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BACKGROUND: Multiple target-organ damages (TODs) in the same patient are common and further increase the risk of cardiovascular disease. However, the relationship between ambulatory central systolic blood pressure (SBP) and multiple TODs has yet to be explored. METHODS AND RESULTS: MobilO-Graph PWA was used to monitor the participants' ambulatory blood pressure, and the presence of left ventricular hypertrophy, carotid hypertrophy, and kidney injury were used to define TOD. Logistic regression analyses and receiver operating characteristic analyses were used to explore the correlation between SBP and TOD. Overall, 2018 nondialysis patients with chronic kidney disease were included and 580 (28.74%) had multiple TODs. Twenty-four-hour central SBP with c2 calibration exhibited a stronger correlation with the increasing number of TOD compared with 24-hour brachial SBP in ordinal logistic regression analyses. In the multivariable analyses with the presence of multiple TODs, the odds ratios were 1.786 (95% CI, 1.474-2.165; P<0.001) for 24-hour brachial SBP and 1.949 (95% CI, 1.605-2.366; P<0.001) for 24-hour central SBP with c2 calibration. The receiver operating characteristic analyses also showed that 24-hour central SBP with c2 calibration had higher discrimination than 24-hour brachial SBP regarding multiple TODs (P<0.001). In addition, using 130/135 mm Hg as the threshold for 24-hour brachial SBP/central SBP with c2 calibration to cross-classify, the prevalence of multiple TODs was greater in cases of concordant hypertension compared with cases of isolated brachial hypertension and concordant normotension, with no difference between the latter 2 conditions. CONCLUSIONS: Twenty-four-hour central SBP with c2 calibration was more associated with the presence of multiple TODs compared with 24-hour brachial SBP and was helpful in risk classification of multiple TODs among nondialysis patients with chronic kidney disease.
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Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea , Insuficiência Renal Crônica , Humanos , Feminino , Masculino , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Pessoa de Meia-Idade , Pressão Sanguínea/fisiologia , Idoso , Fatores de Risco , Medição de Risco/métodos , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertensão/fisiopatologia , Hipertensão/epidemiologia , Hipertensão/diagnóstico , Hipertensão/complicações , Fatores de Tempo , Estudos TransversaisRESUMO
Background: Recent studies have shown that the baseline values of absolute aortic root diameter (ARD) and indexed diameter are associated with all-cause mortality and cardiovascular events in the general population, even in the absence of aneurysmal aortic disease. However, there is limited available data on the association between ARD and prognosis in end-stage renal disease (ESRD) patients receiving maintenance hemodialysis (MHD). Accordingly, the purpose of this study is to investigate the predictive value of ARD for all-cause mortality and cardiovascular events in this specific population.Methods: ARD was measured by echocardiography at the level of the sinuses of Valsalva at end diastole and indexed to body surface area (BSA). The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), including cardiovascular mortality, myocardial infarction and stroke. Cox proportional hazards models were conducted to evaluate the association between baseline ARD/BSA and clinical outcomes.Results: A total of 391 patients were included in this study. The primary endpoint occurred in 95 (24.3%) patients while the secondary endpoint occurred in 71 (18.2%) patients. Multivariate Cox regression analysis showed that ARD/BSA was an independent prognostic factor for all-cause mortality (HR, per 1-SD increase, 1.403; 95% CI, 1.118-1.761; p = 0.003) as well as MACE (HR, per 1-SD increase, 1.356; 95% CI, 1.037-1.772; p = 0.026).Conclusions: Our results show that ARD/BSA is predictive of all-cause mortality and MACE in MHD patients with ESRD and support the view that assessment of ARD/BSA may refine risk stratification and preventive strategies in this population.
