Suppression of SREBP-1 Expression by Simvastatin Decreases Visfatin-Induced Chemoresistance to Sunitinib in Human Renal Carcinoma 786-O Cells.

The resistance of renal cell carcinoma (RCC) to sunitinib impedes the success of chemotherapy in cancer treatment. Although several sunitinib resistance mechanisms have been proposed, little is known concerning the impact of obesity and adipokines in RCC cells. The upregulation of sterol-regulatory element-binding protein-1 (SREBP-1) has been reported to modulate the progression of tumor cells. The present study investigated the effect of visfatin on sunitinib-induced cytotoxicity in RCC cells through SREBP-1 expression. We found that visfatin-induced Akt and p70S6K activation increased SREBP-1 expression in 786-O cells. The visfatin-induced SREBP-1 mRNA and protein levels were attenuated through the inactivation of Akt and p70S6K by pharmacological inhibitors. In addition, the SREBP-1 knockdown using siRNA enhanced the cytotoxic effects of sunitinib. Our results also revealed the roles of simvastatin in attenuating the effects of visfatin on 786-O cells by inhibiting the production of reactive oxygen species. In particular, simvastatin co-treatment increased the cell cytotoxicity of sunitinib in visfatin-treated 786-O cells, which were associated with down-regulation of SREBP-1 expression. Our results suggest an important role of SREBP-1 in visfatin-induced drug resistance of RCC cells to sunitinib. The cytotoxic mechanism of simvastatin on RCC cells may provide a new strategy to improve therapeutic outcomes for the RCC treatment.

Digitizing Scoring Systems With Extended Online Feedback: A Novel Approach to Interactive Teaching and Learning in Formative OSCE.

OBJECTIVES: Objective structured clinical examinations (OSCEs) are common for formative assessment. We developed an Online Smart Communicative Education System and aimed to explore the factors that affect the perceptions of both teachers and students for teaching and learning. METHODS AND ANALYSIS: A two-year cross-sectional cohort study was undertaken. The program includes three parts. Part I Pre-OSCE: an online flipped class in preparation for task-related knowledge and skills. Part II OSCE-day: 10 tasks in one track formative OSCE. Part III Post-OSCE: extended online feedback for participants with further questions after the exam and raters with more feedback after reviewing their performance online. Principal component analysis with varimax rotation was performed to analyze the perceptions of students and teachers to the Online System by means of questionnaires. RESULTS: Seventy-six pharmacy students (male 32.9%) took the exam and 24 raters (male, 25%) participated in the scoring during the OSCEs. The mean G coefficient was 0.88. Seventy-six questionnaires from the students were obtained for the analysis. Results explained the cumulative variance of 73.9% for component (1) "Effects of extended online feedback": 40% and (2) "Facilitation of learning": 33.9%. Thirty-nine questionnaires from the raters who experienced the Online System were obtained for the analysis (male 23.1%). Results explained a cumulative variance of 77.3% for component (1) "Effects of extended online feedback": 36.6%, (2) "Facilitation of scoring and feedback": 24.5%, and (3) "Feasibility of online platform": 16.2%, respectively. CONCLUSION: We demonstrated good reliability for digitizing the scoring system with educational support to facilitate teaching. "Effects of extended online feedback" was the major aspect in explaining the variance from the perceptions of students and raters by factor analysis. In comparison with traditional formative OSCEs, extended online feedback is a novel approach, which extends the process of learning and teaching among the learners and raters and overcomes the barriers of time limitation and distance.

Association between regional economic status and renal recovery of dialysis-requiring acute kidney injury among critically ill patients.

