The Prognostic Role of Serum ß-Trace Protein Levels among Patients on Maintenance Hemodialysis.

Cardiovascular (CV) diseases are the most commonly encountered etiology of mortality in patients having kidney failure. ß-Trace protein (BTP) is a biomarker of glomerular filtration function as well as a potential predictor of adverse CV outcomes. This study aimed to determine the prognostic value of BTP in patients on chronic hemodialysis (HD). A total of 96 patients undergoing HD were enrolled. Baseline variables were collected, and the patients were tracked for 3 years. Twenty-five patients died at 3 years. Those who experienced mortality were noted to have higher serum concentrations of BTP and a higher incidence of diabetes mellitus (DM). The area under the receiver operating characteristic curve for serum BTP distinguishing mortality from survival was 0.659 (95% confidence interval [CI], 0.555-0.752; p = 0.027). After the adjustment of variables potentially affecting survival rates, BTP levels above the median (adjusted hazard ratio [aHR]: 2.913, 95% CI, 1.256-6.754; p = 0.013), the presence of DM (aHR: 2.474, 95% CI, 1.041-5.875; p = 0.040), and low serum albumin (aHR: 0.298, 95% CI, 0.110-0.806; p = 0.017) independently correlated with survival in HD patients. Serum BTP is a novel biomarker for predicting overall outcomes in HD patients.

Ellagic acid ameliorates renal fibrogenesis by blocking epithelial-to-mesenchymal transition.

Objectives: Ellagic acid (EA), a kind of polyphenol found in numerous fruits and vegetables, has anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-fibrotic effects against a variety of diseases, but its role in mediating renal fibrogenesis remains unknown. Materials and Methods: We used an in vivo mouse unilateral ureteral obstruction (UUO) model and an in vitro model with HK-2 cell lines treated with EA and transforming growth factor ß1 (TGF-ß1). The expression of epithelial-to-mesenchymal transition (EMT)-related proteins of UUO mice was examined using immunohistochemical staining. Liver function and renal function were evaluated using biochemical testing. Western blot analysis was used to determine the proteins related to EMT, and MTT assay was used to determine cell viability. Results: In UUO mice fed EA, both microscopical examination with immunohistochemical staining and western blotting protein analysis showed reduced expression of fibrotic (α-SMA, fibronectin, and collagen I)- and EMT (vimentin and N-cadherin)-related proteins, compared with sham control. In HK-2 cells treated with TGF-ß1, EA decreased motility as well as expression of α-SMA, collagen-I, fibronectin, N-cadherin, and vimentin. Conclusion: EA reduced the progression of the morphological transformations and concomitantly suppressed the expression of fibrotic- and EMT-related proteins in vitro and in vivo. These findings improved our understanding of the role of EA in suppressing renal fibrogenesis and demonstrated the promising role EA may play in the management of chronic kidney disease.

Diabetes mellitus modifies the association between chronic kidney disease-mineral and bone disorder biomarkers and aortic stiffness in peritoneal dialysis patients.

This study aimed to investigate the relationship of four chronic kidney disease-mineral and bone disorder (CKD-MBD) biomarkers, including intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), soluble klotho, and fetuin-A, with aortic stiffness in peritoneal dialysis (PD) patients, comparing those with and without diabetes mellitus (DM). A total of 213 patients (mean age 58 ± 14 years; 81 (38.0%) patients with DM) were enrolled. Their aortic pulse wave velocity (PWV) was measured using pressure applanation tonometry, while serum intact PTH, FGF23, α-klotho, and fetuin-A levels were measured using enzyme-linked immunosorbent assay. Overall, patients with DM had higher aortic PWV than those without (9.9 ± 1.8 vs. 8.6 ± 1.4 m/s, p < 0.001). Among the four CKD-MBD biomarkers, FGF23 levels were significantly lower in DM group (462 [127-1790] vs. 1237 [251-3120] pg/mL, p = 0.028) and log-FGF23 independently predicted aortic PWV in DM group (ß: 0.61, 95% confidence interval: 0.06-1.16, p = 0.029 in DM group; ß: 0.10, 95% confidence interval: - 0.24-0.45, p = 0.546 in nonDM group; interaction p = 0.016). In conclusion, the association between FGF23 and aortic PWV was significantly modified by DM status in PD patients.

