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Evidence to date suggests that ß-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of ß-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5 U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h. In ß-arrestin 2 KO mouse hearts, deletion of ß-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10-9-10-6 M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-κB signaling and ERK1/2 phosphorylation, whereas knockdown of ß-arrestin 2 blocked AVP-induced IL-6 increase, NF-κB activation and ERK1/2 phosphorylation. Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-κB activation and IL-6 production. The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-κB phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2 mg/kg, iv) abolished AVP-induced NF-κB activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V1A receptor-mediated ß-arrestin2/ERK1/2/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/ß-arrestin 2/ERK1/2/NF-κB signaling pathway.
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Arginina Vasopresina/farmacología , Corazón/fisiopatología , Interleucina-6/metabolismo , Arrestina beta 2/genética , Animales , Arginina Vasopresina/administración & dosificación , Relación Dosis-Respuesta a Droga , Fibroblastos/metabolismo , Técnicas de Silenciamiento del Gen , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones , Ratones Noqueados , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Vasopresinas/metabolismoRESUMEN
OBJECTIVE: Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Anti-complement factor H (CFH) antibodies were thought to participate in the pathogenesis of aHUS. The aim of this study was to address the functions and properties of CFH autoantibodies in a Chinese Han cohort of aHUS patients. METHODS: Thirty-six anti-CFH antibody-positive aHUS patients at the acute phase of the disease were involved in this study. Clinical data of the patients were collected. Anti-CFH immunoglobulin G (IgG) subclasses and antibody isotypes were detected by ELISA. Epitope mapping was performed using recombinant CFH fragments (SCRs 1-4, SCR 7, SCRs 11-14, and SCRs 19-20). Purified IgG from plasma from seven patients were used for functional analyses. RESULTS: All patients presented with the classic triad of HUS. The anti-CFH autoantibodies mostly bound to the SCRs 19-20 domains of CFH but not the SCRs 1-4 domains. CFI cofactor activity was not disturbed by the anti-CFH antibody in any of the seven patients. Purified IgG interfered with the binding of CFH to C3b and CFH-mediated sheep erythrocyte protection in all seven patients. IgG from 4/5 (80%) patients tested inhibited the binding of CFH to glomerular endothelial cells. CONCLUSIONS: Our study suggests that the properties of CFH antibodies from patients with aHUS, including the recognition of SCRs and IgG subclasses, can influence and impair the biological role of CFH and therefore contribute to aHUS susceptibility.
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Síndrome Hemolítico Urémico Atípico/inmunología , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Síndrome Hemolítico Urémico Atípico/sangre , Autoanticuerpos/sangre , Niño , Preescolar , China , Factor H de Complemento/inmunología , Susceptibilidad a Enfermedades/inmunología , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunoglobulina G/sangre , Masculino , Dominios Proteicos/inmunología , Proteínas Recombinantes/inmunologíaRESUMEN
BACKGROUND: Anti-complement factor H (CFH) autoantibody-associated hemolytic uremic syndrome (HUS) is a severe sub-type of HUS. METHODS: We assessed the clinical and renal pathological features, circulating complement levels, and genetic background of Chinese pediatric patients with this sub-type of HUS. Thirty-three consecutive patients with acute kidney injury who tested positive for serum anti-CFH autoantibodies were enrolled in this study. RESULTS: All of the eight patients who underwent renal biopsies presented with changes typical of thrombotic microangiopathy, especially changes in chronic characteristics. Compared to patients in remission and normal control subjects, patients with acute disease had significantly lower plasma CFH levels and significantly higher plasma complement 3a (C3a), C5a, and terminal complement complex (SC5b-9) levels. The CFH-anti-CFH immunoglobin G (IgG) circulating immunocomplex (CFH-CIC) titers were more closely correlated with CFH plasma levels than anti-CFH IgG levels. Of the 22 patients, four (18%) were homozygous for CFHR3-1Δ and ten were heterozygous for CFHR1 or CFHR3 deletions. Most patients responded well to a combination of plasma and immunosuppressive therapies, with a remission rate of 87%. At the end of the follow-up, nine patients reached the combined end-points, including two with end-stage renal disease and seven with relapses. CONCLUSION: Plasma C3a, C5a, and SC5b-9 levels predicted disease activity in anti-CFH autoantibody-associated HUS patients enrolled in this study. These patients responded well to plasma therapy combined with immunosuppression.
