabolism of the most potent Show more
It is well documented that human breast is actively involved in the local formation of estrogens. To determine the site(s) of action of enzymes involved in synthesis and metabolism of the most potent estrogen estradiol (E2), we have studied the expression of the following enzymes: 3beta-hydroxysteroid dehydrogenase (3-HSD), 17beta-HSD types 1, 2, 5, 7 and 12, aromatase, steroid sulfatase (STS) and estrogen sulfotransferase (EST) 1E1 at the cellular level in breast. Both in situ hybridization and immunocytochemistry were used for enzyme localization in normal breast tissues. For immunocytochemistry, we used rabbit antibodies, while in situ hybridization studies were performed using (35S)-labeled cRNA probes. Similar results were obtained with both approaches. All the enzymes (3beta-HSD; 17beta-HSD types 1, 5, 7 and 12; aromatase) involved in the conversion of circulating dehydroepiandrosterone (DHEA) to E2 as well as STS which converts estradiol sulfate (E2-S) to E2 have been found to be expressed in epithelial cells of acini and/or ducts as well as the stromal cells. Moreover, 17beta-HSD type 2 and EST1E1, two enzymes which inactivate E2, have been also localized in the same cell types. The present results indicate the enzymes which play a role in the synthesis and metabolism of E2 are expressed in both epithelial and stromal cells in human breast. Show less
Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. There are no effective neuroprotectants to treat this disorder. Brain-derived neu Show more
Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. There are no effective neuroprotectants to treat this disorder. Brain-derived neurotrophic factor (BDNF) is well known to transiently delay RGC death in ocular hypertensive eyes. The CNS-specific leucine-rich repeat protein LINGO-1 contributes to the negative regulation to some trophic pathways. We thereby examined whether BDNF combined with LINGO-1 antagonists can promote long-term RGC survival after ocular hypertension. In this study, intraocular pressure was elevated in adult rats using an argon laser to photocoagulate the episcleral and limbal veins. BDNF alone shows slight neuroprotection to RGCs after a long-term progress of 4 weeks following the induction of ocular hypertension. However, combination of BDNF and LINGO-1-Fc prevents RGC death in the same condition. We further identified that (1) LINGO-1 was co-expressed with BDNF receptor, TrkB in the RGCs, and (2) BDNF combined with LINGO-1-Fc activated more TrkB in the injured retina compared to BDNF alone. These results indicate that the combination of BDNF with LINGO-1 antagonist can provide long-term protection for RGCs in a chronic ocular hypertension model. TrkB may be the predominant mediator of this neuroprotection. Show less
Adenoid cystic carcinoma (ACC) is a slow growing but highly invasive cancer with a high recurrence rate. Id (inhibitor of DNA binding) proteins are dominant regulators of basic helix-loop-helix transc Show more
Adenoid cystic carcinoma (ACC) is a slow growing but highly invasive cancer with a high recurrence rate. Id (inhibitor of DNA binding) proteins are dominant regulators of basic helix-loop-helix transcription factors that control malignant cell behavior in many different tissues. This study aimed to identify the potential role of inhibiting DNA binding-1 (Id-1) in human salivary adenoid cystic carcinoma (SACC) progression. First, we compared the Id-1 protein expression in a human salivary adenoid cystic carcinoma cell line (ACCM) against three other cell lines and found that Id-1 protein expression in ACCM to be significantly higher. Then we measured Id-1 mRNA and protein expression in ACCM before and after RNA interference (RNAi), which showed successful inhibition of Id-1. Further studies then demonstrated that the proliferation and invasiveness of ACCM cells were dramatically down-regulated, and increased numbers of apoptotic cells were detected after Id-1 silencing. Consequently, our data suggest that Id-1 is a potential target in the treatment of human salivary adenoid cystic carcinoma. Show less
Chromosomal translocations generating fusion proteins are frequently found in human leukemias. The fusion proteins play an important role in leukemogenesis by subverting the function of one or both pa Show more