Corosolic acid inhibits metastatic response of human renal cell carcinoma cells by modulating ERK/MMP2 signaling.

Corosolic acid (CA), a plant-derived pentacyclic triterpenoid, has potent anti-inflammatory, anti-metabolic, and anti-neoplastic actions against a variety of human cancers. However, the specific mechanism by which CA inhibits the progression of renal cell carcinoma (RCC) is yet unclear. We found that CA (≤8 µM) had no influence on either the growth or viability of RCC cell lines (786-O, ACHN, and Caki-1) or normal HK2 cells. However, in a dose-dependent manner, CA prevented the invasion and migration of RCC cells. Human protease array analysis showed that CA reduced MMP2 expression. At increasing concentrations of CA, the expression of MMP2 was dose-dependently reduced, as shown by western blot and RT-PCR analyses as well as immunofluorescence staining. CA also stimulated ERK1/2 phosphorylation in 786-O and Caki-1 cells. Transfection of CA-treated RCC cells with siRNA-ERK restored MMP2 protein expression and the motility and invasion capabilities of RCC cells. Molecular docking study results showed that CA and MMP2 interact strongly. These findings elucidate the mechanism by which CA prevents RCC cells from migrating and invading, and these findings indicate that CA may be a potential anti-metastatic therapy for RCC.

Associations of Glucometabolic Indices with Aortic Stiffness in Patients Undergoing Peritoneal Dialysis with and without Diabetes Mellitus.

Disruptions in glucose metabolism are frequently observed among patients undergoing peritoneal dialysis (PD) who utilize glucose-containing dialysis solutions. We aimed to investigate the relationship between glucometabolic indices, including fasting glucose, insulin resistance, advanced glycation end products (AGEs), PD-related glucose load, and icodextrin usage, and aortic stiffness in PD patients with and without diabetic mellitus (DM). This study involved 172 PD patients (mean age 58.3 ± 13.5 years), consisting of 110 patients without DM and 62 patients with DM. Aortic stiffness was assessed using the carotid-femoral pulse wave velocity (cfPWV). Impaired fasting glucose was defined as a fasting glucose level ≥ 100 mg/dL. Homeostatic model assessment for insulin resistance (HOMA-IR) scores, serum AGEs, dialysate glucose load, and icodextrin usage were assessed. Patients with DM exhibited the highest cfPWV (9.9 ± 1.9 m/s), followed by those with impaired fasting glucose (9.1 ± 1.4 m/s), whereas patients with normal fasting glucose had the lowest cfPWV (8.3 ± 1.3 m/s), which demonstrated a significant trend. In non-DM patients, impaired fasting glucose (ß = 0.52, 95% confidence interval [CI] = 0.01-1.03, p = 0.046), high HOMA-IR (ß = 0.60, 95% CI = 0.12-1.08, p = 0.015), and a high PD glucose load (ß = 0.58, 95% CI = 0.08-1.08, p = 0.023) were independently associated with increased cfPWV. In contrast, none of the glucometabolic factors contributed to differences in cfPWV in DM patients. In conclusion, among PD patients without DM, impaired fasting glucose, insulin resistance, and PD glucose load were closely associated with aortic stiffness.

Endocan as a Potential Marker for Predicting All-Cause Mortality in Hemodialysis Patients.

Endocan, a pro-inflammatory cytokine and pro-angiogenic factor, is a marker of endothelial dysfunction and has been proven to correlate with cardiovascular disease. In hemodialysis (HD) patients, cardiovascular disease is the major cause of mortality. Our study aimed to investigate the relationship between serum endocan and all causes of mortality in HD patients. A total of 103 patients, aged over 20 years old and undergoing HD for more than 3 months, were included and followed for 36 months. Mortality events, serum endocan, biochemical data, body mass index, systolic and diastolic blood pressure, baseline characteristics, and the use of antihypertensive and lipid-lowering drugs were recorded. In our study, a total of 26 deaths (25.2%) occurred. Hemodialysis patients with diabetes mellitus, older age, higher serum endocan, and lower creatinine and albumin levels had a higher risk of mortality. Adjusting for prognostic variables, HD patients with higher serum endocan (p = 0.010) and lower serum creatinine (p = 0.034) demonstrated significantly higher all-cause mortality. In our study, increased endocan and lower creatinine are associated with all-cause mortality in HD patients. Serum endocan levels could serve as a biomarker for a high mortality risk in HD patients.

