To establish 2-dimensional gel electrophoresis images and compare the differences of serum proteins of oral lichen planus patients before and after hydroxychloroquine therapy. The serum of oral lichen Show more
To establish 2-dimensional gel electrophoresis images and compare the differences of serum proteins of oral lichen planus patients before and after hydroxychloroquine therapy. The serum of oral lichen planus patients before and after hydroxychloroquine therapy were collected, and total protein were extracted. Differential proteome profiles were established and analysed by means of 2-DE and MALDI-TOF-MS. The types and functions of protein were analyzed. SAS 9.12 software package was used for statistical analysis. Six proteins were well characterized including plasminogen precursor,Apo A-IV precursor, C4A/C4B complement, C2 precursor, Vitamin D binding protein and hypothetical protein. The differences were statistically significant. Plasminogen precursor, Apo A-IV precursor, C4A/C4B complement, C2 precursor, Vitamin D binding protein and hypothetical protein are differentially expressed in oral lichen planus patients before and after hydroxychloroquine therapy, but the results need to be validated by other biochemical technologies. Show less
Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of Show more
Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of NOS1AP for type 2 diabetes susceptibility in the Chinese population. In this study, we analyzed the total serum profiling among three genotypes of rs12742393 to discover potential crosstalk under the variant and the disease through proteomic analyses for the first time. We used OFFGEL peptide fractionation, LC-MS/MS analysis, and label-free quantification to profile the fasting human serum samples of the genotypes in rs12742393 (n = 4, for CC, AC, and AA, resp.). Four proteins were identified, including apoA4, alpha1-ACT, HABP2, and keratin 10, with blood levels changed significantly between CC and AA homozygotes of rs12742393. Compared with AA group, the levels of apoA4 increased (P = 0.000265), whereas the concentration of alpha1-ACT, HABP2, and keratin 10 decreased in CC group (P = 0.011116, 0.021175, and 0.015661, resp.). Then we selected additional fasting serum samples for ELISA and western blot validation. However, no significant differences were identified by neither ELISA nor western blot (P > 0.05). The protein profiling changes between the genotypes of rs12742393 indicated that this SNP might play a role in the development of type 2 diabetes. Show less
Apolipoprotein A-IV (apoA-IV) is synthesized by the intestine and secreted when dietary fat is absorbed and transported into lymph associated with chylomicrons. We have recently demonstrated that loss Show more
Apolipoprotein A-IV (apoA-IV) is synthesized by the intestine and secreted when dietary fat is absorbed and transported into lymph associated with chylomicrons. We have recently demonstrated that loss of apoA-IV increases chylomicron size and delays its clearance from the blood. There is still uncertainty, however, about the precise role of apoA-IV on the transport of dietary fat from the intestine into the lymph. ApoA-IV knockout (KO) mice do not have a gross defect in dietary lipid absorption, as measured by oral fat tolerance and fecal fat measurements. Here, using the in vivo lymph fistula mouse model, we show that the cumulative secretion of triglyceride (TG) into lymph in apoA-IV KO mice is very similar to that of wild-type (WT) mice. However, the apoA-IV KO mice do have subtle changes in TG accumulation in the intestinal mucosa during a 6-h continuous, but not bolus, infusion of lipid. There are no changes in the ratio of esterified to free fatty acids in the intestinal mucosa of the apoA-IV KO, however. When we extended these findings, by giving a higher dose of lipid (6 μmol/h) and for a longer infusion period (8 h), we found no effect of apoA-IV KO on intestinal TG absorption. This higher lipid infusion most certainly stresses the intestine, as we see a drastically lower absorption of TG (in both WT and KO mice); however, the loss of A-IV does not exacerbate this effect. This supports our hypothesis that apoA-IV is not required for TG absorption in the intestine. Our data suggest that the mechanisms by which the apoA-IV KO intestine responds to intestinal lipid may not be different from their WT counterparts. We conclude that apoA-IV is not required for normal lymphatic transport of TG. Show less
Apolipoprotein A5 (APOA5) and C3 (APOC3) genes are involved in the PPAR lipid metabolism pathway and thus associated with elevated triglyceride levels. However, whether APOA5 and APOC3 genetic polymor Show more