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Autoanticuerpos/análisis , Factor H de Complemento/inmunología , Síndrome Hemolítico-Urémico/inmunología , Síndrome Hemolítico-Urémico/fisiopatología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/inmunología , Adolescente , Pueblo Asiatico/genética , Secuencia de Bases , Niño , Preescolar , Proteínas del Sistema Complemento/análisis , Proteínas del Sistema Complemento/inmunología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Síndrome Hemolítico-Urémico/genética , Humanos , Inmunosupresores , Lactante , Riñón/patología , Fallo Renal Crónico/etiología , Masculino , Microangiopatías Trombóticas/patología , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore the effects of nicotinic acid intervention on vascular endothelial dysfunction mediated by oxidized low density lipoprotein (ox-LDL)/lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) in diet-induced obese immature rats and its possible mechanism through detecting the expression levels of ox-LDL and LOX-1 in abdominal aorta. METHODS: A model of diet-induced obese immature rats was established by high-fat diet. And 30 immature rats were divided randomly and equally into control (n = 10), high-fat (n = 10) and drug control (n = 10) groups. At the end of 12 weeks, the levels of serum total cholesterol (TC), triglyceride (TG), LDL and high-density lipoprotein (HDL) were examined. The levels of ox-LDL, soluble intercellular adhesion molecule-1 (sICAM-1), endothelin and nitric oxide (NO) were detected. The gene and protein expressions of LOX-1 and ICAM-1 in abdominal aorta were detected. And the location protein expressions of LOX-1 and ICAM-1 were examined. RESULTS: High-fat diet induced hyperlipidemia and obesity in immature rats. The serum levels of TG, TC, LDL, ox-LDL and endothelin in high-fat and drug control groups were all higher than control group ((0.98 ± 0.12) and (0.69 ± 0.06) vs (0.49 ± 0.06) mmol/L, (2.11 ± 0.16) and (1.62 ± 0.12) vs (1.30 ± 0.12) mmol/L, (0.71 ± 0.04) and (0.50 ± 0.03) vs (0.30 ± 0.04) mmol/L, (44.2 ± 5.1) and (33.7 ± 2.1) vs (26.6 ± 2.9) µg/L, (187 ± 10) and (157 ± 6) vs (118 ± 7) pg/ml). The indices in high-fat group were higher than those in drug control group (all P < 0.01) . The levels of HDL and NO in high-fat and drug control groups were lower than those in control group (all P < 0.01); the levels of HDL and NO in high-fat group lower than those in drug control group (all P < 0.01). And the levels of LOX-1, ICAM-1 protein and mRNA in high-fat group were higher than those in drug control and control groups (all P < 0.01).ox-LDL was correlated positively with LOX-1, TC, TG, LDL, endothelin and ICAM-1 (r = 0.918, 0.867, 0.857, 0.834, 0.869, 0.644, all P < 0.01) , but negatively with NO and HDL (r = -0.823, -0.872, P < 0.01) . CONCLUSION: Early treatment of nicotinic acid can protect endothelial function through inducing therapeutic effects on hyperlipidemia and antioxidation and down-regulating the expression level of ox-LDL/LOX-1 in vascular endothelium.
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Endotelio Vascular/fisiopatología , Hiperlipidemias/fisiopatología , Lipoproteínas LDL/metabolismo , Niacina/farmacología , Obesidad/metabolismo , Animales , Endotelio Vascular/metabolismo , Hiperlipidemias/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Obesidad/fisiopatología , Ratas , Ratas Wistar , Receptores de LDL Oxidadas/metabolismoRESUMEN
The diagnosis and treatment pattern using combination of disease and syndrome, fully developing the advantages of both traditional Chinese medicine (TCM) and Western medicine (WM) and being widely used clinically, has been constructed in the long history of TCM. Prof. MA Rou, as a hematology specialist of integrative medicine (IM), uses modern medical equipment to diagnose diseases and takes traditional Chinese medical methods to treat diseases. He is loyal to TCM sciences and refers to the advantages of WM. He holds the essence of MDS lies in toxic stasis according to its pathogenic features. He detoxifies and removes stasis using Qinghuang Powder. Meanwhile, according to patients' clinical manifestations, he summarized two common syndrome types, Pi-Shen yang deficiency syndrome and Gan-Shen yin deficiency syndrome. Better efficacy could be achieved by combining Chinese herbs for tonifying Pi-Shen. In recent years the application of Qinghuang Powder won some achievements in clinical study and experimental study, thus providing scientific reliance for Prof. MA Rou's academic thought on treating MDS.