The association between regional economic status and the probability of renal recovery among patients with dialysis-requiring AKI (AKI-D) is unknown. The nationwide prospective multicenter study enrolled critically ill adult patients with AKI-D in four sampled months (October 2014, along with January, April, and July 2015) in Taiwan. The regional economic status was defined by annual disposable income per capita (ADIPC) of the cities the hospitals located. Among the 1,322 enrolled patients (67.1 ± 15.5 years, 36.2% female), 833 patients (63.1%) died, and 306 (23.1%) experienced renal recovery within 90 days following discharge. We categorized all patients into high (n = 992) and low economic status groups (n = 330) by the best cut-point of ADIPC determined by the generalized additive model plot. By using the Fine and Gray competing risk regression model with mortality as a competing risk factor, we found that the independent association between regional economic status and renal recovery persisted from model 1 (no adjustment), model 2 (adjustment to basic variables), to model 3 (adjustment to basic and clinical variables; subdistribution hazard ratio, 1.422; 95% confidence interval, 1.022-1.977; p = 0.037). In conclusion, high regional economic status was an independent factor for renal recovery among critically ill patients with AKI-D.

The antagonism of 6-shogaol in high-glucose-activated NLRP3 inflammasome and consequent calcification of human artery smooth muscle cells.

BACKGROUND: Vascular calcification is the major reason for high mortality of cardiovascular complications for diabetes. Interleukin (IL)-1ß has been implicated in this pathogenesis, but its precise role and clinical evidence have not been clearly identified. Hence, this study was aimed to investigate whether high concentration of glucose (HG), which mimics the hyperglycemia environment, could initiate vascular calcification through NLRP3/IL-1ß inflammasome and the underlying mechanism. Recently, 6-shogaol, a major ginger derivate, has been elucidated its pharmaceutic role for various diseases. Therefore, the aims of this study also determined 6-shogaol effect in vascular calcification of HG initiation. RESULT: Human artery smooth muscle cells (HASMCs) were used in this study. Glucose concentrations at 5 and 25 mM were defined as normal and HG status, respectively. The results showed that HG could increase the NLRP3, cleaved caspase 1, and pro/mature IL-1ß levels to induce the expressions of bone-related matrix proteins and subsequent HASMC calcification. This process was regulated by Akt activation and reactive oxygen species (ROS) production. Moreover, 6-shogaol could inhibit the Akt/ROS signaling and NLRP3/caspase 1/IL-1ß inflammasome and hence attenuated HASMC calcification. CONCLUSIONS: This study elucidates the detailed mechanism of HG-initiated HASMC calcification through NLRP3/caspase 1/IL-1ß inflammasome and indicates a potential therapeutic role of 6-shogaol in vascular calcification complication of diabetes.

Characterization of Adult Canine Kidney Epithelial Stem Cells That Give Rise to Dome-Forming Tubular Cells.

Dome formation can occur in cultured tubular epithelial cells originating from various tissues, including the mammary gland and the kidney. The isolation and characterization of normal kidney epithelial stem cells that give rise to dome-forming tubular cells have never been reported. We attempted to isolate and characterize canine kidney epithelial stem cells using a simple cell culture method that we have previously used to isolate other adult human stem cells. Dome-forming kidney epithelial cells were derived from dissociated adult canine kidney tissues that were cultured in a modified keratinocyte serum-free medium supplemented with N-acetyl-l-cysteine, l-ascorbic acid 2-phosphate, nicotinamide, and fetal bovine serum. These cells exhibited high self-renewal capacity in long-term culture (growth for >13 months and 30 cumulative population doublings) and exhibited characteristics of stem cells, including (1) deficiency in gap junctional intercellular communication, (2) anchorage-independent growth, (3) expression of stem cell markers octamer-binding transcription factor 4 and SRY (sex determining region Y)-box 2, (4) expression of cell surface markers CD24 and CD133, and (5) multipotent differentiation into osteoblasts, adipocytes, chondrocytes, and dome-forming tubular cells. Most of these characteristics are shared by the well-known canine renal tubule-derived immortalized Madin-Darby Canine Kidney cell line. Furthermore, the putative canine kidney stem cells developed in this study formed budding tubule-like organoids on Matrigel and required high cell density (>4,000 cells/cm2) for sustained growth and confluency for dome formation. The signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitor, AG490, inhibited colony-forming efficiency and dome formation, whereas lipopolysaccharide, an activator of STAT3, increased colony-forming efficiency in a dose-dependent manner. These results are consistent with the hypothesis that high cell density induces STAT3 expression, which promotes both stem cell self-renewal and differentiation into tubular cells. Our novel cell culture method should be useful for the future development of normal human kidney stem cells for clinical applications and for studying mechanisms of nephrotoxicity.