Chromosomal translocations generating fusion proteins are frequently found in human leukemias. The fusion proteins play an important role in leukemogenesis by subverting the function of one or both partner proteins. The leukemogenic CALM-AF10 fusion protein is capable of interacting with the histone H3 lysine 79 (H3K79)-specific methyltransferase hDOT1L through the fused AF10 moiety. This interaction leads to local H3K79 hypermethylation on Hoxa5 loci, which up-regulates the expression of Hoxa5 and contributes to leukemogenesis. However, the long latency of leukemogenesis of CALM-AF10 transgenic mice suggests that the direct effects of fusion oncogene are not sufficient for the induction of leukemia. In this study, we show that the CALM-AF10 fusion protein can also greatly reduce global H3K79 methylation in both human and murine leukemic cells by disrupting the AF10-mediated association of hDOT1L with chromatin. Cells with reduced H3K79 methylation are more sensitive to gamma-irradiation and display increased chromosomal instability. Consistently, leukemia patients harboring CALM-AF10 fusion have more secondary chromosomal aberrations. These findings suggest that chromosomal instability associated with global epigenetic alteration contributes to malignant transformation in certain leukemias, and that leukemias with this type of epigenetic alteration might benefit from treatment regimens containing DNA-damaging agents. This study is registered with www.clinicaltrials.gov as NCT00266136. Show less
Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is Show more
Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies. We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype-CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL-are suggested by SNPs associated with the combination of small/medium LDL and large HDL. PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD. Show less
Ming Huo, Hui-ling Zang, Dong-juan Zhang+7 more · 2009 · Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · added 2026-04-24
To study the role of the carbohydrate response element binding protein (ChREBP) in excessive lipid deposition in the liver of db/db mouse. The deposition of neutral lipids in the liver was evaluated b Show more
To study the role of the carbohydrate response element binding protein (ChREBP) in excessive lipid deposition in the liver of db/db mouse. The deposition of neutral lipids in the liver was evaluated by Oil Red O staining. Immunohistochemical assay was utilized to determine the localization of ChREBP protein expression in mouse liver. The expressions of ChREBP and its target genes including acetyl-coenzyme A carboxylase 1 (Acc-1), fatty acid synthase (Fas), glycerol-3-phosphate acyltransferase (Gpat) were analyzed by Real-time PCR and Western blot. Significant lipid droplet deposition was detected in the livers of db/db mice. ChREBP was diffusely expressed in heptocytes with relative higher expression levels around portal and central veins. ChREBP was predominantly located in the cytosol in non-diabetic db/m mice, but was translocated to the nucleus in db/db mice. Nuclear ChREBP protein levels were 8.2-fold higher in db/db mice than in db/m mice(P<0.01). In contrast, another lipogenic transcription factor, sterol regulatory element binding protein-1(SREBP-1), remained unchanged. Consistent with increased nuclear ChREBP levels, expressions of ChREBP target genes involved in lipogenesis including Acc-1, Fas and Gpat were upregulated by 2-fold(P<0.05),1.7-fold (P<0.05) and 4.2-fold(P<0.05), respectively, in db/db mice. The db/db mouse exhibits significantly higher liver ChREBP activity, which may be associated with the development of hepatic steatosis frequently occurring in type 2 diabetes. Targeting ChREBP might represent a new intervention strategy for fatty liver. Show less
Previously, a genome-wide scan has identified a nonsynonymous single nucleotide polymorphism (rs3812316, G771C, Gln241His) in the MLXIPL gene that is associated with the level of plasma triglycerides. Show more
Previously, a genome-wide scan has identified a nonsynonymous single nucleotide polymorphism (rs3812316, G771C, Gln241His) in the MLXIPL gene that is associated with the level of plasma triglycerides. However, no data are available on the association of this polymorphism with coronary artery disease (CAD) in the Chinese population. The aim of this study was to evaluate the association between a gene polymorphism related to triglyceride metabolism and CAD. The genotype of the polymorphism in the MLXIPL gene was determined in 352 CAD patients and 152 CAD-free subjects. All of the participants were selected to study the MLXIPL gene rs3812316 polymorphism using the polymerase chain reaction restriction fragment length polymorphism method. In Chinese participants, we observed that there was a significant difference in genotype between the cases and controls (p = 0.002). After allowance for potential confounders, unconditional logistic analysis revealed that the SNP was significantly related to a risk in CAD patients (adjusted OR 2.96, 95% CI 1.30-5.08; p =0.004). We also found that there was a significant association between the single nucleotide polymorphism and plasma triglyceride levels (OR 1.28, 95% CI 1.061-1.542; p < 0.05). The gene sequence variation in the MLXIPL gene may serve as a novel genetic marker for the risk of significant CAD. Show less
