Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis.

To explore the serum levels of IL-39, CXCL14, and IL-19 in patients with tuberculosis (TB) along with their clinical significances and their concentration changes in macrophages after Bacille Calmette-Guérin vaccine (BCG) or Mycobacterium tuberculosis (M. tb) H37Rv stimulation in vitro. The serum levels of IL-39, CXCL14, and IL-19 of 38 TB patients, and 20 healthy staff members were measured by enzyme-linked immunosorbent assay. Moreover, the levels of IL-19, CXCL14, and IL-39 in cultured THP-1 macrophages were detected at 12, 24, and 48 h after stimulation with BCG or M. tb H37Rv strains. It was found the serum level of IL-39 was significantly reduced and CXCL14 was remarkably elevated in TB patients. In vitro, at 48 h after stimulation, IL-39 level of cultured THP-1 macrophages in the H37Rv group was significantly lower than that in the BCG and control groups, and the CXCL14 level of cultured THP-1 macrophages in the H37Rv stimulation group was remarkably higher than that in the control group. Therefore, IL-39 and CXCL14 may be involved the pathogenesis of TB, and serum IL-39 and CXCL14 could potentially serve as a new biomarker of TB.

[Anti-tumor target prediction and activity verification of Ganoderma lucidum triterpenoids].

It has reported that Ganoderma lucidum triterpenoids had anti-tumor activity. However, the anti-tumor target is still unclear. The present study was designed to investigate the anti-tumor activity of G. lucidum triterpenoids on different tumor cells, and predict their potential targets by virtual screening. In this experiment, molecular docking was used to simulate the interactions of 26 triterpenoids isolated from G. lucidum and 11 target proteins by LibDock module of Discovery Studio2016 software, then the anti-tumor targets of triterpenoids were predicted. In addition, the in vitro anti-tumor effects of triterpenoids were evaluated by MTT assay by determining the inhibition of proliferation in 5 tumor cell lines. The docking results showed that the poses were greater than five, and Libdock Scores higher than 100, which can be used to determine whether compounds were activity. Eight triterpenoids might have anti-tumor activity as a result of good docking, five of which had multiple targets. MTT experiments demonstrated that the ganoderic acid Y had a certain inhibitory activity on lung cancer cell H460, with IC50 of 22.4 µmol•L ⁻¹, followed by 7-oxo-ganoderic acid Z2, with IC50 of 43.1 µmol•L ⁻¹. However, the other triterpenoids had no anti-tumor activity in the detected tumor cell lines. Taking together, molecular docking approach established here can be used for preliminary screening of anti-tumor activity of G.lucidum ingredients. Through this screening method, combined with the MTT assay, we can conclude that ganoderic acid Y had antitumor activity, especially anti-lung cancer, and 7-oxo-ganoderic acid Z2 as well as ganoderon B, to a certain extent, had anti-tumor activity. These findings can provide basis for the development of anti-tumor drugs. However, the anti-tumor mechanisms need to be further studied.

APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review.

Adenomatous polyposis coli (APC) promoter hypermethylation has been frequently observed in colorectal cancer (CRC). The association between APC promoter methylation and clinicopathological significance in CRC is under investigation. We performed a meta-analysis to quantitatively evaluate the significance of APC methylation in CRC. The study included a total of 24 articles and 2025 CRC patients. The frequency of APC promoter hypermethylation was significantly higher in colorectal adenoma than in normal colorectal tissue, OR was 5.76, 95% CI, 2.45-13.56; p<0.0001, I2=0%. APC promoter more frequently hypermethylated in CRC stage I compared to normal colorectal tissue, OR was 13.42, 95% CI, 3.66-49.20; p<0.0001, I2=31%. The risk of incidence of CRC was significantly correlated to APC promoter hypermethylation, pooled OR was 9.80, 95%CI, 6.07-15.81; p<0.00001, I2=43%. APC methylation was not associated with grade, stage of CRC as well as tumor location, patients' gender, and smoking behavior. The results indicate that APC promoter hypermethylation is an early event in carcinogenesis of CRC, could be a valuable diagnostic marker for early-stage CRC. APC methylation is not significantly associated with overall survival in patients with CRC. APC is a potential drug target for development of personalized treatment.