Remote and onsite scoring of OSCEs using generalisability theory: A three-year cohort study.

Introduction: Onsite scoring is common in traditional OSCEs although there is the potential for an audience effect facilitating or inhibiting performance. We aim to (1) analyze the reliability between onsite scoring (OS) and remote scoring (RS); and (2) explore the factors that affect the scoring in different locations. Methods: A total of 154 students and 84 raters were enrolled in a single-site during 2013-2015. We selected six stations randomly from a 12-station national high-stakes OSCE. We applied generalisability theory for the analysis and investigated the perceptions that affected RS scoring. Results: The internal consistency reliability Cronbach's α of the checklists was 0.92. The kappa agreement was 0.623 and the G value was 0.93. The major source of variance comes from the students themselves, but some from locations and raters. The three-component analysis including Technical Feasibility, Facilitates Wellbeing, and Observational and Attention Deficits explained 73.886% of the total variance in RS scoring. Conclusions: Our study has demonstrated moderate agreement and good reliability between OS and RS ratings. We validated the factors of facility operation and quality for RS raters. Remote scoring can provide an alternative forum for the raters to overcome the barriers of distance, space, and avoid the audience effect.

Regulation of calcification in human aortic smooth muscle cells infected with high-glucose-treated Porphyromonas gingivalis.

Porphyromonas (P.) gingivalis infection leading to the periodontitis has been associated with the development of systemic diseases, including cardiovascular diseases and diabetes. However, the effect of a high concentration of glucose (HG) on the invasion efficiency of P. gingivalis and the consequent modulation of pathogenesis in vascular cells, especially in the vascular smooth muscle cells (VSMCs), remains unclear. Hence, the aim of this study was to investigate whether treating P. gingivalis with HG could change its invasion capability and result in VSMC calcification and the underlying mechanism. Human aortic SMCs (HASMCs) and P. gingivalis strain CCUG25226 were used in this study. We found that HGPg infection of HASMCs could initiate the HASMC calcification by stimulating the autocrine regulation of bone morphogenetic protein (BMP) 4 in HASMCs. The upregulation of BMP4 expression in HASMCs was mediated by toll-like receptor 4 and ERK1/2-p38 signaling after P. gingivalis infection. Moreover, the autocrine action of BMP4 in HGPg infection-initiated HASMC calcification upregulated BMP4-specific downstream smad1/5/8-runx2 signaling to increase the expressions of bone-related matrix proteins, that is, osteopontin, osteocalcin, and alkaline phosphatase. This study elucidates the detailed mechanism of HGPg infection-initiated calcification of HASMCs and indicates a possible therapeutic role of BMP4 in P. gingivalis infection-associated vascular calcification.

The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells.

The stromal cell-derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC) progression. In addition, metastatic CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA) and 5-Fluorouracil (5FU) to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model) with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBß, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC's resistance to chemotherapy.

A nationwide survey of clinical characteristics, management, and outcomes of acute kidney injury (AKI) - patients with and without preexisting chronic kidney disease have different prognoses.

