Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on lon Show more
Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants. In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD. We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk. Show less
Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modi Show more
Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modification. A plethora of studies have highlighted the function specifications among CBX family members in various cancer, including lung cancer, colon cancer and breast cancer. Nevertheless, the functions and prognostic roles of distinct CBX family members in breast cancer (BC) remain elusive. In this study, we reported the prognostic values of CBX family members in patients with BC through analysis of a series of databases, including Show less
To develop a cost-effective molecular regulator to improve growth metabolism and immunity of animals, a recombinant plasmid co-expressing fatty acid desaturase (mFat-1) and pig insulin growth like fac Show more
To develop a cost-effective molecular regulator to improve growth metabolism and immunity of animals, a recombinant plasmid co-expressing fatty acid desaturase (mFat-1) and pig insulin growth like factor 1 (IGF-1) genes was constructed by the 2 A self-cleavage technique. After entrapment within modified chitosan nanoparticles (chitosan modified with polyethyleneglycol-polyethylenimine, CPP), the recombinant plasmid was injected intramuscularly into mice. Compared with controls, co-expression of mFat-1 and IGF-1 significantly raised the level of serum IGF-1, and increased the liver and muscle docosa hexaenoic acid (DHA) content. Th and Tc cell levels were also elevated, as were expression levels of serum IL-4 and IL-6 genes. These results demonstrate that the immunity and metabolism of an animal can be effectively improved by co-expression of mFat-1 and IGF-1 genes in vivo, which may contribute to further development of novel immunomodulators with beneficial effects on growth metabolism and immunity. Show less
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in s Show more
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC Show less
To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Co Show more
To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD. Show less
Non-small cell lung cancer (NSCLC) has led to the highest cancer-related mortality for decades. To enhance the efficiency of early diagnosis and therapy, more efforts are urgently needed to reveal the Show more
Non-small cell lung cancer (NSCLC) has led to the highest cancer-related mortality for decades. To enhance the efficiency of early diagnosis and therapy, more efforts are urgently needed to reveal the origins of NSCLC. In this study, we explored the effect of miR-542-5p in NSCLC with clinical samples and in vivo models and further explored the prospective function of miR-542-5p though bioinformatics methods. A total of 125 NSCLC tissue samples were collected, and the expression of miR-542-5p was detected by qRT-PCR. The relationship between miR-542-5p level and clinicopathological features was analyzed. The effect of miR-542-5p on survival time was also explored with K-M survival curves and Cox's regression. The effect of miR-542-5p on the tumorigenesis of NSCLC was verified with a chick chorioallantoic membrane (CAM) model. The potential target genes were predicted by bioinformatics tools, and relevant pathways were analyzed by GO and KEGG. Several hub genes were validated by Proteinatlas. The expression of miR-542-5p was down-regulated in NSCLC tissues, and consistent results were also found in the subgroups of adenocarcinoma and squamous cell carcinoma. Down-regulation of miR-542-5p was found to be connected with advanced TNM stage, vascular invasion, lymphatic metastasis and EGFR. Survival analyses showed that patients with lower miR-542-5p levels had markedly poorer prognosis. Both tumor growth and angiogenesis were significantly suppressed by miR-542-5p mimic in the CAM model. The potential 457 target genes of miR-542-5p were enriched in several key cancer-related pathways, such as morphine addiction and the cAMP signaling pathway from KEGG. Interestingly, six genes (GABBR1, PDE4B, PDE4C, ADCY6, ADCY1 and GIPR) from the cAMP signaling pathway were confirmed to be overexpressed in NSCLCs tissues. This evidence suggests that miR-542-5p is a potential tumor-suppressed miRNA in NSCLC, which has the potential to act as a diagnostic and therapeutic target of NSCLC. Show less
We investigated the association of single nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster with coronary artery disease (CAD) in a case-control study and evaluated the Show more
We investigated the association of single nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster with coronary artery disease (CAD) in a case-control study and evaluated the possible influence of genetic variation on total cholesterol (TC) and triglyceride concentrations in the controls. In total, 497 CAD patients and 495 unrelated controls were genotyped for eight SNPs in the FADS gene cluster, and the blood lipid levels of subjects were measured. Three genetic models, including codominant, dominant and recessive, were used to analyze the genotypic relationship with CAD and plasma lipid levels. Single locus genotypic analysis revealed that rs1000778 in FADS3 under a recessive model (AA vs. GG-GA) was significantly associated with CAD adjusted for risk factors. The rs1000778 minor allele AA was associated with a lower risk of CAD (OR =0.37, 95% CI: 0.15-0.89, P=0.025). In the control group, there were significant differences in TC concentrations under a recessive genetic model for rs174575 (C/G) in FADS2 and for rs174450 (A/C) and rs7115739 (G/T) in FADS3 (P=0.053, 0.016 and 0.018, respectively). The rs1000778-G variant in FADS3 may contribute to the susceptibility of CAD, but the result needs to be further confirmed because of small sample size in our study. Genetic variations in FADS2 and FADS3 influence TC concentration in the northern Chinese Han population. Show less
