Publications by authors named "Changchun Cao"

48 Publications

Association between nonalcoholic fatty liver disease and incident diabetes mellitus among Japanese: a retrospective cohort study using propensity score matching.

Lipids Health Dis 2021 Jun 15;20(1):59. Epub 2021 Jun 15.

Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, Guangdong Province, China.

Background: Previous studies have demonstrated that nonalcoholic fatty liver disease (NAFLD) is a significant risk factor for diabetes mellitus (DM). However, these studies did not completely determine the relationship between NAFLD and DM due to unbalanced confounding factors. The propensity score (PS) is the conditional probability of having a particular exposure, given a set of baseline measured covariates. Propensity score matching (PSM) analysis could minimise the effects of potential confounders. Thus, this study aimed to use PSM analysis to explore the association between NAFLD and DM in a large Japanese cohort.

Methods: This retrospective PSM cohort study was performed on 14,280 Japanese participants without DM at baseline in Murakami Memorial Hospital between 2004 and 2015. The independent variable was NAFLD at baseline, and the outcome was the incidence of DM during follow-up. One-to-one PSM revealed 1671 participants with and without NAFLD. A doubly robust estimation method was applied to verify the correlation between NAFLD and DM.

Results: The risk of developing DM in participants with NAFLD increased by 98% according to the PSM analysis (HR = 1.98, 95% confidence interval [CI]: 1.41-2.80, P < 0.0001). The risk of developing DM in the NAFLD participants was 2.33 times that of the non-NAFLD participants in the PSM cohort after adjusting for the demographic and laboratory biochemical variables (HR = 2.33, 95% CI: 1.63-3.32, P < 0.0001). The participants with NAFLD had a 95% increased risk of DM after adjusting for PS (HR = 1.95, 95% CI: 1.39-2.75, P = 0.0001). All potential confounding variables were not significantly associated with NAFLD and DM after PSM in the subgroup analysis. In the sensitivity analysis, the participants with NAFLD had a 2.17-fold higher risk of developing DM in the original cohort (HR = 2.17, 95% CI: 1.63-2.88, P < 0.0001) and were 2.27-fold more likely to develop DM in the weighted cohort (HR = 2.27, 95% CI: 1.91-2.69, P < 0.00001).

Conclusions: NAFLD was an independent risk factor for the development of DM. The risk of developing DM in the NAFLD participants was 2.33 times that of the non-NAFLD participants in the PSM cohort after adjusting for the demographic and laboratory biochemical variables. The participants with NAFLD had a 95% increased risk of DM after adjusting for PS.
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http://dx.doi.org/10.1186/s12944-021-01485-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207755PMC
June 2021

Indoleamine-2,3-Dioxygenase Activates Wnt/β-Catenin Inducing Kidney Fibrosis after Acute Kidney Injury.

Gerontology 2021 Jun 15:1-9. Epub 2021 Jun 15.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Introduction: As disorder of tryptophan metabolism is common in CKD, the rate-limiting enzyme of tryptophan, indoleamine-2,3-dioxygenase (IDO), has been reported to be involved in CKD, while the accurate mechanism remains unknown. This study was designed to explore correlations between IDO and kidney fibrosis after ischemia-reperfusion injury (IRI).

Methods: Wild-type (WT) mice and IDO knockout (IDO-/-) mice were divided into the sham group and acute kidney injury (AKI) group. Mice in the sham group underwent dorsal incision and exposure of renal pedicle without clamping renal artery, while mice in the AKI group received unique renal artery IRI, and the contralateral kidney was removed at day 13 after IRI. Blood and IRI kidneys were collected at day 14. Kidney function was analyzed by measuring serum Cr and BUN. Morphology was analyzed by tissue periodic acid-Schiff (PAS) staining and Masson staining. Further, fibrosis markers and Wnt/β-catenin pathway proteins were determined by Western blot. Prostaglandin E2 (PGE2) was administrated for 2 weeks after the IRI mice model was established to observe whether it ameliorates kidney fibrosis after IRI.

Results: WT AKI mice revealed elevated expression of IDO compared with WT sham mice. Kidney function of IDO-/- AKI mice showed better than that of WT AKI mice. PAS staining exhibited less loss of tubular epithelial cells and atrophy tubules in IDO-/- AKI mice. Furthermore, kidney fibrosis areas and the expressions of fibrosis markers, including α-SMA, fibronectin, and vimentin, were increased in WT AKI mice. In addition, GSK-3β and β-catenin were significantly declined in IDO-/- AKI mice. On top of that, PGE2 administration revealed inhibited IDO expression and that reducing GSK-3β and β-catenin resulting in lower expressions of α-SMA, fibronectin, and vimentin in WT AKI mice.

Conclusions: IRI could increase IDO expression to activate Wnt/β-catenin pathway resulting kidney fibrosis. PGE2 could ameliorate kidney fibrosis via inhibiting IDO expression.
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http://dx.doi.org/10.1159/000515041DOI Listing
June 2021

ITPRIP promotes glioma progression by linking MYL9 to DAPK1 inhibition.

Cell Signal 2021 Jun 7;85:110062. Epub 2021 Jun 7.

Department of Neurosurgery, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaian 223300, China. Electronic address:

Epigenetic gene silencing of the tumor suppressor death-associated protein kinase 1 (DAPK1) is implicated in the progression of malignant gliomas. However, the mechanism underlying the repression of DAPK1 in gliomas remains elusive. In this study, we identified the existence of DAPK1-inositol 1,4,5-trisphosphate receptor (IPR)-interacting protein (ITPRIP) -myosin regulatory light polypeptide 9 (MYL9) complex in malignant glioma cells. Lentivirus co-infection and coimmunoprecipitation showed that ITPRIP bound with the death domain (DD) of DAPK1 in vitro. Further, dissociating ITPRIP-DAPK1 interaction inhibited glioma tumor growth in vitro but not in vivo. Moreover, knockdown of ITPRIP or DAPK1 impaired the ternary complex formation, whereas MYL9 knockdown did not affect ITPRIP-DAPK1 association. We further found that ITPRIP recruited MYL9 to the kinase domain (KD) of DAPK1, and in turn impeded the phosphorylation of MYL9. Accordingly, interference of ITPRIP enhanced the suppressive effects of DAPK1-KD on glioma progression both in vitro and in vivo. Our results demonstrate that ITPRIP plays a crucial role in the inhibition of DAPK1 and enhancement of tumorigenic properties of malignant glioma cells.
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http://dx.doi.org/10.1016/j.cellsig.2021.110062DOI Listing
June 2021

Impact of acute kidney injury on in-hospital outcomes in Chinese patients with community acquired pneumonia.

BMC Pulm Med 2021 May 1;21(1):143. Epub 2021 May 1.

Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu, China.

Background: Acute kidney injury (AKI) is a frequent complication of community acquired pneumonia (CAP). However, the impact of AKI on in-hospital outcomes of patients with CAP in the Chinese population remains unclear.

