Research Progress of Targeting uPA-uPAR System in Tumor Therapy / 肿瘤防治研究

The uPA-uPAR system is highly expressed in various tumor tissues. This system can promote the degradation of extracellular matrix proteins, as well as combine with vitronectin and integrin to transmit intracellular signal transduction. Subsequently, it mediates the occurrence and development of tumors. In recent years, a series of therapeutic programs that target this system has achieved notable results in tumor treatment, and some of them have been under the clinical trial stage, thus providing new ideas for tumor targeted therapy. Therefore, this paper intends to provide a review of research progress on the gene therapy, drug therapy, and immunotherapy targeting uPA-uPAR system.

Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

Fibrinólisis y SARS-CoV-2 / Fibrinolysis and SARS - CoV - 2

La regulación del sistema de la fibrinólisis está mediada por interacciones moleculares específicas entre sus principales componentes y por la síntesis y posterior liberación a partir de las células endoteliales de los activadores e inhibidores del plasminógeno. Por tanto, un incremento de la actividad del sistema de la fibrinólisis favorece la aparición de trastornos hemorrágicos, mientras que el defecto de la actividad fibrinolítica puede predisponer a la trombosis. En los pacientes con SARS-CoV-2 también se han reportado alteraciones en la fibrinólisis. La atenuación del sistema de activación del plasminógeno conduce a un recambio anormal de fibrina en el espacio alveolar con la aparición de trombosis. Se ha informado que los niveles plasmáticos de PAI-1 son un factor de riesgo de mal pronóstico y mortalidad en los pacientes con COVID-19.

The regulation of the fibrinolysis system is mediated by specific molecular interactions between its main components and by the synthesis and subsequent release from endothelial cells of plasminogen activators and inhibitors. Therefore, an increase in the activity of the fibrinolysis system favors the appearance of bleeding disorders, while a defect in fibrinolytic activity may predispose to thrombosis. Alterations in fibrinolysis have also been reported in patients with SARS-CoV-2. Attenuation of the plasminogen activation system leads to abnormal fibrin turnover in the alveolar space with the development of thrombosis. Plasma PAI-1 levels have been reported to be a risk factor for poor prognosis and mortality in patients with Covid-19.

Decreased expression of microRNA-17 in hippocampal tissues and blood from mice with depression up-regulates the expression of PAI-1 mRNA and protein

This study determined the expression of plasminogen activator inhibitor-1 (PAI-1) and microRNA (miR)-17 in a mouse depression model. Forty male mice were divided evenly into control and depression groups. A chronic unpredictable mild stress (CUMS) model was constructed. qRT-PCR was used to determine the expression of PAI-1 mRNA and miR-17. Western blotting and ELISA were used to determine expression of PAI-1 protein. Dual luciferase reporter assay was carried out to identify direct interaction between miR-17 and PAI-1 mRNA. The mice with depression had elevated PAI-1 mRNA and protein in hippocampal tissues and blood. Expression of miR-17 was decreased in hippocampal tissues and blood from mice with depression. miR-17 bound with the 3′-UTR of PAI-1 mRNA to regulate its expression. This study demonstrated that miR-17 expression in hippocampal tissues and blood from mice with depression was decreased while expression of PAI-1 mRNA and protein was up-regulated. miR-17 participated in depression in mice by regulating PAI-1.

Móleculas protrombóticas en niños con Diabetes Mellitus Tipo 1 / Study of prothrombotic molecules in type 1 diabetes mellitus children

Introducción: la hiperglucemia contribuye a cambios moleculares que alteran la hemostasia. Objetivos: determinar moléculas circulantes que indiquen la presencia de un estado protrombótico en una población infanto juvenil con diabetes mellitus tipo 1 (DM1), sin manifestación clínica de enfermedad vascular, y compararla con una población control. Pacientes y métodos: se estudiaron 35 pacientes con DM1, de 11,0±2,5 años de edad y 3,7±2,0 años de evolución de la enfermedad, sin complicaciones vasculares y 20 controles sanos de edad, sexo e IMC semejantes. Se determinaron: fibrinógeno (Fg), inhibidor del activador del plasminógeno 1 (PAI-1), antígeno del factor von Willebrand (FvW:Ag), ligando CD40 soluble (sCD40L) y pruebas globales de coagulación como recuento de plaquetas, tiempo de protrombina (TP) y tiempo de tromboplastina parcial activado (APTT). El control glucémico se evaluó mediante glucemia en ayunas y A1c, y se descartó la presencia de retinopatía y nefropatía. Los datos se analizaron con el programa SPSS 20 para Windows y se expresaron como media±DE. El coeficiente de Pearson se usó para investigar las correlaciones entre las variables estudiadas. Resultados: los pacientes con DM1 presentaron valores significativamente mayores de Fg (308±66 vs 246±18 mg/dL, p=0,0001), PAI-1 (41,6±12 vs 11,7±1,0 ng/mL, p=0,0001), FvW:Ag (284±55 vs 121±19 %, p=0,0001) y sCD40L (1608±109 vs 149±17 pg/mL, p=0,0001). Sin embargo las pruebas globales de hemostasia no mostraron diferencias entre ambos grupos. El PAI-1 y sCD40L se correlacionaron con glucemia, A1c, Fg y FvW:Ag. Conclusiones: los niveles elevados de Fg, PAI-1, FvW:Ag y sCD40L sugieren la presencia de un estado protrombótico en la población infanto juvenil con DM1