Transport and uptake of clausenamide enantiomers in CYP3A4-transfected Caco-2 cells: An insight into the efflux-metabolism alliance.

The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide (CLA) enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients (Papp) of (-) and (+)CLA were higher in the absorptive direction than those in the secretory direction with efflux ratios (ER) of 0.709±0.411 and 0.867±0.250 (×10(-6)cm/s), respectively. Their bidirectional transports were significantly reduced by 75.6-87.5% after treatment with verapamil (a P-glycoprotein inhibitor) that increased the rate of metabolism by CYP3A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of (-) and (+)CLA with ERs being 2.934±1.432 and 1.877±0.148(×10(-6)cm/s) respectively. These changes could be blocked by the duel CYP3A4/P-glycoprotein inhibitor cyclosporine A, consequently, Papp values for CLA enantiomers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following (-) or (+)-isomer treatment alone. Furthermore, the uptake of (-)CLA was more than that of (+)CLA in the transfected cells. Incubation with ketoconazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexamethasone. These results indicated that CYP3A4 could influence P-gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P-glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharmacology of (-)CLA as a candidate drug for treatment of Alzheimer's disease.

Stereoselective Regulation of P-gp Activity by Clausenamide Enantiomers in Caco-2, KB/KBv and Brain Microvessel Endothelial Cells.

The (-)- and (+)-clausenamide (CLA) enantiomers have different pharmacokinetic effects in animals, but their association with putative stereoselective regulation of P-glycoprotein (P-gp) remains unclear. Using three cells expressing P-gp-Caco-2, KBv and rat brain microvessel endothelial cells(RBMEC), this study investigated the association of CLA enantiomers with P-gp. The results showed that the rhodamine 123 (Rh123) accumulation, an indicator of P-gp activity, in Caco-2, KBv and RBMECs was increased by (-)CLA (1 or 5 µmol/L) at 8.2%-28.5%, but reduced by (+)CLA at 11.7%-25.9%, showing stereoselectivity in their regulation of P-gp activity. Following co-treatment of these cells with each CLA enantiomer and verapamil as a P-gp inhibitor, the (+)-isomer clearly antagonized the inhibitory effects of verapamil on P-gp efflux, whereas the (-)-isomer had slightly synergistic or additive effects. When higher concentrations (5 or 10 µmol/L) of CLA enantiomers were added, the stimulatory effects of the (+)-isomer were converted into inhibitory ones, leading to an enhanced intracellular uptake of Rh123 by 24.5%-58.2%; but (-)-isomer kept its inhibition to P-gp activity, causing 30.0%-63.0% increase in the Rh123 uptake. The biphasic effects of (+)CLA were confirmed by CLA uptake in the Caco-2 cells. (+)CLA at 1 µmol/L had significantly lower intracellular uptake than (-)CLA with a ratio[(-)/(+)] of 2.593, which was decreased to 2.167 and 1.893 after CLA concentrations increased to 2.5 and 5 µmol/L. Besides, in the non-induced KB cells, (+)CLA(5 µmol/L) upregulated P-gp expression at 54.5% relative to vehicle control, and decreased Rh123 accumulation by 28.2%, while (-)CLA(5 µmol/L) downregulated P-gp expression at 15.9% and increased Rh123 accumulation by 18.0%. These results suggested that (-)CLA could be a P-gp inhibitor and (+)CLA could be a modulator with concentration-dependent biphasic effects on P-gp activity, which may result in drug-drug interactions when combined with other P-gp substrate drugs.

Structural investigation of a uronic acid-containing polysaccharide from abalone by graded acid hydrolysis followed by PMP-HPLC-MSn and NMR analysis.

