Comprehensive clinicopathological significance and putative transcriptional mechanisms of Forkhead box M1 factor in hepatocellular carcinoma.

BACKGROUND: The Forkhead box M1 factor (FOXM1) is a crucial activator for cancer cell proliferation. While FOXM1 has been shown to promote hepatocellular carcinoma (HCC) progression, its transcriptional mechanisms remain incompletely understood. METHODS: We performed an in-house tissue microarray on 313 HCC and 37 non-HCC tissue samples, followed by immunohistochemical staining. Gene chips and high throughput sequencing data were used to assess FOXM1 expression and prognosis. To identify candidate targets of FOXM1, we comprehensively reanalyzed 41 chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets. We predicted FOXM1 transcriptional targets in HCC by intersecting candidate FOXM1 targets with HCC overexpressed genes and FOXM1 correlation genes. Enrichment analysis was employed to address the potential mechanisms of FOXM1 underlying HCC. Finally, single-cell RNA sequencing analysis was performed to confirm the transcriptional activity of FOXM1 on its predicted targets. RESULTS: This study, based on 4235 HCC tissue samples and 3461 non-HCC tissue samples, confirmed the upregulation of FOXM1 in HCC at mRNA and protein levels (standardized mean difference = 1.70 [1.42, 1.98]), making it the largest multi-centered study to do so. Among HCC patients, FOXM1 was increased in Asian and advanced subgroups, and high expression of FOXM1 had a strong ability to differentiate HCC tissue from non-HCC tissue (area under the curve = 0.94, sensitivity = 88.72%, specificity = 87.24%). FOXM1 was also shown to be an independent exposure risk factor for HCC, with a pooled hazard ratio of 2.00 [1.77, 2.26]. The predicted transcriptional targets of FOXM1 in HCC were predominantly enriched in nuclear division, chromosomal region, and catalytic activity acting on DNA. A gene cluster encoding nine transcriptional factors was predicted to be positively regulated by FOXM1, promoting the cell cycle signaling pathway in HCC. Finally, the transcriptional activity of FOXM1 and its targets was supported by single-cell analysis of HCC cells. CONCLUSIONS: This study not only confirmed the upregulation of FOXM1 in HCC but also identified it as an independent risk factor. Moreover, our findings enriched our understanding of the complex transcriptional mechanisms underlying HCC pathogenesis, with FOXM1 potentially promoting HCC progression by activating other transcription factors within the cell cycle pathway.

(4,5,8)-Connected Cationic Coordination Polymer Material as Explosive Chemosensor Based on the in Situ Generated AIE Tetrazolyl-Tetraphenylethylene Derivative.

A multidentate tetrazole molecule based on a TPE core, tetrakis[4-(1H-tetrazol-5-yl)phenyl]ethylene (H4ttpe) with combined advantages of two functional groups, was synthesized by cycloaddition reaction of the corresponding organic benzonitrile derivative and azide salt. Coordination self-assembly of the in situ formed aggregation-induced emission polytetrazole luminogen with cadmium(II) ion produces an unprecedented tetrazolyl-TPE-based microporous cationic metal-organic framework (MOF) with an unusual (4,5,8T14)-connected net of {[Cd4(H4ttpe)2Cl5]·(N3)3}, in which the H4ttpe serves as the first undeprotonated tetrazole ligand of octa-coordinating bridging mode. We investigate, for the first time, the utilization of the luminescent MOF containing a TPE core decorated with tetrazolyl terminals for explosive detection based on the change in fluorescence intensity, which shows high selectivity and efficiency in fluorescence quenching toward TNP detection in water solution.

Expression of Cell Division Cycle Protein 45 in Tissue Microarrays and the CDC45 Gene by Bioinformatics Analysis in Human Hepatocellular Carcinoma and Patient Outcomes.

BACKGROUND Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene (CDC45) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. MATERIAL AND METHODS In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. RESULTS CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45. NUDT1, E2F1, CCNE2, MCM5, and CENPM were identified as the most significantly co-expressed genes. CONCLUSIONS CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1, E2F1, CCNE2, MCM5, and CENPM.

Confinement Growth of Layered WS2 in Hollow Beaded Carbon Nanofibers with Synergistic Anchoring Effect to Reinforce Li+ /Na+ Storage Performance.

