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
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
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated w Show more
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. 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
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibitio Show more
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .). Show less
Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The spectraplakin protein microtubule actin Show more
Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The spectraplakin protein microtubule actin cross-linking factor 1 (MACF1) plays an essential function in various cellular processes, including cell proliferation, migration, signaling transduction and embryo development. MACF1 is also involved in processes such as metastatic invasion in which cytoskeleton organization is a critical element that contributes to tumor progression in various human cancers. Aberrant expression of MACF1 initiates the tumor cell proliferation, and migration and metastasis in numerous cancers, such as breast cancer, colon cancer, lung cancer and glioblastoma. In this review, we summarized the current knowledge of MACF1 and its critical role in different human cancers. This will be helpful for researchers to investigate the novel functional role of MACF1 in human cancers and as a potential target to enhance the efficacy of therapeutic treatment modalities. Show less
Quantitative trait loci (QTLs) are widely used as instruments to infer causal risk factors of diseases based on the idea of mendelian randomization. Plasma metabolites can serve as risk factors of can Show more
Quantitative trait loci (QTLs) are widely used as instruments to infer causal risk factors of diseases based on the idea of mendelian randomization. Plasma metabolites can serve as risk factors of cancer, and the heritability of many circulating metabolites was high. We conducted a metabolome-wide association study (MWAS) to systematically investigate the effects of genetic variants on metabolites and lung cancer based on published genome-wide association study (GWASs) and metabolic-QTL (mQTL) study. Then we confirmed the results by subsequent genetic and metabolic validations and inferred the causal relationship between identified metabolites and lung cancer through genetic variant(s). We firstly identified six polyunsaturated fatty acids (PUFAs) represented by rs174548-linked haplotype were significantly associated with lung cancer risk in a Chinese GWAS (2311 cases and 3077 controls). Rs174548 was further confirmed to be associated with lung cancer in 13 821 Europeans and 18 471 Asians (ORmeta = 0.87, Pmeta = 1.76 × 10-15) and the effect was much stronger in females (Pinteraction = 6.00 × 10-4). We next validated rs174548-plasma PUFA association in 253 Chinese subjects (β = -0.57, P = 1.68 × 10-3). Rs174548 was also found associated with FADS1 (the major fatty acid desaturase of identified PUFAs) expression in liver tissues. Taken together, we found that rs174548 was associated with both PUFAs and lung cancer. Because rs174548 was the only mQTL variant of PUFAs reported by previous GWASs and explained a large proportion of heritability, we proposed that plasma PUFAs could be causally associated with lung cancer based on the idea of mendelian randomization. These findings provide a diet-related risk factor and may have important implications for prevention on lung cancer. 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
Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes. This study investigated whether apolipoprotein (apo) A-IV was glycated in patients Show more
Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes. This study investigated whether apolipoprotein (apo) A-IV was glycated in patients with type 2 diabetes mellitus (T2DM) and whether apoA-IV glycation was related to coronary artery disease (CAD). The study also determined the biological effects of glycated apoA-IV. The authors consecutively enrolled 204 patients with T2DM without CAD (Group I), 515 patients with T2DM with CAD (Group II), and 176 healthy subjects (control group) in this study. ApoA-IV was precipitated from ultracentrifugally isolated high-density lipoprotein, and its glycation level was determined based on Western blotting densitometry (relative intensity of apoA-IV glycation). ApoA-IV NƐ-(carboxylmethyl) lysine (CML) modification sites were identified by mass spectrometry in 37 control subjects, 63 patients in Group I, and 138 patients in Group II. Saline or glycated apoA-IV (g-apoA-IV) generated by glyoxal culture was injected into apoE The relative intensity and the abundance of apoA-IV glycation were associated with the presence and severity of CAD in patients with T2DM (all p < 0.05). The experiments showed that g-apoA-IV induced proinflammatory reactions in vitro and promoted atherogenesis in apoE ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE Show less
Apolipoprotein A5 (apoA5) has been implicated in the formation of hepatocyte lipid droplets, a histological hallmark of non-alcoholic fatty liver disease (NAFLD). Recent evidence demonstrated that liv Show more
Apolipoprotein A5 (apoA5) has been implicated in the formation of hepatocyte lipid droplets, a histological hallmark of non-alcoholic fatty liver disease (NAFLD). Recent evidence demonstrated that liver X receptor α (LXRα), a transcription factor involved in down-regulation of 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
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
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
Axis inhibition protein 1 (AXIN1) is characterized as a tumor suppressor in numerous types of cancer. However, the functional role of AXIN1 in the testicular germ cell tumors (TGCTs) remains unclear. Show more
