Ginsenoside Rb1 reduces H2O2­induced HUVEC dysfunction by stimulating the sirtuin­1/AMP­activated protein kinase pathway.

Endothelial dysfunction and senescence are closely associated with cardiovascular diseases including atherosclerosis and hypertension. Ginsenoside Rb1 (Rb1), the major active constituent of ginseng, has been investigated intensively because of its anti­obesity and anti­inflammatory effects. In a previous study, hydrogen peroxide (H2O2) was applied to induce human umbilical vein endothelial cell (HUVEC) aging. It was demonstrated that Sirtuin­1 (SIRT1) was activated by Rb1 to protect HUVECs from H2O2­induced senescence. However, the mechanisms are not fully understood. The present study examined the role of AMP­activated protein kinase (AMPK), an energy sensor of cellular metabolism, in the signaling pathway of SIRT1 during H2O2­stimulated HUVEC aging. It was identified that Rb1 restored the H2O2­induced reduction of SIRT1 expression, which was consistent with our previous study, together with the activation of AMPK phosphorylation. Using compound C, an AMPK inhibitor, the role of AMPK in the protective effect of Rb1 against H2O2­induced HUVEC senescence was examined. It was identified that the induction of phosphorylated AMPK by Rb1 markedly increased endothelial nitric oxide synthase expression and nitric oxide production, and suppressed PAI­1 expression, which were abrogated in HUVECs pretreated with compound C. Further experiments demonstrated that nicotinamide, a SIRT1 inhibitor, downregulated the phosphorylation of AMPK and reduced the protective effects of Rb1 against H2O2­induced endothelial aging. Taken together, these results provide new insights into the possible molecular mechanisms by which Rb1 protects against H2O2­induced HUVEC senescence via the SIRT1/AMPK pathway.

Improving precision of glomerular filtration rate estimating model by ensemble learning.

BACKGROUND: Accurate assessment of kidney function is clinically important, but estimates of glomerular filtration rate (GFR) by regression are imprecise. METHODS: We hypothesized that ensemble learning could improve precision. A total of 1419 participants were enrolled, with 1002 in the development dataset and 417 in the external validation dataset. GFR was independently estimated from age, sex and serum creatinine using an artificial neural network (ANN), support vector machine (SVM), regression, and ensemble learning. GFR was measured by 99mTc-DTPA renal dynamic imaging calibrated with dual plasma sample 99mTc-DTPA GFR. RESULTS: Mean measured GFRs were 70.0 ml/min/1.73 m2 in the developmental and 53.4 ml/min/1.73 m2 in the external validation cohorts. In the external validation cohort, precision was better in the ensemble model of the ANN, SVM and regression equation (IQR = 13.5 ml/min/1.73 m2) than in the new regression model (IQR = 14.0 ml/min/1.73 m2, P < 0.001). The precision of ensemble learning was the best of the three models, but the models had similar bias and accuracy. The median difference ranged from 2.3 to 3.7 ml/min/1.73 m2, 30% accuracy ranged from 73.1 to 76.0%, and P was > 0.05 for all comparisons of the new regression equation and the other new models. CONCLUSIONS: An ensemble learning model including three variables, the average ANN, SVM, and regression equation values, was more precise than the new regression model. A more complex ensemble learning strategy may further improve GFR estimates.

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

BACKGROUND: Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. AIMS: To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. METHODS: A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. RESULTS: Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. CONCLUSION: This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients.

Serum irisin levels correlated to peritoneal dialysis adequacy in nondiabetic peritoneal dialysis patients.

