Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpre Show more
Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer. Show less
Smooth muscle 22α (SM22α) is involved in stress fiber formation and enhances contractility in vascular smooth muscle cells (VSMCs). In many cases, SM22α acts as an adapter protein to assemble signalin Show more
Smooth muscle 22α (SM22α) is involved in stress fiber formation and enhances contractility in vascular smooth muscle cells (VSMCs). In many cases, SM22α acts as an adapter protein to assemble signaling complexes and regulate signaling, but whether SM22α regulates contractile signaling induced by angiotensin II (AngII) remains unclear. To address this issue, we established a hypertension model of Sm22α(-/-) mice, and demonstrated that hypertension induced by AngII was attenuated in Sm22α(-/-) mice. A decreased vasoconstriction was observed in aortic rings from Sm22α(-/-) mice. Furthermore, loss of SM22α resulted in a reduced contractile response to AngII in VSMCs in vitro. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by AngII was impaired following depletion of SM22α, in parallel with a reduced contractility. The decay of ERK1/2 activity was associated with increased expression of mitogen-activated protein kinase phosphatase 3 (MKP3). Inhibition of MKP3 activity rescued ERK1/2 activity. SM22α depletion caused an enhanced interaction of MKP3 with ERK1/2, and a reduced ubiquitination and degradation of MKP3. Knockdown of SM22α extended the half-life of MKP3. In conclusion, SM22α promotes AngII-induced contraction by maintenance of ERK1/2 signaling cascades through facilitating ubiquitination and degradation of MKP3. The vasoconstriction is attenuated in aortic rings from Sm22α(-/-) mice. MKP3 mediates dephosphorylation of ERK1/2 in AngII-induced VSMC contraction. SM22α inhibits the interaction of ERK1/2 with MKP3. SM22α promotes ubiquitination and degradation of MKP3. SM22α facilitates AngII-induced contraction by maintenance of ERK1/2 signaling. Show less
To improve an asialoglycoprotein receptor (ASGPR)-based enrichment method for detection of circulating tumor cells (CTCs) of hepatocellular carcinoma (HCC). Peripheral blood samples were collected fro Show more
To improve an asialoglycoprotein receptor (ASGPR)-based enrichment method for detection of circulating tumor cells (CTCs) of hepatocellular carcinoma (HCC). Peripheral blood samples were collected from healthy subjects, patients with HCC or various other cancers, and patients with hepatic lesions or hepatitis. CTCs were enriched from whole blood by extracting CD45-expressing leukocytes with monoclonal antibody coated-beads following density gradient centrifugation. The remaining cells were cytocentrifuged on polylysine-coated slides. Isolated cells were treated by triple immunofluorescence staining with CD45 antibody and a combination of antibodies against ASGPR and carbamoyl phosphate synthetase 1 (CPS1), used as liver-specific markers, and costained with DAPI. The cell slide was imaged and stained tumor cells that met preset criteria were counted. Recovery, sensitivity and specificity of the detection methods were determined and compared by spiking experiments with various types of cultured human tumor cell lines. Expression of ASGPR and CPS1 in cultured tumor cells and tumor tissue specimens was analyzed by flow cytometry and triple immunofluorescence staining, respectively. CD45 depletion of leukocytes resulted in a significantly greater recovery of multiple amounts of spiked HCC cells than the ASGPR(+) selection (Ps < 0.05). The expression rates of either ASGPR or CPS1 were different in various liver cancer cell lines, ranging between 18% and 99% for ASGPR and between 9% and 98% for CPS1. In both human HCC tissues and liver cancer cell lines, there were a few HCC cells that did not stain positive for ASGPR or CPS1. The mixture of monoclonal antibodies against ASGPR and CPS1 identified more HCC cells than either antibody alone. However, these antibodies did not detect any tumor cells in blood samples spiked with the human breast cancer cell line MCF-7 and the human renal cancer cell line A498. ASGPR(+) or/and CPS1(+) CTCs were detected in 29/32 (91%) patients with HCC, but not in patients with any other kind of cancer or any of the other test subjects. Furthermore, the improved method detected a higher CTC count in all patients examined than did the previous method (P = 0.001), and consistently achieved 12%-21% higher sensitivity of CTC detection in all seven HCC patients with more than 40 CTCs. Negative depletion enrichment combined with identification using a mixture of antibodies against ASGPR and CPS1 improves sensitivity and specificity for detecting circulating HCC cells. Show less
Both genetic predisposition and lifestyle factors are associated with the risk for obesity. Multiple obesity loci have been identified using genome-wide association studies mainly in European populati Show more