To detect gene mutations associated with hypertrophic cardiomyopathy (HCM) in Chinese patients and possible correlations between genotype and phenotype. Twenty-one unrelated patients with hypertrophic Show more
To detect gene mutations associated with hypertrophic cardiomyopathy (HCM) in Chinese patients and possible correlations between genotype and phenotype. Twenty-one unrelated patients with hypertrophic cardiomyopathy were studied. The clinical data including symptoms, physical examination, echocardiography and electrocardiography were collected. The full ecoding exons of cardiac myosin-binding protein C gene (cMYBPC3) were amplified with PCR and the products were sequenced. Two mutations were identified in probands from two families. One mutation was frame shift mutation Pro1208fs in the exon 32 of the cMYBPC3 gene. Pro1208fs mutation was identified in a 59 years old female patient with familial hypertrophic cardiomyopathy. Symptom onset was late and a favorable clinical course was evidenced in this patient. Another mutation was missence mutation Gly507Arg in the exon 17 of the MYBPC3 gene identified in a 24 years old male patient. Diffuse thickness of left ventricular wall, impaired diastolic function and enlarged left atria were evidenced in echocardiography. No mutation was identified in the 80 control healthy individuals. cMYBPC3 might be the disease-causing genes in Chinese patients with hypertrophic cardiomyopathy. Show less
To screen the MYBPC3 gene mutations in Han Chinese patients with hypertrophic cardiomyopathy (HCM). Sixty-six patients with HCM were enrolled for the study. The exons in the functional regions of MYBP Show more
To screen the MYBPC3 gene mutations in Han Chinese patients with hypertrophic cardiomyopathy (HCM). Sixty-six patients with HCM were enrolled for the study. The exons in the functional regions of MYBPC3 were amplified with PCR and the products were sequenced. Four novel mutations and four common polymorphisms were identified in this patient cohort. A Lys301fs mutation in exon10 was evidenced in a H30, and when he was 47 years old, he had the chest tightness, shortness of breath with septal hypertrophy of 18.7mm; a Asp463stop mutation in exon17 was detected in a H48, he was 24 years old 24-year-old when a medical examination showed ventricular septal hypertrophy of 15.4 mm; both Gly523Arg mutation in exon18 and Tyr847His mutation in exon26 were found in a H53 with onset age 36 years old, feeling chest tightness after excise and his ventricular septal hypertrophy was 27 mm that time. MYBPC3 mutations occurred in 4.5% patients in this cohort. These mutations were not found in 100 non-HCM control patients. MYBPC3 mutation is presented in a small portion of Han Chinese patients with HCM. Show less
To investigate the expression of liver X receptors (LXR) in hypertrophic myocardium and the effect of LXR agonist T0901317 on angiotensin II (AngII) induced cardiomyocyte hypertrophy. Transverse aorti Show more
To investigate the expression of liver X receptors (LXR) in hypertrophic myocardium and the effect of LXR agonist T0901317 on angiotensin II (AngII) induced cardiomyocyte hypertrophy. Transverse aortic coarctation (TAC) or sham operation were performed in 2-month-old wide type mice (C57/B6). Two weeks later, the expression of LXR in myocardium was detected by quantitative real-time PCR analysis and Western blot analysis. The effect of LXR agonist T0901317 on AngII-induced hypertrophy in cultured neonatal rat cardiomyocytes was also assessed. Quantitative real-time PCR analysis and Western blot analysis showed that LXRalpha but not LXRbeta expression was upregulated post TAC both at mRNA and protein levels (All P < 0.05). AngII induced increased [(3)H] leucine incorporation and cardiomyocyte hypertrophy were significantly reduced by T0901317 in a dose-dependent manner (P < 0.05). T0901317 also dose-dependently inhibited atrial natriuretic peptide (ANP) gene expression in cardiomyocytes (P < 0.05). Our findings strongly suggest that LXR is a potent mediator of cardiomyocyte hypertrophy and LXR activation could attenuate AngII induced cardiomyocyte hypertrophy in vitro. Show less