Apolipoprotein A5 (APOA5) and C3 (APOC3) genes are involved in the PPAR lipid metabolism pathway and thus associated with elevated triglyceride levels. However, whether APOA5 and APOC3 genetic polymorphisms affect intramuscular fat deposition and other meat quality traits remains unknown in pigs. One hundred and seventy-one Kele pigs were sampled to investigate genetic variants in the APOA5 and APOC3 genes and their association with seven pork quality traits. We identified 5 single nucleotide polymorphisms (SNPs) in the promoter region of the APOA5 gene and 17 SNPs in the APOC3 gene. Linkage disequilibrium analysis revealed 5 complete linkage disequilibria among these 22 SNPs. We found that 10 SNPs were significantly correlated with meat quality traits, including the mutation A5/-769 in the APOA5 gene, which was significantly associated with cooked weight percentage, and 9 SNPs in the APOC3 gene that were significantly associated with drip loss rate, meat color value of longissimus dorsi muscle and shear force. Therefore, these SNP markers will be useful for marker-assisted selection for improved pork quality. Show less
The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility. Bibliographic databases were searched from 1970 to Dec 2012 for studies that report Show more
The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility. Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes. A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (OR = 0.71, 95% CI = 0.55-0.92, P = 0.01), IL2RA rs11594656 (OR = 0.86, 95% CI = 0.82-0.91, P<0.00001), and CLEC16A rs725613 (OR = 0.71, 95% CI = 0.55-0.92, P = 0.01). APOA5 -1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, OR = 1.27, 95% CI = 1.03-1.57, P = 0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C. Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 -1131T/C are risky factors of T1D and T2D, respectively. Show less
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trai Show more
Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies. Show less
The Apolipoprotein A5 (APO A5) -1131T/C, fibrinogen β (FgB) -455G/A, -148C/T, and cholesteryl ester transfer protein (CETP) TaqIB gene polymorphisms have been indicated to be associated with the coron Show more
The Apolipoprotein A5 (APO A5) -1131T/C, fibrinogen β (FgB) -455G/A, -148C/T, and cholesteryl ester transfer protein (CETP) TaqIB gene polymorphisms have been indicated to be associated with the coronary artery disease (CAD) risk, but the individual study results are still inconsistent. To explore the relationship between APO A5 -1131T/C, FgB -455G/A, -148C/T, and CETP TaqIB gene polymorphisms and CAD in the Chinese population, the current meta-analysis involving 15,055 subjects from 40 individual studies was conducted. The pooled odds ratio (OR) for the association between APO A5 -1131T/C, FgB -455G/A, -148C/T, and CETP TaqIB gene polymorphisms and CAD and its corresponding 95 % confidence interval (95 % CI) were evaluated by random or fixed effect model. A significant association between APO A5 -1131T/C gene polymorphism and CAD in the Chinese population was found under an allelic (OR: 1.33, 95 % CI: 1.22-1.44, P < 0.00001), recessive (OR: 1.67, 95 % CI: 1.25-2.25, P = 0.0006), dominant (OR: 0.820, 95 % CI: 0.767-0.876, P = 1.0 × 10(-10)), homozygous (OR: 2.36, 95 % CI: 1.55-3.58, P < 0.0001) and heterozygous genetic models (OR: 1.136, 95 % CI:1.075-1.200, P = 1.0 × 10(-10)). A significant association between FgB -455G/A gene polymorphism and CAD was also detected in the Chinese population under an allelic (OR: 1.50, 95 % CI: 1.25-1.81, P < 0.0001), dominant (OR: 0.864, 95 % CI: 0.819-0.912, P = 1.0 × 10(-10)), homozygous (OR: 1.616, 95 % CI: 1.213-2.152, P = 0.001) and heterozygous genetic models (OR: 1.245, 95 % CI:1.138-1.361, P = 1.0 × 10(-10)). No significant association was found between them under a recessive genetic model (OR: 1.124, 95 % CI: 0.844-1.497, P = 0.424). A significant association was also found between FgB -148C/T gene polymorphism and CAD in the Chinese population under an allelic (OR: 1.34, 95 % CI: 1.06-1.71, P = 0.02), recessive (OR: 1. 65, 95 % CI: 1.02-2.69, P = 0.04), dominant (OR: 0.924, 95 % CI: 0.872-0.978, P = 0.007) and homozygous genetic models (OR: 0.968, 95 % CI: 0.942-0.995, P = 0.018). No significant association was found between them under a heterozygous genetic model (OR: 0.979, 95 % CI: 0.937-1.023, P = 0.342). In the whole Chinese population, no significant association between the CETP TaqIB gene polymorphism and CAD was found under an allelic (OR: 1.17, 95 % CI: 0.94-1.45, P = 0.15), dominant (OR: 1.46, 95 % CI: 0.80-2.67, P = 0.22) or recessive genetic models (OR: 0.68, 95 % CI: 0.32-1.44, P = 0.31). However, in the subgroup analysis stratified by ethnicity, there was a significant association between them under an allelic (OR: 1.27, 95 % CI: 1.07-1.52, P = 0.007) and dominant genetic model (OR: 2.04, 95 % CI: 1.49-2.79, P < 0.00001) in the Han subgroup. In the Chinese population, the APO A5 -1131T/C and FgB -455G/A, -148C/T gene polymorphisms were implied to be associated with CAD susceptibility. The APO A5 -1131C, FgB -455A, and -148T alleles might confer susceptibility to CAD. CETP TaqIB gene polymorphism was suggested to be associated with CAD susceptibility in the Chinese Han population. Carriers with B1 allele of CETP TaqIB gene might be predisposed to CAD in the Chinese Han population. Show less
Multi-causality and heterogeneity of phenotypes and genotypes characterize complex diseases. In a database with comprehensive collection of phenotypes and genotypes, we compared the performance of com Show more