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Ecocardiografia , Falência Renal Crônica , Diálise Renal , Humanos , Masculino , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Aorta/diagnóstico por imagem , Aorta/patologia , Estudos Retrospectivos , Modelos de Riscos Proporcionais , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/etiologia , Fatores de RiscoRESUMO
Introduction: Sodium homeostasis is intimately associated with blood pressure (BP) rhythm, and potassium excretion is closely associated with sodium excretion in the general population. However, the association between circadian sodium and potassium pattern excretion and nocturnal BP in patients with chronic kidney disease (CKD) is not elucidated. Methods: We evaluated the correlation between the day-to-night ratio of urinary sodium and potassium excretion rate, nocturnal blood pressure, and nocturnal BP dipping in a CKD cohort. Results: A total of 3152 (56.76% males, mean age 47.63 years) individuals with CKD were included in the study. Patients in quartile 1 (with the lowest ratio) exhibited a 12 mmHg or 9 mmHg higher nocturnal systolic blood pressure (SBP) and blunted SBP dipping than those in quartile 4 when urinary sodium or potassium excretion rate was divided into day-to-night ratios (both P < 0.001). In multivariate analyses, lower day-to-night ratio of urinary sodium was independently linked to higher nocturnal SBP and blunted SBP dipping (linear regression coefficient (95% confidence interval [CI]): -6.89 (-9.48 to -4.31), and -3.64 (-5.48 to -1.80), respectively; both P < 0.001). Similarly, compared with the highest quartile of day-to-night ratio of urinary potassium excretion rate, linear regression coefficient (95% CI) for the lowest quartile was -5.60 (-8.13 to -3.07) for nocturnal SBP, and -2.47 (-4.28 to -0.67) for SBP dipping (both P < 0.001). Moreover, urine flow rate and concentrates of sodium or potassium in the urine were positively associated with urinary sodium or potassium excretion during daytime (P < 0.001). Conclusion: A higher nocturnal BP and a blunted nocturnal BP dipping were both independently linked to a lower excretion of sodium or potassium during the day in patients with CKD. Furthermore, a decreased urine flow rate and a diminished capacity to concentrate sodium or potassium in the urine appear to be the key contributors to a low day-to-night ratio of urinary sodium excretion or potassium rate.
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BACKGROUND: (Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown. METHODS: In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to dipeptidyl peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining. RESULTS: Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death. CONCLUSIONS: This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD.
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Nefropatias Diabéticas , Receptor de Pró-Renina , Animais , Humanos , Camundongos , Diabetes Mellitus , Nefropatias Diabéticas/metabolismo , Dipeptidil Peptidase 4 , Células Epiteliais , Sistema de Sinalização das MAP Quinases , Receptor de Pró-Renina/metabolismo , PiroptoseRESUMO
Rescue of acute poisoning is a race against time, and it is particularly important to remove toxic substances in time. Traditional methods include gastric lavage, promoting elimination, chelating agents, and other treatments. Hemoperfusion is a common blood purification technique. In the clinical practice of acute poisoning, hemoperfusion can directly remove toxic substances through its unique adsorption effect, showing its excellent efficacy. This paper reviews the experience of hemoperfusion in the treatment of various drug overdoses, pesticides, biological toxins, and industrial poisons, even drug addiction. It is hoped to provide a reference for clinicians in acute poisoning rescue.
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Hemoperfusão , Intoxicação , Venenos , Humanos , Hemoperfusão/métodos , Intoxicação/terapiaRESUMO
PURPOSE: We aimed to explore the association between urinary tract infection (UTI) in adults and serum 25-hydroxyvitamin D (25OHD), which was used to access vitamin D status. METHODS: Serum levels of 25OHD were retrospectively analyzed in 234 subjects (190 females and 44 males): 120 UTI patients (females = 103) and 114 age- and sex-matched healthy controls (females = 87). Serum 25OHD concentrations were categorized as follows: (1) < 20 ng/mL, 20 to < 30 ng/mL, and ≥ 30 ng/mL; (2) < 20 ng/mL and ≥ 20 ng/mL. RESULTS: Serum 25OHD levels were lower in patients with UTI (p < 0.01). Women with UTI presented significantly lower 25OHD concentrations than those without UTI (p < 0.01). No association between serum 25OHD levels and UTI in men was found (p > 0.05). The multivariable logistic regression models showed significant associations between UTI and 25OHD, female sex, neutrophilic lymphocyte ratio and C-reactive protein (p < 0.05). CONCLUSION: Lower 25OHD concentrations associated with UTI were most prominent among women. The associations between UTI and low serum 25OHD levels as well as female sex were independent of each other.
