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Sample records for ii-stimulated pai-1 expression

  1. [Regulation of PAI-1 expression].

    Science.gov (United States)

    Wyrzykowska, Paulina; Kasza, Aneta

    2009-01-01

    PAI-1 (plasminogen activator inhibitor-1) is a member of plasminogen cascade with an inhibitory role in plasmin activation. Plasmin is a protease capable of acting on wide range of substrates and, together with metaloproteinases, is a main proteolytic enzyme. Except its role in plasminogen cascade, PAI-1 has an affinity to vitronectin and uPA/uPAR what involves PAI-1 in cell's motility. PAI-1 gene is regulated in response to cytokines, hormones and many growth factors among which TGFbeta is the most important one. The PAI-1 promoter contains SBE, CAGA box, HRE, ERE, NFkB - binding sites, Sp-1, AP-1 and other. Cooperation between transcription factors bound to promoter and cross-talks between kinases and other upstream proteins decide about gene expression. This work describes the present knowledge in this field.

  2. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and endometriosis. Influence of PAI-1 polymorphism on PAI-1 antigen and mRNA expression.

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    Ramón, Luis A; Gilabert-Estellés, Juan; Cosín, Raul; Gilabert, Juan; España, Francisco; Castelló, Remedios; Chirivella, Melitina; Romeu, Alberto; Estellés, Amparo

    2008-01-01

    Endometriosis is a benign gynecologic disease with a high prevalence. It is a multifactorial and polygenic entity in which the fibrinolytic system may be implicated. The objective of this study was to evaluate the plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism in a group of women with and without endometriosis and to analyze the influence of this polymorphism in PAI-1 expression in endometrial tissue and peritoneal fluid. In 389 women (170 patients with endometriosis and 219 controls) PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Quantitative real-time RT-PCR assay was used to quantify PAI-1 mRNA and PAI-1 antigen (ag) levels were quantified by ELISA. The genotype and allele frequencies of PAI-1 4G/5G polymorphism did not differ significantly between patients and controls. Control women with the 4G/4G genotype had higher endometrial PAI-1ag (P=0.026) and mRNA (P=0.014) levels than those with the 5G/5G genotype. Control carrying the 4G/4G genotype tended to have higher peritoneal fluid PAI-1ag levels than those carrying the 5G/5G genotype. Moreover, PAI-1ag levels in peritoneal fluid were higher in patients than in controls (P=0.003). The PAI-1 genotype distribution was similar in patients and controls. PAI-1 levels in endometrial tissue and peritoneal fluid seem to be associated with PAI-1 4G/5G polymorphism in controls. The increased PAI-1ag levels observed in peritoneal fluid from patients could contribute to increase the peritoneal adhesions observed in endometriosis.

  3. PAI-1 mRNA expression and plasma level in rheumatoid arthritis: relationship with 4G/5G PAI-1 polymorphism.

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    Muñoz-Valle, José Francisco; Ruiz-Quezada, Sandra Luz; Oregón-Romero, Edith; Navarro-Hernández, Rosa Elena; Castañeda-Saucedo, Eduardo; De la Cruz-Mosso, Ulises; Illades-Aguiar, Berenice; Leyva-Vázquez, Marco Antonio; Castro-Alarcón, Natividad; Parra-Rojas, Isela

    2012-12-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, cartilage and bone. PAI-1 is a key regulator of the fibrinolytic system through which plasminogen is converted to plasmin. The plasmin activates the matrix metalloproteinase system, which is closely related with the joint damage and bone destruction in RA. The aim of this study was to investigate the relationship between 4G/5G PAI-1 polymorphism with mRNA expression and PAI-1 plasma protein levels in RA patients. 113 RA patients and 123 healthy subjects (HS) were included in the study. The 4G/5G PAI-1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism method; the PAI-1 mRNA expression was determined by real-time PCR; and the soluble PAI-1 (sPAI-1) levels were quantified using an ELISA kit. No significant differences in the genotype and allele frequencies of 4G/5G PAI-1 polymorphism were found between RA patients and HS. However, the 5G/5G genotype was the most frequent in both studied groups: RA (42%) and HS (44%). PAI-1 mRNA expression was slightly increased (0.67 fold) in RA patients with respect to HS (P = 0.0001). In addition, in RA patients, the 4G/4G genotype carriers showed increased PAI-1 mRNA expression (3.82 fold) versus 4G/5G and 5G/5G genotypes (P = 0.0001), whereas the sPAI-1 plasma levels did not show significant differences. Our results indicate that the 4G/5G PAI-1 polymorphism is not a marker of susceptibility in the Western Mexico. However, the 4G/4G genotype is associated with high PAI-1 mRNA expression but not with the sPAI-1 levels in RA patients.

  4. Ligustrazini Inhibits Endotoxin Induced PAI-1 Expression in Human Umbilical Vein Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    阮秋蓉; 邓仲端; 宋建新

    2001-01-01

    Plasminogen activator inhibitor 1 (PAI-1) is one of important coagulant factors. Endotoxin lipopolysaccharide (LPS) induces thrombosis by stimulating PAI-1 secretion of vascular cells (EC). Using sandwich enzyme-linked immunosorbent assay (ELISA) and Northern blot, was investigated the effects of Chinese medicine ligustrazini on PAI-1 expression in EC and LPS-stimulated EC. The results showed that ligustrazini inhibited both basal and LPS-induced PAI-1 mRNA expression in EC. The effect of ligustrazini on LPS-induced PAI-1 secretion worked in a dose-dependent manner. This study provided theoretic and experimental evidence for use of ligustrazini against septic shock and cardiovascular diseases.

  5. Intracellular Expression of PAI-1 Specific Aptamers Alters Breast Cancer Cell Migration, Invasion and Angiogenesis

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    Fortenberry, Yolanda M.; Brandal, Stephanie M.; Carpentier, Gilles; Hemani, Malvi; Pathak, Arvind P.

    2016-01-01

    Plasminogen activator inhibitor-1 (PAI-1) is elevated in various cancers, where it has been shown to effect cell migration and invasion and angiogenesis. While, PAI-1 is a secreted protein, its intercellular levels are increased in cancer cells. Consequently, intracellular PAI-1 could contribute to cancer progression. While various small molecule inhibitors of PAI-1 are currently being investigated, none specifically target intracellular PAI-1. A class of inhibitors, termed aptamers, has been used effectively in several clinical applications. We previously generated RNA aptamers that target PAI-1 and demonstrated their ability to inhibit extracellular PAI-1. In the current study we explored the effect of these aptamers on intracellular PAI-1. We transiently transfected the PAI-1 specific aptamers into both MDA-MB-231 human breast cancer cells, and human umbilical vein endothelial cells (HUVECs) and studied their effects on cell migration, invasion and angiogenesis. Aptamer expressing MDA-MB-231 cells exhibited a decrease in cell migration and invasion. Additionally, intracellular PAI-1 and urokinase plasminogen activator (uPA) protein levels decreased, while the PAI-1/uPA complex increased. Moreover, a significant decrease in endothelial tube formation in HUVECs transfected with the aptamers was observed. In contrast, conditioned media from aptamer transfected MDA-MB-231 cells displayed a slight pro-angiogenic effect. Collectively, our study shows that expressing functional aptamers inside breast and endothelial cells is feasible and may exhibit therapeutic potential. PMID:27755560

  6. Intracellular Expression of PAI-1 Specific Aptamers Alters Breast Cancer Cell Migration, Invasion and Angiogenesis.

    Science.gov (United States)

    Fortenberry, Yolanda M; Brandal, Stephanie M; Carpentier, Gilles; Hemani, Malvi; Pathak, Arvind P

    2016-01-01

    Plasminogen activator inhibitor-1 (PAI-1) is elevated in various cancers, where it has been shown to effect cell migration and invasion and angiogenesis. While, PAI-1 is a secreted protein, its intercellular levels are increased in cancer cells. Consequently, intracellular PAI-1 could contribute to cancer progression. While various small molecule inhibitors of PAI-1 are currently being investigated, none specifically target intracellular PAI-1. A class of inhibitors, termed aptamers, has been used effectively in several clinical applications. We previously generated RNA aptamers that target PAI-1 and demonstrated their ability to inhibit extracellular PAI-1. In the current study we explored the effect of these aptamers on intracellular PAI-1. We transiently transfected the PAI-1 specific aptamers into both MDA-MB-231 human breast cancer cells, and human umbilical vein endothelial cells (HUVECs) and studied their effects on cell migration, invasion and angiogenesis. Aptamer expressing MDA-MB-231 cells exhibited a decrease in cell migration and invasion. Additionally, intracellular PAI-1 and urokinase plasminogen activator (uPA) protein levels decreased, while the PAI-1/uPA complex increased. Moreover, a significant decrease in endothelial tube formation in HUVECs transfected with the aptamers was observed. In contrast, conditioned media from aptamer transfected MDA-MB-231 cells displayed a slight pro-angiogenic effect. Collectively, our study shows that expressing functional aptamers inside breast and endothelial cells is feasible and may exhibit therapeutic potential.

  7. Tissue-specific PAI-1 gene expression and glycosylation pattern in insulin-resistant old rats.

    Science.gov (United States)

    Serrano, R; Barrenetxe, J; Orbe, J; Rodríguez, J A; Gallardo, N; Martínez, C; Andrés, A; Páramo, J A

    2009-11-01

    Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with obesity, aging, insulin resistance, and type 2 diabetes, conditions that contribute to increased cardiovascular risk. PAI-1 is expressed in a variety of tissues, but the cellular origin of plasma PAI-1 is unknown. To link insulin resistance, aging, and cardiovascular disease, we examined the expression and glycosylation pattern of PAI-1 in liver and white adipose tissue (WAT) from adult (3 mo) and insulin-resistant old (24 mo) Wistar rats. Glycosylated PAI-1 protein was also purified by affinity chromatography from endothelial culture supernatans to analyze its inhibitory activity. We also analyzed the contribution of adipocytes and stromal vascular cells from WAT to PAI-1 levels with aging. Aging caused a significant increase of PAI-1 mRNA (P < 0.001) in WAT that was predominantly due to the adipocytes and not to stroma-vascular cells, while there was no modification in liver from aged rats. Moreover, PAI-1 expression increased during preadipocyte differentiation (P < 0.001). Furthermore, we found a tissue-dependent PAI-1 glycosylation pattern: adipose tissue only expresses the glycosylated PAI-1 form, whereas the liver mainly expresses the nonglycosylated form. Finally, we also found evidences suggesting that the glycosylated PAI-1 form shows higher inhibitory activity than the nonglycosylated. Our data suggest that WAT may be a major source of the elevated plasma levels of PAI-1 in insulin-resistant old rats. Additionally, the high degree of PAI-1 glycosylation and activity, together with the significant increase in visceral fat in old rats, may well contribute to an increased cardiovascular risk associated with insulin-resistant states.

  8. Resveratrol Suppresses PAI-1 Gene Expression in a Human In Vitro Model of Inflamed Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Ivana Zagotta

    2013-01-01

    Full Text Available Increased plasminogen activator inhibitor-1 (PAI-1 levels are associated with a number of pathophysiological complications; among them is obesity. Resveratrol was proposed to improve obesity-related health problems, but the effect of resveratrol on PAI-1 gene expression in obesity is not completely understood. In this study, we used SGBS adipocytes and a model of human adipose tissue inflammation to examine the effects of resveratrol on the production of PAI-1. Treatment of SGBS adipocytes with resveratrol reduced PAI-1 mRNA and protein in a time- and concentration-dependent manner. Further experiments showed that obesity-associated inflammatory conditions lead to the upregulation of PAI-1 gene expression which was antagonized by resveratrol. Although signaling via PI3K, Sirt1, AMPK, ROS, and Nrf2 appeared to play a significant role in the modulation of PAI-1 gene expression under noninflammatory conditions, those signaling components were not involved in mediating the resveratrol effects on PAI-1 production under inflammatory conditions. Instead, we demonstrate that the resveratrol effects on PAI-1 induction under inflammatory conditions were mediated via inhibition of the NFκB pathway. Together, resveratrol can act as NFκB inhibitor in adipocytes and thus the subsequently reduced PAI-1 expression in inflamed adipose tissue might provide a new insight towards novel treatment options of obesity.

  9. PAI-1 expression and its regulation by promoter 4G/5G polymorphism in clear cell renal cell carcinoma.

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    Choi, Jung-Woo; Lee, Ju-Han; Park, Hong Seok; Kim, Young-Sik

    2011-10-01

    To characterise patients with high plasminogen activator inhibitor-1 (PAI-1) expression as oral PAI-1 antagonists are currently in preclinical trials, and to determine whether the PAI-1 promoter 4G/5G polymorphism regulates PAI-1 expression in clear cell renal cell carcinoma (CCRCC). PAI-1 expression was examined by immunohistochemistry in 69 CCRCC specimens. In addition, the promoter 4G/5G polymorphism was investigated by both allele-specific PCR and direct DNA sequencing. PAI-1 was overexpressed in 25/69 (36.2%) patients with CCRCC. PAI-1 staining was intense in tumour cells with a high Fuhrman nuclear grade and in spindle-shaped tumour cells. PAI-1 expression was significantly associated with older age at diagnosis (p=0.027), high nuclear grade (p4G/4G, 43.5% (30/69) 4G/5G and 31.9% (22/69) 5G/5G. The homozygous 4G/4G or 5G/5G group showed a tendency for a high nuclear grade (p=0.05) but the 4G/5G polymorphism was not related to other prognostic parameters. PAI-1 expression was poorly correlated with its promoter 4G/5G polymorphism (Spearman ρ=0.088). CCRCC with high PAI-1 expression is characterised by older age, high nuclear grade, advanced stage, distant metastasis and/or shortened disease-free survival. PAI-1 expression is not affected by the promoter 4G/5G polymorphism.

  10. The effect of thyroid hormones on the white adipose tissue gene expression of PAI-1 and its serum concentration

    Directory of Open Access Journals (Sweden)

    C. Biz

    2009-12-01

    Full Text Available Metabolic syndrome is associated with an increased risk of developing cardiovascular diseases and Plasminogen activator inhibitor 1 (PAI-1 overexpression may play a significant role in this process. A positive correlation between adipose tissue gene expression of PAI-1 and its serum concentration has been reported. Furthermore, high serum levels of thyroid hormones (T3 and T4 and PAI-1 have been observed in obese children. The present study evaluates the impact of thyroid hormone treatment on white adipose tissue PAI-1 gene expression and its serum concentration. Male Wistar rats (60 days old were treated for three weeks with T4 (50 µg/day, Hyper or with saline (control. Additionally, 3T3-L1 adipocytes were treated for 24 h with T4 (100 nM or T3 (100 nM. PAI-1 gene expression was determined by real-time PCR, while the serum concentration of PAI-1 was measured by ELISA using a commercial kit (Innovative Research, USA. Both the serum concentration of PAI-1 and mRNA levels were similar between groups in retroperitoneal and epididymal white adipose tissue. Using 3T3-L1 adipocytes, in vitro treatment with T4 and T3 increased the gene expression of PAI-1, suggesting non-genomic and genomic effects, respectively. These results demonstrate that thyroid hormones have different effects in vitro and in vivo on PAI-1 gene expression in adipocytes.

  11. Compression-induced HIF-1 enhances thrombosis and PAI-1 expression in mouse skin.

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    Kaneko, Maki; Minematsu, Takeo; Yoshida, Mikako; Nishijima, Yoshimi; Noguchi, Hiroshi; Ohta, Yasunori; Nakagami, Gojiro; Mori, Taketoshi; Sanada, Hiromi

    2015-09-01

    Pressure ulcers result from tissue hypoxia caused by external forces. Thrombosis due to external forces is considered important, and hypoxia inducible factor-1 (HIF-1) is a master regulator of pressure ulcer development. To date, however, their causal relationship has not been determined. This study therefore investigated the mutual relationship between thrombosis and HIF-1 activation in compressed mouse skin, based on a hypothesis that HIF-1 regulation by plasminogen activator inhibitor-1 (PAI-1) enhances thrombosis. Compression of mouse skin significantly increased the numbers of thrombi and HIF-1α-positive cells compared with control skin. A thrombosis inhibitor significantly reduced the numbers of HIF-1α-positive cells and an HIF-1 inhibitor significantly inhibited thrombosis in compressed skin tissue, suggesting a mutual relationship between thrombosis and HIF-1 activation. Compression of mouse skin also enhanced the level of Pai-1 messenger RNA expression, but this increase was significantly reduced by treatment with an HIF-1 inhibitor, whereas a thrombosis inhibitor had no effect. These results suggested the involvement of PAI-1 in HIF-1-enhanced thrombosis and that an additional factor participates in regulating Pai-1 expression in compressed skin. These findings may suggest new strategies in pressure ulcer management.

