Effects of low-flux and high-flux hemodialysis on the survival of elderly maintenance hemodialysis patients.

BACKGROUND: Elderly hemodialysis (HD) patients have a high risk of death. The effect of different types of HD membranes on survival is still controversial. The purpose of this study was to determine the relationship between the use of low-flux or high-flux membranes and all-cause and cardiovascular mortality in elderly hemodialysis patients. METHODS: This was a retrospective clinical study involving maintenance hemodialysis patients which were categorized into low-flux and high-flux groups according to the dialyzer they were using. Propensity score matching was used to balance the baseline data of the two groups. Survival rates were compared between the two groups, and the risk factors for death were analyzed by multivariate Cox regression. RESULTS: Kaplan-Meier survival analysis revealed no significant difference in all-cause mortality between the low-flux group and the high-flux group (log-rank test, p = 0.559). Cardiovascular mortality was significantly greater in the low-flux group than in the high-flux group (log-rank test, p = 0.049). After adjustment through three different multivariate models, we detected no significant difference in all-cause mortality. Patients in the high-flux group had a lower risk of cardiovascular death than did those in the low-flux group (HR = 0.79, 95% CI, 0.54-1.16, p = 0.222; HR = 0.58, 95% CI, 0.37-0.91, p = 0.019). CONCLUSIONS: High-flux hemodialysis was associated with a lower relative risk of cardiovascular mortality in elderly MHD patients. High-flux hemodialysis did not improve all-cause mortality rate. Differences in urea distribution volume, blood flow, and systemic differences in solute clearance by dialyzers were not further analyzed, which are the limitations of this study.

Association between the triglyceride to high-density lipoprotein cholesterol ratio and mortality in Chinese maintenance haemodialysis patients: a retrospective cohort study.

OBJECTIVE: To investigate the relationship between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and all-cause and cardiovascular (CV) mortality in Chinese haemodialysis (HD) patients. DESIGN: Retrospective cohort study. SETTING: Patients from June 2015 to September 2016 and followed through September 2021 were categorised into quartiles according to the follow-up averaged TG/HDL-C ratio. The association between TG/HDL-C and mortality was examined by univariate and multivariate time-varying Cox regression analyses. The C-index was used to assess the predictive accuracy of the Cox regression models. PARTICIPANTS: A total of 534 maintenance HD patients were enrolled. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcomes were all-cause death and CV mortality. RESULTS: During the median follow-up of 61 months, 207 patients died, with 94 (45.4%) classified as CV death. After adjusting for confounders, multivariate time-varying Cox regression analysis showed that the quartile 4 group (TG/HDL-C ≥2.64) was associated with decreased all-cause mortality (adjusted HR 0.51, 95% CI 0.33-0.77, p=0.001) and CV mortality (adjusted HR 0.31; 95% CI 0.16 to 0.62; p=0.001) in maintenance HD patients. Model 1 of all-cause mortality achieved a C-index of 0.72 (95% CI 0.68 to 0.75), and model 2 achieved a C-index of 0.77 (95% CI 0.73 to 0.82). The C-index for model 1 in CV mortality was 0.74 (95% CI 0.70 to 0.77), and the C-index for model 2 was 0.80 (95% CI 0.75 to 0.84). CONCLUSIONS: High TG/HDL-C was associated with decreased all-cause and CV mortality in HD patients.

Left ventricular hypertrophy and left atrial diameter are associated with mortality risk in haemodialysis patients: a retrospective cohort study.

