LncRNA HOXA11-AS promotes migration and invasion through modulating miR-148a/WNT1/ß-catenin pathway in gastric cancer.

Increasing researches have focused on the biological functions of long noncoding RNAs (lncRNAs) in human cancers. HOXA11-AS, a widely known lncRNA, has been confirmed to be involved in the progression of several cancers, including gastric cancer (GC). Whereas, the detailed mechanism of this lncRNA in GC remains to be further illuminated. The abundances of HOXA11-AS, miR-148a and WNT1 in GC tissues and cell lines were examined by qRT-PCR. Clinicopathological and Kaplan-Meier survival analyses were determined to explore the relationship between HOXA11-AS expression and outcomes of patients. Transwell assay was performed for the evaluation of cell migration and invasion. Bioinformatics, dual-luciferase reporter and RNA immunoprecipitation assays were employed to analyze the correlation between HOXA11-AS and miR-148a or miR-148a and WNT1. The protein levels of WNT1 and ß-catenin were assessed by western blot assay. Results showed that HOXA11-AS and WNT1 expression levels were upregulated, while miR-148a level was downregulated in GC tissues and cell lines relative to matched controls. Elevated expression of HOXA11-AS was associated with increased tumor size, lymph node metastasis, advanced TNM stage, as well as reduced survival of GC patients. HOXA11-AS induced migration and invasion of GC cells through serving as a molecular sponge for miR-148a. Furthermore, miR-148a inactivated WNT1/ß-catenin signaling pathway via directly targeting WNT1. HOXA11-AS increased WNT1/ß-catenin pathway activity, which was abolished by miR-148a overexpression in GC cells. In conclusion, overexpression of HOXA11-AS contributed to migration and invasion of GC cells via activation of WNT1/ß-catenin signaling pathway through repressing miR-148a, providing a prospective therapeutic target for GC.

[Changes and clinical significance of serum proteinase 3 in latent autoimmune diabetes in adults].

Objective: To investigate the changes of circulating proteinase 3 (PR3) in latent autoimmune diabetes mellitus in adults (LADA) patients, type 2 diabetes mellitus (T2DM) patients, obese patients without diabetes and healthy controls, and explore the value of serum PR3 in differentiating LADA and T2DM. Methods: Forty LADA patients, 29 T2DM patients, 26 obesity patients without diabetes, and 76 healthy controls were enrolled in Department of Metabolism & Endocrinology, the Second Xiangya Hospital, Central South University. Serum PR3 was detected by enzyme-linked immunosorbent assay (ELISA). The differences of serum PR3 among the four groups were compared. The correlation between serum PR3 and other metabolic indexes was analyzed. The value of serum PR3 in the differential diagnosis between LADA and T2DM was evaluated. Results: There was no significant difference in age among LADA patients, T2DM patients, obesity patients without diabetes and healthy controls [(50±13) years, (49±6) years, (49±6) years vs (47±7) years, P=0.254], while there was significant difference in gender among the four groups (χ(2)=18.28, P<0.001). Serum PR3 was significantly increased in LADA patients compared to the other three groups [195.4 (127.6, 288.1) µg/L vs 43.4 (30.9, 53.7) µg/L, 36.0 (29.2, 46.4) µg/L, 41.2 (30.2, 52.8) µg/L, all P<0.01], whereas there was no significant differences among the other three groups. After adjustment for age, gender and body mass index (BMI), serum PR3 remained higher in LADA patients compared to the other three groups. Correlation analysis indicated that PR3 correlated positively with fasting and 2-hour postprandial blood glucose (r=0.346, r=0.357, both P<0.001). Receiver operating characteristic (ROC) curve showed that the cut-off value of PR3 (71.7 µg/L) for differentiating LADA and T2DM had a sensitivity of 97.5% and specificity of 89.7% and rendered an area under the curve of 0.955 (95%CI: 0.894~1.000, compared to 0.5, P<0.01). Conclusion: Serum PR3 significantly elevated in LADA patients, and may serve as a biomarker for differentiating LADA and T2DM patients.