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Medicina Integrativa , Síndromes Mielodisplásicos/terapia , Humanos , Medicina Tradicional China , Síndromes Mielodisplásicos/diagnóstico , Deficiencia Yang , Deficiencia YinRESUMEN
BACKGROUND/AIMS: MiR-93 was observed in various types of cancers. This study is to investigate a role of miR-93 in the carcinogenesis of HCC. METHODOLOGY: The expression of miR-93 in HepG2 cells and prima-ry human hepatocytes (PHHC) was measured by RT-PCR. HepG2 cells were transfected with miR-93 inhibitor or negative control. The cell proliferation was determined by using the CellTiter 96® Aqueous One Solution Cell Proliferation Assay kit. The migration and clonogenicity in vitro were measured by cell migration assay, colony formation analysis and anchorage-in-dependent growth assay. The apoptosis and cell cycle were detected by flow cytometry analysis. The mRNA and protein levels of transforming growth factor-beta type II receptor (TGFBR2) and integrin beta8 (ITGB8)were evaluated by RT-PCR and western blot analysis. RESULTS: MiR-93 was upregulated in HepG2 cells compared with PHHC and inhibition of miR-93 significantly suppressed HepG2 cell proliferation, migration and col-ony formation. The expressions of TGFBR2 and ITGB8 were upregulated when miR-93 was inhibited. CONCLUSIONS: Our results reveal an important contribution for miR-93 in hepatocarcinogenesis and suggest a role for TGFBR2 and ITGB8 dysregulation in this process. Thus,the use of synthetic inhibitor of miR-93 may prove to bea promising approach to liver cancer treatment.
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Carcinoma Hepatocelular/genética , Proliferación Celular , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Apoptosis/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Adhesión Celular/genética , Puntos de Control del Ciclo Celular/genética , Movimiento Celular/genética , Regulación hacia Abajo , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Ensayo de Tumor de Célula MadreRESUMEN
Deficient DNA repair capacity is associated with genetic lesions accumulation and susceptibility to carcinogenesis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate various cellular pathways including DNA repair. Here we hypothesized that the existence of HBV products may interfere with cellular nucleotide excision repair (NER) through microRNA-mediated gene regulation. We found that NER was impaired in HepG2.2.15 cells, a stable HBV-expressing cell line, compared with its parental cell line HepG2. Altered miRNA expression profile, in particular the significant upregulation of miR-192, was observed in HepG2.2.15 cells. Additionally, ERCC3 and ERCC4, two key factors implicated in NER, were identified as targets of miR-192 and over-expressing miR-192 significantly inhibited cellular NER. These results indicated that persistent HBV infection might trigger NER impairment in part through upregulation of miR-192, which suppressed the levels of ERCC3 and ERCC4. It provides new insight into the effect of chronic HBV infection on NER and genetic instability in cancer.
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ADN Helicasas/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Inestabilidad Genómica , Virus de la Hepatitis B , Hepatitis B Crónica/genética , MicroARNs/fisiología , Línea Celular Tumoral , Células HeLa , Humanos , MicroARNs/genéticaRESUMEN
Objective: The aim of this study was to explore the clinical features, pathological characteristics, and the prognosis of children with microscopic polyangiitis (MPA). Methods: Ten children with MPA that were hospitalized in our hospital were included in this study. The children's pre-diagnosis status, clinical manifestations, renal pathology, treatment, and prognosis data were analyzed retrospectively. Results: All 10 cases included female patients with a median age of 8.9 years old at the time of diagnosis. MPO-ANCA antibody was positive in all cases, combined with a positive anti-GBM antibody in two cases. Nine cases had primary AAV and one had antithyroid drug (ATD)-associated MPA (secondary to methimazole). Renal involvement was found in all 10 patients, lung impairment was present in eight cases, and anemia was present in nine patients. Renal biopsies were performed in all 10 patients. Segmental focal or global glomerular necrosis was observed in 70% of the patients (7/10). The treatment mainly included steroid use combined with Cyclophosphamide and Mycophenolate. The follow-up s of the patients revealed normal renal function in eight patients and progression to end-stage renal disease (ESRD) in two patients. Conclusions: Female predisposition and positive MPO-ANCA antibody were prominent in children with MPA. The patients' kidneys and lungs were the most frequently involved organs. Corticosteroid combined with immunosuppressive therapy was recommended for the treatment of MPA. Early diagnosis, prompt aggressive treatment, and regular follow-ups are also very important factors associated with a good prognosis.