Introduction: hyperglycemia contributes to molecular changes that alter hemostasis. Objectives: to determine molecules of a prothrombotic state in a child-juvenile population with type 1 diabetes (T1D), without clinical manifestation of vascular disease, and compare it with a control population. Patients and methods: thirty-five patients with T1D (11.0±2.5 years and 3.7±2.0 years of disease duration), without vascular complications and 20 healthy controls were studied. Plasma fibrinogen (Pf), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor antigen vWF:Ag and soluble CD40 ligand (sCD40L) and coagulation global tests such as platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) were determined. The data obtained were analized by Statistics SPSS 20 software and were expressed as the mean±standard desviation. Pearson coefficient was used to investigate correlations between variables. Results: diabetic patients presented significantly higher values of glycaemia, A1c, Fg (308± 66 vs 246±18 mg/dL, p=0.0001), PAI-1 (41.6±12 vs 11.7±1, 0 ng/mL, p=0.0001), vWF:Ag (284±55 vs 121±19%, p= 0.0001) and sCD40L (1608±109 vs 149±17 pg/mL, p=0.0001). However, overall hemostasis tests showed no differences between both groups, PAI-1 and sCD40L correlated with glycemia, A1c, Fg and vWF:Ag. Conclusions: high levels of Fg, PAI-1, vWF:Ag and sCD40L suggest the presence of a prothrombotic state in the infant population juvenil with DT1

Clinical Efficacy of Modified Qingqi Huatan Wan in Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Its Effect on Inflammatory Reaction, Airway Remodeling and Thrombokinesis / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of Modified Qingqi Huatan Wan in treatment of acute exacerbation of chronic obstructive pulmonary disease and its effect on inflammatory reaction, airway remodeling and thrombokinesis. Method:A total of 80 patients of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) were randomly divided into control group (40 cases) and therapy group (40 cases) by random number table. The control group was treated with conventional therapy. In addition to the therapy for the control group, the patients in therapy group also received modified Qingqi Huatan Wan. The treatment course was 14 days for both groups. Scores of traditional Chinese medicine(TCM) syndrome, chronic obstructive pulmonary disease and asthma physiology Score (CAPS), and chronic obstructive pulmonary disease patients self-assessment test questionnaire (CAT) were compared. The secondary indicators were pulmonary function, arterial blood gas analysis, and blood rheology indexes. In addition, the levels of serum nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), transforming growth factor-beta1 (TGF-β1) and plasma tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von-willebrand factor (v-WF), clinical efficacy and safety were evaluated. Result:The total clinical effective rate was 94.74% in therapy group,which was higher than 78.38% in control group (χ2=4.341,P2, serum NF-κB, IL-6, IL-8, MMP-2, TIMP-2, TGF-β1 and plasma PAI-1, v-WF in therapy group were lower than those in control group(P2, PaO2, FEV1, FEV1%, FEV1/FVC in therapy group were higher than those in control group(PPConclusion:Modified Qingqi Huatan Wan can control the symptoms safely, alleviate CAPS and lung function, effectively reduce the inflammatory response and inhibit the formation of airway remodeling and thrombosis, and its mechanism may be protect the lung tissue by reducing the level of inflammatory cytokines, regulating the balance of MMP-2/TIMP-2 and t-PA/PAI-1 and improving extracellular matrix and vascular endothelial function.

