Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of Show more
Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones. Mutations in Exostosin-1/Exostosin-2 (EXT1/EXT2) genes are the main molecular basis of MO. EXT1 and EXT2 genes encode exostosin 1 and exostosin 2, respectively, both of which are transmembrane glycosyltransferases that elongate the chains of heparin sulfate (HS) at HS proteoglycans (HSPGs). HSPGs are considered to be involved in regulating the proliferation and differentiation of chondrocytes. Owing to large size of EXT1/EXT2 genes and lack of mutation hotspots, molecular diagnosis of MO is challenging. Here, we applied targeted next-generation sequencing (t-NGS) in mutation screening of EXT1/EXT2 genes for 10 MO patients. The results were compared and validated with Sanger sequencing. Overall, nine mutations identified by t-NGS were confirmed with Sanger sequencing, excluding two variants of false positive, suggesting the reliability of mutation screening by t-NGS. The nine mutations identified by t-NGS include two missense mutations (EXT1: c.1088G>A and c.2120C>T), one splicing mutation (EXT2: c.744-1G>T), and six nonsense mutations (EXT1: c.351C>G, c.1121G>A, and c.1843₁₈₄₆dup; EXT2: c.67C>T, c.561delG, and c.575T>A). In summary, our paper provides the primary data of the application of t-NGS in MO molecular diagnosis, including six newly identified mutations (EXT1: c.1843₁₈₄₆dup, c.1088G>A, c.351C>G, and c.2120C>T and EXT2: c.744-1G>T and c.575T>A), which further enrich the mutation database of MO from the Chinese population. 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
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
Diabetic retinopathy (DR) is a complication of diabetes mellitus (DM) and is the leading cause of vision loss globally. However, the pathogenic mechanism and clinical therapy still needs further impro Show more
Diabetic retinopathy (DR) is a complication of diabetes mellitus (DM) and is the leading cause of vision loss globally. However, the pathogenic mechanism and clinical therapy still needs further improvement. The biologic significance of myocardial infarction associated transcript (MIAT) in DR remains unknown. Here, we aim to explore the mechanism between MIAT and DR, which is essential for RD. Streptozotocin (STZ) was used to induce DM mice and high glucose was used to stimulate cells. ChIP was used to detect the binding activity between nuclear factor κB (NF-κB) and the promoter of the MIAT gene, luciferase activity assay was used to detect the target-specific selectivity between 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
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
Mutations in many centriolar protein-encoding genes cause primary microcephaly. Using super-resolution and electron microscopy, we find that the human microcephaly protein, RTTN, is recruited to the p Show more
Mutations in many centriolar protein-encoding genes cause primary microcephaly. Using super-resolution and electron microscopy, we find that the human microcephaly protein, RTTN, is recruited to the proximal end of the procentriole at early S phase, and is located at the inner luminal walls of centrioles. Further studies demonstrate that RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN gene knockout in p53-deficient cells induce amplification of primitive procentriole bodies that lack the distal-half centriolar proteins, POC5 and POC1B. Additional analyses show that RTTN serves as an upstream effector of CEP295, which mediates the loading of POC1B and POC5 to the distal-half centrioles. Interestingly, the naturally occurring microcephaly-associated mutant, RTTN (A578P), shows a low affinity for STIL binding and blocks centriole assembly. These findings reveal that RTTN contributes to building full-length centrioles and illuminate the molecular mechanism through which the RTTN (A578P) mutation causes primary microcephaly.Mutations in many centriolar protein-encoding genes cause primary microcephaly. Here the authors show that human microcephaly protein RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles. Show less
The aim of the study was to investigate the relationship between genetic factors and primary restless legs syndrome (RLS) in Chinese population. A total of 116 RLS patients and 200 controls were recru Show more
The aim of the study was to investigate the relationship between genetic factors and primary restless legs syndrome (RLS) in Chinese population. A total of 116 RLS patients and 200 controls were recruited and the diagnosis of RLS was based on the criteria of International RLS Study Group. Polymer chain reaction (PCR) and sequencing were used to detect 19 single nucleotide polymorphisms (SNPs) in six genetic loci (MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3, and Intergenic region of 2p14). Our study found that one SNP increased the risk of RLS in Chinese population: rs6494696 of MAP2K5/SKOR1 (odds ratio [OR] = 0.09, p < .0001, recessive model). A further meta-analysis of RLS in Asian population found that two SNPs of BTBD9 increased the risk of RLS: rs9296249 of BTBD9 (OR = 1.44, p = .000, T allele), rs9357271 of BTBD9 (OR = 1.38, p = .021, dominant model). Our results confirmed the association of BTBD9 and MAP2K5/SKOR1 with primary RLS in Chinese population. 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
Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment t Show more
Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; 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
The aim of this study was to investigate the independent and combined effects of fatty acid desaturase 1 (FADS1) gene polymorphism and fish consumption on oral cancer. A hospital-based case-control st Show more