RESUMEN
OBJECTIVE: The present study was designed to explore the roles of MMP-2/TIMP-2 in cardiac fibrosis and to study the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI) on cardiac remodelling in streptozotocin(STZ)-induced diabetic rats. METHODS AND RESULTS: Male Wistar rats were randomly divided into three groups: a normal control group (NC), a diabetes mellitus-untreated group (DM) and a diabetes mellitus benazepril-treated group (DB). Diabetes mellitus was induced in the DM and DB groups by intraperitoneal injection of streptozotocin (60 mg/kg). DB rats were treated with benazepril 10 mg/kg/day for 12 weeks by remedial perfusing of the stomach. In the DM group, compared with the NC group, the gene and protein expression of MMP-2 decreased while the TIMP-2 gene and protein expression increased in heart tissues, along with a markedly cardiac collagen deposition.All the above changes were attenuated by benazepril treatment in the DB group. CONCLUSIONS: The imbalance of MMP-2 and TIMP-2 expressions in heart tissues might participate in interstitial fibrosis in diabetic myocardiopathy. Benazepril may ameliorate cardiac fibrosis partly by regulating the MMP-2/TIMP-2 system.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Benzazepinas/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Miocardio/patología , Análisis de Varianza , Animales , Glucemia/metabolismo , Peso Corporal , Colágeno/metabolismo , Fibrosis/tratamiento farmacológico , Técnicas para Inmunoenzimas , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Tamaño de los Órganos , Distribución Aleatoria , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Coloración y Etiquetado , Estreptozocina , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
Resistin, a novel adipokine, was recently suggested to be involved in the development of endothelial dysfunction. However, the mechanisms of how resistin works are still unknown. This study was performed to investigate the relationship between resistin and phosphatidylinositol 3-kinase (PI3K), with the aim of gaining insight to the mechanisms by which resistin induces changes of secretion function of vascular endothelium. This study was conducted on 60 male 4-week-old Sprague-Dawley rats, which were randomly divided into four groups: resistin group (RS; n = 8), normal saline group (NS; n = 8), high-fat diet group (HF; n = 36), and control group (CO; n = 8). The resistin group was administered two injections of rat recombinant resistin. The diet-induced hyperresistinemia rats were selected from the HF group after the HF group was administered a high-fat diet for 8 weeks. The diet-induced hyperresistinemia rats were randomized into the antibody group (AB; n = 8) and hyperresistinemia group (HR; n = 8). The antibody group was given injections of resistin antibody twice per day and for 3 days. Immunohistochemistry was employed to examine the expression of PI3K p85alpha subunit and endothelial nitric oxide synthase (eNOS) in thoracic artery endothelium. In the resistin group, the levels of endothelin (ET), plasminogen activator inhibitor (PAI), and von Willebrand factor (vWF) were higher and NO was lower than those in the normal saline group. The NO level increased and ET, PAI, and vWF levels decreased in the antibody group when compared with the hyperresistinemia group. After administration of resistin antibody, the expression of PI3Kp85alpha and eNOS proteins in the antibody group was significantly increased but still differed significantly from those in the control group. PI3K grey value was correlated with resistin, PAI-1, vWF, NO, and the expression of eNOS (p < .05), after controlling for the effect of insulin. Resistin can affect the protein expression of PI3Kp85alpha, stimulate release of PAI-1, vWF, and ET, and down-regulate eNOS. The effect of resistin on PI3K signaling pathway might contribute to the development of endothelial secretion dysfunction in young rats.
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Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Resistina/farmacología , Animales , Glucemia , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Insulina/sangre , Masculino , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Resistina/sangreRESUMEN
OBJECTIVE: The present study was designed to examine the changes of MMP-2/TIMP-2 in the hearts of streptozotocin-induced diabetic rats and gain insight into their roles in extracellular matrix (ECM) remodelling on an experimental animal model of diabetic cardiomyopathy. METHODS AND RESULTS: Sixteen male Wistar rats were randomly divided into two groups: normal control and diabetic rats. Diabetes mellitus was induced in rats by streptozotocin injection. All rats were fed with standard chow and water ad libitum for 4 weeks. At 4 weeks diabetic rats were associated with a lower body weight (BW) and heart weight (HW) but a higher HW/BW. In the diabetic group, serum MMP-2 level had a tendency to increase but not significantly, while serum TIMP-2 significantly increased. Both the activity and expression of MMP-2 weakened in the hearts of diabetic rats. TIMP-2 gene expression in myocardium enhanced significantly. TIMP-2 protein level in diabetic heart was strengthened slightly but not significantly. VG staining showed a marked deposition of collagen in the diabetic group. Multivariate analysis revealed that total collagen content correlated negatively with the activity and gene expression of MMP-2 in the myocardium, and correlated positively with TIMP-1 mRNA expression. CONCLUSIONS: The decrease in MMP-2 activity and expression and increase in TIMP-2 gene expression in the myocardium of diabetic rats may lead to impairment of collagen degradation and contribute to the matrix deposition in diabetic myocardiopathy. The correlation between the serum level and cardiac expression of TIMP-2 in diabetic rats suggested that serum TIMP-2 level may be a viable marker for early diagnosis of diabetic myocardiopathy.