Effect of Puerarin Combined with Tanshinone ⅡA on t-PA, PAI-1 and Oxidative Stress in DM Rats with Vascular Lesions / 中国实验方剂学杂志

Objective:To observe the protective effect and mechanism of combination of puerarin combined with tanshinone ⅡA on diabetes mellitus (DM) rats with vascular lesions. Method:The SD rats (fed with high-fat diet) were administrated with streptozotocin(STZ) through intravenous injection to make the model of diabetic vascular lesions. The successfully modeled rats were randomly divided into the model control group, the high-dose group (0.5 g·kg-1+1.0 g·kg-1), the middle-dose group (0.25 g·kg-1+0.5 g·kg-1), the low-dose group (0.05 g·kg-1+0.1 g·kg-1), the puerarin group (0.25 g·kg-1), the tanshinone ⅡA group (0.5 g·kg-1) and the positive control group (Metformin, 0.09 g·kg-1). Each group was administrated with drugs respectively by gavage for 70 days. After intervention in each group, the general conditions and body weight of the rats were observed. The contents of blood grucose and blood lipids were determined by automatic biochemical analyzer. The contents of insulin, advanced glycation end products (AGEs), superoxide dismutase(SOD), glutathione peroxidase (GSH-Px) in serum, the contents of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and thromboxane B2 (TXB2) in plasma, as well as the contents of AGEs and oxidized low-density lipoprotein(ox-LDL) in aorta homogenate were detected by enzyme-linked immunosorbent assay(ELISA). The content of malondialdehyde(MDA) in serum was determined by chemical colorimetry. Pathological changes of coronary tissue were observed by htoxylin eosin(HE) staining. The expression of PAI-1 protein of aorta was observed by immunohistochemistry. Result:Compared with the normal control group, in the model group, the levels of blood grucose and blood lipids (PPPP2 in plasma (PPPPPPPPP2 in plasma (PPPPPPPConclusion:Puerarin combined with Tanshinone ⅡA could relieve vascular lesions of DM rats. The mechanisms may be related to the reduction of oxidative stress and the regulation of coagulation-fibrinolysis system.

Expression and clinical significance of phosphoenolpyruvate carboxykinas and plaminogen activator inhibitor-1 in pleomorphic adenoma and adjacent tumor tissues of parotid gland / 实用医学杂志

Objective To explore the expression and clinical significance of phosphoenolpyruvate carboxykinase (PCK) and plaminogen activator inhibitor-1 (PAI-1) in pleomorphic adenoma and adjacent tumor tissues of parotid gland. Methods Immunohistoehemistry was used to detect the expression of PCK and PAI-1 in10 cases of normal parotid glands, 38 cases of pleomorphic adenoma (0 cm) , adjacent tumor tissues (0.5, 1.0, 1.5, 2.0 cm from the pleomorphic adenoma). Results PCK expressed in all cases of normal parotid glands and adjacent tumor tissues, while PAI-1 expressed in 4 cases of normal parotid glands. Except 18 samples of 2.0 cm apart from pleomorphic adenoma, PAI-1 was expressed in the other adjacent tumor tissues. There was no obvious difference of PCK expression among normal, pleomorphic adenoma and adjacent tumor tissues of parotid glands (P> 0.05). The difference of PAI-1 expression was detected between pleomorphic adenoma (0 cm) and normal parotid glands and adjacent tumor tissues (2.0 cm from the tumor, P < 0.05). Conclusion During the development of pleomorphic adenoma, the expression level of PAI-1 is progressively increased while no change of PCK expression is found. It is rather remarkable that translocation of PAI-1 and PCK expression from cytoplasm and plasma membrane to nucleus occurs. The results mentioned above suggest that PCK and PAI-1 might play important roles in the progress of pleomorphic adenoma.

Salvianolic acid B exerts anti-hepatic fibrosis-carcinoma effect via mediation of pSmad3C/pSmad3L / 中国药理学通报