Axis inhibition protein 1 (AXIN1) is characterized as a tumor suppressor in numerous types of cancer. However, the functional role of AXIN1 in the testicular germ cell tumors (TGCTs) remains unclear. The human embryonal carcinoma-derived cell line NTera2 was transfected with a recombinant AXIN1 expression vector (pcDNA3.1-AXIN1) and/or a small interfering RNA (siRNA) directed against AXIN1 (siAXIN). Following transfection, the mRNA and protein levels of AXIN1 were determined via reverse transcription-quantitative polymerase chain reaction analysis and western blotting, respectively. In addition, cell viability, apoptosis and the expression of apoptosis-associated proteins [apoptosis regulator Bax (Bax) and B-cell lymphoma (Bcl)-2] and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway proteins [phosphorylated (p)-mTOR, mTOR, p-AKT, AKT, P-70S ribosomal protein S6 (S6) and S6] were assessed. AXIN1 mRNA and protein levels were increased following transfection with pcDNA3.1-AXIN1 and decreased following transfection with siAXIN1 compared with their respective control groups. After overexpression of AXIN1, NTera2 cell viability and expression of Bcl-2, p-mTOR p-AKT and p-S6 protein was decreased, while apoptosis and Bax protein levels were increased, compared with the control group. However, there was no significant difference in AXIN1 mRNA expression, apoptosis or Bax/Bcl-2 protein expression when NTera2 cells were simultaneously transfected with pcDNA3.1-AXIN1+siAXIN1. In conclusion, the results of the present study indicate that overexpression of AXIN1 protects against TGCTs via inhibiting the PI3K/AKT/mTOR signaling pathway, suggesting that AXIN1 may be a potential target for gene therapy in TGCTs. Show less
Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have lin Show more
Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in the liver, the effect of hepatic ChREBP on insulin sensitivity remains unknown. To clarify the importance of hepatic ChREBP on glucose homeostasis, we have generated a knockout mouse model that lacks this protein specifically in the liver (Liver-ChREBP KO). Using Liver-ChREBP KO mice, we investigated whether hepatic ChREBP deletion influences insulin sensitivity, glucose homeostasis and the development of hepatic steatosis utilizing various dietary stressors. Furthermore, we determined gene expression changes in response to fasted and fed states in liver, white, and brown adipose tissues. Liver-ChREBP KO mice had impaired insulin sensitivity as indicated by reduced glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamps on both chow (25% lower) and high-fat diet (33% lower) (p < 0.05). This corresponded with attenuated suppression of hepatic glucose production. Although Liver-ChREBP KO mice were protected against carbohydrate-induced hepatic steatosis, they displayed worsened glucose tolerance. Liver-ChREBP KO mice did not show the expected gene expression changes in liver in response to fasted and fed states. Interestingly, hepatic ChREBP deletion also resulted in gene expression changes in white and brown adipose tissues, suggesting inter-tissue communication. This included an almost complete abolition of BAT ChREBPβ induction in the fed state (0.15-fold) (p = 0.015) along with reduced lipogenic genes. In contrast, WAT showed inappropriate increases in lipogenic genes in the fasted state along with increased PEPCK1 in both fasted (3.4-fold) and fed (5.1-fold) states (p < 0.0001). Overall, hepatic ChREBP is protective in regards to hepatic insulin sensitivity and whole body glucose homeostasis. Hepatic ChREBP action can influence other peripheral tissues and is likely essential in coordinating the body's response to different feeding states. Show less
Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world pop Show more
Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. Show less
A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemi Show more
A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC Show less
Carbamoyl phosphate synthase 1 (CPS1) is the rate-limiting enzyme in the first step of the urea cycle and an indispensable enzyme in the metabolism of human liver. However, CPS1 epigenetic regulation Show more
Carbamoyl phosphate synthase 1 (CPS1) is the rate-limiting enzyme in the first step of the urea cycle and an indispensable enzyme in the metabolism of human liver. However, CPS1 epigenetic regulation involves promoter analysis and the role of liver-enriched transcription factors (LETFs), which is not fully elucidated. In this work, the promoter region of hCPS1 gene was cloned, and its activity was investigated. An LETF, hepatocyte nuclear factor 3-beta (HNF3β), was found to promote the transcriptional expression of CPS1 in liver-derived cell lines. In addition, dual-luciferase reporter assay shows that the essential binding sites of the HNF3β may exist in the oligonucleotide -70 nt to +73 nt. Two putative binding sites are available for HNF3β. Mutation analysis results show that the binding site 2 of HNF3β was effective, and the transcriptional activity of CPS1 promoter significantly decreased after mutation. Electrophoretic mobile shift assay (EMSA) and ChIP assay confirmed that HNF3β can interact with the binding site in the CPS1 promoter region of -70 nt to +73 nt promoter region in vivo and in vitro to regulate the transcription of CPS1. Moreover, HNF3β overexpression enhanced the transcription of CPS1 and consequently improved the mRNA and protein levels of CPS1, whereas the knockdown of HNF3β showed the opposite effects. Finally, urea production in cells was measured, and ammonia detoxification improved significantly in cells after transfection with HNF3β. HNF3β plays a vital role in regulation of CPS1 gene and could promote the metabolism of ammonia by regulating CPS1 expression. Show less
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However Show more