Novel nitrogen doped (N-doped) hollow beaded structural composite carbon nanofibers are successfully applied for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). Tungsten disulfide (WS2 ) nanosheets are confined, through synergistic anchoring, on the surface and inside of hollow beaded carbon nanofibers (HB CNFs) via a hydrothermal reaction method to construct the hierarchical structure HB WS2 @CNFs. Benefiting from this unique advantage, HB WS2 @CNFs exhibits remarkable lithium-storage performance in terms of high rate capability (≈351 mAh g-1 at 2 A g-1 ) and stable long-term cycle (≈446 mAh g-1 at 1 A g-1 after 100 cycles). Moreover, as an anode material for SIBs, HB WS2 @CNFs obtains excellent long cycle life and rate performance. During the charging/discharging process, the evolution of morphology and composition of the composite are analyzed by a set of ex situ methods. This synergistic anchoring effect between WS2 nanosheets and HB CNFs is capable of effectively restraining volume expansion from the metal ions intercalation/deintercalation process and improving the cycling stability and rate performance in LIBs and SIBs.

Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study.

Ankylosing spondylitis (AS) is an autoimmune disease characterized by fibroblasts ossification. However, effective drug therapy for AS is lacking. As an antidiabetic drug, metformin has demonstrated an antiosteogenic effect on osteoblasts in vitro. And it is also a kind of specific agonists for adenosine 5'-monophosphate activated protein kinase (AMPK), which is blocked in the process of AS. Given the role in antiosteogenesis and AMPK activating, metformin was investigated of its effect on fibroblasts harvested from capsular ligament of patients with femoral neck fracture and AS. Osteogenic specific makers (Alp, Bglap, Runx2, Bmp2, and Col1) in fibroblasts administered with metformin (20 µg/mL) were detected by ALP staining, alizarin red staining, qPCR, and Western blotting after 7 and 14 days of culture. Inflammation genes (il1-ß and il6) and pathway (Pi3k, Akt, and Ampk) associated markers were also evaluated. Our results showed that osteogenic specific markers were greatly downregulated and ossification was effectively inhibited in AS fibroblasts after addition of metformin. Levels of inflammation markers were also decreased by metformin. Thus, metformin exerts potent effect on suppression of ossification and inflammation in AS fibroblasts via the activation of Pi3k/Akt and AMPK pathways, which may be developed as a potential agent for treatment of AS.

Collagen, agarose, alginate, and Matrigel hydrogels as cell substrates for culture of chondrocytes in vitro: A comparative study.

Autologous chondrocyte implantation (ACI) has emerged as a new approach to cartilage repair through the use of harvested chondrocytes. But the expansion of the chondrocytes from the donor tissue in vitro is restricted by limited cell numbers and dedifferentiation of chondrocytes. In this study, we used four types of hydrogels including agarose, alginate, Matrigel, and collagen type I hydrogels to serve as cell substrates and investigated the effect on proliferation and phenotype maintenance of chondrocytes. As a substrate for monolayer culture, collagen facilitated cell expansion and effectively suppressed the dedifferentiation of chondrocytes, as evidenced by fluorescein diacetate/propidium iodide (FDA/PI), hematoxylin-eosin staining (HE), Safranin O, immunofluorescenceassay, biochemistry analysis, and quantitative real-time polymerase chain reaction (qRT-PCR). Compared with that in agarose gels, alginate, and Matrigel, collagen accelerated cell proliferation and enhanced the expression of cartilage specific genes such as ACAN, SOX9, and COLII more markedly. Furthermore, significantly lower expression of COL I (an indicator of dedifferentiation) and COL X (the chondrocyte hypertrophy marker) was present in collagen group than in other groups. This indicated that collagen substrate can better support chondrocyte growth and maintain cell phenotype, due to that it might serve as a cartilage-like ECM to provide adhesive site for chondrocytes. In summary, collagen hydrogel is a promising cell substrate for chondrocytes culture for ACI.

A Novel Synthesized Sulfonamido-Based Gallate-JEZTC Blocks Cartilage Degradation on Rabbit Model of Osteoarthritis: An in Vitro and in Vivo Study.