Urinary Klotho Excretion: A Key Regulator of Sodium Homeostasis in Chronic Kidney Disease Stage 2-4.

BACKGROUND Soluble alpha-klotho (klotho) is considered an important regulator of mineral homeostasis in patients with chronic kidney disease (CKD). Since the mineral transport proteins are located on the apical membrane of renal tubular cells, we hypothesized that urine klotho may also be involved in their homeostasis. We aimed to investigate the associations between serum and urine klotho and their impacts on mineral homeostasis in patients with stage 2 to 4 CKD. MATERIAL AND METHODS Serum, spot urine, and 24-h urine of klotho were measured by using enzyme-linked immunosorbent assay. Fractional excretion of sodium, potassium, calcium, phosphate, magnesium, and klotho were calculated. RESULTS A total of 53 patients with CKD stages 2 to 4 were enrolled in this cross-sectional study. The mean age was 71.1±10.5 years, and 68% were men. Linear regression analysis showed that serum log-transformed klotho was negatively associated with log-transformed fractional excretion of klotho (log-FEKlotho) (ß=-0.085, P=0.02), showing that urinary klotho excretion could negatively regulate serum klotho levels. Moreover, our multivariate stepwise regression showed log-fractional excretion of sodium was positively associated with log-FEKlotho (ß=0.138, P=0.032). This implied urinary klotho excretion positively regulated urinary sodium excretion. CONCLUSIONS Our study showed that urine klotho excretion resulted in decreased serum klotho levels and enhanced urinary sodium excretion in patients with CKD stages 2 to 4. In addition to serum klotho, we found, for the first time, that urine klotho also played a significant role in sodium homeostasis.

Alpha-mangostin alleviate renal interstitial fibrosis via suppression of TGF-ß1/Smad/ERK signaling axis in vitro and in vivo.

α-mangostin (α-MG), a natural derivative of coumarin, exhibits anti-inflammatory, antioxidant and anti-fibrotic effects. This study aimed to determine the effect of α-MG treatment in mediating the process of renal interstitial fibrosis. We found that α-MG could alleviate tubule-interstitial damage and decrease fibrotic (α-smooth muscle actin [α-SMA], fibronectin, and collagen I), and epithelial-mesenchymal transition (EMT) protein (N-cadherin, Snail, Slug, TGF-ß1 and vimentin) expression in unilateral ureteral obstruction (UUO) mice with chronic kidney disease. α-MG significantly decreased motility as well as inhibited expression of fibrotic- and EMT-related proteins in TGF-ß1-induced HK2 cells. To clarify the molecular mechanisms of α-MG in reducing renal interstitial fibrosis, we used a MEK inhibitor (U0126) or Smad inhibitor (SB431542) cotreatment with α-MG. This is the first study is to demonstrate the antifibrotic effects of α-MG by targeting the TGF-ß1/ERK/Smad-mediated EMT signaling pathway, is even more effective against renal interstitial fibrosis.

Serum Osteoprotegerin Levels and the Vascular Reactivity Index in Patients with Hypertension.