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Infecções Urinárias , Deficiência de Vitamina D , Vitamina D , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Estudos Retrospectivos , Infecções Urinárias/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/microbiologiaRESUMO
BACKGROUND: Biomarkers of oxidative stress (OS) have been poorly explored in fungal peritonitis (FP). Potassium is a regulator of pro-oxidants and antioxidants. Albumin and vitamin B12 (B12) are vital antioxidant agents in the circulatory system. This study aimed to investigate the antioxidative role of serum potassium, albumin and B12 in FP. METHODS: Serum levels of potassium, albumin and B12 were retrospectively analyzed in 21 patients with a confirmed diagnosis of FP, 105 bacterial peritonitis (BP) patients and 210 patients receiving peritoneal dialysis without peritonitis. RESULTS: Serum levels of potassium, albumin and B12 were lower in FP patients than in BP patients. Serum potassium concentration was statistically related to albumin concentration in peritonitis patients. Univariate and multivariate binary logistic regression analysis suggested that serum level of potassium and albumin were independent risk factors of FP when compared with BP. Lower potassium and B12 levels were independently associated with higher rates of technique failure in peritonitis. CONCLUSION: These findings suggest lower serum potassium, albumin and B12 as potential oxidative stress markers of FP and raise the hypothesis that an increased level of OS could contribute to FP.KEY MESSAGESFP remains a serious complication of peritoneal dialysis (PD), with higher morbidity (1-23.8%) and mortality (2-25%), and oxidative stress plays a role in it.Our study suggested serum potassium, albumin and vitamin B12 as potential oxidative stress markers of fungal peritonitis.
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Micoses/diagnóstico , Peritonite/diagnóstico , Potássio/sangue , Albumina Sérica , Vitamina B 12/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Infecções Bacterianas/complicações , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Micoses/complicações , Estresse Oxidativo/fisiologia , Peritonite/sangue , Peritonite/microbiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Both morning hypertension (MH) and nocturnal hypertension (NH) are associated with severe target organ damage in patients with chronic kidney disease (CKD). However, the isolated or combined effects of MH and NH on target organ damage are less well-defined. A cross-sectional study was conducted among 2386 non-dialysis CKD patients with ambulatory blood pressure monitoring. The authors categorized patients into four groups based on the presence or absence of MH and NH. Multivariate logistic analyses were used to evaluate the correlation between hypertension subtypes and target organ damage, including left ventricular hypertrophy (LVH), abnormal carotid intima-media thickness (CIMT), low estimated glomerular filtration rate (eGFR), and albuminuria. The percentages of isolated MH, isolated NH, and combined MH and NH were 2.3%, 24.0%, and 49.3%, respectively. Compared to patients without MH and NH, isolated MH was only related to low eGFR (2.26 [95% confidence interval: 1.00-5.09]) and albuminuria (2.17 [95% CI: 1.03-4.54]). Meanwhile, combined MH and NH group compared to the group without MH and NH had a higher risk of LVH (2.87 [95% CI: 2.01-4.09]), abnormal CIMT (2.01 [95% CI: 1.47-2.75]), low eGFR (3.18 [95% CI: 2.23-4.54]), and albuminuria (1.79 [95% CI: 1.33-2.40]), even in patients without daytime hypertension. The risk of cardiovascular and renal damage was also observed in the isolated NH group. In conclusion, morning hypertension is associated with kidney dysfunction and has combined effects with nocturnal hypertension on cardiovascular damage in chronic kidney disease patients.