A new strategy was applied to elucidate the structure of a polysaccharide from abalone gonad (AGSP). It was hydrolyzed by 0.05 M, 0.2 M, 0.5 M, and 2.0 M TFA at 100 °C for 1 h, sequentially. Every hydrolysate was ultrafiltrated (3000 Da) to collect oligo- and monosaccharides, and the final retentate was further hydrolyzed with 2.0 M TFA at 110 °C and 121 °C for 2 h, respectively. 1-Phenyl-3-methyl-5-pyrazolone (PMP) derivatization followed by HPLC-MSn analysis was applied to detect the sugar residues in these hydrolysates, which allowed proposing their location in the polysaccharide structure. The retentate after 0.5 M TFA hydrolysis was confirmed as the polysaccharide backbone, and it was further analyzed by 1D and 2D NMR spectroscopy. Thus, the structural elucidation of AGSP was accomplished, and it has a backbone of →4)-ß-GlcA(1→2)-α-Man(1→ repeating unit with Fuc, Xyl and Gal in the branch. The analytical strategy demonstrated was useful to characterize the structure of polysaccharides.

ABO blood type is associated with endometrial cancer risk in Chinese women / 癌症

ABO blood type has been associated with risk of several malignancies. However, results are not consistent. In this population-based case-control study including 1204 incident endometrial cancer cases and 1212 population controls, we examined the association of self-reported serologic blood type with endometrial cancer risk using a logistic regression model. Women with endometrial cancer were more likely to have blood type A. Compared to women with blood type O, the adjusted odds ratios for endometrial cancer were 1.00 [95% confidence interval (CI), 0.79-1.28] for type B, 1.24 (95% CI, 0.90-1.69) for type AB, and 1.50 (95% CI, 1.19-1.90) for type A. A significant dose-response relationship was observed for cancer risk and level of antigen A (P for trend = 0.0003). The positive association of blood type A with cancer risk was observed regardless of menopausal status, body mass index, oral contraceptive use, or family cancer history. Our results suggest that ABO blood type may be involved in the development of endometrial cancer.

Epidemiological characteristics of obesity and its relation to chronic diseases among middle aged and elderly men / 中华流行病学杂志

Objective To investigate the epidemiological characteristics of obesity and how they related to chronic diseases among middle aged and elderly men in urban Shanghai.Methods A cross-sectional analysis was conducted using data from a baseline survey from an on-going cohort study of 61 500 men between 40-74 of age in urban Shanghai.Study subjects were recruited from 8 communities of an urban district in Shanghai during 2002 to 2006.General obesity was measured by body mass index (BMI≥28) and,central obesity by waist to hip ratio (WHR≥0.9).Unconditional logistic regression model was used to estimate the odds ratio and 95% confidence interval of chronic diseases associated with obesity after adjustment for potential confounding factors.Results The aged-adjusted prevalence rates of overweight,overall obesity and central obesity were 36.8%,7.7% and 49.7% respectively.In this population,66.7% subjects had ever been diagnosed with one or more kinds of chronic diseases,in which hypertension ranked first with an age-adjusted prevalence rate of 26.5%.After mutual adjustment for WHR and BMI,obesity (BMI≥28) appeared to be associated with increased prevalence rates of hypertension,coronary heart disease,gallstone,urinary tract calculus and stroke comparing to men having normal BMI (18.5≤BMI＜24) with ORs ranged from 1.16 to 3.13.However,to the lowest quartile,the ORs associated with the highest WHR were between 1.20 and 1.69 for these 5 diseases.All P values for trend tests were less than 0.05.WHR was positively associated with diabetes,with OR as 2.40 (95% CI:2.14-2.70) for the highest quartile comparing to the lowest quartile.BMI was unrelated to the diabetes prevalence.Prevalence of chronic obstructive pulmonary disease decreased with increasing BMI,but increased with WHR.The corresponding OR was 0.87 (95% CI:0.77-0.98)for the obese men compared to those with normal BMI while 1.26(95%CI:1.14-1.40) for the subjects with the highest WHR comparing to those with the lowest WHR.Conclusion The prevalence rates of hypertension,gallstone,urinary tract calculus,cardiovascular and cerebrovascular diseases were higher in obesity men.Central obesity seemed to be related to high prevalence of diabetes.

