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Ai-Hua Zhang,1 Guang-Xia Dai,2 Qi-Dong Zhang,1 Hong-Dong Huang,1 Wen-Hu Liu1 1Nephrology Department, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, People’s Republic of China; 2Endocrinology Department, Beijing Nanyuan Hospital, Beijing, People’s Republic of ChinaCorrespondence: Hong-Dong Huang; Wen-Hu Liu, Nephrology Department, Capital Medical University Affiliated Beijing Friendship Hospital, No. 95 Yong An Road, Xi Cheng District, Beijing, 100050, People’s Republic of China, Tel +86-10 63138579, Fax +86-10 63139144, Email huangHD201902@163.com; l13901163354@163.comBackground: Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Forty percent of the patients continue to progress and eventually develop into chronic renal failure. Although phospholipase A2 receptor (PLA2R) is the major antigen of PMN, the clinical features do not often parallel with the antibody titers. Therefore, it is significant to find relative credible markers to predict the treatment response.Methods: One hundred and eighteen PMN patients were recruited. The response to treatment was defined as ALB≥ 30g/L at 6 months and complete remission (CR) or not at the end of the follow-up. Renal outcome endpoint was defined as 50% or more Cr increase at the end.Results: The patients with poor treatment effects had numerically higher platelet-lymphocytes ratio (PLR). For patients with CR or not, the difference was near to statistic significant (P=0.095). When analyzing CR or not, the fitting of the binary logistic regression model including both PLA2R Ab titer and PLR (Hosmer–Lemeshow test: χ2=8.328, P = 0.402; OR (PLA2R Ab titer) = 1.002 (95% CI 1.000– 1.004, P = 0.042); OR (PLR) = 1.006 (95% CI 0.999– 1.013, P = 0.098)) was markedly better than that with only PLA2R Ab titer (Hosmer–Lemeshow test: χ2=13.885, P = 0.016). The patients with renal function deterioration showed significantly higher monocyte-lymphocyte ratio (MLR) (0.26 (0.22– 0.31) vs 0.18 (0.13– 0.22), P = 0.012).Conclusion: PMN patients with poor treatment response tended to have higher PLR at the time of renal biopsy, and a higher MLR was associated with poor renal outcomes. Our findings suggested that PLR and MLR might be used to predict treatment efficacy and prognosis for PMN patients, respectively.Keywords: membranous nephropathy, peripheral blood cell ratios, platelet-lymphocytes ratio, monocyte–lymphocyte ratio, treatment response, outcome

Introduction: Apoptosis of vascular smooth muscle cells induced by hyperphosphatemia is a critical mechanism of chronic kidney disease-related vascular disorders. The present study investigated whether extracellular calcium-sensing receptor (CaSR) regulates stanniocalcin 2 (STC2) expression in HAoSMCs and subsequently protects HAoSMCs from high-phosphate-induced apoptosis. Methods: HAoSMCs were cultured, and STC2 expression was determined by qPCR. A calcimimetic (NPS R-568) or calcilytic (NPS-2143) was applied to HAoSMCs. STC2 mRNA and protein levels were measured by qPCR and Western blot, respectively, and confocal microscopy was employed to investigate subcellular localization. STC2 overexpression and silencing were induced to assess the effects of STC2 on high-phosphate-induced apoptosis, which was determined by caspase-3 levels and TUNEL staining. The anti-apoptotic effect of CaSR-induced STC2 was confirmed by interfering with STC2 expression in the presence of NPS R-568. Results: The constitutive expression of STC2 was confirmed. STC2 mRNA and protein levels were increased by NPS R-568 with or without high phosphate. NPS-2143 resulted in decreased STC2 mRNA levels, but decreased STC2 protein levels were only found under the high-phosphate condition. Confocal microscopy demonstrated the colocalization of STC2 and plasma membrane or endoplasmic reticulum markers. STC2 overexpression reduced HAoSMCs apoptosis, which were reversed with STC2 silencing. NPS R-568 treatment reduced HAoSMCs apoptosis, but STC2 silencing abolished the protective effect. Conclusion: This is the first evidence that STC2 is regulated by CaSR in HAoSMCs. CaSR activation-induced STC2 has putative anti-apoptotic effects against high phosphate. Calcimimetics are promising agents to treat uremic vascular injury.

Vascular calcification (VC) and myocardial hypertrophy are very common in patients on hemodialysis (HD). Previous studies have only assessed the cross-sectional associations of VC with left ventricular mass (LVM) and the predictive value of individual factors. The present study investigated the relationship between abdominal aortic calcification (AAC) and LVM increment over time, and the combined effect of these factors on the outcomes of HD patients. 104 HD patients were enrolled. AAC scores were evaluated on left lateral lumbar spine radiographs. Echocardiography was performed to calculate the LVM changes during a 2-year period. At baseline, 91 patients (87.5%) had varying degrees of AAC (median score 6.0, range 2.0 - 11.0). After 2 years, the mean LVM change was 7.49 g (range -5.03 - 26.00 g), and 68 patients (65%) had an increased LVM. Patients with higher baseline AAC scores had significantly larger LVM and LVM index increments. Patients with increased LVM had significantly higher baseline AAC scores and hemoglobin, serum phosphate, and hypersensitive C-reactive protein levels. Multiple stepwise linear regression demonstrated that the baseline AAC was the only independent predictor of increased LVM after 2 years. 28 patients (26.9%) died in the subsequent 5 years. Patients with lower baseline AAC scores had a significantly higher cumulative survival rate than those with higher AAC scores. However, the LVM change (either alone or in combination with the AAC score) had no significant effect on survival. In conclusion, AAC is an independent predictor of LVM increase over time in HD patients. Prevention and treatment of VC may be a promising intervention target to improve left ventricular remodeling and outcomes in HD patients.