BACKGROUND/AIMS: 3, 4, 5-trihydroxy-N-{4-[(5-methylisoxazol-3-yl) sulfamoyl] phenyl} benzamide (JEZTC), synthesized from gallic acid (GA) and sulfamethoxazole (SMZ), was reported with chondroprotective effects. However, the effects of JEZTC on osteoarthritis (OA) are still unclear. The goal of this study was to investigate the anti-osteoarthritic properties of JEZTC on interleukin-1-beta (IL-1ß) stimulated chondrocytes in vitro and a rabbit anterior cruciate ligament transaction (ACLT) OA model in vivo. METHODS: Changes in matrix metalloproteinases (MMPs) and apoptosis genes (bax, caspase 3 and tnf-α) and OA-specific protein (MMP-1) expression in vitro and in vivo were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The production of reactive oxygen species (ROS) were investigated upon the treatment of JEZTC in chondrocytes processed with IL-1ß in vitro and OA in vivo. Effect of JEZTC on OA was further studied by the macroscopic and histological evaluation and scores. The key proteins in signaling pathways inMAPK/P38, PI3KAkt and NF-κB also determined using western blot (WB) analysis. RESULTS: JEZTC could significantly suppress the expression of MMPs and intracellular ROS, while meaningfully increase the gene expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Moreover, there was less cartilage degradation in JEZTC group compared with the phosphate-buffered saline (PBS) group in vivo. Results also indicated that JEZTC exerts effect on OA by regulating MAPKs and PI3K/Akt signaling pathways to activate NF-κB pathway, leading to the down-regulation of MMPs. The chondro-protective effect of JEZTC may be related with its ability to inhibit chondrocyte apoptosis by reduction of ROS production. CONCLUSION: JEZTC may be a possible therapeutic agent in the treatment of OA.

Expression Signature and Role of miR-30d-5p in Non-Small Cell Lung Cancer: a Comprehensive Study Based on in Silico Analysis of Public Databases and in Vitro Experiments.

BACKGROUND/AIMS: The purpose of this study was to probe the clinico-pathological significance and the underlying mechanism of miR-30d-5p expression in non-small cell lung cancer (NSCLC). METHODS: We initially examined the level of miR-30d-5p expression in NSCLC and non-cancer tissues using RT-qPCR. Then, a series of validation analyses including a meta-analysis of data from microarray chips in Gene Expression Omnibus (GEO), data mining of the cancer genome atlas (TCGA) and an integrated meta-analysis incorporating GEO microarray chips, TCGA data, in-house RT-qPCR and literature studies were performed to examine the clinico-pathological value of miR-30d-5p expression in NSCLC. In vitro experiments were further conducted to investigate the impact of miR-30d-5p on NSCLC cell growth. The molecular mechanism by which miR-30d-5p regulates the pathogenesis of NSCLC was probed through a bioinformatics analysis of its target genes. Moreover, dual luciferase reporter assay was conducted to verify the targeting regulatory relationship between miR-30d-5p and CCNE2. RESULTS: Based on results from RT-qPCR, GEO meta-analysis, TCGA data mining and the integrated meta-analysis incorporating GEO microarray chips, TCGA data, in-house RT-qPCR and literature studies, miR-30d-5p expression was decreased in NSCLC tissues, and patients with NSCLC who presented with lower miR-30d-5p expression tended to display an advanced clinical progression. Significant pathways including the Mucin type O-glycan biosynthesis pathway, cell cycle pathway and cysteine and methionine metabolism pathway (all P< 0.05) revealed potential roles of the target genes of miR-30d-5p in the oncogenesis of NSCLC. Results from in vitro experiments indicated that miR-30d-5p could attenuate proliferation and viability of NSCLC cells. Among the 12 identified hub genes, nine genes including E2F3, CCNE2, SKP2, CDK6, TFDP1, LDHA, GOT2, DNMT3B and ST6GALNAC1 were validated by Pearson's correlation test and the human protein atlas (HPA) database as targets of miR-30d-5p with higher probability. Specifically, dual luciferase reporter assay confirmed that CCNE2 was directly targeted by miR-30d-5p. CONCLUSION: In summary, miR-30d-5p expression is decreased in NSCLC, and it might play the role as tumor suppressor in NSCLC by regulating target genes.

A Human Chondrocyte-Derived In Vitro Model of Alcohol-Induced and Steroid-Induced Femoral Head Necrosis.