Acute kidney injury (AKI) is a common complication in hospitalized patients. The International Society of Nephrology implemented the "0 by 25" initiative aimed at preventing deaths from treatable AKI worldwide by 2025 and conducted a global snapshot survey in 2014. We joined in the project and conducted this study to compare the epidemiology, risk factors, and prognosis between patients with pure AKI and those with acute-on-chronic kidney disease (ACKD). In this study, we prospectively collected demographic parameters and data on clinical characteristics, baseline comorbidities, management, and outcomes of 201 AKI patients in 18 hospitals in Taiwan from September 2014 to November 2014. The in-hospital mortality rate was 16%. AKI was mostly attributed to sepsis (52%). Multivariate logistic regression indicated that oliguria was a positive independent predictor of in-hospital mortality, whereas preexisting CKD and exposure to nephrotoxic agents were negative independent predictors. The prevalence of vasopressor use, intensive care unit care, and mortality were significantly higher in pure AKI patients than in ACKD patients. Moreover, serum creatinine (SCr) levels significantly increased within 7 days after AKI diagnosis in nonsurvivors but not in survivors in the pure AKI group. By contrast, SCr levels were persistently lower in nonsurvivors than in survivors in the ACKD group during the same period. We thus determined that the prognosis of ACKD patients differed from that of pure AKI patients. Considering the CKD history in the future AKI staging system may improve prognosis prediction.

Nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study: Design and methods.

AIM: Acute kidney injury (AKI) carries an increasing incidence rate worldwide and increases the risk of developing end-stage renal disease (ESRD) as well as the medical expenses during the post-AKI course. The Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKs) has thus launched a nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study, which prospectively enrols critically ill patients with AKI. Through thoroughly evaluating the risk and prognostic factors of AKI, we hope to lower the incidence of AKI and ESRD from the perspective of AKI-ESRD interaction. METHODS: The CAKs includes 30 hospitals which distribute widely through the four geographical regions (north, middle, south, and east) of Taiwan, and have a 1:1 ratio of medical centres to regional hospitals in each region. The NEP-AKI-D study enrols intensive care unit-based AKI patients who receive dialysis in the four seasonal sampled months (October 2014, along with January, April, and July 2015) in the included hospitals. The collected data include demographic information, pertaining laboratory results, dialysis settings and patient outcomes. The data are uploaded in a centre website and will be audited by on-site principal investigators, computer logic gates, and the CAKs staffs. The outcomes of interest are in-hospital mortality, dialysis-dependency and readmission rate within 90 days after discharge. CONCLUSION: The NEP-AKI-D study enrols a large number of representative AKI patients throughout Taiwan. The results of the current study are expected to provide more insight into the risk and prognostic factors of AKI and further attenuated further chronic kidney disease transition.

Hericium erinaceus mycelium and its isolated erinacine A protection from MPTP-induced neurotoxicity through the ER stress, triggering an apoptosis cascade.

BACKGROUND: Hericium erinaceus is an edible mushroom; its various pharmacological effects which have been investigated. This study aimed to demonstrate whether efficacy of oral administration of H. erinaceus mycelium (HEM) and its isolated diterpenoid derivative, erinacine A, can act as an anti-neuroinflammatory agent to bring about neuroprotection using an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease, which results in motor disturbances, in addition to elucidating the mechanisms involved. METHODS: Mice were treated with and without HEM or erinacine A, after MPTP injection for brain injuries by the degeneration of dopaminergic nigrostriatal neurons. The efficacy of oral administration of HEM improved MPTP-induced loss of tyrosine hydroxylase positive neurons and brain impairment in the substantia nigra pars compacta as measured by brain histological examination. RESULTS: Treatment with HEM reduced MPTP-induced dopaminergic cell loss, apoptotic cell death induced by oxidative stress, as well as the level of glutathione, nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE). Furthermore, HEM reversed MPTP-associated motor deficits, as revealed by the analysis of rotarod assessment. Our results demonstrated that erinacine A decreases the impairment of MPP-induced neuronal cell cytotoxicity and apoptosis, which were accompanied by ER stress-sustained activation of the IRE1α/TRAF2, JNK1/2 and p38 MAPK pathways, the expression of C/EBP homologous protein (CHOP), IKB-ß and NF-κB, as well as Fas and Bax. CONCLUSION: These physiological and brain histological changes provide HEM neuron-protective insights into the progression of Parkinson's disease, and this protective effect seems to exist both in vivo and in vitro.

Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis.

Background:Porphyromonas gingivalis is a major bacterial species implicated in the progression of periodontal disease, which is recognized as a common complication of diabetes. The interleukin (IL)-1ß, processed by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a target for pathogenic infection of the inflammatory response. However, the effect of P. gingivalis in a high-glucose situation in the modulation of inflammasome activation in human gingival fibroblasts (HGFs) is not well-understood. Methods:P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the regulation of HGF NLRP3 expression by the infection of high-glucose-treated P. gingivalis (HGPg). Results: HGF infection with HGPg increases the expression of IL-1ß and NLRP3. We further demonstrated that the upregulation of sterol regulatory element-binding protein (SREBP)-1c by activation of the Akt and p70S6K pathways is critical for HGPg-induced NLRP3 expression. We showed that the inhibition of Janus kinase 2 (JAK2) blocks the Akt- and p70S6K-mediated SREBP-1c, NLRP3, and IL-1ß expression. The effect of HGPg on HGF signaling and NLRP3 expression is mediated by ß1 integrin. In addition, gingival tissues from diabetic patients with periodontal disease exhibited higher NLRP3 and SREBP-1c expression. Conclusions: Our findings identify the molecular pathways underlying HGPg-dependent NLRP3 inflammasome expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs.

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes.

BACKGROUND: Homocysteine and pro-inflammatory mediators such as cyclooxygenase-2 (COX-2) have been linked to vascular dysfunction and risks of cardiovascular diseases. Fulvic acid (FA), a class of compounds of humic substances, possesses various pharmacological properties. However, the effect of FA on inflammatory responses of the monocytes remains unclear. We investigated the regulatory effect of FA on homocysteine-induced COX-2 expression in human monocytes. METHODS: Peripheral blood monocytes and U937 cells were used for all experiments. Real-time PCR and ELISA assay were used to analyze the COX-2 mRNA expression and PGE2 secretion, respectively. Specific inhibitors were used to investigate the mechanism of homocysteine-mediating COX-2 mRNA expression and PGE2 secretion. Luciferase assay, transcription factor ELISA, and chromatin immunoprecipitation were used to determine the role of nuclear factor-κB in FA-mediated inhibition of homocysteine effect on monocytes. RESULTS: The results show that pretreating monocytes with FA inhibited the homocysteine-induced COX-2 expression in a dose-dependent manner. Stimulation of U937 monocytes with homocysteine induced rapid increases in the phosphorylation of ERK and JNK; the inhibitor for ERK and JNK attenuated the homocysteine-induced nuclear factor-κB activation and COX-2 expression. Transcription factor ELISA and chromatin immunoprecipitation assays showed that FA blocked the homocysteine-induced increases in the binding activity and in vivo promoter binding of nuclear factor-κB in monocytes. CONCLUSIONS: Our findings provide a molecular mechanism by which FA inhibits homocysteine-induced COX-2 expression in monocytes, and a basis for using FA in pharmaceutical therapy against inflammation.

Differential regulation of human aortic smooth muscle cell proliferation by monocyte-derived macrophages from diabetic patients.