Methods: Patients diagnosed with CAP were evaluated in this retrospective observational study. Multiple Cox regression models were employed to identify the association between AKI and in-hospital mortality and 30-day mortality, respectively.

Results: A total of 4213 patients were recruited; 950 (22.5%) patients were diagnosed with AKI. Independent risk factors for AKI were age, male gender, hypertension, cardiac dysfunction, diabetes, chronic kidney disease, acute respiratory failure, use of diuretics, use of vasoactive drugs, and CURB-65. Cox proportional hazards regression revealed AKI, use of angiotensin receptor blocker, hypertension, CURB-65, acute respiratory failure, and use of vasoactive drugs to be independent risk factors for both in-hospital and 30-day mortality. Compared to patients without AKI, those suffering AKI were found to have 1.31-fold (HR 1.31, 95% CI, 1.04-1.66; P = 0.023) and 1.29-fold (HR 1.29, 95% CI, 1.02-1.62; P = 0.033) increased in-hospital and 30-day mortality risks, respectively. In addition, patients with AKI were likely to require admission to intensive care unit (ICU) (42.9% versus 11.4%; P < 0.001), mechanical ventilation (33.8% versus 9.3%; P < 0.001), invasive mechanical ventilation (25.9% versus 5.8%; P < 0.001), non-invasive mechanical ventilation (25.4% versus 7.1%; P < 0.001), and experienced a longer duration of hospital stay (14 days versus 10 days; P < 0.001) than those without AKI. However, no significant difference in ICU stay (11 days versus 10 days; P = 0.099) and duration of mechanical ventilation (8 days versus 8 days; P = 0.369) between AKI and non-AKI groups was found.

Conclusion: AKI was common in Chinese patients with CAP. Patients with CAP who developed AKI had worse in-hospital outcomes.
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http://dx.doi.org/10.1186/s12890-021-01511-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088559PMC
May 2021

Correlation of Indoleamine-2,3-Dioxygenase and Chronic Kidney Disease: A Pilot Study.

J Immunol Res 2021 6;2021:8132569. Epub 2021 Jan 6.

Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

Objective: To explore the correlation of indoleamine-2,3-dioxygenase (IDO) and chronic kidney disease (CKD).

Methods: A total of 154 CKD patients and 42 non-CKD patients were recruited. Patients were grouped into ACR1~ACR3 (<30 mg/g, 30-300 mg/g, and >300 mg/g). Biomarkers in different groups were compared by ANOVA. Correlation was calculated by Pearson or Spearman analysis and binary logistic regression. The ROC curve was also performed.

Results: The levels of albumin, serum creatinine (sCr), and IDO in non-CKD patients were significantly different from those in CKD3-CKD5 stages ( < 0.05). IDO was correlated with age, proteinuria, ACR, and eGFR ( < 0.01). After adjusting for CKD-related indices, ln(IDO) was an independent risk factor for CKD (3.48, < 0.05). The analysis of ROC curve revealed a best cut-off for IDO was 0.0466 and yielded a sensitivity of 83.8% and a specificity of 75%. Hemoglobin, total protein, and albumin in the ACR1 group were significantly higher than those in the ACR2 and ACR3 groups ( < 0.01), while sCr and IDO levels were significantly lower than those in the ACR2 and ACR3 groups ( < 0.01 or < 0.05). After adjusting for CKD-related indices, ln(IDO) was still an independent risk factor for ACR (OR = 2.7, < 0.05). The analysis of ROC curve revealed a best cut-off for IDO was 0.075 and yielded a sensitivity of 71.9% and a specificity of 72.2%.

Conclusion: IDO may be a promising biomarker to predict CKD and assess kidney function.
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http://dx.doi.org/10.1155/2021/8132569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806403PMC
January 2021

Serum cystatin C: A potential predictor for hospital-acquired acute kidney injury in patients with acute exacerbation of COPD.

Chron Respir Dis 2020 Jan-Dec;17:1479973120940677

Department of Nephrology, 385685Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

Hospital-acquired acute kidney injury (HA-AKI) is associated with poor prognosis. In this study, we evaluated whether serum cystatin C on admission could predict AKI in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The retrospective study was conducted using data on adult inpatients with AECOPD from January 2014 to January 2017. A total of 1035 patients were included, among which 79 (7.6%) with HA-AKI were identified. Univariate and multivariate logistic regression analyses were used to investigate predictors of HA-AKI in patients with AECOPD. HA-AKI was associated with poor prognosis, and patients with HA-AKI had higher inpatient mortality (34.2% vs. 2.6%, < 0.001). Furthermore, after adjusting for confounders, HA-AKI was an independent risk factor for inpatient mortality for patients with AECOPD (odds ratio (OR) 11.02; 95% confidence interval (CI) 4.77-25.45; < 0.001). Four independent risk factors for HA-AKI (age, levels of urea and cystatin C, and platelet count on admission) were identified in patients with AECOPD. Cystatin C (OR 5.22; 95% CI 2.49-10.95; < 0.001) was a significant independent predictor of AKI in patients with AECOPD. HA-AKI in patients with AECOPD could be identified with a sensitivity of 73.5% and a specificity of 75.9% (area under the curve (AUC) = 0.803, 95% CI 0.747-0.859) by cystatin C level (cutoff value = 1.3 mg/L) and with a sensitivity of 75.9% and a specificity of 82.0% (AUC = 0.853, 95% CI 0.810-0.896) using a model comprising all significant predictors. Serum cystatin C has the potential for use to predict the risk of HA-AKI in patients with AECOPD.
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http://dx.doi.org/10.1177/1479973120940677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493270PMC
September 2020

Retinoic Acid Alleviates Cisplatin-Induced Acute Kidney Injury Through Activation of Autophagy.

Front Pharmacol 2020 3;11:987. Epub 2020 Jul 3.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Cisplatin-induced acute kidney injury (CIAKI) is a common complication in patients receiving cisplatin-based chemotherapy. But the effective therapies for CIAKI are not available. Retinoic acid (RA), the main derivative of vitamin A, has the potential to reduce inflammation and fibrosis in renal injury. However, the effect and mechanism of RA on CIAKI are still unclear. The aim of this study is to investigate whether RA can alleviate CIAKI through activation of autophagy. In this study, we evaluated the effect of RA, RA's effect on autophagy and apoptosis after cisplatin-induced injury on renal tubular epithelial cells (RTECs) by LDH assay, immunoblotting and TUNEL staining. Then we established Atg5:Cagg-Cre mice in which Cagg-Cre is tamoxifen inducible, and Atg5 is conditional deleted after tamoxifen injection. The effect of RA and RA's effect on autophagy on CIAKI model were evaluated by biochemical assessment, hematoxylin and eosin (HE) staining, and immunoblotting in the control and autophagy deficient mice. , RA protected RTECs against cisplatin-induced injury, activated autophagy, and inhibited cisplatin-induced apoptosis. , RA attenuated cisplatin-induced tubular damage, shown by improved renal function, decreased renal cast formation, decreased NGAL expression, and activated autophagy in the control mice. Furthermore, the nephrotoxicity of cisplatin was aggravated, and the protective effect of RA was attenuated in autophagy deficient mice, indicating that RA works in an autophagy-dependent manner on CIAKI. RA activates autophagy and alleviates CIAKI and .Thus RA may be a renoprotective adjuvant for cisplatin-based chemotherapy.
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http://dx.doi.org/10.3389/fphar.2020.00987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348052PMC
July 2020

Incidence, Risk Factors, and Prognostic Implications of Acute Kidney Injury in Patients with Acute Exacerbation of COPD.

