RESUMO
BACKGROUND: Tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are recent promising markers for identification of cardiac surgery-associated acute kidney injury (CSA-AKI). The aim of this study was systematically and quantitatively to evaluate the accuracy of urinary TIMP-2 and IGFBP7 for the diagnosis of CSA-AKI. METHODS: Three databases including PubMed, ISI web of knowledge, and Embase were systematically searched from inception to March 2018. Two investigators conducted the processes of literature search study selection, data extraction, and quality evaluation independently. Meta-DiSc and STATA were used for all statistical analyses. RESULTS: A total of 8 studies comprising 552 patients were included in this meta-analysis. Pooled sensitivity and specificity with corresponding 95% confidence intervals (CIs) were 0.79 (95% CI, 0.71-0.86, I 2 = 74.2%) and 0.76 (95% CI, 0.72-0.80, I 2 = 80.8%), respectively. Pooled positive likelihood ratio (LR), negative LR, and diagnostic odds ratio were 3.49 (95% CI, 2.44-5.00, I 2 = 61.5%), 0.31(95% CI, 0.19-0.51, I 2 = 51.8%), and 14.89 (95% CI, 7.31-30.32, I 2 = 27.9%), respectively. The area under curve estimated by summary receiver operating characteristic was 0.868 (standard error [SE] 0.032) with a Q* value of 0.799 (SE 0.032). Sensitivity analysis demonstrated that one study notably affected the stability of pooled results. One of the subgroups investigated-AKI threshold-could account for partial heterogeneity. CONCLUSION: Urinary TIMP-2 and IGFBP7 is a helpful biomarker for early diagnosis of CSA-AKI. And, the potential of this biomarker with a broader spectrum of clinical settings may be the focus of future studies.
Assuntos
Injúria Renal Aguda/diagnóstico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/urina , Complicações Pós-Operatórias/diagnóstico , Inibidor Tecidual de Metaloproteinase-2/urina , Injúria Renal Aguda/etiologia , Adulto , Biomarcadores/urina , Diagnóstico Precoce , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Nephropathy develops in many patients with type 1 diabetes mellitus (T1DM). However, the specific mechanisms and therapies remain unclear. For this purpose we investigated the effects of hydrogen sulfide (H2S) on renal fibrosis in streptozotocin (STZ) induced diabetic rats and its underlying mechanisms. Experimental rats were randomly divided into four groups: Control group (normal rats), DM group (diabetes rats), DM + NaHS group [diabetes rats treated with sodium hydrosulfide (NaHS)], and NaHS group (normal rats treated with NaHS). The diabetic models were established by intraperitoneal injection of STZ. The NaHS-treated rats were injected with NaHS as an exogenous donor of H2S. At the same time, control group and DM group were administrated with equal doses of normal saline (NS). After eight weeks, the rats' urine samples were collected to measure the renal hydroxyproline content by basic hydrolysis method with a hydroxyproline detection kit. Collagen I and III content was detected by immunohistochemical method, and the pathology morphology of kidney was analyzed by Masson staining. Protein expressions of transforming growth factor beta 1 (TGF-ß1), ERK1/2, TIMP1, TIMP2, MMP-2, MMP-7, MMP-8, MMP-11, and MMP-14 were assessed by western blotting. The results showed that significant fibrosis occurred in the kidney of diabetes rats. NaHS treatment downregulated TGF-ß1, ERK1/2, TIMP1, TIMP2, MMP-2, MMP-7, MMP-8, MMP-11, and MMP-14 expressions in the kidney of these diabetes rats (p<.01). This result suggests that NaHS treatment could attenuate renal fibrosis by TGF-ß1 signaling, and its mechanisms may be correlated with ERK1/2 expression and modulation of MMPs/TIMPs expression. Therefore, H2S may provide a promising option for defensing against diabetic renal fibrosis through TGF-ß1 signaling, equilibrating the balance between profibrotic and antifibrotic mediators.