  12. Hyperglycaemia-induced reciprocal changes in miR-30c and PAI-1 expression in platelets.

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    Luo, Mao; Li, Rong; Ren, Meiping; Chen, Ni; Deng, Xin; Tan, Xiaoyong; Li, Yongjie; Zeng, Min; Yang, Yan; Wan, Qin; Wu, Jianbo

    2016-11-07

    Type 2 diabetic mellitus (DM2) is associated with accelerated thrombotic complications and is characterized by high levels of plasminogen activator inhibitor-1 (PAI-1). Recent studies show that human platelets have high levels of miR-30c and synthesize considerable active PAI-1. The underlying mechanism of how PAI-1 expression is upregulated in DM2 is poorly understood. We now report that hyperglycaemia-induced repression of miR-30c increases PAI-1 expression and thrombus formation in DM2. Bioinformatic analysis and identification of miRNA targets were assessed using luciferase assays, quantitative real-time PCR and western blots in vitro and in vivo. The changes in miR-30c and PAI-1 levels were identified in platelets from healthy and diabetic individuals. We found that miR-30c directly targeted the 3' UTR of PAI-1 and negatively regulated its expression. miR-30c was negatively correlated with glucose and HbA1c levels in DM2. In HFD-fed diabetic mice, increasing miR-30c expression by lenti-miR-30c significantly decreased the PAI-1 expression and prolonged the time to occlusion in an arterial thrombosis model. Platelet depletion/reinfusion experiments generating mice with selective ablation of PAI-1 demonstrate a major contribution by platelet-derived PAI-1 in the treatment of lenti-miR-30c to thrombus formation. These results provide important implications regarding the regulation of fibrinolysis by platelet miRNA under diabetic mellitus.

  13. Suppression of PAI-1 expression through inhibition of the EGFR-mediated signaling cascade in rat kidney fibroblast by ascofuranone.

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    Cho, Hyun-Ji; Kang, Jeong-Han; Kim, Teoan; Park, Kwang-Kyun; Kim, Cheorl-Ho; Lee, In-Seon; Min, Kwan-Sik; Magae, Junji; Nakajima, Hiroo; Bae, Young-Seuk; Chang, Young-Chae

    2009-05-15

    Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)-beta, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)-1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI-1 induced by TGF-beta in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf-1, MEK-1/2, and ERK-1/2. PAI-1 transcription also is suppressed by treatment with kinase inhibitors for MEK-1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI-1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR-dependent signal transduction pathway activated by metalloproteinases.

  14. The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes.

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    Ko, Hyun Myung; Lee, Sung Hoon; Kim, Ki Chan; Joo, So Hyun; Choi, Wahn Soo; Shin, Chan Young

    2015-08-01

    Plasminogen activator inhibitor-1 (PAI-1) is an endogenous inhibitor of tissue plasminogen activator (tPA) that acts as a neuromodulator in various neurophysiological and pathological conditions. Several researchers including us reported the induction of PAI-1 during inflammatory condition; however, the mechanism regulating PAI-1 induction is not yet clear. In this study, we investigated the role of non-receptor tyrosine kinase Fyn in the regulation of lipopolysaccharide (LPS)-induced upregulation of PAI-1 in rat primary astrocyte. The activation of toll-like receptor 4 (TLR4) signaling, induced by its ligand LPS, stimulated a physical interaction between TLR4 and Fyn along with phosphorylation of tyrosine residue in both molecules as determined by co-immunoprecipitation experiments. Immunofluorescence staining also showed increased co-localization of TLR4-Fyn on cultured rat primary astrocytes after LPS treatment. The increased TRLR4-Fyn interaction induced expression of PAI-1 through the activation of PI3k/Akt/NFĸB pathway. Treatment with Src kinase inhibitor (PP2) or transfection of Fyn small interfering RNA (siRNA) into cultured rat primary astrocytes inhibited phosphorylation of tyrosine residue of TLR4 and blocked the interaction between TLR4 and Fyn resulting to the inhibition of LPS-induced expression of PAI-1. The activation of PI3K/Akt/NFĸB signaling cascades was also inhibited by Fyn knockdown in rat primary astrocytes. The induction of PAI-1 in rat primary astrocytes, which resulted in downregulation of tPA activity in culture supernatants, inhibited neurite outgrowth in cultured rat primary cortical neuron. The inhibition of neurite extension was prevented by PP2 or Fyn siRNA treatment in rat primary astrocytes. These results suggest the critical physiological role of TRL4-Fyn interaction in the modulation of PAI-1-tPA axis in astrocytes during neuroinflammatory responses such as ischemia/reperfusion injuries.

  15. The expression and significance of u-PA and PAI-1 in human lupus nephritis%狼疮性肾炎中u-PA和PAI-1的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    洪寅峰; 张志刚; 高山

    2001-01-01

    Objective To investigate the expression and significance of urokinase-type plasminogen activator (uPA) and type Ⅰ plasminogen activator inhibitor (PAI-1) in human lupus nephritis (LN). Method Immunohistochemistry and imaging analysis were used for detecting the intensity of expression of u-PA and PAI-1 in renal biopsied tissue of 50 cases with various types of LN and 10 cases with minor glomerular lesions (control group), the results were analyzed correlatively with PCNA cells and type IV collagen. Results The levels of u-PA and PAI-1 expression were different in various type of LN , in which, both were significantly higher than those of the minor glomerular lesion group (P<0.05), and the highest was LN-IV group. The staining intensity of PAI-1 expression was significantly stronger than that of u-PA in various type of LN (P <0.05), the increased expression of u-PA and PAI-1 were positively correlated with increased number of PCNA + cell (P <0.05), while the expression of PAI-1 was also closely related to increased deposition of type IV collagen in the glomeruli ( P <0.05). Conclusion The abnormal expression of u-PA and PAI-1 were associated with the extent of injury and types of LN and may be one of important factor in contributing to the progression and inimry in LN. (Shanghai Med J, 2001,24:169)%目的了解尿激酶型纤溶酶原激活物(u-PA)及其Ⅰ型抑制因子(PAI-1)在狼疮性肾炎(LN)肾小球病变中的表达及其意义。方法对50例不同类型的LN和10例原发性肾小球轻微病变的肾活检组织,采用免疫组化及图象分析法比较观察了u-PA和PAI-1在肾小球的表达强度,并与肾小球增殖细胞核抗原(PCNA)阳性细胞数和Ⅳ型胶原染色强度作相关分析。结果u-PA和PAI-1在各型LN病变肾小球中的表达,均比肾小球轻微病变明显增强(P<0.05或<0.01),并以LN-IV型为最明显。PAI-1的染色反应强于同组的u-PA,两者有显著差异(P<0.05)。肾小球u-PA和PAI

  16. Crohn's disease but not chronic ulcerative colitis induces the expression of PAI-1 in enteric neurons

    DEFF Research Database (Denmark)

    Laerum, O.D.; Illemann, M.; Skarstein, A.

    2008-01-01

    OBJECTIVES: Chronic inflammation of the intestinal wall is the common characteristic of Crohn's disease and ulcerative colitis; disorders, which in some cases can be difficult to distinguish. The inflammation also affects the local neuronal plexuses of the enteric nervous system. It is known...... by immunohistochemical techniques. RESULTS: PAI-1 was found in a subset of neurons primarily located in the submucosal plexus of the small and large intestine in 24 of 28 cases (86%) with Crohn's disease, but in none of 17 cases with chronic ulcerative colitis and other severe inflammatory conditions in the intestinal....... CONCLUSIONS: PAI-1-positive neurons in inflammatory bowel disease are linked to chronic inflammation in Crohn's disease, implying PAI-1 as a potential parameter for the differential diagnosis between Crohn's disease and ulcerative colitis. The findings also suggest that PAI-1 in neurons is related to pain...

  17. Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells.

    Science.gov (United States)

    Cho, Hyun-Ji; Kang, Jeong-Han; Jeong, Ji-Hak; Jeong, Yun-Jeong; Park, Kwan-Kyu; Park, Yoon-Yub; Moon, Yong-Suk; Kim, Hong-Tae; Chung, Il-Kyung; Kim, Cheorl-Ho; Chang, Hyeun-Wook; Chang, Young-Chae

    2012-04-01

    Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-β1 (TGF-β1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-β1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-β1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-β1-induced expression of PAI-1 without the inhibition of TβRII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.

  18. Radiation induced changes in the expression of fibronectin, Pai-1, MMP in rat glomerular epithelial cell

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    Park, Woo Yoon; Kim, Won Dong; Zheng, Ying; Ha, Tae Sun [Chungbuk National University, Cheongju (Korea, Republic of); Kim, Jae Sung [Seoul National University, Seoul (Korea, Republic of); Cho, Moon June [Chungnam National University, Daejeon (Korea, Republic of)

    2006-03-15

    Renal irradiation can lead to the development of radiation nephropathy, and this is characterized by the accumulation of extracellular matrix and final fibrosis. To determine the possible role of the glomerular epithelial cell, the radiation-induced changes in the expression of its genes associated with the extracellular matrix were analyzed. Rat glomerular epithelial cells (GEpC) were irradiated with a single dose of 0, 2, 5, 10 and 20 Gy with using 6 MV LINAC (Siemens, USA), and the samples were collected 6, 24, 48 and 72 hours post-irradiation, respectively. Northern blotting, western blotting and zymography were used to measure the expression level of fibronectin (Fn), plasminogen activator inhibitor-1 (Pai-1), matrix metalloproteinases-2, 9 (MMP-2, 9), tissue inhibitor of metalloproteinases-2 (TIMP-2), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Irradiation with a single dose of 10 Gy resulted in a significant increase in Fn mRNA since 24 hours post-irradiation, and a single dose of 5 and 10 Gy significantly increased the Fn immunoreactive protein measured 48 hours post-irradiation. An increase in Pai-mRNA and protein was also observed and especially, a single dose of 10 Gy significantly increased the mRNA measured 24 and 48 hours post-irradiation. The active MMP-2 measured 24 hours post-irradiation slightly increased in a dose dependent manner, but this increase did not reach statistical significance. The levels of MMP-9, TIMP-2, t-PA and u-PA appeared unaltered after irradiation. Irradiation of the glomerular epithelial cells altered the expression of genes associated with the extracellular matrix, implying that the glomerular epithelial cell may be involved in the development of radiation nephropathy.

  19. 加减抵当汤对胰岛素抵抗大鼠血浆t-PA PAI-1水平及脂肪PAI-1基因表达的影响%Effect of Modified Didang Decoction on t - PA, PAI - 1 and PAI - 1 Gene Express in Fat in Insulin Resistance Rats

    Institute of Scientific and Technical Information of China (English)

    钱俊文; 柴可夫; 沈祥峰

    2009-01-01

    目的:探讨加减抵当汤对IR大鼠血浆t-PA、PAI-1水平及脂肪PAI-1mRNA表达的影响.方法:造模大鼠随机分成正常组、模型组、加减抵当汤高、中、低剂量组、文迪雅组,用发色底物法检测t-PA、PAI-1水平;RT-PCR方法检测加减抵当汤对IR大鼠脂肪PAI-1 mRNA表达的影响.结果:加减抵当汤高、中剂量组能明显升高IR大鼠血浆t-PA水平,降低PAI-1水平(P<0.05和P<0.01),下调PAI-1mRNA的表达.结论:加减抵当汤能升高血浆t-PA,降低PAI-1;并能下调脂肪PAI-1mRNA的表达,可能是其改善IR的机理之一.

  20. Functional importance of PAI-1 glycosylation

    DEFF Research Database (Denmark)

    Christensen, Anni; Naessens, Dominik; Skottrup, Peter Durand

    Structure-function studies of plasminogen activator inhibitor-1 (PAI-1) have previously been performed mostly with non-glycosylated material expressed in E. coli. We have now studied the importance of PAI-1 glycosylation for its functional properties. PAI-1 has 3 potential sites for N-linked glyc...

  1. The Epigenetic Reader BRD2 as a Specific Modulator of PAI-1 Expression in Lipopolysaccharide-Stimulated Mouse Primary Astrocytes.

    Science.gov (United States)

    Choi, Chang Soon; Hong, Seong Hwi; Sim, Seobo; Cho, Kyu Suk; Kim, Ji-Woon; Yang, Sung Min; Jeon, Se Jin; You, Jueng Soo; Shin, Chan Young

    2015-11-01

    The post translational modification of lysine acetylation is a key mechanism that regulates chromatin structure. Epigenetic readers, such as the BET domains, are responsible for reading histone lysine acetylation which is a hallmark of open chromatin structure, further providing a scaffold that can be accessed by RNA polymerases as well as transcription factors. Recently, several reports have assessed and highlighted the roles of epigenetic readers in various cellular contexts. However, little is known about their role in the regulation of inflammatory genes, which is critical in exquisitely tuning inflammatory responses to a variety of immune stimuli. In this study, we investigated the role of epigenetic readers BRD2 and BRD4 in the lipopolysaccharide (LPS)-induced immune responses in mouse primary astrocytes. Inflammatory stimulation by LPS showed that the levels of Brd2 mRNA and protein were increased, while Brd4 mRNA levels did not change. Knocking down of Brd2 mRNA using specific small interfering RNA (siRNA) in cultured mouse primary astrocytes inhibited LPS-induced mRNA expression and secretion of plasminogen activator inhibitor-1 (PAI-1). However, no other pro-inflammatory cytokines, such as Il-6, Il-1β and Tnf-α, were affected. Indeed, treatment with bromodomain-containing protein inhibitor, JQ1, blocked Pai-1 mRNA expression through the inhibition of direct BRD2 protein-binding and active histone modification on Pai-1 promoter. Taken together, our data suggest that BRD2 is involved in the modulation of neuroinflammatory responses through PAI-1 and via the regulation of epigenetic reader BET protein, further providing a potential novel therapeutic strategy in neuroinflammatory diseases.

  2. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  3. Research on the expression of PAI-1 in C57BL/6 mice feeding high-fat diet and the effect of rosiglitazone treatment%高脂饮食C57BL/6小鼠PAI-1表达及罗格列酮干预效果研究

    Institute of Scientific and Technical Information of China (English)

    刘莉; 刘亚莉; 赵越; 杨军

    2011-01-01

    expression of PAI-1 mRNA of epididymal adipose tissues in all groups was all significantly higher than subcutaneous adipose tissues. RSG treatment could decrease the expression of PAI-1 mRNA in subcutaneous adipose tissues, but had no effect in epididymal adipose tissues. Conclusion; The level of serum PAI- 1 and the expression of PAI- 1 mRNA were different between visceral and subcutaneous adipose tissues in both normal and obese mice. RSC treatment contributed to the decrease of blood lipid, serum PAI- 1 level and the expression of PAI- 1 mRNA in subcutaneous adipose tissues.%目的:研究正常体重和肥胖C57BL/6小鼠血浆纤溶酶原激活物抑制物-1(PAI-1)水平、内脏和皮下脂肪组织mRNA的表达情况及罗格列酮(RSG)的干预效果.方法:雄性C57BL/6小鼠按体重随机分为对照组、高脂组和RSG组,分别喂饲不同饲料12周,测定血脂、血清PAI-1水平及附睾、皮下脂肪组织PAI-1mRNA的表达情况.结果:RSG组小鼠体重显著高于高脂组和对照组,RSG干预可降低总甘油三酯水平.高脂组血清PAI-1水平显著高于对照组,RSG干预可降低血清PAI-1水平.3组小鼠附睾脂肪组织PAI-1mRNA表达均显著高于皮下脂肪组织;RSG干预可显著降低皮下脂肪组织PAI-1表达,而对附睾脂肪组织却无明显影响.结论:正常体重与肥胖小鼠血清PAI-1水平及内脏、皮下脂肪组织PAI-1的表达均存在差异,RSG有助于改善血脂、降低血清PAI-1水平及皮下脂肪组织PAI-1 mRNA表达.