Multi-causality and heterogeneity of phenotypes and genotypes characterize complex diseases. In a database with comprehensive collection of phenotypes and genotypes, we compared the performance of common machine learning methods to generate mathematical models to predict diabetic kidney disease (DKD). In a prospective cohort of type 2 diabetic patients, we selected 119 subjects with DKD and 554 without DKD at enrolment and after a median follow-up period of 7.8 years for model training, testing and validation using seven machine learning methods (partial least square regression, the classification and regression tree, the C5.0 decision tree, random forest, naïve Bayes classification, neural network and support vector machine). We used 17 clinical attributes and 70 single nucleotide polymorphisms (SNPs) of 54 candidate genes to build different models. The top attributes selected by the best-performing models were then used to build models with performance comparable to those using the entire dataset. Age, age of diagnosis, systolic blood pressure and genetic polymorphisms of uteroglobin and lipid metabolism were selected by most methods. Models generated by support vector machine (svmRadial) and random forest (cforest) had the best prediction accuracy whereas models derived from naïve Bayes classifier and partial least squares regression had the least optimal performance. Using 10 clinical attributes (systolic and diastolic blood pressure, age, age of diagnosis, triglyceride, white blood cell count, total cholesterol, waist to hip ratio, LDL cholesterol, and alcohol intake) and 5 genetic attributes (UGB G38A, LIPC -514C > T, APOB Thr71Ile, APOC3 3206T > G and APOC3 1100C > T), selected most often by SVM and cforest, we were able to build high-performance models. Amongst different machine learning methods, svmRadial and cforest had the best performance. Genetic polymorphisms related to inflammation and lipid metabolism warrant further investigation for their associations with DKD. Show less
Glycosylation is one of the most important post-translational modifications to mammalian proteins. Distribution of different glycoisoforms of certain proteins may reflect disease conditions and, there Show more
Glycosylation is one of the most important post-translational modifications to mammalian proteins. Distribution of different glycoisoforms of certain proteins may reflect disease conditions and, therefore, can potentially be utilized as biomarkers. Apolipoprotein C3 (ApoC3) is one of the many plasma glycoproteins extensively studied for association with disease states. ApoC3 exists in three main glycoisoforms, including ApoC3-1 and ApoC3-2, which contain an O-linked carbohydrate moiety consisting of three and four monosaccharide residues, respectively, and ApoC3-0 that lacks the entire glycosylation chain. Changes in the ratio of different glycoisoforms of ApoC3 have been observed in pathological conditions such as kidney disease, liver disease, and diabetes. They may provide important information for diagnosis, prognosis, and evaluation of therapeutic response for metabolic conditions. In this current work, a liquid chromatography (LC)-high-resolution (HR) time-of-flight (TOF) mass spectrometry (MS) method was developed for relative quantitation of different glycoisoforms of intact ApoC3 in human plasma. The samples were processed using a solid-phase extraction (SPE) method and then subjected to LC-full scan HRMS analysis. Isotope peaks for each targeted glycoisoform at two charge states were extracted using a window of 50 mDa and integrated into a chromatographic peak. The peak area ratios of ApoC3-1/ApoC3-0 and ApoC3-2/ApoC3-0 were calculated and evaluated for assay performance. The results indicated that the ratio can be determined with excellent reproducibility in multiple subjects. It has also been observed that the ratios remained constant in plasma exposed to room temperature, freeze-thaw cycles, and long-term frozen storage. The method was applied in preliminary biomarker research of diabetes by analyzing plasma samples collected from normal, prediabetic, and diabetic subjects. Significant differences were revealed in the ApoC3-1/ApoC3-0 ratio and in the ApoC3-2/ApoC3-0 ratio among the three groups. The workflow of intact protein analysis using full scan HRMS established in this current work can be potentially extended to relative quantitation of other glycosylated proteins. To our best knowledge, this is the first time that a systematic approach of relative quantitation of targeted intact protein glycoisoforms using LC-MS has been established and utilized in biomarker research. Show less
Ubiquitination plays important and diverse roles in modulating protein functions. As a C2-WW-HECT-type ubiquitin ligase, Smad ubiquitination regulatory factor 1 (Smurf1) commonly serves to regulate ub Show more