Both genetic predisposition and lifestyle factors are associated with the risk for obesity. Multiple obesity loci have been identified using genome-wide association studies mainly in European populations. The aims of this study were to examine the associations of these loci with obesity and gene×dietary behavior interactions among Chinese children and adolescents. Nineteen candidate SNPs were genotyped using Sequenom technology in the Chinese children (N=2977, 853 obese and 2124 controls, aged 7-17). Dietary behaviors were assessed using self-administered questionnaires. After adjusting for age, sex and multiple testing, MC4R rs17782313, SEC16B rs543874, MAP2K5 rs2241423 and KCTD15 rs11084753 were associated with obesity and obesity-related traits (all P<0.005), with odd ratios ranging from 1.22 to 2.15. Dose-response association was significant between genetic risk score, which was calculated by summing the risk alleles, and the risk of obesity (P<0.001). Multiplicative interaction was found between rs543874 and salt preference on obesity with an OR of 4.40 (95% CI, 1.12-17.30). Additive interactions with salt preference were found in rs17782313 and rs11084753. Our findings indicated that rs17782313, rs543874, rs2241423 and rs11084753 were associated with the risk for children obesity in China, and interaction of genetic variants with diet behaviors on obesity. Show less
Here, we investigated the role of LXRα in capsaicin mediated anti-inflammatory effects. Results revealed that capsaicin inhibits LPS-induced IL-1β, IL-6 and TNF-α production in a time- and dose-depend Show more
Here, we investigated the role of LXRα in capsaicin mediated anti-inflammatory effects. Results revealed that capsaicin inhibits LPS-induced IL-1β, IL-6 and TNF-α production in a time- and dose-dependent manner. Moreover, capsaicin increases LXRα expression through PPARγ pathway. Inhibition of LXRα activation by siRNA diminished the inhibitory action of capsaicin on LPS-induced IL-1β, IL-6 and TNF-α production. Additionally, LXRα siRNA abrogated the inhibitory action of capsaicin on p65 NF-κB protein expression. Thus, we propose that the anti-inflammatory effects of capsaicin are LXRα dependent, and LXRα may potentially link the capsaicin mediated PPARγ activation and NF-κB inhibition in LPS-induced inflammatory response. Show less
Microtubule actin crosslinking factor 1 (MACF1), a widely expressed cytoskeletal linker, plays important roles in various cells by regulating cytoskeleton dynamics. However, its role in osteoblastic c Show more
Microtubule actin crosslinking factor 1 (MACF1), a widely expressed cytoskeletal linker, plays important roles in various cells by regulating cytoskeleton dynamics. However, its role in osteoblastic cells is not well understood. Based on our previous findings that the association of MACF1 with F-actin and microtubules in osteoblast-like cells was altered under magnetic force conditions, here, by adopting a stable MACF1-knockdown MC3T3-E1 osteoblastic cell line, we found that MACF1 knockdown induced large cells with a binuclear/multinuclear structure. Further, immunofluorescence staining showed disorganization of F-actin and microtubules in MACF1-knockdown cells. Cell counting revealed significant decrease of cell proliferation and cell cycle analysis showed an S phase cell cycle arrest in MACF1-knockdown cells. Moreover and interestingly, MACF1 knockdown showed a potential effect on cellular MTT reduction activity and mitochondrial content, suggesting an impact on cellular metabolic activity. These results together indicate an important role of MACF1 in regulating osteoblastic cell morphology and function. Show less
Endothelial dysfunction, common in chronic kidney disease (CKD), significantly increases cardiovascular disease risk in CKD patients. This study investigates whether different vitamin D receptor agoni Show more
Endothelial dysfunction, common in chronic kidney disease (CKD), significantly increases cardiovascular disease risk in CKD patients. This study investigates whether different vitamin D receptor agonists exhibit different effects on endothelial function and on aortic gene expression in an animal CKD model. The 5/6 nephrectomized (NX) rat was treated with or without alfacalcidol (0.02, 0.04 and 0.08μg/kg), paricalcitol (0.04 and 0.08μg/kg), or VS-105 (0.004, 0.01 and 0.16μg/kg). All three compounds at the test doses suppressed serum parathyroid hormone effectively. Alfacalcidol at 0.08μg/kg raised serum calcium significantly. Endothelial function was assessed by pre-contracting thoracic aortic rings with phenylephrine, followed by treatment with acetylcholine or sodium nitroprusside. Uremia significantly affected endothelial-dependent aortic relaxation, which was improved by all three compounds in a dose-dependent manner with alfacalcidol and paricalcitol exhibiting a lesser effect. DNA microarray analysis of aorta samples revealed that uremia impacted the expression of numerous aortic genes, many of which were normalized by the vitamin D analogs. Real-time RT-PCR analysis confirmed that selected genes such as Abra, Apoa4, Fabp2, Hsd17b2, and Hspa1b affected by uremia were normalized by the vitamin D analogs with alfacalcidol exhibiting less of an effect. These results demonstrate that different vitamin D analogs exhibit different effects on endothelial function and aortic gene expression in 5/6 NX rats. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. Show less