Management of ligament/tendon-to-bone-junction healing remains a formidable challenge in the field of orthopedic medicine to date, due to deficient vascularity and multi-tissue transitional structure Show more
Management of ligament/tendon-to-bone-junction healing remains a formidable challenge in the field of orthopedic medicine to date, due to deficient vascularity and multi-tissue transitional structure of the junction. Numerous strategies have been employed to improve ligament-bone junction healing, including delivery of stem cells, bioactive factors, and synthetic materials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by physically modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The differentiation potential of rabbit bone marrow stromal cells on the modified ECM were examined in vitro. The results demonstrated that the modified ECM enhanced expression of chondrogenesis and osteogenesis-associated epigenetic genes (Jmjd1c, Kdm6b), transcription factor genes (Sox9, Runx2) and extracellular matrix genes (Col2a1, Ocn), resulting in higher osteoinductivity than the untreated tendon ECM in vitro. In the rabbit anterior cruciate ligament (ACL) reconstruction model in vivo, micro-computed tomography (Micro-CT) and histological analysis showed that the modified Random-Aligned-Random composite scaffold enhanced bone and fibrocartilage formation at the interface, more efficaciously than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair. The native transitional region consists of several distinct yet contiguous tissue regions, composed of soft tissue, non-calcified fibrocartilage, calcified fibrocartilage, and bone. A stratified graft whose phases are interconnected with each other is essential for supporting the formation of functionally continuous multi-tissue regions. Various techniques have been attempted to improve adherence of the ligament/tendon graft to bone, including utilization of stem cells, growth factors and biomaterials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by physically modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The modified ECM enhanced expression of chondrogenesis and osteogenesis-associated epigenetic genes expression in vitro. In the rabbit anterior crucial ligament reconstruction model in vivo, results showed that the modified Random-Aligned-Random composite enhances the bone and fibrocartilage formation in the interface, proving to be more efficient than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair. Show less
In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IB Show more
In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD. Show less
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI data Show more
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI databases for published studies relating to analyses of these associations. Case-control and comparative studies of the association between the APOA5 c.553G>T variant and altered triglyceride levels were included. In total, the meta-analysis involved 10 studies on HTG, which provided 2219 cases and 3401 controls. To measure the correlation between the c.553G>T polymorphism and HTG susceptibility, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The overall OR was calculated using a random-effects model. Compared with APOA5 c.553 GG carriers, c.553T carriers displayed an increased risk of HTG in the Asian population, with an overall random effects OR of 3.55 (95% CI: 2.46-5.13) in the dominant model. There was significant heterogeneity among the studies (P Our results suggest that APOA5 c. 553T is an independent risk factor for HTG and increased triglyceride levels in the Asian population. APOA5 c. 553T could be employed as a genetic risk marker for HTG and increased triglyceride levels. Show less
Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow- Show more
Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow-derived mesenchymal stem cells (rBMSCs) transduced with a mutant caveolin-1(F92A-Cav1) could enhance endothelial nitric oxide synthase (eNOS) activity and improve pulmonary vascular remodeling, but the potential mechanism is not yet fully explored. The present study was to investigate the gene expression profile upon rBMSCs/F92A-Cav1delivered to PAH rat to evaluate the role of F92A-Cav1 in its regulation. PAH was induced with monocrotaline (MCT, 60mg/kg) prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1 or F92A-Cav1. Gene expression profiling was performed using Rat Signal Transduction PathwayFinder array. The expression changes of 84 key genes representing 10 signal transduction pathways in rat following rBMSCs/F92A-Cav1 treatment was examined. Screening with the Rat Signal Transduction PathwayFinder R rBMSCs/F92A-Cav1 inhibits inflammation and cell proliferation by regulating signaling pathways that related to inflammation, proliferation, cell cycle and oxidative stress. Show less
Xian-Bin Lin, Lei Jiang, Mao-Hua Ding+13 more · 2016 · Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · Springer · added 2026-04-24
Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function Show more
Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells. Show less
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signal Show more
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression. Show less
Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spina Show more
Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spinal cord injury (SCI). The Notch pathway inhibits the differentiation of neural stem/progenitor cells and Lingo-1 is a strong negative regulator for myelination and axon growth. While Lingo-1 shRNA and N-[N-(3, 5-difluorophenacetyl)-1-alanyl]-S-Phenylglycinet-butylester (DAPT), a Notch pathway inhibitor, have been used separately to help repair SCI, the results have been unsatisfactory. Here we investigated and elucidated the preliminary mechanism for the effect of Lingo-1 shRNA and DAPT on neural stem/progenitor cells differentiation. We found that neural stem/progenitor cells from E14 rat embryos expressed Nestin, Sox-2 and Lingo-1, and we optimized the transduction of neural stem/progenitor cells using lentiviral vectors encoding Lingo-1 shRNA. The addition of DAPT decreased the expression of Notch intracellular domain (NICD) as well as the downstream genes Hes1 and Hes5. Expression of NeuN, CNPase and GFAP in DAPT treated cells and expression of NeuN in Lingo-1 shRNA treated cells confirmed differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes. These results revealed that while Lingo-1 shRNA and Notch signaling inhibitor DAPT both promoted differentiation of neural stem cells into neurons, only DAPT was capable of driving neural stem/progenitor cells differentiation into oligodendrocytes and astrocytes. Since we were able to show that both Lingo-1 shRNA and DAPT could drive neural stem/progenitor cells differentiation, our data might aid the development of more effective SCI therapies using Lingo-1 shRNA and DAPT. Show less
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possi Show more
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis. Show less
Moringa oleifera is a promising plant species for oil and forage, but its genetic improvement is limited. Our current breeding program in this species focuses on exploiting the functional genes associ Show more
Moringa oleifera is a promising plant species for oil and forage, but its genetic improvement is limited. Our current breeding program in this species focuses on exploiting the functional genes associated with important agronomical traits. Here, we screened reliable reference genes for accurately quantifying the expression of target genes using the technique of real-time quantitative polymerase chain reaction (RT-qPCR) in M. oleifera. Eighteen candidate reference genes were selected from a transcriptome database, and their expression stabilities were examined in 90 samples collected from the pods in different developmental stages, various tissues, and the roots and leaves under different conditions (low or high temperature, sodium chloride (NaCl)- or polyethyleneglycol (PEG)- simulated water stress). Analyses with geNorm, NormFinder and BestKeeper algorithms revealed that the reliable reference genes differed across sample designs and that ribosomal protein L1 (RPL1) and acyl carrier protein 2 (ACP2) were the most suitable reference genes in all tested samples. The experiment results demonstrated the significance of using the properly validated reference genes and suggested the use of more than one reference gene to achieve reliable expression profiles. In addition, we applied three isotypes of the superoxide dismutase (SOD) gene that are associated with plant adaptation to abiotic stress to confirm the efficacy of the validated reference genes under NaCl and PEG water stresses. Our results provide a valuable reference for future studies on identifying important functional genes from their transcriptional expressions via RT-qPCR technique in M. oleifera. Show less
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have Show more
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have provided a line of evidence confirming that EVA1A (eva-1 homolog A)/TMEM166 (transmembrane protein 166) is associated with autophagosomal membrane development. This notion is based on dotted EVA1A structures that colocalize with ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7 and LAMP1, which represent different stages of the autophagic process. It is required for autophagosome formation as this phenotype was significantly decreased in EVA1A-silenced cells and Eva1a KO MEFs. EVA1A-induced autophagy is independent of the BECN1-PIK3C3 (phosphatidylinositol 3-kinase, catalytic subunit type 3) complex but requires ATG7 activity and the ATG12-ATG5/ATG16L1 complex. Here, we present a molecular mechanism by which EVA1A interacts with the WD repeats of ATG16L1 through its C-terminal and promotes ATG12-ATG5/ATG16L1 complex recruitment to the autophagic membrane and enhances the formation of the autophagosome. We also found that both autophagic and apoptotic mechanisms contributed to EVA1A-induced cell death while inhibition of autophagy and apoptosis attenuated EVA1A-induced cell death. Overall, these findings provide a comprehensive view to our understanding of the pathways involved in the role of EVA1A in autophagy and programmed cell death. Show less
5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular m Show more
5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis. Show less
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the mainte Show more
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment. Show less
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, a Show more