Int J Chron Obstruct Pulmon Dis 2020 15;15:1085-1092. Epub 2020 May 15.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

Purpose: Little is known about the incidence, risk factors, and prognostic implications of acute kidney injury (AKI) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in China. In this study, we investigated the incidence, risk factors, and short-term outcomes of AKI in these patients.

Patients And Methods: We analyzed the records of 1768 patients admitted to Nanjing First Hospital with a principal diagnosis of AECOPD. Of these, 377 patients had AKI.

Results: AKI occurred in 377 patients (21%). Independent risk factors for AKI in patients with AECOPD were advanced age, coronary artery disease, anemia, cancer, chronic kidney disease, hypercapnic encephalopathy, acute respiratory failure, and mechanical ventilation. Patients with AKI had worse prognostic implications and were more likely to require mechanical ventilation (38.7% vs 19.1%, <0.001); non-invasive mechanical ventilation (38.2% vs 18.9%, <0.001); invasive mechanical ventilation (18.3% vs 3.1%, <0.001); intensive care unit (ICU) admission (33.7% vs 12.9%, <0.001); had a longer ICU stay (9 days vs 8 days, =0.033) and longer hospitalization (13 days vs 10 days, <0.001); and higher in-hospital mortality (18.0% vs 2.7%, <0.001) than those without AKI. Multivariable analysis indicated that compared to patients without AKI, those with stage 1, 2, or 3 AKI had a 1.9-fold, 2.1-fold, or 6.0-fold increased risk of in-hospital death, respectively.

Conclusion: AKI is common in patients with AECOPD requiring hospitalization. Patients with AKI have worse short-term outcomes. Thus, AKI may be a prognostic predictor of patient survival.
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http://dx.doi.org/10.2147/COPD.S238343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237118PMC
June 2021

Kidney injury induced by elevated histones in community-acquired pneumonia.

Mol Cell Biochem 2020 Aug 9;471(1-2):155-163. Epub 2020 Jun 9.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, 109 Longmian Road, Nanjing, 211166, Jiangsu, China.

Previous studies showed that extracellular histones could damage organs, but the role of extracellular histones in pneumonia patients with acute kidney injury (AKI) is unknown. This study aims to investigate the impact of extracellular histones on patients with community-acquired pneumonia (CAP) developed AKI. Blood samples were obtained within 24 h after admission to hospital from patients who were diagnosed with CAP. According to the discharge diagnosis, the patients were divided into 2 groups (Non-AKI and AKI). In vitro, A549 cells were treated with lipopolysaccharides (LPS) and conditioned media were collected. HK2 cells were exposed to the conditioned media or not. Cells proliferation and apoptosis of HK2 were determined. Clinically, Log Histones (OR 3.068; 95% CI 1.544-6.097, P = 0.001) and estimated glomerular filtration rate (eGFR) (OR 0.945; 95% CI 0.914-0.978, P = 0.001) were predictors of AKI in CAP patients. Compared to the lower histones group, patients in the higher histones group were more likely to be admitted to ICU, receive mechanical ventilation, and have a longer length of in-hospital stay. In vitro, A549 cells injured by LPS released extracellular histones, in conditioned media which significantly promoted HK2 cells apoptosis. Extracellular histones was a high risk factor for developing AKI in CAP patients and a predictor of worse short-term outcomes. We also showed that extracellular histones in conditioned media damaged HK2 cells.Trial registration number: KY20181102-03; Date of registration: 20181102.
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http://dx.doi.org/10.1007/s11010-020-03775-xDOI Listing
August 2020

Efficacy and Safety of Ureteral Catheter Use During Arteriovenous Fistula in End-Stage Renal Disease Patients with Poor Vascular Status.

Med Sci Monit 2020 May 29;26:e920421. Epub 2020 May 29.

Kidney Disease Center, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China (mainland).

BACKGROUND The aim of this study was to evaluate the efficacy and safety of use of a ureteral catheter during arteriovenous fistula in end-stage renal disease patients with poor vascular status. MATERIAL AND METHODS Fifty patients with standard arteriovenous fistulas at Sir Run Run Hospital of Nanjing Medical University from April 2018 to April 2019 were included. Based on the use of ureteral catheter exploration and tourniquet hydraulic dilatation, patients were divided into study and control groups. The operative success rate, inner diameter of cephalic vein 1 day post-operatively, blood flow in the internal fistula, patency rate and blood flow in the internal fistula 3 months post-operatively, and complications 6 months post-operatively were compared between the 2 groups. RESULTS There were 25 cases in each group, with no significant differences in sex or age between the 2 groups. The operative success rate in the study group was higher than in the control group (96% vs. 88%) (F=1.087, P=0.297). The patency rates at 3 and 6 months post-operatively in the study group were higher than in the control group. The inner diameter of the cephalic vein 1 day post-operatively, the blood flow in the internal fistula, and the complications 6 months post-operatively in the study group were significantly superior to those of the control group (P=0.002). CONCLUSIONS In standard arteriovenous fistula, especially vascular catheter exploration of unhealthy vessels, the application of a ureteral catheter can improve the operative success rate and promote internal fistula maturity, with low cost and ease of use.
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http://dx.doi.org/10.12659/MSM.920421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282533PMC
May 2020

Initial serum creatinine concentration affects clinical outcomes in patients with IgA nephropathy treated with mycophenolate mofetil combined with low-dose prednisone.

Exp Ther Med 2020 May 5;19(5):3369-3376. Epub 2020 Mar 5.

Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China.