Yanfei Zhu, Yousheng Li · 2009 · Clinical and investigative medicine. Medecine clinique et experimentale · added 2026-04-24
Atherosclerosis is the primary independent risk factor of cardiovascular disease, and Liver X Receptors (LXRalpha and LXRbeta) activation may play an anti-atherosclerosis effect. In this article, we s Show more
Atherosclerosis is the primary independent risk factor of cardiovascular disease, and Liver X Receptors (LXRalpha and LXRbeta) activation may play an anti-atherosclerosis effect. In this article, we summarize the current state of knowledge of roles of LXRs in physiology and homeostasis as well as the links between LXR action and atherosclerosis, and discuss the potential therapeutic effects of LXR agonists. A MEDLINE database search was performed to identify relevant articles using the keywords "liver X receptors", "LXRs", and "atherosclerosis". Additional papers were identified by a manual research of the references from the key articles. Both LXR isoforms promote reverse cholesterol transport (RCT) and have anti-inflammatory activity. LXRalpha is the predominant receptor in the liver regulating triglyceride synthesis. The antiatherosclerotic ability of LXRs makes them attractive targets for drugs for the treatment of cardiovascular disease. However, LXR activation induces lipogenesis and hypertriglyceridemia. The first-generation synthetic ligands of LXR increase hepatic lipogenesis and plasma triglyceride levels. New LXR ligands need to be designed without undesirable side effects. LXR beta-selective agonists and LXR modulators, which act as agonists in macrophages and induce cholesterol efflux while as antagonists of lipogenesis in the liver, are two critical and attractive approaches to treat atherosclerosis and cardiovascular diseases. Show less
Haibiao Gong, Jinhan He, Jung Hoon Lee+5 more · 2009 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
The liver X receptors (LXRs) have been known as sterol sensors that impact cholesterol and lipid homeostasis, as well as inflammation. Although the hepatic functions of LXRs are well documented, wheth Show more
The liver X receptors (LXRs) have been known as sterol sensors that impact cholesterol and lipid homeostasis, as well as inflammation. Although the hepatic functions of LXRs are well documented, whether and how LXRs play a pathophysiological role in the lung remain largely unknown. Here we show that LXRalpha and LXRbeta are expressed in both type I and type II mouse lung epithelial cells, as well as in human lung cancer cells. To study the role of LXRalpha in vivo including the pulmonary function of this LXR isoform, we created LXRalpha knock-in (LXR-KI) mice in which a constitutively activated LXRalpha (VP-LXRalpha) was inserted into the mouse LXRalpha locus. We show that activation of LXR in LXR-KI mice or LXR agonist-treated wild type mice induced pulmonary expression of genes encoding multiple antioxidant enzymes. Consistent with the induction of antioxidant enzymes, LXR-KI mice and LXR ligand-treated wild type mice showed a substantial resistance to lipopolysaccharide-induced lung injury and decreased production of reactive oxygen species. In summary, we have uncovered a novel role of LXR in regulating antioxidant enzymes in the lung and the implication of this regulation in pulmonary tissue protection. Show less
Nuclear factor-kappaB (NF-kappaB) plays a critical role in cell growth and inflammation during the progression of cardiac hypertrophy and heart failure. Several members of nuclear receptor superfamily Show more
Nuclear factor-kappaB (NF-kappaB) plays a critical role in cell growth and inflammation during the progression of cardiac hypertrophy and heart failure. Several members of nuclear receptor superfamily, including liver X receptors (LXRalpha and LXRbeta), have been shown to suppress inflammatory responses, but little is known about their effects in cardiomyocytes. We investigated LXR expression patterns in pressure overload-induced hypertrophic hearts and the hypertrophic growth of the LXRalpha-deficient hearts from mice (C57/B6) in response to pressure overload. The underlying mechanisms were also explored using cultured myocytes. We found that cardiac expression of LXRalpha was upregulated in pressure overload-induced left ventricular hypertrophy