Macrophage accumulation in the arterial wall and smooth muscle cell (SMC) proliferation are features of type 2 diabetes mellitus (DM) and its vascular complications. However, the effects of diabetic monocyte-derived macrophages on vascular SMC proliferation are not clearly understood. In the present study, we investigated the pro-proliferative effect of macrophages isolated from DM patients on vascular SMCs. Macrophage-conditioned media (MCM) were prepared from macrophages isolated from DM patients. DM-MCM treatment induced HASMC proliferation, decreased p21(Cip1) and p27(Kip1) expressions, and increased microRNA (miR)-17-5p and miR-221 expressions. Inhibition of either miR-17-5p or miR-221 inhibited DM-MCM-induced cell proliferation. Inhibition of miR-17-5p abolished DM-MCM-induced p21(Cip1) down-regulation; and inhibition of miR-221 attenuated the DM-MCM-induced p27(Kip1) down-regulation. Furthermore, blocking assays demonstrated that PDGF-CC in DM-MCM is the major mediators of cell proliferation in SMCs. In conclusion, our present data support the hypothesis that SMC proliferation stimulated by macrophages may play critical roles in vascular complications in DM patients and suggest a new mechanism by which arterial disease is accelerated in diabetes.

Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts.

BACKGROUND: Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN: 2 prospective observational cohort studies. SETTING & PARTICIPANTS: From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS: Peginterferon alfa-2b monotherapy, 1.0 µg/kg/wk, versus peginterferon alfa-2b, 1.0 µg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS: End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS: Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS: Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS: Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Comparison between calcitriol and calcitriol plus low-dose cinacalcet for the treatment of moderate to severe secondary hyperparathyroidism in chronic dialysis patients.

AIM: Uremic hyperparathyroidism (UHPT) has been shown to contribute to the development and progression of chronic kidney disease-mineral bone disorder. UHPT is frequently observed in chronic dialysis patients, and patients with UHPT are associated with increased risk of all-cause and cardiovascular mortality. Cinacalcet is a novel agent that increases sensitivity to the calcium-sensing receptor and is approved for control of UHPT. Nevertheless, cinacalcet is costly and information regarding efficacy of low-dose cinacalcet on UHPT is limited. METHODS: We conducted a retrospective study to evaluate treatment with either low-dose calcitriol combined with low-dose cinacalcet (25 mg) (d-cinacalcet) or calcitriol alone (VitD) in dialysis patients with moderate to severe UHPT. A total of 81 dialysis patients were enrolled (40 subjects in d-cinacalcet group and 41 subjects in VitD group). Demographic data including age, gender, duration on dialysis and biochemical data were reviewed and recorded. RESULTS: At the end of the study, the intact parathyroid hormone (iPTH) levels of the d-cinacalcet group declined significantly (from 1166.0 ± 469.3 pg/mL to 679.8 ± 421.6 pg/mL, p < 0.0001), while there was no significant change in the VitD group. Significant decrease of serum calcium (Ca: 9.9 ± 0.6 mg/dL vs. 9.6 ± 0.8 mg/dL, p = 0.002), phosphorus (P: 5.9 ± 1.3 mg/dL vs. 4.9 ± 0.9 mg/dL, p < 0.0001) and calcium phosphate product (Ca × P: 58.7 ± 15.0 mg2/dL2 vs. 46.9 ± 8.9 mg2/dL2, p < 0.0001) were observed in the d-cinacalcet group. In addition, the subjects in the d-cinacalcet group had a greater proportion to achieve Kidney Disease Outcomes Quality Initiative (KDOQI)-recommended biochemical targets than the subjects in the VitD group (Ca: 48% vs. 24%; P: 78% vs. 32%; Ca × P: 85% vs. 37%; iPTH: 15% vs. 0%). CONCLUSIONS: We conclude that combination therapy of low-dose cinacalcet and calcitriol is more effective than calcitriol alone as a treatment for moderate and severe UHPT in chronic dialysis patients. Furthermore, this therapy is associated with improvement in hyperphosphatemia and hypercalcemia.

Free p-cresol sulfate is associated with survival and function of vascular access in chronic hemodialysis patients.