Aim To observe the effect of Salvianolic-aid B ( Sal B ) on the progression of hepatic fibrosis-carcinoma in mice induced by diethylnitrosamine ( DEN ) and investigate the mechanism of Sal B in-volved in the shift between pSmad 3 C/p21-mediated tumor suppressive signaling and pSmad 3L/PAI-1/c-Myc-mediated pro-fibrogenic/oncogenic signaling . Methods A total of 100 male Kunming mice were randomly grouped , DEN-induced hepatic fibrosis-car-cinoma model of mice was established , which was in-tragastrically treated by Sal B with two dosages ( 15 , 30 mg · kg -1 ) and colchicine with one dosage ( 0.2 mg· kg -1 ) , respectively.The mice were sacrificed at 12th week or 16th week after the start of DEN adminis-tration.Pathological changes of livers in each group were assessed by liver biopsy , hematoxylin-eosin ( HE ) staining and Van Gieson ( VG ) staining .The protein expressions of pSmad3C, pSmad3L, p21, plas-minogen activator inhibitor-1 ( PAI-1 ) and c-Myc in liver tissues were assayed by Western blot .Results In the normal control group , the surface of mouse liver was smooth and soft , and the structure of the hepatic lobule was intact.In the DEN alone group, at 12th week, the surface of mouse liver was rough and hard , the hepatic lobule was encysted or separated by colla-gen bundles, and pseudolobules emerged.At 16th week, the surface of mouse liver in the DEN alone group was rough with some nodules. HE and VG staining showed that the hepatocytes of nodules with obvious atypia and hyperchromatic nuclei were veri-fied.However, these pathological changes were evi-dently improved in Sal B treatment groups compared with the DEN group , which was proved by reductive cirrhotic nodules and alleviative fibrosis at 12th week, and decreasing cancerous nodes and ameliorative dif-ferentiation via Sal B treatment at 16th week.Western blot results showed that the protein expression of pS-mad3C, pSmad3L, PAI-1 were less, and c-Myc ex-pression was scarcely found in normal group; in DEN alone group, at 12th week, the protein expression of pSmad3C had no significant change , while the protein levels of pSmad3L, PAI-1, p21 were up-regulated, and at 16th week, the protein expressions of pS-mad3C, pSmad3L, p21, PAI-1 and c-Myc increased. In Sal B treatment group, the expressions of p21 and pSmad3C increased significantly , pSmad3L and PAI-1 protein levels markedly decreased at 12th week, the expression of pSmad3C increased obviously , p21 was almost unchanged , and the expression of pSmad 3L, PAI-1 and c-Myc were significantly reduced at 16th week .Conclusions Sal B could delay the progression of hepatic fibrosis-carcinoma in mice induced by DEN , and the mechanism may involve mediating the shift of pSmad3C/p21 and pSmad3L/PAI-1/c-Myc signaling.

Effects of Salvia Miltiorrhiza and Rrhizoma Alismatis on Lipid Metabolism and Fibrinolytic System in Rats with Non-alcoholic Fatty Liver / 中国药师

Objective:To preliminarily discuss the mechanism of Salvia miltiorrhiza and Rrhizoma alismatis in the prevention and treatment of lipid metabolism through regulating the imbalance of fibrinolytic system in rats with non-alcoholic fatty liver. Methods:The model of non-alcoholic fatty liver in rats was duplicated by high-fat diet feeding. Totally 60 adult Wistar rats were randomly divided into 6 groups (n=10 per group), namely the control group, the model group, Salvia miltiorrhiza group, Rrhizoma alismatis group, Salvia miltiorrhiza and Rrhizoma alismatis group,and Dongbaogantai group. The control group and the model group were given distilled water,and the other group was given Salvia miltiorrhiza,Rrhizoma alismatis,Salvia miltiorrhiza combined with Rrhizoma alismatis and Dongbaogantai,respectively. Rhizoma Alismatis decoction at high dose and low dose as well as Dongbaogantai was respectively adminis-trated in the designed groups,and the corresponding indices were detected 4 weeks later. Results:In the model control group,the con-tents of TC、TG、FFA in serum and the expression of PAI-1 were significantly elevated(P<0.05 or P<0.01),while the expression of t-PA was significantly reduced(P<0.01).After treatment,the contents of TC、TG、FFA in serum and the expression of PAI-1 in every treatment groups were reduced(P<0.01),while the expression of t-PA was elevated(P<0.01).Conclusion: Increasing the expres-sion of t-PA and reducing the expression of PAI-1 might be viewed as the mechanisms of Salvia miltiorrhiza and Rrhizoma alismatis in the prevention and treatment of non-alcoholic fatty liver disease.

Research Progress of SERPINE Family in Fibrosis Disease / 现代生物医学进展

Serine protease inhibitor (serpin) is a kind of serine protease activity regulator,which including nine subfamilies (SERPIN A ～ I).SERPINE (Serpin Peptidase Inhibitor,Clade E) can regulate many important life processes.In this paper,the physical and chemical properties,mechanisms and regulatory factors of SERPINE1 and SERPINE2 in the two important members of SERPINE family are introduced,and the research progress of SERPINE family in the fibrosis related diseases is described.