Brain iron deposition in hemodialysis (HD) patients increases over time. Iron deficiency in gray matter nuclei has been reported to lead to idiopathic restless legs syndrome (RLS) symptoms. Regardless of unpleasant RLS sensations, the patterns of iron deposition between hemodialysis patients with RLS (HD-RLS) and hemodialysis patients without RLS (HD-nRLS) are still unclear. To evaluate the differences in iron deposition patterns between HD-RLS and HD-nRLS patients, we utilized quantitative susceptibility mapping (QSM).In sum, 24 HD-RLS patients, 25 HD-nRLS patients and 30 age- and sex-matched healthy controls (HCs) were enrolled. The QSM was used to assess susceptibility values of the regions of interest (ROIs), including the caudate nucleus (CN), putamen (PUT), globus pallidus (GP), thalamus (THA), substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN).HD duration was significantly longer in HD-RLS patients than in HD-nRLS patients (P 0.05). The susceptibility of HD-RLS and HD-nRLS patients in PUT was higher than that in HCs (P 0.05), illustrating elevated iron content in the nucleus. Compared with HD-nRLS patients, HD-RLS patients demonstrated reduced susceptibility in CN and PUT (both P 0.05). Compared with HCs, HD-RLS patients displayed decreased susceptibility in DN (P 0.05).Different iron deposition patterns between HD-RLS and HD-nRLS patients in PUT and DN, which further support disturbed sensory processing in RLS, may be involved in RLS pathogenesis in HD patients.

Trastuzumab resistance is one of the principal causes of failure in tumor chemotherapy. Previous studies showed that the DNA-binding activity of GATA6, a transcription factor, had a remarkable enhancement in trastuzumab resistant gastric cancer cells (NCI N87/R), while its correlation to resistance remains unclear. In this study, Crispr/Cas9 was employed to establish a GATA6 knock-out cell line (NCI N87R/GATA6). The signaling pathways regulated by GATA6 and related to trastuzumab resistance were investigated based on label-free quantitative proteomics combined with bioinformatics. The extracted proteins were alkylated, and digested using filter aided sample preparation (FASP), and the peptides were separated via high performance liquid chromatography (HPLC) and thereafter quantified by liquid chromatography coupled with tandem mass spectroscopy (LC-MS/MS). Differentially expressed proteins were screened by fold change and student's t-test between NCI N87/R and NCI N87R/GATA6 cells. WebGestalt website was adopted for Gene ontology analysis, and GeneAnalytics database was utilized for pathway enrichment analysis. The results demonstrated that GATA6 knock-out enhanced the antiproliferative effect of trastuzumab on NCI N87/R cells and suppressed their invasion ability. A total of 5792 proteins were quantified by LC-MS/MS, among which 305 proteins were up-regulated in NCI N87R/GATA6 cells while 182 ones down-regulated. Pathway enrichment analysis revealed that mitochondrial transport, apoptosis, DNA damage, glucose metabolism, pyruvate metabolism and TCA cycle, and Wnt/β-catenin degradation pathways exhibited significant changes. Western blotting manifested that the expression of mitochondrial dyneins OPA1 and DNM1L, apoptosis protein caspase-9, TCA metabolic enzymes SUCLG2 and MDH1, and glycogen metabolic enzyme PYGL changed significantly in NCI N87R/GATA6 cells, manifesting that GATA6 knock-out gave rise to mitochondrial dysfunction and abnormal energy metabolism, and therefore inducing the apoptosis of NCI N87R/GATA6 cells. These results implicated that inhibiting the transcriptional activity of GATA6 could be an effective strategy to reverse trastuzumab resistance in gastric cancer cells.

Background: Alcohol abuse resulted in high prevalence of alcoholic cardiac and hepatic disorders. Any agent(s) with the bio-activities to suppress mitochondrial apoptotic pathway, and attenuate apoptotic and oxidative stresses might be able to protect cardiac and hepatic cells against ethanol. Objective(s): Phytochemical composition of aqueous extract prepared from steamed daylily flower (DAE) was determined. The protective effects of DAE for H9c2 and L-02 cells against ethanol were evaluated. Materials and Methods: The amount of total phenolic acids, total flavonoids, total anthocyanins and total triterpenoids in DAE was analyzed. H9c2 or L-02 cells were first treated with 0.25, 0.5 or 1% DAE, and followed by 150 mM ethanol exposure. Results: Results: The amount of total phenolic acids, flavonoids, anthocyanins and triterpenoids in DAE was in the range of 1219-2045 mg/100 g dry weight. DAE treatments at 0.5 and 1% increased the viability of H9c2 cells, but at three test concentrations enhanced the survival of L-02 cells. DAE at 0.5 and 1% up-regulated Bcl-2 mRNA expression, down-regulated Bax mRNA expression, decreased Bax/Bcl-2 ratio, and lowered caspase-3 activity in both cell lines. Ethanol increased reactive oxygen species level, decreased glutathione content, and glutathione peroxidase and catalase activities in both cell lines. DAE at test concentrations reversed these changes in both cell lines. DAE at 0.5 and 1% reduced cytochrome P450 2E1 and NADPH oxidase activities, and lowered p47phox mRNA expression. However, DAE at three test concentrations decreased gp91phox mRNA expression in both cell lines. DAE at 0.5 and 1% up-regulated factor E2-related factor 2 and heme oxygenase-1 mRNA expression in both cell lines. Conclusions: These results suggested that this aqueous extract might be a potent function food supplement to benefit heart and liver against ethanol induced injury.

Aims. This study aimed to compare the accuracy of the choroidal vascularity index (CVI) and diabetic retinopathy (DR) in the diagnosis of diabetic nephropathy (DN). Methods. We performed a cross-sectional study of 117 patients with proteinuria and diabetes mellitus (DM) in which 45 patients were diagnosed with DN by renal pathology. Demographic information, clinical features, and laboratory data were collected. A total of 234 eyes underwent evaluation of DR and the CVI using enhanced depth imaging-optical coherence tomography scans. We analyzed the association between the CVI and DN and compared the CVI and DR for diagnosing DN using area under receiver operating characteristic curves (AUROCs). Results. The severe nonproliferative DR and proliferative DR groups showed a lower CVI than the no DR and mild/moderate nonproliferative DR groups ( P < 0.01 or P < 0.001 ). There was a significantly lower CVI in patients with DN stage III (63.01% ± 1.47%) compared with those in DN stages IIa (62.1% ± 1.41%, P < 0.001 ) and IIb (59.85% ± 1.98%, P < 0.01 ). The sensitivity and specificity of the CVI for diagnosing DN were 84% (71%–94%) and 95% (88%–99%), respectively, which were preferable to those of DR. The AUROCs for the CVI and DR for diagnosing DN were 0.932 and 0.831, respectively. The CVI outperformed DR for diagnosing DN ( P < 0.05 ). The cutoff value of the CVI was 63.13%. Conclusion. The CVI might be a reliable noninvasive technique for predicting the pathological stage of DN and is superior to DR in diagnosing DN.