in mice. Transverse aorta coarctation-induced left ventricular hypertrophy was exacerbated in LXRalpha-null mice relative to control mice. A synthetic LXR ligand, T1317, suppressed cardiomyocyte hypertrophy in response to angiotensin II and lipopolysaccharide treatments. In addition, LXR activation suppressed NF-kappaB signalling and the expression of associated inflammatory factors. Overexpression of constitutively active LXRalpha and beta in cultured myocytes suppressed NF-kappaB activity. LXRs are negative regulators of cardiac growth and inflammation via suppressing NF-kappaB signalling in cardiomyocytes. This should provide new insights into novel therapeutic targets for treating cardiac hypertrophy and heart failure. Show less
The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. Liver X Show more
The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by increasing the amount of free cholesterol in the plasma membrane through inducing NPC1 expression. NO-1886 has been proven to be highly effective at increasing liver X receptor alpha expression and promoting cellular cholesterol efflux. In this study, the effects of NO-1886 on NPC1 expression were investigated in THP-1 macrophage-derived foam cells. Results showed that NO-1886 markedly increased expression of NPC1 at both mRNA level and protein level in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by NO-1886 treatment. In addition, LXR alpha was also up-regulated by NO-1886 treatment. And LXR alpha small interfering RNA completely abolished the promotion effect which was induced by NO-1886. These results provide evidence that NO-1886 up-regulates expression of NPC1 through LXR alpha pathway in THP-1 macrophage- derived foam cells. Show less
Compare the expression and regulation of nuclear receptors (NRs) in osteoarthritic and normal human articular cartilage. The transcriptional levels of 48 NRs and additional related proteins were measu Show more
Compare the expression and regulation of nuclear receptors (NRs) in osteoarthritic and normal human articular cartilage. The transcriptional levels of 48 NRs and additional related proteins were measured in mRNA from human articular cartilage from subjects with osteoarthritis (OA) and compared to samples from subjects without OA, using microarrays, individual quantitative reverse transcriptase polymerase chain reaction assays, and a custom human NR TaqMan Low Density Array (TLDA). The functional effect of liver X receptor (LXR) activity in cartilage was studied by measuring proteoglycan (PG) synthesis and degradation in articular cartilage explant cultures following treatment with the synthetic LXR agonist T0901317. Thirty-one of 48 NRs analyzed by TLDA were found to be measurably expressed in human articular cartilage; 23 of these 31 NRs showed significantly altered expression in OA vs unaffected cartilage. Among these, LXRalpha and LXRbeta, and their heterodimeric partners retinoid X receptor (RXR)alpha and RXRbeta were all expressed at significantly lower levels in OA cartilage, as were LXR target genes ABCG1 and apolipoproteins D and E. Addition of LXR agonist to human OA articular chondrocytes and to cartilage explant cultures resulted in activation of LXR-mediated transcription and significant reduction of both basal and interleukin (IL)-1-mediated PG degradation. Articular cartilage expresses a substantial number of NRs, and a large proportion of the expressed NRs are dysregulated in OA. In particular, LXR signaling in OA articular cartilage is impaired, and stimulation of LXR transcriptional activity can counteract the catabolic effects of IL-1. We conclude that LXR agonism may be a possible therapeutic option for OA. Show less
Huaixin Dang, Yan Liu, Wei Pang+4 more · 2009 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
The liver X receptors (LXRs) sense oxysterols and regulate genes involved in cholesterol metabolism. Synthetic agonists of LXRs are potent stimulators of fatty acid synthesis, which is mediated largel Show more