Protective effects of superfine powder of Erigeron Breviscapus on chronic renal failure rats induced by adenine / 中草药

Objective To observe the effects of superfine powder of Erigeron breviscapus on chronic renal failure (CRF) in rats induced by adenine. Methods SD rats were randomly divided into control group, model group, superfine powder and common powder of E. breviscapus groups, 10 rats in each group. The control group received routine feeding, while the other three groups received intragastrically (ig) with adenine (250 mg/kg) for 21 d to establish rat CRF models. Then, the rats in the control group and model group were received ig with equal volume of distilled water. Also, the rats in the superfine powder and common powder of E. breviscapus group were administered ig with E. breviscapus (3 g/kg) for 42 d. During the experiment, the general condition of each group of rats were observed and the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were determined. Expressions of transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1) at mRNA level were determined by qRT-PCR. Concentrations of kidney tissue inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. Moreover, the kidney tissue was taken for histopathological observation. Results The rats in CRF model group after treatment with superfine and common powder of E. breviscapus appeared different levels of decrease of Scr, BUN, TNF-α, IL-1β, and mRNA expression of TGF-β1 and PAI-1 (P < 0.05). The pathologic changes of kidney tissue were also alleviated in different degrees. The treatment effect of superfine powder of Erigeron breviscapus was better than that of common powder group. Conclusion E. breviscapus has a good renal protective effect in rats with CRF. Furthermore, the superfine powder is more effective than the common powder in the protective effects of renal.

PAI-1 haplogenotype confers genetic susceptibility for obesity and hypertriglyceridemia in Mexican children. / Un haplogenotipo de PAI-1 confiere susceptibilidad genética para la obesidad y la hipertrigliceridemia en niños mexicanos

The presence of childhood obesity predisposes to the development of cardio vascular and metabolic diseases, such as coronary artery disease and type 2 diabetes mellitus, in adulthood. The polymorphisms described in PAI-1 gene have been linked with obesity and metabolic syndrome in several populations. The aim of this study was to investigate the as sociation of the -844 G/A (rs2227631), -675 4G/5G (rs1799889) and HindIII C/G (rs757716) PAI-1 polymorphisms with obesity and dyslipidemia in a sample of Mexican children. A cross-sectional study was performed in 222 children with an age range between 6-11 years; 104 children were classified as obese and 118 children with normal-weight. The PAI-1 poly morphisms were analyzed by PCR-RFLP. Linkage disequilibrium (LD) and haplogenotype analysis among the three polymorphisms were determined. The results showed significant as sociations with obesity of the -844 G/A genotype and the A allele (OR= 2.75, p<0.001 and OR= 1.76, p=0.01, respectively). The -844 G/A polymorphism was found in LD with -675 4G/5G PAI-1 polymorphism (D’= 0.77). We found that G-4G-C/A-5G-G is a risk haplogeno type for obesity [OR=2.6; 95% confidence interval (CI) 1.17-4.22; p= 0.01] and with marginal association with hypertriglyceridemia(OR= 2.6; 95% CI 1.04-6.35; p= 0.05). The G-4G-C/A 5G-G PAI-1 haplogenotype may be a genetic marker of susceptibility for obesity and hypertri glyceridemia in Mexican children.

La presencia de la obesidad en la infancia predispone al desarrollo de enfermedades cardiovasculares y metabólicas, como la enfermedad arterial coronaria y la diabetes mellitus tipo 2 en la edad adulta. Algunos polimorfismos en el gen PAI-1 se han relacionado con la obesidad y el síndrome metabólico en varias poblaciones. El objetivo del estudio fue investigar la asociación de los polimorfismos -844 G/A (rs2227631), -675 4G/5G (rs1799889) y HindIII C/G (rs757716) en el gen PAI-1 con la obesidad y las dislipidemias en una muestra de niños mexicanos. Se realizó un estudio transversal en 222 niños con un rango de edad de 6-11 años, de los cuales 104 niños fueron clasificados con obesidad y 118 con peso normal. Los poli morfismos en el gen PAI-1 fueron analizados por PCR-RFLP. También se determinó el desequilibrio de ligamiento y el análisis de haplogenotipos de los tres polimorfismos. Los resultados mostraron la asociación significativa de la obesidad con el genotipo -844 G/A y el alelo A (OR= 2,75, p<0,001 y OR= 1,76, p=0,01, respectivamente). El polimorfismo -844 G/A se encontró en desequilibrio de ligamiento con el -675 4G/5G (D’= 0.77). También se encontró que el haplogenotipo G-4G-C/A-5G-G es un marcador de riesgo para la obesidad [OR=2,6; 95% intervalo de confianza (CI) 1,17-4,22; p= 0,01], además de que este haplogenotipo presentó una asociación marginal con la hipertrigliceridemia (OR= 2,6; 95% CI 1,04-6,35; p= 0,05). El haplogenotipo G-4G-C/A-5G-G en el gen PAI-1 puede ser un marcador genético de susceptibilidad para obesidad e hipertrigliceridemia en niños mexicanos.