Indicators for predicting the efficacy of mycophenolate mofetil (MMF) have so far remained elusive. The present study aimed to identify predictive indicators of the efficacy of MMF combined with low-dose prednisone in patients with IgA nephropathy. A total of 598 patients presenting with primary IgA nephropathy at our center were screened. Patients were followed up for 18 months, where the end-point was defined as complete clinical remission. Cox proportional hazards models were performed for analyzing the initial serum creatinine (SCr) concentration to predict incomplete clinical remission. In total, 7 of 71 patients (9.86%) were in complete clinical remission at the final visit. Logistic regression indicated that the hazard ratio (HR) for quartile 4 was significantly higher than the HR for quartile 1 (quartile 4 vs. quartile 1: HR, 2.51; 95% CI, 1.20-5.21; P=0.01). Additional adjustment for the confounding variables, including age, sex, systolic BP, diastolic BP, proteinuria, uric acid, serum triglyceride, hemoglobin, serum albumin, serum total cholesterol and The Oxford classification of the models, did not reduce the HRs for the association between the initial SCr concentration and risk of incomplete clinical remission (quartile 4 vs. quartile 1: HR, 7.27; 95% CI, 1.21-43.63; P=0.03). Each unit increase in the initial SCr concentration was associated with a 67 and 194% increase in the risk of incomplete clinical remission based on model 1 (95% CI, 1.02-2.73; P=0.04) and model 2 (95% CI, 1.01-8.60; P=0.048), respectively. In conclusion, in the present cohort of patients with IgA nephropathy treated with MMF plus low-dose prednisone, the initial SCr concentration was an independent risk factor for incomplete clinical remission.
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http://dx.doi.org/10.3892/etm.2020.8573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132257PMC
May 2020

Renin-angiotensin-aldosterone system blockade is associated with higher risk of contrast-induced acute kidney injury in patients with diabetes.

Aging (Albany NY) 2020 04 2;12(7):5858-5877. Epub 2020 Apr 2.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu, China.

As the incidence of diabetes and cardiovascular comorbidities continues to rise, driven by increased prevalence of obesity and an aging population, so does the demand for percutaneous coronary intervention (PCI) to restore cardiac blood flow. Renin-angiotensin-aldosterone system (RAAS) inhibitors are commonly prescribed to hypertensive diabetic patients to prevent diabetic nephropathy. However, evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of contrast-induced acute kidney injury (CIAKI) following coronary angiography (CAG) and PCI. We therefore conducted a retrospective, multicenter study applying the propensity score matching method to evaluate the impact of RAAS inhibition on CIAKI in diabetic patients undergoing CAG/PCI. Among 2240 subjects that met the inclusion criteria, 704 patients in the ACEIs/ARBs group were successfully matched to eligible control patients. The incidence of CIAKI (serum creatinine increase ≥0.5 mg/dl or ≥25% from baseline within 72 h post-CAG/PCI) was significantly higher in the ACEIs/ARBs group than in the control group (26.6% vs. 16.2%, <0.001). However, control patients showed increased risk of overall adverse cardiovascular events (4.1% vs. 1.8% for ACEIs/ARBs; =0.016). These data indicate that RAAS inhibition increases the risk of CIAKI in diabetic patients, but confers protection against early cardiovascular events.
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http://dx.doi.org/10.18632/aging.102982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185147PMC
April 2020

Interaction of calcium binding protein S100A16 with myosin-9 promotes cytoskeleton reorganization in renal tubulointerstitial fibrosis.

Cell Death Dis 2020 02 24;11(2):146. Epub 2020 Feb 24.

Department of Pathophysiology, Nanjing Medical University, 211166, Nanjing, China.

Renal fibrosis arises by the generation of matrix-producing fibroblasts and myofibroblasts through the epithelial-mesenchymal transition (EMT), a process in which epithelial cells undergo a transition into a fibroblast phenotype. A key feature of the EMT is the reorganization of the cytoskeletons, which may involve the Ca-binding protein S100A16, a newly reported member of the S100 protein family. However, very few studies have examined the role of S100A16 in renal tubulointerstitial fibrosis. In this study, S100A16 expression was examined by immunohistochemical staining of kidney biopsy specimens from patients with various nephropathies and kidney tissues from a unilateral ureteral obstruction (UUO) mouse model. Renal histological changes were investigated in S100A16, S100A16, and WT mouse kidneys after UUO. The expression of epithelia marker E-cadherin, mesenchymal markers N-cadherin, and vimentin, extracellular matrix protein, and S100A16, as well as the organization of F-actin, were investigated in S100A16 overexpression or knockdown HK-2 cells. Mass spectrometry was employed to screen for S100A16 binding proteins in HK-2 cells. The results indicated that S100A16 is high expressed and associated with renal tubulointerstitial fibrosis in patient kidney biopsies and in those from UUO mice. S100A16 promotes renal interstitial fibrosis in UUO mice. S100A16 expression responded to increasing Ca and interacted with myosin-9 during kidney injury or TGF-β stimulation to promote cytoskeleton reorganization and EMT progression in renal tubulointerstitial fibrosis. Therefore, S100A16 is a critical regulator of renal tubulointerstitial fibroblast activation and is therefore a potential therapeutic target for the treatment of renal fibrosis.
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http://dx.doi.org/10.1038/s41419-020-2337-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039973PMC
February 2020

A Novel Prognostic Index Based on Alternative Splicing in Papillary Renal Cell Carcinoma.

Front Genet 2019 29;10:1333. Epub 2020 Jan 29.

Department of Urology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Background: Papillary renal cell carcinoma (pRCC) is a heterogeneous multifocal or isolated tumor with an invasive phenotype. Previous studies presented that alternative splicing, as a crucial posttranscriptional regulator in gene expression, is associated with tumorigenesis. However, the association between alternative splicing and pRCC has not been clarified.

Methods: The RNA sequencing data and clinical information were downloaded from The Cancer Genome Atlas database and mRNA splicing profiles from TCGASpliceSeq. The percent spliced in data of alternative splicing merged with survival information was firstly calculated by univariate Cox regression analysis to screen for survival-associated alternative splicing events, and survival-associated alternative splicing events were then analyzed by Gene Ontology categories using Kyoto Encyclopedia of Genes and Genomes. Meanwhile, the least absolute shrinkage and selection operator Cox analysis and multivariate Cox analysis were performed to calculate the prognostic index for each alternative splicing type. In addition, clinical factors were introduced to assess the performance of prognostic index.

Results: A total of 4,084 candidate survival-associated alternative splicing events in 2,558 genes were screened out. Patients were divided into the low-risk group and the high-risk group based on the median prognostic index value. The Kaplan-Meier survival analysis (p < 0.05) and receiver operating characteristics curves (AUC>0.9) indicated that prognostic index was effective and stable for predicting the prognosis of pRCC patients. Furthermore, a regulatory network was constructed incorporating alternative splicing events and survival-associated splicing factors.

Conclusion: Our study provides new insights into the mechanism of alternative splicing events in tumorigenesis and their clinical potential for pRCC.
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http://dx.doi.org/10.3389/fgene.2019.01333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999693PMC
January 2020

HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis.

FASEB J 2020 03 4;34(3):4591-4601. Epub 2020 Feb 4.

Department of Pathophysiology, Nanjing Medical University, Nanjing, China.