BACKGROUND: Cardiovascular death is the main cause of death in patients with end-stage kidney disease (ESKD). Left ventricular hypertrophy (LVH) and left atrial diameter (LAD) enlargement are frequent cardiac alterations in patients with ESKD and are major risk factors for cardiovascular events. However, it remains unclear whether there is an association between combined LAD or LVH and all-cause or cardiovascular mortality in this population. METHODS: A single-centre, retrospective cohort study including 576 haemodialysis (HD) patients was conducted. Patients were evaluated by cardiac ultrasound, and the study cohort was divided into four groups according to LAD and LVH status: low LAD and non-LVH; low LAD and LVH; high LAD and non-LVH; and high LAD and LVH. We used Kaplan-Meier analysis and Cox proportional hazard regression to analyse all-cause and cardiovascular mortality after multivariate adjustment. RESULTS: LAD was associated with an increased risk of all-cause mortality (HR 2.371, 1.602-3.509; p < 0.001). No significant differences were found between LVH and the risk of all-cause mortality. Patients with high LAD and LVH had significantly greater all-cause and cardiovascular mortality than did those with low LAD and non-LVH after adjustments for numerous potential confounders (HR 3.080, 1.608-5.899; p = 0.001) (HR 4.059, 1.753-9.397; p = 0.001). CONCLUSION: Among maintenance haemodialysis (MHD) patients, LAD was more strongly associated with mortality than was LVH. A high LAD and LVH are associated with a greater risk of mortality. Our results emphasize that the occurrence of LAD and LVH in combination provides information that may be helpful in stratifying the risk of MHD patients.

A high platelet-to-lymphocyte ratio predicts all-cause mortality and cardiovascular mortality in maintenance hemodialysis patients.

PURPOSE: The aim of this study was to further assess whether the platelet-to-lymphocyte ratio (PLR) is independently associated with all-cause mortality and cardiovascular mortality in maintenance hemodialysis (MHD) patients. METHODS: From January 1, 2014, to December 31, 2014, patients undergoing regular hemodialysis in the Blood Purification Center of the General Hospital of Northern Theatre Command were retrospectively selected. A total of 303 MHD patients were enrolled in accordance with the inclusion and exclusion criteria. For each patient, the endpoint of follow-up was either death or December 31, 2021. The primary endpoints were all-cause and cardiovascular death. A receiver operating characteristic (ROC) curve was drawn to detect the predictive ability of PLR, and the optimal critical value of PLR was determined to be 107.57. Kaplan-Meier curves and Cox proportional analysis were used to assess the prognostic value of PLR. We used the same method to evaluate the correlation between the neutrophil-to-lymphocyte ratio (NLR) and the prognosis of MHD patients. RESULTS: At the end of follow-up, 128 MHD patients had progressed to all-cause death, and 73 MHD patients had progressed to cardiovascular death. In multivariate Cox regression, both the high PLR group and the high NLR group were independently associated with all-cause mortality (HR 2.608, 95% CI 1.579-4.306, p < .001 vs. HR 1.634, 95% CI 1.023-2.610, p = .04). Only high PLR expression was associated with cardiovascular mortality (HR 3.379, 95% CI 1.646-6.936, p = .001). CONCLUSIONS: High PLR levels can independently predict all-cause and cardiovascular mortality in MHD patients.

Abdominal aortic calcification score can predict all-cause and cardiovascular mortality in maintenance hemodialysis patients.

Purpose: Abdominal aortic calcification (AAC) assessed by using standard lateral lumbar radiographs can be graded, and composite summary scores (range, 0-24) have been shown to be highly predictive of subsequent cardiovascular morbidity and mortality in hemodialysis (HD) patients. However, few studies have sought to determine the optimal AAC score cutoff values for the prediction of mortality among HD patients.Methods: This retrospective cohort study included 408 hemodialysis patients. AAC severity was quantified by the AAC score, which was measured by lateral lumbar radiography with complete follow-up data from January 2015 to December 2021. We used receiver operating characteristic (ROC) analysis to find the cutoff AAC value for the prediction of mortality. The Kaplan-Meier method was used to analyze all-cause and cardiovascular mortality.Results: The cutoff calcification score for the prediction of mortality was 4.5 (sensitivity, 67.3%; specificity, 70.4%). The patients with AAC scores above 4.5 had significantly higher all-cause (log-rank p < 0.001) and cardiovascular (log-rank p < 0.001) mortality rates than those with AAC scores below 4.5. In the multivariate regression analyses, an AAC score above 4.5 was a significant factor associated with all-cause mortality (HR: 2.079, p = 0.002) and cardiovascular mortality (HR: 2.610, p < 0.001).Conclusions: AAC is a reliable aortic calcification marker. HD patients with an AAC score > 4.5 have significantly elevated all-cause and cardiovascular mortality compared with those with an AAC score ≤ 4.5. AAC was a better predictor than cardiac valve calcification for mortality in HD patients.