The liver X receptors (LXRs) sense oxysterols and regulate genes involved in cholesterol metabolism. Synthetic agonists of LXRs are potent stimulators of fatty acid synthesis, which is mediated largely by sterol regulatory element-binding protein-1c (SREBP-1c). Paradoxically, an improved hepatic lipid profile by LXR was observed in mice fed a Western high fat (HF) diet. To explore the underlying mechanism, we administered mice normal chow or an HF diet and overexpressed LXRalpha in the liver. The HF diet with tail-vein injection of adenovirus of LXRalpha increased the expression of LXR-targeted genes involved in cholesterol reverse transport but not those involved in fatty acid synthesis. A similar effect was also observed with the use of 22R-hydroxycholesterol, an LXR ligand, in cultured hepatocytes. Consequently, SREBP-1c maturation was inhibited by the HF diet, which resulted from the induction of Insig-2a. Importantly, increased cholesterol level suppressed the expression of 2,3-oxidosqualene cyclase (OSC), which led to an increase in endogenous LXR ligand(s). Furthermore, siRNA-mediated knockdown of OSC expression enhanced LXR activity and selectively up-regulated LXR-targeted genes involved in cholesterol reverse transport. Thus, down-regulation of OSC may account for a novel mechanism underlying the LXR-mediated lipid metabolism in the liver of mice fed an HF diet. Show less
Hyperlipidemia is one of the most important risk factors for atherosclerosis. This can be amplified by a localized inflammatory response mediated by macrophages. Macrophages are capable of taking up e Show more
Hyperlipidemia is one of the most important risk factors for atherosclerosis. This can be amplified by a localized inflammatory response mediated by macrophages. Macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria by steroidogenic acute regulatory (StAR) protein is the rate-limiting step for cholesterol degradation in the liver. It has also been shown that overexpression of StAR in hepatocytes dramatically increases the amount of regulatory oxysterols in the nucleus, which play an important role in the maintenance of intracellular lipid homeostasis. The goal of the present study was to determine whether StAR plays a similar role in macrophages. We have found that overexpression of StAR in human THP-1 monocyte-derived macrophages decreases intracellular lipid levels, activates liver X receptor alpha (LXRalpha) and proliferation peroxysome activator receptor gamma (PPARgamma), and increases ABCG1 and CYP27A1 expression. Furthermore, it reduces the secretion of inflammatory factors, and prevents apoptosis. These results suggest that StAR delivers cholesterol to mitochondria where regulatory oxysterols are generated. Regulatory oxysterols can in turn activate nuclear receptors, which increase expression of cholesterol efflux transporters, and decrease secretion of inflammatory factors. These effects can prevent macrophage apoptosis. These results imply a potential role of StAR in the prevention of atherosclerosis. Show less
Interferon gamma (IFN-gamma) is an immunomodulatory and anti-microbial cytokine, which has a variety of proatherogenic effects. It has been reported that IFN-gamma can down-regulate ABCA1 expression. Show more
Interferon gamma (IFN-gamma) is an immunomodulatory and anti-microbial cytokine, which has a variety of proatherogenic effects. It has been reported that IFN-gamma can down-regulate ABCA1 expression. However, its mechanism is elusive. In the present study, we have investigated the effect of IFN-gamma on ABCA1 expression and cholesterol efflux in THP-1 macrophage-derived foam cells. IFN-gamma decreased ABCA1 expression at both transcriptional and translational levels in a dose-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by IFN-gamma treatment. Liver X receptor alpha (LXRalpha), which can regulate the expression of ABCA1, was also down-regulated by IFN-gamma treatment. LXRalpha-specific activation by LXRalpha agonist almost compensated the down-regulation of ABCA1 expression by IFN-gamma, while siRNA of LXRalpha led to down-regulation of ABCA1 expression more significantly than IFN-gamma. IFN-gamma induced phosphorylation of STAT1 and expression of STAT1alpha in the nucleus, which was inhibited by a JAK inhibitor AG-490. Treatment with STAT1 siRNA further enhanced down-regulation of LXRalpha mRNA by IFN-gamma. Furthermore, AG-490 and STAT1 siRNA almost compensated the effect of IFN-gamma on ABCA1 expression and cholesterol efflux. In conclusion, IFN-gamma may first down-regulate expression of LXRalpha through the JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study may be useful in understanding the critical effect of IFN-gamma in pathogenesis of atherosclerosis. Show less
POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem (ES) cells but also acts as a cell fate determinant through a ge Show more
POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem (ES) cells but also acts as a cell fate determinant through a gene dosage effect. However, the molecular mechanisms that control the intracellular OCT4 protein level remain elusive. Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. We first demonstrated that endogenous OCT4 in human ES cells can be post-translationally modified by Ub. Furthermore, we found that WWP2 promoted degradation of OCT4 through the 26S proteasome in a dosage-dependent manner, and the active site cysteine residue of WWP2 was required for both its enzymatic activity and proteolytic effect on OCT4. Remarkably, our data show that the endogenous OCT4 protein level was significantly elevated when WWP2 expression was downregulated by specific RNA interference (RNAi), suggesting that WWP2 is an important regulator for maintaining a proper OCT4 protein level in human ES cells. Moreover, northern blot analysis showed that the WWP2 transcript was widely present in diverse human tissues/organs and highly expressed in undifferentiated human ES cells. However, its expression level was quickly decreased after human ES cells differentiated, indicating that WWP2 expression might be developmentally regulated. Our findings demonstrate that WWP2 is an important regulator of the OCT4 protein level in human ES cells. Show less
Weihua Huang, Ming D Li · 2009 · The international journal of neuropsychopharmacology · added 2026-04-24
Nicotine stimulation regulates expression of a diversity of genes, but the underlying mechanisms are largely unknown. MicroRNAs (miRNAs) are short endogenous RNAs known to post-transcriptionally regul Show more
Nicotine stimulation regulates expression of a diversity of genes, but the underlying mechanisms are largely unknown. MicroRNAs (miRNAs) are short endogenous RNAs known to post-transcriptionally regulate gene expression. To test our hypothesis that miRNAs could mediate nicotine's effect on gene expression regulation, we profiled miRNA expression to explore to what extent miRNAs are modulated by nicotine. Using a rodent miRNA microarray and rat PC12 cell model, we revealed that nicotine selectively modulates expression of multiple miRNAs, indicating that the miRNA pathway is one of cellular mechanisms involved in gene expression regulated by nicotine. Specifically, we demonstrated that nicotine increases expression of miR-140*, coordinated with the nicotine-augmented expression of its host gene WWP2. Further, we demonstrated that miR-140* targets the 3'-untranslated region of dynamin 1 gene (Dnm1), by direct base-pairing. This targeting represses gene translation in the luciferase reporter assay and induces messenger RNA degradation in Dnm1 expression analysis. Consequently, our data indicate that nicotine regulates Dnm1 expression via the miRNA pathway. Because dynamin 1 has an essential role in synaptic endocytosis in the central nervous system, nicotine-induced miRNA-mediated dynamin 1 expression regulation may illustrate its importance in neural plasticity, which underlies a molecular mechanism of nicotine addiction. Show less
To seek differentially expressed serum proteins in recovered SARS patients complicating avascular necrosis of femoral head (AVNFH). 2-DE and MALDI-TOF MS were used to study the comparative serum prote Show more
To seek differentially expressed serum proteins in recovered SARS patients complicating avascular necrosis of femoral head (AVNFH). 2-DE and MALDI-TOF MS were used to study the comparative serum proteomics among female SARS AVNFH group, female SARS non-AVNFH group and female healthy group. ELISA method was used to detect serum amyloid P component in individual serum; specificity and sensitivity of serum amyloid P component were analyzed. Average protein points on 2-DE of 3 groups were 632 +/- 28, 671 +/- 55, 688 +/- 42 respectively, and the matching rate of protein points was ranged from 85% to 95%; eighteen differentially expressed proteins were discovered including transthyretin, serpin peptidase inhibitor, alpha-1-antitrypsin precursor, serum amyloid P components, etc. Compared to healthy group and SARS non-AVNFH group, transthyretin, C4B3, fibrinogen gamma, apolipoprotein L, apolipoprotein A-IV precursor, albumin and prealbumin showed lower expression, inversely serpin peptidase inhibitor, alpha-1-antitrypsin precursor and serum amyloid P components showed higher expression in serum in the SARS AVNFH necrosis group. The serum amyloid P component in 3 groups were 0.54 +/- 0.30 ng/ml, 0.83 +/- 0.39 ng/ml, 1.21 +/- 0.29 ng/ml respectively. The areas under the ROC curve on serum amyloid P component was 0.854, the specificity was 77.8% and the sensitivity was 85.2%. There were differentially expressed serum proteins in three groups. Serum amyloid P components might be one of the potential biomarkers in serum of recovered SARS patients complicating avascular necrosis of femoral head. Show less