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Cardiomiopatías/fisiopatología , Complicaciones de la Diabetes , Diabetes Mellitus Experimental , Diabetes Mellitus/fisiopatología , Matriz Extracelular , Metaloproteinasa 2 de la Matriz/fisiología , Inhibidor Tisular de Metaloproteinasa-2/fisiología , Animales , Cardiomiopatías/etiología , Expresión Génica , Inmunohistoquímica , Modelos Animales , ARN Mensajero , Ratas , Ratas WistarRESUMEN
BACKGROUND: Excessive deposition of extracellular matrix (ECM) in the kidney is the hallmark of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting. The renal protective effect of these pathways on matrix accumulation has not been fully elucidated. The present study was undertaken to investigate the activity of matrix metalloproteinase-2 (MMP-2), the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) in kidney tissues of diabetic rats, and to explore the degradative pathway of type IV collagen (IV-C) and the renal protective effects of ACE inhibition-benazepril. METHODS: Twenty-four healthy male Wistar rats were divided randomly into normal control group (NC group), untreated diabetes mellitus group (DM group), and diabetes mellitus group treated with benazepril (DL group). The rat model of diabetes mellitus was induced by intraperitoneal injection of streptozocin (60 mg/kg). After the establishment of DM model, benazepril (10 mg.kg(-1).d(-1)) was given to the DL group for 12 weeks, and the same volume of water was given to the other two groups. At the end of 12 weeks, renal function was evaluated with 24-hour urinary protein (Upro), clearance of creatinine (Ccr), and blood urea nitrogen (BUN). MMP-2 activity was determined by gelatin zymography. The levels of MMP-2, TIMP-2 and collagen IV (IV-C) protein in the kidney tissue were assessed by immunohistochemistry. The gene expression of MMP-2 and TIMP-2 was measured by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The levels of BUN, Upro and Ccr in the DM group were higher than those in the NC group. In the DM group, the mRNA, enzymatic activity and proteins of MMP-2 decreased, but the expressions of IV-C and TIMP-2 increased. All diabetes-associated changes in renal function and MMP/TIMP were attenuated after benazepril treatment with reduced IV-C accumulation. CONCLUSIONS: The changes of MMP-2 and TIMP-2 expressions in kidney tissues of diabetes rats may contribute to the occurrence and progression of diabetic nephropathy. Benazepril could exert protective effects on diabetic nephropathy, owing to the upregulation of MMP-2 and downregulation of TIMP-2 expressions, which further inhibits the excessive deposition of extracellular matrix in the glomerulus.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Benzazepinas/farmacología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/prevención & control , Riñón/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/análisis , Inhibidor Tisular de Metaloproteinasa-2/análisis , Animales , Glucemia/análisis , Peso Corporal , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/patología , Riñón/metabolismo , Glomérulos Renales/patología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Tamaño de los Órganos , Ratas , Ratas Wistar , Estreptozocina , Inhibidor Tisular de Metaloproteinasa-2/genéticaRESUMEN
OBJECTIVE: To investigate the prevention by Tongxinluo capsule (TXL) of vascular lesions and its effect on the levels of protein and gene expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) of vascular wall in rabbits with atherosclerosis (AS), and to explore its possible mechanism against AS. METHODS: AS models were established by feeding New Zealand white rabbits with high-cholesterol diet, and 24 immature rabbits were randomly divided into the control group, model group and treated group (treated with TXL capsule). The indexes of total cholesterol (TC) and low density lipoprotein (LDL) levels were measured at the 16th week. The intima thickness and the plaque area of abdominal aorta were quantitatively analyzed by pathological morphological analysis, the expression of macrophage and smooth muscle cell (SMC) in intima were detected by immunohistochemical method and histologic segments were stained by Hematoxilin-Eosin (HE) to identify the degree of atherosclerotic lesion in the model group and the prevention by TXL. The LOX-1 gene and protein expression in abdominal aorta was detected by semi-quantitative RT-PCR and immunohistochemistry, respectively. RESULTS: In the model group, the levels of TC and LDL were significantly elevated, aortic intima thickened extensively, the intima area enhanced, and macrophages expression increased; the levels of LOX-1 gene and protein expression was up-regulated in endothelium and neo-intima of the abdominal aorta. The treatment with TXL reduced blood lipids, attenuated arterial intimal proliferation, markedly inhibited the expression of macrophage and excessively expressed the level of LOX-1. CONCLUSION: TXL has an inhibitory effect on blood lipids, and it can prevent the occurrence of vascular lesion and cure its development, and its protection against AS was possibly associated with a crucial endothelial protective action through lowering the expression of LOX-1 in vascular walls.