  4. The basic helix-loop-helix/leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth.

    Science.gov (United States)

    Qi, Li; Higgins, Craig E; Higgins, Stephen P; Law, Brian K; Simone, Tessa M; Higgins, Paul J

    2014-10-01

    Plasminogen activator inhibitor type-1 (PAI-1), a major regulator of the plasmin-dependent pericellular proteolytic cascade, is prominently expressed during the tissue response to injury although the factors that impact PAI-1 induction and their role in the repair process are unclear. Kinetic modeling using established biomarkers of cell cycle transit (c-MYC; cyclin D1; cyclin A) in synchronized human (HaCaT) keratinocytes, and previous cytometric assessments, indicated that PAI-1 transcription occurred early after serum-stimulation of quiescent (G0) cells and prior to G1 entry. It was established previously that differential residence of USF family members (USF1→USF2 switch) at the PE2 region E box (CACGTG) characterized the G0  → G1 transition period and the transcriptional status of the PAI-1 gene. A consensus PE2 E box motif (5'-CACGTG-3') at nucleotides -566 to -561 was required for USF/E box interactions and serum-dependent PAI-1 transcription. Site-directed CG → AT substitution at the two central nucleotides inhibited formation of USF/probe complexes and PAI-1 promoter-driven reporter expression. A dominant-negative USF (A-USF) construct or double-stranded PE2 "decoy" attenuated serum- and TGF-β1-stimulated PAI-1 synthesis. Tet-Off induction of an A-USF insert reduced both PAI-1 and PAI-2 transcripts while increasing the fraction of Ki-67(+) cells. Conversely, overexpression of USF2 or adenoviral-delivery of a PAI-1 vector inhibited HaCaT colony expansion indicating that the USF1 → USF2 transition and subsequent PAI-1 transcription are critical events in the epithelial go-or-grow response. Collectively, these data suggest that USF2, and its target gene PAI-1, regulate serum-stimulated keratinocyte growth, and likely the cadence of cell cycle progression in replicatively competent cells as part of the injury repair program.

  5. Effect of PAI-1 antisense RNA on vascular endothelial growth factor expression in aorta smooth muscle cells cultured in vitro%PAI-1反义RNA对人主动脉平滑肌细胞中 血管内皮生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    富路; 梅宇; 李晖

    2001-01-01

    Objective  To investigate the role of plasminogen activator inhibitor-1(PAI-1) antisense RNA in regulating the expression of PAI-1 and vascular endothelial growth factor(VEGF) in aorta smooth muscle cells cultured in vitro. Methods  The second extron of PAI-1 was amplified with polymerase chain reaction(PCR), the production was inserted into eukaryotic cell expression vector pcDNA3.1 after it had been purified and cloned so as to construct PAI-1 antisence RNA recombination plasmid. The recombination plasmid was transfected into SMC. PAI-1 expression was detected by immumohistochemistry, Western blod and ELISA; the effects of PAI-1 variation on VEGF was examined by immunofluorescence. Results  PAI-1 antigen was the lowest in cells on the third day after transfection; the expression of VEGF was also decreased. PAI-1 antigen gradually increased on the fifth day and VEGF increased correspondently. On the seventh day, PAI-1 antigen and VEGF increased to nearly normal level. Conclusion  PAI-1 antisense RNA can block the translation progress of PAI-1 proteins effectively and inhibit the expression of VEGF in aorta smooth muscle cells.%目的探讨纤溶酶原激活物抑制剂-1(plasminogen activatorinhibitor-1,PAI-1)反义RNA对离体培养的主动脉平滑肌细胞(smooth muscle cell,SMC)PAI-1表达的作用及对血管内皮生长因子(vascular endothelial growth factor,VEGF)表达的影响。方法PCR扩增PAI-1第2外显子,将PCR产物纯化克隆后连入真核细胞表达载体pcDNA3.1,构建PAI-1反义RNA重组质粒。将pcDNA3.1-反义PAI-1重组质粒转染SMC中。通过免疫组化、Western印迹、ELISA检测细胞中PAI-1表达的改变;通过免疫荧光技术观察细胞中PAI-1表达量的变化对VEGF的影响。结果转染后第3天,细胞中PAI-1含量最低,VEGF的表达也减少。第5天,PAI-1含量逐渐升高,VEGF也相应增加。第7天,PAI-1含量接近于正常,VEGF也增至正常水平。结论反义PAI-1RNA能有效阻断SMC中PAI

  6. Functional importance of PAI-1 glycosylation

    DEFF Research Database (Denmark)

    Christensen, Anni; Naessens, Dominik; Skottrup, Peter

    2001-01-01

    Structure-function studies of plasminogen activator inhibitor-1 (PAI-1) have previously been performed mostly with non-glycosylated material expressed in E. coli. We have now studied the importance of PAI-1 glycosylation for its functional properties. PAI-1 has 3 potential sites for N......-linked glycosylation. Biochemical analysis of PAI-1 variants with substitutions of the Asn residues in each of these sites and expression in human embryonic kidney 293 (HEK293) cells showed that only Asn211 and Asn 267, but not Asn331 are glycosylated, and revealed a differential composition of the carbohydrate...... attached at the 2 sites. Analysing the susceptibility of glycosylated and non-glycosylated PAI-1 to activity neutralisation by monoclonal antibodies, we found that the IC50-values for neutralisation by some monoclonal antibodies differed strongly between glycosylated and non-glycosylated PAI-1. The most...

  7. PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma.

    Science.gov (United States)

    Hirahata, Mio; Osaki, Mitsuhiko; Kanda, Yusuke; Sugimoto, Yui; Yoshioka, Yusuke; Kosaka, Nobuyoshi; Takeshita, Fumitaka; Fujiwara, Tomohiro; Kawai, Akira; Ito, Hisao; Ochiya, Takahiro; Okada, Futoshi

    2016-05-01

    Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  8. PULMONARY LOCALIZATION AND EXPRESSION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) IN HEALTHY OR HYPERTENSIVE RATS EXPOSED TO PARTICULATE MATTER (PM)

    Science.gov (United States)

    PULMONARY LOCALIZATION AND EXPRESSION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) IN HEALTHY OR HYPERTENSIVE RATS EXPOSED TO PARTICULATE MATTER (PM). GS Backus1, R Vincent2, UP Kodavanti2, 1Curriculum in Toxicology, UNC, Chapel Hill; 2NHEERL, ORD, US EPA, Research Triangle Park,...

  9. Significances of PAI - 1 and TGF - β1 expressions in cervical squamous cell carcinoma and their relationships with HPV16 infection%宫颈鳞状细胞癌PAI-1、TGF-β1表达意义及与HPV16感染关系

    Institute of Scientific and Technical Information of China (English)

    史永华; 卿松; 拉莱·苏祖克

    2012-01-01

    Objective: To explore the significances of plasminogen activator inhibitor -1 ( PAI -1) and transforming growth factor - (31 (TGF - pi ) expressions in cervical squamous cell carcinoma and their relationships with human papillomavims ( HPV) 16 infection. Methods; Immunohistochemical method was used to detect the expression levels of PAI -1 and TGF - pi in 63 cases of cervical squamous cell carcinoma and 15 cases of normal cervix. In situ hybridization technique was used to detect HPV 16 DNA. Results; The positive rates of HPV 16, PAI -1, and TGF - pi in cervical squamous cell carcinoma were 46.03% , 68. 25% , and 55.56% , respectively. The positive rates of HPV 16, PAI -1, and TGF - pi in normal cervix were 6.67% , 0.00% , and 13. 33% , respectively. There was significant difference in the positive rates of HPV 16, PAI - 1, and TGF - pi between the two groups (P 0.05 ) . TGF - pi expression was correlated with PAI - 1 expression (P < 0.05 ) . Conclusion; The positive expressions of PAI -1 and TGF - pi in cervical squamous cell carcinoma may be correlated with the occurrence and development of cervical squamous cell carcinoma, which can promote its invasion and metastasis, there is no correlation between their expressions and HPV 16 infection.%目的:探讨宫颈鳞状细胞癌中PAI -1、TGF -β1表达意义及其与HPV16感染的关系.方法:免疫组化检测PAI -1、TGF -β1在63例宫颈鳞状细胞癌、15例正常宫颈中的表达,HPV16 DNA的检测应用原位杂交法.结果:HPV16、PAI -1、TGF -β1在宫颈鳞状细胞癌中的阳性率分别为46.03%、68.25%、55.56%;HPV16、PAI -1、TGF -β1在正常宫颈中的阳性率分别为6.67%、0.00%、13.33%.HPV16、PAI -1、TGF -β1在两组间的表达差异有统计学意义(P<0.05).PAI -1、TGF -β1在子宫颈癌HPV阳性和阴性组表达差异无统计学意义(P>0.05),TGF -β1表达与PAI -1有关(P<0.05).结论:宫颈鳞状细胞癌中PAI -1、TGF - β1的阳性表达可能与

  10. 脂肪细胞分化过程中影响PAI-1基因转录表达的Dex和C/EBPs顺式调控元件的分析%Analysis of a Novel Dexamethasone Response Element and a Putative C/EBPs cis-Motif: Controlling PAI-1 Gene Expression During Adipocyte Differentiation

    Institute of Scientific and Technical Information of China (English)

    陈可洋; 马春姑; 汤其群; 宋后燕

    2002-01-01

    在研究胰岛素(Ins)、地塞米松(Dex)和甲基异丁基黄嘌呤(Mix)对脂肪细胞分化过程中PAI-1基因表达的影响基础上,为进一步探讨Ins、Dex调控PAI-1基因转录表达的调控机制,应用DNA重组技术,构建含萤光素酶(luciferase)报告基因和PAI-1启动子不同长度片段的嵌合质粒,转染3T3-L1前脂肪细胞并测定报告基因荧光素酶的活性.结果表明,小鼠PAI-1基因起动子-690至-850碱基序列之间有一个Dex的正调控元件.用计算机软件进行分析发现:Dex顺式元件位于PAI-1启动子的-750至-770碱基序列.其组成为:5′ GGTAACCTCTGTTCTCAT 3′.同时还发现在PAI-1启动子的-720至-740碱基序列中,存在一个C/EBPs的结合元件5′CCAAT3′并用凝胶电泳迁移实验对这些元件进行了鉴定.表明Dex正是通过激活转录因子(糖皮质激素受体,GR)和C/EBPα一起与各自的顺式元件结合来促进PAI-1基因的表达.%It has been reported that there is a significant increase in PAI-1 expression level in obese subjects. To explore the linkage between PAI-1 gene expression and obesity, the restriction enzymes and DNA recombination technologies were used to construct the chimeric plasmids with luciferase and different lengths of PAI-1 promoter. After transfection of the chimeric plasmids into 3T3-L1 preadipocyte and detection of luciferase activity, the results indicated that a positive dexamethasone cis-acting element (bases -690 to -850) may be present in mouse PAI-1 promoter. In addition, computer analysis using Match-Search Software found that a new motif of DexRE (dexamethasone response element) 5′ GGTAACCTCTGTTCTCAT 3′ and a putative C/EBPs binding site (cis-motif) exist respectively in the fragment (nucleotides -751 to -770) of, and a sequence (bases -720 to -740) of, mouse PAI-1 promoter,and GMSA and competition assays identified that the trans-acting factors induced by dexamethasone can specifically bind to those cis-motifs. Meanwhile

  11. THE CONSTRUCTION OF uPA AND PAI-1 EUKARYOTIC EXPRESSIVE VECTOR%uPA和PAI-1基因克隆及真核表达载体的构建及鉴定

    Institute of Scientific and Technical Information of China (English)

    覃捷; 李力; 张洁清; 张纬; 黎丹戎

    2009-01-01

    目的:克隆人卵巢上皮癌组织uPA和PAI-1基因cDNA全长,构建表达uPA和PAI-1基因的真核表达载体.方法:采用RT-PCR技术从人卵巢上皮癌组织总RNA中逆转录uPA和PAI-1基因的cDNA全长,克隆到pGEM-T Easy Vector上,通过酶切和测序进行鉴定;酶切后与真核表达载体pcDNA3.1/myc-his(-)B连接,酶切及测序再次鉴定;采用脂质体法将重组质粒DNA转染至卵巢癌上皮细胞SKOV3细胞;采用有限稀释法和G418分别加压筛选并培养SKOV3-uPA和SKOV3-PAI-1细胞及对照细胞;Western blot 法检测转染前后SKOV3细胞uPA和PAI-1基因的表达.结果:成功扩增出uPA和PAI-1基因的cDNA的全长,并克隆入T载体,DNA测序证实序列正确,通过连接成功构建含正确目的基因的表达载体pcDNA3.1-uPA和pcDNA3.1-PAI-1,Western blot 能检测到uPA和PAI-1基因蛋白分别在SKOV3-uPA和SKOV3-PAI-1细胞中的表达.结论:成功构建了uPA和PAI-1表达基因的真核表达载体,为进一步研究uPA和PAI-1基因在卵巢癌侵袭转移中的作用提供了实验基础.

  12. 高脂饮食小鼠脂肪组织中PAI-1、FOXC2及FOXO1表达的研究%Study of expression of PAI-1, FOXC2 and FOXO1 in adipose tissue of mice with high fat diet

    Institute of Scientific and Technical Information of China (English)

    刘亚莉; 易佳丽; 刘剑辉; 牛丽凤

    2014-01-01

    Objective To study the expression level of PAI-1, FOXC2 and FOXO1 in high fat diet of visceral fat and subcutaneous fat tissue,and to investigate the mechanism of different types of obesity.Methods 20 mouse were randomLy divided into control group and high fat group, and given normal diet and high fat diet for 12 weeks. Serum PAI-1,the expression level of PAI-1, FOXC2 and FOXO1 mRNA in epididymal tissue and subcutaneous fat were determined. Results The body weight, serum PAI-1 levels of high fat group were significantly higher than those of the control group. Within the group, PAI-1,FOXC2, mRNA expression of mouse epididymal adipose tissue were significantly higher than those of the subcutaneous adipose tissue, and the expression of FOXO1mRNA of mouse epididymal adipose tissue was significantly lower than that of subcutaneous adipose tissue, with statistical significance difference. Conclusion Expression levels of serum PAI-1 are different between normal weight mice and obese mice,and expression of fat PAI-1, FOXC2and FOXO1 in visceral fat and subcutaneous are also different. This difference may be one of the mechanisms of different types of obesity.%目的:研究高脂饮食喂养小鼠内脏脂肪和皮下脂肪组织中PAI-1、FOXC2及FOXO1表达水平,探讨不同类型肥胖的机制。方法20只小鼠随机分为对照组和高脂组,分别给予正常饮食和高脂饮食喂养12周。测定血清PAI-1以及附睾周围组织及皮下脂肪中PAI-1、FOXC2及FOXO1 mRNA的表达水平。结果高脂组小鼠体质量、血清PAI-1水平均显著高于对照组。组内比较小鼠附睾周围脂肪组织PAI-1、FOXC2mRNA表达显著高于皮下脂肪组织;FOXO1mRNA表达显著低于于皮下脂肪组织,差异有统计学意义。结论正常体重小鼠和肥胖小鼠血清PAI-1水平表达不同,内脏脂肪和皮下脂肪PAI-1、FOXC2及FOXO1表达也存在差别,这种差别可能是不同类型肥胖的机制之一。

  13. Potential clinical relevance of uPA and PAI-1 levels in node-negative, postmenopausal breast cancer patients bearing histological grade II tumors with ER/PR expression, during an early follow-up.

    Science.gov (United States)

    Buta, Marko; Džodić, Radan; Đurišić, Igor; Marković, Ivan; Vujasinović, Tijana; Markićević, Milan; Nikolić-Vukosavljević, Dragica

    2015-09-01

    We evaluated urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) prognostic value in postmenopausal, node-negative breast cancer patients bearing tumors with estrogen receptor (ER)/progesterone receptor (PR) expression, treated with locoregional therapy alone, within an early follow-up. We focused our analysis on tumors of histological grade II in order to improve its prognostic value and, consequently, to improve a decision-making process. The cytosol extracts of 73 tumor samples were used for assessing several biomarkers. ER and PR levels were measured by classical biochemical method. Cathepsin D was assayed by a radiometric immunoassay while both uPA and PAI-1 level determinations were performed by enzyme-linked immunosorbent assays. HER-2 gene amplification was determined by chromogenic in situ hybridization (CISH) in primary tumor tissue. Patients bearing tumors smaller than or equal to 2 cm (pT1) or those with low PAI-1 levels (PAI-1PAI-1 levels, respectively. Analyses of 4 phenotypes, defined by tumor size and PAI-1 status, revealed that patients bearing either pT1 tumors, irrespective of PAI-1 levels, or pT2,3 tumors with low PAI-1 levels, had similar disease-free interval probabilities and showed favorable outcome compared to those bearing pT2,3 tumors with high PAI-1 levels. Our findings suggest that tumor size and PAI-1, used in combination as phenotypes are not only prognostic but might also be predictive in node-negative, postmenopausal breast cancer patients bearing histological grade II tumors with ER/PR expression, during an early follow-up period.