BACKGROUND: Irisin is a recently discovered myokine thought to be involved in multiple metabolism abnormalities in most dialysis patients. However, the myokine has not been thoroughly studied in peritoneal dialysis. This study aimed to evaluate serum irisin levels and establish their relation to dialysis adequacy, insulin resistance, and bone metabolism status in patients on peritoneal dialysis. METHODS: A total of 59 nondiabetic prevalent peritoneal dialysis patients and 52 age- and sex-matched healthy controls were enrolled in this cross-sectional study. Serum irisin concentration was assessed by enzyme-linked immunosorbent assay. The correlations between serum irisin and dialysis adequacy, clinical, and metabolic variables were investigated. RESULTS: Serum irisin levels were lower in nondiabetic peritoneal dialysis patients (17.02ng/ml) compared with healthy controls (22.17ng/ml, P<0.001). Multivariate regression analysis revealed that fasting glucose levels were correlated inversely with serum irisin levels in peritoneal dialysis patients. Serum irisin levels were associated with neither insulin resistance nor bone metabolism in our patients. Serum irisin levels were positively associated with peritoneal Kt/Vurea (ß = 4.933, 95% confidence interval [CI] = 0.536-9.331, P = 0.029) and peritoneal CCr (ß = 0.259, 95% CI = 0.053-0.465, P = 0.015) among peritoneal dialysis patients. CONCLUSIONS: The study demonstrated that non-diabetic peritoneal dialysis patients have lower serum irisin levels, and the levels were correlated with peritoneal dialysis adequacy, indicating adequate dialysis may improve irisin secretion. Additional studies are needed to provide a confirmation.

[Effect of polydatin on miR-214 expression and liver function in ApoE-/- mice].

OBJECTIVE: To study the effect of polydatin on the expression level of miR-214 and liver function in atherosclerotic mice. METHODS: Forty male ApoE(-/-) mice were randomly allocated into 4 groups (n=10), namely the model group, low- and high-dose polydatin groups, and simvastin group, with 10 male C57BL/6J mice serving as the normal control group. Mouse models of atherosclerosis were established by feeding the ApoE(-/-) mice with a high-fat diet. After 12 weeks of treatment, blood levels of glucose, lipids, AST, and ALT and the contents of T-SOD and MDA in the liver tissue were detected. The pathologies of the liver were examined with HE staining, and miR-214 expression in the liver was detected using quantitative real-time PCR. RESULTS: Compared with the normal control mice, the mice in the model group showed significantly increased blood glucose, serum TC, TG, LDL-C, ALT, and AST levels, and MDA contents in the liver (P<0.01), with significantly decreased serum HDL-C level and SOD and miR-214 levels in liver (P<0.01). Polydatin treatment significantly ameliorated such changes in blood glucose, serum ALT, AST, TC, TG, LDL-C, and HDL-C levels, and MDA, SOD, and miR-214 contents in liver tissue (P<0.05). CONCLUSION: s Polydatin can reduce blood glucose and lipid levels and protect the liver function in atherosclerotic mice possibly by up-regulating the expression of miR-214 and T-SOD and down-regulating MDA in the liver.

Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors.

The data on the impact of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients receiving tyrosine kinase inhibitors (TKIs) are inconsistent. We therefore performed a meta-analysis to assess the prognostic value of pretreatment NLR in patients treated with TKIs for mRCC. We searched the Embase, Medline, PubMed, Cochrane and ISI Web of Knowledge to identify clinical studies that had evaluated the association between the pretreatment NLR and prognosis in mRCC patients. Prognostic outcomes included overall survival (OS) and progression-free survival (PFS). Nine studies encompassing a total of 1091 participants were included. We found that a high NLR was an effective prognostic marker of both OS (pooled HR: 1.93, 95% CI: 1.35-2.77; P = 0.0003) and PFS (pooled HR: 2.12, 95% CI: 1.42-3.17; P = 0.0002). Subgroup analysis revealed that studies reporting a NLR ≥ 3 showed a more significant effect of NLR on both OS (pooled HR: 2.50, 95% CI: 1.99-3.14; P = 0.0003) and PFS (pooled HR: 2.17, 95% CI: 1.26-3.75). This meta-analysis suggests that high pretreatment NLR is associated with a poor prognosis in mRCC patients receiving TKI treatment.

Advanced glycation end products upregulate angiopoietin-like protein 4 expression by activating the renin-angiotensin system in endothelial cells.