[Serotype distribution and drug resistance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated from nasopharynx of Uygur children].

Objective: To investigate the serotype distribution and antimicrobial susceptibility pattern of Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. catarrhalis) isolates collected from nasopharyngeal swabs from Uygur children in Kashi. Methods: Nasopharyngeal swabs were collected from inpatient Uygur children aged from 1 month to 5 years with respiratory infections from the pediatric department, the First People's Hospital of Kashi, Xinjiang Uygur Autonomous Region. Antimicrobial susceptibilities of the isolates were determined with E-test and KB disk diffusion methods. The production of ß-lactamase was detected for H. influenzae and M. catarrhalisisolates using nitrocefin disc method. Quellung test and latex agglutination test were adopted to identify serotypes of S. pneumoniae and H. influenzae isolates. Results: Forty-seven S. pneumoniae, 13 H. influenzae and 16 M. catarrhalis isolates were detected. All of the 47 S. pneumoniae isolates were sensitive to parenteral penicillin, amoxicillin-clavulanic acid, vancomycin and levofloxacin; the susceptibility rates to cefotaxime, imipenem and chloramphenicol were 94% (44/47), 89% (42/47), and 98% (46/47). The resistance rate to erythromycin was 74% (35/47). The most common serotype of S. pneumoniae was serotype 19A (10 strains, 21%). The coverage rate of 13-valent conjugate vaccine (PCV13) was 70% (33/47). None of the 13 H. influenzae isolates could be typed. They were highly susceptible to tested ß-lactams antibiotics, except ampicillin. Only one H. influenzae isolate could produce ß-lactamase, and two isolates were identified as ß-lactamase-negative-ampicillin-resistant ones. The sixteen M. catarrhalis isolates were all positive in ß-lactamase detection, but sensitive to amoxicillin-clavulanic acid, cephalosporins and meropenem. Conclusions: In Kashi, Xinjiang Uygur Autonmous Region, S. pneumoniae isolates from Uygur children were highly sensitive to parenteral penicillin and other ß-lactams antibiotics. H. influenzae isolates from Uygur children were highly susceptible to amoxicillin-clavulanic acid, cephalosporins and ciprofloxacin. All M. catarrhalis isolates from Uygur children could produce ß-lactamase, but were sensitive to the enzyme inhibitors and cephalosporins.

Prognostic significance of long non-coding RNA MALAT-1 in various human carcinomas: a meta-analysis.

The long non-coding RNA MALAT-1 plays an important role in cancer prognosis. The present research aimed to elucidate its precise predictive value in various human carcinomas. A quantitative meta-analysis was performed by searching PubMed, Embase, Web of Science, and Cochrane Library (most recently, January 2015) databases, and extracting data from studies that investigated the association between MALAT-1 expression and survival outcomes in patients of various cancers. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated as a measure of generalized effect. This meta-analysis included 1317 cases from 12 datasets. Our investigation revealed that poor overall survival (OS; HR = 2.14, 95% CI = 1.74-2.64) and shortened disease-free, recurrence-free, disease-specific, or progression-free survival (HR = 2.13, 95% CI = 1.22-3.72) can be predicted by high MALAT-1 expression for various cancers. Moreover, elevated MALAT-1 levels significantly correlated with decreased OS in a renal cell carcinoma (RCC) subgroup (HR = 3.43, 95% CI = 1.80-6.53). These results imply that MALAT-1 can be used to predict unfavorable prognoses for several cancers, particularly RCC.

Lycium barbarum polysaccharides protect rat liver from non-alcoholic steatohepatitis-induced injury.