  14. Determination of expression of PAI-1 in sera of patients with breast cancer by antibody microarray%抗体芯片技术检测乳腺癌患者血清中PAI-1的表达

    Institute of Scientific and Technical Information of China (English)

    宋燕; 刘雪凯; 张青云

    2014-01-01

    目的 采用抗体芯片技术检测乳腺癌患者血清中纤溶酶原激活物抑制因子-1(plasminogen activator inhibitor,PAI-1)的表达.方法 制备鼠抗人PAI-1单抗腹水及多抗,经ProteinA-Sepharose-4B柱纯化后,点至醛基玻片上(点样浓度均分别为1和0.1 mg/ml),制备抗体芯片,加入待测血清(分别进行1∶2、1∶10、1∶100稀释),利用晶芯Luxscan 10K-A芯片扫描仪扫描,芯片图象分析软件晶芯SpotData Pro分析后,获得最适点样浓度和血清稀释倍数.采用优化后的抗体芯片法检测202份乳腺癌患者和204份健康体检者血清样本中PAI-1的表达.结果 确定点样单抗最适浓度为1 mg/ml,血清最适稀释倍数为1∶100.PAI-1在204份健康体检者血清样本中阳性率为4.4%(9/204),在202份乳腺癌患者血清中的总体阳性率为25.2%,特异性为96%;其中119份发生转移和83份未发生转移的乳腺癌患者血清中PAI-1阳性率分别为35.3%(42/119)和10.8%(9 /83),阳性率随肿瘤的分期进展而升高.结论 PAI-1在乳腺癌患者血清中的表达明显高于健康体检者,且随着肿瘤的分期进展阳性率升高,其有望成为新的乳腺癌血清筛查指标.

  15. Expression and clinical significance of DLC1 and PAI-1 protein in ovarian carcinoma%DLC-1和FAI-1蛋白在卵巢癌组织中的表达及其临床意义

    Institute of Scientific and Technical Information of China (English)

    任芳; 史惠蓉; 张瑞涛; 贾艳艳; 冯巍

    2013-01-01

    目的 研究肝癌缺失基因-1(DLC1)和Ⅰ型纤溶酶原激活剂抑制剂(PAI-1)在卵巢上皮性癌组织中的表达情况,探讨DLC1和PAI-1在卵巢癌组织发生发展中的作用.方法 采用免疫组织化学染色法分别检测正常卵巢和卵巢上皮性癌组织中DLC1和PAI-1的蛋白的表达.结果 ①卵巢上皮性癌组织中DLC-1蛋白表达低于正常卵巢组织(P<0.05);DLC1蛋白的低表达与卵巢癌的临床分期、腹水形成和淋巴结转移相关(P<0.05).②卵巢上皮性癌组织中PAI-1蛋白表达高于正常卵巢组织(P <0.05);PAI-1蛋白的高表达与卵巢癌的临床分期、分化程度和淋巴结转移相关(P<0.05).③卵巢癌组织中DLC1与PAI-1的蛋白表达之间呈负相关(rp=-0.256,P=0.027).结论 DLC1低表达或表达缺失和PAI-1的高表达可能与卵巢上皮性癌的发生、发展有关.DLC1和PAI-1的联合检测有助于判断卵巢癌的恶性程度.%Objective To investigate the expression levels of deleted in liver cancer (DLC-1) gene and plasminogen activator inhibitor (PAI-1) gene in epithelial ovarian cancer and the effect of DLC-1 on the occurrence and development of epithelial ovarian cancer.Methods Immunohistochemical staining was used to examine the expression of DLC1 and PAI-1 protein in 25 cases of normal ovarian tissues,52 cases of serous cystadenocarcinoma tissues and 23 cases of mucinous cystadenocarcinoma tissues.Results DLC1 and PAI-1 protein were detected mainly located in the cytoplasm,which was found in ovarian carcinoma and normal ovarian tissues.The expression of DLC1 protein in ovarian carcinoma tissues was significantly lower than that in normal ovarian tissues,whereas it was converse for the expression of PAI-1 protein.The expression of DLC1 and PAI-1 protein were significantly correlated with clinical stage and lymphnode metastasis.The expression of DLC1 was negatively correlated with the expression of PAI-1 protein.Conclusions The expression of DLC1

  16. 益气化痰祛瘀方对冠心病模型大鼠PAI-1、t-PA表达的影响%Effects of Prescription Yiqi Huatan Quyu on the PAI-1,t-PA expression of coronary heart disease rats

    Institute of Scientific and Technical Information of China (English)

    张文立; 赵淑明; 李昌; 高玮; 韩雪; 张一昕

    2011-01-01

    目的 观察益气化痰祛瘀方对冠心病大鼠心肌及主动脉组织PAI-1、t-PA表达的影响及作用机制.方法 采用高脂饲料、脑垂体后叶素腹腔注射建立大鼠冠心病模型,分为正常组、模型组、复方丹参滴丸对照组、益气化痰祛瘀方高、低剂量组,采用免疫组化法检测大鼠心肌和主动脉组织PAI-1、t-PA的表达.结果 模型组大鼠心肌和主动脉组织PAI-1表达增强,t-PA表达减弱(P<0.01);给药后各用药组PAI-1的表达减弱,t-PA的表达增强(P<0.01);高、低剂量组均优于对照组(P<0.05或P<0.01),高、低剂量组间无明显差异(P>0.05).结论 益气化痰祛瘀方可通过调节心肌和主动脉组织PAI-1、t-PA的表达,以达到治疗冠心病的目的.%Objective To observe the effects of Prescription Yiqi Huatan Quyn on the PAI-1 and t-PA expression in the myocardial and aortic organization of the CHD rats and explore the possible mechanism of prescription Yiqi Huatan Quyu in the therapy of CHD. Methods The model of CHD rats was established by feeding high fat forage and injecting pituitrin in the abdominal cavity. Then these rats were divided into normal control, model control, compound danshen drop pill(control) ,high dose,low dose groups. Then the PAI-1 and t-PA expression in the myocardial and aortic organization of the all groups laboratory rats were measured by immunohistochemistry method. Results The PAI-1 expression in the myocardial and aortic organization of the model group were increased (P < 0. 01 ). The t-PA expression in the myocardial and aortic organization of the model group were reduced ( P <0. 01 ). The PAI-1 expression reduced ( P <0. 01 ) and the t-PA expression increased (P <0. 01 ) of each treatment group. The high dose group and low dose group were more better than those of compound danshen drop pill control group( P <0. 05 or P <0. 01 ). But it had no obvious difference between high and low dose group ( P > 0. 05

  17. Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems.

    Science.gov (United States)

    Chau, Cindy H; Clavijo, Carlos A; Deng, Hong-Tao; Zhang, Qunzhou; Kim, Kwang-Jin; Qiu, Yun; Le, Anh D; Ann, David K

    2005-08-01

    We recently showed that Etk/Bmx, a member of the Tec family of nonreceptor protein tyrosine kinases, promotes tight junction formation during chronic hypoxic exposure and augments normoxic VEGF expression via a feedforward mechanism. Here we further characterized Etk's role in potentiating hypoxia-induced gene expression in salivary epithelial Pa-4 cells. Using transient transfection in conditionally activated Etk (DeltaEtk:ER) cells, we demonstrated that Etk enhances hypoxia-response element-dependent reporter activation in normoxia and hypoxia. This Etk-driven reporter activation is ameliorated by treatment with wortmannin or LFM-A13. Using lentivirus-mediated gene delivery and small interfering RNA, we provided direct evidence that hypoxia leads to transient Etk and Akt activation and hypoxia-mediated Akt activation is Etk dependent. Northern blot analyses confirmed that Etk activation led to induction of steady-state mRNA levels of endogenous VEGF and plasminogen activator inhibitor (PAI)-1, a hallmark of hypoxia-mediated gene regulation. We also demonstrated that Etk utilizes a phosphatidylinositol 3-kinase/Akt pathway to promote reporter activation driven by NF-kappaB, another oxygen-sensitive transcription factor, and to augment cytokine-induced inducible nitric oxide synthase expression in endothelial cells. To establish the clinical relevance of Etk-induced, hypoxia-mediated gene regulation, we examined Etk expression in keloid, which has elevated VEGF and PAI-1. We found that Etk is overexpressed in keloid (but not normal skin) tissues. The differential steady-state Etk protein levels were further confirmed in primary fibroblast cultures derived from these tissues, suggesting an Etk role in tissue fibrosis. Our results provide further understanding of Etk function within multiple signaling cascades to govern adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal

  18. Peroxisome proliferator-activated receptor-α-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease.

    Science.gov (United States)

    Gonsalves, Caryn S; Li, Chen; Malik, Punam; Tahara, Stanley M; Kalra, Vijay K

    2015-10-12

    Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1. Herein, we show PlGF treatment of endothelial cells reduced levels of miR-301a and miR-454 from basal levels. In addition, both miRNAs targeted the 3'-UTRs of ET-1 and PAI-1 mRNAs. These results were corroborated in the mouse model of SCD [Berkeley sickle mice (BK-SS)] and in SCD subjects. Plasma levels of miR-454 in SCD subjects were significantly lower compared with unaffected controls, which correlated with higher plasma levels of both ET-1 and PAI-1. Moreover, lung tissues from BK-SS mice showed significantly reduced levels of pre-miR-301a and concomitantly higher levels of ET-1 and PAI-1. Furthermore, we show that miR-301a/miR-454 located in the spindle and kinetochore-associated protein-2 (SKA2) transcription unit was co-transcriptionally regulated by both HIF-1α and peroxisome proliferator-activated receptor-α (PPAR-α) as demonstrated by SKA2 promoter mutational analysis and ChIP. Finally we show that fenofibrate, a PPAR-α agonist, increased the expression of miR-301a/miR-454 and SKA2 in human microvascular endothelial cell line (HMEC) cells; the former were responsible for reduced expression of ET-1 and PAI-1. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-301a/miR-454 expression can ameliorate PH and lung fibrosis by reduction in ET-1 and PAI-1 levels in SCD.

  19. On the role of c-Jun in the induction of PAI-1 gene expression by phorbol ester, serum, and IL-1α in HepG2 cells

    NARCIS (Netherlands)

    Arts, J.; Grimbergen, J.; Toet, K.; Kooistra, T.

    1999-01-01

    We have characterized the regulation of plasminogen activator inhibitor- 1 (PAI-1) gene expression by phorbol 12-myristate 13-acetate (PMA), serum, and interleukin-1α (IL-1α) in the human hepatoma cell line HepG2. PMA, serum, and IL-1α induced a rapid and transient 28-fold (PMA), 9-fold (serum), and

  20. The effect of local sustained delivery of sirolimus on the vascular PAI-1 and t-PA expression after angioplasty%西罗莫司局部缓释对成形术后血管壁PAI-1及t-PA表达的影响

    Institute of Scientific and Technical Information of China (English)

    鄂亚军; 贺能树; 范海伦

    2011-01-01

    Objective To investigate the effect of local sustained delivery of sirolimus on the vascular inhibitor of plasminogen activator-1 (PAI-1) and tissue type plasminogen activator (t-PA) expression after angioplasty. Methods Experimental common carotid artery injury model was established in the rats. A total of 30 male Wistar rats were divided into experimental group (n = 20) and control group (n = 10). Adventitial administration of drug was applied. Pluronic F-127 gel containing sirolimus was administered to the exposed adventitial surface of injured carotid artery. The experimental group was divided into high concentration (600 μg/100 μl)sub-group and low concentration (300 |μg/100 μl)sub-group according to the concentration of sirolimus delivered. The effect of local sustained delivery of sirolimus on vascular PAI-1 and t-PA expression after percutaneous angioplasty was evaluated by immunohistochemistry. Results Compared to control group, 15 and 30 days after injury local sustained delivery of sirolimus in both high concentration and low concentration sub-groups the expression of the PAI-1 in neointima was significantly enhanced (P 0.05). At 15 and 30 days after injury, the expression of t-PA in neointima was decreased in both high and low concentration sub-groups (P< 0.05), and the expression of t-PA in media was significantly decreased in high concentration sub-group (P < 0.05) while on significant difference could be detected in low concentration sub-group. Conclusion Local sustained delivery of sirolimus can induce the high expression of PAI-1 and low expression of t-PA in neointima although it inhibits the proliferation of neointima in the same time, and the imbalanced expression of t-PA and PAI-1 may probably play an important role in the late formation of thrombosis after the placement of drug-eluting stent.%目的 探讨西罗莫司局部缓释对成形术后血管壁纤溶酶原激活物抑制剂1(PAI-1)及组织型纤溶酶原激活

  1. Plasminogen activator inhibitor (PAI)-1 suppresses inhibition of gastric emptying by cholecystokinin (CCK) in mice.

    Science.gov (United States)

    Gamble, Joanne; Kenny, Susan; Dockray, Graham J

    2013-08-10

    The intestinal hormone cholecystokinin (CCK) delays gastric emptying and inhibits food intake by actions on vagal afferent neurons. Recent studies suggest plasminogen activator inhibitor (PAI)-1 suppresses the effect of CCK on food intake. In this study we asked whether PAI-1 also modulated CCK effects on gastric emptying. Five minute gastric emptying of liquid test meals was studied in conscious wild type mice (C57BL/6) and in transgenic mice over-expressing PAI-1 in gastric parietal cells (PAI-1H/Kβ mice), or null for PAI-1. The effects of exogenous PAI-1 and CCK8s on gastric emptying were studied after ip administration. Intragastric peptone delayed gastric emptying in C57BL/6 mice by a mechanism sensitive to the CCK-1 receptor antagonist lorglumide. Peptone did not delay gastric emptying in PAI-1-H/Kβ mice. Exogenous CCK delayed gastric emptying of a control test meal in C57BL/6 mice and this was attenuated by administration of PAI-1; exogenous CCK had no effect on emptying in PAI-1-H/Kβ mice. Prior administration of gastrin to increase gastric PAI-1 inhibited CCK-dependent effects on gastric emptying in C57BL/6 mice but not in PAI-1 null mice. Thus, both endogenous and exogenous PAI-1 inhibit the effects of CCK (whether exogenous or endogenous) on gastric emptying. The data are compatible with emerging evidence that gastric PAI-1 modulates vagal effects of CCK.

  2. 螺内酯对2型糖尿病大鼠血管PAI-1mRNA表达的影响%Influence of Spironolactone on the Expression of PAI-1 mRNA in Aorta of Rats with Type 2 Diabetes Mellitus

    Institute of Scientific and Technical Information of China (English)

    李秀成; 韩刚; 孙侃; 常向云; 李军

    2013-01-01

    [目的]探讨非选择性醛固酮(aldsterone,ALD)受体拮抗剂-螺内酯(Spironolactone,SPI)对2型糖尿病(type 2 diabetic mellitus,T2DM)大鼠血管纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)mRNA的表达的影响.[方法] 高脂高糖喂养加小剂量链脲佐菌素(streptozotocin,STZ)腹腔注射法建立2型糖尿病大鼠模型,将成膜的T2DM大鼠随机分为糖尿病对照组(DM-C组)和SPI干预组(DM-S组),继续高脂高糖喂养,正常对照组(NC组)大鼠继续给予普通饲料喂养,其中DM-S组每天给予SPI 40 mg/(kg·d)灌胃,NC组和DM-C组每天等量蒸馏水灌胃.每2周监测大鼠体重和血糖水平,第16周末处死大鼠,收集血液标本,检测空腹血糖(FBG)、糖化血红蛋白(HbA1c﹪)、甘油三酯(TG)、胆固醇(TG)、血钾(K+).用RT-PCR法检测各组大鼠胸主动脉PAI-1 mRNA表达.[结果]DM-C组和DM-S组大鼠FBG、HbA1c﹪、TG均显著高于NC组(P<0.01),而DM-S组和DM-C组比较差异无统计学意义(P>0.05);三组之间的血K+水平比较差异无统计学意义(P>0.05);DM-C组和DM-S组大鼠胸主动脉PAI-1 mRNA的表达显著高于NC组(P<0.01),且DM-C组高于DM-S组(P<0.05).[结论] SPI能通过下调T2DM大鼠主动脉PAI-1mRNA的表达而发挥血管保护作用.%[Objective]To explore the influence of nonselective aldosterone(ALD) receptor antagonist-spirono-lactone(SPI) on the expression of type-1 plasminogen activator inhibitor(PAI-l) mRNA in rats with type 2 diabetes mellitus(T2DM). [Methods] The model of T2DM rats was established by being fed with high-sucrose-high-fat diet and intraperitoneally injected with low dose streptozotocin(STZ). Rat models of T2DM were randomly divided into diabetes mellitus control group (group DM-C) and SPI intervention group (group DM-S). Each rat in group DM-C and DM-S was continuously fed with high-sucrose-high-fat diet. Rats in normal control group (group NO were fed with routine animal feeds. Group DM-S was

  3. The prevalence of PAI-1 4G/5G gene variant in Serbian population

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available Introduction: Plasminogen activator inhibitor 1 (PAI-1 has a major role in inhibition of firinolysis and normal haemostasis. The presence of the PAI-1 4G/4G genotype leads to increased expression of PAI-1. High blood level of PAI-1 is associated with many diseases such as thrombosis, cerebral insult, myocardial infarction, pregnancy loss, preeclampsia, insulin resistance, type 2 diabetes, breast cancer and asthma. In this study, the prevalence of PAI-1 4G/5G gene variant was determined in healthy subjects from Serbian population. Methods: The study was carried out in a group of 210 healthy subjects (105 women and 105 men. The presence of PAI-1 4G/5G gene variant was detected by PCR-RFLP analysis. Results: The prevalence of PAI-1 4G/4G genotype was 34.76% and it was increased compared to PAI-1 5G/5G genotype (19.05%. The most frequent was PAI-1 4G/5G genotype (46.19%. Allelic frequency for 4G allele was higher (0.58 compared to 5G allele (0.42. Conclusions: The prevalence of PAI-1 4G/5G gene variant in Serbian population is similar to the neighboring populations. Results of this study represent the first data for Serbian population. This study could be useful for further research where the role of PAI-1 4G/5G gene variant will be assessed in the pathogenesis of many diseases.