The aim of the present study was to investigate the effects of advanced glycation end products (AGEs) on the expression of angiopoietin-like protein 4 (ANGPTL4) and the mechanisms of the effects in endothelial cells. Endothelial cells were incubated with various concentrations of AGEs for 24 h and the expression of ANGPTL4 was detected by quantitative polymerase chain reaction and western blot analysis. The concentration of angiotensin II (Ang II) in conditioned media and cell lysates was measured by enzyme-linked immunosorbent assays. Fluorescein isothiocyanate-labeled dextran filtration assays and transendothelial electrical resistance were performed to evaluate endothelial permeability. AGEs (80 µg/ml) increased the expression of ANGPTL4 and the levels of Ang II (P<0.05). Incubation with AGEs also resulted in a significant increase in endothelial permeability (P<0.05). However, pretreatment with the Ang II receptor blocker losartan (10-5 M) reduced the effects of AGEs (P<0.05). AGEs upregulated the expression of ANGPTL4 by activating a local renin-angiotensin system in endothelial cells. This may be a new mechanism by which AGEs increase endothelial permeability.

Disseminated infection caused by Emmonsia pasteuriana in a renal transplant recipient.

Emmonsia pasteuriana is a thermally dimorphic fungus identified in very few human cases. Here, we report a case of a 43-year-old male renal transplant patient from China presenting with multiple painful skin eruptions on his head, nose and left thigh, later accompanied by respiratory failure. Histopathology of the biopsy collected from the left thigh upper ulcer and occipital nodule both demonstrated chronic inflammation with granuloma formation and yeast-like elements. Emmonsia pasteuriana was cultured from two biopsy specimens and their identity was confirmed by sequencing of the rDNA internal transcribed spacer. The patient in intensive care showed marked clinical improvement with antifungal treatment.

Advanced glycation end-products reduce podocyte adhesion by activating the renin-angiotensin system and increasing integrin-linked kinase.

The aim of this study was to investigate the effects of advanced glycation end-products (AGEs) on podocyte adhesion and the underlying mechanisms. Immortalized mouse podocytes were exposed to various conditions and podocyte adhesion was evaluated using a hexosaminidase assay. The expression levels of integrin-linked kinase (ILK) were measured by quantitative polymerase chain reaction (qPCR) and western blotting. Treatment with AGEs resulted in a significant, concentration-dependent reduction in podocyte adhesion (P<0.05) and an incremental rise in ILK expression up to a maximum of 100%. Pretreatment with losartan significantly prevented the upregulation of ILK and attenuated the loss of podocyte adhesion observed in podocytes exposed to AGEs (P<0.05). However, the adhesion of losartan-treated podocytes remained lower than that of the podocytes exposed to bovine serum albumin. The results indicate that AGEs reduce podocyte adhesion via the upregulation of ILK expression, which occurs partly through activation of the renin-angiotensin system in podocytes.

A new equation to estimate glomerular filtration rate in Chinese elderly population.

BACKGROUND: We sought to develop a new equation to estimate glomerular filtration rate (GFR) in Chinese elderly population. METHODS: A total of 668 Chinese elderly participants, including the development cohort (n = 433), the validation cohort (n = 235) were enrolled. The new equation using the generalized additive model, and age, gender, serum creatinine as predictor variables was developed and the performances was compared with the CKD-EPI equation. RESULTS: In the validation data set, both bias and precision were improved with the new equation, as compared with the CKD-EPI equation (median difference, -1.5 ml/min/1.73 m(2) vs. 7.4 ml/min/1.73 m(2) for the new equation and the CKD-EPI equation, [P<0.001]; interquartile range [IQR] for the difference, 16.2 ml/min/1.73 m(2) vs. 19.0 ml/min/1.73 m(2) [P<0.001]), as were accuracies (15% accuracy, 40.4% vs. 30.6% [P = 0.02]; 30% accuracy, 71.1% vs. 47.2%, [P<0.001]; 50% accuracy, 90.2% vs. 75.7%, [P<0.001]), allowing improvement in GFR categorization (GFR category misclassification rate, 37.4% vs. 53.2% [P = <0.001]). CONCLUSIONS: A new equation was developed in Chinese elderly population. In the validation data set, the new equation performed better than the original CKD-EPI equation. The new equation needs further external validations. Calibration of the GFR referent standard to a more accurate one should be an useful way to improve the performance of GFR estimating equations.