BACKGROUND Worldwide, femoral head necrosis (FHN), which is also known as avascular necrosis of the femoral head or osteonecrosis of the femoral head, affects millions of people. Excess alcohol intake and steroid use are two common associations with FHN, but their pathogenesis remains unknown. The aim of this study was to develop an in vitro model using human chondrocytes to study alcohol-induced and steroid-induced FHN. MATERIAL AND METHODS In this study, the in vitro model used a monolayer culture of articular chondrocytes derived from patients with non-traumatic FHN (Ficat and Arlet, Stage III). Normal chondrocytes were obtained from patients with femoral neck fracture resulting from road traffic accident (Garden, Stage IV). Alcohol-stimulated and steroid-stimulated articular chondrocytes were evaluated by a cell proliferation assay, measurement of calcium levels (alizarin red), measurement of alkaline phosphatase (ALP) levels, detection of glycosaminoglycan (GAG) secretion using safranin O histochemical staining, and analysis of cartilage-specific genes, ACAN, SOX9, OPG, TGF-ß, RANKL, and RUNX2, using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS Both alcohol and steroids, but especially steroids, accelerated the degradation of cartilage by suppression of chondrogenesis while promoting chondrocyte hypertrophy and activating osteogenic differentiation, as assessed by cell proliferation assay, detection of glycosaminoglycan (GAG) secretion, and analysis of cartilage-specific genes. CONCLUSIONS A human chondrocyte-derived in vitro model of alcohol-induced and steroid-induced FHN demonstrated chondrocyte hypertrophy and activated osteogenic differentiation.

Agkihpin, a Distinct SVTLE from the Venom of Gloydius halys Pallas: Purification, Characterization and Structure-Activity Determination.

Blood clots produced by snake-venom thrombin-like enzymes (SVTLEs) are cleared rapidly, which makes SVTLEs attractive as potential candidates for antithrombotic therapy. We isolated a SVTLE, agkihpin, from the venom of Gloydius halys Pallas. Agkihpin was confirmed to a single-chain TLE with molecular mass of 25.5 kD, pI of 7.43, optimal pH of 8.0 (hydrolyzing TAME), linked carbohydrate absent, and weak fibrinogen clotting activity. It was also found that (i) G. halys might be the latest species in SVTLEs phylogenetic tree; (ii) different level of conservation was shown among the SVTLEs from the Viperidae snakes. Some of those site may account for different activities exhibited by those SVTLEs, especially position 181, at which a fibrinogenolytic activity increase was found when a basic and larger amino acid substituted by a neutral and smaller one; (iii) an extra α-helix constructed with a 'Pro + acidic amino acid + aromatic amino acid' pattern was found in the SVTLEs from Gloydius and Agkistrodon snakes, although it does not necessarily imply an effect on the fibrinogenolytic activity of the SVTLEs. This study provided some new insight into the activity of SVTLE.

Expression, purification and characterization of a novel recombinant SVTLE, r-agkihpin-2, from Gloydius halys Pallas venom gland in Escherichia coli.

In our previous work, a thrombin-like enzyme (TLE), agkihpin, was successfully isolated, purified, cloned and named from the venom of Gloydius halys Pallas, having fibrinolytic, fibrinogenolytic and thrombosis-reduced activities, attenuating migration of liver cancer cell, and without bleeding risk. To explore the possibility of agkihpin as a thrombolytic and/or anti-metastasis agent in the future, in this study recombinant agkihpin was expressed and purified in Escherichia coli, and its biological activities investigated. Thus, r-agkihpin-2 was successfully expressed and purified and confirmed by Western blot and peptide mass fingerprinting. After purification and renaturation, 46 mg (399 U) of active r-agkihpin-2 was obtained from 1 L bacterial culture. The results of the arginine esterase activity assay, fibrin plate test fibrinogenolytic activity assay, thrombin-induced venous thrombosis assay, Scratch-Wound assay and bleeding assay showed that active r-agkihpin-2 had slightly lower TAME hydrolytic, fibrinolytic, fibrinogenolytic, thrombus-reduced and migration-attenuated activities than those of native agkihpin, and had no bleeding risk. These findings confirmed that, active r-agkihpin-2 could be further investigated for thrombolytic and/or anti-metastasis drug discovery in the future.