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Aorta Abdominal/metabolismo , Aterosclerosis/prevención & control , Medicamentos Herbarios Chinos/farmacología , Receptores Depuradores de Clase E/metabolismo , Actinas/metabolismo , Animales , Aorta Abdominal/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Inmunohistoquímica , Lípidos/sangre , Macrófagos/patología , Masculino , Músculo Liso Vascular/patología , ARN Mensajero/análisis , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Depuradores de Clase E/genéticaRESUMEN
BACKGROUND: Lipid abnormalities are often complicated by renal dysfunction. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line choice for lowering cholesterol levels. The present study was designed to investigate whether statins could prevent and invert the development of renal injury in cholesterol-fed rabbits and to find the possible mechanism of their effects by detecting gene and protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the renal artery. METHODS: Twenty-four male New Zealand white rabbits were divided into three groups: (1) control group, regular granules chow; (2) HC-diet group, granules chow with 1% cholesterol and 5% lard oil; and (3) fluvastatin group, 1% cholesterol and 5% lard oil diet plus fluvastatin [10 mg.kg(-1).d(-1)]. After 16 weeks, serum total cholesterol (TC), low-density lipoprotein (LDL) and creatinine (Cr) levels were measured. Renal hemodynamics and function, mainly including glomerular filtration rate (GFR) in vivo were quantified using (99m)Tc-DTPA single photon emission computed tomograph ((99m)Tc-DTPA SPECT). The thickness of the renal artery intima was quantitated in HE-stained segments by histomorphometry. Gene expression of LOX-1 in the renal artery was examined by semi-quantitative RT-PCR and its protein expression was evaluated by immunohistochemistry. RESULTS: High cholesterol diet induced hypercholesterolemia (HC) complicated by renal dysfunction with increased levels of serum lipid and Cr, decreased GFR and delayed excretion and extensively thickened renal arterial intima in the HC-diet group. Rabbits in the control group showed a minimal LOX-1 expression (mRNA and protein) in the endothelium and neointima of the renal artery. Intimal proliferation of the renal artery in the HC-diet group was associated with a marked increase of LOX-1 expression (protein and mRNA). Treatment with fluvastatin improved renal function, attenuated intimal proliferation of the renal artery and markedly decreased the enhanced LOX-1 expression in the endothelium and neointima of the renal artery in rabbits. CONCLUSIONS: Fluvastatin treatment could prevent the development of renal injury in patients with HC and early atherosclerosis (AS). This beneficial effect might be mediated by its pleiotropic effects including a decrease in total cholesterol exposure level and prevention of LOX-1 expression in atherosclerotic arteries.