  4. Effects of Hirudo on the Expression of Plasminogen Activator Inhibitor-1 in Rats with Pulmonary Fibrosis%水蛭对肺纤维化大鼠PAI-1的影响

    Institute of Scientific and Technical Information of China (English)

    李晓娟; 张骞云; 蔡志刚; 崔卫正; 石玉珍

    2012-01-01

    Objective; To investigate the effects of hirudo on the expression of plasminogen activator inhibitor -1 (PAI-1) in rats with pulmonary fibrosis, and to explore the mechanisms. Methods; The pulmonary fibrosis rat model was established by intratracheal instillation of bleomycin. Model rats were divided into bleomycin group (group MD) and hirudo group (group HD) with 8 rats in each group, and control group (group NC) composed of 8 healthy rats was set up. The rats of group MD were given normal saline 6 ml/d by gavage. The rats of group HD were given hirudo power 4g/( kg o d) by ga-vage. Plasma PAI-1 level and its activity were detected by ELISA, and hydroxyproline (HYP) contents of lung tissues were detected. Results; The PAI-1 level and its activity in group NC were significantly lower than those in the other two groups (P<0. 01). The PAI-1 level and its activity in group MD were higher than those in group HD (P < 0. 01). The HYP content in group NC and group HD were lower than that in MD group (P < 0. 01). Conclusions; Hirudo can protect the lung tissue of rats with bleomycin-induced pulmonary fibrosis by decreasing thrombin expression in the lungs, inhibiting PAI-1 generation and its activity, increasing urokinase plasminogen activator(uPA) activity and reducing the fibrous protein deposition.Objective: To observe the effect of fluoride on the expressions of Twist mRNA and protein in bone tissue of rats, and to explore the role of Twist in pathogenesis of skeletal fluorosis. Methods; Thirty-six SD rats were randomly divided into 3 groups with 12 rats in each and half male half female. Controls were fed with tap water, rats of low fluoride and high fluoride groups were fed with water containing fluoride 5 mg/L and 50 mg/L respectively to establish fluorosis models. Rats were sacrificed in 6 months by femoral artery exsanguination. Urinary fluoride and bone fluoride contents of rats were detected by fluoride ion-selective electrode method. HE staining was used to

  5. Design and screening of antisense oligodeoxynucleotides against PAI-1 mRNA in endothelial cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Qi-sheng JIANG; Sheng-qi WANG

    2006-01-01

    Aim: To design and screen antisense oligodeoxynucleotides (ASODNs), which inhibit type-1 plasminogen activator inhibitor (PAI-1) expression in human umbilical vein endothelial cells (HUVEC) in vitro. Methods: Twenty seven ASODNs against different sites of PAI-1 mRNA were designed and transfected to HUVEC by lipofectin in vitro. The effects of ASODNs on PAI-1 antigen, PAI-1 activity and PAI-1 mRNA expression were detected by ELISA, amidolytical assay and RT-PCR, respectively. Results: Transforming growth factor β1 (TGF-β1)-treated HUVEC increased the expression of PAI-1 compared with the normal HUVEC. Five among twenty seven designed ASODNs were effective in inhibiting the increase in PAI-1 antigen and PAI-1 activity in a dose-dependent manner after 48-h transfection. In particular, ASODN 14 (AO14) exhibited the best inhibitory effect. The control sequences of AO14, including sense, scramble, and mismatch sequences, did not significantly inhibit PAI-1 activity. It was revealed that the inhibitory efficacy of AO14 was in a sequence-specific manner. RT-PCR showed that ASODN 1, 7, 8, 14, and 15 decreased PAI-1 mRNA expression induced by TGF-β1 and AO14 showed the best inhibitory effect. Conclusion: ASODN 1,7,8, 14, and 15, among twenty seven designed ASODNs against PAI-1 mRNA, significantly decreased PAI-1 antigen and PAI-1 activity induced by TGF-β1 in a dosedependent manner in HUVEC in vitro. AO14 showed the best inhibitory effect on PAI-1 expression in a sequence-specific manner. The results of RT-PCR indicated that inhibitory effects of ASODNs on PAI-1 biosynthesis occurred at the mRNA level. Four among five effective target sites of ASODNs located at the translation initiation site or within the translation area of PAI-1 mRNA, suggesting that these sites may be promising sites for the design of effective ASODNs.

  6. Functional importance of PAI-1 glycosylation

    DEFF Research Database (Denmark)

    Christensen, Anni; Naessens, Dominik; Skottrup, Peter

    -helix F, respectively. We hypothesise that the carbohydrate moieties affect antibody neutralisation by affecting the movements of b-sheet C and thereby those of the reactive centre loop. Our results indicate that non-glycosylated PAI-1 may not be suited for studying the mechanism of action of PAI-1...

  7. Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury.

    Science.gov (United States)

    Simone, Tessa M; Longmate, Whitney M; Law, Brian K; Higgins, Paul J

    2015-06-01

    Objective: Aberrant plasminogen activator inhibitor-1 (PAI-1) expression and activity have been implicated in bleeding disorders, multiorgan fibrosis, and wound healing anomalies. This study details the physiological consequences of targeted PAI-1 functional inhibition on cutaneous injury repair. Approach: Dorsal skin wounds from FVB/NJ mice, created with a 4 mm biopsy punch, were treated topically with the small-molecule PAI-1 antagonist tiplaxtinin (or vehicle control) for 5 days and then analyzed for markers of wound repair. Results: Compared to controls, tiplaxtinin-treated wounds displayed dramatic decreases in wound closure and re-epithelialization. PAI-1 immunoreactivity was evident at the migratory front in all injury sites indicating these effects were due to PAI-1 functional blockade and not PAI-1 expression changes. Stimulated HaCaT keratinocyte migration in response to recombinant PAI-1 in vitro was similarly attenuated by tiplaxtinin. While tiplaxtinin had no effect on keratinocyte proliferation, cell cycle progression, or apoptosis, it effectively reduced collagen deposition, the number of Ki-67(+) fibroblasts, and incidence of differentiated myofibroblasts (i.e., smooth muscle α-actin immunoreactive cells), but not fibroblast apoptosis. Innovation: The role for PAI-1 in hemostasis and fibrinolysis is established; involvement of PAI-1 in cutaneous wound healing, however, remains unclear. This study tests the effect of a small-molecule PAI-1 inhibitor in a murine model of skin wound repair. Conclusion: Loss of PAI-1 activity significantly impaired wound closure. Re-epithelialization and fibroblast recruitment/differentiation were both reduced in tiplaxtinin-treated mice. Therapies directed at manipulation of PAI-1 expression and/or activity may have applicability as a treatment option for chronic wounds and scarring disorders.

  8. Effect of CD86 blockage on the expressions of TGF-β1, MMP-9, TIMP-3 and PAI-1 proteins and outcome of pregnancy in murine abortion-prone model

    Institute of Scientific and Technical Information of China (English)

    FU XI ZHAO; YUAN YUAN ZHANG; RUN HUA LIU; SHUAN MING LI

    2006-01-01

    In the present study, the effect of blockage of the costimulatory signal CD86 at time of implantation on the expressions of TGF-β1, MMP-9, TIMP-3 and PAI-1 proteins at the maternal-fetal interface and the outcome of pregnancy in murine abortion-prone model was investigated, in which the CBA/J × DBA/2 matings were used as the abortion-prone model and the CBA/J × BALB/c matings used as the normal pregnant model. The study was performed in following three groups: 2 groups of the abortion-prone model, which were experimental group and control experimental group, and 1 group of normal pregnant model, and each group had 10 pregnant CBA/J mice exclusively. Female pregnant CBA/J mice in the experimental group received an intraperitoneal (i. p.) injection of 100 μg of antimouse CD86 mAb in 200 μl of PBS at day 4.5 of gestation, and the irrelevant-isotope matched rat IgG2b was administrated in the control experimental group with the same dosage and at same time. For the normal pregnant group, no treatment was given. The pregnant CBA/J mice were killed on day 13.5 of gestation. Then, the embryo resorption rate was calculated and the expressions of TGF-β1, MMP-9,TIMP3 and PAI-1 were detected by using immunohistochemical methods. It was demonstrated that the embryo resorption rate in the experimental group was significantly reduced in comparison with that in the control experimental group (χ2=7.441, P=0.006), but there was no significant difference with that in normal pregnant group (χ2=0.016, P=0.898). The expressions of TGF-β1 and PAI-1 in the experimental group were significantly increased in comparison with that in the control experimental group (P =0.010, P = 0.003, respectively), with no significant difference from that in the normal pregnant group (P = 0.500). However, the expression of MMP-9 in the experimental group was significantly reduced in comparison with that in the control experimental group (P=0.012) with no significant difference from that in the

  9. PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease.

    Science.gov (United States)

    Lima, Luciana Moreira; Carvalho, Maria das Graças; Fonseca Neto, Cirilo Pereira; Garcia, José Carlos Faria; Sousa, Marinez Oliveira

    2011-12-01

    Type-1 plasminogen activator inhibitor (PAI-1) 4G/5G polymorphism may influence the PAI-1 expression. High plasma levels of PAI-1 are associated with coronary artery disease (CAD). This study investigated the influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and its association with CAD assessed by coronary angiography. Blood sample of 35 individuals with angiographically normal coronary arteries, 31 individuals presenting mild/moderate atheromatosis, 57 individuals presenting severe atheromatosis and 38 healthy individuals (controls) were evaluated. In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Plasma PAI-1 levels were quantified by ELISA assay (American Diagnostica). No difference was found between groups regarding age, gender and body mass index. Plasma PAI-1 levels and 4G/4G genotype frequency were significantly higher in the severe atheromatosis group compared to the other groups (p5G/5G genotype (r=0.02, p=0.4511). In addition, in a multiple logistic regression model, adjusted for all the other variables, PAI-1 was observed to be independently associated with CAD > 70% (p<0.001). The most important finding of this study was the association between 4G/4G genotype, high plasma PAI-1 levels and coronary stenosis higher than 70% in Brazilian individuals. Whether high plasma PAI-1 levels are a decisive factor for atherosclerosis worsening or it is a consequence remains to be established.

  10. Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer.

    Science.gov (United States)

    Palmirotta, Raffaele; Ferroni, Patrizia; Savonarola, Annalisa; Martini, Francesca; Ciatti, Filippo; Laudisi, Anastasia; Sini, Valentina; Del Monte, Girolamo; Guadagni, Fiorella; Roselli, Mario

    2009-09-01

    Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients. PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status. No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p=0.002), particularly in patients with large tumors (p<0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p<0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p=0.02). We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.

  11. Association between PAI-1 polymorphisms and plasma PAI-1 level with sepsis in severely burned patients.

    Science.gov (United States)

    Chi, Y F; Chai, J K; Yu, Y M; Luo, H M; Zhang, Q X; Feng, R

    2015-08-21

    We investigated the association between plasminogen activator inhibitor-1 (PAI-1) polymorphisms and plasma PAI-1 level with sepsis in severely burned patients. A total of 182 patients with burn areas lager than 30% of the body surface area were enrolled in this study. Peripheral blood samples were obtained from 103 patients with sepsis (sepsis group) and 79 patients without sepsis (control group). An allele-specific polymerase chain reaction assay was used to determine PAI-1 polymorphism 4G/5G distribution. Plasma PAI-1 levels were detected using an enzyme-linked immunosorbent assay. The frequency of the 4G/4G genotype and the 4G allele frequency in the sepsis group were 42.7 and 62.1% respectively, which were significantly higher than those in the control group (P PAI-1 level than the control group (P PAI-1 concentrations were significantly higher in the 4G/4G genotype (P PAI-1 gene may be related to the susceptibility to burn sepsis and that the 4G/4G genotype may be an important genetic risk factor of burn sepsis. Additionally, PAI-1 concentrations in the serum are increased in patients with burn sepsis.

  12. Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts.

    Science.gov (United States)

    Zhong, Jianyong; Yang, Hai-Chun; Kon, Valentina; Fogo, Agnes B; Lawrence, Daniel A; Ma, Ji

    2014-06-01

    Plasminogen activator inhibitor-1 (PAI-1) promotes or abates fibrotic processes occurring in different organs. Binding of PAI-1 to vitronectin, an extracellular matrix component, may inhibit vitronectin-integrin complex-mediated cellular responses in pathophysiological conditions. To investigate the importance of plasmin suppression vs vitronectin-binding pathways of PAI-1 in cardiac fibrosis, we studied uninephrectomized mice fed a high salt diet and infused with angiotensin II (Ang II) together with different PAI-1 variants, including PAI-1AK (AK) that inhibits plasminogen activators but does not bind vitronectin, PAI-1RR (RR) that binds vitronectin but does not have protease inhibitory effects or control PAI-1 (CPAI), the control mutant that has similar molecular backbone and half-life as AK and RR while retaining all functions of native PAI-1. Compared with RR and CPAI, non-vitronectin-binding AK significantly increased expression of cardiac fibroblast marker, periostin (Ang+AK 8.40±3.55 vs Ang+RR 2.23±0.44 and Ang+CPAI 2.33±0.12% positive area, both PPAI-1 against fibrosis, fibroblasts from normal adult human ventricles were stimulated with Ang and different PAI-1 variants. Protease inhibitory AK and CPAI increased supernatant fibronectin, while decreasing plasminogen activator/plasmin activities and matrix metalloproteinase. RR and CPAI variants significantly reduced fibroblast expression of integrin β3, vitronectin level in the supernatant and fibroblast adhesion to vitronectin compared with the non-vitronectin-binding AK. Further, RR and CPAI preserved apoptotic, decreased anti-apoptotic and proliferative activities in fibroblasts. Thus, PAI-1 promotes or protects against development of cardiac fibrosis differentially through the protease inhibitory pathway or through its binding to vitronectin.

  13. 流产鼠Caspase-3与laminin B和PAI-1的表达及对妊娠结局的影响%Study of the expression of caspase - 3, laminin B and PAI- 1 proteins and outcome of pregnancy in murine abortion- prone model

    Institute of Scientific and Technical Information of China (English)

    李拴明; 赵富玺; 刘润花; 杨秀兰; 闫平

    2007-01-01

    目的:研究阻断CD86协同刺激分子对自然流产模型孕鼠母胎界面Caspase-3、laminin B和PAI-1的表达及对妊娠结局的影响.方法:实验组于妊娠第4.5天腹腔注射大鼠抗小鼠CD86单抗,实验对照组注射大鼠同型IgG2b,正常妊娠组不作任何处理.于妊娠第13.5天计算胚胎吸收率,用免疫组化测定Caspase-3、laminin B和PAI-1的表达,并进行图像分析、检测免疫组化染色灰度值(A).结果:①实验组的胚胎吸收率显著低于实验对照组(P<0.05);②实验组中Caspase-3蛋白灰度值明显高于实验对照组(P<0.05),实验组中laminin B和PAI-1蛋白灰度值均明显低于实验对照组(P<0.05).结论:妊娠早期阻断CD86协同刺激分子可使母胎界面中的Caspase-3、laminin B和PAI-1分别通过各自不同的途径发挥免疫耐受作用并且使自然流产模型孕鼠的胚胎吸收率降低至正常妊娠水平.

