Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To Show more
Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To identify the genetic variants associated with MetS and metabolic components, we conducted a genome-wide association study followed by replications in totally 12,720 participants from the north, north-eastern and eastern China. In combined analyses, independent of the top known signal at rs651821 on APOA5, we newly identified a secondary triglyceride-associated signal at rs180326 on BUD13 (P Show less
Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone Show more
Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-β2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-β2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT Show less
The aim of the study is to investigate whether endothelial cells (ECs) promoted the capacity of stem-like cell formation in medulloblastoma (MB) and whether the mechanism of action was associated with Show more
The aim of the study is to investigate whether endothelial cells (ECs) promoted the capacity of stem-like cell formation in medulloblastoma (MB) and whether the mechanism of action was associated with mediation of Notch signaling pathway. Co-culture experiment was conducted to particularly understand the potential role of ECs in promoting phenotype and gene expression of MB stem-like cells. Self-renewal capacity and tumor cell population were measured by sphere-forming assay and flow cytometry, respectively. To further clarify the effects of ECs on the formation of MB stem-like cells, the expression of genes and protein in MB stem-like cells (CCND1, CDK6, c-MYC, and Bmi-1) and Notch (Notch2, Jagged 1, Hes-1, and Hey-2) was quantified by quantitative real-time PCR (qRT-PCR) and western blot, respectively. Also, observed mediation of ECs in regulation of tumor cell stemness by Notch activation was observed when the co-cultures were treated with γ-secretase inhibitor (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT)). Further investigation was conducted for the effects of ECs on the tumorigenesis in vivo of MB cells when co-cultures were inoculated into a nude mouse after treated with DAPT. Afterwards, tumor size and volume were measured. The sphere-forming rate and cell ratio of stem-like cells were significantly increased. Furthermore, the expression of genes and protein in stem-like cells and Notch was obviously upregulated although treated with γ-secretase inhibitor. Moreover, tumor size and volume were dramatically magnified. This study revealed that Notch pathway activation played a key role in the formation of stem-like cells in MB and had valuable meaning for further investigation of targeted therapies. Show less
MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated Show more
MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at 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
Exploring the biological functions of long non-coding RNAs (lncRNAs) has come to the foreground in recent years. Studies have indicated that the lncRNA metastasis‑associated lung adenocarcinoma transc Show more
Exploring the biological functions of long non-coding RNAs (lncRNAs) has come to the foreground in recent years. Studies have indicated that the lncRNA metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) not only regulates tumorigenesis in hepatocellular carcinoma, but also controls cell cycle progression in hematopoietic cells. The present study was designed to investigate the biological role of lncRNA MALAT1 in liver regeneration. We carried out a series of assays during liver regeneration following 2/3 partial hepatectomy in mice. We explored the functions of lncRNA MALAT1 with a series of functional analyses in vitro. We found that MALAT1 was upregulated during liver regeneration. Moreover, MALAT1 accelerated hepatocyte proliferation by stimulating cell cycle progression from the G1 to the S phase and inhibiting apoptosis in vitro. In addition, our findings also demonstrated that MALAT1 was regulated by p53 during liver regeneration, and that p53 may be a key upstream regulator of MALAT1 activity. Mechanistically, we found that MALAT1 activated the Wnt/β‑catenin pathway by inhibiting the expression of Axin1 and adenomatous polyposis coli (APC), and subsequently promoting the expression of cyclin D1. On the whole, the findings of this study suggest that MALAT1 is a critical molecule for liver regeneration. Pharmacological interventions targeting MALAT1 may thus prove to be therapeutically beneficial in liver failure or liver transplantation by promoting liver regeneration. Show less