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Hipertensão , Insuficiência Renal Crônica , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Espessura Intima-Media Carotídea , Estudos Transversais , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Prevalência , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologiaRESUMO
The aim of this study was to investigate associations between age-dependent variations in isolated systolic/diastolic hypertension (ISH/IDH) with target organ damage in chronic kidney disease (CKD). A cross-sectional study was conducted among 2,459 CKD patients with ambulatory blood pressure monitoring. Blood pressure was categorized into four groups: normotension, ISH, IDH, and systolic-diastolic hypertension. The outcome measurements were left ventricular mass index (LVMI), estimated glomerular filtration rate(eGFR), and urinary albumin creatinine ratio (ACR). Older patients (≥60-years-old) had a higher prevalence of ISH and a lower prevalence of IDH than younger patients (<60-years-old). In multivariate analysis, compared with the normotension group, younger patients with ISH were associated with higher LVMI (+14.4 g/m2), lower eGFR (-0.2 log units), and higher ACR (+0.5 log units); but younger patients with IDH were only associated with lower eGFR (-0.2 log units) and higher ACR (+0.4 log units). Among older patients, ISH was correlated with higher LVMI (+8.8 g/m2), lower eGFR (-0.2 log units), and higher ACR (+1.0 log units), whereas IDH was not associated with these renal/cardiovascular parameters. In conclusion, ISH was associated with a relatively high risk of target organ damage irrespective of age, whereas IDH was only correlated with renal injury in younger CKD patients.
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Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea/fisiologia , Diástole/fisiologia , Hipertensão/epidemiologia , Insuficiência Renal Crônica/complicações , Sístole/fisiologia , Adulto , Fatores Etários , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Insuficiência Renal Crônica/fisiopatologiaRESUMO
BACKGROUND: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease. METHODS: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m2), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD. RESULTS: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m2, ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP. CONCLUSIONS: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.
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Monitorização Ambulatorial da Pressão Arterial , Doenças das Artérias Carótidas/epidemiologia , Taxa de Filtração Glomerular , Glomerulonefrite/fisiopatologia , Hipertensão/diagnóstico , Hipertrofia Ventricular Esquerda/epidemiologia , Placa Aterosclerótica/epidemiologia , Adulto , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Creatinina/metabolismo , Feminino , Glomerulonefrite/complicações , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite Membranoproliferativa/fisiopatologia , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/fisiopatologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nefrose Lipoide/complicações , Nefrose Lipoide/fisiopatologia , Placa Aterosclerótica/etiologia , Prognóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Albumina Sérica/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To determine the prevalence of masked morning hypertension and investigate its role in target organ damage in nondialysis patients with chronic kidney disease. METHODS: A total of 1841 patients with chronic kidney disease admitted to our hospital were recruited. According to measurements of clinic blood pressure and ambulatory blood pressure, they were divided into four groups: normotension, white-coat hypertension, masked morning hypertension, and sustained hypertension. Multivariate logistic regression analyses were used to evaluate the association between masked morning hypertension and cardiovascular and renal parameters. RESULTS: Overall, 288 (15.6%) patients were diagnosed with masked morning hypertension. Patients with masked morning hypertension had a higher prevalence of left ventricular hypertrophy, abnormal carotid intima-media thickness, and impaired renal function when compared with normotensive patients, although lower than those with sustained hypertension. After adjustment for demographics and clinical characteristics, masked morning hypertension was related to cardiovascular damage and renal dysfunction compared with normotension. The odds ratio for left ventricular hypertrophy, abnormal carotid intima-media thickness and impaired renal function was 1.955 [95% confidence interval (CI), 1.247-3.065], 1.469 (95% CI: 1.011-2.133), and 1.819 (95% CI: 1.112-2.976), respectively. Masked morning hypertension correlated with target organ damage even when patients with a history of cardiovascular disease were excluded. CONCLUSION: The prevalence of masked morning hypertension in nondialysis chronic kidney disease patients was high, and masked morning hypertension was associated with target organ damage in chronic kidney disease patients.
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Hipertensão Mascarada , Insuficiência Renal Crônica , Pressão Sanguínea/fisiologia , Espessura Intima-Media Carotídea , Humanos , Hipertrofia Ventricular Esquerda , Hipertensão Mascarada/complicações , Hipertensão Mascarada/epidemiologia , Hipertensão Mascarada/fisiopatologia , Prevalência , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologiaRESUMO
Background: Acute myeloid leukemia (AML) is a common hematological malignancy treated with regimens containing anthracycline, an agent with cardiotoxicity. However, the cardiac-specific mortality in AML patients receiving chemotherapy remains unknown. Methods: In this population-based study, patients diagnosed with AML between 1973 and 2015 were identified in the Surveillance, Epidemiology, and End Results database. Cumulative mortality by cause of death was calculated. To quantify the excessive cardiac-specific death compared with the general population, standardized mortality ratios (SMRs) were calculated. Multivariate Cox regression analyses were performed to identify risk factors associated with cardiac-specific death and AML-specific death. Results: A total of 64,679 AML patients were identified between 1973 and 2015; 68.48% of patients (44,292) received chemotherapy. Among all possible competing causes of death, AML was associated with the highest cumulative mortality. The AML patients who received chemotherapy showed excessive cardiac-specific mortality compared with the general population, with an SMR of 6.35 (95% CI: 5.89-6.82). Age, year of diagnosis, sex, and marital status were independently associated with patient prognosis. Conclusion: Cardiac-specific mortality in AML patients receiving chemotherapy is higher than that in the general population.