  14. 自然流产患者绒毛组织PAI-14G/5G多态性和uPA基因的表达及其意义%Expression and Clinical Significance of PAI-1 4G/5G Polymorphism and uPA in the Villus of Spontaneous Abortion

    Institute of Scientific and Technical Information of China (English)

    杨玲竹; 瞿小玲; 李亚敏

    2011-01-01

    目的:探讨纤溶酶原激活物抑制剂-1(PAI-1)4G/5G多态性和纤溶酶原激活剂(uPA)与自然流产的关系及其在妊娠中的作用.方法:正常早孕(对照组)人工流产和自然流产(实验组)稽留流产的绒毛组织各30例,应用免疫组织化学PV法检测绒毛组织中PAI-1和uPA蛋白表达情况,等位基因特异性-PCR(AS-PCR)法检测PAI-14G/5G多态性的表达情况,RT-PCR法检测uPA mRNA表达情况.结果:① PAI-1蛋白主要在绒毛组织的滋养细胞质中表达,其表达对照组低于实验组(P<0.05).uPA与PAI-1蛋白在细胞中分布一致,其表达水平对照组高于实验组(P<0.05).②PAI-14G/4G基因型和4G等位基因表达水平对照组低于实验组(P<0.05),uPA mRNA表达水平对照组高于实验组(P<0.05).③PAI-1和uPA蛋白在自然流产患者绒毛组织中的表达呈负相关(r=-0.639).结论:PAI-14G/5G多态性和uPA异常表达可能与自然流产的发生有关.%Objective: To explore the correlation of PAI-14G/5G polymorphism and uPA with spontaneous abortion and their effect during pregnancy. Methods: Each of 30 samples was from the villus of normal pregnancy (control group) and spontaneous abortion (experimental group), respectively. Immunchistochchemistry analysis was used to detect the protein expression of PAI-1 and uPA. AS-PCR analysis was used to detect PAI-1 4G/5G polymorphism expression and RT-PCR analysis was used to detect uPA mRNA expression. Results: 1) The expression of PAI-1 protein in spontaneous abortion villus was higher than that of normal pregnancy (P< 0.05)and it was mainly expressed in the trophocyte cytoplasm. The expression of uPA protein in spontaneous abortion villus was lower than that of normal pregnancy (P<0.05) and it's distribution was consistent with the PAI-1.2)The frequencies of 4G/4G genotype and 4G alleles of PAI- 1 were signicantly higher in abortions compared with the control. The expression of uPA mRNA was significantly lower in abortions

  15. (-)-Epigallocatechin gallate inhibits TNF-α-induced PAI-1 production in vascular endothelial cells.

    Science.gov (United States)

    Cao, Yanli; Wang, Difei; Wang, Xiaoli; Zhang, Jin; Shan, Zhongyan; Teng, Weiping

    2013-11-01

    : (-)-Epigallocatechin gallate (EGCG), the major catechin derived from green tea, reduces the incidence of cardiovascular diseases such as atherosclerosis. Plasminogen activator inhibitor-1 (PAI-1) accelerates thrombus formation upon ruptured atherosclerotic plaques. However, it is not known whether or not EGCG inhibits PAI-1 production induced by tumor necrosis factor-α (TNF-α) in endothelial cells. This study tested the hypothesis that EGCG might have an inhibitory effect on PAI-1 production induced by TNF-α. Human umbilical vein endothelial cells were cultured and incubated with TNF-α and/or EGCG. The expression of p-extracellular regulated protein kinases (p-ERK1/2) and tumor necrosis factor receptor (TNFR1) protein was quantified by Western blotting, and PAI-1 levels were measured by enzyme-linked immunosorbent assay. The results showed that TNF-α increased PAI-1 production in both a dose-dependent and time-dependent manner, and EGCG prevented TNF-α-mediated PAI-1 production and reduced phosphorylation of ERK1/2. The ERK1/2 inhibitor, PD98059 (20 μmol/L), downregulated TNF-α-induced PAI-1 expression 57.69 ± 2.46% (P TNF-α stimulation resulted in a significant decrease in TNFR1, an effect that was abolished by pretreatment with EGCG. These results suggest that EGCG could provide vascular benefits in inflammatory cardiovascular diseases such as decreased thrombus formation associated with ruptured atherosclerotic plaques.

  16. [Reproductive problems in women with PCOS, the impact of PAI-1 carriers of 4G PAI-1 polymorphism and BMI].

    Science.gov (United States)

    Komsa-Penkova, R; Golemanov, G; Georgieva, G; Popovski, K; Slavov, N; Ivanov, P; Kovacheva, K; Atanasova, M; Blajev, A

    2014-01-01

    Approximately 7-12% of women in reproductive age are affected by PCOS[2] and 40 to 70 percent of them are overweight contributing to the clinical picture of PCOS and increased reproductive and metabolic disorder. In order to investigate the role of PAl-1 as a possible risk factor for the development of PCOS a group of 67 women with polycystic ovarian disease and 70 healthy controls were investigated for levels of PAl-1 and carriage of the promoter polymorphism 675 4G/5G in gene of PAI-1. The correlation with BMI was checked. The results of the DNA analysis showed a high carriage of polymorphism 675 4G/4G in promoter of PAl-1 gene in women with PCOS but not significant (OR = 1.655; p = 0.141), as well in the total group of the patient (OR =1.474; p>0.05). Serum levels of PAI-1 were significantly higher in total group of patients compared to controls. The levels of PAI-1 is correlated with carriage of 675 4G/5G polymorphism in the gene for PAI-1 (r=0.534; p=0.03) as well as with BMI, like correlation coefficients were higherin the group with PCOS (0.572; p=0.04). Data from the disease history showed a higher percentage of women with reproductive problems: early pregnancy loss 48.5% and infertility 23.2%, significantly higher in the group with PCOS (58.1% compared to 32.4%). The carriers of polymorphism 4G are at greater risk for early pregnancy loss than those with 5G (61.45% as compared to 36.8%), which confirms that carriage of the polymorphism 4G/5G 675 gene PAl-1 has a specific in multifactorial pathogenesis and expression of PCOS.

  17. Impact of Mesenchymal Stem Cell secreted PAI-1 on colon cancer cell migration and proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Hogan, Niamh M. [Discipline of Surgery, School of Medicine, National University of Ireland, Galway (Ireland); Joyce, Myles R. [Department of Colorectal Surgery, University College Hospital, Galway (Ireland); Murphy, J. Mary; Barry, Frank P.; O’Brien, Timothy [Regenerative Medicine Institute, National University of Ireland, Galway (Ireland); Kerin, Michael J. [Discipline of Surgery, School of Medicine, National University of Ireland, Galway (Ireland); Dwyer, Roisin M., E-mail: roisin.dwyer@nuigalway.ie [Discipline of Surgery, School of Medicine, National University of Ireland, Galway (Ireland)

    2013-06-14

    Highlights: •MSCs were directly co-cultured with colorectal cancer (CRC) cells on 3D scaffolds. •MSCs influence CRC protein/gene expression, proliferation and migration. •We report a significant functional role of MSC-secreted PAI-1 in colon cancer. -- Abstract: Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds. Conditioned media containing all secreted factors was harvested at day 1, 3 and 7. Chemokine secretion and expression were analyzed by Chemi-array, ELISA (Macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs + antibody to PAI-1 was analyzed using Transwell inserts and an MTS proliferation assay respectively. Chemi-array revealed secretion of a wide range of factors by each cell population, including PAI-1and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67–88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the

  18. Association of PAI-1 gene polymorphism with survival and chemotherapy-related vascular toxicity in testicular cancer

    NARCIS (Netherlands)

    de Haas, Esther C.; Zwart, Nynke; Meijer, Coby; Suurmeijer, Albert J. H.; Meijer, Karina; Guchelaar, Henk Jan; Hoekstra, Harald J.; van Leeuwen, Flora E.; Sleijfer, Dirk Th; Boezen, H. Marike; Gietema, Jourik A.

    2010-01-01

    BACKGROUND: High Plasminogen-Activator Inhibitor 1 (PAI-1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI-1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the P

  19. Monitoring PAI-1 and VEGF Levels in 6 Human Squamous Cell Carcinoma Xenografts During Fractionated Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Bayer, Christine, E-mail: christine.bayer@yahoo.com [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); Kielow, Achim [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); Schilling, Daniela [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); HelmholtzZentrum Muenchen, German Research Center for Environmental Health, Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus University of Technology, Dresden (Germany); Maftei, Constantin-Alin [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); Zips, Daniel; Yaromina, Ala; Baumann, Michael [OncoRay Center for Radiation Research, Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus University of Technology, Dresden (Germany); Molls, Michael [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); Multhoff, Gabriele [Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich (Germany); HelmholtzZentrum Muenchen, German Research Center for Environmental Health, Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus University of Technology, Dresden (Germany)

    2012-11-01

    Purpose: Previous studies have shown that the plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are regulated by hypoxia and irradiation and are involved in neoangiogenesis. The aim of this study was to determine in vivo whether changes in PAI-1 and VEGF during fractionated irradiation could predict for radiation resistance. Methods and Materials: Six xenografted tumor lines from human squamous cell carcinomas (HSCC) of the head and neck were irradiated with 0, 3, 5, 10, and 15 daily fractions of 2 Gy. The PAI-1 and VEGF antigen levels in tumor lysates were determined by enzyme-linked immunosorbent assay kits. The amounts of PAI-1 and VEGF were compared with the dose to cure 50% of tumors (TCD{sub 50}). Colocalization of PAI-1, pimonidazole (hypoxia), CD31 (endothelium), and Hoechst 33342 (perfusion) was examined by immunofluorescence. Results: Human PAI-1 and VEGF (hVEGF) expression levels were induced by fractionated irradiation in UT-SCC-15, UT-SCC-14, and UT-SCC-5 tumors, and mouse VEGF (msVEGF) was induced only in UT-SCC-5 tumors. High hVEGF levels were significantly associated with radiation sensitivity after 5 fractions (P=.021), and high msVEGF levels were significantly associated with radiation resistance after 10 fractions (P=.007). PAI-1 staining was observed in the extracellular matrix, the cytoplasm of fibroblast-like stroma cells, and individual tumor cells at all doses of irradiation. Colocalization studies showed PAI-1 staining close to microvessels. Conclusions: These results indicate that the concentration of tumor-specific and host-specific VEGF during fractionated irradiation could provide considerably divergent information for the outcome of radiation therapy.

  20. PAI-1基因的克隆

    Institute of Scientific and Technical Information of China (English)

    覃捷; 张洁清; 李力; 黎丹戎; 张纬

    2007-01-01

    目的构建PAI-1真核细胞表达质粒。方法根据GenBank中PAI-1的序列,利用RT—PCR从人卵巢癌组织中进行扩增PAI-1基因全长片段,将其克隆人真核表达质粒pcDNA3.1/myc—his(-)B,建立PAI-1的表达质粒pcDNA3.1-PAI-1,并对克隆的全长片段进行DNA序列测定。结果经与GenBank分布的序列进行分析比较证实,构建的真核表达重组质粒pcDNA3.1-PAI-1含有PAI-1全长cDNA编码序列。结论PAI-1能成功地从人卵巢癌组织中克隆,构建了真核细胞表达质粒pcDNA3.1-PAI-1,测序表明其携带有PAI-1的全长序列,为进一步研究PAI-1在卵巢癌侵袭转移中的作用奠定了基础。

  1. PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2.

    Science.gov (United States)

    Kozlova, Nina; Jensen, Jan K; Chi, Tabughang Franklin; Samoylenko, Anatoly; Kietzmann, Thomas

    2015-05-01

    Plasminogen activator inhibitor-1 (PAI-1) is the major and most specific acting urokinase (uPA) and tissue plasminogen activator (tPA) inhibitor. Apart from its function in the fibrinolytic system, PAI-1 was also found to contribute to processes like tissue remodelling, angiogenesis, and tumour progression. However, the role of PAI-1 in those processes remains largely controversial with respect to the influence of PAI-1 on cell signalling pathways. Although PAI-1 does not possess its own cellular receptor, it can be bound to low-density lipoprotein receptor-related protein 1 (LRP1) which was proposed to modulate the β-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the β-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that β-catenin is important for that response. In addition, expression of β-catenin and β-catenin-dependent transcriptional activity were induced by PAI-1 in wild type MEFs, but not in LRP1-deficient cells. Moreover, PAI-1-induced ERK1/2 activation was more prominent in the LRP1-deficient cells and interestingly knockdown of β-catenin abolished this effect. Together, the data of the current study show that PAI-1 can promote cell migration via LRP1-dependent activation of the β-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels.

  2. PAI-1 transcriptional regulation during the G0 --> G1 transition in human epidermal keratinocytes.

    Science.gov (United States)

    Qi, Li; Allen, Rosalie R; Lu, Qi; Higgins, Craig E; Garone, Rosemarie; Staiano-Coico, Lisa; Higgins, Paul J

    2006-10-01

    Plasminogen activator inhibitor type-1 (PAI-1) is the major negative regulator of the plasmin-dependent pericellular proteolytic cascade. PAI-1 gene expression is normally growth state regulated but frequently elevated in chronic fibroproliferative and neoplastic diseases affecting both stromal restructuring and cellular migratory activities. Kinetic modeling of cell cycle transit in synchronized human keratinocytes (HaCaT cells) indicated that PAI-1 transcription occurred early after serum stimulation of quiescent (G0) cells and prior to entry into a cycling G1 condition. PAI-1 repression (in G0) was associated with upstream stimulatory factor-1 (USF-1) occupancy of two consensus E box motifs (5'-CACGTG-3') at the PE1 and PE2 domains in the PF1 region (nucleotides -794 to -532) of the PAI-1 promoter. Chromatin immunoprecipitation (ChIP) analysis established that the PE1 and PE2 site E boxes were occupied by USF-1 in quiescent cells and by USF-2 in serum-activated, PAI-1-expressing keratinocytes. This reciprocal and growth state-dependent residence of USF family members (USF-1 vs. USF-2) at PE1/PE2 region chromatin characterized the G0 --> G1 transition period and the transcriptional status of the PAI-1 gene. A consensus E box motif was required for USF/E box interactions, as a CG --> AT substitution at the two central nucleotides inhibited formation of USF/probe complexes. The 5' flanking sites (AAT or AGAC) in the PE2 segment were not necessary for USF binding. USF recognition of the PE1/PE2 region E box sites required phosphorylation with several potential involved residues, including T153, maping to the USF-specific region (USR). A T153A substitution in USF-1 did not repress serum-induced PAI-1 expression whereas the T153D mutant was an effective suppressor. As anticipated from the ChIP results, transfection of wild-type USF-2 failed to inhibit PAI-1 induction. Collectively, these data suggest that USF family members are important regulators of PAI-1 gene

  3. Effect of PAI-1 on the Biological Behavior of Ovarian Cancer Epithelial Cell SKOV3%PAI-1对卵巢癌上皮细胞SKOV3生物学行为的影响

    Institute of Scientific and Technical Information of China (English)

    覃捷; 张洁清; 李力; 黎丹戎; 张纬

    2011-01-01

    To investigate the impact of plasminogen activator receptor-l( PAI-1 )gene on the biological behavior of ovarian cancer cells SKOV3 in vivo and in vitro. Methods The PAI-1 gene was transfected into SKOV3 cells. The cell cycle was detected by cell growth curve, colony formation test and flow cytometry assay. The function of PAI-1 in SKVO3 cells were investigated by detecting the capability of invasion,migration,adhesion. Results PAI-1 gene could be successfully transfected and expressed steadily. The PAI-1 protein could be detected by Western blot in target cells. The assay results of cell cycle and colony formation showed that PAI-1 enhanced cell proliferation of SKOV3 significantly. In addition, PAI-1 was upregulated in SKOV3 cells could also contribute to the ability of cell invasion,migration and adhesion. Conclusion PAI-1 can enhance the ability of cell proliferation,invasion, migration and adhesion in ovarian cancer cells SKOV3. Therefore,PAI-1 may be plays a dual role in tumor cell invasion and metastasis.%目的 探讨PAI-1基因在体外实验中对卵巢癌细胞SKOV3生物学行为的影响.方法 将PAI-1基因转到入人卵巢癌细胞SKOV3中,通过细胞生长曲线、细胞克隆形成实验、流式细胞仪检测细胞周期,测定细胞侵袭迁移黏附能力,研究PAI-1基因在卵巢癌上皮细胞SKOV3中的功能.结果 PAI-1基因被转入靶细胞中并稳定表达,Western blot能检测到PAI-1基因蛋白在靶细胞中的表达;在细胞生长周期的测定和克隆形成实验中,转导入PAI-1基因后的细胞(SKOV3-PAI-1)较未转导PAI-1基因的SKOV3细胞增殖能力明显增强;经流式细胞仪检测,转导PAI-1基因的SKOV3细胞增殖能力亦明显增强;PAI-1基因的表达显著增强了SKOV3细胞的体外侵袭迁移黏附能力.结论 PAI-1的表达增强了SKOV3卵巢癌上皮细胞增殖和体外侵袭、迁移及黏附能力,PAI-1可能在肿瘤细胞侵袭和转移中起着双重作用.