Potential unfavorable impacts of BDNF Val66Met polymorphisms on metabolic risks in average population in a longevous area.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive performance and the modulation of several metabolic parameters in some disease models, but its potential roles in successful aging remain unclear. We herein sought to define the putative correlation between BDNF Val66Met and several metabolic risk factors including BMI, blood pressure, fasting plasma glucose (FPG) and lipid levels in a long-lived population inhabiting Hongshui River Basin in Guangxi. METHODS: BDNF Val66Met was typed by ARMS-PCR for 487 Zhuang long-lived individuals (age ≥ 90, long-lived group, LG), 593 of their offspring (age 60-77, offspring group, OG) and 582 ethnic-matched healthy controls (aged 60-75, control group, CG) from Hongshui River Basin. The correlations of genotypes with metabolic risks were then determined. RESULTS: As a result, no statistical difference was observed on the distribution of allelic and genotypic frequencies of BDNF Val66Met among the three groups (all P > 0.05) except that AA genotype was dramatically higher in females than in males of CG. The HDL-C level of A allele (GA/AA genotype) carriers was profoundly lower than was non-A (GG genotype) carriers in the total population and the CG (P = 0.009 and 0.006, respectively), which maintained in females, hyperglycemic and normolipidemic subgroup of CG after stratification by gender, BMI, glucose and lipid status. Furthermore, allele A carriers, with a higher systolic blood pressure, exhibited 1.63 folds higher risk than non-A carriers to be overweight in CG (OR = 1.63, 95% CI: 1.05 - 2.55, P = 0.012). Multiple regression analysis displayed that the TC level of LG reversely associated with BDNF Val66Met genotype. CONCLUSIONS: These data suggested that BDNF 66Met may play unfavorable roles in blood pressure and lipid profiles in the general population in Hongshui River area which might in part underscore their poorer survivorship versus the successful aging individuals and their offspring.

[Genetic analysis of a pedigree affected with inherited thrombocytopenia caused by a novel mutation of MYH9 gene].

OBJECTIVE: To study genetic mutations and clinical features of a pedigree affected with MYH9-related disorders from Guangxi. METHODS: Blood platelets were counted with a hemocytometer. Blood smear was carried out to detect the inclusion body in peripheral blood neutrophils. DNA and mRNA samples were extracted from blood samples from the members of the pedigree. Fragments of the MYH9 gene were amplified with PCR and directly sequenced. RESULTS: The affected individuals presented with a triad of giant platelets, decreased platelet count and inclusion bodies in the neutrophils with variable expressivity. A heterozygous deletional mutation (c.5803delG) in exon 41 of the MYH9 gene was found in all of the 8 affected individuals, which led to a frame-shift and change of 26 amino acids at the C-end of the tail domain of nonmuscle myosin heavy chain IIA (NMMHC-IIA) (p.Ala1935Profs*12). The same mutation was not found among healthy members of the pedigree. CONCLUSION: The c.5803delG mutation probably underlies the MYH9-related disorders in this pedigree. The mutation has altered the C-end of the tail domain of the NMMHC-IIA protein, resulting in mild clinical symptoms in the affected individuals.

Agkihpin, a novel SVAE may inhibit the migration and invasion of liver cancer cells associated with the inversion of EMT induced by Wnt/ß-catenin signaling inhibition.

In our previous work, agkihpin, a snake venom arginine esterase (SVAE), was isolated from the Gloydius halys Pallas, which could attenuate the migration of liver cancer cells. However, the mechanism of the effect of agkihpin on attenuating migration of liver cancer cell is unknown yet. Here, to learn more about agkihpin and explore the possibility of agkihpin as an anti-metastatic drug in the future, a series of experiments about the migration and invasion of liver cancer cells with agkihpin, HepG 2 and SMMC-7721, was conducted. Epithelial-mesenchymal transition (EMT) is an initial step and a major phenotype of cancer metastasis and invasion, while a number of EMT opposite phenomenons were observed, for example, epithelial marker E-cadherin was up-regulated, mesenchymal markers N-cadherin and Vimentin, and transcription regulators Snail and twist were down-regulated after treating with agkihpin in liver cancer cells; canonical Wnt/ß-catenin pathway, one of the signals initiated EMT, was inhibited by decreased expressions of FZD7 and ß-catenin, phosphorylation of GSK3ß (Ser9), and nuclear ß-catenin accumulation in agkihpin treated cancer cells. By using bioinformatics analysis and protease activity analysis in vitro we also found that agkihpin might bind and degrade FZD7. As a result, we hypothesized that agkihpin could inhibit the Wnt/ß-catenin signaling pathway by cleaving FZD7, leading to the inactivation of the TCF/LEF transcription factor, which contributed to the inversion of EMT, and finally attenuated the migration and invasion of liver cancer cells. Therefore, our findings provided novel mechanistic insights into the role of SVAEs in liver cancer controlling, and raised the possibility that agkihpin may be used therapeutically in liver cancer.