BACKGROUND: Lycium barbarum polysaccharides (LBPs) are antioxidant and neuroprotective derivative from Wolfberry. However, whether LBP has a protective effect in non-alcoholic steatohepatitis (NASH)-induced hepatic injury is still unknown. OBJECTIVE: We aimed to study the possible hepatoprotective effects and mechanisms of LBP on a diet-induced NASH rat model. METHODS AND DESIGN: In this study, female rats were fed a high-fat diet to induce NASH with or without an oral 1 mg kg(-1) LBP feeding daily for 8 weeks. After 8 weeks, blood serum and liver samples from each rat were subjected to histological analysis, biochemical and molecular measurements. RESULTS: Compared with control rats, NASH rats showed typical NASH features including an increase in liver injury, lipid content, fibrosis, oxidative stress, inflammation and apoptosis. In contrast, NASH+LBP-co-treated rats showed (1) improved histology and free fatty acid levels; (2) re-balance of lipid metabolism; (3) reduction in profibrogenic factors through the TGF-ß/SMAD pathway; (4) improved oxidative stress through cytochrome P450 2E1-dependent pathway; (5) reduction in hepatic pro-inflammatory mediators and chemokines production; and (6) amelioration of hepatic apoptosis through the p53-dependent intrinsic and extrinsic pathways. The preventive effects of LBP were partly modulated through the PI3K/Akt/FoxO1, LKB1/AMPK, JNK/c-Jun and MEK/ERK pathways and the downregulation of transcription factors in the liver, such as nuclear factor-κB and activator protein-1. CONCLUSION: LBP is a novel hepatoprotective agent against NASH caused by abnormal liver metabolic functions.

Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats.

Previous studies have shown that a 2-week treatment with 40 mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running-elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5 days) and chronic (4 weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non-runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a significant alteration in hippocampal levels, suggesting that treatment with running/CORT for 4 weeks may induce a change in central levels of hippocampal BDNF level, which may not lead to a significant change in peripheral levels.

The clinicopathological significance of BUBR1 overexpression in hepatocellular carcinoma.

BACKGROUND AND AIMS: BUBR1 is a key component of the mitotic spindle checkpoint, and its roles in human cancers are controversial and unclear. The aim of this study was to investigate the clinicopathological significance of BUBR1 expression in hepatocellular carcinoma (HCC). METHODS: The BUBR1 protein and its mRNA levels were measured in 58 HCCs, nine high-grade dysplastic nodules and their paired non-tumorous liver tissues by quantitative real-time polymerase chain reaction (qPCR) and western blot, respectively. In addition, immunochemical analysis of the BUBR1 protein was performed in 458 HCCs and 46 dysplastic nodules, and the clinicopathological significance of the BUBR1 expression was evaluated. RESULTS: The BUBR1 expression at both mRNA and protein levels was elevated in two of nine high-grade dysplastic nodules and in 37 of 58 (64%) HCCs. BUBR1 was overexpressed in 207 of 458 (45%) HCCs by immunohistochemistry. Intriguingly, high expression of the BUBR1 was correlated with larger tumour size, higher histological grade, advanced pathological stage, and poor overall and recurrence-free survival. There was a higher frequency of BUBR1 overexpression in cases with positive serum HBsAg than those with negative HBsAg. Moreover, BUBR1 overexpression was associated with P53 staining and high Ki67 labelling indices in HCC tissues. CONCLUSIONS: BUBR1 was overexpressed in about 45% HCCs, and its overexpression may be a relative lately event in HCC progression. Overexpression of BUBR1 was associated with worse prognosis and is a potential prognostic factor for patients with HCC.

Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake.