We aim to validate the effects of glucose-dependent insulinotropic polypeptide (GIP) on fat distribution and glucose metabolism in Han Chinese populations. We genotyped six tag single-nucleotide polym Show more
We aim to validate the effects of glucose-dependent insulinotropic polypeptide (GIP) on fat distribution and glucose metabolism in Han Chinese populations. We genotyped six tag single-nucleotide polymorphisms (SNPs) of GIP and four tag SNPs of glucose-dependent insulinotropic polypeptide receptor (GIPR) among 2884 community-based individuals from Han Chinese populations. Linear analysis was applied to test the associations of these variants with visceral fat area (VFA) and subcutaneous fat area (SFA) quantified by magnetic resonance imaging as well as glucose-related traits. We found that the C allele of rs4794008 of GIP tended to increase the VFA and the VFA/SFA ratio in all subjects (P=0.050 and P=0.054, respectively), and rs4794008 was associated with the VFA/SFA ratio in males (P=0.041) after adjusting for the BMI. The VFA-increasing allele of rs4794008 was not related to any glucose metabolism traits. However, rs9904288 of GIP was associated with the SFA in males as well as glucose-related traits in all subjects (P range, 0.004-0.049), and the GIPR variants displayed associations with both fat- and glucose-related traits. The results could provide the evidence that GIP might modulate visceral fat accumulation via incretin function or independent of incretin. Show less
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition, and the lipid metabolism disorder is common in the development of this disease. This prospective ob Show more
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition, and the lipid metabolism disorder is common in the development of this disease. This prospective observational study aimed to define the characteristics of plasma apolipoprotein A-V (apoA-V) in long-term outcome prediction of HBV-ACLF, and a total of 330 HBV-ACLF patients were included and followed for more than 12 months. In this cohort, the 4-week, 12-week, 24-week and 48-week cumulative mortality of HBV-ACLF was 18.2%(60/330), 50.9%(168/330), 59.7%(197/330) and 63.3%(209/330), respectively. As compared to survivors, the non-survivors had significantly lower concentrations of plasma apoA-V on admission. Plasma apoA-V concentrations were positively correlated with prothrombin time activity (PTA), and negatively correlated with interleukin-10, tumor necrosis factor-α, and iMELD scores. Though plasma apoA-V, PTA, total bilirubin(TBil) and blood urea nitrogen(BUN) were all independent factors to predict one-year outcomes of HBV-ACLF, plasma apoA-V had the highest prediction accuracy. And its optimal cutoff value for one-year survival prediction was 480.00 ng/mL, which had a positive predictive value of 84.68% and a negative predictive value of 92.23%. In summary, plasma apoA-V decreases significantly in non-survivors of HBV-ACLF, and it may be regarded as a new predictive marker for the prognosis of patients with HBV-ACLF. Show less
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utiliz Show more
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10 Show less
With emerging evidence connecting cholesterol dysregulation with disturbed pulmonary homeostasis, we are wondering if diet induced hypercholesterolemia would influence the susceptibility to chemical i Show more
With emerging evidence connecting cholesterol dysregulation with disturbed pulmonary homeostasis, we are wondering if diet induced hypercholesterolemia would influence the susceptibility to chemical induced lung tumorigenesis in mice. Six to eight week-old male C57BL/6J mice were fed with either a high-cholesterol atherogenic diet (HCD) or matching normal diet (ND), respectively. Following 3 weeks diet adapting, a multi-dose intraperitoneal injections of ethyl carbamate (urethane, 1 g/kg body weight) were established and lung tumorigenesis assessments were taken after 15 weeks latency period. Compared to the urethane treated ND-fed mice, the HCD-fed mice exhibited significantly decreased lung tumor multiplicity and attenuated pulmonary inflammation, which including reduced influx of leukocytes and down regulated tumor-promoting cyto-/chemokine profile in bronchoalveolar lavage fluid, decreased TLR2/4 expression and NF-κB activation in the lung. As a sensor regulating intracellular cholesterol homeostasis, nuclear receptor LXR-α was up-regulated significantly in the urethane treated HCD-fed mice lungs compared to the ND-fed mice lungs, accompanied with decreased pulmonary free cholesterol content and suppressed tumor cell proliferation. These results suggested that intrapulmonary cholesterol homeostasis, other than systematic cholesterol level, is important in lung tumorigenesis, and LXR activation might partly contribute to the inhibitory role of atherogenic diet on lung tumorigenesis. Show less