Injury of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. HUWE1, an E3 ubiquitin ligase, acts by participating in ubiquitination and degradation of its target proteins. However, the detailed mechanisms by which HUWE1 might regulate fibrosis in renal tubular epithelial cells have not been established. Here, the possible regulation of renal tubulointerstitial fibrosis by HUWE1 was investigated by examining the expression of HUWE1 and EGFR in unilateral ureteral obstruction (UUO) mice. Markedly consistent reciprocal changes in HUWE1 and EGFR expression were observed at the protein and mRNA levels in the kidney after UUO injury. Expression of HUWE1 inhibited TGF-β-induced injury to HK-2 cells, while HUWE1 overexpression decreased the expression of EGFR. Further analysis indicated that HUWE1 physically interacted with EGFR and promoted its ubiquitination and degradation. HUWE1 expression also showed clinical relevance in renal disease, as it notably decreased in multiple types of clinical nephropathy, while EGFR expression significantly increased when compared to the normal kidney. Therefore, this study demonstrated that HUWE1, which serves as an E3 ubiquitin ligase specific for EGFR, promotes EGFR ubiquitination and degradation, thereby regulating EGFR expression and providing protection against kidney injury.
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http://dx.doi.org/10.1096/fj.201902751RDOI Listing
March 2020

Complement C3 and Nonalcoholic Fatty Liver Disease in Chronic Kidney Disease Patients: A Pilot Study.

Kidney Blood Press Res 2020 22;45(1):61-69. Epub 2020 Jan 22.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,

Context: Evidences have suggested complement C3 is a biomarker for nonalcoholic fatty liver disease (NAFLD) in the general population.

Objective: The present study was conducted to explore the predictive function of C3 for NAFLD in chronic kidney disease (CKD) patients.

Design, Setting, And Participants: CKD patients were recruited for evaluation of their liver function, kidney function, serum lipids, glycated hemoglobin, blood, and immune function. The glomerular filtration rate was calculated using the CKD-EPI equation. NAFLD was diagnosed according to predefined ultrasonographic criteria.

Results: A total of 648 consecutive CKD patients were included, with 216 (33.3%) patients diagnosed with NAFLD. The NAFLD group had significant higher levels of serum protein, serum albumin, triglycerides, glycated hemoglobin, complement C3, hemoglobin (p = 0.001), alanine aminotransferase (p = 0.002), estimated glomerular filtration rate (p = 0.007), and C4 (p = 0.043) and lower levels of cystatin C, β2-microglobulin, proteinuria (p = 0.001), and high-density lipoprotein cholesterol (p = 0.008). In a logistic regression model, only complement C3 (OR = 1.003; 95% CI 1.002-1.004, p = 0.001) was associated with a higher likelihood of being diagnosed with NAFLD. Finally, we constructed ROC curves for complement C3 for prediction of having NAFLD. The best cut-off for complement C3 was 993.5 mg/L and it yielded a sensitivity of 63.9% and a specificity of 70.1%.

Conclusion: Our study revealed that complement C3 can be used as a surrogate biomarker of NAFLD in CKD patients.
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http://dx.doi.org/10.1159/000504172DOI Listing
October 2020

Long Non-coding RNA SNHG12 Functions as a Competing Endogenous RNA to Regulate MDM4 Expression by Sponging miR-129-5p in Clear Cell Renal Cell Carcinoma.

Front Oncol 2019 22;9:1260. Epub 2019 Nov 22.

Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.

Clear cell renal cell carcinoma (ccRCC), the most common histological subtype of kidney cancer, shows poor prognosis, and non-sensitivity to radiotherapy or chemotherapy. The lncRNA small nucleolar RNA host gene 12 (SNHG12) has been revealed to play a carcinogenic role in various neoplasms, but the underlying mechanism in ccRCC is still unclear. To explore the potential role of SNHG12 in ccRCC, the data downloaded from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) Data Portal was used to compare the expression of SNHG12 in tumors and adjacent normal tissues. MRNA microarray and quantitative real-time PCR revealed that SNHG12 was overexpressed in the ccRCC tissues and cell lines. Functional inhibition of SNHG12 suppressed the viability and mobility of ccRCC cells. Mechanistically, dual luciferase assay and RNA immunoprecipitation (RIP) assay showed that miR-129-5p could bind to SNHG12 directly. There was a negative relationship between SNHG12 and miR-129-5p. What's more, we used bioinformatics-based prediction software to predict the target genes of miR-129-5p. Through data analysis and experimental verification, we found MDM4, a regulatory factor in p53 pathway, was involved in this ceRNA network. Our findings demonstrated that SNHG12 served as a sponge for miR-129-5p to regulate the expression of MDM4 and p53 pathway in the development of ccRCC.
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http://dx.doi.org/10.3389/fonc.2019.01260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882951PMC
November 2019

Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA phosphorylation in experimental ischemic stroke.

Cell Signal 2020 02 9;66:109467. Epub 2019 Nov 9.

Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, China. Electronic address:

The activation of corticotrophin-releasing hormone receptor (CRHR) 1 is implicated in neuronal injury in experimental stroke. However, little is known about the relationship between CRHR1 activation and brain endothelial barrier impairment after ischemia and reperfusion (I/R). Recently we have demonstrated that the activation of extracellular signal-regulated kinase (Erk) 1/2 as well as p38 is required for hydrogen peroxide (HO)-increased cytosolic phospholipase A (cPLA) phosphorylation in bEnd3 cells. Using this in vitro ischemic-like model, we found that both blockade and interference of CRHR1 inhibited HO-enhancd p38, Erk1/2 and cPLA phosphorylation and in turn suppressed monolayer hyperpermeability and ZO-1 redistribution. Then using the transient middle cerebral artery occlusion (tMCAO) mouse model, we revealed that CRHR1 antagonist NBI27914 pretreatment attenuated cPLA phosphorylation, Evans blue dye (EBD) extravasation, tight junction disruption and mitochondrial cytochrome c release. CRHR1 interference also inhibited cortical vascular hyperpermeability. Furthermore, NBI27914 administration attenuated neurovascular injury. After 30 min MCAO with 7 days reperfusion CRHR1 interference alleviated hippocampal blood-brain barrier (BBB) leakage and improved spatial cognitive dysfunction. Thus, our study demonstrates that during ischemic stroke the activation of endothelial CRHR1 contributes to BBB impairment via cPLA phosphorylation.
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http://dx.doi.org/10.1016/j.cellsig.2019.109467DOI Listing
February 2020

A Clinical Risk Scoring System of Acute Respiratory Distress Syndrome-Induced Acute Kidney Injury.

Med Sci Monit 2019 Jul 28;25:5606-5612. Epub 2019 Jul 28.

Department of Nephrology, Sir Run Run Shaw Hospital, Nanjing Medical University, Nanjing, Jiangsu, China (mainland).