Left ventricular mass (LVM) is related to poor outcomes of HD patients. Possible contributions of vascular calcification to LVM changes over time have not been well established. This is a prospective cohort study. At baseline, left lateral lumbar spine radiograph was conducted. The echocardiogram was performed respectively at baseline and 2 years later. The dialysis records were documented in the first week of the first month for each quarter during the two years. Fasting blood samples were collected. The averages were calculated. After the second echocardiogram, patients were followed up for another five years. One hundred and four patients were enrolled, with 57 males (54.8%) and an average age of 60.0 ± 11.1 years. Ninety-one patients had AAC (87.5%). The average level of LVMI changes 2 years later was 3.31 (− 1.51 ~ 8.18) g/m2.7, and 68 patients had increased LVMI. After another five years, 28 patients died (26.9%). Patients with worsening LVMI had significantly higher baseline AAC scores (8.0 (3.0 ~ 12.0) vs 4.0 (1.3 ~ 7.0), P = 0.022). The 5-year mortality rate was also higher (23/68 vs 5/31, P = 0.029). Multiple stepwise regression analysis demonstrated that baseline AAC was an independent predictor for increased LVMI (P = 0.005). For one point increase in AAC scores, LVMI increased by 0.27g/m2.7 2 years later. The independent correlated factors baseline AAC were age and hs-CRP. In conclusion, AAC is an independent predictor of LVMI deterioration over time in HD patients. Whether direct intervention for LVM can benefit MHD patients is controversial. Prevention and treatment of VC may be an important intervention target to improve LVM and prognosis.

Objective: This study's objective is to explore the effect of venous calcium (Ca) load on Ca metabolism using an isotope tracer in both healthy rats and rats with chronic renal failure (CRF). Materials and Methods: The methods included inducing CRF by feeding rats with food that containing 0.75% adenine. Both the rats in the control and CRF group received an intravenous injection of 100 mg/kg CaCl2 mixed with 0.5 mg/kg 42Ca for over 2 minutes in order to induce hypercalcemia. Blood samples, urine, and feces were collected for Ca kinetics and metabolism testing before and 24 hours after the injection. Results: Peak blood Ca levels were presented at 5 minutes in both groups but returned to baseline levels differently: within 3 hours in the CRF group and 1 hour in the control group. 24-hour hypercalciuria and a higher weight-corrected fecal Ca loss were consistently detected in the CRF rats before and after the injection, along with a decrease in the percent fractional Ca absorption and true fractional calcium absorption compared to the control group. The increased fecal Ca in the CRF rats primarily resulted from changes in decreased absorption rate, which indirectly lead to an increase in endogenous fecal Ca (EFC). Body weightcorrected EFC levels in the CRF group were significantly higher than those in the control group (207.58 ± 107.18 mg/kg/day vs. 62.44 ± 20.49 mg/kg/day). In addition, EFC was 22.6% and 26.02% of the total fecal Ca in the CRF group and the control group. Conclusion: These results may be useful in the evaluation of calcium metabolism and may have important implications for stable isotopes that are widely used in exploring calcification studies in the CRF.

To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine.Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients.Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes60 months (OR=3.562, P=0.010), anemia (OR=4.176, P0.001), hyperuricemia (OR=3.352, P0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD.Male, course of diabetes60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).

HLE-B3 cell line, a human lens epithelial cell line, was used to examine the anti-glycative and anti-oxidative protection of aqueous extract prepared from steamed red amaranth leaves against high glucose induced injury. Phytochemical profile of this aqueous extract was analyzed. HLE-B3 cells were pretreated by this aqueous extract at 0.25%, 0.5%, or 1%, and followed by high glucose treatment. Results showed that the content of phenolic acids, flavonoids, anthocyanins, carotenoids, and triterpenoids in this aqueous extract was in the range of 1,107-2,861 mg/100 g dry weight. High glucose decreased cells viability and suppressed Bcl-2 mRNA expression. This aqueous extract pretreatments raised 11-42% cell survival and upregulated 20-47% Bcl-2 mRNA expression. High glucose reduced Na+ -K+ ATPase activity and mitochondrial membrane potential (MMP). This aqueous extract raised 27-40% Na+ -K+ ATPase activity, and 18-51% MMP. High glucose stimulated the generation of total advanced glycative endproducts (AGEs), methylglyoxal, and reactive oxygen species (ROS). This aqueous extract pretreatments lowered total AGEs, methylglyoxal, and ROS levels in the range of 0.38-1.17 folds, 1.7-4.9 nmol/mg protein, and 0.35-1.06 relative fluorescence unit/mg protein. High glucose upregulated mRNA expression of aldose reductase, nuclear factor kappa B, and p38. This aqueous extract pretreatments decreased mRNA expression of these factors in the range of 75-159%, 57-151%, and 54-166%. High glucose downregulated mRNA expression of nuclear factor E2-related factor 2 (Nrf2). This aqueous extract pretreatments increased 12-38% Nrf2 mRNA expression. These results suggested that this aqueous extract might be a potent nutritional supplement to prevent diabetic retinopathy.

BACKGROUND: Hemodialysis (HD) causes various nervous system abnormalities. Alterations in white matter (WM) microstructure after long-term HD have been reported in a few previous studies; however, no studies have been performed to investigate enlarged perivascular spaces (PVS) in WM regions. We measured cerebral blood flow (CBF) and white matter volume (WMV) in HD patients to assess enlarged PVS severity in the WM across the whole brain and suggest possible explanations for this. METHODS: Fifty-one HD patients and 51 age-, sex-, and education-matched healthy controls (HCs) were recruited. The number of enlarged PVS in the centrum semiovale (CS), cerebral watershed (CW), and basal ganglia (BG) regions were assessed by T2-weighted MRI. CBF was estimated by arterial spin labeling (ASL), which is a non-invasive perfusion imaging technique. WMV was assessed by the computational anatomy toolbox (CAT12), which is a statistical analysis package. Differences in descriptive variables (two-tailed t-tests, χ(2) tests, Mann-Whitney U tests, and Friedman M tests), an intra-class correlation between radiologists, the relationship between enlarged PVS number and HD duration, normalized CBF and WMV (multiple regression), and group differences in CBF and WMV {voxel-wise t-tests with age and sex as covariates [cluster size >50 voxels, false discovery rate (FDR) corrected, P