Genome-wide association studies (GWAS) of chronic obstructive pulmonary disease (COPD) have identified disease-susceptibility loci, mostly in subjects of European descent. We hypothesized that by stud Show more
Genome-wide association studies (GWAS) of chronic obstructive pulmonary disease (COPD) have identified disease-susceptibility loci, mostly in subjects of European descent. We hypothesized that by studying Hispanic populations we would be able to identify unique loci that contribute to COPD pathogenesis in Hispanics but remain undetected in GWAS of non-Hispanic populations. We conducted a metaanalysis of two GWAS of COPD in independent cohorts of Hispanics in Costa Rica and the United States (Multi-Ethnic Study of Atherosclerosis [MESA]). We performed a replication study of the top single-nucleotide polymorphisms in an independent Hispanic cohort in New Mexico (the Lovelace Smokers Cohort). We also attempted to replicate prior findings from genome-wide studies in non-Hispanic populations in Hispanic cohorts. We found no genome-wide significant association with COPD in our metaanalysis of Costa Rica and MESA. After combining the top results from this metaanalysis with those from our replication study in the Lovelace Smokers Cohort, we identified two single-nucleotide polymorphisms approaching genome-wide significance for an association with COPD. The first (rs858249, combined P value = 6.1 × 10(-8)) is near the genes KLHL7 and NUPL2 on chromosome 7. The second (rs286499, combined P value = 8.4 × 10(-8)) is located in an intron of DLG2. The two most significant single-nucleotide polymorphisms in FAM13A from a previous genome-wide study in non-Hispanics were associated with COPD in Hispanics. We have identified two novel loci (in or near the genes KLHL7/NUPL2 and DLG2) that may play a role in COPD pathogenesis in Hispanic populations. Show less
Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and i Show more
Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE－/－ mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor α (LXRα) activation, which was confirmed by the observation that LXRα siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Taken together, our results showed that UFM1 could suppress foam cell formation via the LXRα-dependent pathway. Show less
In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, Show more
In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1), seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3), and one for average daily gain (COL27A1). Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection. Show less
Understanding the consequences of tuning TCR signaling on selection, peripheral T cell function, and tolerance in the context of native TCR repertoires may provide insight into the physiological contr Show more
Understanding the consequences of tuning TCR signaling on selection, peripheral T cell function, and tolerance in the context of native TCR repertoires may provide insight into the physiological control of tolerance. In this study, we show that genetic ablation of a natural tuner of TCR signaling, mir-181a-1/b-1, in double-positive thymocytes dampened TCR and Erk signaling and increased the threshold of positive selection. Whereas mir-181a-1/b-1 deletion in mice resulted in an increase in the intrinsic reactivity of naive T cells to self-antigens, it did not cause spontaneous autoimmunity. Loss of mir-181a-1/b-1 dampened the induction of experimental autoimmune encephalomyelitis and reduced basal TCR signaling in peripheral T cells and their migration from lymph nodes to pathogenic sites. Taken together, these results demonstrate that tolerance can be modulated by microRNA gene products through the control of opposing activities in T cell selection and peripheral T cell function. Show less
Little is known about the association of the FADS1/FADS2 SNPs and serum lipid levels and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Chinese southern population. The pres Show more