Estimating glomerular filtration rates in elderly Chinese patients with chronic kidney disease: performance of six modified formulae developed in Asian populations.

OBJECTIVES: The aim of the present study was to evaluate modified glomerular filtration rate (GFR) prediction formulae in an elderly Chinese population with chronic kidney disease (CKD). METHODS: A total of 378 elderly Chinese patients with CKD were enrolled. The GFR was estimated with six modified GFR prediction formulae. The performances of the estimated GFRs were compared with those of the standard GFRs measured by technetium-99m diethyl-enetraminepentaacetic acid. RESULTS: Biases were similar for Chinese formula 1, the Asian formula, and Chinese formula 2 (median difference, 2.22 mL/min/1.73 m(2) and 2.59 mL/min/1.73 m(2) for Chinese formula 1 and the Asian formula, respectively, versus (vs) 3.69 mL/min/1.73 m(2) for Chinese formula 2 [P = 0.298 and P = 0.913, respectively]). Precision was improved with the Japanese formula (interquartile range of the difference, 3.14 mL/min/1.73 m(2) of the Japanese formula versus 15.53-23.06 mL/min/1.73 m(2) of the other formulae). The accuracy of Chinese formula 2 was the highest (30% accuracy, 59.3% vs range 37.8-54.0% [P < 0.05 for all comparisons]). However, none of the modified formulae surpassed the acceptable tolerance (>70%), and the GFR category misclassification rates for all the formulae exceeded 50%. CONCLUSION: Our findings suggest that all six modified formulae developed in Asian populations may show great bias in elderly Chinese patients with CKD. Also, our study suggests the need for uniform measures for the assessment of CKD in the elderly to guarantee better sensitivity and specificity.

Assessment of glomerular filtration rate in elderly patients with chronic kidney disease.

PURPOSE: We sought to evaluate various glomerular filtration rate (GFR) estimating equations in elderly patients with chronic kidney disease (CKD). METHODS: A total of 332 Chinese elderly patients with CKD who had undergone technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) renal dynamic imaging were enrolled. The MDRD equation, the re-expressed MDRD equation, the Chinese equation, the Ruijin equation, the previously Japanese equation, the new Japanese equation, the CKD-EPI equation, and the BIS1 equation were compared. RESULTS: The median of difference between estimated GFR and standard GFR ranged from -9.78 to 1.79 ml/min/1.73 m(2). The interquartile range of difference ranged from 12.38 to 20.87 ml/min/1.73 m(2). Accuracy with a deviation <30 % ranged from 44.9 to 66.3 %. However, none of the equations had accuracy up to the 70 % level. Bland-Altman analysis demonstrated that the precision ranged from 50.5-87.6 ml/min/1.73 m(2). The slopes of regression line ranged from -0.26 to 0.55 and the intercepts ranged from -18.71 to 11.07. In both the overall performance and the performances in different stage of CKD, GFR estimated by the BIS1 equation performed better results. CONCLUSION: None of the GFR estimating equations are suitable for the specific Chinese population tested. At present, the BIS1 equation may be the optimal one for elderly Chinese CKD patients.