Development of a prediction model to estimate the 5-year risk of cardiovascular events and all-cause mortality in haemodialysis patients: a retrospective study.

Background: Cardiovascular disease (CVD) is a major cause of mortality in patients on haemodialysis. The development of a prediction model for CVD risk is necessary to help make clinical decisions for haemodialysis patients. This retrospective study aimed to develop a prediction model for the 5-year risk of CV events and all-cause mortality in haemodialysis patients in China. Methods: We retrospectively enrolled 398 haemodialysis patients who underwent dialysis at the dialysis facility of the General Hospital of Northern Theater Command in June 2016 and were followed up for 5 years. The composite outcome was defined as CV events and/or all-cause death. Multivariable logistic regression with backwards stepwise selection was used to develop our new prediction model. Results: Seven predictors were included in the final model: age, male sex, diabetes, history of CV events, no arteriovenous fistula at dialysis initiation, a monocyte/lymphocyte ratio greater than 0.43 and a serum uric acid level less than 436 mmol/L. Discrimination and calibration were satisfactory, with a C-statistic above 0.80. The predictors lay nearly on the 45-degree line for agreement with the outcome in the calibration plot. A simple clinical score was constructed to provide the probability of 5-year CV events or all-cause mortality. Bootstrapping validation showed that the new model also has similar discrimination and calibration. Compared with the Framingham risk score (FRS) and a similar model, our model showed better performance. Conclusion: This prognostic model can be used to predict the long-term risk of CV events and all-cause mortality in haemodialysis patients. An MLR greater than 0.43 is an important prognostic factor.

Cardiac valve calcification is associated with mortality in hemodialysis patients: a retrospective cohort study.

BACKGROUND: Cardiac valve calcification (CVC) is common in end-stage renal disease (ESRD). We investigated the effect of CVC on all-cause and cardiovascular (CV) mortality in maintenance hemodialysis (MHD) patients. METHODS: A retrospective cohort study was conducted on 434 hemodialysis patients who underwent echocardiography for qualitative assessment of valve calcification with complete follow-up data from January 1, 2014, to April 30, 2021. The baseline data between the CVC and non-CVC groups were compared. The Kaplan-Meier method was used to analyse all-cause and cardiovascular mortality. The association of CVC with all-cause and cardiovascular mortality was evaluated using multivariate Cox regression analysis. RESULTS: Overall, 27.2% of patients had mitral valve calcification (MVC), and 31.8% had aortic valve calcification (AVC) on echocardiography. Patients with CVC showed significantly higher all-cause (log-rank P < 0.001) and cardiovascular (log-rank P < 0.001) mortality rates than patients without CVC. In multivariate regression analyses, MVC (HR: 1.517, P = 0.010) and AVC (HR: 1.433, P = 0.028) were significant factors associated with all-cause mortality. MVC (HR: 2.340, P < 0.001) and AVC (HR: 2.410, P < 0.001) were also significant factors associated with cardiovascular mortality. CONCLUSIONS: MVC and AVC increased the risk of all-cause and cardiovascular mortality in MHD patients. Regular follow-up with echocardiography could be a useful method for risk stratification in MHD patients.

Erratum to renal progenitor cells modulated by angiotensin II receptor blocker (ARB) medication and differentiation towards podocytes in anti-thy1.1 nephritis.

[This corrects the article DOI: 10.21037/atm.2020.02.58.].

Renal progenitor cells modulated by angiotensin II receptor blocker (ARB) medication and differentiation towards podocytes in anti-thy1.1 nephritis.