To clarify the differential expression of the genes related to the lipid metabolism in the early stage of atherosclerosis in the young LDLR-/- mice of different ages. A RT-PCR assay was used to analys Show more
To clarify the differential expression of the genes related to the lipid metabolism in the early stage of atherosclerosis in the young LDLR-/- mice of different ages. A RT-PCR assay was used to analyse the gene expression patterns in the livers of LDLR-/- mice and wild type (WT) mice from 14 to 90 days. The characteristics of early lipid deposition in intima were evaluated using biochemical and pathological techniques. In LDLR-/- mice, when compared to WT mice, the mRNA level of the apolipoprotein A IV (apoA IV), fatty acid translocase (Fat/CD36) and carnitine palmitoyl transferase I (CPT I) changed prominently at the age of 14-days (P < 0.05). At 30 days, the mRNA level of apolipoprotein A I (apoA I) was up regulated, but apolipoprotein F (apoF), CD36 and CPT I were down regulated (P < 0.05). At 60 days, the mRNA levels of apoA I, CPT I and liver X receptor alpha (LXRalpha) were up regulated, but apoA IV was down regulated (P < 0.05). At 90 days, the level of the apoA I was higher, but the expression of the apoA IV, apoF and acyl-coenzymeA oxidase 1 (ACOX1) were down regulated (P < 0.05), whereas the expression of apolipoprotein A V (apoA V), apolipoprotein E (apoE), peroxidase proliferator-activated receptor alpha (PPARalpha) and angiopoietin-like protein 3 (angptl 3) had no significant changes (P > 0.05). The serum levels of TC (P < 0.05), TG (P < 0.05) and LDLC (P < 0.05) in LDLR-/- mice were significantly higher than those in wild type mice with the same age. The mRNA levels of the apoA I, apoA IV, apoF, FAT/CD36, CPT I, ACOX1 and LXRalpha of the LDLR-/- mice were significantly changed compared to the WT mice. The genes may be of some relevance to the complicated lipid metabolism network, and have effect in the early stage of atherogenesis. Show less
Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and s Show more
Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and characterization of new serological biomarkers (identified since 2007). These include five new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibodies against chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-like receptors (TLR) 2 and 4, and beta-defensin-1. Furthermore, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and multiplex enzyme-linked immunosorbent assay (ELISA)'s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more clinically useful novel diagnostic algorithms by incorporating new technologies in serological biomarker profiling and integrating multiple biomarkers with bioinformatics analysis/modeling are also discussed. Show less
Ya-Jun Li, Yu-Sheng Wei, Xiang-Hui Fu+6 more · 2008 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
The apolipoprotein (apo) AI/CIII/AIV/AV cluster genes are expressed at different levels in the liver and intestine. The apoCIII enhancer, a common regulatory element, regulates the tissue-specific exp Show more
The apolipoprotein (apo) AI/CIII/AIV/AV cluster genes are expressed at different levels in the liver and intestine. The apoCIII enhancer, a common regulatory element, regulates the tissue-specific expression of apoAI, apoCIII, and apoAIV but not apoAV. To study this regulation at the chromatin level, the histone modifications and intergenic transcription in the human apoAI/CIII/AIV/AV cluster were investigated in HepG2 and Caco-2 cells and in the livers of transgenic mice carrying the human gene cluster constructs with or without the apoCIII enhancer. We found that both the promoters and the intergenic regions of the apoAI/CIII/AIV genes were hyperacetylated and formed an open subdomain that did not include the apoAV gene. Hepatic and intestinal intergenic transcripts were identified to transcribe bidirectionally with strand preferences along the cluster. The deletion of the apoCIII enhancer influenced both histone modification and intergenic transcription in the apoAI/CIII/AIV gene region. These results demonstrate that the apoCIII enhancer contributes to the maintenance of an active chromatin subdomain of the apoAI/CIII/AIV genes, but not apoAV. Show less
To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6 Show more
To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls. Show less