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Background: Galectin-3 is implicated in the pathogenesis of inflammation and atherosclerosis. Peripheral arterial disease (PAD), characterized by a reduced ankle-brachial index (ABI), is a prognostic marker for mortality in patients on hemodialysis. We investigated the relationship between serum galectin-3 levels and PAD in patients undergoing regular hemodialysis. Methods: We carried out a cross-sectional study at a medical center, involving 92 participants. Serum galectin-3 levels were assessed by a commercially available enzyme-linked immunosorbent assay. ABI measurement was done with an automatic device based on oscillometry. Participants were categorized into two groups, normal and low ABI, based on a 0.9 cut-off point. Results: Eighteen patients (19.6%) exhibited a low ABI. In individuals with low ABIs, we observed a greater prevalence of diabetes mellitus, elevated serum C-reactive protein (CRP) levels, increased galectin-3 levels, and lower serum creatinine levels. Furthermore, serum galectin-3 levels (odds ratio [OR]: 1.056, 95% confidence interval [CI]: 1.003-1.112, p = 0.037) and CRP (per 0.1 mg/dL increment, OR: 1.195, 95% CI: 1.032-1.383, p = 0.017) were identified as independent predictors of PAD. Serum galectin-3 and log-transformed CRP levels were also independently and significantly negatively correlated with the left and right ABI values. Conclusions: Serum galectin-3 levels correlate with PAD in patients undergoing maintenance hemodialysis.
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BACKGROUND Lipoprotein (a) [Lp(a)] is associated with atherosclerosis and cardiovascular mortality in patients with kidney failure. Aortic stiffness (AS), measured primarily by carotid-femoral pulse wave velocity (cfPWV), reflects vascular aging and precedes end-organ failure. This study aimed to evaluate the association between serum Lp(a) levels and cfPWV in patients undergoing peritoneal dialysis (PD). MATERIAL AND METHODS In this cross-sectional study, which included 148 patients with long-term PD for end-stage kidney failure, cfPWV was measured using a cuff-based method. AS was defined as a cfPWV exceeding 10 m/s, and an enzyme-linked immunosorbent assay was used to determine serum Lp(a) levels. Univariate and multivariate regression analyses were performed to identify the clinical correlates of AS. RESULTS There were 32 (21.6%) patients diagnosed with AS. Based on the multivariate logistic regression analysis, the odds ratio for AS was 1.007 (95% confidence interval, 1.003-1.011; P=0.001) for every 1 mg/L increase in Lp(a) levels. Multivariate linear regression analysis showed that Lp(a) (P<0.001), age (P=0.003), waist circumference (P=0.008), systolic blood pressure (P=0.010), and diabetes mellitus (P<0.001) were positively associated with cfPWV. The area under the receiver operating characteristic curve for Lp(a) in differentiating AS from non-AS was 0.770 (95% confidence interval, 0.694-0.835; P<0.0001). CONCLUSIONS Serum Lp(a) level was independently associated with cfPWV and AS in patients with PD.
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Falência Renal Crônica , Lipoproteína(a) , Diálise Peritoneal , Análise de Onda de Pulso , Rigidez Vascular , Humanos , Masculino , Diálise Peritoneal/métodos , Rigidez Vascular/fisiologia , Feminino , Lipoproteína(a)/sangue , Pessoa de Meia-Idade , Estudos Transversais , Análise de Onda de Pulso/métodos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Falência Renal Crônica/fisiopatologia , Adulto , Idoso , Fatores de Risco , Curva ROCRESUMO
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.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão GênicaRESUMO
Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.