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

BACKGROUND Endovascular treatment of acute thrombosed arteriovenous grafts performed completely under ultrasound guidance has rarely been reported. We compared the efficacy of a new endovascular thrombectomy technique (percutaneous manual thromboaspiration through the introducer sheath) with classical hybrid thrombectomy (minimally invasive surgical thrombectomy combined with high-pressure angioplasty) performed completely under ultrasound guidance, for arteriovenous graft thrombosis. METHODS This was a retrospective cohort study involving patients receiving hemodialysis who underwent arteriovenous graft thrombectomy between January 2014 and December 2017. We divided 130 participants into an intervention (endovascular) group (N.=65) and a control (classical hybrid) group (N.=65) according to the thrombectomy technique. The procedural success rate, immediate outcomes and patency were compared between the groups. RESULTS There was no significant difference in the procedural success rate (92.31% vs. 89.23%, P=0.55) between the intervention and control groups, respectively. No major complications were noted, but two cases of vessel rupture occurred in the control group and three cases of vessel rupture occurred in the intervention group. The procedure time in the intervention group was significantly shorter than that in the control group (74±14.21 min vs. 109.05±19.20 min, respectively; P

Hemodialysis with restless legs syndrome (HD-RLS) is associated with alterations in neuronal function, the blood-brain barrier and iron deposition, thus affecting cerebral metabolism and perfusion. This study utilized three-dimensional arterial spin labeling (ASL) to identify HD-RLS-related perfusion patterns and potential relationships with disease severity. Twenty-six HD-RLS patients, 30 hemodialysis patients without restless legs syndrome (HD-nRLS) and 30 age-, sex-, and education-matched healthy controls were included in this study. One-way analysis of covariance and post hoc analyses were used to assess differences in cerebral blood flow (CBF) values, demographics and clinical data among the three groups. Pearson’s correlation analysis was conducted between altered CBF values in the HD-RLS group and clinical data. Compared with HD-nRLS patients, HD-RLS patients showed increased CBF in the right primary motor cortex (false discovery rate [FDR]-corrected P

PURPOSE The purpose of this study was to investigate the differences of gray matter volume (GMV) alteration patterns between hemodialysis with restless legs syndrome (HD-RLS) and hemodialysis without restless legs syndrome (HD-nRLS) patients using voxel-based morphometry. METHODS Twenty-three HD-RLS patients, 27 HD-nRLS patients, and 27 age-, sex-, and education-matched healthy controls were included in this study. One-way analysis of covariance and post hoc analyses were used to assess differences in GMV, demographics, and clinical data among the 3 groups. Pearson correlation analysis was conducted between altered GMV in the HD-RLS group and clinical data. RESULTS Compared with HD-nRLS patients, HD-RLS patients showed decreased GMV in the left primary motor cortex (false discovery rate corrected, P < 0.05). Compared with the healthy controls, both HD subgroups (ie, those with and without RLS) exhibited consistent GMV changes, including decreased GMV in the bilateral anterior cingulate and paracingulate gyrus and left middle temporal gyrus (false discovery rate corrected, P < 0.05). The GMV values in the left precentral gyrus were negatively correlated with the RLS rating scores (r = 0.2138, P = 0.0263). CONCLUSIONS This abnormal decreased GMV in the sensorimotor cortex provides evidence for a sensory processing disorder in RLS that may be involved in the pathogenesis of RLS in HD patients.

Recent studies have demonstrated that hemodialysis patients exhibit disruptions in functional networks with invisible cerebral alterations. We explored the alterations of functional connectivity in hemodialysis patients using the graph-theory method. A total of 46 hemodialysis patients (53.11 ± 1.58 years, 28 males) and 47 healthy controls (55.57 ± 0.86 years, 22 males) were scanned by using resting-state functional magnetic resonance imaging. The brains of these patients were divided into 90 regions and functional connectivity was constructed with the automatic anatomical labeling atlas. In the defined threshold range, the graph-theory analysis was performed to compare the topological properties including global, regional and edge parameters between the hemodialysis and the healthy control groups. Both hemodialysis patients and healthy control subjects demonstrated common small-world property of the brain functional connections. At the global level, the parameters normalized clustering coefficients and small-worldness were significantly decreased in hemodialysis patients compared with those noted in healthy controls. At the regional level, abnormal nodal metrics (increased or decreased nodal degree, betweenness centrality and efficiency) were widely found in hemodialysis patients compared with those of healthy controls. The network-based statistical method was employed and two disrupted neural circuits with 18 nodes and 19 edges (P = 0.0139, corrected) and 10 nodes and 11 edges (P = 0.0399, corrected) were detected. Of note, the edge-increased functional connectivity was associated with the salience network and the frontal-temporal-basal ganglia connection, whereas the edge-decreased functional connectivity was associated with the frontoparietal network. The graph-theory method may be one of the potential tools to detect disruptions of cerebral functional connectivity and provide important evidence for understanding the neuropathology of hemodialysis patients from the disrupted network organization perspective.

Structural and functional brain alterations have been always observed in end-stage renal disease (ESRD) patients undergoing hemodialysis. The present study aimed to investigate the gray matter volume (GMV) changes in hemodialysis patients compared with those noted in healthy subjects, as well as explore the associated functional connectivity alterations based on the abnormal GMV regions. The experiments revealed the effects of regional morphometry aberrance on the brain functional integrity. A total of 46 hemodialysis patients (53.11 ± 1.58 years, 28 males) and 47 healthy subjects (55.57 ± 0.86 years, 22 males) were enrolled in the present study. All subjects underwent high-resolution T1-weighted imaging, resting-state functional MR imaging, and laboratory examinations were performed in hemodialysis patients. The GMV deficits were analyzed using voxel-based morphometry (VBM) and regions with GMV alteration were defined as seeds for functional connectivity analysis. Correlation analyses between significantly different regions and the results of the blood examination were further performed. We found that bilateral thalamus exhibited significantly increased volumes in the hemodialysis patients compared with those of the healthy subjects. However, the bilateral rectus, bilateral caudate, and bilateral temporal gyrus demonstrated significantly decreased volumes. When the regions with GMV alterations were defined as seeds, the hemodialysis patients exhibited decreased integrations in the thalamo-cortical network and within the basal-ganglia connection. The present study revealed the presence of different types of structural and functional brain impairments in hemodialysis patients.