Little is known about the association of the FADS1/FADS2 SNPs and serum lipid levels and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Chinese southern population. The present study aimed to determine such association in the Chinese southern population. A total of 1,669 unrelated subjects (CAD, 534; IS, 553; and healthy controls, 582) were recruited in the study. Genotypes of the FADS1 rs174546 SNP and the FADS2 rs174601 SNP were determined by the SNaPshot Multiplex Kit. The T allele and TT genotype frequencies of the two SNPs were predominant in our study population. The T alleles were associated with increased risk of CAD and IS. Correspondingly, the C alleles were associated with reduced risk of CAD and IS. Haplotype analyses showed that the haplotype of T-T (rs174546-rs174601) was associated with an increased risk for IS, and the haplotype of C-C (rs174546-rs174601) was associated with a reduced risk for CAD and IS. The two SNPs were likely to influence serum lipid levels. The T allele carriers of the two SNPs and rs174601 TT genotype were associated with decreased serum HDL-C and ApoAI levels in the patient groups and with an increased risk of CAD and IS. The present study suggests that the FADS1 rs174546 SNP and the FADS2 rs174601 SNP are associated with the risk of CAD and IS, and are likely to influence serum lipid levels. However, further functional studies are needed to clarify how the two SNPs actually affect serum lipid levels and the risk of CAD and IS. Show less
Ammonia detoxification is essential for physiological well-being, and the urea cycle in liver plays a predominant role in ammonia disposal. Nobiletin (NOB), a natural dietary flavonoid, is known to ex Show more
Ammonia detoxification is essential for physiological well-being, and the urea cycle in liver plays a predominant role in ammonia disposal. Nobiletin (NOB), a natural dietary flavonoid, is known to exhibit various physiological efficacies. In the current study, we investigated a potential role of NOB in ammonia control and the underlying cellular mechanism. C57BL/6 mice were fed with regular chow (RC), high-fat (HFD) or high-protein diet (HPD) and treated with either vehicle or NOB. Serum and/or urine levels of ammonia and urea were measured. Liver expression of genes encoding urea cycle enzymes and C/EBP transcription factors was determined over the circadian cycle. Luciferase reporter assays were carried out to investigate function of CCAAT consensus elements on the carbamoyl phosphate synthetase (Cps1) gene promoter. A circadian clock-deficient mouse mutant, Clock (Δ19/Δ19) , was utilized to examine a requisite role of the circadian clock in mediating NOB induction of Cps1. NOB was able to lower serum ammonia levels in mice fed with RC, HFD or HPD. Compared with RC, HFD repressed the mRNA and protein expression of Cps1, encoding the rate-limiting enzyme of the urea cycle. Interestingly, NOB rescued CPS1 protein levels under the HFD condition via induction of the transcription factors C/EBPα and C/EBPβ. Expression of other urea cycle genes was also decreased by HFD relative to RC and again restored by NOB to varying degrees, which, in conjunction with Cps1 promoter reporter analysis, suggested a C/EBP-dependent mechanism for the co-induction of urea cycle genes by NOB. In comparison, HPD markedly increased CPS1 levels relative to RC, yet NOB did not further enrich CPS1 to a significant extent. Using the circadian mouse mutant Clock (Δ19/Δ19) , we also showed that a functional circadian clock, known to modulate C/EBP and CPS1 expression, was required for NOB induction of CPS1 under the HFD condition. NOB, a dietary flavonoid, exhibits a broad activity in ammonia control across varying diets, and regulates urea cycle function via C/EBP-and clock-dependent regulatory mechanisms. Show less
GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the fu Show more
GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation. Show less
This study is to evaluate the anti-obese effects of glucosamine (GLC) and chitosan oligosaccharide (COS) on high-fat diet-induced obese rats. The rats were randomly divided into twelve groups: a norma Show more
This study is to evaluate the anti-obese effects of glucosamine (GLC) and chitosan oligosaccharide (COS) on high-fat diet-induced obese rats. The rats were randomly divided into twelve groups: a normal diet group (NF), a high-fat diet group (HF), Orlistat group, GLC high-, middle-, and low-dose groups (GLC-H, GLC-M, GLC-L), COS1 (COS, number-average molecular weight ≤1000) high-, middle-, and low-dose groups (COS1-H, COS1-M, COS1-L), and COS2 (COS, number-average molecular weight ≤3000) high-, middle-, and low-dose groups (COS2-H, COS2-M, COS2-L). All groups received oral treatment by gavage once daily for a period of six weeks. Rats fed with COS1 gained the least weight among all the groups (P < 0.01), and these rats lost more weight than those treated with Orlistat. In addition to the COS2-H and Orlistat groups, the serum total cholesterol (CHO) and low-density lipoprotein cholesterol (LDL-C) levels were significantly reduced in all treatment groups compared to the HF group (P < 0.01). The various doses of GLC, COS1 and COS2 reduced the expression levels of PPARγ and LXRα mRNA in the white adipose tissue. The results above demonstrated that GLC, COS1, and COS2 improved dyslipidemia and prevented body weight gains by inhibiting the adipocyte differentiation in obese rats induced by a high-fat diet. Thus, these agents may potentially be used to treat obesity. Show less
RUNX1-RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting Show more