BACKGROUND: Mesangial proliferative glomerulonephritis (MsPGN) is an epidemic disease with increasing occurrence. As important as mesangial cells, podocytes are key innate cells for MsPGN prognosis and recovery. Renal progenitor cells, located at the urinary pole (UP) of Bowman's capsule (BC), could alleviate kidney injury through their capacity to differentiate into podocytes. METHODS: Seventy-two male rats were categorized randomly into the sham (n=24), untreated Thy-1 (n=24) and losartan-treated (n=24) groups. We administered vehicle or losartan (50 mg/kg by gavage) daily to treat rats with anti-thy1.1 nephritis, an ideal model to simulate human MsPGN. Two weeks after the intravenous injection of antibody, urinary protein and blood samples were analyzed, pathological changes were examined, the number of podocytes was determined, and renal progenitor cells were studied. RESULTS: Anti-thy1.1 nephritis was significantly alleviated after losartan treatment, as reported previously and as expected. Compared with the untreated Thy-1 group, the number of podocytes in the losartan group increased, and the area of renal progenitor cells significantly increased. The protein expression of components of the p-ERK pathway was determined during the development of renal progenitor cells differentiating into podocytes. CONCLUSIONS: The data in this paper show the direct glomerular cell action of angiotensin II receptor blocker (ARB) treatment in improving outcomes in anti-thy1.1 nephritis. The positive effects of ARB medication on anti-thy1.1 nephritis were due to an increase in the number of renal epithelial progenitor cells (defined as PECs that expressed only stem cell markers without podocyte proteins).

Suppressor of Cytokine Signaling-1/STAT1 Regulates Renal Inflammation in Mesangial Proliferative Glomerulonephritis Models.

Mesangial proliferative glomerulonephritis (MsGN) is a significant global threat to public health. Inflammation plays a crucial role in MsGN; however, the underlying mechanism remains unknown. Herein, we demonstrate that suppression of the cytokine signaling-1 (SOCS1)/signal transducer and activator of transcription 1 (STAT1) signaling pathway is associated with renal inflammation and renal injury in MsGN. Using MsGN rat (Thy1.1 GN) and mouse (Habu GN) models, renal SOCS1/STAT1 was determined to be associated with CD4+ T cell infiltration and related cytokines. In vitro, SOCS1 overexpression repressed IFN-γ-induced MHC class II and cytokine levels and STAT1 phosphorylation in mesangial cells. SOCS1 and STAT1 inhibitors significantly inhibited IFN-γ-induced CIITA promoter activity and MHC class II expression. In conclusion, our study emphasizes the pivotal role of the SOCS1/STAT1 axis in the regulation of inflammation in MsGN.

IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway.

Mesenchymal stem cells (MSCs) are effective for the management of experimental ischemia-reperfusion acute kidney injury (IRI-AKI). Immune modulation is one of the important mechanisms of MSCs treatment. Interleukin-17A (IL-17A) pretreated MSCs are more immunosuppressive with minimal changes in immunogenicity in vitro. Here, we demonstrated that administration of IL-17A-pretreated MSCs resulted in significantly lower acute tubular necrosis scores, serum creatinine, and BUN of mice with IRI-AKI, compared with the administration of MSCs. Of the co-cultured splenocytes, IL-17A-pretreated MSCs significantly increased the percentages of CD4+Foxp3+ Tregs and decreased concanavalin A-induced T cell proliferation. Furthermore, mice with IRI-AKI that underwent IL-17A-pretreated MSC therapy had significantly lower serum IL-6, TNF-α, and IFN-γ levels, a higher serum IL-10 level, and higher spleen and kidney Treg percentages than the mice that underwent MSCs treatment. Additionally, the depletion of Tregs by PC61 (anti-CD25 antibody) reversed the enhanced treatment efficacy of the IL-17A-pretreatedMSCs on mice with IRI-AKI. Additionally, IL-17A upregulated COX-2 expression and increased PGE2 production. The blockage of COX-2 by celecoxib reversed the benefit of IL-pretreated 17A-MSCs on the serum PGE2 concentration, spleen and kidney Tregs percentages, serum creatinine and BUN levels, renal acute tubular necrosis scores, and serum IL-6, TNF-α, IFN-γ, and IL-10 levels of IRI-pretreated mice with AKI, compared with MSCs. Thus, our results suggest that IL-17A pretreatment enhances the efficacy of MSCs on mice with IRI-AKI by increasing the Treg percentages through the COX-2/PGE2 pathway.