We aimed to characterize common genetic variants that influence saturated fatty acid concentrations in East Asians. Meta-analysis of genome-wide association studies for circulating SFAs was conducted Show more
We aimed to characterize common genetic variants that influence saturated fatty acid concentrations in East Asians. Meta-analysis of genome-wide association studies for circulating SFAs was conducted in two population-based cohorts comprising 3521 participants of Chinese ancestry. We identified two novel 14:0-associated loci at LMX1A (LIM homeobox transcription factor 1) and AMPD3 (AMP deaminase 3) (P = 5.08 × 10 To our knowledge, this is the first GWAS analysis to examine SFA concentrations in East Asian populations. Our findings provide novel evidence that genetic variations of several genes from multiple pathways are associated with SFA concentrations in human body. Show less
Ting-Huan Chen, Chen-Yu Chen, Hui-Chin Wen+4 more · 2017 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the ea Show more
Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. In this study, we generated C2C12 stable cell lines that expressed YAP (C2C12-YAP cells) and found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker. Western blot analysis revealed that Src and c-Abl (Abelson murine leukemia viral oncogene homolog 1) activation were enhanced in C2C12-YAP cells. Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts. Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments. MEKK3 contains the PPGY motif (aa 178-181), which may interact with YAP. Site-directed mutagenesis experiments revealed that expression of MEKK3 Y181F mutant inhibited MEK5/ERK5 activation and myogenic differentiation. These results suggest that YAP promotes muscle differentiation by activating the Abl/Src/MEKK3/MEK5/ERK5 kinase cascade.-Chen, T.-H., Chen, C.-Y., Wen, H.-C., Chang, C.-C., Wang, H.-D., Chuu, C.-P., Chang, C.-H. YAP promotes myogenic differentiation Show less
Xiansheng Huang, Rong Li, Luzhu Chen+1 more · 2017 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
To investigate the role of apolipoprotein A5 (apoA5) in the pathogenesis of obesity-related hypertriglyceridemia and the related therapeutic effects of metformin. Methods: The ob/ob mice were treated Show more
To investigate the role of apolipoprotein A5 (apoA5) in the pathogenesis of obesity-related hypertriglyceridemia and the related therapeutic effects of metformin. Methods: The ob/ob mice were treated with regular chow diet and metformin for 4 weeks, and the levels of hepatic triglyceride (TG) and apoA5 were measured. Hepatic IAR20 cells were treated with metformin and/or apoA5 siRNAs, and then cellular TG contents and apoA5 expression were determined. Results: High plasma and hepatic levels of apoA5 and TG were found in ob/ob mice. The plasma levels of apoA5 were positively correlated with plasma TG in these mice. Metformin could dose-dependently decrease the plasma and hepatic levels of apoA5 and TG in ob/ob mice. Metformin could also dose-dependently reduce cellular TG contents and apoA5 expression, these effects were attenuated by knockdown of apoA5. Conclusion: Hepatic apoA5 is up-regulated in ob/ob mice, which contributes to the elevation of plasma TG. Metformin could inhibit hepatic apoA5 expression, leading to the reduction of the plasma level of TG. Show less
Usnea is a lichen of Usnea diffracta Vain and Usnea longissima Ach, which belongs to the genus Usnea Adans of Usneaceae. Usnea exerts numerous pharmacological activities, while its lipid regulatory ac Show more
Usnea is a lichen of Usnea diffracta Vain and Usnea longissima Ach, which belongs to the genus Usnea Adans of Usneaceae. Usnea exerts numerous pharmacological activities, while its lipid regulatory activities remain unreported. This study aims to evaluate the effects of aqueous and ethanol extracts of Usnea on the regulation of lipid metabolism and to explore the possible mechanism. Hyperlipidemia rat model was established by feeding with high-fat diet for 45days. Therapy rats were intragastrically administered with simvastatin (0.004g/kg/d), Usnea aqueous extract (2.766g/kg/d), or Usnea ethanol extract (2.766g/kg/d) for 20days. Pharmacodynamic effects, including body weight, serum and liver lipid levels, total bile acid (TBA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), liver index, and hepatic morphological changes were