Assuntos
Nefropatias Diabéticas/prevenção & controle , Sulfeto de Hidrogênio/farmacologia , Rim/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Animais , Colágeno Tipo I/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Fibrose , Masculino , Metaloproteinases da Matriz/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Estreptozocina , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
OBJECTIVE: To explore the effect of gefitinib-coated balloon suppressive action on the excessive hyperplasia of intima after balloon injury of common carotid artery in rats and on the PI3K/AKT signal pathway. METHODS: MTT method and the expression of Bcl-2 and Caspase-3 proteins were detected in vitro; Adult SD rats were randomly split into 5 groups, namely sham group, model group, low-dosage gefitinib-coated balloon group, high-dosage gefitinib-coated balloon group, and paclitaxel-coated balloon group. The intimal proliferation of arteries, PCNA, P-AKT and PI3K protein expression, the cell apoptosis, expression of MMP9, TGFß and IL6 mRNA were measured by hematoxylin and eosin (H&E) staining, immunohistochemistry, TUNEL staining, and RT-qPCR. RESULTS: At the same time and concentration, Gefitinib suppressed the proliferation of smooth muscle cell more significantly than paclitaxel. Bcl-2 and Caspase-3 in vascular smooth muscle and endothelial cells (VSMC, EC) were significantly down-regulated and up-regulated after the cells were treated with gefitinib and paclitaxel. In gefitinib- and paclitaxel-coated balloon groups, significant up-regulations were found in the area of lumen. Furthermore, the expression of PCNA suggested that all coated balloons could suppress the excessive proliferation of smooth muscle cells in the hyperplastic intima compared with the control group. In gefitinib- and paclitaxel-coated balloon group, the expression of PI3K/AKT was significantly down-regulated. The use of drug-coated balloons mitigated the cell apoptosis in TUNEL. The expressions of MMP9, TGFß and IL6 mRNA in the model group were obviously up-regulated; and they were obviously down-regulated in the high-dose gefitinib-coated balloon group compared with the model group. CONCLUSIONS: Gefitinib-coated balloons were able to suppress the excessive proliferation in the common carotid arterial intima of rats more effectively than the paclitaxel-coated ones. The underlying mechanism may cover the PI3K/AKT signal pathway.
Assuntos
Angioplastia Coronária com Balão , Lesões das Artérias Carótidas , Materiais Revestidos Biocompatíveis , Gefitinibe/administração & dosagem , Hiperplasia/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Lesões das Artérias Carótidas/cirurgia , Paclitaxel/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Lesões do Sistema VascularRESUMO
The present study aimed to explore the effect of hydrogen sulfide (H2S) on renal tissue fibrosis and its mechanism in diabetic rats. Rats were randomly divided into four groups (n=13/group): Control group; induced diabetes mellitus group (STZ); induced diabetes mellitus treated with H2S group (STZ + H2S); normal rats treated with H2S group (H2S). The diabetic model was induced by intraperitoneal (i.p.) injections of 40 mg/kg body weight streptozotocin (STZ); the control group was treated with saline every day (i.p); NaHS (100 µmol/kg i.p.) was administered to rats of STZ + H2S group and H2S group. After 8 weeks, rat body weight and 24 h proteinuria levels were determined in each group, renal pathological morphology was analyzed by Masson's trichrome staining, collagen IV content was detected by immunohistochemistry, and periodic acidSchiff (PAS) staining was performed on renal glomerular and tubular basement membranes. The expression levels of matrix metalloproteinase 9 (MMP9), MMP7, tissue inhibitor of metalloproteinase 1 (TIMP1), superoxide dismutase (SOD), serine/threonine kinase AKT, transforming growth factor (TGF)ß1, nuclear factor (NF)κB and several autophagy related proteins were assessed by western blot analysis. Compared with the control group, renal tissue fibrosis was observed, collagen IV expression and the 24 h proteinuria quantity was markedly increased and the amount of PAS positive material in renal glomerular and tubular basement membranes was notably increased in STZtreated rats. Furthermore, the expression levels of MMP9, MMP7, TIMP1, autophagyassociated proteins, AKT, TGFß1 and NFκB protein were significantly increased, and SOD expression levels were significantly decreased in the STZ group compared with the control (P<0.05). In the H2S+STZ group, renal tissue fibrosis and the expression of collagen IV were improved, 24 h proteinuria was decreased, the amount of PAS positive material in renal glomerular and tubular basement membranes was decreased, the expression levels MMP9, MMP7, TIMP1, autophagyassociated proteins, AKT, TGFß1 and NFκB protein were significantly decreased, and the expression levels of SOD were significantly increased compared with the STZ group (P<0.05). In conclusion, H2S may improve renal tissue fibrosis by inhibiting autophagy, upregulating SOD and downregulating AKT, TGFß1 and NF-κB.