Effects of Capparis Spinosa Total Alkaloid on MMP-9 and TIMP-1 Levels in Systemic Sclerosis Mice / 中国中医药信息杂志

Objective To investigate the effects of capparis spinosa total alkaloid on type collagen (ColⅣ - ),Ⅳmatrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in bleomycin-induced systemic sclerosis (SSc) mice; To explore the effective mechanism of capparis spinosa total alkaloid on fibrosis of SSc. Methods Totally 90 BALB/c mice were randomly divided into control group, model group, penicillamine group and capparis spinosa total alkaloid low-, medium- and high-dose group. Mice models with SSc were established by repeated local injections of bleomycin in mice back, except for the control group. Mice in medication groups received external application with capparis spinosa total alkaloid cream;mice in penicillamine group were given penicillamine for gavage; mice in the control and model group received external application without substance, one time a day, for 60 days. The contents of MMP-9, TIMP-1 and PAI-1 in serum and Col- in skin tissue were dⅣ etected respectively by ELISA after the last medication. Results Compared with the model group, the levels of MMP-9 and ratio of MMP-9/TIMP-1 markedly increased and the levels of Col-Ⅳand TIMP-1 markedly decreased in medium and high- dose of capparis spinosa total alkaloid group (P0.05). Conclusion Capparis spinosa total alkaloid is effective in treating fibrosis of SSc by adjusting imbalance of MMP-9/TIMP-1 and decreasing expression of Col-Ⅳ.

Effects of simvastatin on expressions of uPA/PAI-1 in neutrophils in rats with septic shock / 实用医学杂志

Objective To explore the effects of simvastatin on the protein expressions of urokinase-typeplasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1). Methods Male Sprague–Dawley rats were divided into saline group , LPS group and LPS plus simvastatin group , and were then pretreated with simvastatin (1 mg/kg) for 30 minutes before addition of LPS (8 mg/kg). Changes in left ventricular pressure were recorded. Ninety minutes after LPS injection, whole blood was collected from the inferior vena cava, and neutrophils were separated. The neutrophils were then lysed to detect levels of uPA and PAI-1. Results Left ventricular systolic pressure (LVSP: mmHg), maximal differential of left ventricular pressure (+dp/dtmax:mmHg/s), and heart rate (beats/min) were markedly decreased at different time points after administration of LPS, and maximal differential of left ventricular pressure increased in the rats receiving LPS as compared with those receiving saline, although the differences between the control and LPS groups were not statistically significant. LPS caused a great decline in uPA content and an elevation in PAI-1 content in neutrophils, but simvastatin diminished the impact of LPS on neutrophils. Conclusion Simvastatin plays a role in protection of cardiac function in rats with LPS-induced septic shock , and controls expressions of uPA and PAI-1 in neutrophils.

Moléculas de adhesión endotelial (ICAM-1) e inhibidor del activador del plasminógeno (PAI-1) / Endothelial adhesion molecules (ICAM-1) and plasminogen activator inhibitor (PAI-1)

Se ha demostrado que los factores de riesgo clásicos no explican por completo la ocurrencia de enfermedad cardiovascular en poblaciones estudiadas, por lo que nuevos marcadores podrían servir en la identificación de pacientes que podrían estar en riesgo. El objetivo del estudio fue relacionar los niveles de ICAM-1 y PAI- 1 en pacientes estratificados según el riesgo cardiovascular global (RCVG), que asistieron a la consulta de Medicina Interna del Ambulatorio I San Diego, durante el período 2011 - 2012. Se trató de un estudio observacional, descriptivo, de corte transversal, de muestreo intencional, que incluyó 202 pacientes a los cuales se les aplicó una encuesta, se les midió presión arterial y circunferencia abdominal. Adicionalmente, se determinó en muestras de suero: glicemia, colesterol, HDL-c, LDL-c, ICAM-1, PAI-1, y se estratificaron según el riesgo cardiovascular global. Para establecer puntos de cortes de los parámetros ICAM-1 y PAI-1, se evaluaron 42 pacientes aparentemente sanos. Los resultados mostraron alteraciones en los parámetros: presión arterial sistólica (PAS), triglicéridos e ICAM- 1 de la población en estudio, así como correlación entre ICAM-1 y PAI-1 con la edad y PAS. Al estratificar los pacientes según el riesgo cardiovascular global se encontró que 56,4% presentaron riesgo bajo; 36,6% riesgo moderado y 6,9% riesgo alto. Al comparar entre las categorías de riesgo cardiovascular global, se encontraron diferencias significativas para el ICAM-1 y el PAI-1, a medida que se incrementó el riesgo. Se requieren estudios prospectivos que corroboren los resultados obtenidos.