evaluated. To explore the mechanisms, the lipase activities and protein expressions related to lipid metabolism were detected. Compared with the model group, aqueous and ethanol extracts of Usnea can slow down the weight gain of rats, significantly reduce the serum levels of total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and the liver contents of TG, LDL-C, as well as significantly increase the contents of high-density lipoprotein cholesterol in serum. In addition, aqueous and ethanol extracts of Usnea can significantly reduce the serum contents of AST and ALT. Furthermore, ethanol extract of Usnea can also significantly reduce the TBA content in serum and liver index. Liver tissue pathological observation showed that aqueous and ethanol extracts of Usnea can improve cell degeneration to a certain extent. Aqueous and ethanol extracts of Usnea can significantly reduce sterol regulatory element-binding proteins-1c, and liver X receptor α (LXR-α) protein expressions. Furthermore, aqueous extract of Usnea can significantly increase hepatic lipase activity and promote apoprotein A5 (ApoA5) protein expression. These findings strongly suggest that the aqueous and ethanol extracts of Usnea play significant roles in regulating lipid metabolism, and the ethanol extract exhibits higher activity than the aqueous extract. The mechanism of the regulation of lipid metabolism by Usnea aqueous extract may involve the increased ApoA5 protein expression via inhibition of the LXR-α signal pathway; however, the mechanism of the regulation of lipid metabolism by Usnea ethanol extract remains to be further studied. Show less
To analyze the related pathogenicity gene mutations in a sudden death of hypertrophic cardiomyopathy （HCM） on whole exome level. Whole exome sequencing （WES） was been performed on a sudden death case Show more
To analyze the related pathogenicity gene mutations in a sudden death of hypertrophic cardiomyopathy （HCM） on whole exome level. Whole exome sequencing （WES） was been performed on a sudden death case sample with pathological features of HCM by Illumina® Hiseq 2500 platform. Using hg19 as the reference sequences, the sequencing data were analyzed. Suspicious single nucleotide variants （SNV） were screened, and the conservatism and function were analyzed by the software such as PhyloP, PolyPhen-2, SIFT, etc. After screening, a heterozygous mutation C719R was finally identified in the gene The molecular anatomy on whole exome level by second generation sequencing technology can help to define the molecular mechanism of HCM and provide a new mothed and thought for analysis of death cause. Show less
Fa Chen, Baochang He, Lingjun Yan+3 more · 2017 · Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons · Elsevier · added 2026-04-24
The fatty acid desaturase 1 (FADS1) gene variant is a novel susceptibility marker for laryngeal squamous cell carcinoma identified by a recent genome-wide association study, but it is still unclear wh Show more
The fatty acid desaturase 1 (FADS1) gene variant is a novel susceptibility marker for laryngeal squamous cell carcinoma identified by a recent genome-wide association study, but it is still unclear whether this genetic variant continues to influence oral cancer recurrence or death. The purpose of this study was to evaluate the role of FADS1 rs174549 polymorphism and its interaction with postoperative chemoradiotherapy in the prognosis of oral cancer. A prospective cohort study involving 304 oral cancer patients with surgical resection was conducted in Fujian, China. Demographic and clinical data (adjuvant therapy types, histologic types, clinical stage, etc.) were extracted from medical records, and follow-up data were obtained by telephone interviews. We collected 5 to 8 mL of venous blood from all patients for DNA extraction, and rs174549 genotypes were determined by TaqMan assays (Life Technologies, Carlsbad, CA). A Cox proportional hazards model and Kaplan-Meier curve were used to assess the association between FADS1 rs174549 polymorphism and progression-free survival (PFS), as well as overall survival, in oral cancer. Carrying the AA genotype was significantly associated with a decreased risk of PFS: The hazard ratio was 0.52 (95% confidence interval, 0.29 to 0.93) for the codominant model and 0.54 (95% confidence interval, 0.31 to 0.94) for the recessive model. Moreover, better PFS was particularly obvious in patients who had received chemoradiotherapy. A positive multiplicative interaction between FADS1 rs174549 polymorphism and chemoradiotherapy was observed for PFS (P = .036). No significant association was found between FADS1 rs174549 polymorphism and overall survival. Our study suggests, for the first time, that FADS1 rs174549 polymorphism is a potentially independent and favorable factor in predicting oral cancer PFS especially for patients who undergo chemoradiotherapy, and it may serve as a potential target for individualized treatment in the future. Show less