Background and Objectives: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the mediator in the process of vascular endothelial dysfunction. Impaired endothelial function has an intimate link with hypertension (HTN) and is associated with significant morbidity and mortality. This study was to investigate the connection between OPG and endothelial dysfunction in patients having HTN. Materials and Methods: There are 102 patients with HTN included. For the purpose of determining the levels of OPG, a commercial enzyme-linked immunosorbent test kit was applied. The vascular reactivity index (VRI), which is assessed via the digital thermal monitoring, provides information on endothelial function. Results: Ten patients with HTN (9.8%) were classified as having poor vascular reactivity (VRI < 1.0), 46 HTN patients (45.1%) as having intermediate vascular reactivity (1.0 ≤ VRI < 2.0), and 46 HTN patients (45.1%) were classified as having high vascular reactivity (VRI ≥ 2.0). A greater serum OPG level (p < 0.001) and older age (p = 0.022) were linked to impaired vascular reactivity. The estimated glomerular filtration rate (r = 0.196, p = 0.048) was positively correlated with VRI values in hypertensive participants, while advanced age (r = -0.222, p = 0.025) and the log-transformed OPG level (log-OPG, r = -0.357, p < 0.001) were negatively correlated with VRI. Serum log-OPG level was shown to be strongly and independently correlated with VRI values in HTN individuals after multivariable forward stepwise linear regression analysis (ß = -0.357, adjusted R2 change = 0.119, p < 0.001). Conclusions: In patients with HTN, serum OPG levels were adversely correlated with VRI and probably had a role in endothelial dysfunction.

Serum Trimethylamine N-Oxide Level Is Positively Associated with Aortic Stiffness Measured by Carotid-Femoral Pulse Wave Velocity in Patients Undergoing Maintenance Hemodialysis.

Trimethylamine N-oxide (TMAO) is a biomarker that is effective in predicting major adverse cardiovascular (CV) events. Age-related vascular problems are significantly affected by aortic stiffness (AS), which is independently linked to CV morbidity and mortality. This study aimed to determine the association between serum TMAO levels and carotid-femoral pulse wave velocity (cfPWV) in patients receiving hemodialysis (HD) therapy. In total, 115 patients with HD were enrolled in this study. The AS group included patients whose cfPWV was >10 m/s. Using high-performance liquid chromatography and mass spectrometry, the levels of serum TMAO were measured. The AS group included 42 (36.5%) patients, and compared with the non-AS group, the rates of diabetes, hypertension, older age, systolic blood pressure, serum glucose, and TMAO levels were high. In the multivariate logistic regression analysis, serum TMAO and age were independently linked with AS after correcting for the factors significantly associated with AS. Following multivariate stepwise linear regression analysis, serum TMAO in these individuals was found to be strongly correlated with cfPWV values (p < 0.001). In patients on chronic HD, serum TMAO level is an independent measure of AS and strongly correlated with cfPWV.

Positive Association of Serum Galectin-3 with the Development of Aortic Stiffness of Patients on Peritoneal Dialysis.

A novel cardiovascular stress biomarker known as galectin-3 might be useful for anticipating adverse cardiovascular outcomes. The objective of the current investigation was to assess the association between serum galectin-3 levels and aortic stiffness (AS) in 196 patients on peritoneal dialysis. An enzyme-linked immunosorbent examination and a cuff-based volumetric displacement were employed to determine the levels of serum galectin-3 and the carotid-femoral pulse wave velocity (cfPWV), respectively. The AS group had 48 patients in total (24.5%) with cfPWV greater than 10 m/s. The AS group, when compared with the group without AS, had a significantly higher prevalence of diabetes mellitus and hypertension in addition to greater fasting glucose levels, waist circumference, systolic blood pressure, and serum galectin-3 levels. Multivariate logistic and linear regression analysis demonstrated that serum glactin-3 levels, in addition to gender and age, were significantly and independently associated with cfPWV and AS. Serum galectin-3 levels were linked with AS, according to a receiver operating characteristic curve analysis, with an area under the curve of 0.648 (95% confidence interval, 0.576-0.714; p = 0.0018). In summary, there was a significant correlation between serum galectin-3 levels and cfPWV in patients undergoing peritoneal dialysis therapy for end-stage kidney disease.

Carotid-Femoral Pulse Wave Velocity Could Be a Marker to Predict Cardiovascular and All-Cause Mortality of Hemodialysis Patients.