BACKGROUND This study investigated the risk factors affecting development and prognosis of acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS). MATERIAL AND METHODS A total of 501 ARDS cases were retrospectively enrolled (296 males and 205 females) admitted to the First People's Hospital of Lianyungang from Aug 2015 to Aug 2017. Multivariable logistic modeling was conducted to select significant variables, and the assigned integer score was proportional to the adjusted odds ratio (OR). Then, the sum of weighted variables was utilized to estimate the score in patients. RESULTS Patients with ARDS who had unconsciousness (OR=2.778, 95% CI: 1.396-5.528), hypertension (OR=1.771, 95% CI: 1.089-2.881), ARDS (moderate-severe) (OR=1.630, 95% CI: 1.027-2.588), AST (OR=2.093, 95% CI: 1.251-3.499), and D-dimer (OR=2.372, 95% CI: 1.316-4.275) were more likely to also have AKI. The score was allocated in proportion to the corresponding adjusted OR, hypertension, ARDS (moderate-severe), aspartate aminotransferase (AST), D-dimer (2 points each), and unconsciousness (3 points). The incidences of AKI in group A (score 0-2, n=9), group B (score 3-4, n=16), group C (score 5-6, n=33), and group D (score ≥7, n=72) were 10.98%, 16.00%, 31.13%, and 49.66%, respectively (P<0.001). Higher scores were associated with higher prevalence of AKI, and the trend was statistically significant (P<0.001). CONCLUSIONS This scoring system may provide a risk-integrative evaluation for AKI in patients with ARDS.
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http://dx.doi.org/10.12659/MSM.915905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685404PMC
July 2019

Relationships of Chronic Kidney Disease and Thyroid Dysfunction in Non-Dialysis Patients: A Pilot Study.

Kidney Blood Press Res 2019 23;44(2):170-178. Epub 2019 Apr 23.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,

Context: Patients with chronic kidney disease (CKD) usually manifest with disorder of thyroid hormone; however, the correlation is unknown.

Objective: The study was designed to explore the relationships between CKD and thyroid dysfunction.

Design, Setting, And Participants: A total number of 905 non-dialysis participants were collected at Nanjing First Hospital from August 2009 to October 2012 according to the case records system. Patients were grouped via the estimated glomerular filtration rate (eGFR) according to the KDIGO guideline. Levels of thyroid hormone and biomarkers in different CKD groups were compared by ANOVA. Prevalence of different thyroid diseases was calculated by χ2 test.

Results: We found that FT3 or T3 became more prevalent with increasing eGFR with the lowest level in CKD5 (p < 0.01). No significant differences were found between groups in FT4, T4, or TSH (p > 0.05). Frequency of euthyroid sick syndrome (ESS) in CKD groups was high, especially in CKD stage 5 (69.1%, p < 0.01). eGFR had positive correlation with T3 and FT3 (r = 0.239, p = 0.0001; r = 0.292, p = 0.0001). ESS had correlations with prealbumin, β2-microglobin, eGFR, and C-reactive protein (r = 0.095, p = 0.004; r = -0.12, p = 0.001; r = 0.091, p = 0.007; r = -0.096, p = 0.008; r = 0.154, p = 0.001). After adjustment for prealbumin, uric acid, HbA1c, age, gender, eGFR, and β2-microglobin, binary regression revealed that hemoglobin, C-reactive protein, and albumin were independent influence factors of ESS (p = 0.016, r = 1.014; p = 0.023, r = 1.007; p = 0.029, r = 0.996).

Conclusion: CKD patients have a high morbidity of ESS, mainly low T3 syndrome. Anemia, inflammation, and malnutrition may contribute to ESS in CKD.
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http://dx.doi.org/10.1159/000499201DOI Listing
December 2019

Retinoic acid attenuates contrast-induced acute kidney injury in a miniature pig model.

Biochem Biophys Res Commun 2019 04 13;512(2):163-169. Epub 2019 Mar 13.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China. Electronic address:

Background: Contrast-induced acute kidney injury (CI-AKI) has been the third leading cause of hospital-acquired AKI. Retinoic acid (RA), the main derivative of vitamin A, has preventative and therapeutic effects in ischemia-reperfusion-AKI and UUO models, but little is known about its effects on CI-AKI. This study aimed to explore the effects of RA on CI-AKI as well as the underlying mechanisms.

Methods: We established a new miniature pig model of CI-AKI by catheterizing the external jugular vein and injecting a single dose of iohexol after dehydration. Bun, Scr, serum and urinary RBP and β-MG levels were measured. Renal histological, TEM examination, LDH assays, TUNEL assays, GFP-LC3 plasmid transfection and western blotting were performed.

Results: The levels of Bun, Scr, serum and urinary RBP and β-MG were increased after CI-AKI and decreased by RA pretreatment. The renal histology showed foamy degeneration and dilated tubules after CI-AKI, and the tissue damage was alleviated significantly by RA pretreatment. RA mitigated renal fibrosis after CI-AKI. In vitro, RA protected proximal TECs against iohexol-induced injury. RA inhibited TECs apoptosis and activated autophagy in vivo and in vitro.

Conclusions: RA alleviates CI-AKI and mitigates renal fibrosis after CI-AKI. Autophagy activation and apoptosis inhibition are involved in the protective effect of RA on CI-AKI. RA may be a new agent for the prevention and therapeutic treatment of CI-AKI in the future.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.013DOI Listing
April 2019

Disabling of nephrogenesis in porcine embryos via CRISPR/Cas9-mediated SIX1 and SIX4 gene targeting.

Xenotransplantation 2019 05 9;26(3):e12484. Epub 2019 Jan 9.

Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.

SIX1 and SIX4 genes play critical roles in kidney development. We evaluated the effect of these genes on pig kidney development by generating SIX1 and SIX1 /SIX4 pig foetuses using CRISPR/Cas9 and somatic cell nuclear transfer. We obtained 3 SIX1 foetuses and 16 SIX1 /SIX4 foetuses at different developmental stages. The SIX1 foetuses showed a migration block of the left kidney and a smaller size for both kidneys. The ureteric bud failed to form the normal branching and collecting system. Abnormal expressions of kidney development-related genes (downregulation of PAX2, PAX8, and BMP4 and upregulation of EYA1 and SALL1) were also observed in SIX1 foetal kidneys and confirmed in vitro in porcine kidney epithelial cells (PK15) following SIX1 gene deletion. The SIX1 /SIX4 foetuses exhibited more severe phenotypes, with most foetuses showing retarded development at early stages of gestation. The kidney developed only to the initial stage of metanephros formation. These results demonstrated that SIX1 and SIX4 are key genes for porcine metanephros development. The creation of kidney-deficient porcine foetuses provides a platform for generating human kidneys inside pigs using blastocyst complementation.
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http://dx.doi.org/10.1111/xen.12484DOI Listing
May 2019

LINC00961 restrains cancer progression via modulating epithelial-mesenchymal transition in renal cell carcinoma.

J Cell Physiol 2019 05 26;234(5):7257-7265. Epub 2018 Oct 26.