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Background: Arterial stiffness (AS) can be used to predict future cardiovascular diseases. High lipoprotein(a) (Lp(a)) levels were independently correlated with cardiovascular (CV) morbidity and death in patients with chronic renal insufficiency. The cardio-ankle vascular index (CAVI) is a useful biomarker of arteriosclerotic disorders and has a close relationship with a variety of CV events. This study aimed to investigate the correlation between serum Lp(a) levels and AS in patients on peritoneal dialysis (PD) using the CAVI. Methods: A total of 86 adult patients who were on regular PD for at least 3 months were recruited in this study. The CAVI values were determined using the waveform device (VaSera VS-1000). A CAVI value of ≥ 9.0 on either side was defined as high. Serum Lp(a) levels were measured by an enzyme-linked immunosorbent assay. Results: Among these participants, 35 of 86 (40.7%) belonged to the high CAVI group. In contrast to those with a normal CAVI, PD recipients in the high CAVI group had higher serum levels of total cholesterol (p = 0.003), triglycerides (p = 0.044), C-reactive protein (p < 0.001), and Lp(a) (p < 0.001), whereas their albumin levels were significantly lower (p = 0.026). Based on multivariable logistic regression analysis, serum Lp(a) (odds ratio [OR] 1.025, 95% confidence interval [CI] 1.010-1.040, p = 0.001), total cholesterol (OR 1.042, 95% CI 1.005-1.081, p = 0.027), and C-reactive protein (each increase 0.1 mg/dL, OR 1.217, 95% CI 1.008-1.469, p = 0.041) levels were found as the parameters that could independently predict AS in patients on PD. Further, using Spearman's correlation analysis, both the left and right CAVIs revealed a significantly positive correlation with log-transformed Lp(a) levels (r = 0.588, p < 0.001; r = 0.639, p < 0.001, respectively). Conclusions: Serum Lp(a) levels were postulated to participate in the pathogenic processes of AS in adult patients undergoing PD.
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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.
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Diabetes Mellitus , Resistência à Insulina , Diálise Peritoneal , Rigidez Vascular , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Icodextrina , Análise de Onda de Pulso , Glucose , Soluções para DiáliseRESUMO
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.
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Aterosclerose , Hipertensão , Humanos , Osteoprotegerina , Hipertensão/complicações , Análise de Regressão , Modelos Lineares , BiomarcadoresRESUMO
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.
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Osteocalcina , Osteoporose , Insuficiência Renal Crônica , Absorciometria de Fóton , Biomarcadores/sangue , Densidade Óssea , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/etiologia , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Osteocalcina/sangue , Osteoporose/sangue , Osteoporose/diagnóstico por imagem , Osteoporose/etiologia , Hormônio Paratireóideo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Calcificação Vascular/sangue , Calcificação Vascular/etiologiaRESUMO
Background and Objectives: Sclerostin and Dickkopf-1 (DKK1) modulate osteoblastogenesis, but their role in bone loss in hemodialysis (HD) patients is inconclusive. This study investigated relationships among lumbar bone mineral density (BMD), serum sclerostin, and DKK1 in HD patients. Materials and Methods: Blood samples were obtained from 75 HD patients. Dual-energy X-ray absorptiometry measured lumbar BMD of the lumbar vertebrae (L2−L4). Enzyme-linked immunosorbent assay revealed serum sclerostin and DKK1 concentrations. Results: There were 10 (13.3%), 20 (26.7%), and 45 (60%) patients defined as presenting with osteoporosis, osteopenia, or normal BMD, respectively. Age, alkaline phosphatase, urea reduction rate, fractional clearance index for urea, sclerostin level, and percentage of female patients are significantly negatively associated with the lumbar BMD and T-score, while the body mass index and waist circumference significantly positively associated with the lumbar BMD and T-score. Multivariate forward stepwise linear regression analysis indicated that serum sclerostin (ß = −0.546, adjusted R2 change = 0.454; p < 0.001), age (ß = −0.216, adjusted R2 change = 0.041; p = 0.007), and percentage of female HD patients (ß = −0.288, adjusted R2 change = 0.072; p = 0.0018) were significantly negatively associated with lumbar BMD in HD patients. Conclusions: Advanced age, female gender, and serum sclerostin level, but not DKK1, were negatively associated with BMD in HD patients.