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Sulfeto de Hidrogênio/farmacologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fibrose , Imuno-Histoquímica , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/metabolismo , Proteinúria/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sulfetos/administração & dosagem , Superóxido Dismutase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Myocardial fibrosis is the predominant pathological characteristic of diabetic myocardial damage. Previous studies have indicated that hydrogen sulfide (H2S) has beneficial effects in the treatment of various cardiovascular diseases. However, there is little research investigating the effect of H2S on myocardial fibrosis in diabetes. The present study aimed to investigate the effects of H2S on the progression of myocardial fibrosis induced by diabetes. Diabetes was induced in rats by intraperitoneal injection of streptozotocin. Sodium hydrosulfide (NaHS) was used as an exogenous donor of H2S. After 8 weeks, expression levels of cystathionine-γ-lyase were determined by western blot analysis and morphological changes in the myocardium were assessed by hematoxylin and eosin staining and Masson staining. The hydroxyproline content and fibrosis markers were determined by a basic hydrolysis method and western blot analysis, respectively. Autophagosomes were observed under transmission electron microscopy. Expression levels of autophagy-associated proteins and their upstream signaling molecules were also evaluated by western blotting. The results of the current study indicated that diabetes induced marked myocardial fibrosis, enhanced myocardial autophagy and suppressed the phosphatidylinositol-4,5-bisphosphate 3-kinase/RAC-α serine/threonine-protein kinase (PI3K/AKT1) signaling pathway. By contrast, following treatment with NaHS, myocardial fibrosis was ameliorated, myocardial autophagy was decreased and the PI3K/AKT1 pathway suppression was reversed. The results of the present study demonstrated that the protective effect of H2S against diabetes-induced myocardial fibrosis may be associated with the attenuation of autophagy via the upregulation of the PI3K/AKT1 signaling pathway.
Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Sulfeto de Hidrogênio/farmacologia , Miocárdio/enzimologia , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo II/metabolismo , Cistationina gama-Liase/metabolismo , Diabetes Mellitus Experimental/enzimologia , Fibrose , Hidroxiprolina/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Endoplasmic reticulum (ER) stress is critical in the occurrence and development of diabetic cardiomyopathy (DC). Hydrogen sulfide (H2S) has been found to be the third gaseous signaling molecule with antiER stress effects. Previous studies have shown that H2S acts as a potent inhibitor of fibrosis in the heart of diabetic rats. This study aimed to demonstrate whether H2S exhibits protective effects on the myocardium of streptozotocin (STZ)induced diabetic rats by suppressing ER stress. In this study, diabetic models were established by intraperitoneal (i.p.) injection of 40 mg/kg STZ. The STZtreated mice were divided into three groups, and subsequently treated with normal saline, 30 µmol/kg or 100 µmol/kg NaHS, i.p., respectively, for 8 weeks. The extent of myocyte hypertrophy was measured using hematoxylin and eosinstained sections and collagen components were investigated using immunostaining. The expression of glucose-regulated protein (Grp78), C/EBPhomologous protein (CHOP) and caspase12 in the heart tissue of each group was detected by western blot analysis. It was demonstrated that H2S could improve myocardial hypertrophy and myocardial collagen deposition in diabetic rats. In addition, it could reduce the expression of Grp78, caspase-12 and CHOP. In conclusion, these findings demonstrate that H2S suppresses STZinduced ER stress in the hearts of rats, and it may serve as a novel cardioprotective agent for DC.