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BACKGROUND: In this study, we hypothesized that the combination of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) alters the expression of connexin 43 (Cx43) and results in a reduced frequency of induced ventricular arrhythmia in rats after myocardial infarction (MI) and explored the preliminary mechanisms involved. METHODS: Cardiomyocytes were cultured in vitro in medium with PBS, HGF, IGF-1, GFs (HGF + IGF-1), HGF + p38 inhibitor, HGF + ERK inhibitor, IGF-1 + p38 inhibitor or IGF-1 + ERK inhibitor. The expression of Cx43 was tested by real-time PCR and Western blotting after 48 hours. MI was induced in 48 male Sprague-Dawley rats. The rats were randomly divided into four groups and received an injection of PBS, HGF, IGF-1 or GFs into the infarct border zone two weeks after MI. Six weeks after injection, the expression levels of Cx43 and programmed stimulation-induced ventricular arrhythmias were examined. RESULTS: In vitro, the expression of Cx43 mRNA and the Cx43 protein in cardiomyocytes was higher in the HGF, IGF-1, and GFs groups than in the PBS group. GFs had a combinatorial effect on the Cx43 mRNA level but not on the Cx43 protein level. There was a significant reduction in Cx43 mRNA and Cx43 protein levels in the IGF-1 + p38 inhibitor group and IGF-1 + ERK inhibitor group compared to the IGF-1 group. In vivo, programmed stimulation significantly decreased the frequency of ventricular arrhythmia in the GFs, HGF and IGF-1 groups, and this effect was accompanied by increased immunohistochemical staining for Cx43, myocardial Cx43 protein levels and Cx43 mRNA levels in the infarct border zone of the left ventricle compared with those in the PBS group. The combinatorial effect of GFs on Cx43 expression was only observed at the mRNA level. CONCLUSIONS: Both HGF and IGF-1 enhanced the expression of Cx43 and improved induced ventricular arrhythmia in rats with MI. Both synergistic and antagonistic effects of HGF and IGF-1 were not observed. In addition, IGF-1 may function through the MAPK/p38 and ERK1/2 signaling pathways to regulate Cx43 expression.
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Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3ß phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.
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Capilares/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Glomérulos Renais/irrigação sanguínea , Proteínas Nogo/metabolismo , Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/genética , Humanos , Glomérulos Renais/metabolismo , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Nogo/sangue , Proteínas Nogo/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND/AIMS: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. METHODS: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. RESULTS: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. CONCLUSIONS: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.
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Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sirtuína 1/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Creatinina/urina , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Glucose/farmacologia , Humanos , Hidroquinonas/farmacologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Superóxidos/metabolismoRESUMO
BACKGROUND: The effect of triptolide (TPL) on cardiac fibroblasts (CFbs) and cardiac fibrosis remain unknown till now. This study was conducted to explore the effects of TPL on proliferation and apoptosis of angiotensin II (Ang II)-induced CFbs. MATERIALS AND METHODS: Ang II was used to promote proliferation of CFbs. Two dosages of TPL (10ng/ml and 100ng/ml) were chosen. MTT assay was used to detect cell survival rate in vitro. Flow cytometer was performed to analyze apoptosis of CFbs. Hydroxyproline concentration was detected with hydroxyproline assay kit. Quantitative real-time PCR was used to detect the expression of TGF-ß1 and Smad3 mRNA. RESULTS: Ang II promoted CFbs proliferation significantly. Compared to Ang II group, TPL markedly reduced the viability of CFbs and its Hydroxyproline concentration (P<0.05). Besides, TPL can significantly promote apoptosis of CFbs (P<0.05). Furthermore, TPL reduced the expressions of TGF-ßΙ and Smad3 mRNA in Ang II-induced CFbs (P<0.05). CONCLUSION: TPL can inhibit the proliferation of CFbs in rats by down-regulating TGF-ß1/Smad3 signaling pathway. TPL might be a promising therapeutic drug for myocardial fibrosis.