A case-control study on genetic polymorphism of CYP17 MspA(1)I and its association with endometrial cancer risk / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To assess whether the polymorphisms of CYP17 MspA(1)I are associated with the susceptibility of endometrial cancer.</p><p><b>METHODS</b>The allelic discrimination of the CYP17A1 gene polymorphisms were assessed with the ABI PRISM 7900 Sequence Detection Systems using TaqMan genotyping assay. Unconditional logistic regression was applied to assess odds ratio and 95% CI and evaluate the association between different genotypes and endometrial cancer development.</p><p><b>RESULTS</b>The frequencies of wild-type, heterozygote and homozygote for the CYP17 MspA(1)I in control women in Shanghai were 17.8%, 49.3% and 32.9%, respectively. No significant difference was found in the distribution of various genotypes of CYP17 MspA(1)I between patients and controls. Pregnancy was associated with reduced risk of endometrial cancer in pre-menopausal women with A2 allele, OR = 0.66, 95% CI: 0.44 approximately 0.99. In post-menopausal women with A2 allele, more pregnancies ( > 2) and shorter time of menstruation ( < or = 32 yrs) were associated with reduced risk of endometrial cancer.</p><p><b>CONCLUSION</b>No significant relationship was found between CYP17 MspA(1)I genotypes and endometrial cancer risk.</p>

Green tea consumption and the risk of endometrial cancer: a population-based case-control study in urban Shanghai / 中华流行病学杂志

<p><b>OBJECTIVE</b>To assess the effect of tea consumption on the risk of endometrial cancer.</p><p><b>METHODS</b>In a population based case-control study conducted in urban Shanghai, face-to-face interviews were completed for 995 incidence cases aged 30 - 69 from January 1997 to December 2002 and 1087 controls that frequency-matched to cases on age. Unconditional logistic model was used for analysis.</p><p><b>RESULTS</b>An inverse association was observed in tea drinking and endometrial cancer risk. Compared to non-tea drinkers, regular tea drinkers had reduced risk of endometrial cancer (OR = 0.74; 95% CI: 0.54 - 1.01) in premenopausal women. Green tea had a protective effect on endometrial cancer among non-smoking or non-alcohol drinking women (OR = 0.77, P = 0.0199) and the ORs reduced with the increasing concentration of tea being served (P for trend = 0.0493). The multivariate ORs for drinking green tea < 7 times/week and >or= 7 times/week were 0.90 (95% CI: 0.53 - 1.54) and 0.76 (95% CI: 0.60 - 0.95) with the trend test of P = 0.0163.</p><p><b>CONCLUSION</b>Tea drinking, with green tea in particurlar, seemed to have weak but inverse association with endometrial cancer risk, but this effect of protection might only limit to premenopausal women.</p>

Methods for time trend analysis of cancer incidence rates / 中华流行病学杂志

<p><b>OBJECTIVE</b>To introduce statistical methods of time trend analysis on cancer rates.</p><p><b>METHODS</b>Cancer incidence data collected by the Shanghai Cancer Registry during 1991 to 1999 was used in the analysis to calculate the crude and age-adjusted rates, percent changes (PCs) and annual percent changes (APCs). APCs were estimated by a linear regression of the logarithm on the incidence rates during the nine years. It also introduced a method for partitioning a linear trend in age-adjusted rates into site-specific contributions to the overall floating trend. 95% confidence intervals for the APCs and contributions were described in the paper.</p><p><b>RESULTS</b>A decreasing rates were observed for cancers of stomach and esophagus among both men and women in urban Shanghai from 1991 to 1999. The increasing rates among men would include cancers of colon, rectum, gall bladder, pancreas, prostate, urinary bladder, kidney and leukemia. The rates of cancers among women increased for colon, rectum, lung, breast, gall bladder, endometrium, ovary, urinary bladder and kidney. The changes of above cancers over time were statistically significant (P < 0.05 or P < 0.01), but rates for other cancer sites changed little. The APCs (weighted method) and contributions for the cancers of stomach, esophagus, colon, rectum and prostate were -2.99% and -65.72%, -2.90% and -17.07%, 12.30% and 21.46%, 2.94% and 18.62%, and 3.11% and 15.09% among men, and -6.05% and -39.55%, -1.08% and -35.19%, 2.81% and 28.64%, and 3.69% and 15.70% for the cancers of stomach, esophagus, breast and colon in women, respectively.</p><p><b>CONCLUSION</b>APC, and related statistics could be used to describe and analyze the time trend of cancer rates rather than PC or/and graphical method alone.</p>