The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma.

Human leukocyte antigen (HLA)-DRB1 has been reported to influence individual's susceptibility to nasopharyngeal carcinoma (NPC) by many studies in recent years; however, these studies provided controversial results. The meta-analysis was thus conducted here to estimate the relationship between HLA-DRB1 polymorphisms and NPC. After an extensive review of journals from various databases (PubMed, the Web of Science, Embase, China National Knowledge Internet (CNKI), and Wanfang Database), 8 out of 69 case-control studies, including 778 cases and 1148 controls, were extracted. The results showed that 4 of 13 polymorphisms allele are statistically significantly associated with NPC, among them, HLA-DRB1*3, HLA-DRB1*9, and HLA-DRB1*10 may increase the risk of NPC while HLA-DRB1*01 has the opposite effect. The pooled odds ratio and 95 % confidence interval (CI) were 1.702 [95 % CI (1.047, 2.765)], 1.363 [95 % CI (1.029, 1.806)], 1.989 [95 % CI (1.042, 3.799)], and 0.461 [95 % CI (0.315, 0.676)], respectively. In a further ethnicity-based subgroup analysis, HLA-DRB1*08, HLA-DRB1*11, and HLA-DRB1*16 were found to be linked with NPC in Asian, Tunisian, and Caucasian, respectively. In Asian, HLA-DRB1*03, 08, and 10 may elevate the risk whereas HLA-DRB1*09 could lower it. In Tunisian, HLA-DRB1*01 and 11 are the protective factors while HLA-DRB1*03 is the only risk factor. In Caucasian, HLA-DRB1*01 and 03 increase the risk and HLA-DRB1*16 lowers it. The most frequent statistically associated gene is found to be HLA-DRB1*03 which has protective influence on Asian and Tunisian. In conclusion, HLA-DRB1*01, DRB1*03, DRB1*09, and DRB1*10 are related with NPC susceptibility, and the association of HLA-DRB1*08, DRB1*11, and DRB1*16 with NPC risk are significantly different in different ethnicities.

Andrographolide Exerts Pro-Osteogenic Effect by Activation of Wnt/ß-Catenin Signaling Pathway in Vitro.

BACKGROUND/AIMS: Osteoporosis is a metabolic bone disorders that tortures about millions of people worldwide. Recent studies showed that Andrographolide (AP) is a promising natural compound for the treatment of osteoclast-related bone diseases. However, its potential in treatment of osteoporosis has not been fully explored. METHODS: In this study, the effect of AP on osteoblasts metabolism was investigated via the detection of cell proliferation, cell viability, ALP activity, the expression of osteogenic specific genes including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), osteocalcin (OCN), Bone morphogenic protein-2 (BMP2) and Alkaline phosphatase(ALP) for 3, 5 and 7 days respectively. Further exploration of the association of AP with WNT/ß-catenin signaling pathway was performed by examination of the expression of WNT related genes and proteins. RESULTS: Results showed that AP of 4.46 and 8.92 µM, especially 8.92 µM was beneficial to osteogenic differentiation by upregulating ALP activity and expression of osteogenic related genes (P<0.05). Pathway analyses identify canonical WNT/ß-catenin pathway as an important mediator in AP-induced osteogenesis. CONCLUSION: This study indicates that AP exerts its pro-osteogenic potential via activation of the WNT/ß-catenin in osteoblasts and thus may represent a candidate of therapeutic agent for osteoporosis.

PPARD +294C overrepresentation in general and long-lived population in China Bama longevity area and unique relationships between PPARD +294T/C polymorphism and serum lipid profiles.