The aim of this study was to investigate the independent and combined effects of fatty acid desaturase 1 (FADS1) gene polymorphism and fish consumption on oral cancer. A hospital-based case-control study was performed including 305 oral cancer patients and 579 cancer-free controls. The genotypes were determined by TaqMan genotyping assay. Non-conditional logistic regression model was used to assess the effects of FADS1 rs174549 polymorphism and fish intake. Subjects carrying A allele of rs174549 significantly reduced the risk of oral cancer (AA VS GG, OR: 0.65, 95% CI: 0.42-0.99; AA VS AG+GG, OR: 0.67, 95% CI: 0.46-0.98). Moreover, the statistically significant reverse associations were especially evident in men, smokers, alcohol drinkers and those age ≤ 60 years. Additionally, fish intake ≥7 times/week showed a 73% reduction in risk for oral cancer compared to those who ate fish less than 2 times/week (OR: 0.27, 95% CI: 0.18-0.42). Furthermore, a significant gene-diet multiplicative interaction was observed between FADS1 rs174549 polymorphism and fish intake for oral cancer (P=0.028). This preliminary study suggests that FADS1 rs174549 polymorphism and fish consumption may be protective factors for oral cancer, with a gene-diet multiplicative interaction. Functional studies with larger samples are required to confirm our findings. 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
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
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
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
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
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
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
Chronic alcohol exposure induces pronounced changes in GPCR-mediated G-protein signaling. Recent microarray and RNA-seq analyses suggest associations between alcohol abuse and the expression of genes Show more
Chronic alcohol exposure induces pronounced changes in GPCR-mediated G-protein signaling. Recent microarray and RNA-seq analyses suggest associations between alcohol abuse and the expression of genes involved in G-protein signaling. The activity of G-proteins (e.g. Gαi/o and Gαq) is negatively modulated by regulator of G-protein signaling (RGS) proteins which are implicated in drugs of abuse including alcohol. The present study used 7days of chronic intermittent ethanol exposure followed by 24h withdrawal (CIE) to investigate changes in mRNA and protein levels of G-protein subunit isoforms and RGS protein subtypes in rat prefrontal cortex, a region associated with cognitive deficit attributed to excessive alcohol drinking. We found that this ethanol paradigm induced differential expression of Gα subunits and RGS subtypes. For example, there were increased mRNA and protein levels of Gαi1/3 subunits and no changes in the expression of Gαs and Gαq subunits in ethanol-treated animals. Moreover, CIE increased the mRNA but not the protein levels of Gαo. Additionally, a modest increase in Gαi2 mRNA level by CIE was accompanied by a pronounced increase in its protein level. Interestingly, we found that CIE increased mRNA and protein levels of RGS2, RGS4, RGS7 and RGS19 but had no effect on the expression of RGS5, RGS6, RGS8, RGS12 or RGS17. Changes in the expression of Gα subunits and RGS subtypes could contribute to the functional alterations of certain GPCRs following chronic ethanol exposure. The present study suggests that RGS proteins may be potential new targets for intervention of alcohol abuse via modification of Gα-mediated GPCR function. 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
Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modi Show more
Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modification. A plethora of studies have highlighted the function specifications among CBX family members in various cancer, including lung cancer, colon cancer and breast cancer. Nevertheless, the functions and prognostic roles of distinct CBX family members in breast cancer (BC) remain elusive. In this study, we reported the prognostic values of CBX family members in patients with BC through analysis of a series of databases, including Show less
CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. We g Show more
CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B-containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells. These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits. 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
Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neov Show more
Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 × 10 Show less
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
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
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
Dual specificity phosphatase 6 (DUSP6), a member of the dual specificity protein phosphatase subfamily, can inactivate ERK1/2. However, its possible role in glutamate-induced oxidative cytotoxicity ef Show more
Dual specificity phosphatase 6 (DUSP6), a member of the dual specificity protein phosphatase subfamily, can inactivate ERK1/2. However, its possible role in glutamate-induced oxidative cytotoxicity effects is not clear.Here, we aimed to investigate whether DUSP6 was neuroprotective against glutamate-induced cytotoxicity in HT22 mouse hippocampal cells and primary cultured hippocampal neurons (pc-HNeu). HT22 and pc-HNeu cells were treated with varying concentrations of glutamate (from 0.05mM to 5.0mM) and DUSP6 protein expression were detected by western blotting. DUSP6-overexpressing HT22 and pc-HNeu cells were generated by transfection with DUSP6-overexpressing plasmid. The effects of DUSP6 overexpression on glutamate-induced cytotoxicity, cell death, cell apoptosis, and cell autophagy were determined by cell proliferation assays, flow cytometry, transmission electron microscopy, and western blotting. Glutamate treatment from 0.5mM to 5.0mM downregulated DUSP6 protein expression in both HT22 and pc-HNeu cells. DUSP6 overexpression ameliorated glutamate-induced cell death, apoptosis, and autophagy in both HT22 and pc-HNeu cells. Furthermore, ERK1/2 phosphorylation was decreased by DUSP6 overexpression. In conclusion, DUSP6 has neuroprotective effects against glutamate-induced cytotoxicity in HT22 and pc-HNeu cells. Targeting DUSP6 may be a useful strategy to prevent neuronal death in neurodegenerative diseases including AD. 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