RUNX1-RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a coactivator for RUNX1-RUNX1T1 and is required for its transcriptional program. JMJD1C is directly recruited by RUNX1-RUNX1T1 to its target genes and regulates their expression by maintaining low H3K9 dimethyl (H3K9me2) levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for RUNX1-RUNX1T1's ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors. Show less
Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic trait Show more
Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis. Show less
Y Sun, R B Zhou, D M Chen · 2015 · Genetics and molecular research : GMR · added 2026-04-24
The aim of this study was to investigate correlations between apolipoprotein A-V (APOA5) -1131T>C and apolipoprotein C-III (APOC3) -455T>C polymorphisms and coronary heart disease (CHD). PubMed, Ovid, Show more
The aim of this study was to investigate correlations between apolipoprotein A-V (APOA5) -1131T>C and apolipoprotein C-III (APOC3) -455T>C polymorphisms and coronary heart disease (CHD). PubMed, Ovid, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched using combinations of keywords relating to these polymorphisms and CHD. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria, and Comprehensive Meta-Analysis Version 2.0 software was used for statistical analyses. In total, 115 studies were initially retrieved and after further selection, 11 were included in the meta-analysis. These 11 articles comprised 4840 patients with CHD in the case group and 4913 healthy participants in the control group. Meta-analysis revealed that APOA5 -1131T>C and APOC3 -455T>C polymorphisms increased CHD risk. In addition, subgroup analysis by ethnicity showed that while the -1131T>C polymorphism elevated the risk of CHD in the Caucasian population under both allelic and dominant models, this increased risk was observed only under a dominant model in the Asian population. The results of our meta-analysis point to a strong link between both APOA5 -1131T>C and APOC3 -455T>C polymorphisms and an increased risk of CHD. Thus, these polymorphisms constitute important predictive indicators of CHD susceptibility. Show less
Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis. By conducting whole-genome sequencing and high-throughput viral integration detection, we identified 3,667 HPV Show more
Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis. By conducting whole-genome sequencing and high-throughput viral integration detection, we identified 3,667 HPV integration breakpoints in 26 cervical intraepithelial neoplasias, 104 cervical carcinomas and five cell lines. Beyond recalculating frequencies for the previously reported frequent integration sites POU5F1B (9.7%), FHIT (8.7%), KLF12 (7.8%), KLF5 (6.8%), LRP1B (5.8%) and LEPREL1 (4.9%), we discovered new hot spots HMGA2 (7.8%), DLG2 (4.9%) and SEMA3D (4.9%). Protein expression from FHIT and LRP1B was downregulated when HPV integrated in their introns. Protein expression from MYC and HMGA2 was elevated when HPV integrated into flanking regions. Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways. Our data provide insights into HPV integration-driven cervical carcinogenesis. Show less
Adjuvant chemotherapy (ACT) is used after surgery to prevent recurrence or metastases. However, ACT for non-small cell lung cancer (NSCLC) is still controversial. This study aimed to develop predictio Show more
Adjuvant chemotherapy (ACT) is used after surgery to prevent recurrence or metastases. However, ACT for non-small cell lung cancer (NSCLC) is still controversial. This study aimed to develop prediction models to distinguish who is suitable for ACT (ACT-benefit) and who should avoid ACT (ACT-futile) in NSCLC. We identified the ACT correlated gene signatures and performed several types of ANN algorithms to construct the optimal ANN architecture for ACT benefit classification. Reliability was assessed by cross-data set validation. We obtained 2 probes (2 genes) with T-stage clinical data combination can get good prediction result. These genes included 208893_s_at (DUSP6) and 204891_s_at (LCK). The 10-fold cross validation classification accuracy was 65.71%. The best result of ANN models is MLP14-8-2 with logistic activation function. Using gene signature profiles to predict ACT benefit in NSCLC is feasible. The key to this analysis was identifying the pertinent genes and classification. This study maybe helps reduce the ineffective medical practices to avoid the waste of medical resources. Show less
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 valu Show more
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists. Show less
Mengyang Liu, Yuanli Chen, Ling Zhang+10 more · 2015 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X re Show more
Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X receptor (LXR). Etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors. Etoposide has been reported to inhibit atherosclerosis in rabbits with un-fully elucidated mechanisms. In this study we determined if Topo II activity can influence cholesterol metabolism by regulating hepatic CETP expression. Inhibition of Topo II by etoposide, teniposide, or Topo II siRNA increased CETP expression in human hepatic cell line, HepG2 cells, which was associated with increased CETP secretion and mRNA expression. Meanwhile, inhibition of LXR expression by LXR siRNA attenuated induction of CETP expression by etoposide and teniposide. Etoposide and teniposide induced LXRα expression and LXRα/β nuclear translocation while inhibiting expression of receptor interacting protein 140 (RIP140), an LXR co-repressor. In vivo, administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. Our study demonstrates a novel function of Topo II inhibitors in cholesterol metabolism by activating hepatic CETP expression and reverse cholesterol transport. Show less
Inflammation and lipids play significant roles in the progression of chronic kidney disease. This study was designed to investigate whether inflammation disrupts cellular cholesterol homeostasis and c Show more
Inflammation and lipids play significant roles in the progression of chronic kidney disease. This study was designed to investigate whether inflammation disrupts cellular cholesterol homeostasis and causes the lipid nephrotoxicity in vitro and in vivo, and explored its underlying mechanisms. Inflammatory stress was induced by cytokines (interleukin-1β (IL-1β); tumor necrosis factor α (TNF-α)) to human mesangial cells (HMCs) in vitro and by subcutaneous casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress exacerbated renal cholesterol ester accumulation in vitro and in vivo. Inflammation increased cellular cholesterol uptake and synthesis via upregulating the expression of low-density lipoprotein receptor (LDLr) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoA-R), while it decreased cholesterol efflux via downregulating the expression of liver X receptor alpha and ATP-binding cassette transporter A1. The increased lipid accumulation by inflammatory stress induced reactive oxygen species (ROS) and increased levels of endoplasmic reticulum (ER) stress markers (inositol-requiring protein 1 and activating transcription factor 6) in HMCs and kidneys of C57BL/6J mice. This study implied that inflammation promoted renal lipid accumulation and foam cell formation by disrupting cellular cholesterol homeostasis. Increased intracellular lipids under inflammatory stress caused oxidative stress and ER stress in vitro and in vivo which may contribute to renal injury and progression of chronic kidney disease. Show less
Whether polymorphisms rs11856808 and rs9652490 of the Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein-1 (LINGO1) gene, as well as rs10968280, rs13362909 and rs7033345 o Show more
Whether polymorphisms rs11856808 and rs9652490 of the Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein-1 (LINGO1) gene, as well as rs10968280, rs13362909 and rs7033345 of the LINGO2 gene, increase the risk for Parkinson's disease (PD) is controversial. Considering the overlap of the clinical and pathological characteristics among PD and multiple system atrophy (MSA), we explored the associations between these five polymorphisms and PD and MSA in a Chinese population. A total of 1055 PD patients, 320 MSA patients, and 810 healthy controls (HCs) were genotyped for these five polymorphisms in LINGO1 and LINGO 2 using Sequenom iPLEX Assay technology. Moreover, after combining our results with available published data, a meta-analysis was conducted to investigate the associations between LINGO 1 rs11856808 and rs9652490 and the risk of PD. The frequency of the minor alleles "T" of LINGO1 rs11856808 was significantly lower in PD than that in HCs (p = 0.011, OR 0.89, 95 % CI 0.81-0.97), but not in MSA. Moreover, there were no significant differences in the minor allele frequency distributions of the other four polymorphisms between PD and HCs, and between MSA and HCs. The meta-analysis showed a lack of association of rs9652490 and PD, regardless of the genetic model or ethnic origin. However, the rs11856808 allele decreased the risk of PD in patients of Asian origin in a dominant genetic model. Our findings suggest that rs11856808 plays a protective role by decreasing the risk for PD, but not for MSA, in Asian population, the other four polymorphisms do not contribute to the risk for PD and MSA. Show less
The unwinding of nucleic acid secondary structures within cells is crucial to maintain genomic integrity and prevent abortive transcription and translation initiation. DHX36, also known as RHAU or G4R Show more