Effect of Huaier On the Proliferation of Mesangial Cells in Anti-Thy-1 Nephritis.

BACKGROUND/AIMS: To determine whether an aqueous extract of Trametes robiniophila Murr. (Huaier) suppresses anti-Thy-1 mesangial proliferative glomerulonephritis (MsPGN) in vivo and platelet-derived growth factor (PDGF)-BB-induced mesangial cell proliferation in vitro. METHODS: Male Wistar rats were randomly categorized into 5 groups: Sham, Thy-1, and 3 Huaier-treated groups (low, medium, and high dose). Two weeks after treatment, urinary proteins were quantified and renal pathological changes were examined. MAX interactor 1 (Mxi-1) and proliferating cell nuclear antigen (PCNA) expression levels in isolated glomeruli, rat mesangial cell viability, cell-cycle distribution, and cell-cycle pathways were assessed. RESULTS: Huaier diminished the proliferative damages and urinary protein secretion in Thy-1 rats. PCNA was downregulated, whereas Mxi-1 was upregulated in the isolated glomeruli of Huaier-treated groups compared with the Thy-1 group. Huaier inhibited PDGF-BB- stimulated proliferation of rat mesangial cells in a time- and dose-dependent manner (50% inhibitory concentration = 6.19 mg/mL) and induced G2 cell-cycle arrest. Cell-cycle pathway proteins were downregulated, whereas Mxi-1 was upregulated in Huaier-treated mesangial cells compared with PDGF-BB-stimulated cells. CONCLUSION: Huaier reduces urinary protein excretion and relieves hyperplasia in mesangial cells in anti-Thy-1 MsPGN as well as inhibits PDGF-BB-stimulated proliferation and DNA synthesis of rat mesangial cells in vitro, suggesting its novel therapeutic potential in MsPGN.

Risk factors of prognosis after acute kidney injury in hospitalized patients.

The risk factors, especially laboratory indicators, of prognosis after acute kidney injury (AKI) remain unclear. We conducted a retrospective survey of Chinese People's Liberation Army General Hospital from January 1, 2012 to December 31, 2012 according to the AKI diagnosis standard issued by Kidney Disease Improving Global Outcomes. The epidemiological features and factors influencing hospital mortality and renal function recovery were evaluated through logistic regression analysis. Among 77 662 cases of hospitalized patients, 1387 suffered from AKI. The incidence rate and mortality of AKI were 1.79% and 14.56%, respectively. Multivariate logistic regression analysis revealed that high AKI stage, age greater than 80 years, neoplastic disease, low cardiac output, increased white blood cell count, and decreased platelet count and serum albumin levels were the risk factors affecting the mortality of AKI patients. Conversely, body mass index between 28 and 34.9 was a protective factor. Increased AKI stage, tumor disease, post-cardiopulmonary resuscitation, and RRT were the risk factors of renal function recovery upon discharge. In addition to traditional risk factors, white blood cell count, platelet count, albumin, and BMI were the predictors of the mortality of AKI patients. No laboratory indicators were found to be the risk factors of renal function recovery in AKI patients.

Erythropoietin Inhibits Hypoxia-Induced Epithelial-To-Mesenchymal Transition via Upregulation of miR-200b in HK-2 Cells.

BACKGROUND/AIMS: Renal tubular epithelial-mesenchymal transition (EMT) is regarded as an important factor leading to renal interstitial fibrosis. Erythropoietin (EPO) has been reported to attenuate renal fibrosis. The mechanism underlying this protective effect of EPO remains unclear. In this study, we aim to identify possible mechanisms of the EPO renoprotective effect. METHODS: Hypoxia was induced in vitro by incubating human proximal tubular epithelial cell line HK-2 cells in 1% O2 and 5% CO2. Western blotting and reverse transcription polymerase chain reaction analyses were used to evaluate the expression of epithelial and mesenchymal markers in the cell samples. The expression of miR-200b in the HK-2 cells under hypoxia or treatment with EPO was examined. RESULTS: EPO represses hypoxia-induced EMT by upregulating miR-200b in HK-2 cells. Overexpression of miR-200b represses the effect of ETS proto-oncogene 1 (Ets-1)-induced EMT in HK-2 cells. CONCLUSION: miR-200 mediates the protective effects of EPO on EMT in hypoxic HK-2 cells. EPO attenuated hypoxia-induced EMT by increasing miR-200 expression via the repression of Ets-1.