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Doenças Ósseas Metabólicas , Osteoporose , Absorciometria de Fóton , Densidade Óssea , Feminino , Humanos , Masculino , Osteoporose/etiologia , Diálise Renal/efeitos adversosRESUMO
BACKGROUND: The role of indoxyl sulfate (IS), an important protein-bound uremic toxin, in arterial stiffness (AS) in patients with chronic kidney disease (CKD) is unclear. MATERIALS AND METHODS: We investigated the association between serum IS levels and AS in a cross-sectional study of 155 patients with CKD. Patients in the AS group was defined as carotid-femoral pulse wave velocity (cfPWV) value >10 m/s measured by a validated tonometry system (SphygmoCor), while values ≤10 m/s were regarded as without AS group Serum IS was measured by liquid chromatography-mass spectrometry analysis. RESULTS: Of these CKD patients, AS was present in 51 (32.9%) patients, who were older, had a higher rate of diabetes, higher systolic blood pressure (SBP), and higher IS levels compared to those without AS. By multivariable logistic regression analysis, IS (adjusted odds ratio [aOR] 1.436, 95% confidence interval [CI] 1.085-1.901, p = 0.011), age (aOR 1.058, 95% CI 1.021-1.097, p = 0.002), and SBP (aOR 1.019, 95%CI 1.000-1.038, p = 0.049) were independent predictors of AS. By multivariable stepwise linear regression analysis, logarithmically transformed IS, age, DM, and SBP were significantly correlated with cfPWV. The area under the receiver-operating characteristic curve for serum log-IS was 0.677 (95%CI 0.598-0.750, p = 0.0001) to predict the development of AS in patients with CKD. CONCLUSION: These finding demonstrate that in addition to older and higher SBP, a high serum IS level is a significant biomarker associated with AS in patients with CKD.
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Indicã/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Rigidez Vascular , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Velocidade da Onda de Pulso Carótido-Femoral , Comorbidade , Estudos Transversais , Suscetibilidade a Doenças , Feminino , Humanos , Testes de Função Renal , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Insuficiência Renal Crônica/etiologia , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: Osteoprotegerin (OPG), a potent osteoclast activation inhibitor, decreases bone resorption and plays a role in mediating bone mineral density (BMD). Our aim was to evaluate the relationship between BMD and serum OPG in maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: Fasting blood samples were obtained from 75 MHD patients. BMD was measured by dual-energy X-ray absorptiometry in lumbar vertebrae (L2-L4). The WHO classification criteria were applied to define osteopenia and osteoporosis. A commercial enzyme-linked immunosorbent assay was used to measure serum OPG values. RESULTS: Among all MHD patients, seven (9.3%) and 20 patients (26.7%) were defined as osteoporosis and osteopenia, respectively. Female patients had lower lumbar BMD than males (p = 0.002). Older age (p = 0.023), increased serum OPG (p < 0.001) urea reduction rate (p = 0.021), Kt/V (p = 0.027), and decreased body mass index (p = 0.006) and triglycerides (p = 0.020) were significantly different between the normal, osteopenia, and osteoporosis groups. Lumbar spine BMD was positively correlated with body mass index (BMI) (p < 0.001) but negatively correlated with OPG (p < 0.001) and age (p = 0.003). After grouping patients into T scores < -1 and < -2.5, female sex and OPG (adjusted odds ratio [aOR] 1.022, 95% confidence interval [C.I.] 1.011-1.034, p < 0.001) were predictors of T scores < -1, whereas only OPG was predictive of T scores < -2.5 (aOR 1.015, 95% C.I. 1.005-1.026, p = 0.004) by multivariate stepwise logistic regression analysis. The areas under the curve for predicting T scores < -1 or < -2.5 were 0.920 (95% C.I. 0.834-0.970, p < 0.001) and 0.958 (95% C.I. 0.885-0.991, p < 0.001), respectively. CONCLUSIONS: Increased serum OPG negatively correlated with lumbar BMD and could be a potential biomarker predictive of osteoporosis in MHD patients.