It has been shown that traditional risk factors do not fully explain the occurrence of cardiovascular disease in the populations studied, so new markers could be used in identifying patients who may be at risk. The objective of the study was to relate the levels of ICAM-1 and PAI-1 in patients stratified by global cardiovascular risk, who attended the Internal Medicine consultation at San Diego Outpatient Centre I, during the period 2011-2012. This was an observational, descriptive, cross-sectional, purposive sampling study, which included 202 patients who were surveyed and measured their blood pressure and waist circumference. Additionally, glucose, cholesterol, HDL-c, LDL-c, ICAM-1, PAI-1, were determined in serum samples and were stratified according to the global cardiovascular risk. To set cut-off points of parameters ICAM-1 and PAI-1, 42 apparently healthy patients were assessed. The results showed changes in the parameters: systolic blood pressure (SBP), triglycerides and ICAM- 1 of the study population as well as correlation between ICAM-1 and PAI-1 with age and PAS. When stratifying patients according to the global cardiovascular risk, it was found that 56.4% had low risk, 36.6% moderate risk and 6.9% high risk. When comparing among the global cardiovascular risk categories, significant differences were found for ICAM-1 and PAI-1, as the risk increased. Prospective studies are required to support the obtained results.

Adiposidade corporal, mas não resistência insulínica, associa-se ao polimorfismo -675 4G/5G no gene PAI-1 em uma amostra de crianças mexicanas / Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children

OBJETIVO: Elaboramos este estudo para avaliar se o polimorfismo -675 4G/5G no gene inibidor 1 do ativador do plasminogênio se associa à obesidade e à resistência insulínica em crianças mexicanas. MÉTODOS: Foi realizado um estudo transversal em 174 crianças, 89 delas com peso normal e 85 obesas, variando sua idade de 6 a 13 anos. Todas as crianças eram do estado de Guerrero e foram recrutadas de três escolas primárias na cidade de Chilpancingo, México. Os níveis de insulina foram determinados por prova imunoenzimática. Foi usado o modelo de avaliação da homeostase para determinar resistência insulínica. O polimorfismo -675 4G/5G no gene PAI-1 foi analisado pelo método reação de polimerase em cadeia-polimorfismo no comprimento dos fragmentos de restrição. RESULTADOS: A prevalência de resistência insulínica no grupo obeso foi mais alta (49,41%) do que no grupo com peso normal (16,85%). O polimorfismo 4G/5G do PAI-1 foi encontrado em equilíbrio de Hardy Weinberg. O genótipo 4G/5G contribuiu para um aumento significativo da relação cintura-quadril (β = 0,02, p = 0,006), da circunferência da cintura (β = 4,42, p = 0,009) e da espessura da prega subescapular (β = 1,79, p = 0,04), mas não se relacionou com a resistência insulínica. CONCLUSÃO: O genótipo -675 4G/5G do gene PAI-1 se associou a aumento da adiposidade corporal em crianças mexicanas.

OBJECTIVE: To assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. METHODS: A cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β = 0.02, p = 0.006), waist circumference (β = 4.42, p = 0.009), and subscapular skinfold thickness (β = 1.79, p = 0.04); however, it was not related with insulin resistance. CONCLUSION: The -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.

Experimental study on the change of dynamic expression of t-PA and PAI-1 during early venous crisis after free perforator flap transplantation / 中华显微外科杂志

Objective To investigate the change of dynamic expression of t-PA and PAI-1 during early venous crisis after free perforator flap transplantation.Methods Thirty healthy New Zealand white rabbits weighed 2.5-3.0 kg were chosen and randomly divided into experimental group (n =15) and control group (n =15).Free transplantation of superficial epigastric artery perforator flap (SEAPF) was implemented in all rabbits firstly.Then the model of venous crisis was established by ligating the anastomosis vein in order to interrupt venous blood outflow in experimental group.The blood supply of all flaps was monitored by observing their color,swelling degree and the filling reaction of the capillaries after operation.Peripheral blood was drawn from femoral artery at different time point for measuring the concentration of t-PA and PAI-1 by Elisa.Partial flap tissue was harvested for pathological examination at corresponding time point.Data analysis was performed by using SPSS 17.0 statistical software.P ＜ 0.05 was considered statistically significant.Results One rabbit died of anesthesia,and the venous congestion was observed in 1 rabbit in control group.The models of free transplantation of SEAPF and venous crisis were established successfully in the remaining rabbits.No significant appearance change was observed within 1 h after the outflow vein being ligated,while typical appearance of venous crisis could be observed 2 hours after the outflow vein being ligated.Compared with the control group,the concentration of t-PA was lower,but the concentration of PAI-1 was higher in experimental group at 2 hours,4 hours,6 hours,8 hours after the outflow vein being ligated(P ＜ 0.05).However,there was no obvious differences between two groups at other time points (P ＞ 0.05).The pathological examination showed the red cells gradually got together and adhered to the venous wall,eventually the microcirculation had been blocked completely and theflap became necrosis after venous crisis being occurred.Conclusion t-PA and PAI-1 can't be used to diagnose early venous crisis of perforator flap transplantation.