AIMS/HYPOTHESIS: Carnitine palmitoyltransferase-1 (CPT1)c is a novel isoform in the CPT1 family and is found specifically in the brain. Cpt1c knockout (KO) mice are more susceptible to high-fat diet (HFD)-induced obesity. However, the underlying mechanism of this phenotype and the question of whether CPT1c is involved in the pathogenesis of diet-induced insulin resistance are unclear. METHODS: To assess the potential role of CPT1c in the regulation of whole-body glucose homeostasis, we generated Cpt1c KO mice and challenged them with HFD or standard chow. Glucose homeostasis of each group was assessed weekly. RESULTS: After 8 weeks of HFD feeding, Cpt1c KO mice developed a phenotype of more severe insulin resistance than that in wild-type controls. The increased susceptibility of Cpt1c KO mice to HFD-induced insulin resistance was independent of obesity. Impaired glucose tolerance in Cpt1c KO mice was attributable to elevated hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. These effects correlated with decreased hepatic and intramuscular fatty acid oxidation and expression of oxidative genes as well as with elevated triacylglycerol content in these tissues. Interestingly, Cpt1c deletion caused a specific elevation of hypothalamic CPT1a and CPT1b isoform expression and activity. We demonstrated that elevated plasma NEFA concentration is one mechanism via which this compensatory effect is induced. CONCLUSIONS/INTERPRETATION: These results further establish the role of CPT1c in controlling whole-body glucose homeostasis and in the regulation of hypothalamic Cpt1 isoform expression. We identify changes in hepatic and skeletal muscle glucose metabolism as important mechanisms determining the phenotype of Cpt1c KO mice.

Primary and recurrent embryonal sarcoma of the liver: clinicopathological and immunohistochemical analysis.

AIMS: To evaluate primary and recurrent embryonal sarcoma of the liver and to improve recognition of its morphological variants and immunohistochemical features. METHODS AND RESULTS: Fourteen primary and two recurrent cases of hepatic embryonal sarcoma were evaluated histologically and investigated immunohistochemically with a panel of antibodies using the EnVision+ system. They were usually single, large, globular masses with solid and cystic gelatinous areas. Microscopic features included spindle, oval, stellate, epithelioid or multinucleated cells loosely or densely arranged in a myxomatous matrix. Entrapped bile ducts and hepatic cords were often present at the periphery of the tumours. Intracellular and extracellular periodic acid-Schiff-positive, diastase-resistant hyaline globules were commonly present. Recurrent tumours showed greater cellularity, anaplasia and pluripotential differentiation compared with the primary tumour. Immunohistochemistry showed evidence of widely divergent differentiation into mesenchymal and epithelial phenotypes. CONCLUSIONS: Embryonal sarcoma of the liver may undergo pluripotential differentiation and diagnosis should be based mainly on morphological features. Immunohistochemistry has no specific or diagnostic relevance, but, by using a panel of antibodies, may help to exclude other tumours.

Nitrosation of tryptophan residue(s) in serum albumin and model dipeptides. Biochemical characterization and bioactivity.

Nitrosation of bovine serum albumin with acidified NaNO2 was compared to that of carboxymethyl-bovine serum albumin in which the thiol group is covalently blocked. Differential ultraviolet-visible (UV-Vis) spectroscopy and a modified Saville assay indicated that a non-cysteine residue(s) in carboxymethyl-bovine serum albumin was nitrosated. The nitrosated carboxymethyl-bovine serum albumin exhibited similar vasorelaxation activity as that observed with nitrosated bovine serum albumin. Identification of the nitrosated non-cysteine residue(s) was studied using 16 model dipeptides, each of which contained a glycyl residue and a variable residue. Using photolysis-chemiluminescence analysis, modified Saville assay, differential UV-Vis spectroscopy, and bioassays, L-glycyl-L-tryptophan (Gly-Trp) was found to be the only dipeptide that underwent significant nitrosation under these conditions. Liquid chromatography-UV-Vis spectroscopy-mass spectrometry showed that the NO group was attached to the indole nitrogen of tryptophan. Nitrosated Gly-Trp exhibited dose-dependent vasorelaxation and platelet inhibiting activity with apparent EC50 values of 1.1 +/- 0. 3 and 3.5 +/- 0.9 microM, respectively. Because N-nitroso-Gly-Trp does not release NO radical via spontaneous homolytic N-NO bond fission nor freely diffuse through cellular membranes, the ability of this compound to induce NO.-like biological effects suggests the existence of a (membrane-associated) transnitrosation system that facilitates delivery of -NO to its specific biologic target(s).