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Densidade Óssea , Osteoporose , Absorciometria de Fóton , Idoso , Feminino , Humanos , Masculino , Osteoporose/epidemiologia , Osteoporose/etiologia , Osteoprotegerina , Diálise RenalRESUMO
Arecoline, a component of betel nuts, is a known carcinogen that causes oral cancers among those who chew betel nuts. Betel nut chewing is also associated with an increased risk of chronic kidney disease (CKD), but the role of arecoline in this association is unclear. This in vitro study investigates the effects of arecoline on cultured human kidney (HK2) cells. We observed that arecoline had no effect on cell viability but increased cell migration in a dose-dependent manner. Western blot analysis showed that arecoline treatment caused a dose-dependent decrease in E-cadherin expression and dose-dependent increases in N-cadherin, vimentin, α-SMA, and collagen expression; reverse transcriptase-polymerase chain reaction analysis revealed dose-dependent increases in α-SMA and collagen mRNA. Arecoline treatment upregulated the expression of phosphorylated extracellular signal-regulated kinase through epithelial mesenchymal transition and renal fibrosis in HK2 cells. These findings demonstrate that arecoline plays a role in inducing the epithelial mesenchymal transition and fibrogenesis in renal tubule cells and suggest that arecoline promotes the progression of CKD.
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Areca/toxicidade , Arecolina/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Areca/química , Caderinas/genética , Caderinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/genética , Fibrose , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Sistema de Sinalização das MAP Quinases/genética , Fosforilação , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Regulação para CimaRESUMO
Osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease complications and severity. Peripheral arterial disease (PAD) is associated with an increased risk of death in patients on peritoneal dialysis (PD). Therefore, this study aimed to evaluate the relationship between serum OPG levels and PAD by measuring the ankle-brachial index (ABI) of patients on PD. A commercial enzyme-linked immunosorbent assay kit was used to measure OPG values. Left or right ABI values of <0.9 were categorized as the low ABI group. Among 70 patients on PD, 13 (18.6%) were categorized in the low ABI group. Patients in the low ABI group had higher prevalence of diabetes mellitus (p = .044) and higher serum C-reactive protein (CRP) (p < .001) and OPG levels (p < .001) but lower creatinine (p = .013) and peritoneal Kt/V (p = .048) levels than those in the normal ABI group. Results of multivariable logistic regression analysis revealed that OPG [adjusted odds ratio (aOR) 1.027, 95% confidence interval (CI) 1.010-1.045, p = .002] and CRP (aOR 1.102, 95% CI 1.006-1.207, p = .037) levels were independent predictors of PAD in patients on PD. OPG can also be used to predict PAD development with the area under the receiver operating characteristic curve of 0.823 (95% CI: 0.714-0.904, p < .001) in patients on PD. Therefore, serum OPG and CRP levels can be considered as risk factors for PAD development in patients on PD.
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Índice Tornozelo-Braço , Osteoprotegerina/sangue , Doença Arterial Periférica/etiologia , Diálise Peritoneal/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Curva ROC , Fatores de RiscoRESUMO
BACKGROUND/AIMS: α-mangostin has anti-carcinogenic effects against several cancers. We investigated the molecular mechanism of this compound on the metastasis of human renal carcinoma cells. METHODS: Cell viability was measured using the MTT assay, and cell cycle distribution using flow cytometry. A Matrigel-based assay was used to measure in vitro cell migration and invasion. MAPK-related proteins and matrix metalloproteinase (MMP)-9 and MMP-2 expression were measured by western blotting, and MMP2/-9 activities were determined by gelatin zymography. RT-qPCR and a luciferase assay were used to examine the transcriptional activity of MMP-9. RESULTS: α-mangostin inhibited the migration and invasion of RCC cells in a dose-dependent manner, but had no evident cytotoxic effects. Treatment of 786-O cells with α-mangostin inhibited activation of MEK and ERK. Treatment with a specific MEK inhibitor (U0126) enhanced the inhibitory effects of α-mangostin on cell migration and invasion, and the phosphorylation of ERK and MEK. Moreover, α-mangostin inhibited the expression of the MMP-9 mRNA levels as well as the activity of MMP-9 promoter, and these suppressive effects were further enhanced by U0126. CONCLUSIONS: Our results suggest that α-mangostin suppresses cell migration and invasion via MEK/ERK/MMP9 pathway, and might be a promising anti-metastatic agent against human renal cell carcinoma.