Among hemodialysis (HD) patients, cardiovascular disease (CVD) is recognized as a major contributor to the high risk of mortality, and emerging evidence has ascertained arterial stiffness as an independent predictor of adverse cardiovascular (CV) outcomes. We aimed to investigate the efficacy of arterial stiffness measurement in predicting CV and all-cause mortality in patients on HD (n = 130). Carotid-femoral pulse wave velocity (cfPWV) was measured by a validated tonometry system. A cfPWV of >10 m/s was used to assign patients to the arterial stiffness group (n = 64). Baseline and biochemical characteristics, as well as all-cause and CV mortality, were recorded. During the 3-year follow-up period, a total of 32 deaths (25%) occurred. The patients who died had clinically significant high cfPWV levels; were relatively old; and had hypoalbuminemia, low creatinine levels, and diabetes. After adjustment for the prognostic variables, patients with elevated cfPWV had significantly higher all-cause (p = 0.036) and CV mortality (p = 0.017), compared with the mortality rates in the normal group. In this study, cfPWV was found to be an independent predictor of all-cause and CV mortality in HD patients.

Licochalcone A Suppresses Renal Cancer Cell Proliferation and Metastasis by Engagement of Sp1-Mediated LC3 Expression.

Licochalcone A (LicA) is a strong anti-inflammatory, antioxidant, and anticarcinogenic substance that is useful against a variety of human malignancies. However, its precise mechanism in mediating the development of renal cell carcinoma (RCC) is not entirely understood. In this work, LicA was discovered to limit cell growth and survival, induce cell cycle arrest, promote autophagy and LC3B expression, and inhibit the migration and invasion of RCC cells. In addition, the proliferation, migration, and invasion inhibited by LicA were restored by the transfection of siRNA-LC3. The effects of LC3B on the metastatic phenotype of ACHN cells was enhanced with the overexpression of Sp1 or suppressed by inhibiting the phosphorylation of FAK and Src. Finally, LicA showed antitumor properties against RCC in an in vivo xenograft model. In conclusion, our study demonstrated the chemotherapeutic potential of LicA on proliferation, migration, invasion, and autophagy through the activation of LC3B expression, ultimately modulating FAK/Src signaling pathway-mediated Sp1 expression. These findings illustrate the novel role and molecular mechanisms of LicA against RCC cells.

Serum Angiopoietin-like Protein 3 Levels Are Associated with Endothelial Function in Patients with Maintenance Hemodialysis.

Angiopoietin-like protein 3 (ANGPTL3) plays an important role in lipid and lipoprotein trafficking and metabolism and is positively correlated with cardiovascular disease. Our objective was to evaluate the association between serum ANGPTL3 levels and endothelial function in patients on maintenance hemodialysis (MHD). We enrolled 116 patients on MHD and obtained their blood test results from their medical records. Using a noninvasive digital thermal monitor, we determined the vascular reactivity index (VRI) as a measure of endothelial function. Serum ANGPTL3 concentration was measured by a commercial-enzyme-linked immunosorbent assay. Vascular reactivity was classified as poor in 17 (14.7%) patients, intermediate (1.0 ≤ VRI < 2.0) in 50 (43.1%) patients, and high (VRI ≥ 2.0) in 49 (42.2%) patients. Serum levels of ANGPTL3 (p < 0.001) and alkaline phosphatase (ALP, p = 0.025) increased significantly as the VRI decreased. The log-transformed serum ALP (log-ALP, r = -0.187, p = 0.045) and log-ANGPTL3 (r = -0.319, p < 0.001) showed a negative correlation with the VRI on univariate linear regression analysis. A significant negative correlation was found between log-ANGPTL3 and VRI (p < 0.001) on multivariate stepwise linear regression analysis. The findings of our investigation showed that, in patients with MHD, the ANGPTL3 concentration had a negative correlation with the VRI.

Serum Trimethylamine N-Oxide Level Is Associated with Peripheral Arterial Stiffness in Advanced Non-Dialysis Chronic Kidney Disease Patients.

Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin involved in cardiovascular diseases (CVD). Peripheral arterial stiffness (PAS), measured by the brachial-ankle pulse wave velocity (baPWV) is a valuable indicator of the existence of CVD alongside other diseases. The study recruited 157 patients with chronic kidney disease (CKD) stages 3 to 5, and aimed to determine the correlation between serum TMAO and PAS, defined as a baPWV of >18.0 m/s. Patients with CKD who were diagnosed with PAS (68 patients, 43.3%) were older, had a higher percentage of hypertension or diabetes mellitus, higher systolic blood pressure, and higher fasting glucose, C-reactive protein, and TMAO levels. Furthermore, besides old age and SBP, patients with CKD who had higher serum TMAO were more likely to have PAS, with an odds ratio of 1.016 (95% confidence interval = 1.002−1.029, p = 0.021) by multivariate logistic regression analysis. Correlation analysis demonstrated that serum TMAO was positively correlated with C-reactive protein level and either left or right baPWV. Thus, we supposed that serum TMAO levels were associated with PAS in patients with advanced non-dialysis CKD.