Assuntos
Angiotensina II/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/administração & dosagem , Fibroblastos/citologia , Fenantrenos/administração & dosagem , Animais , Compostos de Epóxi/administração & dosagem , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Coração/efeitos dos fármacos , Miocárdio/citologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: The potential benefits and risks of extended thienopyridine therapy beyond 12 months after drug-eluting stent (DES) implantation remain unclear. METHODS: Randomized controlled trials (RCTs) were searched in PubMed, EMBASE, the Cochrane Library and China National Knowledge Infrastructure databases. The adverse clinical endpoints were compared between 12 months group (aspirin alone) and >12 months group (additional thienopyridine plus aspirin after 12-month dual antiplatelet therapy). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used as summary statistics. A random-effect model was used in the meta-analysis process. RESULTS: Finally, three RCTs incorporating 16,265 participants were included in this meta-analysis. The results indicated that the incidences of myocardial infarction (1.55% vs. 2.90%; OR =0.58; 95% CI, 0.40-0.84; P=0.004) and stent thrombosis (0.32% vs. 0.98%; OR =0.35; 95% CI, 0.20-0.62; P<0.001) in the >12 months group were significantly lower than the 12 months group. However, compared to the 12 months group, the extended thienopyridine therapy markedly increased the risk of bleeding events (2.09% vs. 1.28%; OR =1.64; 95% CI, 1.23-2.17; P<0.001). The risks of stroke (0.78% vs. 0.84%; P=0.67) and cardiac death (0.94% vs. 0.89%; P=0.61) were similar between the two groups. CONCLUSIONS: The synthesis of available evidence indicates that a regimen of extended thienopyridine therapy beyond 12 months may significantly reduce the risks of myocardial infarction and stent thrombosis but increase the risk of bleeding events in the patients who have received DESs implantation.
RESUMO
BACKGROUND: Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Vorapaxar, a protease-activated receptor-1 (PAR-1) antagonist, is a novel antiplatelet agent that may provide us a new way in antithrombotic therapy. Several studies had been conducted to evaluate the efficacy of vorapaxar in the treatment of CAD, but the results were inconsistent. Here a meta-analysis was made to assess the efficacy and safety of vorapaxar in reducing adverse cardiac events in patients with CAD. METHODS: A comprehensive literature search was conducted. The primary efficacy endpoint was the major adverse cardiac events, which was defined as a composite of cardiovascular death, myocardial infarction (MI), stroke, urgent coronary revascularization, or recurrent ischemia with rehospitalization. The primary safety endpoint was the composite of major or minor bleeding events. Pooled effects were measured by odds ratios (ORs) with 95% confidence intervals (CIs). A random-effect or fixed model was used in this meta-analysis. RESULTS: Totally, 31,388 patients from four randomized controlled trials (RCTs) were included in this meta-analysis. Patients who took vorapaxar combined with standard dual anti-platelet therapy (aspirin and thienopyridine) showed a lower incidence in major adverse cardiac events (OR, 0.86, 95% CI: 0.75-0.99, P=0.03), MI (OR, 0.79, 95% CI: 0.67-0.95, P=0.01) and ischemic stroke (OR, 0.72, 95% CI: 0.58-0.89, P=0.003) than those who only took placebo instead. But there was no significant reduction in cardiovascular death (OR, 0.95, 95% CI: 0.82-1.09, P=0.45). Nevertheless, the vorapaxar group were associated with a higher risk of bleeding events (P<0.001). CONCLUSIONS: The result of this meta-analysis indicated that adding vorapaxar to the standard dual anti-platelet therapy may be efficient in reducing the incidence of major adverse cardiac events at the cost of increasing risk of bleeding events.