Ubiquitination plays important and diverse roles in modulating protein functions. As a C2-WW-HECT-type ubiquitin ligase, Smad ubiquitination regulatory factor 1 (Smurf1) commonly serves to regulate ubiquitin-dependent protein degradation in a number of signaling pathways. Here, we report a novel function of Smurf1 in regulating Wnt/β-catenin signaling through targeting axin for nonproteolytic ubiquitination. Our data unambiguously demonstrate that Smurf1 ubiquitinates axin through Lys 29 (K29)-linked polyubiquitin chains. Unexpectedly, Smurf1-mediated axin ubiquitination does not lead to its degradation but instead disrupts its interaction with the Wnt coreceptors LRP5/6, which subsequently attenuates Wnt-stimulated LRP6 phosphorylation and represses Wnt/β-catenin signaling. The inhibitory function of Smurf1 on Wnt/β-catenin signaling is further evidenced by analysis with Smurf1 knockout murine embryonic fibroblasts. We next identified K789 and K821 in axin as the ubiquitination sites by Smurf1. Consistently, Smurf1 could neither disrupt the interaction of an axin(K789/821R) double mutant with LRP5/6 nor attenuate the phosphorylation of LRP6 in axin(K789/821R)-expressing cells. Collectively, our studies uncover Smurf1 as a new regulator for the Wnt/β-catenin signaling pathway via modulating the activity of axin. Show less
We previously reported that Axin1 (Axin) is down-regulated in many cases of lung cancer, and X-ray irradiation increased Axin expression and inhibited lung cancer cells. The mechanisms, however, were Show more
We previously reported that Axin1 (Axin) is down-regulated in many cases of lung cancer, and X-ray irradiation increased Axin expression and inhibited lung cancer cells. The mechanisms, however, were not clear. Four lung cancer cell lines were used to detect the methylation status of Axin with or without X-ray treatment. Real-time PCR was used to quantify the expression of Axin, and western blot analysis was applied to measure protein levels of Axin, β-catenin, Cyclin D1, MMP-7, DNMTS, MeCP2 and acetylated histones. Flow cytometric analysis, colony formation assay, transwell assay and xenograft growth experiment were used to study the biological behavior of the cells with hypermethylated or unmethylated Axin gene after X-ray treatment. Hypermethylated Axin gene was detected in 2 of 4 cell lines, and it correlated inversely with Axin expression. X-ray treatment significantly up-regulated Axin expression in H446 and H157 cells, which possess intrinsic hypermethylation of the Axin gene (P<0.01), but did not show up-regulation in LTE and H460 cells, which have unmethylated Axin gene. 2Gy X-ray significantly reduced colony formation (from 71% to 10.5%) in H157 cells, while the reduction was lower in LTE cells (from 71% to 20%). After X-ray irradiation, xenograft growth was significantly decreased in H157 cells (from 1.15 g to 0.28 g) in comparison with LTE cells (from 1.06 g to 0.65 g). Significantly decreased cell invasiveness and increased apoptosis were also observed in H157 cells treated with X-ray irradiation (P<0.01). Down-regulation of DNMTs and MeCP2 and up-regulation of acetylated histones could be detected in lung cancer cells. X-ray-induced inhibition of lung cancer cells may be mediated by enhanced expression of Axin via genomic DNA demethylation and histone acetylation. Lung cancer cells with a different methylation status of the Axin gene showed different radiosensitivity, suggesting that the methylation status of the Axin gene may be one important factor to predict radiosensitivity of the tumor. Show less
α-Thalassemia is an inherited autosomal recessive disorder. It is one of the most common monogenic abnormalities known in the world and is prevalent in tropical and subtropical regions. α-Thalassemia Show more
α-Thalassemia is an inherited autosomal recessive disorder. It is one of the most common monogenic abnormalities known in the world and is prevalent in tropical and subtropical regions. α-Thalassemia is more frequently caused by deletional type than non-deletional type. Recently, we identified a novel large deletional type of α-thalassemia named --(FZ)/αα from a family in South China. Multiplex ligation-dependent probe amplification was used for diagnosing the carrier and prenatal diagnosing for a fetus. Real-time PCR was employed for characterizing the deletion breakpoints and the deletional segment was determined as 300 kb in length extending from the telomere to AXIN1 gene on the short arm of chromosome 16. The carriers in the family members were detected by real-time PCR using designed primers. Show less
In recent years, long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of biological function. A recent study reported that lncRNAs control cell proliferation in hepatocell Show more