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Anticarcinógenos/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Xantonas/toxicidade , Anticarcinógenos/química , Butadienos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Nitrilas/farmacologia , Xantonas/químicaRESUMO
Traumatic and nontraumatic rhabdomyolysis can lead to acute renal failure (ARF), and acute alcohol intoxication can lead to multiple abnormalities of the renal tubules. We examined the effect of acute alcohol intoxication in a rat model of rhabdomyolysis and ARF. Intravenous injections of 5 g/kg ethanol were given to rats over 3 h, followed by glycerol-induced rhabdomyolysis. Biochemical parameters, including blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and creatine phosphokinase (CPK), were measured before and after induction of rhabdomyolysis. Renal tissue injury score, renal tubular cell expression of E-cadherin, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) were determined. Relative to rats in the vehicle group, rats in the glycerol-induced rhabdomyolysis group had significantly increased serum levels of BUN, Cre, GOT, GPT, and CPK, elevated renal tissue injury scores, increased expression of NF-κB and iNOS, and decreased expression of E-cadherin. Ethanol exacerbated all of these pathological responses. Our results suggest that acute alcohol intoxication exacerbates rhabdomyolysis-induced ARF through its pro-oxidant and inflammatory effects.
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Injúria Renal Aguda/sangue , Intoxicação Alcoólica/sangue , Alcoolismo/sangue , Rabdomiólise/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/complicações , Injúria Renal Aguda/patologia , Intoxicação Alcoólica/complicações , Intoxicação Alcoólica/patologia , Alcoolismo/complicações , Alcoolismo/patologia , Alquil e Aril Transferases/sangue , Animais , Nitrogênio da Ureia Sanguínea , Caderinas/metabolismo , Creatinina/sangue , Etanol/toxicidade , Glicerol/toxicidade , Humanos , Rim/metabolismo , Rim/patologia , NF-kappa B , Óxido Nítrico Sintase Tipo II/sangue , Ratos , Espécies Reativas de Oxigênio/metabolismo , Rabdomiólise/induzido quimicamente , Rabdomiólise/complicações , Rabdomiólise/patologia , Transferases (Outros Grupos de Fosfato Substituídos)/sangueRESUMO
AIM: Serum adipokines have a role in the development of arterial stiffness. We aimed to investigate the risk factors of developing arterial stiffness and the association of leptin and arterial stiffness in hypertensive (HTN) patients. METHODS: There were 101 HTN patients enrolled. Fasting blood samples and baseline characteristics were obtained and carotid-femoral pulse wave velocity (cfPWV) was measured with the SphygmoCor system. A cfPWV > 10 m/s was defined as high arterial stiffness, and ≤ 10 m/s as low arterial stiffness. RESULT: Forty-seven patients (46.5 %) had high arterial stiffness, and had a higher percentage of diabetes (P = 0.044), , older age (P < 0.001), higher pulse pressure (P = 0.049), and higher serum blood urea nitrogen (P = 0.029), creatinine (P = 0.027), intact parathyroid hormone (P = 0.004), serum leptin level (P = 0.002), C-reactive protein (P < 0.001), but lower estimated glomerular filtration rate (P = 0.006) compared to patients with low arterial stiffness. After adjusting for factors significantly associated with arterial stiffness by multivariate logistic regression analysis, it revealed that leptin (aOR = 1.037, 95% CI = 1.007-1.067, P = 0.014), having DM (aOR = 4.885, 95% CI = 1.590-15.006, P = 0.006), and elevated CRP (aOR = 1.503, 95% CI = 1.110-2.0371,P = 0.009) were significant independent predictors of arterial stiffness in HTN patients. CONCLUSIONS: Serum leptin level could be a predictor for arterial stiffness in HTN patients.