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Ácidos Grasos Monoinsaturados/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipercolesterolemia/tratamiento farmacológico , Indoles/farmacología , Riñón/efectos de los fármacos , Receptores de LDL/análisis , Animales , Colesterol/sangre , Creatinina/sangre , Fluvastatina , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Inmunohistoquímica , Riñón/patología , Masculino , ARN Mensajero/análisis , Conejos , Receptores de LDL/genética , Receptores de LDL Oxidadas , Receptores Depuradores de Clase E , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
OBJECTIVE: To examine the effects of niacin on lysophosphatidylcholine (LPC)-induced intercellular adhesion molecule-1 (ICAM-1), and gained insight to the mechanisms. METHOD: Human umbilical vein endothelial cell line was cultured using Medium 200 medium in incubator at 37 °C and 5% CO2 condition.Experimental groups:(1) the negative control group:medium; (2) LPC different time groups:the medium added with 20 µmol/L final concentration of LPC, were cultured for 10 min and 8 h, 24 h; (3) LPC+ p38-mitogen-activated protein kinase (p38MAPK) inhibitor (SB203580) group:the medium added with 10 µmol/L p38MAPK inhibitor (SB203580) was cultured for 1 h, then human umbilical vein endothelial cells (HUVECs) added with the LPC were cultured for 10 min, 8 h and 24 h.(4) LPC+different niacin dose group:after separately adding with 0.25, 0.5, 1 mmol/L niacin, the cells were cultured for 18 h, then HUVECs added with the LPC were cultured for 10 min, 8 h and 24 h. Cell concentration in each group was 5×10(5)/ml, inoculated in 6-well plates, each well 1 ml. Detected by Western blot analysis of pp38MAPK, ICAM-1 protein content, real-time quantitative PCR to detect endothelial cell ICAM-1 mRNA expression, cell immunofluorescence to detect LPC-induced ICAM-1 protein expression. RESULT: In LPC 24 h group, the expression of ICAM-1 protein was significantly increased 0.786 ± 0.02, the LPC+niacin group, ICAM-1 protein levels (0.487 ± 0.015) was significantly lower than the LPC 24 h group (P < 0.01), in LPC+SB203580 intervention group, ICAM-1 protein levels (0.461 ± 0.011) was significantly lower than that of the LPC 24 h group (P < 0.01), but did not reach the level of the control group. Adding LPC to culture for 10 min, phosphorylation of p38MAPK (pp38MAPK) reached its peak (0.47 ± 0.02), niacin could reduce the pp38MAPK (0.07 ± 0.02), SB203580 could also reduce its activity (0.11 ± 0.02). Adding LPC to culture for 8 h, ICAM-1 mRNA expression (8.16 ± 0.15) compared with the control group (1.00 ± 0.02) had a significant increase (t = 24.34, P < 0.01). Compared with the LPC 8 h, niacin reduced LPC-induced ICAM-1 mRNA expression (3.85 ± 0.14), and showed a dose-dependent manner (F = 8.06, P < 0.01), while SB203580 could not effectively reduce the ICAM-1 mRNA (8.09 ± 0.11). CONCLUSION: Niacin prevented LPC-induced endothelial dysfunction by reducing expression of ICAM-1. These mechanisms appeared to be at least partly mediated by suppression of the pp38MAPK in endothelial cells. These pleiotropic effects of niacin may potentially contribute to the beneficial effects of risk reduction for atherosclerotic disease.
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Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Imidazoles/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Niacina/farmacología , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Imidazoles/administración & dosificación , Molécula 1 de Adhesión Intercelular/genética , Lisofosfatidilcolinas/administración & dosificación , Lisofosfatidilcolinas/farmacología , Niacina/administración & dosificación , Piridinas/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Objective To observe the changes of esophageal pressure in patients with achalasia (AC) before and after peroral endoscopic myotomy (POEM), and to explore the value of high-resolution manometry (HRM) in evaluating the efficacy of POEM. Methods 38 cases were diagnosed as achalasia and treated with POEM from August 2015 to November 2016. Upper esophageal sphincter resting pressure (UESP), lower esophageal sphincter resting pressure (LESP), esophageal sphincter 4s integrated relaxation pressure (4sIRP) were detected by HRM before operation, at 1 week, 1 month after operation to evaluate the efficacy. Results A total of 38 patients with AC received POEM. At one week, one month after operation, the UESP were (45.34 ± 26.52) mmHg, (41.27 ± 20.09) mmHg, compared with that of before operation (49.58 ± 26.47) mmHg and the differences were not statistically significant. The differences in LESP, 4sIRP between before operation and at one week, one month after operation were statistically significant, P < 0.05. The differences in UESP, LESP and 4sIRP between 1 week and 1 month after operation were not statistically significant. Conclusion The pressure of lower esophageal sphincter was significantly reduced and the dysphagia was improved. HRM might play an important role in the assessment of AC received POEM.
RESUMEN
Objective To observe the changes of esophageal pressure in patients with achalasia (AC) before and after peroral endoscopic myotomy (POEM), and to explore the value of high-resolution manometry (HRM) in evaluating the efficacy of POEM. Methods 38 cases were diagnosed as achalasia and treated with POEM from August 2015 to November 2016. Upper esophageal sphincter resting pressure (UESP), lower esophageal sphincter resting pressure (LESP), esophageal sphincter 4s integrated relaxation pressure (4sIRP) were detected by HRM before operation, at 1 week, 1 month after operation to evaluate the efficacy. Results A total of 38 patients with AC received POEM. At one week, one month after operation, the UESP were (45.34 ± 26.52) mmHg, (41.27 ± 20.09) mmHg, compared with that of before operation (49.58 ± 26.47) mmHg and the differences were not statistically significant. The differences in LESP, 4sIRP between before operation and at one week, one month after operation were statistically significant, P < 0.05. The differences in UESP, LESP and 4sIRP between 1 week and 1 month after operation were not statistically significant. Conclusion The pressure of lower esophageal sphincter was significantly reduced and the dysphagia was improved. HRM might play an important role in the assessment of AC received POEM.