Variability of glomerular filtration rate estimation equations in elderly Chinese patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is recognized worldwide as a public health problem, and its prevalence increases as the population ages. However, the applicability of formulas for estimating the glomerular filtration rate (GFR) based on serum creatinine (SC) levels in elderly Chinese patients with CKD is limited. MATERIALS AND METHODS: Based on values obtained with the technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) renal dynamic imaging method, 319 elderly Chinese patients with CKD were enrolled in this study. Serum creatinine was determined by the enzymatic method. The GFR was estimated using the Cockroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Jelliffe-1973 equation, and the Hull equation. RESULTS: The median of difference ranged from -0.3-4.3 mL/min/1.73 m(2). The interquartile range (IQR) of differences ranged from 13.9-17.6 mL/min/1.73 m(2). Accuracy with a deviation less than 15% ranged from 27.6%-32.9%. Accuracy with a deviation less than 30% ranged from 53.6%-57.7%. Accuracy with a deviation less than 50% ranged from 74.9%-81.5%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from the standard glomerular filtration rate (sGFR). Bland-Altman analysis demonstrated that the mean difference ranged from -3.0-2.4 mL/min/1.73 m(2). However, the agreement limits of all the equations, except the CG equation, exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m(2). When the overall performance and accuracy were compared in different stages of CKD, GFR estimated using the CG equation showed promising results. CONCLUSIONS: Our study indicated that none of these equations were suitable for estimating GFR in the elderly Chinese population investigated. At present, based on overall performance, as well as performance in different CKD stages, the CG equation may be the most accurate for estimating GFR in elderly Chinese patients with CKD.

Diagnostic significance of hepatitis B viral antigens in patients with glomerulonephritis-associated hepatitis B virus infection.

Hepatitis B viral infection can lead to hepatitis B virus-associated glomerulonephritis, a clinically significant subtype of secondary nephritis. In the present study, we examined the presence of PreS1/S2 antigen in renal tissues by use of immunohistochemistry and investigated the use of PreS1/S2 and 2 HBV serum antigens, HBe-Ag and HBs-Ag, in the diagnosis. We assessed the presence of these 3 antigens in patients with confirmed hepatitis B virus-associated glomerulonephritis (n = 22) and patients without this disease (n = 19). Our results indicate that the combined use of PreS1/S2-Ag and serum HBe-Ag in the diagnosis of hepatitis B virus-associated glomerulonephritis had good positive predictive value (0.89), modest negative predictive value (0.77), and substantial agreement based on Cohen's kappa coefficient (κ = 0.660, P < 0.001). We suggest that our results be considered in the development of more definitive diagnostic criteria for hepatitis B virus-associated glomerulonephritis.

The synergistic effects of cytomegalovirus IE2 and myocardin on cardiomyocyte hypertrophy.

Human cytomegalovirus immediate early proteins (CMV IEs) are involved in transcriptional activities of both host and virus gene expression. This study shows that the transcriptional activity of myocardin in regulating cardiomyocyte hypertrophy is enhanced by co-expressing CMV IE2. Forced expression of IE2 increases the augmented cell size of neonatal rat cardiac myocytes induced by myocardin, as well as the mRNA and protein levels of hypertrophic genes, whereas deletion of CArG boxes in the atrial natriuretic factor (ANF) promoter attenuates the effect of CMV IE2 with myocardin. In conclusion, CMV IE2 synergistically stimulates myocardin transactivity in the hypertrophic marker gene ANF in a CArG box-dependent manner. Our study indicates that the association of CMV IEs with myocardin-induced transcription may be involved in myocardin-mediated cardiac hypertrophy.

[Quercetin inhibits growth and induces apoptosis of human gastric carcinoma cells].

AIM: To study the effect of quercetin on the growth and apoptosis of human gastric carcinoma cell line MGC-803. METHODS: The measurement of inhibitory rate and apoptotic index(AI) of quercetin were done by MTT assay and TUNEL assay. The positive expression rate of P53, C-myc and P16 were detected by immunocytochemical staining. RESULTS: Quercetin at concentrations ranging from 40 mumol/L to 100 mumol/L significantly inhibited the proliferation of MGC-803 cells in a dose- and time-dependent manner (P<0.01). TUNEL assay indicated that the number of apoptotic cells in quercetin-treated group was greater than that in the control group (P<0.01). Expression of P53 and C-myc protein decreased following quercetin induction in a dose-dependent manner, whereas P16 expression increased significantly compared with that of the control group (P<0.01). CONCLUSION: Quercetin can inhibit the growth and induce apoptosis of MGC-803 cells in a dose- and time-dependent manner. Its mechanisms may be relevant to the down-regulation of P53 and C-myc protein expression as well as up-regulation of P16 expression.