Xuezhikang (XZK), an extract of Chinese red yeast rice, is recommended as an optimal choice for patients with coronary heart disease (CHD) with markedly elevated triglyceride (TG) levels. This study w Show more
Xuezhikang (XZK), an extract of Chinese red yeast rice, is recommended as an optimal choice for patients with coronary heart disease (CHD) with markedly elevated triglyceride (TG) levels. This study was designed to compare the hypotriglyceridemic effects between XZK and simvastatin. The role of apolipoprotein A5 (apoA5), a key regulator of TG metabolism and a target gene of peroxisome proliferator-activated receptor α (PPARα), was to be identified in XZK-related hypotriglyceridemic actions. For these goals, hypertriglyceridemia of rats was induced by a high-fructose diet. In order to investigate the hypotriglyceridemic effects of XZK and simvastatin on these animals based on an equivalent low-density lipoprotein cholesterol (LDL-C) lowering power, we titrated their doses (XZK 80 mg/kg/d versus simvastatin 1 mg/kg/d) according to plasma LDL-C reduction of rats. Similarly, we titrated the target doses of the two agents (XZK 500 μg/ml versus simvastatin 10 μM) according to hepatocyte LDL receptor expressions, and then compared the effects of the two agents on TG and apoA5 of hepatocytes in vitro. Our results showed that XZK (80 mg/kg/d) had higher hypotriglyceridemic performance than simvastatin (1 mg/kg/d) on these animals albeit their equivalent LDL-C lowering power. Higher plasma apoA5 levels and hepatic apoA5 expressions were observed in rats treated with XZK (80 mg/kg/d) than simvastatin (1 mg/kg/d). Further, XZK (80 mg/kg/d) contributed to higher hepatic PPARα expressions of rats than simvastatin (1 mg/kg/d). Although the two agents led to an equivalent up-regulation of LDL receptors of hepatocytes, more TG reduction and apoA5 elevation were detected in hepatocytes treated with XZK (500 μg/ml) than simvastatin (10 μM). However, PPARα knockdown eliminated the above effects of XZK on hepatocytes. Therefore, our study indicates that XZK has greater hypotriglyceridemic performance than simvastatin in the setting of an equivalent LDL-C lowering power, which is attributed to more apoA5 up-regulation by this agent via the PPARα signaling pathway. Show less
To investigate the role of microtubule-actin crosslinking factor 1 (MACF1) in the response of glioma cells to temozolomide (TMZ). TMZ was applied to a human gliomablastoma cell line (U87) and changes Show more
To investigate the role of microtubule-actin crosslinking factor 1 (MACF1) in the response of glioma cells to temozolomide (TMZ). TMZ was applied to a human gliomablastoma cell line (U87) and changes in the protein expression and cellular localization were determined with Western blot, RT-PCR, and immunofluorescence. The responses of the cells with MACF1 expression knockdown by RNA interference to TMZ were assessed. TMZ-induced effects on MACF1 expression were also assessed by immunohistochemistry in a nude mouse model bearing human glioblastoma xenografts. TMZ resulted in significantly increased MACF1 expression (by about 2 folds) and changes in its localization in the gliomablastoma cells both in vitro and in vivo (P<0.01). Knockdown of MACF1 reduced the proliferation (by 45%) of human glioma cell lines treated with TMZ (P<0.01). TMZ-induced changes in MACF1 expression was accompanied by cytoskeletal rearrangement. MACF1 may be a potential therapeutic target for glioblastoma. Show less
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of Show more
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10 Show less
DExD/H-box helicase 36 (DHX36) is known to be an ATP-dependent RNA helicase that unwinds the guanine-quadruplexes DNA or RNA, but emerging data suggest that it also functions as pattern recognition re Show more
DExD/H-box helicase 36 (DHX36) is known to be an ATP-dependent RNA helicase that unwinds the guanine-quadruplexes DNA or RNA, but emerging data suggest that it also functions as pattern recognition receptor in innate immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Show less
The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L A Show more