In recent years, long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of biological function. A recent study reported that lncRNAs control cell proliferation in hepatocellular carcinoma (HCC). However, the role of lncRNAs in liver regeneration and the overall mechanisms remain largely unknown. To address this issue, we carried out a genome-wide lncRNA microarray analysis during liver regeneration in mice after 2/3 partial hepatectomy (PH) at various timepoints. The results revealed differential expression of a subset of lncRNAs, notably a specific differentially expressed lncRNA associated with Wnt/β-catenin signaling during liver regeneration (an lncRNA associated with liver regeneration, termed lncRNA-LALR1). The functions of lncRNA-LALR1 were assessed by silencing and overexpressing this lncRNA in vitro and in vivo. We found that lncRNA-LALR1 enhanced hepatocyte proliferation by promoting progression of the cell cycle in vitro. Furthermore, we showed that lncRNA-LALR1 accelerated mouse hepatocyte proliferation and cell cycle progression during liver regeneration in vivo. Mechanistically, we discovered that lncRNA-LALR1 facilitated cyclin D1 expression through activation of Wnt/β-catenin signaling by way of suppression of Axin1. In addition, lncRNA-LALR1 inhibited the expression of Axin1 mainly by recruiting CTCF to the AXIN1 promoter region. We also identified a human ortholog RNA of lncRNA-LALR1 (lncRNA-hLALR1) and found that it was expressed in human liver tissues. lncRNA-LALR1 promotes cell cycle progression and accelerates hepatocyte proliferation during liver regeneration by activating Wnt/β-catenin signaling. Pharmacological intervention targeting lncRNA-LALR1 may be therapeutically beneficial in liver failure and liver transplantation by inducing liver regeneration. Show less
Lian-he Yang, Hong-tao Xu, Qing-Chang Li+5 more · 2013 · Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · Springer · added 2026-04-24
Axin is an important negative regulator of Wnt pathway. We have reported that reduced expression of Axin could be detected in lung cancer tissues, but the mechanism is not clear. By analyzing the geno Show more
Axin is an important negative regulator of Wnt pathway. We have reported that reduced expression of Axin could be detected in lung cancer tissues, but the mechanism is not clear. By analyzing the genomic sequence, we note that Axin gene promoter is rich in CpGs. Little is known about the methylation status of Axin gene in lung cancer. So, nested MSP and RT-PCR were used to study the methylation status and mRNA expression of Axin gene in lung cancer tissues and cell lines. The results showed that hypermethylated Axin gene promoter and reduced mRNA expression level of Axin could be detected in lung cancer tissues but not in their paired autologous normal lung tissues (P < 0.01). The hypermethylated Axin gene promoter significantly correlated with the degree of differentiation (P = 0.03), lymph node metastasis (P = 0.048) and TNM classifications (P = 0.032). Demethylation reagent 5-aza-2-deoxycytidine significantly up-regulate Axin expression in BE1 cells (with hypermethylated Axin gene promoter) but not in H460 cells (with unmethylated Axin gene promoter). MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and transwell matrigel invasion assay showed that 5-aza-2-deoxycytidine treatment inhibited cell growth and invasion more significantly in BE1 cells than that in H460 cells. Our data indicate that hypermethylated Axin gene significantly correlates with the progression of lung cancer and might serve as a new target of clinical therapy for lung cancer patients in future. Show less
Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc cons Show more
Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit. Show less
Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several Show more
Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52 × 10(-16), 1.38 × 10(-6) and 5.59 × 10(-9), respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population. Show less
The dried succulent stem of Cistanche tubulosa (Schenk) R. Wight is one component of traditional Chinese medicine prescriptions for diabetes. However, there have been no modern scientific reports to c Show more
The dried succulent stem of Cistanche tubulosa (Schenk) R. Wight is one component of traditional Chinese medicine prescriptions for diabetes. However, there have been no modern scientific reports to confirm this traditional claim for the Cistanche species until now. Thus, we investigated the effects of Cistanche tubulosa on glucose homeostasis and serum lipids in male BKS.Cg-Dock7(m) +/+ Lepr(db)/J (db/db) mice, a model of type 2 diabetes. The verbascoside and echinacoside contents of Cistanche tubulosa powder were evaluated using HPLC. The total phenolic content, polysaccharide content and antioxidant activity of Cistanche tubulosa powder were also evaluated. Then, different doses of Cistanche tubulosa (equivalent to 120.9, 72.6 or 24.2mg verbascoside/kg) were administered orally once daily for 45 days to male db/db mice. Age matched db/+ mice were used as normal controls. Body weight, fasting blood glucose, postprandial blood glucose and insulin tolerance test were measured during the experiment. At the time of sacrifice, blood was collected for measurement of insulin level, the homeostatic model assessment of insulin resistance (HOMA-IR), and total cholesterol, triglyceride, HDL-c, LDL-c and VLDL-c levels; liver and muscle were harvested for measurement of glycogen levels. Cistanche tubulosa significantly suppressed the elevated fasting blood glucose and postprandial blood glucose levels, improved insulin resistance and dyslipidemia, and suppressed body weight loss in db/db mice. However, Cistanche tubulosa did not significantly affect serum insulin levels or hepatic and muscle glycogen levels. This study provides scientific evidence for the traditional use of Cistanche tubulosa to treat diabetes, suggesting that Cistanche tubulosa has the potential for development into a functional food ingredient or drug to prevent hyperglycemia and treat hyperlipidemia. Show less