The unwinding of nucleic acid secondary structures within cells is crucial to maintain genomic integrity and prevent abortive transcription and translation initiation. DHX36, also known as RHAU or G4R1, is a DEAH-box ATP-dependent helicase highly specific for DNA and RNA G-quadruplexes (G4s). A fundamental mechanistic understanding of the interaction between helicases and their G4 substrates is important to elucidate G4 biology and pave the way toward G4-targeted therapies. Here we analyze how the thermodynamic stability of G4 substrates affects binding and unwinding by DHX36. We modulated the stability of the G4 substrates by varying the sequence and the number of G-tetrads and by using small, G4-stabilizing molecules. We found an inverse correlation between the thermodynamic stability of the G4 substrates and rates of unwinding by DHX36. In stark contrast, the ATPase activity of the helicase was largely independent of substrate stability pointing toward a decoupling mechanism akin to what has been observed for many double-stranded DEAD-box RNA helicases. Our study provides the first evidence that DHX36 uses a local, non-processive mechanism to unwind G4 substrates, reminiscent of that of eukaryotic initiation factor 4A (eIF4A) on double-stranded substrates. Show less
The objective of this study was to investigate the multiple relations between the preliminary molecular structural characteristics and antioxidant activities of polysaccharides from Canarium album (Lo Show more
The objective of this study was to investigate the multiple relations between the preliminary molecular structural characteristics and antioxidant activities of polysaccharides from Canarium album (Lour.) Raeusch (CPS). Three polysaccharide fractions, CPS1, CPS2, and CPS3, were isolated from CPS by column chromatography. CPS1 and CPS3 were mainly composed of neutral polysaccharides linked by α- and β-glycosidic linkages while CPS2 was pectin polysaccharides mainly linked by β-glycosidic linkages. According to the SEC-MALLS-RI system, the molecular weight of CPS1 was greater compared to CPS2 and CPS3, and the molecular weight and radius of CPS did not display positive correlation. The chain conformation analysis indicated CPS1 and CPS2 were typical highly branched polysaccharides while CPS3 existed as a globular shape in aqueous. Furthermore, the antioxidant activity of CPS2 was better than that of CPS3, while that of CPS1 was the weakest. The antioxidant activities of polysaccharide fractions were affected by their monosaccharide composition, glycosidic linkage, molecular weight, and chain conformation. This functional property was a result of a combination of multiple molecular structural factors. CPS2 was the major antioxidant component of CPS and it could be exploited as a valued antioxidant product. The molecular structural characteristics, antioxidant activities, and structure-function relationships of polysaccharide fractions from Canarium album were first investigated in this study. The results provided background and practical knowledge for the deep-processed products of C. album with high added value. CPS2 was the major antioxidant component of CPS, which could be exploited as a valued antioxidant ingredient in food and pharmaceutical industries. Show less
Glycosaminoglycans are important regulators of multiple signaling pathways. As a major constituent of the heart extracellular matrix, glycosaminoglycans are implicated in cardiac morphogenesis through Show more
Glycosaminoglycans are important regulators of multiple signaling pathways. As a major constituent of the heart extracellular matrix, glycosaminoglycans are implicated in cardiac morphogenesis through interactions with different signaling morphogens. Ext1 is a glycosyltransferase responsible for heparan sulfate synthesis. Here, we evaluate the function of Ext1 in heart development by analyzing Ext1 hypomorphic mutant and conditional knockout mice. Outflow tract alignment is sensitive to the dosage of Ext1. Deletion of Ext1 in the mesoderm induces a cardiac phenotype similar to that of a mutant with conditional deletion of UDP-glucose dehydrogenase, a key enzyme responsible for synthesis of all glycosaminoglycans. The outflow tract defect in conditional Ext1 knockout(Ext1f/f:Mesp1Cre) mice is attributable to the reduced contribution of second heart field and neural crest cells. Ext1 deletion leads to downregulation of FGF signaling in the pharyngeal mesoderm. Exogenous FGF8 ameliorates the defects in the outflow tract and pharyngeal explants. In addition, Ext1 expression in second heart field and neural crest cells is required for outflow tract remodeling. Our results collectively indicate that Ext1 is crucial for outflow tract formation in distinct progenitor cells, and heparan sulfate modulates FGF signaling during early heart development. Show less
Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e Show more
Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health. The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers. We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts. Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans. Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat. Show less
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflamma Show more
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process. Show less