The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L AGEs or bovine serum albumin (BSA) and assayed for cell viability, cell cycle, and apoptosis. We performed real-time PCR and Western blot analysis for RNA and protein levels of carbohydrate responsive element-binding protein (ChREBP) in AGEs- or BSA-treated HepG2 cells. We analyzed the level of reactive oxygen species (ROS) in HepG2 cells treated with AGEs or BSA.We found that increased S-phase cell percentage and decreased apoptosis contributed to AGEs-induced liver cancer cell proliferation. Real-time PCR and Western blot analysis showed that AGEs stimulated RNA and protein levels of ChREBP, a transcription factor promoting glycolysis and maintaining cell proliferation in liver cancer cells. Intriguingly, the level of ROS was higher in AGEs-treated liver cancer cells. Treating liver cancer cells with antioxidant N-acetyl cystein (NAC) partly blocked AGEs-induced ChREBP expression and cell proliferation.Our results suggest that the AGEs-ROS-ChREBP pathway plays a critical role in promoting ChREBP expression and liver cancer cell proliferation. Show less
Colorectal cancer (CRC) is one of the leading cancers worldwide. Surgery is the main therapeutic modality for stage II CRC. However, the implementation of adjuvant chemotherapy remains controversial a Show more
Colorectal cancer (CRC) is one of the leading cancers worldwide. Surgery is the main therapeutic modality for stage II CRC. However, the implementation of adjuvant chemotherapy remains controversial and is not universally applied so far. In this study, we found that the protein expression of lysosomal acid phosphatase 2 (ACP2) was increased in CRC and that stage II CRC patients with high ACP2 expression showed a poorer outcome than those with low ACP2 expression (p = 0.004). To investigate this discrepancy, we analyzed the relation between ACP2 expression and several clinical cofactors.Among patients who received chemotherapy, those with an high expression of ACP2 showed better survival in both stage II and III CRC than those with low ACP2 expression. In stage II CRC patients, univariate analysis showed ACP2 expression and T stage to be cofactors significantly associated with overall survival (ACP2: p = 0.006; T stage: p = 0.034). Multivariate Cox proportion hazard model analysis also revealed ACP2 to be an independent prognostic factor for overall survival (ACP2: p = 0.006; T stage: p = 0.041). Furthermore, ACP2-knockdown CRC cells showed an increase in chemoresistance to 5-FU treatment and increased proliferation marker in the ACP2 knockdown clone.Taken together, our results suggested that ACP2 is an unfavorable prognostic factor for stage II CRC and may serve as a potential chemotherapy-sensitive marker to help identify a subset of stage II and III CRC patients for whom chemotherapy would improve survival.Highlights1. To the best of our knowledge, the study is the first report to show ACP2 overexpression in human colorectal cancer (CRC) and its association with poor outcome in stage II CRC.2. Patients with stage II and III CRCs with high expression of ACP2 were more sensitive to chemotherapy than those with a low expression.3. ACP2 expression may serve as a marker for CRC patients receiving chemotherapy and help identify the subset of CRC patients who would benefit from chemotherapy. Show less
In quantitative analysis of protein biomarkers and therapeutic proteins by liquid chromatography/mass spectrometry (LC/MS), it is a preferred and well-established approach to digest with proteolytic e 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 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
The SstI polymorphism in the apolipoprotein 3 gene (apoC3) has been identified in many ethnic groups. In addition, the S2 allele of the SstI polymorphism is shown to be associated with increased plasm Show more
The SstI polymorphism in the apolipoprotein 3 gene (apoC3) has been identified in many ethnic groups. In addition, the S2 allele of the SstI polymorphism is shown to be associated with increased plasma triglyceride (TG) levels. Plasma apoCIII is an important atherogenic factor, which interrupts lipid metabolism and is positively associated with plasma TG levels. However, the existence of the SstI polymorphism in the Li ethnic group in China remains to be confirmed. The relationship between the S2 allele of the SstI polymorphism and plasma apoCIII or TG and their roles in atherosclerosis are also unknown. A cohort of 628 participants was recruited (316 atherosclerotic patients and 312 healthy controls) from both the Li and Han ethnic groups. Blood samples were obtained to evaluate the SstI polymorphism in the apoC3 and lipid profiles. Chi-squared and t-tests and multiple unconditional logistic regression were