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The host genetic compound plays a vital role in determining clinical outcomes of hepatitis B virus (HBV) infection. The tumor necrosis factor receptor-associated factor family member-associated nuclear factor-κB (NF-κB) activator (TANK) takes part in the tumor necrosis factor-α (TNF-α)-mediated NF-κB signaling pathway and the interferon (IFN)-induction pathways that have relevance to HBV-related liver disease. In this report, we explored whether the intronic polymorphism rs3820998 of the TANK gene was associated with outcomes of HBV infection by binary logistic regression analysis. A total of 1305 unrelated Han Chinese patients recruited from Wuhan, including 180 acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients, 331 HBV-related liver cirrhosis (LC) patients, 308 HBV-related hepatocellular carcinoma (HCC) patients, and 486 asymptomatic HBV carriers (AsC) were genotyped using the TaqMan probe method. Logistic analysis revealed that the single-nucleotide polymorphism (SNP) rs3820998 was significantly associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034). These results indicate that the G > T variant is a protective factor in the development of ACLF-HBV and LC, and that the SNP rs3820998 in the TANK gene may play a role in mediating susceptibility to ACLF-HBV and LC in a Chinese Han population.
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Proteínas Adaptadoras Transductoras de Señales/genética , Pueblo Asiatico/genética , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/etnología , Hepatitis B Crónica/genética , Polimorfismo de Nucleótido Simple , Carcinoma Hepatocelular/etnología , Carcinoma Hepatocelular/genética , Portador Sano/etnología , Portador Sano/virología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/virología , Humanos , Cirrosis Hepática/etnología , Cirrosis Hepática/genética , Cirrosis Hepática/virología , Fallo Hepático/etnología , Fallo Hepático/genética , Fallo Hepático/virología , Neoplasias Hepáticas/etnología , Neoplasias Hepáticas/genética , Modelos Logísticos , MasculinoAsunto(s)
Aneurisma Falso/terapia , Biopsia/efectos adversos , Embolización Terapéutica/métodos , Riñón/patología , Arteria Renal/patología , Adolescente , Aneurisma Falso/etiología , Angiografía , Humanos , Masculino , Arteria Renal/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Ultrasonografía Doppler en ColorRESUMEN
OBJECTIVE: To observe the clinical effectiveness of Qinghuang Powder (QHP) combined with Bupi Yishen Decoction (, BPYS) in treating myelodysplastic syndrome (MDS), and its relationship with France, America, and Britain (FAB) type, international prognosis scaling system (IPSS) risk, and chromosome karyotype. METHODS: There were 124 MDS patients subjected to the tests. By FAB typing, 91 patients were typed as refractory anemia (RA) type and 33 as refractory anemia with excess of blasts (RAEB) type; by IPSS scale, 21 were sorted to low risk, 77 to moderate risk I, 20 to moderate risk II, and 6 to high risk; 78 of them had normal chromosome and 46 with abnormal chromosome, including 26 of trisomy 8. All patients were treated with QHP+BPYS, and the changes of peripheral blood figure and bone marrow were observed. RESULTS: After treatment, the general effective rate was 72.58% (90/124), which in the patients of RA type was 80.22% (73/91) and in RAEB type 51.52% (17/33). The former was better than that in the later (P<0.01). For the analysis in the patients of different IPSS risk degrees, the effective rate was 95.24% (20/21) in the lowrisk group, 72.73% (56/77) in moderate risk I, 65.00% (13/20) in moderate-risk II, and 16.67% (1/6) in high-risk group. Those in the first two groups were superior to that in the latter two (P<0.01). The effective rate was 79.49% (61/78) in the patients with normal chromosome and was 60.87% (28/46) in the patients with abnormal chromosome, showing a significant difference between them. While in the patients of trisomy 8, it was 73.08% (19/26), which was parallel to that in the patients with normal chromosome. CONCLUSION: The effectiveness of QHP+BPYS comprehensive therapy for MDS is unquestionably good, and it is markedly correlated with the FAB type and IPSS risk degree of the disease, as well as the normality of chromosome in the patient.