BACKGROUND: Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (p-CS) have been implicated as an important factor in uremic syndrome. Recent evidence indicates that both IS and p-CS are predictors of cardiovascular as well as all-cause mortality among chronic dialysis patients. We conducted a study to analyze the relationship between IS and p-CS and vascular access (VA) outcome in chronic hemodialysis (HD) patients. METHODS: A total of 91 chronic stable HD patients were divided into groups according to survival of VA and frequency of VA dysfunction. Demographic and biochemical data were reviewed and recorded. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, and the total and free forms of IS and p-CS were determined. RESULTS: Patients with a history of frequent VA failure and dysfunction had lower albumin and higher levels of ICAM-1, free IS, free and total p-CS. Diabetes was associated with higher IS and p-CS. Logistic regression revealed that diabetes and free p-CS were independent factors associated with poor outcome of VA. CONCLUSION: Endothelial dysfunction and uremic toxins were associated with survival and function of VA. Diabetes and free p-CS were significantly related to the outcome of VA among chronic HD patients.

Relationship between Kt/V urea-based dialysis adequacy and nutritional status and their effect on the components of the quality of life in incident peritoneal dialysis patients.

BACKGROUND: It is well known that the quality of life of patients with chronic kidney disease can be improved by dialysis. While previous studies have used retrospective designs and adhered to a standard target prescribed by clinical guidelines, our study prospectively investigates the association between the adequacy of peritoneal dialysis (PD) and measures of nutritional status on quality-of-life domains in a cohort of incident PD patients. METHODS: It was a prospective 6-month observational study. Eighty incident PD participants who were treated in a hospital-based PD center were enrolled. The period of enrollment was January 2009-June 2010; follow-up continued until December 2010. PD adequacy indices, including Kt/V urea, weekly Ccr (WCcr), measures of nutritional status (albumin, BMI), and nPCR were measured at 1 month and 6 months after PD initiation. SF-36 health survey questionnaires were used to measure the quality of life. The outcomes were used to measure the changes in the domains of the SF-36 after 6 months of PD therapy. RESULTS: Seventy-seven incident patients who underwent PD for 6 months were included in the study. The mean age was 47.3 years, and the male-to-female ratio was 38:39. A peritoneal Kt/V urea value of 1.2, which was also the baseline cutoff value, was found to have the highest influence on SF-36 domains. Patients with baseline peritoneal Kt/V urea value of <1.2 showed improvement in the physical functioning and role limitation of physical functioning components after 6 months of PD. In contrast, patients with baseline peritoneal Kt/V urea values of ≥1.2 showed remarkable improvement in the general health, physical functioning, role limitation caused by physical problems, and bodily pain components. However, the trend of improvement decreased in patients with baseline nPCR of <1.2. Baseline renal WCcr did not influence the improvement in the SF-36 domains. LIMITATIONS: A small cohort and a short observation period. CONCLUSIONS: The baseline level of peritoneal Kt/V urea affected the components of the quality of life after PD initiation. In contrast, a lower baseline nPCR level was associated with deterioration in the quality of life after PD therapy.

Proteomic analysis of the effects of baicalein on colorectal cancer cells.

Baicalein is the flavonoids with multiple pharmacological activities. The aim of our study was to investigate the effects of baicalein on colorectal cancer (CRC) and to recognize the targets of baicalein treatment. To better understand baicalein's target, proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS-PAGE) to elucidate proteins differential display. Results from this study investigate that baicalein treatment of CRC cells results in reduced cell proliferation. As a result, differential protein displays between baicalein-treated and untreated CRC were determined and validated. There were 11 differentially expressed proteins between baicalein-treated and untreated CRC. Furthermore, we demonstrate that baicalein inhibits cancer cell proliferation and reduced reactive oxygen species (ROS) by up-regulating the levels of peroxiredoxin-6 (PRDX6). Knockdown of PRDX6 in baicalein-treated CRC cells by specific small interfering RNA resulted in ROS production and proliferation, opposite of the baicalein treatment scenario as indicated by cell cycle distribution. These results illustrate that baicalein up-regulates the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells, whereas baicalein treatment have no effect on normal epithelial cells.