employed to analyze the genotypic and allelic frequencies and lipid profiles using SPSS version 20.0 software. The SstI polymorphism in the apoC3 was identified in the Li ethnic group. The S2 allele and plasma apoCIII and TG levels were associated with the development of atherosclerosis (P < 0.01, S2 allele and apoCIII; P < 0.05, TG) in the Li ethnic group. The S2 allele was associated with increased plasma apoCIII levels in the atherosclerotic group (P < 0.01), but with increased plasma apoCIII and TG levels in control group (both P < 0.01). In addition to the increases in the S2 allele frequency and plasma TG and apoCIII levels, atherosclerotic patients in the Li ethnic group also exhibited increased apoB, decreased HDL-C and apoAI and a lower apoAI:apoB ratio (all P < 0.01). Our results indicate that the S2 allele of the SstI polymorphism in the apoC3 gene is associated with plasma apoCIII levels in the Li population. In combination with unfavorable lipid profiles, this might contribute to susceptibility to atherosclerosis. Show less
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps Show more
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation. Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. Consequently, NRBF2 in its unphosphorylated form promotes PtdIns3K lipid kinase activity and autophagy flux, whereas its phosphorylated form blocks them. This study reveals NRBF2 as a critical molecular switch of PtdIns3K and autophagy activation, and its on/off state is precisely controlled by MTORC1 through phosphorylation. Show less
Neuronal regeneration and axonal regrowth mechanisms in the injured mammalian central nervous system are largely unknown. As part of a major pathway for inhibiting axonal regeneration, activated neuro Show more
Neuronal regeneration and axonal regrowth mechanisms in the injured mammalian central nervous system are largely unknown. As part of a major pathway for inhibiting axonal regeneration, activated neuronal glycosylphosphatidylinositol-anchored Nogo receptor (NgR) interacts with LINGO-1 and p75NTR to form a complex at the cell surface. However, it was found in our previous report that upregulation of NgR stimulated by injury plays a key role in neuronal regeneration in the neonatal cortex freeze-lesion model, but its downstream signalling remains elusive. In the present study, the novel regulatory role of NgR in a serine-threonine kinase WNK1 was identified. NgR's transcriptional regulation of WNK1 was identified by RT-qPCR and semiquantitative western blot after the overexpression or knockdown of NgR, and the regulation is specific to WNK1, which is not the same for its family members, WNK2, WNK3 and WNK4. Furthermore, NgR inhibition by NEP fails to affect WNK1, which indicates that WNK1 functions outside of the Nogo-A/NgR pathway. By performing a proliferation, migration and axonal extension assay, we also identified that overexpressed NgR critically regulated these processes and impairment by overexpressing NgR was rescued with coexpression of WNK1, indicating the partial role of WNK1 in NgR-mediated morphological regulation. Our study identifies a separation of functions for the NgR-regulated WNK1 in mediating proliferation, migration and axonal extension in PC12 cells as well as a specific regulatory role between NgR and WNK1 that is important for recovery from central nervous system injury. Show less
Hepatic fibrosis may ultimately result in organ failure and death, a reality compounded by the fact that most drugs for liver fibrosis appear to be effective only if given as a prophylactic or early t Show more
Hepatic fibrosis may ultimately result in organ failure and death, a reality compounded by the fact that most drugs for liver fibrosis appear to be effective only if given as a prophylactic or early treatment. In a dimethylnitrosamine-induced liver fibrotic model, aspartate aminotransferase/alanine aminotransferase levels could not precisely distinguish the differences between the initial stage of liver fibrosis and normal control, whereas histological examination indicated that dimethylnitrosamine treatment for two weeks has resulted in hepatic fibrogenesis. Comprehensive proteomics identified 12 proteins mainly associated with the interleukin 6-stimulated inflammatory pathway. Coordinately, cytokine profiles showed that dimethylnitrosamine administration would stimulate various signaling pathways leading to liver fibrosis. Of note, apolipoprotein A4 in serum samples obtained from patients in the early stage of liver fibrosis were significantly increased compared to the healthy controls ( 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