  4. Association of plasminogen-activator inhibitor 1 (PAI-1) 4G/5G gene polymorphism with survival and chemotherapy-related vascular toxicity in non-seminomatous testicular cancer (TC)

    NARCIS (Netherlands)

    de Haas, E. C.; Zwart, N.; Meijer, C.; Boezen, H. M.; Suurmeijer, A. J.; van der Meer, J.; Hoekstra, H. J.; van Leeuwen, F. E.; Sleijffer, D. T.; Gietema, J. A.

    2009-01-01

    5083 Background: High PAI-1 expression by tumor has been associated with poor prognosis in different cancer types, while high systemic PAI-1 levels may increase the risk of vascular thrombosis. We investigated whether the 4G/5G del/ins polymorphism in the PAI-1 promoter (rs1799889; 4G might lead to

  5. Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells.

    Science.gov (United States)

    Roy, Ananya; Coum, Antoine; Marinescu, Voichita D; Põlajeva, Jelena; Smits, Anja; Nelander, Sven; Uhrbom, Lene; Westermark, Bengt; Forsberg-Nilsson, Karin; Pontén, Fredrik; Tchougounova, Elena

    2015-09-15

    Glioblastoma (GBM) is a high-grade glioma with a complex microenvironment, including various inflammatory cells and mast cells (MCs) as one of them. Previously we had identified glioma grade-dependent MC recruitment. In the present study we investigated the role of plasminogen activator inhibitor 1 (PAI-1) in MC recruitment.PAI-1, a primary regulator in the fibrinolytic cascade is capable of forming a complex with fibrinolytic system proteins together with low-density lipoprotein receptor-related protein 1 (LRP1). We found that neutralizing PAI-1 attenuated infiltration of MCs. To address the potential implication of LRP1 in this process, we used a LRP1 antagonist, receptor-associated protein (RAP), and demonstrated the attenuation of MC migration. Moreover, a positive correlation between the number of MCs and the level of PAI-1 in a large cohort of human glioma samples was observed. Our study demonstrated the expression of LRP1 in human MC line LAD2 and in MCs in human high-grade glioma. The activation of potential PAI-1/LRP1 axis with purified PAI-1 promoted increased phosphorylation of STAT3 and subsequently exocytosis in MCs.These findings indicate the influence of the PAI-1/LRP1 axis on the recruitment of MCs in glioma. The connection between high-grade glioma and MC infiltration could contribute to patient tailored therapy and improve patient stratification in future therapeutic trials.

  6. PAI-1对子宫内膜异位症发生发展及临床分期的作用研究%Effect of PAI-1 on development and clinical stages of endometriosis

    Institute of Scientific and Technical Information of China (English)

    陈露; 有风芝; 孙利环; 胡孟彩

    2014-01-01

    Objective To investigate the effect of plasminogen activator inhibitor-1 (PAI-1) on genesis and development of endometriosis.Methods Immunohistochemistry method was used to detect the expression of PAI-1 protein in 40 cases of ectopic endometrium,40 cases of eutopic endometrium and 30 cases of endometrium without endometriosis.Results PAI-1 protein maily localized in cytoplasm,and was expressed in stromal and epithelial cells of ecpotic,eutopic and normal endometrium.The level of PAI-1 protein was significantly higher in stromal cells than that in epithelial cells of ectopic endometrium(P < 0.05).Endometriotic stromal cells showed significant increasing level of PAI-1 protein,compared with stromal cells of eutopic and normal endometrium (P < 0.05).The level of PAI-1 protein in stage Ⅲ-Ⅳ was significantly higher than that in stage Ⅰ-Ⅱ and normal endometrium (P < 0.05).Conclusions The overexpression of PAI-1 protein in endometriotic stromal cells might be of importance for the migratory,adherance,invasion and growth,which maybe result in endomrtriosis in the end.Studying on the effect of PAI-1 has a certain guiding significance for clinical treatment of endometriosis.%目的 探讨纤溶酶原激活物抑制剂-1(PAI-1)对子宫内膜异位症发生发展的作用.方法 应用免疫组化方法检测PAI-1蛋白在40例子宫内膜异位症组异位内膜及在位内膜、30例对照组子宫内膜的表达.结果 ①PAI-1蛋白主要定位于细胞浆,在异位内膜、在位内膜、对照组内膜的腺上皮细胞及间质细胞均表达;②PAI-1蛋白在异位内膜间质细胞表达高于腺上皮细胞(P<0.05);③PAI-1蛋白在间质细胞表达异位内膜高于在位内膜及对照组内膜(P<0.05);④PAI-1蛋白在血管内皮细胞呈阳性表达;⑤PAI-1蛋白在异位内膜Ⅲ-Ⅳ期的表达高于Ⅰ~Ⅱ期及对照组内膜(P<0.05).结论 PAI-1在异位内膜间质细胞高表达促使其转移、黏附、侵袭、生长,导致

  7. uPA and PAI-1-Related Signaling Pathways Differ between Primary Breast Cancers and Lymph Node Metastases12

    Science.gov (United States)

    Malinowsky, Katharina; Wolff, Claudia; Berg, Daniela; Schuster, Tibor; Walch, Axel; Bronger, Holger; Mannsperger, Heiko; Schmidt, Christian; Korf, Ulrike; Höfler, Heinz; Becker, Karl-Friedrich

    2012-01-01

    The supporting role of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor 1 (PAI-1) in migration and invasion is well known. In addition, both factors are key components in cancer cell-related signaling. However, little information is available for uPA and PAI-1-associated signaling pathways in primary cancers and corresponding lymph node metastases. The aim of this study was to compare the expression of uPA and PAI-1-associated signaling proteins in 52 primary breast cancers and corresponding metastases. Proteins were extracted from formalin-fixed paraffin-embedded tissue samples of the primary tumors and metastases. Protein lysates were subsequently analyzed by reverse phase protein array for the expression of members of the PI3K/AKT (FAK, GSK3-β, ILK, pGSK3-β, PI3K, and ROCK) and the MAPK pathways (pp38, pSTAT3, and p38). A solid correlation of uPA expression existed between primary tumors and metastases, whereas PAI-1 expression did not significantly correlate between them. The correlations of uPA and PAI-1 with signaling pathways found in primary tumors did not persist in metastases. Analysis of single molecules revealed that some correlated well between tumors and metastases (FAK, pGSK3-β, ILK, Met, PI3K, ROCK, uPA, p38, and pp38), whereas others did not (PAI-1 and GSK3-β). Whether the expression of a protein correlated between tumor and metastasis or not was independent of the pathway the protein is related to. These findings hint at a complete deregulation of uPA and PAI-1-related signaling in metastases, which might be the reason why uPA and PAI-1 reached clinical relevance only for lymph node-negative breast cancer tissues. PMID:22496926

  8. uPA and PAI-1-Related Signaling Pathways Differ between Primary Breast Cancers and Lymph Node Metastases.

    Science.gov (United States)

    Malinowsky, Katharina; Wolff, Claudia; Berg, Daniela; Schuster, Tibor; Walch, Axel; Bronger, Holger; Mannsperger, Heiko; Schmidt, Christian; Korf, Ulrike; Höfler, Heinz; Becker, Karl-Friedrich

    2012-04-01

    The supporting role of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor 1 (PAI-1) in migration and invasion is well known. In addition, both factors are key components in cancer cell-related signaling. However, little information is available for uPA and PAI-1-associated signaling pathways in primary cancers and corresponding lymph node metastases. The aim of this study was to compare the expression of uPA and PAI-1-associated signaling proteins in 52 primary breast cancers and corresponding metastases. Proteins were extracted from formalin-fixed paraffin-embedded tissue samples of the primary tumors and metastases. Protein lysates were subsequently analyzed by reverse phase protein array for the expression of members of the PI3K/AKT (FAK, GSK3-β, ILK, pGSK3-β, PI3K, and ROCK) and the MAPK pathways (pp38, pSTAT3, and p38). A solid correlation of uPA expression existed between primary tumors and metastases, whereas PAI-1 expression did not significantly correlate between them. The correlations of uPA and PAI-1 with signaling pathways found in primary tumors did not persist in metastases. Analysis of single molecules revealed that some correlated well between tumors and metastases (FAK, pGSK3-β, ILK, Met, PI3K, ROCK, uPA, p38, and pp38), whereas others did not (PAI-1 and GSK3-β). Whether the expression of a protein correlated between tumor and metastasis or not was independent of the pathway the protein is related to. These findings hint at a complete deregulation of uPA and PAI-1-related signaling in metastases, which might be the reason why uPA and PAI-1 reached clinical relevance only for lymph node-negative breast cancer tissues.

  9. Propofol treatment modulates neurite extension regulated by immunologically challenged rat primary astrocytes: a possible role of PAI-1.

    Science.gov (United States)

    Ko, Hyun Myung; Joo, So Hyun; Lee, Sung Hoon; Kim, Hee Jin; Lee, Seung-Hyun; Cheong, Jae Hoon; Ryu, Jong Hoon; Kim, Jeong Min; Koo, Bon-Nyeo; Shin, Chan Young

    2015-04-01

    Propofol, a widely used anesthetic, regulates neurological processes including neurotoxicity, neuroprotection, glial activation, synaptic plasticity and neuronal maturation. Tissue plasminogen activator/tissue plasminogen activator inhibitor-1 (tPA/PAI-1) in CNS acts as a neuromodulator regulating synaptic plasticity, neurite outgrowth, seizure spreading and cell survival. Here, we investigated the effects of propofol on tPA/PAI-1 system using cultured neurons and astrocytes and their role in the regulation of neurite extension. Cultured rat primary astrocytes were treated with propofol (1-10 µM) and LPS (10 ng/ml). The expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and RT-PCR. Alternatively, culture supernatants were added to cultured rat primary neuron to investigate the effects on neurite extension. Propofol alone did not affect tPA activity in rat primary cortical neuron. Similarly, propofol alone changed neither tPA nor PAI-1 activity in rat primary astrocytes. In immunologically challenged situation using LPS, propofol synergistically increased expression of PAI-1 in rat primary astrocytes without affecting tPA expression in a manner dependent on MAPKs activation. Increased expression of PAI-1 reduced tPA activity in LPS plus propofol-treated rat primary astrocytes. Consistent with the critical role of tPA activity in the regulation of neurite extension (Cho et al. 2013), the diminished tPA activity in astrocyte culture supernatants resulted in decreased neurite extension when administered to cultured rat primary cortical neuron. The results from the present study suggest that propofol, especially in immunologically-challenged situation, dysregulates tPA/PAI-1 system in brain. Whether the dysregulated tPA/PAI-1 activity adversely affects neural differentiation as well as regeneration of neuron in vivo should be empirically determined in the future.

  10. Differential baseline expression and angiotensin II stimulation of leukemia-associated RhoGEF in vascular smooth muscle cells of spontaneously hypertensive rats

    Directory of Open Access Journals (Sweden)

    Chiu WC

    2012-12-01

    Full Text Available Wei-Chiao Chiu,1 Jyh-ming Juang,1,2 Shen-nan Chang,2 Cho-kai Wu,2 Chia-ti Tsai,2 Chuen-den Tseng,2 Yung-zu Tseng,1,2 Ming-Jai Su,3 Fu-tien Chiang1,2,41Graduate Institute of Physiology, National Taiwan University College of Medicine, 2Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, 3Graduate Institute of Pharmacology, National Taiwan University College of Medicine, 4Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of ChinaPurpose: Studies to explore angiotensin II (Ang II and its downstream signaling pathways via Rho guanine nucleotide exchange factors (RhoGEFs and RhoA signaling are crucial to understanding the mechanisms of smooth muscle contraction leading to hypertension. This study aimed to investigate the Ang II–induced expression of RhoGEFs in vascular smooth muscle cells (VSMCs of spontaneously hypertensive rats (SHRs and to identify the possible regulator associated with hypertension.Methods: Cultured VSMCs of the aorta from SHRs and Wistar-Kyoto (WKY rats were treated with or without Ang II or Ang II plus Ang II type 2 receptor antagonists. The expression levels of RhoGEF messenger RNA (mRNA and protein were determined. To evaluate the changes of aortic ring contractile force in response to Ang II, a nonviral carrier system was adopted to deliver the leukemia-associated RhoGEF (LARG small interfering RNA via nanoparticles into aortic rings.Results: The baseline mRNA levels of three RhoGEFs in cultured VSMCs of WKY rats did not increase with age, but they were significantly higher in 12-week-old SHRs than in 5-week-old SHRs. Expression levels of LARG mRNA were higher in SHRs than in age-matched WKY rats. The baseline LAGR protein of 12-week-old SHRs was about four times higher than that of WKY rats of the same age. After Ang II stimulation, LAGR protein expression was significantly

  11. The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS.

    Science.gov (United States)

    Tsangaris, Iraklis; Tsantes, Argiris; Bonovas, Stefanos; Lignos, Michalis; Kopterides, Petros; Gialeraki, Argiro; Rapti, Evdoxia; Orfanos, Stylianos; Dimopoulou, Ioanna; Travlou, Anthi; Armaganidis, Apostolos

    2009-04-01

    Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with worse outcome in ALI/ARDS. A single guanosine insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene, may play an important role in the regulation of PAI-1 expression. The objective of the study was to evaluate the effect of this polymorphism on the outcome of critically ill patients with ALI/ARDS. 52 consecutive ventilated patients with ALI/ARDS were studied. Bronchoalveolar lavage was performed within 48 hours from diagnosis. Measurement of plasma and BALF PAI-1 activity and D-dimers levels, and 4G/5G genotyping of PAI-1 were carried out. The primary outcome was 28-day mortality, and secondary outcomes included organ dysfunction and ventilator-free days. 17 patients were homozygotes for the 4G allele. Severity scores were not different between subgroups upon study enrollment. 28-day mortality was 70.6% and 42.9% for the 4G-4G and the non-4G-4G patients, respectively (p=0.06). PAI-1 activity levels and D-dimer in plasma and BALF were not significantly different between the 4G-4G and the non-4G-4G subgroups. In the multivariate analysis, genotype 4G/4G was the only variable independently associated with 28-day mortality (Odds Ratio=9.95, 95% CI: 1.79-55.28, p=0.009). Furthermore, genotype 4G/4G and plasma PAI-1 activity levels were independently negatively associated with ventilator free days (p=0.033 and p=0.008, respectively). ALI/ARDS patients, homozygous for the 4G allele of the PAI-1 gene, experienced higher 28-day mortality. This genotype was associated with a reduction in the number of days of unassisted ventilation and was inversely associated with the number of days without organ failure.

  12. Povezava med metabolnim sindromom, inhibitorjem aktivatorja plazminogena (PAI-1) in aterosklerozo: Metabolic syndrome, plasminogen activator inhibitor (PAI-1) and atherosclerosis:

    OpenAIRE

    2005-01-01

    Background. Metabolic syndrome is associated with high cardiovascular morbidity and mortality and its increasing prevalence is becoming one of the major health problems. Atherothrombotic process is accelerated in the metabolic syndrome and this is attributed to metabolic abnormalities, hypofibrinolysis due to increased plasma PAI-1 levels, and inflammation. Proinflammatory cytokines, particularly tumour necrosis factor-a may have an important role in PAI-1 overexpresion in the adipose tissue....

  13. Mitochondria-targeted esculetin inhibits PAI-1 levels by modulating STAT3 activation and miR-19b via SIRT3: Role in acute coronary artery syndrome.