Relationship between plasminogen activator inhibitor type-1 (PAI-1) gene polymorphisms and osteoporosis in Turkish women

OBJECTIVE: The development of osteoporosis is associated with several risk factors, such as genetic structures that affect bone turnover and bone mass. The impact of genetic structures on osteoporosis is not known. Plasminogen activator inhibitor type-1 regulates the bone matrix and bone balance. This study assessed the correlation between plasminogen activator inhibitor type-1 gene 4G/5G polymorphisms and osteoporosis in a population of Turkish women. METHODS: A total of 195 postmenopausal female patients who were diagnosed with osteoporosis (Group I) based on bone mineral density measurements via dual-energy x-ray absorptiometry and 90 females with no osteoporosis (Group II) were included in this study. Correlations between PAI-1 gene 4G/5G polymorphisms and osteoporosis were investigated through the identification of PAI-1 gene 4G/5G polymorphism genotypes using the polymerase chain reaction. RESULTS: No significant differences in the genotype and allele frequency of 4G/5G plasminogen activator inhibitor type-1 polymorphisms were observed between the two groups, and both groups exhibited the most frequently observed 4G5G genotype. CONCLUSION: No correlation between the development of osteoporosis in the female Turkish population and 4G/5G plasminogen activator inhibitor type-1 gene polymorphisms was observed.

The mechanisms of ARPD in treating radiation-induced lung fibrosis in rats / 中华放射医学与防护杂志

Objective To investigate the therapeutic effects and mechanism of anti-radiation pneumonia decoction(ARPD) on radiation induced lung fibrosis in rats.Methods One hundred and five male SD rats in a SPF grade were divided into Chinese medicine group,single radiation group and control group by random digits table method,with 35 in each group.After anesthetization,rats in Chinese medicine and single radiation groups were exposed to 6 MV X-rays at the dose of 15Gy.Rats in Chinese medicine group were treated with ARPD at the dosage of 10 ml·kg-1 ·d-1 once a day,but rats in single radiation group did not receive ARPD treatment.Rats in control group were treated with neither irradiation nor drugs.Five rats of each group were killed and the lung tissues and blood samples were collected at 15,30,60,75,90,105 and 140 d.The pathological changes of lung tissues were observed and the tissue protein and gene expressions of TGF-β1,PAI-1 and collagen type Ⅲ(C Ⅲ) were assayed by Western blot and RT-PCR.ELISA was used to detect serum TGF-β1 and plasma PAI-1.Tissue and serum HYP were determined by acid hydrolysis and alkaline hydrolysis methods respectively.Results Inflammation was found in the lung tissues of all the exposed rats.Obvious pathological lung fibrosis was found at 60 d,the inflammation and the fibrosis in treated group were slighter than those in single radiation group.In Chinese medicine group,the protein and gene expression levels of TGF-β1,PAI-1,C Ⅲ 30 d(Protein:t =2.49-3.74,t =2.63-4.57 and t =2.76-3.83;Gene:t =2.59-4.33,t =2.83-4.62 and t =2.83-3.96,P＜0.05),serum TGF-β1 and plasma PAI-1 15 dlater (t =2.85-6.27 and t =3.69-5.27,P＜0.05),and the levels of tissue and serum HYP60 dlater (t=3.65-4.40 and t =6.56-3.75,P＜0.05),all of them were lower than those in single radiation groups.There were significant positive correlations between tissue TGF-β1 and PAI-1 as well as C Ⅲ (Protein expression:r =0.604,0.759,P ＜0.05;Gene expression:r=0.519,0.816,P＜0.05).Conclusions ARPD may inhibit the pulmonary fibrosis by decreasing the levels of TGF-β1,PAI-1 and C Ⅲ.