Department of Urology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Recently, long noncoding RNA have been identified as new gene regulators and prognostic biomarkers in various cancers, including renal cell carcinoma (RCC). The expression and biological roles of LINC00961 have been reported in many human cancers. However, up to date, no study of LINC00961 has been shown in RCC. Currently, we aimed to investigate the function of LINC00961 in RCC progression. Interestingly, we observed that LINC00961 could act as a novel biomarker in predicting the diagnosis of RCC. Then, we found that LINC00961 was greatly downregulated in RCC cell lines (Caki-1, Caki-2, 786-O, A498, and ACHN cells) compared with normal renal cell lines (HK-2 cells). Then, 786-O cells and ACHN cells were infected with LV-LINC00961. As displayed in our current study, LINC00961 overexpression could obviously suppress the proliferation and survival of RCC cells in vitro. In addition, RCC cell apoptosis was greatly induced and cell cycle progression was blocked in G1 phase by upregulation of LINC00961 in 786-O cells and ACHN cells. Subsequently, we found that LV-LINC00961 was able to restrain RCC cell migration and cell invasion capacity. Meanwhile, the messenger RNA and protein expression levels of epithelial-mesenchymal transition (EMT)-associated markers Slug and N-cadherin in RCC cell lines were dramatically inhibited by overexpressing LINC00961. Finally, the in vivo experiment was carried out and we observed that LINC00961 could inhibit RCC development through modulating EMT process. Taken these together, it was indicated in our study that LINC00961 was involved in RCC progression through targeting EMT pathway.
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http://dx.doi.org/10.1002/jcp.27483DOI Listing
May 2019

S1PR2 antagonist alleviates oxidative stress-enhanced brain endothelial permeability by attenuating p38 and Erk1/2-dependent cPLA phosphorylation.

Cell Signal 2019 01 2;53:151-161. Epub 2018 Oct 2.

Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211116, Jiangsu, China. Electronic address:

Both sphingosine-1-phosphate receptor-2 (S1PR2) and cytosolic phospholipase A (cPLA) are implicated in the disruption of cerebrovascular integrity in experimental stroke. However, the role of S1PR2 in induction of cPLA phosphorylation during cerebral ischemia-induced endothelial dysfunction remains unknown. This study investigated the effect of S1PR2 blockade on oxidative stress-induced cerebrovascular endothelial barrier impairment and explored the possible mechanisms. In bEnd3 cells, cPLA inhibitor CAY10502 as well as S1PR2 antagonist JTE013 profoundly suppressed hydrogen peroxide (HO)-induced changes of paracellular permeability and ZO-1 localization. Besides p38, extracellular signal-regulated kinase (Erk) 1/2 is required for HO-increased cPLA phosphorylation and endothelial permeability. Pharmacological and genetic inhibition of S1PR2 significantly suppressed their phosphorylation in response to HO. Especially lentivirus-mediated knockdown of S1PR2 inhibited HO-induced ZO-1 redistribution and paracellular hyperpermeability. Using the permanent middle cerebral artery occlusion (pMCAO) mouse model, we found JTE013 pretreatment markedly reduced Evans blue dye (EBD) extravasation and reversed the decrease in VE-cadherin, occludin, claudin-5 and CD31 expression in infarcted hemisphere. Lentivirus-mediated S1PR2 knockdown also attenuated EBD extravasation. Furthermore, JTE013 pretreatment attenuated neurological deficit, brain edema and infarction volume. Therefore, our findings suggest the protective effect of JTE013 on brain endothelial barrier integrity is likely mediated by suppressing p38 and Erk1/2-dependent cPLA phosphorylation under oxidative stress.
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http://dx.doi.org/10.1016/j.cellsig.2018.09.019DOI Listing
January 2019

Upregulated immune checkpoint HHLA2 in clear cell renal cell carcinoma: a novel prognostic biomarker and potential therapeutic target.

J Med Genet 2019 01 2;56(1):43-49. Epub 2018 Jul 2.

Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant urogenital cancer with high mortality; however, current progress in understanding its molecular mechanism and predicting clinical treatment outcome is limited. Therefore, this study is to evaluate the clinical significance of immune inhibitory molecular human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) in ccRCC prognosis and transcriptional regulatory network.

Methods: Expression of in ccRCC was examined by an online database platform ONCOMINE. The ONCOMINE result was independently validated by qRT-PCR and immunohistochemistry. Kaplan-Meier survival was generated using IBM SPSS Statistics V.22. ccRCC tissues cells with high HHLA2 were sorted and subjected to microarray transcriptional profiling and analysis.

Results: It was shown that expression of HHLA2 was statistically significantly increased in ccRCC tissues compared with normal renal tissues at both transcriptional and protein level. Moreover, the expression of HHLA2 was closely correlated with multiple clinicopathological features including tumour size, clinical stage and histological grade. High HHLA2 expression was associated with poor overall survival and clinical outcome. Comprehensive microarray analysis further identified thousands of HHLA2 targets including mRNA, long non-coding RNA and circular RNA that might function in various biological processes, especially, immune response.

Conclusion: Increased HHLA2 expression was observed in ccRCC tumour tissue, which leads to a remarkable shorter overall survival and poorer prognosis. Together with other molecular evidence, we have demonstrated that HHLA2 could be a potential prognostic biomarker for ccRCC.
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http://dx.doi.org/10.1136/jmedgenet-2018-105454DOI Listing
January 2019

Effect of glycine on reaction of cysteine-xylose: Insights on initial Maillard stage intermediates to develop meat flavor.

Food Res Int 2017 09 3;99(Pt 1):444-453. Epub 2017 Jun 3.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Laboratory for Food Quality and Safety, Beijing Technology and Business University (BTBU), Beijing 100048, China.

The meat-like reactions of l-cysteine and d-(+)-xylose with or without glycine were investigated. LC-MS was used to quantitatively determine the initial stage intermediates including 2-threityl-thiazolidine-4-carboxylic acid, Cys-Amadori, and Gly-Amadori in the reaction mixtures. The results showed that the addition of glycine was only in positive correlation with the browning feature of cyseine-xylose reaction. When excessive glycine was added, a high browning rate would be achieved, but it did not benefit the formation of meaty compounds. For a complex meat-like reaction system containing cysteine, reducing sugars and glycine, to overcome the low rate of reaction, and particularly, to minimize the inhibitive effect of cysteine in the generation of meaty flavors, selection of an appropriate ratio between cysteine and glycine is important in an effort to make amounts of the intermediates of Cys-Amadori and Gly-Amadori approximately equally consist in the reaction mixture.
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http://dx.doi.org/10.1016/j.foodres.2017.06.012DOI Listing
September 2017

Reassessment of Acute Kidney Injury after Cardiac Surgery: A Retrospective Study.

Intern Med 2017 1;56(3):275-282. Epub 2017 Feb 1.

Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, China.