The posterior lateral line primordium (PLLp) migrates caudally and periodically deposits neuromasts. Coupled, but mutually inhibitory, Wnt-FGF signaling systems regulate proto-neuromast formation in t Show more
The posterior lateral line primordium (PLLp) migrates caudally and periodically deposits neuromasts. Coupled, but mutually inhibitory, Wnt-FGF signaling systems regulate proto-neuromast formation in the PLLp: FGF ligands expressed in response to Wnt signaling activate FGF receptors and initiate proto-neuromast formation. FGF receptor signaling, in turn, inhibits Wnt signaling. However, mechanisms that determine periodic neuromast formation and deposition in the PLLp remain poorly understood. Previous studies showed that neuromasts are deposited closer together and the PLLp terminates prematurely in lef1-deficient zebrafish embryos. It was suggested that this results from reduced proliferation in the leading domain of the PLLp and/or premature incorporation of progenitors into proto-neuromasts. We found that rspo3 knockdown reduces proliferation in a manner similar to that seen in lef1 morphants. However, it does not cause closer neuromast deposition or premature termination of the PLLp, suggesting that such changes in lef1-deficient embryos are not linked to changes in proliferation. Instead, we suggest that they are related to the role of Lef1 in regulating the balance of Wnt and FGF functions in the PLLp. Lef1 determines expression of the FGF signaling inhibitor Dusp6 in leading cells and regulates incorporation of cells into neuromasts; reduction of Dusp6 in leading cells in lef1-deficient embryos allows new proto-neuromasts to form closer to the leading edge. This is associated with progressively slower PLLp migration, reduced spacing between deposited neuromasts and premature termination of the PLLp system. Show less
Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explo Show more
Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17β-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. Show less
Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin present in the phenolic components extracted from the dried rhizome of Curcuma longa L. BDMC demonstrated potential chemotherapeutic act Show more
Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin present in the phenolic components extracted from the dried rhizome of Curcuma longa L. BDMC demonstrated potential chemotherapeutic activities but the underlying mechanisms have not been fully clarified. In the present study, the role of reactive oxidative species (ROS) in the anti-cancer effects of BDMC was investigated. MCF-7 cells were exposed to BDMC, and then the cell proliferation, colony formation ability and cell cycle profile were analyzed. Cellular ROS level was determined by flow cytometry and fluorescent microscope observation using specific fluorescent probes. Mitochondrial membrane potential (ψm) was assessed using JC-1. In addition, effects of BDMC on senescence-related molecules were analyzed by western blot assay. BDMC significantly inhibited MCF-7 breast cancer cell proliferation, while a rapid rise of the intracellular ROS level accompanied with a reduction of Dym were observed. In addition, BDMC activated the pro-apoptotic protein p53 and its downstream effector p21 as well as the cell cycle regulatory proteins p16 and its downstream effector retinoblastoma protein (Rb). All of these BDMC-induced effects were counteracted with the pre-incubation of the antioxidant N-acetylcysteine (NAC). These results suggested that BDMC-induced ROS accumulation may contribute to its inhibitory effect on MCF-7 cell viability through regulation of p53/p21 and p16/Rb pathways. Show less
Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been s Show more
Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been successfully used to identify pathogenic gene mutations. In this study, exome sequencing followed by Sanger sequencing validation was first used to screen gene mutations in two representative MO patients from a Chinese family. After filtering the data from the 1000 Genome Project and the dbSNP database (build 132), the detected candidate gene mutations were further validated via Sanger sequencing of four other members of the same MO family and 200 unrelated healthy subjects. Immunohistochemisty and multiple sequence alignment were performed to evaluate the importance of the identified causal mutation. A novel frameshift mutation, c.1457insG at codon 486 of exon 6 of EXT1 gene, was identified, which truncated the glycosyltransferase domain of EXT1 gene. Multiple sequence alignment showed that codon 486 of EXT1 gene was highly conserved across various vertebrates. Immunohistochemisty demonstrated that the chondrocytes with functional EXT1 in MO were less than those in extragenetic solitary chondromas. The novel c.1457insG deleterious mutation of EXT1 gene reported in this study expands the causal mutation spectrum of MO, and may be helpful for prenatal genetic screening and early diagnosis of MO. Show less