Correlation between Serum 25-Hydroxyvitamin D Level and Peripheral Arterial Stiffness in Chronic Kidney Disease Stage 3-5 Patients.

Vitamin D deficiency and high brachial-ankle pulse wave velocity (baPWV) are each independently associated with higher incidence of mortality and cardiovascular (CV) disease or CV events, respectively. This study aimed to evaluate the relationship between serum 25-hydroxyvitamin D levels and baPWV in non-dialysis patients with stage 3−5 chronic kidney disease (CKD). We enrolled 180 CKD patients. A commercial enzyme-linked immunosorbent assay was used to measure 25-hydroxyvitamin D levels. BaPWV values were measured using an automatic pulse wave analyzer. Either left or right baPWV > 18.0 m/s was considered indicative of peripheral arterial stiffness (PAS). In this study, 73 (40.6%) patients were found to have PAS. Compared to those without PAS (control group), patients with PAS were older and had higher incidence of diabetes mellitus, higher systolic and diastolic blood pressure, higher levels of intact parathyroid hormone, and C-reactive protein, and lower levels of 25-hydroxyvitamin D. Multivariate logistic regression analysis found 25-hydroxyvitamin D levels (odds ratio [OR]: 0.895, 95% confidence interval [CI] 0.828−0.968, p = 0.005) and old age (OR: 1.140, 95% CI 1.088−1.194, p < 0.001) to be independently associated with PAS in patients with stage 3−5 CKD. Lower serum 25-hydroxyvitamin D levels and older age were associated with PAS in these patients.

Frailty, Health Literacy, and Self-Care in Patients with Chronic Kidney Disease in Taiwan.

Chronic kidney disease (CKD) is a chronic and often irreversible disease that requires active self-care to mitigate adverse outcomes. This study aimed to analyze the associations of demographic and disease data, frailty, health literacy (HL), and CKD self-care (CKDSC) in patients with CKD. We conducted a cross-sectional study at two hospitals in Taiwan. A total of 144 CKD patients with a mean age of 66.8 ± 9.1 years were included in the study. Among them, 79.2% were in CKD G3, and the mean time since diagnosis of CKD was 86 ± 48 months. Approximately 62.5% were identified as non-frail. The mean of HL and CKDSC were 11.76 ± 4.10 and 62.12 ± 9.31. In multivariate linear regression analysis, age ≥ 65 years (odds ratio (OR) = 5.67, 95% confidence interval (CI) 1.59-9.75), non-frailty (OR = 2.19, 95% CI 0.02-5.40), and high critical HL (OR = 1.43, 95% CI 0.13-2.90) showed significant positive correlation with CKDSC. Therefore, management of patients with CKD should focus on the young population, reinforcing health education strategies that improve critical HL and preventing frailty that may interfere with self-care. In addition, the patient's social support resources should be expanded to achieve the goal of CKDSC.

Melatonin combined with sorafenib synergistically inhibit the invasive ability through targeting metastasis-associated protein 2 expression in human renal cancer cells.

Objectives: Renal cell carcinoma (RCC) was the most common and lethal urological malignancy with the dismal outcome when distant metastasis. Melatonin was known as a potential oncostatic agent against several types of malignancy and sorafenib had been considered as an agent to treat RCC, but the synergistic effects of melatonin and sorafenib on human RCC have not been elucidated. Materials and Methods: Human renal cancer cell lines (Caki-1 and ACHN) were treated with melatonin combined with sorafenib were detected the cell growth and cell cycle by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and flow cytometry. The ability of cell migration/invasion was performed with in vitro migration and invasion assay. The proteins and mRNA expression of metastasis-associated protein 2 (MTA2) from the RCC cells were measured by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical significance of MTA2 in RCC tissues was analyzed from The Cancer Genome Atlas database by using TISIDB software. Results: Our results showed that melatonin combined with sorafenib, sorafenib or melatonin-treated alone did not induce the cytotoxic effects or cell cycle arrest in human RCC cells and HK2 cells. Additionally, cotreatment with melatonin and sorafenib synergistically reduced migration and invasion in human Caki-1 and ACHN cells through synergistically suppression of MTA2 expression. Bioinformatics analysis showed that MTA2 expression significantly correlated with overall survival (P < 0.002), tumor grade (P < 0.001) and tumor stage (P < 0.001) in human RCC. Conclusion: Our results demonstrated that concomitantly used melatonin and sorafenib could significantly reduce the abilities of migration and invasion of RCC cells through inhibiting MTA2. We considered that this novel promising combination strategy towards the treatment of RCC, but further studies are warranted.