BACKGROUND: The +294T/C polymorphism in the peroxisome proliferator-activated receptor delta (PPARD) gene is associated with hyperlipidemia in several younger populations, but results are still inconsistence across ethnic groups and its possible impact on the lipid profiles of long-lived individuals remains unexploited. Here, we aimed to evaluate the possible correlation between PPARD +294T/C and serum lipid levels in a long-lived population in Bama, a region known for longevity situated in Guangxi, China. METHODS: Genotyping of PPARD +294T/C polymorphism was conducted in 505 long-lived inhabitants (aged 90 and above, long-lived group, LG) and 468 healthy controls (aged 60-75, non-long-lived group, non-LG) recruited from Bama area. RESULTS: No difference in allelic and genotypic frequencies was found between the two groups (P>0.05). However, C-allele and C-genotype (TC and CC) were significantly more frequent in the females of non-LG than were LG after sex stratification. CC carriers exhibited higher LDL-C level in LG (P<0.05) but lower TC, TG and LDL-C in non-LG (P<0.05 for each) than TT carriers; C allele carriers (TC/CC) in LG exhibited higher TC, TG, and LDL-C levels as compared with the same genotype and the same lipid parameter in non-LG (P<0.05 for each). LDL-C in LG was correlated with genotypes while TC, TG, and LDL-C in non-LG were correlated with genotypes (P<0.05-0.001). CONCLUSION: Our results suggest that there were different impact patterns of PPARD +294T/C polymorphism on lipid profiles between long-lived cohort and average population in Bama area and this may be one of the genetic bases of its longevity.

Chondroprotective effects of taurine in primary cultures of human articular chondrocytes.

Articular cartilage is characterized by the lack of blood vessels and has a poor self-healing potential. Limited cell numbers and dedifferentiation of chondrocytes when expanded in vitro are the major obstacles of autologous chondrocyte implantation. Autologous chondrocyte implantation is a cell-based treatment that can be used as a second-line measure to regenerate chondral or osteochondral defects in younger, active patients. There is an urgent need to find an effective chondrogenic protection agent alleviating or inhibiting chondrocyte dedifferentiation. In this study, we explored the effect of taurine (2-aminoethane sulfonic acid) on proliferation and phenotype maintenance of human articular chondrocytes by analyzing the cell proliferation, morphology, viability, and expression of cartilage specific mRNAs and proteins. Primary chondrocytes were isolated from human articular cartilage tissues. Results showed that taurine effectively promoted chondrocyte growth and enhanced accumulation of glycosaminoglycans and collagens in the conditioned media of chondrocytes. Moreover, taurine exposure caused significant increases in the relative expression levels of mRNAs for cartilage specific markers, including aggrecan, collagen type II and SOX9. Aggrecan is a cartilage-specific proteoglycan, and SOX9 is a chondrogenic transcription factor. In contrast, the mRNA expression of collagen type I, a marker for chondrocyte dedifferentiation, was significantly decreased in cells treated with taurine, indicating that taurine inhibits the chondrocyte dedifferentiation. This study reveals that taurine is effective in proliferation promotion and phenotype maintenance of chondrocytes. Thus, taurine may be a useful pro-chondrogenic agent for autologous chondrocyte implantation in the treatment of cartilage repair.

Population dynamics of an Acinetobacter baumannii clonal complex during colonization of patients.

Acinetobacter baumannii has emerged as one of the leading pathogens causing hospital-acquired infection. The success of A. baumannii as a pathogen has to a large extent been attributed to its capacity to remodel its genome. Several major epidemic clonal complexes of A. baumannii spread across different health care facilities around the world, each of which contains a subset of diversified strains. However, little is known about the population dynamics during colonization of A. baumannii within hosts. Here, whole-genome sequencing was used to analyze population dynamics of A. baumannii strains isolated from a group of patients at different time points as well as from different sites of a particular patient. Seven out of nine of the sampled A. baumannii strains belonged to the international clone II (CC92 clonal complex). While the A. baumannii strains were found to be stable in three patients, there was a change of A. baumannii strains in one patient. Comparative genomic analysis revealed that the accessory genome of these strains contained a large set of virulence-encoding genes and these virulence factors might play a role in determining population dynamics. Microscale genome modification has been revealed by analysis of single nucleotide polymorphisms (SNPs) between A. baumannii strains isolated from the same patient. Parallel evolutionary traits have been observed during genome diversification when A. baumannii colonize in different patients. Our study suggested that both antibiotic usage and host environment might impose selective forces that drive the rapid adaptive evolution in colonizing A. baumannii.