Hyperphosphatemia is an important symptom of chronic kidney disease-mineral bone disorder (CKD-MBD). Various oral phosphate binders have been used, but have not been very effective, especially for severe secondary hyperparathyroidism (SHPT) in patients undergoing maintenance dialysis. Maintenance dialysis patients with severe SHPT can develop hypophosphatemia for several months after parathyroidectomy without elevated alkaline phosphatase. Based on these clinical phenomena, we hypothesized that high levels of parathyroid hormone (PTH) might inhibit intestinal phosphorus absorption which mediated by sodium-dependent phosphorus transporters.Forty BALB/c mice were divided into four groups. Mice in group 1 were given an intravenous injection of normal saline as the control group. Mice in groups 2, 3, and 4 were given PTH(1- 34) in doses of 40 μg/100 g, 200 μg/100 g, and 400 μg/100 g body weight intravenously, respectively. All mice were euthanized 8 hours after the injection. The mRNA and protein expression of sodium-dependent phosphorus transporter NPT-2b and Pit-1 on the membrane of the intestinal epithelial cells was detected by real-time polymerase chain reaction (PCR) and western blot analysis, respectively.In group 4, intestinal epithelial NPT-2b and Pit-1 protein expression was significantly decreased, whereas in groups 2 and 3, no significant changes were found.A high PTH level decreases the protein expression of NPT-2b and Pit-1 in the intestinal mucosa.

Gynura bicolor leaf aqueous extract (GAE) is rich in phytochemicals including phenolic acids, flavonoids, carotenoids, and anthocyanins. Effects of GAE upon hepatic injury in mice with chronic ethanol intake were examined. Lieber-DeCarli liquid diet with ethanol was used to induce hepatic lipid accumulation, oxidative, glycative, and inflammatory injury. GAE at 0.25% or 0.5% was added in feeds, and supplied to mice consumed Lieber-DeCarli liquid diet with ethanol for 6 wk. Blood and liver were collected for analyses. Results showed that ethanol increased plasma and hepatic triglyceride and cholesterol content, and affected plasma levels of insulin, adiponectin, leptin, and ghrelin. GAE at both doses decreased lipid accumulation, and at high dose improved hormones abnormality. Histological data revealed that GAE supplement mitigated hepatic lipid deposit. Ethanol increased plasma Ne -(carboxyethymethyl)-lysine and pentosidine levels. GAE at high doses lowered those glycative factors. Ethanol depleted glutathione content, increased CYP2E1 activity and reactive oxygen species production, and reduced the activity of glutathione peroxide, glutathione reductase and catalase in liver. GAE supplement at both doses reversed these alterations and attenuated hepatic oxidative stress. GAE supplement also at both doses decreased hepatic inflammatory cytokines release in ethanol treated mice. These findings support that leaves of G. bicolor is a functional food with liver protective activities against ethanol.

A high-precision coastal acoustic tomography (CAT) experiment for reconstructing the current variation in Dalian Bay (DLB) was successfully conducted by 11 coastal acoustic tomography systems during March 7–8, 2015. The horizontal distributions of tidal currents and residual currents were mapped well by the inverse method, which used reciprocal travel time data along 51 successful sound transmission rays. The semi-diurnal tide is dominant in DLB, with a maximum speed of 0.69 m s−1 at the eastern and southwestern parts near the bay mouth that gradually decreases toward the inner bay with an average velocity of 0.31 m s−1. The residual current enters the observational domain from the two flanks of the bay mouth and flows out in the inner bay. One anticyclone and one cyclone were noted inside DLB as was one cyclone at the bay mouth. The maximum residual current in the observational domain reached 0.11 m s−1, with a mean residual current of 0.03 m s−1. The upper 15-m depth-averaged inverse velocities were in excellent agreement with the moored Acoustic Doppler Current Profiler (ADCP) at the center of the bay, with a root–mean–square difference (RMSD) of 0.04 m s−1 for the eastward and northward components. The precision of the present tomography measurements was the highest thus far owing to the largest number of transmission rays ever recorded. Sensitivity experiments showed that the RMSD between CAT and moored-ADCP increased from 0.04 m s−1 to 0.08 m s−1 for both the eastward and northward velocities when reducing the number of transmission rays from 51 to 11. The observational accuracy was determined by the spatial resolution of acoustic ray in the CAT measurements. The cost-optimal scheme consisted of 29 transmission rays with a spatial resolution of acoustic ray of 2.03 k m 2 / r a y n u m b e r s . Moreover, a dynamic analysis of the residual currents showed that the horizontal pressure gradient of residual sea level and Coriolis force contribute 38.3% and 36.0%, respectively. This indicates that the two terms are the dominant factors of the residual currents in DLB.

Background Altered cerebral blood flow (CBF) and amplitude of low-frequency fluctuation (ALFF) have been reported in hemodialysis patients. However, neurovascular coupling impairments, which provide a novel insight into the human brain, have not been reported in hemodialysis patients. Methods We combined arterial spin labeling (ASL) and blood oxygen level dependent (BOLD) techniques to investigate neurovascular coupling alterations and its relationships with demographic and clinical data in 46 hemodialysis patients and 47 healthy controls. To explore regional neuronal activity, ALFF was obtained from resting-state functional MRI. To measure cerebral vascular response, CBF was calculated from ASL. The across-voxel CBF–ALFF correlations for global neurovascular coupling and CBF/ALFF ratio for regional neurovascular coupling were compared between hemodialysis patients and healthy controls. Two-sample t-tests were used to compare the intergroup differences in CBF and ALFF. Multiple comparisons were corrected using a voxel-wise false discovery rate (FDR) method (P < 0.05). Results All hemodialysis patients and healthy controls showed significant across-voxel correlations between CBF and ALFF. Hemodialysis patients showed a significantly reduced global CBF–ALFF coupling (P = 0.0011) compared to healthy controls at the voxel-level. Of note, decreased CBF/ALFF ratio was exclusively located in the bilateral amygdala involved in emotional regulation and cognitive processing in hemodialysis patients. In hemodialysis patients, the decreased CBF (right olfactory cortex, anterior cingulate gyrus and bilateral insula) and ALFF (bilateral precuneus and superior frontal gyrus) were mainly located in the default mode network and salience network-related regions as well as increased CBF in the bilateral thalamus. Conclusions These novel findings reveal that disrupted neurovascular coupling may be a potential neural mechanism in hemodialysis patients.