Netrin-1 attenuates the progression of renal dysfunction by blocking endothelial-to-mesenchymal transition in the 5/6 nephrectomy rat model.

BACKGROUND: Endothelial-to-mesenchymal transition (EndoMT) is a crucial event during kidney interstitial fibrosis and it is believed to be inhibited by netrin-1. Our aim was to determine the influence of netrin-1 on renal EndoMT in chronic kidney disease by studying its effect in 5/6 nephrectomized (Nx) rats. METHODS: Male Sprague-Dawley rats were divided into three groups (10 rats/group): sham-operated rats treated with control adenovirus; 5/6 Nx rats treated with control adenovirus; and 5/6 Nx rats treated with recombinant adenovirus expressing the netrin-1 gene (Ad-netrin-1). Rats were sacrificed 13 weeks after surgery. Blood urea nitrogen (BUN) and serum creatinine (Scr) levels were measured regularly after surgery. After the rats were sacrificed, pathological changes in renal tissues were analyzed histologically. Immunofluorescence was performed to evaluate the co-expression of CD31 and α-SMA. CD31, α-SMA and Snail mRNA were detected by RT-PCR. Protein expression was detected by western blot. RESULTS: Renal function and histopathological damage were significantly improved in Ad-netrin-1-treated 5/6 Nx rats. In the sham and control-treated 5/6 Nx rats, the percentage of CD31(+)/α-SMA(+) cells increased, which indicated EndoMT. However, the percentage of CD31(+)/α-SMA(+) cells were reduced in the netrin-1-treated 5/6 Nx rats, which indicates netrin-1-induced blocking of EndoMT. CONCLUSION: From the results, it seems that netrin-1 attenuates the progression of renal dysfunction by inhibiting EndoMT in 5/6 Nx rats. Netrin-1 can therefore be considered as a potential therapeutic agent for the treatment of renal fibrosis.

Identification of potential biomarkers for clear cell renal cell carcinoma based on microRNA-mRNA pathway relationships.

BACKGROUND: MicroRNAs (miRNAs) play important roles in tumor genesis. miRNA dysregulation has been widely studied and demonstrated in clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We applied a newly proposed method for selecting miRNAs that discriminate between healthy controls and cancers. We initially extracted different miRNAs and mRNAs and then selected miRNA-mRNA dysregulation pairs. The pathways that involved mRNAs were acquired according to the functional enrichment. We integrated the miRNAs, mRNAs, and pathways and constructed the miRNA-mRNA pathway relationships based on the derived significant miRNAs. RESULTS: We acquired 566 antiregulated miRNA-mRNA pairs including 56 miRNAs and 485 mRNAs. Three significant pathways related to ccRCC, namely, arginine and proline metabolism, aldosterone-regulated sodium reabsorption, and oxidative phosphorylation, were observed. Based on the miRNA-mRNA pathway relationships, five significant miRNAs were identified as potential biomarkers: hsa-miR-425, hsa-miR-136, hsa-miR-335, hsa-miR-340, and hsa-miR-320d. CONCLUSION: This integrative network approach revealed important miRNAs in the ccRCC that can identify specific disease biomarkers, which can be used as targets for cancer treatment.

Tele-ICU: the way forward in geriatric care?