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3β protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug. Show less
Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the Show more
Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson's disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1's roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies. 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
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
Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determin Show more
Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors. 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
To investigate whether genetic variations on the estrogen metabolic pathway would be associated with risk of Alzheimer's disease (AD). Cross-sectional study. Individuals were recruited at the Memory C Show more
To investigate whether genetic variations on the estrogen metabolic pathway would be associated with risk of Alzheimer's disease (AD). Cross-sectional study. Individuals were recruited at the Memory Clinic, Queen Mary Hospital, Hong Kong. Chinese individuals with (n = 426) and without (n = 350) AD. All subjects underwent a standardized cognitive assessment and genotyping of four candidate genes on the estrogen metabolic pathway (estrogen receptor α gene (ESR1), estrogen receptor β gene (ESR2), cytochrome P450 19A1 gene (CYP19A1), cytochrome P450 11A1 gene (CYP11A1)). Apart from consistent results showing an association between apolipoprotein (APO)E and AD, strong evidence of disease associations were found for polymorphisms in ESR2 and CYP11A1 based on the entire data set. For ESR2, significant protective effects were found for A alleles of rs4986938 (permuted P = .02) and rs867443 (permuted P = .02). For CYP11A1, significant risk effects were found for G alleles of rs11638442 (permuted P = .03) and rs11632698 (permuted P = .03). Stratifying subjects according to APOE ε4 status, their genetic effects continued to be significant in the APOE ε4-negative subgroup. Associations between CYP11A1 polymorphisms (rs2279357, rs2073475) and risk of AD were detected in women but not men. Further gene-level analysis confirmed the above association between ESR2 and CYP11A1, and pathway-level analysis highlighted the genetic effect of the estrogen metabolic pathway on disease susceptibility (permuted pathway-level P = .03). Consistent with previous biological findings for sex steroid hormones in the central nervous system, genetic alterations on the estrogen metabolic pathway were revealed in the Chinese population. Confirmation of these present findings in an independent population is warranted to elucidate disease pathogenesis and to explore the potential of hormone therapy in the treatment of AD. Show less
Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. Genome-wide alternative splicing Show more
Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. Genome-wide alternative splicing profiling in lung cancer remains largely unstudied. We generated alternative splicing profiles in 491 lung adenocarcinoma (LUAD) and 471 lung squamous cell carcinoma (LUSC) patients in TCGA using RNA-seq data, prognostic models and splicing networks were built by integrated bioinformatics analysis. A total of 3691 and 2403 alternative splicing events were significantly associated with patient survival in LUAD and LUSC, respectively, including EGFR, CD44, PIK3C3, RRAS2, MAPKAP1 and FGFR2. The area under the curve of the receiver-operator characteristic curve for prognostic predictor in NSCLC was 0.817 at 2000 days of overall survival which were also over 0.8 in LUAD and LUSC, separately. Interestingly, splicing correlation networks uncovered opposite roles of splicing factors in LUAD and LUSC. We created prognostic predictors based on alternative splicing events with high performances for risk stratification in NSCLC patients and uncovered interesting splicing networks in LUAD and LUSC which could be underlying mechanisms. 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
Axin1 is a scaffold protein in the β-catenin destruction complex, which, if disrupted, contributes to pathogenesis of various human diseases, including colorectal carcinogenesis and inflammatory bowel Show more
Axin1 is a scaffold protein in the β-catenin destruction complex, which, if disrupted, contributes to pathogenesis of various human diseases, including colorectal carcinogenesis and inflammatory bowel diseases (IBD). We have previously demonstrated that Salmonella infection promotes the degradation and plasma sequestration of Axin1, leading to bacterial invasiveness and inflammatory responses. Vitamin D and the vitamin D receptor (VDR) appear to be important regulators of IBD and colon cancer. Although VDR and Axin1 are all involved in intestinal inflammation, it remains unclear whether these processes are related or function independently. In the current study, we hypothesize that VDR is an important regulator for the maintenance of physiological level of Axin1. Using the intestinal epithelial conditional VDR knockout mouse model (VDR We found that VDR deletion led to lower protein and mRNA levels of Axin1, whereas knockdown of Axin1 did not change the expression level of VDR protein. Immunoprecipitation data did not support physical interaction between VDR and Axin1. The VDR regulation of Axin1 was through a VDR genomic binding site for Axin1 gene on the regulatory region. Fractionation data showed that cytosolic Axin1 was significantly reduced due to VDR deletion, leaving the nuclear fraction unchanged. In ileum, Axin1 was distributed in the cytosol of apical epithelium and crypts. VDR is important for the maintenance of physiological level of Axin1. The discovery of Axin1 as a VDR target gene provides novel and fundamental insights into the interactions between the VDR and β-catenin signaling pathways. 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