Objective The current study aimed to investigate the prevalence and risk factors of restless legs syndrome (RLS) in patients undergoing hemodialysis, as well as the mortality and risks of cardiovascular and cerebrovascular events. Methods A total of 354 hemodialysis patients from four hospitals were enrolled. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria. The patients were evaluated face-to-face using the IRLSSG rating scale, Epworth Sleepiness Scale (ESS), Hamilton Anxiety Scale, Hamilton Depression Scale, and Pittsburgh Sleep Quality Index (PSQI). The patients were followed up for 9 months. Death was considered an endpoint event. The cardiovascular and cerebrovascular events were investigated. Results The prevalence of RLS in hemodialysis patients was 40.7% and was associated with factors such as duration of hemodialysis, hypersensitive C-reactive protein, hyperparathyroidism, glycosylated serum protein, and erythropoietin treatment. The scores of the PSQI, ESS, and Hamilton Depression Scale in the RLS group were significantly higher than those in the non-RLS group (p < 0.05). During follow-ups, the incidence rate of cardiovascular diseases was 18.8% in the RLS group and 8.6% in the non-RLS group (p < 0.005). The IRLSSG rating scores were significantly higher in RLS patients with kidney transplantation failure compared with those without transplantation (p < 0.05). Conclusion The prevalence of RLS was high in hemodialysis patients. The risk factors of RLS included duration of hemodialysis, hypersensitive C-reactive protein, hyperparathyroidism, glycosylated serum protein, and erythropoietin treatment. RLS affected sleep quality and emotion and increased the risk of cardiovascular diseases in hemodialysis patients. RLS was more severe in patients with kidney transplantation failure compared with those without transplantation.

The aim of this paper was to investigate the effects of curcumin on the proliferation,migration,invasion and apoptosis of human gastric cancer cells and to explore the potential mechanisms. SGC7901,MKN45 and NCI N87 cells lines were cultured under different concentrations of curcumin( 2. 5,5,10,20,40,80 and 160 μmol·L~(-1)) at different time points( 12,24,48 and 72 h),and the effect of curcumin on cell proliferation was detected by CCK-8 assay. The migration and invasiveness of cells were determined by wound healing and Transwell assays,the apoptosis rate was assessed by flow cytometry,the expression of N-cadherin,E-cadherin,snail1,Wnt3 a,p-β-catenin,p-LRP6,Bcl-2 and Bax were detected by Western blot,and the enzymatic activity of caspase-3,caspase-8 and caspase-9 was evaluated via caspase kit. RESULTS:: indicated that the proliferation of MKN45 cells was significantly inhibited by curcumin in a dose-and time-dependent manner( IC50= 21. 93 μmol·L~(-1)). Moreover,curcumin could inhibit the migration and invasion of MKN45 cells,downregulate the expression of N-cadherin,snail1,Wnt3 a,p-β-catenin,p-LRP6 and Bcl-2,and upregulate the expression of E-cadherin and Bax,it could increase the activity of caspase-3,caspase-8,caspase-9 and induce apoptosis as well. The potential mechanism is through inhibiting the Wnt3 a/β-catenin/EMT pathway,regulating Bcl-2 signaling and caspase pathway,which might provide new potential strategies for gastric cancer treatment.

Objective To preliminarily validate the clinical usability of the ameliorated Kawashima Itch Scale(Xie-Kawashima Itch Scale) among adult pruritic patients on maintenance hemodialysis. Methods Xie-Kawashima Itch Scale was developed on the basis of Kawashima Itch Scale. Patients were asked to record their pruritus condition according to Xie-Kawashima Itch Scale or visual analogue scale(VAS) during daytime and night for two weeks. The record at the second week was used for analyzing the correlation between Xie-Kawashima Itch Scale and VAS. Results Totally 134 patients were enrolled in this study,among whom 128 entered the final analysis. Xie-Kawashima Itch Scale was positively correlated with VAS(r

Resistance to trastuzumab, which specifically target HER2-positive breast and gastric cancer, can develop ultimately in cancer patients. However, the underlying mechanisms of resistance in gastric cancer have not been fully elucidated. Here, we established trastuzumab-resistant MKN45 and NCI N87 gastric cancer sublines from their parental cells. The resistant cells exhibited characteristics of epithelial-mesenchymal transition (EMT) and acquired higher migratory and invasive capacities. To exploit the activated pathways and develop new strategies to overcome trastuzumab resistance, we investigated MKN45 and MKN45/R cells via label-free quantitative proteomics, and found pathways that were altered significantly in MKN45/R cells, with the Wnt/&beta, catenin pathway being the most significant. We further confirmed the activation of this pathway by detecting its key molecules in MKN45/R and NCI N87/R cells via Western blot, in which Wnt3A, FZD6, and CTNNB1 increased, whereas GSK-3&beta, decreased, manifesting the activation of the Wnt/&beta, catenin pathway. Correspondingly, inhibition of Wnt/&beta, catenin pathway by ICG-001, a specific Wnt/&beta, catenin inhibitor, preferentially reduced proliferation and invasion of trastuzumab-resistant cells and reversed EMT. Concurringly, CTNNB1 knockdown in stable cell lines potently sensitized cells to trastuzumab and induced more apoptosis. Taken together, our study demonstrates that the Wnt/&beta, catenin pathway mediates trastuzumab resistance, and the combination of Wnt/&beta, catenin inhibitors with trastuzumab may be an effective treatment option.

Gynura bicolor leaf aqueous extract (GAE) is rich in phytochemicals including phenolic acids, flavonoids, carotenoids, and anthocyanins. Effects of GAE upon hepatic injury in mice with chronic ethanol intake were examined. Lieber-DeCarli liquid diet with ethanol was used to induce hepatic lipid accumulation, oxidative, glycative, and inflammatory injury. GAE at 0.25% or 0.5% was added in feeds, and supplied to mice consumed Lieber-DeCarli liquid diet with ethanol for 6 wk. Blood and liver were collected for analyses. Results showed that ethanol increased plasma and hepatic triglyceride and cholesterol content, and affected plasma levels of insulin, adiponectin, leptin, and ghrelin. GAE at both doses decreased lipid accumulation, and at high dose improved hormones abnormality. Histological data revealed that GAE supplement mitigated hepatic lipid deposit. Ethanol increased plasma N