Assuntos
Hipertensão/sangue , Hipertensão/fisiopatologia , Leptina/sangue , Rigidez Vascular , Idoso , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Humanos , Hipertensão/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Valor Preditivo dos Testes , Análise de Onda de Pulso , Fatores de Risco , Regulação para CimaRESUMO
BACKGROUND/AIMS: Tubulointerstitial fibrosis can lead to end-stage renal disease. Pentraxin 3 (PTX3) is an acute phase protein produced by resident and innate immunity cells. We investigated the effect of PTX3 on cultured human proximal tubular epithelial (HK-2) cells and a rat unilateral ureteral obstruction (UUO) model of renal fibrosis. METHODS: Gain-of-function experiments were used to examine the effect of recombinant human PTX3 (Rh-PTX3) on HK-2 cells. Cell proliferation (MTT assay) and in vitro cell migration were measured. The levels of PTX3, p-JNK, and EMT markers were measured using immunohistochemistry, RT-PCR, and western blotting in UUO rats and HK-2 cells. RESULTS: HK-2 cells treated with Rh PTX3 did not affect cell viability, but significantly increased cell migration. Moreover, Rh-PTX3 increased the expression of snail, slug, N-cadherin, and vimentin, decreased the expression of E-cadherin, and increased the phosphorylation of JNK. SP600126 (a specific JNK inhibitor) enhanced the effects of Rh-PTX3. Rats with UUO exhibited time-dependent increased levels of PTX3, p-JNK, and vimentin, and decreased expression of E-cadherin. CONCLUSIONS: Our results suggest that PTX3 induces cell migration via upregulation of EMT in a JNK-dependent mechanism, and highlight the role of PTX3 in the pathogenesis renal fibrosis.
Assuntos
Proteína C-Reativa/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Rim/enzimologia , Rim/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Componente Amiloide P Sérico/farmacologia , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Fibrose , Humanos , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Masculino , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Obstrução Ureteral/patologiaRESUMO
INTRODUCTION: Resuscitation after hemorrhagic shock (HS) could result in increased pro-inflammatory cytokines and then multiple organ dysfunctions. Calcitriol exerts pleiotropic effects in a wide variety of target tissues and has a role against anti-inflammation. The present study was aimed to investigate the modulatory effects of calcitriol on the pathophysiological and inflammatory markers following HS in rats. MATERIALS AND METHODS: By withdrawing 60% of the total blood volume over 30min via a femoral artery catheter in rats, HS was induced. Afterwards, 10ng/kg calcitriol was injected intravenously in rats. After performing these procedures, hemodynamic status of mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 12h. Hemoglobin, lactic dehydrogenase (LDH), creatine phosphokinase (CPK), liver and renal function were measured at 30min before the induction of HS and 0, 1, 3, 6, 9, and 12h after HS, while an equal volume of normal saline as replacement fluid. At 1 and 12h after inducing HS, serum levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured, and the livers, kidneys and lungs were taken out and then examined histo-pathologically at 48h after inducing HS. RESULTS: Hemoglobin and MAP were significantly decreased, liver and renal function were significantly impaired, but HR and the levels of LDH, CPK, TNF-α and IL-6 were significantly increased after HS in rats. After being treated with calcitriol following HS resulted in better survival rate, lower serum levels of TNF-α and IL-6, and lesser hepatic, renal, and pulmonary histo-pathologic scores of injury in rats. CONCLUSION: Being treated with calcitriol after HS could ameliorate the pro-inflammatory reactions by modulating the effects of cytokines, which lead to prevention of subsequent major organ damages.
Assuntos
Calcitriol/farmacologia , Interleucina-6/sangue , Insuficiência de Múltiplos Órgãos , Choque Hemorrágico , Fator de Necrose Tumoral alfa/sangue , Animais , Creatina Quinase/sangue , L-Lactato Desidrogenase/sangue , Masculino , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Ratos , Ratos Endogâmicos WKY , Choque Hemorrágico/sangue , Choque Hemorrágico/tratamento farmacológicoRESUMO
Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.