Aging population is set to increase in the near future, and will need specialized care when admitted to ICUs. The elderly are beset with chronic conditions, such as cardiovascular, COPD, diabetes, renal complications and depression. Specialist opinions can now be made available through telemedicine facilities. Tele-ICU is a specialized hub consisting of highly skilled staff trained in critical care able to deliver timely, quality care service to patients admitted to ICUs in remote areas using highly advanced information technology services. These specialists in the tele-ICU hub are able to analyze and gather data arriving at timely interventional management decisions and provide this vital feedback to the nursing staff and doctors manning remote ICU locations where specialized intensivist may not be available. Known clinical benefits of such a system include better patient outcomes, reduced medical errors, mortality and reduced hospital length of stay. The main disadvantage in implementation could be the upfront high cost involved, for which low-cost models are being explored. In the face of delivering such remote care, it is up to the local health policy to make legislative changes to include associated legal and ethical issues. Considering the burgeoning aging population, tele-ICU could become the way forward in delivering geriatric critical care.

Tamoxifen represses miR-200 microRNAs and promotes epithelial-to-mesenchymal transition by up-regulating c-Myc in endometrial carcinoma cell lines.

Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it.

Netrin-1 attenuates the progression of renal dysfunction by inhibiting peritubular capillary loss and hypoxia in 5/6 nephrectomized rats.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of netrin-1 on peritubular capillary (PTC) loss and hypoxia in 5/6 nephrectomized (Nx) rats. METHODS: Male Sprague-Dawley rats were divided into three groups (n = 10 rats/group): sham-operated rats treated with control adenovirus; 5/6 Nx rats treated with control adenovirus; and 5/6 Nx rats treated with recombinant adenovirus mediated netrin-1 gene (Ad-netrin-1) therapy. Rats were killed 12 weeks after surgery. Blood urea nitrogen (BUN), serum creatinine (Scr) and 24-h urinary albumin excretion rates were measured. Pathological changes in renal tissues were analyzed histologically. The concentration of netrin-1, CD34, and hypoxia-inducible factor-1α (HIF-1α) were analyzed by immunohistochemistry, Western blotting and real-time PCR. RESULTS: Renal function and histopathological damage were significantly improved in Adnetrin-1 treated 5/6 Nx rats, compared with rats treated with the control adenovirus in the 5/6 Nx group. Furthermore, Ad-netrin-1 treatment induced a significant increase in renal PTC density, accompanied by a significant decrease in HIF-1α expression. CONCLUSION: Adenovirus mediated netrin-1 treatment attenuates PTC damage, relieves tissues hypoxia and improves renal function, thus alleviating renal pathological changes and interstitial fibrosis in 5/6 Nx rats.

TSA suppresses miR-106b-93-25 cluster expression through downregulation of MYC and inhibits proliferation and induces apoptosis in human EMC.

Histone deacetylase (HDAC) inhibitors are emerging as a novel class of anti-tumor agents and have manifested the ability to decrease proliferation and increase apoptosis in different cancer cells. A significant number of genes have been identified as potential effectors responsible for the anti-tumor function of HDAC inhibitor. However, the molecular mechanisms of these HDAC inhibitors in this process remain largely undefined. In the current study, we searched for microRNAs (miRs) that were affected by HDAC inhibitor trichostatin (TSA) and investigated their effects in endometrial cancer (EMC) cells. Our data showed that TSA significantly inhibited the growth of EMC cells and induced their apoptosis. Among the miRNAs that altered in the presence of TSA, the miR-106b-93-25 cluster, together with its host gene MCM7, were obviously down-regulated in EMC cells. p21 and BIM, which were identified as target genes of miR-106b-93-25 cluster, increased in TSA treated tumor cells and were responsible for cell cycle arrest and apoptosis. We further identified MYC as a regulator of miR-106b-93-25 cluster and demonstrated its down-regulation in the presence of TSA resulted in the reduction of miR-106b-93-25 cluster and up-regulation of p21 and BIM. More important, we found miR-106b-93-25 cluster was up-regulated in clinical EMC samples in association with the overexpression of MCM7 and MYC and the down-regulation of p21 and BIM. Thus our studies strongly indicated TSA inhibited EMC cell growth and induced cell apoptosis and cell cycle arrest at least partially through the down-regulation of the miR-106b-93-25 cluster and up-regulation of it's target genes p21 and BIM via MYC.