The apoptotic effects of maslinic acid (MA) at 4, 8, 16, 32 and 64 μmol/L on human lung cancer A549 cells under normoxic and hypoxic conditions were examined. MA at 4–64 and 16–64 μmol/L lowered Bcl-2 expression under normoxic and hypoxic conditions, respectively (p &lt, 0.05). This agent at 4–64 μmol/L decreased Na+-K+-ATPase activity and increased caspase-3 expression under normoxic conditions, but at 8–64 μmol/L it caused these changes under hypoxic conditions (p &lt, 0.05). MA up-regulated caspase-8, cytochrome c and apoptosis-inducing factor expression under normoxic and hypoxic conditions at 8–64 μmol/L and 32–64 μmol/L, respectively (p &lt, 0.05). MA down-regulated hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), survivin and inducible nitric oxide synthase (iNOS) expression under normoxic and hypoxic conditions at 8–64 and 16–64 μmol/L, respectively (p &lt, 0.05). After cells were pre-treated with YC-1, an inhibitor of HIF-1α, MA failed to affect the protein expression of HIF-1α, VEGF, survivin and iNOS (p &gt, 0.05). MA at 8-64 and 32-64 μmol/L reduced reactive oxygen species and nitric oxide levels under both conditions (p &lt, 0.05). These findings suggest that maslinic acid, a pentacyclic triterpenic acid, exerted its cytotoxic activities toward A549 cells by mediating mitochondrial apoptosis and the HIF-1α pathway.

BACKGROUND The phytochemical composition of aqueous and ethanol extracts from Gynura bicolor DC., a vegetable, was determined. Human umbilical vein endothelial (HUVE) cells were used to examine the antioxidative and anti-inflammatory potentials of these extracts at 1, 2 or 4% (v/v) against high-glucose-induced injury. RESULTS Both aqueous and ethanol extracts contained phenolic acids, flavonoids, carotenoids and anthocyanins in the ranges 1428–1569, 1934–2175, 921–1007 and 2135–2407 mg per 100 g dry weight respectively. Both extracts were rich in quercetin, lutein, malvidin and pelargonidin. Addition of these extracts at test doses decreased reactive oxygen species formation, preserved glutathione content and retained glutathione peroxide and catalase activities in high-glucose-treated HUVE cells (P < 0.05). Treatments with these extracts at 2 and 4% lowered interleukin-6, tumor necrosis factor-alpha and prostaglandin E2 production and reduced cyclooxygenase-2 activity (P < 0.05). CONCLUSION These findings suggest that this vegetable could be considered as a functional food and might provide antioxidative and anti-inflammatory protection. © 2014 Society of Chemical Industry

Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is a key event in renal interstitial fibrosis and the progression of chronic kidney disease (CKD). Apelin is a regulatory peptide involved in the regulation of normal renal hemodynamics and tubular functions, but its role in renal fibrosis remains unknown. In this study, we examined the inhibitory effects of apelin on transforming growth factor-β1 (TGF-β1)-induced EMT in HK-2 cells, and evaluated its therapeutic efficacy in mice with complete unilateral ureteral obstruction (UUO). In vitro, apelin inhibited TGF-β1-mediated upregulation of α-smooth muscle actin (α-SMA) and downregulation of E-cadherin. Increased levels of phosphorylated Smad-2/3 and decreased levels of Smad7 in TGF-β1-stimulated cells were reversed by apelin co-treatment. In the UUO model, administration of apelin significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin and laminin expression, and markedly suppressed expression of α-SMA, TGF-β1 and its type I receptor, as well as interstitial matrix components. Interestingly, in UUO mice, there was a reduction in the plasma level of apelin, which was compensated by upregulation of APJ expression in the injured kidney. Exogenous supplementation of apelin normalized the level of plasmatic apelin and renal APJ. In conclusion, our study provides the first evidence that apelin is able to ameliorate renal interstitial fibrosis by suppression of tubular EMT through a Smad-dependent mechanism. The apelinergic system itself may promote some compensatory response in the renal fibrotic process. These results suggest that apelin has potential renoprotective effects and may be an effective agent for retarding CKD progression.

H9c2 cardiomyoblast cell line was used to examine the protection of three triterpenes, asiatic acid, boswellic acid, and oleanolic acid, at 5 or 10 μM against high-glucose-induced injury. High glucose stimulated reactive oxygen species (ROS), oxidized glutathione (GSSG), interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 production, as well as decreased glutathione peroxidase (GPX), glutathione reductase (GR) and catalase activities, and protein expression. However, pre-treatments of three triterpenes reserved glutathione, maintained activity and expression of GPX, GR, and catalase, as well as lowered ROS, GSSG, and inflammatory cytokines generation. High glucose reduced Na(+)-K(+)-ATPase activity, raised nuclear factor kappa (NF-κ) B and caspase-3 activities, up-regulated protein expression of NF-κB, mitogen-activated protein kinase, Bax, and cleaved caspase-3, as well as down-regulated Bcl-2 expression. Pre-treatments of three triterpenes retained Na(+)-K(+)-ATPase activity, declined NF-κB and caspase-3 activities, reserved Bcl-2 expression, as well as suppressed protein expression of NF-κB, p-p38, Bax, and cleaved caspase-3. These findings suggest that these triterpenes are potent cardiac-protective agents.

Hypertension is an independent risk factor for mortality in chronic kidney disease (CKD) and is suboptimally controlled worldwide. Therefore, this study aimed to examine the rate of BP control and the main barriers to achieving target BP, according to K/DOQI guidelines, in China. We performed a single-center, prospective cohort study. Two hundred and sixty CKD patients were referred by general physicians to nephrologists, and their BP was treated in accordance with K/DOQI guidelines for a 1-year follow-up. We evaluated improvement of BP target achievement and factors affecting BP control. We defined “not-at-goal” as persistence of systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 80 mmHg after 1 year. The BP decreased from 138 ± 12/84 ± 7 mmHg at baseline to 124 ± 13/73 ± 7 mmHg after 1 year. The rate of achieving the BP goal (

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, accumulates in plasma during chronic kidney disease (CKD). High plasma levels of ADMA can increase transforming growth factor-β (TGF-β) expression, related to renal fibrosis, but the precise molecular mechanism is not explicit. The present study was designed to determine the mechanism through which long-term low-dose ADMA induces TGF-β expression in endothelial cells and to investigate the molecular mechanism of its action. Human umbilical vein endothelial cells (HUVECs) were exposed to low-dose ADMA (5 and 10 µmol/l) for 7 passages and TGF-β expression was determined. Human renal glomerular endothelial cells (HRGECs) were exposed to high-dose ADMA (100 µmol/l) which were used to clarify the molecular mechanism. The results showed that long-term low-dose ADMA (5 and 10 µmol/l) increases TGF-β production in both mRNA and protein levels in HUVECs in a time-dependent manner. We confirmed that exogenous ADMA (100 µmol/l) significantly enhanced stress fiber formation in HRGECs and upregulated TGF-β expression. Such effects of ADMA in HRGECs were inhibited by pre-treatment with actin depolymerizing agent, actin stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In addition, we demonstrated that ADMA (100 µmol/l) significantly activated nuclear factor-κB (NF-κB) in HRGECs, which was markedly attenuated by actin depolymerizing agent, actin stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In brief, the present study demonstrated that long-term low-dose ADMA induces TGF-β expression in endothelial cells at both the gene and protein levels. The actin cytoskeleton may be involved in modulation of ADMA-induced NF-κB activation and the ensuing TGF-β expression in HRGECs.