We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q Show more
We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q23.3-q24.22 deletion detected by array comparative genomic hybridization. The patient was previously misdiagnosed as having Ehlers-Danlos syndrome. However, his clinical findings are in fact correlated with trichorhinophalangeal syndrome type II/Langer-Giedion syndrome and Cornelia de Lange syndrome-4. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TRPS1, RAD21, EXT1 and KCNQ3 in this case. Show less
Yuhong Wu, Xuesha Xing, Shaonian Xu+4 more · 2013 · Journal of orthopaedic research : official publication of the Orthopaedic Research Society · Wiley · added 2026-04-24
Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened Show more
Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened mutations in the EXT1/EXT2 genes in four Chinese MO kindreds by direct sequencing. Three point mutations were detected, including a nonsense mutation in the EXT2 gene (c.544C > T) and two splice site mutations in the EXT1 and EXT2 genes, respectively (EXT1: c.1883 + 1G > A and EXT2: c.1173 + 1G > T). Although splice site mutations constitute at least 10% of all mutations that cause MO, there has been limited research on their pathogenic effect on RNA processing due to poor availability of patient RNA samples. In this study, ex vivo and in vivo splicing assays were used to investigate the effect of EXT1 and EXT2 mutations on aberrant splicing at the mRNA level. Our results indicate that identified splice site mutations can cause either cryptic splice site usage or exon skipping. Show less
To know the involvement of glycosaminoglycans (GAGs) in the metastasis of mouse FBJ osteosarcoma cells, N(α)-lauroyl-O-(β-D-xylopyranosyl)-L-serinamide (Xyl-Ser-C12), which initiates elongation of GAG Show more
To know the involvement of glycosaminoglycans (GAGs) in the metastasis of mouse FBJ osteosarcoma cells, N(α)-lauroyl-O-(β-D-xylopyranosyl)-L-serinamide (Xyl-Ser-C12), which initiates elongation of GAG chains using the glycan biosynthesis system in cells, was administered to FBJ cells with different metastatic capacities. Production of glycosylated products derived from Xyl-Ser-C12, especially heparan sulfate (HS) GAG-type oligosaccharides such as GalNAc-GlcA-GlcNAc-GlcA-Gal-Gal-Xyl-Ser-C12, was indicated in poorly metastatic FBJ-S1 cells more than in highly metastatic FBJ-LL cells by LC-MS. The results of RT-PCR revealed that HS synthases, Ext1 and Ext2, were expressed in FBJ-S1 cells more than in FBJ-LL cells. Furthermore, siRNA against Ext1 suppressed the expression of HS and enhanced the motility of FBJ-S1 cells. In addition, the expression of heparanase (HPSE) was enhanced in Ext-1-knockdown FBJ-S1 cells, and responsible for the increase in cell motility caused by the down-regulation of Ext1 expression. Our data provide the first evidence that Ext1 regulates the expression of HPSE and also indicated that levels of Ext1 and HPSE influenced the motility of FBJ cells. Show less
Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, the factors that determine these differences Show more
Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, the factors that determine these differences remain largely undefined. Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle-like action potentials, increased cardiomyocyte size, and development of extensive T tubules. Changes in atrial characteristics are accompanied by alterations of 2,584 genes, of which 81% were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers atrial identity through direct binding and by modulating expression of a broad spectrum of genes that have an impact on atrial development and function. Show less
Hua Wang, Ye Tian, Jianru Wang+9 more · 2013 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
The objective of the study was to investigate how inflammatory cytokines, IL-1β, and TNF-α control NOTCH signaling activity in nucleus pulposus (NP) cells. An increase in expression of selective NOTCH Show more