Objective To evaluate the incidence, risk, or protective factors of acute kidney injury (AKI) in patients after cardiac surgery based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Methods A retrospective analysis of 2,575 patients undergoing their first documented cardiac surgery with cardiopulmonary bypass (CPB) was conducted. Perioperative variables were collected and analyzed. Univariate and multiple logistic regression models were used for determining the association between the development of AKI and risk factors. Multiple Cox-proportional hazards modeling was performed to evaluate the impact of AKI on the mortality in the intensive care unit and hospital length of stay. Results Of 2,575 patients, 931 (36%) developed AKI. A total of 30 (1.2%) patients required renal replacement therapy. In the multivariate analysis, mechanical ventilation duration (OR1.446, 95% CI 1.195-1.749, p<0.001), CPB duration of ≥110 min (OR 1.314, 95% CI 1.072-1.611, p=0.009), erythrocytes transfusion (OR 1.078, 95% CI 1.050-1.106, p<0.001), and postoperative body temperature greater than 38°C within 3 days (OR 1.234, 95% CI 1.018-1.496, p=0.032) were independent risk factors for CSA-AKI, while ulinastatin use was associated with a reduced incidence of CSA-AKI (OR 0.694, 95% CI 0.557-0.881, p=0.006). CSA-AKI was significantly associated with in-hospital mortality (adjusted HR: 2.218, 95% CI 1.161-4.238, p=0.016), especially in patients needing renal replacement therapy (adjusted HR: 18.683, 95% CI 8.579-40.684, p<0.001). Conclusion Mechanical ventilation duration, erythrocytes transfusion, and postoperative body temperature above 38°C within 3 days were considered independent risk factors for CSA-AKI. The use of ulinastatin was associated with a reduced incidence of CSA-AKI.
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http://dx.doi.org/10.2169/internalmedicine.56.7638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348450PMC
February 2017

Albuminuria is an independent risk factor of T4 elevation in chronic kidney disease.

Sci Rep 2017 01 24;7:41302. Epub 2017 Jan 24.

Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, PR China.

This study was to explore the association between thyroid dysfunction and albuminuria. 581 cases with chronic kidney disease (CKD) were included in this study. The clinical characteristics consisted of sex, age, serum creatinine, urinary albumin-to-creatinine ratio (ACR), thyroid function were recorded. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI four-level race equation. Prevalence of different thyroid diseases was calculated by chi-square test. Levels of thyroid hormone were compared among different albuminuria groups by Kruskal-Wallis test. Spearman's correlation was used to assess the association between albuminuria and thyroid hormone. Our study showed that total T4 and free T4 were significantly different among ACR < 30 mg/g, 30-300 mg/g and >300 mg/g (P < 0.001 and =0.007, respectively). Positive correlation between T4 (total T4 and free T4) and albuminuria was evaluated by correlation analysis (P = 0.001 and <0.001, respectively). Albuminuria was an independent influence factor of T4 after adjustment for age, sex, serum creatinine, albumin, hs-CRP, smoking status, systolic blood pressure, diabetes mellitus, medication use for diabetes mellitus, eGFR, LDL-cholesterol, triglycerides, hypertension, and medication use for hypercholesterinemia. In conclusion, T4 was positively correlated with albuminuria, and it was completely not consistent with our anticipation. Further study is needed to elucidate the causation association between albuminuria and T4.
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http://dx.doi.org/10.1038/srep41302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259789PMC
January 2017

UCN enhances TGF-beta-mediated mitoinhibition of VSMCs via counteracting TGF-beta-induced cPLA2 expression and activation.

Int J Biochem Cell Biol 2016 11 1;80:98-108. Epub 2016 Oct 1.

Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, PR China. Electronic address:

Urocortins (UCNs) and transforming growth factor-beta (TGF-beta) have been demonstrated to participate in various cardiovascular diseases, many of which involve vascular smooth muscle cells (VSMCs) proliferation. Cytosolic phospholipase A2 (cPLA2)-mediated arachidonic acid (AA) release is an important cause of VSMCs proliferation. The work was to investigate the regulation of VSMCs proliferation by UCN/TGF-beta and whether cPLA2 was a link between their signaling pathways. VSMCs proliferation was measured by colorimetric assay and immunofluorescence microscopy. Using cell flow cytometry, the changes in the cell cycle phases were investigated. Lentiviral Vector Particle was performed to overexpress cPLA2 gene. Both UCN and TGF-beta inhibited VSMCs proliferation and an additive effect was observed when the cells were treated with UCN plus TGF-beta. TGF-beta increased the percentage of cells in G1-phase while UCN increased the cell percentage in G2-phase with a concomitant decrease in S-phase. Furthermore, cPLA2 expression was increased by TGF-beta but decreased by UCN and UCN attenuated TGF-beta-induced cPLA2 expression. In primary VSMCs, TGF-beta induced cPLA2 phosphorylation, and this effect was also attenuated by UCN. Similar to UCN, the cPLA2 inhibitor, pyrrophenone (PYR), also played a role in enhancing TGF-beta-mediated mitoinhibition. Inversely, overexpression of cPLA2 eliminated the effect of UCN on the mitoinhibition. The pretreatment with UCN counteracted TGF-beta-mediated cPLA2 expression and activation, thereby contributing to TGF-beta-mediated mitoinhibition of VSMCs.
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http://dx.doi.org/10.1016/j.biocel.2016.09.028DOI Listing
November 2016

Ulinastatin administration is associated with a lower incidence of acute kidney injury after cardiac surgery: a propensity score matched study.

Crit Care 2016 Feb 17;20:42. Epub 2016 Feb 17.

Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu, 210006, China.

Background: Systemic inflammation is involved in the development of acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urinary trypsin inhibitor (UTI), possesses a variety of anti-inflammatory effects. Therefore, we hypothesized that the administration of ulinastatin would reduce the occurrence of AKI in patients undergoing cardiac surgery with CPB.

Methods: A retrospective propensity score matched analysis was used to evaluate the effect of ulinastatin on the development of AKI in patients undergoing first documented cardiac surgery with CPB between January 2008 and December 2012 in our hospital. Multiple logistic regression models were also employed to identify the association between UTI administration and development of AKI.

Results: A total of 2072 patients who underwent cardiac surgery with CPB met the inclusion criteria. Before propensity score matching, variables such as age, baseline creatinine, CPB duration, red blood cells transfused, and hematocrit were statistically different between the ulinastatin (UTI) group and the control group. On the basis of propensity scores, 409 UTI patients were successfully matched to the 409 patients from among those 1663 patients without UTI administration. After propensity score matching, no statistically significant differences in the baseline characteristics were found between the UTI group and the control group. The propensity score matched cohort analysis revealed that AKI and the need for renal replacement therapy occurred more frequently in the control group than in the UTI group (40.83% vs. 30.32%, P = 0.002; 2.44% vs. 0.49%, P = 0.02, respectively). However, there were no significant differences in mortality, length of intensive care unit stay, and length of hospital stay between the UTI group and the control group. Using multivariate logistic regression analysis, we found ulinastatin played a protective role in the development of AKI after cardiac surgery (odds ratio 0.71, 95% confidence interval 0.56-0.90, P = 0.005).

Conclusions: This study shows that ulinastatin was associated with a lower incidence of AKI after cardiac surgery, suggesting that the administration of ulinastatin may be favorable for those patients undergoing cardiac surgery with CPB.
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http://dx.doi.org/10.1186/s13054-016-1207-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756409PMC
February 2016
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