Assuntos
Cardiotônicos/farmacologia , Cardiomiopatias Diabéticas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Fibrose , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , RatosRESUMO
To explore the effects of hydrogen sulfide (H2S) on renal fibrosis and the expressions of connexins and matrix metalloproteinase (MMP) in diabetic rats. METHOD: SD rats were divided into 4 groups randomly: control group(n = 12), STZ group (n = 12), STZ+ H2S group (n = 12), and H2S group (n = 12). Diabetic model was induced by intraperitoneal injections of STZ. After 72 h after injection, the rats whose blood glucose were higher than 16.7 mmol/L. STZ+H2S group and H2S group were injected NaHS by intraperitoneal. Control group and STZ group were injected with the same dose of normal saline (NS) in equal doses every day. 8 weeks later, urine were collected. The expression of connexin and matrix metalloproteinase was analyzed by Western blot. We measured the Kidney hydroxyproline content by hydrolysis method. Type II collagen content was detected by immunohistochemical method and Masson staining. RESULTS: Compared with the control group, collagen accumulation was markedly enhanced, and the content of type II collagen, kidney hydroxyproline and timp-2 were boosted in STZ group mice (P < 0.01), while the expressions of CX40,CX43, CX45, MMP-1 and MMP-2 were obviously deceased (P < 0.01). Compared with STZ group, the expressions of CX40, CX43, CX45, MMP-1 and MMP-2 were significantly increased (P < 0.01), while the content of type II collagen, kidney hydroxyproline and timp-2 expression were markedly deceased in STZ+H2S group. CONCLUSION: H2S may attenuate renal fibrosis by up-regulating the expressions of CX40, CX43, CX45 and regulating the MMPs/TIMPs parameters.
Assuntos
Conexinas/genética , Gasotransmissores/farmacologia , Sulfeto de Hidrogênio/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Animais , Glicemia/metabolismo , Colágeno Tipo II/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Regulação para Baixo , Fibrose/patologia , Hidroxiprolina/metabolismo , Imuno-Histoquímica , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: To explore the effects of hydrogen sulfide (H(2)S) on myocardial fibrosis and expressions of MAPK1/3 and MMP-8 in diabetic rats. METHODS: Forty adult male SD rats were randomized into 4 groups, namely the control group, diabetes mellitus group (STZ group), diabetes mellitus with H(2)S treatment group (STZ+H(2)S group), and normal rats with H(2)S treatment group (H(2)S group). Diabetes was induced by intraperitoneal injections of 40 mg/kg streptozotocin (STZ). The rats in the control group received daily intraperitoneal injections of saline, and those in STZ+H(2)S group and H(2)S group were given NaHS (100 µmol/kg) injections. After 8 weeks, the pathologies of cardiac fibrosis were examined with HE staining, and the expressions of collagen I, MAPK1/3 and MMP-8 were analyzed with Western blotting. RESULTS: Compared with the control group, the diabetic rats showed increased collagen content and obvious interstitial fibrosis in the myocardial tissue with significantly increased expression levels of collagen I, MAPK1/3 and MMP-8 (P<0.05); all these changes were obviously reversed by treatment with H(2)S (P<0.05). Collagen I, MAPK1/3 and MMP-8 expression levels and the degree of myocardial fibrosis were comparable between H(2)S group and control group (P>0.05). CONCLUSION: Hydrogen sulfide can attenuate cardiac fibrosis in diabetic rats, and the mechanism may involve the inhibition of MAPK1/3/MMP-8 signal pathway.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Sulfeto de Hidrogênio/farmacologia , Metaloproteinase 8 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocárdio/patologia , Animais , Colágeno Tipo I/metabolismo , Diabetes Mellitus Experimental/patologia , Fibrose , Injeções Intraperitoneais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
In order to explore the effects of hydrogen sulfide (H2S) on myocardial fibrosis in diabetic rats and its underlying mechanisms, intraperitoneal injections of streptozotocin were used to establish the diabetes models and sodium hydrosulfide (NaHS) was used as an exogenous donor of H2S. Eight weeks later, Van Gieson staining was used to observe pathological changes, and basic hydrolysis methods were adopted to measure hydroxyproline content, while Western Blot was used to determine the expression of MMP2, MMP7, MMP11, MMP13, MMP16, TIMP1 and TGFß1.The results showed that significant myocardial fibrosis, decreased TIMP1 and MMP2 expression and increased MMP7, MMP11, MMP13, MMP16 expressions occurred in diabetic group, but all these changes were significantly reversed in diabetic rats after NaHS treatment. This suggests that H2S could attenuate cardiac fibrosis induced by diabetes and its mechanisms may be related to its modulation of MMPs/TIMPs expression and regulation of TGFß1.