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy. Show less
Leucine-rich repeat and immunoglobulin domain-containing protein (LINGO)-1 is expressed in neural stem cells, and its neutralization results in sustained neuronal immaturity. Thus, targeted inhibition Show more
Leucine-rich repeat and immunoglobulin domain-containing protein (LINGO)-1 is expressed in neural stem cells, and its neutralization results in sustained neuronal immaturity. Thus, targeted inhibition of LINGO-1 via RNA interference may enhance transplanted neural stem cell survival and neuronal differentiation in vivo. Furthermore, LINGO-1 RNA interference in neural stem cells represents a potential therapeutic strategy for spinal cord injury. Department of Spine Surgery, First Affiliated Hospital of Sun Yat-sen University. Translational Medicine Center Research Laboratory, First Affiliated Hospital of Sun Yat-sen University. Female Sprague-Dawley rats. The animals were divided into three groups that underwent laminectomy and complete spinal cord transection accompanied by transplantation of control-RNA interference-treated or LINGO-1-RNA interference-treated neural stem cells at the injured site in vivo. In vitro, neural stem cells were divided into four groups for the following treatments: control, control RNA interference lentivirus, LINGO-1 RNA interference lentivirus and LINGO-1 complementary DNA lentivirusand the Key Projects of the Natural Science Foundation of Guangdong Province (No. S2013020012818). Neural stem cells in each treatment group were examined for cell survival and neuronal differentiation in vitro and in vivo via immunofluorescence and Western blot analysis. Axonal regeneration and tissue repair were assessed via retrograde tracing using Fluorogold, electron microscopy, hematoxylin-eosin staining and MRI. Rats were also examined for functional recovery based on the measurement of spinal cord-evoked potentials and the Basso-Beattie-Bresnahan score. LINGO-1-RNA interference-treated neural stem cell transplantation increased tissue repair and functional recovery of the injured spinal cord in rats. Similarly, LINGO-1 RNA interference increased neural stem cell survival and neuronal differentiation in vitro. The mechanism underlying the effect of LINGO-1 RNA interference on the injured rat spinal cord may be that the significant inhibition of LINGO-1 expression in neural stem cells inactivated the RhoA and Notch signaling pathways, which act downstream of LINGO-1. Our findings indicate that transplantation of LINGO-1-RNA interference-treated neural stem cells facilitates functional recovery after spinal cord injury and represents a promising potential strategy for the repair of spinal cord injury. Show less
Valeriana jatamansi Jones, a plant with heart-shaped leaves in the Valeriana genus of Valerianaceae, is widely used in Chinese folk medicine. Iridoid is an important constituent of V. jatamansi that c Show more
Valeriana jatamansi Jones, a plant with heart-shaped leaves in the Valeriana genus of Valerianaceae, is widely used in Chinese folk medicine. Iridoid is an important constituent of V. jatamansi that contributes to the pharmacological efficacy of the herb. This study aims to investigate the regulation of lipid metabolism and its mechanism of the iridoids rich fraction in V. jatamansi (IRFV). A high fat diet was used to establish the hyperlipidemia rat model, with 2mg/kg/d of simvastatin as a positive control, fed with 7.5, 15, and 30mg/kg/d of IRFV for 20days to investigate the lipid regulation activity and mechanism of IRFV. Body weight, liver index, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and liver, as well as total bile acid (TBA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in serum were measured. The lipoprotein lipase (LPL) and hepatic lipase (HL) activities and the apoprotein A5 (ApoA5), peroxisome proliferator-activated receptor α (PPAR-α), sterol regulatory element-binding proteins (SREBP-1c), and liver X receptor α (LXR-α) protein expressions were observed. Liver pathology was described through hematoxylin-eosin (HE) staining. Compared with the model group, three different IRFV dosages can slow down the weight gain of rats, reduce the contents of TG, and increase the contents of HDL-C in serum. Low IRFV dosage can significantly reduce the AST and ALT contents in serum, liver index, and the TG contents in liver, enhance LPL activity. Medium IRFV dosage can significantly decrease the TG and LDL-C contents in liver. High IRFV dosage can significantly reduce LDL-C, TBA, AST, and ALT contents in serum, and enhance HL activity. Three different IRFV dosages can significantly increase the ApoA5 and PPAR-α protein expression and decrease the SREBP-1c protein expression. Furthermore, the LXR-α protein expression decreased in low- and high-dose groups. Liver tissue pathological observation showed that IRFV can improve cell degeneration to a certain extent. These results strongly suggest that IRFV play significant roles in regulating lipid metabolism, the mechanism may be related to the increased ApoA5 protein expression. Show less
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression l Show more
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans. Nevertheless, there is a lack of supporting evidence from animal studies. We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking the Adcy3 gene. We found that conventional AC3 knockout (KO) mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography recordings indicated that AC3 KO mice have altered sleep patterns characterized by increased percentage of rapid eye movement sleep. AC3 KO mice also exhibit neuronal atrophy. Furthermore, synaptic activity at cornu ammonis 3-cornu ammonis 1 synapses was significantly lower in AC3 KO mice, and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that these defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited prodepression phenotypes without anosmia. This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a contributing factor for MDD. Show less
Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue dis Show more
Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1-3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring. RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005-2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009-2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC). The WS+Hosp group had significantly higher viral load (P<0.001), lower platelet (P<0.001) and lymphocytes counts (P = 0.004) at early infection compared to the Non-WS+Non-Hosp group. From the RNA microarray and protein assays, the top single RNA and protein prognostic models at early infection were CCL8 RNA (AUC:0.73) and IP-10 protein (AUC:0.74), respectively. The model with CCL8, VPS13C RNA, uPAR protein, and with CCL8, VPS13C RNA and platelets were the best biomarker models for stratifying adult dengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively. At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here based on these pathophysiology differences, could offer earlier and complementary indicators to the clinical WHO 2009 WS guide, in order to triage adult dengue patients at early infection. Show less
Searching for new regulators of autophagy involved in selective dopaminergic (DA) neuron loss is a hallmark in the pathogenesis of Parkinson disease (PD). We here report that an endoplasmic reticulum Show more
Searching for new regulators of autophagy involved in selective dopaminergic (DA) neuron loss is a hallmark in the pathogenesis of Parkinson disease (PD). We here report that an endoplasmic reticulum (ER)-associated transmembrane protein SLC35D3 is selectively expressed in subsets of midbrain DA neurons in about 10% TH (tyrosine hydroxylase)-positive neurons in the substantia nigra pars compacta (SNc) and in about 22% TH-positive neurons in the ventral tegmental area (VTA). Loss of SLC35D3 in ros (roswell mutant) mice showed a reduction of 11.9% DA neurons in the SNc and 15.5% DA neuron loss in the VTA with impaired autophagy. We determined that SLC35D3 enhanced the formation of the BECN1-ATG14-PIK3C3 complex to induce autophagy. These results suggest that SLC35D3 is a new regulator of tissue-specific autophagy and plays an important role in the increased autophagic activity required for the survival of subsets of DA neurons. Show less
The biological effects of microRNAs (miRNAs) in the Fragile X Syndrome (FXS) have been widely studied. Dysregulation of miRNAs plays a critical role in the progression of nervous system diseases and i Show more
The biological effects of microRNAs (miRNAs) in the Fragile X Syndrome (FXS) have been widely studied. Dysregulation of miRNAs plays a critical role in the progression of nervous system diseases and in cell proliferation and differentiation. Our previous study validated that miR-19b-3p was associated with FXR1 (Fragile X related gene 1), one of homologous genes of FMR1 (Fragile X mental retardation 1). The purpose of this study was to investigate the relationship of FXR1 and miR-19b-3p, and the crucial role of miR-19b-3p in FXS and to validate whether miR-19b-3p could regulate the growth of SH-SY5Y cells. We determined that miR-19b-3p could regulate the expression of not only USP32, RAB18 and Dusp6 but also FXR1, and FXR1 could in turn regulate the expression of miR-19b-3p. What's more, the overexpression of miR-19b-3p significantly inhibited the proliferation, contributed the apoptosis and slowed down the cycle of SH-SY5Y cells. Taken together, our results indicate that miR-19b-3p plays a significant role in the molecular pathology of FXS by interacting with FXR1 and influencing the growth of SH-SY5Y cells. Show less
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify ge Show more
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression. Show less
Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotrigly Show more
Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotriglyceridemic actions. Two obese mouse models, including high-fat diet-induced obese mice and ob/ob obese mice, were adopted. The effects of low- and high-dose metformin were determined on plasma and hepatic TG and apoA5 of these obese mice. Besides, the effects of metformin on TG and apoA5 were also detected in mouse and human hepatocytes in vitro. (1) Plasma apoA5 levels in the obese mice were markedly elevated and positively correlated with TG. Hepatic TG contents and apoA5 expressions were also remarkably increased in the obese mice. (2) Metformin dose-dependently decreased hepatic and plasma TG and apoA5 in the obese mice. Similarly, metformin dose-dependently reduced cellular TG contents and apoA5 expressions in hepatocytes in vitro. Compared to APOA5 knock-down (KD), metformin plus APOA5 KD resulted in more TG reduction of hepatocytes. Increased hepatic and plasma apoA5 could be a result of obesity-associated hypertriglyceridemia, and metformin displays hypotriglyceridemic effects on obese mice partly via the apoA5 pathway. Show less
Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as m Show more
Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the geneti Show more
Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies. Show less