Peritoneal transport status is important not only for prescription, but also as a prognostic index. Flt-1 and Flk-1, the major vascular endothelial growth factor receptors involved in angiogenesis and hyperpermeability, may play a potent role in determining peritoneal transport characteristics. However, the relationship between them has not been studied to date. We hypothesized that Flt-1 and Flk-1 expression in the peritoneal vasculature of uremic patients could be closely related to baseline peritoneal transport status.Thirty-six new patients without a previous history of peritonitis were enrolled. Clinical parameters such as age, sex, height, weight, causes of renal failure, and residual renal function were assessed. Parietal peritoneal biopsies were obtained during implantation of peritoneal dialytic catheters. Flt-1 and Flk-1 were semi-quantitatively evaluated by immunohistochemical staining. Peritoneal microvascular density (MVD) was counted. Within 6 weeks after commencing peritoneal dialysis, a standard peritoneal equilibration test was performed, and the dialysate-to-plasma concentration ratio for creatinine at 4 h (D4/P Cr) was determined. The patients were divided into two groups based on the D4/P Cr: more than 0.65 (Group H, n = 22) and less than or equal to 0.65 (Group L, n = 14). The 24-h peritoneal protein excretion (PPE) was assayed. Flt-1 and Flk-1 were correlated with peritoneal MVD, D4/P Cr, and PPE.Flt-1 and Flk-1 were detected in the peritoneal vasculature of uremic patients. Flt-1 expression was similar between the two groups, but Flk-1 expression in Group H was significantly higher than that in Group L (p = 0.001). Flt-1 expression did not show significant correlations with peritoneal MVD, D4/P Cr, and PPE. However, Flk-1 expression showed significant correlations with the above three parameters (p0.001 for all).For the first time, the expressions of Flt-1 and Flk-1 in peritoneal vasculature of uremic patients were detected. Flk-1 expression in peritoneal vasculature of uremic patients is closely correlated with the number of peritoneal microvessels, peritoneal small solute transport rate, and PPE. Our findings strongly suggest that Flk-1 may be a crucial determinant of baseline peritoneal transport characteristics. Further interventional studies are needed.

To analyze predictive factors for all-cause mortality, cardiovascular (CV) mortality, nonfatal CV events (CVE) in maintenance hemodialysis (MHD) patients, and to compare the effects of standard hemodialysis (HD) and online hemodiafiltration (HDF) on these factors and outcomes. A total of 333 MHD patients were prospectively followed up for 50 ± 15 months and all-cause death, CV death and CVE were registered. At the baseline, demographic, clinical, and laboratory data of the whole population were recorded. Then, patients were stratified into two groups according to the dialysis modalities, HD (n = 268) and HDF (n = 65). At the end of 6th month, clinical and laboratory data were recorded again. The predictive factors at baseline for all-cause mortality, CV mortality, and CVE were analyzed by Cox regression. The effects of HD and HDF on these factors at the 6th month and long-term outcomes were compared by t-test and Kaplan-Meier method, respectively. Age, gender, left ventricular mass index (LVMI), aortic arch calcification score (AoACS), hemoglobin (Hb)10 g/dL, and ferritin500 ng/mL maintained independent associations with all-cause mortality. C-reactive protein (CRP), LVMI, AoACS, and Hb10 g/dL were associated with CV mortality. Prior cardiovascular disease (CVD), AoACS and LVMI were independent predictors of nonfatal CVE. Higher body mass index (BMI), body weight, total serum cholesterol, Hb concentration, and lower CRP level, LVMI, and AoACS were found in patients on HDF at the end of the 6th month. Improved outcomes with longer survival time for all-cause mortality, CV mortality, and CVE were found in HDF group. Age, gender, LVMI, AoACS, Hb, and ferritin were predictors of all-cause mortality in MHD patients. CRP, LVMI, AoACS, and Hb were associated with CV mortality. Prior CVD, AoACS, and LVMI were independent predictors of nonfatal CVE. HDF could improve BMI, body weight, total serum cholesterol, Hb, CRP, LVMI, AoACS, and long-term outcomes, including all-cause mortality, CV mortality, and CVE.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is associated with vascular dysfunction. The polypeptide apelin mediates two major actions on blood vessels. However, their combined effects on vascular function are not fully understood. The present study aimed to determine the effect of apelin-13 on myosin light chain (MLC) phosphorylation in vascular smooth muscle cells (VSMCs) under ADMA-induced endothelial leakage conditions. To assess the increased permeability induced by ADMA, human umbilical vein endothelium cells (HUVECs) were plated in transwell dishes. The FITC-dextran flux and FITC-apelin-13 flux through the endothelial monolayer were measured. To examine the effect of leakage of apelin-13 on MLC phosphorylation in HUVSMCs, transwell dishes were used to establish a coculture system with HUVECs in upper chambers and HUVSMCs in lower chambers. Western blot was performed to assess the phospho-MLC levels. ADMA increased endothelial permeability in a concentration- and time-dependent manner, accompanied by actin stress fiber assembly and intercellular gap formation. When HUVECs were treated with ADMA, the permeability to both macromolecular dextran and micromolecular apelin-13 increased significantly. Both p38 MAPK inhibitor and NADPH oxidase inhibitor could prevent HUVECs from the increased permeability, and the changes of cytoskeleton and intercellular junction, which were induced by ADMA. Apelin-13 passed through the ADMA-stimulated endothelial monolayer and increased the expression of phospho-MLC in VSMCs. These results suggest that ADMA increases endothelial permeability, which may involve the p38 MAPK and NADPH oxidase pathway. Apelin-13 can pass through the damaged endothelial barrier, and acts directly on VSMCs to increase MLC phosphorylation.