Serum osteocalcin concentration as an independent biomarker of osteoporosis in patients with chronic kidney disease.

OBJECTIVES: Osteocalcin, an osteoblast-derived hormone, is associated with the development of osteoporosis and arteriosclerosis in the general population. However, its role on the pathogenesis of osteoporosis and vascular calcification in patients with chronic kidney disease (CKD) is unclear. Here, we investigated the connection between osteocalcin, bone mineral density (BMD), and abdominal aortic calcification (AAC) in CKD patients. MATERIALS AND METHODS: In total, 95 patients with stage 2 to stage 5 CKD were enrolled. Serum osteocalcin levels were measured using an electrochemiluminescence immunoassay. BMD was determined by dual-energy X-ray absorptiometry, and AAC scores were generated from lateral lumbar radiograph findings. RESULTS: 95 patients were assigned into normal bone density (30.5%, n = 29), osteopenia (45.3%, n = 43), and osteoporosis (24.2%, n = 23) groups. The osteoporosis group was characterized by older age, higher female-to-male ratio, phosphorous levels, calcification scores, osteocalcin levels, and intact parathyroid hormone (PTH) levels, while with lower hemoglobin levels as compared to normal and osteopenia groups. Multivariate multinominal regression analysis showed age, female sex, intact PTH, and serum osteocalcin level were independent determinants of osteoporosis severity in CKD patients. Furthermore, serum osteocalcin level is positively correlated to intact PTH in multivariate linear regression model, indicating that osteocalcin might be a bone turnover marker in patients with CKD. Multivariate stepwise linear regression analysis revealed that age, diabetes mellitus, poorer renal function, rather than osteocalcin, have independent associations with AAC score. CONCLUSION: Elevated serum osteocalcin levels could be considered as a marker of osteoporosis rather than that of vascular calcification in patients with CKD.

Rosmarinic acid ameliorates renal interstitial fibrosis by inhibiting the phosphorylated-AKT mediated epithelial-mesenchymal transition in vitro and in vivo.

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via renal fibrosis. Epithelial-mesenchymal transition (EMT) is a crucial feature of renal fibrosis. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenylacetic acid with a wide range of desirable biological activities. In this study, we investigated whether RA exerted anti-renal fibrosis effects and its related mechanisms in a unilateral ureteral obstruction (UUO) mouse model. C57BL/6 mice were orally administered RA (10 and 20 mg kg-1 d-1) for 7 consecutive days before and after UUO surgery. The mice were then sacrificed to collect the blood and kidneys. Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate the renal injury and function. Immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), and western blotting were used to detect the expression levels of EMT markers. In vitro studies were performed using the IS-stimulated NRK-52E cell line. Here, the pathological changes, collagen deposition, and mRNA and protein expression levels of profibrotic factors and fibrotic markers were found to be significantly elevated in the kidneys of UUO mice. We found that RA administration significantly ameliorated UUO-induced kidney damage by reversing abnormal serum creatinine and blood urea nitrogen levels. It was found that RA treatment decreased the expression levels of alpha-smooth muscle actin (α-SMA), collagen I, fibronectin, transforming growth factor (TGF)-ß1, vimentin and phosphorylated AKT (p-AKT) while increasing the E-cadherin expression in both UUO kidneys and IS-treated NRK-52E cells. Our results demonstrate that RA may be a promising therapeutic agent for renal interstitial fibrosis.