The objective of the study was to investigate how inflammatory cytokines, IL-1β, and TNF-α control NOTCH signaling activity in nucleus pulposus (NP) cells. An increase in expression of selective NOTCH receptors (NOTCH1 and -2), ligand (JAGGED2), and target genes (HES1, HEY1, and HEY2) was observed in NP cells following cytokine treatment. A concomitant increase in NOTCH signaling as evidenced by induction in activity of target gene HES1 and HEY1 promoters and reporter 12xCSL was seen. Moreover, treatment increased activity of a 2-kb NOTCH2 promoter. Treatment of cells with NF-κB and MAPK inhibitors abolished the inductive effect of cytokines on NOTCH2 promoter and its expression. Gain and loss-of-function studies confirmed the inductive effect of p65 on NOTCH2 promoter activity. In contrast, p50 blocked the cytokine induction of promoter activity. Supporting promoter studies, lentiviral delivery of sh-p65, and sh-IKKβ significantly decreased cytokine dependent change in NOTCH2 expression. Interestingly, MAPK signaling showed an isoform-specific control of NOTCH2 promoter; p38α/β2/δ, ERK1, and ERK2 contributed to cytokine dependent induction, whereas p38γ played no role. Analysis of human NP tissues showed that NOTCH1 and -2 and HEY2 expression correlated with each other. Moreover, expression of NOTCH2 and IL-1β as well as the number of cells immunopositive for NOTCH2 significantly increased in histologically degenerate discs compared with non-degenerate discs. Taken together, these results explain the observed dysregulated expression of NOTCH genes in degenerative disc disease. Thus, controlling IL-1β and TNF-α activities during disc disease may restore NOTCH signaling and nucleus pulposus cell function. Show less
Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a m Show more
Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%). Show less
We used a complete spinal cord transection model and locomotor function, histological, and immunohistochemical examinations to evaluate the effects of local injection of lentivirus/LINGO-1-short hairp Show more
We used a complete spinal cord transection model and locomotor function, histological, and immunohistochemical examinations to evaluate the effects of local injection of lentivirus/LINGO-1-short hairpin RNA (VL) on rats with spinal cord injury (SCI). To demonstrate the neuroregenerative and neuroprotective effects of LINGO-1 RNAi on complete transection SCI rats. LINGO-1 has been reported as a negative regulator of axonal sprouting and its antagonist was determined to improve functional outcomes in SCI rats. However, it has not been assessed whether blockade of LINGO-1 mediated by lentivirus vectors could stimulate neural recovery after SCI. Complete spinal cord transection was made at T10 level. Suspension of lentivirus vectors encoding LINGO-1-short hairpin RNA was injected into the lesion gap. Controls received control vectors in the same manner and the sham group was subjected to laminectomy only. The Basso-Beattie-Bresnahan scale and surface righting reflex test were used to evaluate functional outcomes. Finally, the spinal cords were harvested for histological and immunohistochemical analysis. The treatment with VL improved Basso-Beattie-Bresnahan scores and surface righting reflex after SCI. Tissue repair was facilitated and the cavity area was significantly decreased in VL-treated animals. More sprouting and myelinated nerve fibers were detected within the injured site in the VL group as compared with the control. In addition, the number of survival neurons and oligodendrocytes around the epicenter was notably higher under the VL condition. Local injection of lentivirus/LINGO-1-short hairpin RNA after complete transection of spinal cord resulted in meaningful histological and functional outcomes in rats. The mechanism of VL protection may be related to its promotion of axonal sprouting, remyelination, and cell survival. Show less
Lingo-1 is selectively expressed on both oligodendrocytes and neurons in the central nervous system (CNS) and serves as a key negative regulator of nerve regeneration, implying a therapeutic target fo Show more
Lingo-1 is selectively expressed on both oligodendrocytes and neurons in the central nervous system (CNS) and serves as a key negative regulator of nerve regeneration, implying a therapeutic target for spinal cord injury (SCI). Here we described a strategy to knock-down Lingo-1 expression in vivo using lentiviral vectors encoding Lingo-1 short harpin interfering RNA (shRNA) delivered by Pluronic F-127 (PF-127) gel, a non-cytotoxic scaffold and gene delivery carrier, after the complete transection of the T10 spinal cord in adult rats. We showed administration of PF-127 encapsulating Lingo-1 shRNA lentiviral vectors efficiently down-regulated the expression of Lingo-1, and exhibited transduction efficiency comparable to using vectors alone in oligodendrocyte culture in vitro. Furthermore, similar silencing effects and higher transfection efficiency were observed in vivo when Lingo-1 shRNA was co-delivered to the injured site by PF-127 gel with lower viral concentrations. Cografting of gel and Lingo-1 RNAi significantly promoted functional recovery and nerve regeneration, enhanced neurite outgrowth and synapses formation, preserved myelinated axons, and induced the proliferation of glial cells. In addition, the combined implantation also improved neuronal survival and inhibited cell apoptosis, which may be associated with the attenuation of endoplasmic reticulum (ER) stress after SCI. Together, our data indicated that delivering Lingo-1 shRNA by gel scaffold was a valuable treatment approach to SCI and PF-127 delivery of viral vectors to the spinal cord may provide strategy to study and develop therapies for SCI. Show less