    Science.gov (United States)

    Katta, Sujana; Karnewar, Santosh; Panuganti, Devayani; Jerald, Mahesh Kumar; Sastry, B K S; Kotamraju, Srigiridhar

    2018-01-01

    In this study we explored the microRNAs responsible for the regulation of PAI-1 during LPS-stimulated inflammation in human aortic endothelial cells and subsequently studied the effect of a newly synthesized mitochondria-targeted esculetin (Mito-Esc) that was shown for its anti-atherosclerotic potential, in modulating PAI-1 levels and its targeted miRs during angiotensin-II-induced atherosclerosis in ApoE(-/-) mice. LPS-stimulated PAI-1 was accompanied with an upregulation of miR-19b and down-regulation of miR-30c. These effects of LPS on PAI-1 were reversed in the presence of both parent esculetin and Mito-Esc. However, the effect of Mito-Esc was more pronounced in the regulation of PAI-1. In addition, LPS-stimulated PAI-1 expression was significantly decreased in cells treated with Anti-miR-19b, thereby suggesting that miR-19b co-expression plays a key role in PAI-1 regulation. The results also show that incubation of cells with Stattic, an inhibitor of STAT-3, inhibited LPS-stimulated PAI-1 expression. Interestingly, knockdown of SIRT3, a mitochondrial biogenetic marker, enhanced PAI-1 levels via modulation of miR-19b and -30c. Mito-Esc treatment significantly inhibited Ang-II-induced PAI-1, possibly via altering miR-19b and 30c in ApoE(-/-) mice. The association between PAI-1, miR-19b and -30c were further confirmed in plasma and microparticles isolated from patients suffering from acute coronary syndrome of various degrees. Taken together, LPS-induced PAI-1 involves co-expression of miR-19b and down regulation of miR-30c, and Mito-Esc treatment by modulating miR-19b and miR-30c through SIRT3 activation, inhibits PAI-1 levels that, in part, contribute to its anti-atherosclerotic effects. Moreover, there exists a strong positive correlation between miR-19b and PAI-1 in patients suffering from ST-elevated myocardial infarction. © 2017 Wiley Periodicals, Inc.

  14. Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts.

    Science.gov (United States)

    Galgoczi, Erika; Jeney, Florence; Gazdag, Annamaria; Erdei, Annamaria; Katko, Monika; Nagy, Domonkos M; Ujhelyi, Bernadett; Steiber, Zita; Gyory, Ferenc; Berta, Eszter; Nagy, Endre V

    2016-05-01

    During the course of Graves' orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorβ(TGF-β). We examined the effects of increasing cell densities and TGF-β on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-β stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-β. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO.

  15. Induction of plasminogen activator inhibitor type-1 (PAI-1 by hypoxia and irradiation in human head and neck carcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Mengele Karin

    2007-07-01

    Full Text Available Abstract Background Squamous cell carcinoma of the head and neck (SCCHN often contain highly radioresistant hypoxic regions, nonetheless, radiotherapy is a common treatment modality for these tumours. Reoxygenation during fractionated radiotherapy is desired to render these hypoxic tumour regions more radiosensitive. Hypoxia additionally leads to up-regulation of PAI-1, a protein involved in tumour progression and an established prognostic marker for poor outcome. However, the impact of reoxygenation and radiation on PAI-1 levels is not yet clear. Therefore, we investigated the kinetics of PAI-1 expression and secretion after hypoxia and reoxygenation, and determined the influence of ionizing radiation on PAI-1 levels in the two human SCCHN cell lines, BHY and FaDu. Methods HIF-1α immunoblot was used to visualize the degree of hypoxia in the two cell lines. Cellular PAI-1 expression was investigated by immunofluorescence microscopy. ELISA was used to quantify relative changes in PAI-1 expression (cell lysates and secretion (cell culture supernatants in response to various lengths (2 – 4 h of hypoxic exposure (2, reoxygenation (24 h, 20 % O2, and radiation (0, 2, 5 and 10 Gy. Results HIF-1α expression was induced between 2 and 24 h of hypoxic exposure. Intracellular PAI-1 expression was significantly increased in BHY and FaDu cells as early as 4 h after hypoxic exposure. A significant induction in secreted PAI-1 was seen after 12 to 24 h (BHY and 8 to 24 h (FaDu hypoxia, as compared to the normoxic control. A 24 h reoxygenation period caused significantly less PAI-1 secretion than a 24 h hypoxia period in FaDu cells. Irradiation led to an up-regulation of PAI-1 expression and secretion in both, BHY and FaDu cells. Conclusion Our data suggest that both, short-term (~4 – 8 h and long-term (~20 – 24 h hypoxic exposure could increase PAI-1 levels in SCCHN in vivo. Importantly, radiation itself could lead to PAI-1 up-regulation in head and

  16. Plasminogen activator inhibitor-1 (PAI-1 and urokinase plasminogen activator (uPA in sputum of allergic asthma patients.

    Directory of Open Access Journals (Sweden)

    Sebastian Zukowski

    2008-06-01

    Full Text Available Urokinase plasminogen activator (uPA and its inhibitor (PAI-1 have been associated with asthma. The aim of this study was to evaluate concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs. The study was performed on 19 HDM-AAs and 8 healthy nonatopic controls (HCs. Concentration of uPA and PAI-1 was evaluated in induced sputum supernatants using ELISA method. In HDM-AAs the median sputum concentration of uPA (128 pg/ml; 95% CI 99 to 183 pg/ml and PAI-1 (4063 pg/ml; 95%CI 3319 to 4784 pg/ml were significantly greater than in HCs (17 pg/ml; 95%CI 12 to 32 pg/ml; p<0.001 and 626 pg/ml; 95%CI 357 to 961 pg/ml; p<0.001 for uPA and PAI-1 respectively. The sputum concentration of uPA correlated with sputum total cell count (r=0.781; p=0.0001 and with logarithmically transformed exhaled nitric oxide concentration (eNO (r=0.486; p=0.035 but not with FEV1 or bronchial reactivity to histamine. On the contrary, the sputum PAI-1 concentration correlated with FEV1 (r=-0,718; p=0.0005 and bronchial reactivity to histamine expressed as log(PC20 (r=-0.824; p<0.0001 but did not correlate with sputum total cell count or eNO. The results of this study support previous observations linking PAI-1 with airway remodeling and uPA with cellular inflammation. Moreover, the observed effect of uPA seems to be independent of its fibrynolytic activity.

  17. In black south africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time

    NARCIS (Netherlands)

    Z. de Lange (Zelda); D.C. Rijken (Dingeman); T. Hoekstra (Tiny); K.R. Conradie (Karin); J.C. Jerling (Johann); M. Pieters (Marlien)

    2013-01-01

    textabstractData on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysi

  18. Binding of PAI-1 to endothelial cells stimulated by thymosin beta4 and modulation of their fibrinolytic potential.

    Science.gov (United States)

    Boncela, Joanna; Smolarczyk, Katarzyna; Wyroba, Elzbieta; Cierniewski, Czeslaw S

    2006-01-13

    Our previous studies showed that thymosin beta4 (Tbeta4) induced the synthesis of plasminogen activator inhibitor-1 (PAI-1) in cultured human umbilical vein endothelial cells (HUVECs) via the AP-1 dependent mechanism and its enhanced secretion. In this work we provide evidence that the released PAI-1 is accumulated on the surface of HUVECs, exclusively in its active form, in a complex with alpha1-acid glycoprotein (AGP) that is also up-regulated and released from the cells. This mechanism is supported by several lines of experiments, in which expression of both proteins was analyzed by flow cytometry and their colocalization supported by confocal microscopy. PAI-1 did not bind to quiescent cells but only to the Tbeta4-activated endothelial cells. In contrast, significant amounts of AGP were found to be associated with the cells overexpressing enhanced green fluorescent protein (EGFP)-alpha1-acid glycoprotein (AGP) without Tbeta4 treatment. The AGP.PAI-1 complex was accumulated essentially at the basal surface of endothelial cells, and such cells showed (a) morphology characteristic for strongly adhered and spread cells and (b) significantly reduced plasmin formation. Taken together, these results provide the evidence supporting a novel mechanism by which active PAI-1 can be bound to the Tbeta4-activated endothelial cells, thus influencing their adhesive properties as well as their ability to generate plasmin.

  19. The LRP1-independent mechanism of PAI-1-induced migration in CpG-ODN activated macrophages.

    Science.gov (United States)

    Thapa, Bikash; Kim, Yeon Hyang; Kwon, Hyung-Joo; Kim, Doo-Sik

    2014-04-01

    CpG-oligodeoxynucleotides (CpG-ODNs) induces plasminogen activator inhibitor type-1 (PAI-1) expression in macrophages, leading to enhanced migration through vitronectin. However, the precise role of low-density lipoprotein receptor-related protein 1 (LRP1) in PAI-1 induced migration of macrophages in the inflammatory environment is not known. In this study, we elucidated a novel mechanism describing the altered role of LRP1 in macrophage migration depending on the activation state of the cells. Experimental evidence clearly shows that the blocking of LRP1 function inhibited the PAI-induced migration of resting RAW 264.7 cells through vitronectin but exerted a pro-migratory effect on CpG-ODN-activated cells. We also demonstrate that CpG-ODN downregulates the protein and mRNA levels of LRP1 both in vivo and in vitro, a function that depends on the NF-κB signaling pathway, resulting in reduced internalization of PAI-1. This work illustrates the distinct mechanism that PAI-1-induced migration of CpG-ODN-activated cells through vitronectin depends on the interaction of PAI-1 with vitronectin but not LRP1 unlike in the resting cells, where the migration is LRP1 dependent and vitronectin independent. In conclusion, our experimental results demonstrate the altered function of LRP1 in the migration of resting and activated macrophages in the context of microenvironmental extracellular matrix components.

  20. Signalling networks associated with urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in breast cancer tissues: new insights from protein microarray analysis.

    Science.gov (United States)

    Wolff, Claudia; Malinowsky, Katharina; Berg, Daniela; Schragner, Kerstin; Schuster, Tibor; Walch, Axel; Bronger, Holger; Höfler, Heinz; Becker, Karl-Friedrich

    2011-01-01

    The urokinase-type plasminogen activator (uPA) and the main uPA inhibitor PAI-1 play important roles in cell migration and invasion in both physiological and pathological contexts. Both factors are clinically applicable predictive markers in node-negative breast cancer patients that are used to stratify patients for adjuvant chemotherapy. In addition to their classical functions in plasmin regulation, both factors are key components in cancer-related cell signalling. Such signalling cascades are well described in cell culture systems, but a better understanding of uPA- and PAI-1-associated signalling networks in clinical tissues is needed. We examined the expression of uPA, PAI-1, and 21 signalling molecules in 201 primary breast cancer tissues using protein microarrays. Expression of uPA was significantly correlated with the expression of ERK and Stat3, while expression of PAI-1 was correlated with the uPA receptor and Akt activation, presumably via integrin and HER-receptor signalling. Analysis of uPA expression did not reveal any significant correlation with staging, grading or age of the patients. The PAI-1 expression was correlated with nodal stage. Network monitoring for uPA and PAI-1 in breast cancer reveals interactions with main signalling cascades and extends the findings from cell culture experiments. Our results reveal possible mechanisms underlying cancer development.

  1. Effects of Yishentongluo decoction on the expression of PAI-1, biochemical and pathological indicators in rat with experimental membranous nephropathy%益肾通络方对膜性肾病SD大鼠肾组织纤溶酶原激活物抑制因子-1及生化、病理指标的影响

    Institute of Scientific and Technical Information of China (English)

    王刚; 袁国栋; 檀金川

    2012-01-01

    织中的表达,减轻足变融合,促进受损的肾小球基底膜修复,从而减轻肾脏损伤,延缓肾脏慢性病理进展.%Objective To observe the Effects of Yishentongluo Decoction on the expression of PAI - 1 on experimental membranous nephropathy. Methods 40 SD rats were randomly divided into four groups; control group, model group, western medicine group and Chinese herb group ( n = 10, in each group). Model group, western medicine group and Chinese herb group received tail vein injection of 2. 5 mg of cationic bovine serum albumin ( C - BSA) (dissolved in 1 Ml Ph value of 7.4 phosphate buffer) , 3 times a week for 4 weeks. After the modeling, the normal group and model group were fed by saline. Western medicine group received benazepril tablets dissolved in 5ml normal saline at 10 mg/kg daily. Chinese herb group received Yishentongluo decoction 5 Ml, once a day for 4 weeks. Mouse serum albumin (Alb), total protein (TP), triglycerides (TG) and total cholesterol (TC) were detec-ted using automatic biochemical analyzer; the determination ' of 24 h urinary protein was completed by biuret method for; immunoglobulin G ( IgG) and complement 3 ( C3 ) were measured by indirectimmunofluorescence detection, the glo-merular basement membrane and foot process changes were observed using transmission electron microscopy, PAI - 1immunohistochemistry was completed by the use of streptococcus avidin - biotin - peroxidase complex ( SABC) method. Results TP and Alb of the blood serum in model group, western medicine group and Chinese herb group were significantly decreased as compared with those in control group ( P 0.05). IgG and C3 in model group, western medicine and Chinese herb group showed granular climbing along the capillary and part of deposition. Deposition in western medicine group and Chinese herb group was significantly decreased as compared with that in model group (P 0. 05 ). Conclusion Yishentongluo decoction can reduce proteinuria, increase plasma

  2. An exploratory study on mechanism of PPARalpha activators-induced plasminogen activator inhibitor-1 expression in HepG-2 cells%PPARα激活物影响HepG-2细胞PAI-1表达机制初探

    Institute of Scientific and Technical Information of China (English)

    叶平; 贺艳丽; 王琼; 刘永学

    2004-01-01

    目的探讨不同的过氧化体增殖物激活型受体α(PPARα)激活物对HepG-2细胞纤溶酶原激活物抑制剂-1(PAI-1)活性和mRNA表达的影响及其可能的机制.方法分别以亚油酸和非诺贝特刺激HepG-2细胞,检测PAI-1活性和mRNA表达.基因瞬时转染含不同片段缺失的PAI-1启动子序列控制表达的报告基因质粒,测定亚油酸和非诺贝特诱导后的转录活性.结果亚油酸使HepG-2细胞PAI-1mRNA表达及蛋白活性显著增加,而非诺贝特使其著降低.转染HepG-2细胞由PAI-1启动子全长控制的表达质粒,亚油酸诱导PAI-1转录活性显著增加,非诺贝特显著抑制其转录活性;转染PAI-1启动子序列核转录因子κB(NF-κB)反应元件缺失的质粒时,亚油酸和非诺贝特仍显著增加PAI-1转录活性;而转染PAI-1启动子序列极低密度脂蛋白(VLDL)/脂肪酸反应元件缺失的质粒时,亚油酸对PAI-1转录活性无诱导作用,非诺贝特可下调其转录活性.结论 PPARα可能是亚油酸增强PAI-1表达所涉及的转录因子之一;非诺贝特下调PAI-1表达可能涉及对NF-κB信号转导途径的抑制作用.

  3. Inhibition of PAI-1 antiproteolytic activity against tPA by RNA aptamers.

    Science.gov (United States)

    Damare, Jared; Brandal, Stephanie; Fortenberry, Yolanda M

    2014-08-01

    Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) inhibits the plasminogen activators: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Elevated levels of PAI-1 have been correlated with an increased risk for cardiovascular disease. Pharmacologically suppressing PAI-1 might prevent, or successfully treat PAI-1 related vascular diseases. This can potentially be accomplished by using small RNA molecules (aptamers). This study's goal is to develop RNA aptamers to a region of PAI-1 that will prevent the ability of PAI-1 to interact with the plasminogen activators. The aptamers were generated through a systematic evolution of ligands via exponential enrichment approach that ensures the creation of RNA molecules that bind to our target protein, PAI-1. In vitro assays were used to determine the effect of these aptamers on PAI-1's inhibitory activity. Three aptamers that bind to PAI-1 with affinities in the nanomolar range were isolated. The aptamer clones R10-4 and R10-2 inhibited PAI-1's antiproteolytic activity against tPA and disrupted PAI-1's ability to form a stable covalent complex with tPA. Increasing aptamer concentrations correlated positively with an increase in cleaved PAI-1. To the best of our knowledge, this is the first report of RNA molecules that inhibit the antiproteolytic activity of PAI-1.

  4. [Reproductive problems in women with PCOS, the impact of PAL-1 CARRIERS OF 4G PAI -1 polymorphism and BMI].

    Science.gov (United States)

    Komsa-Penkova, R; Golemanov, G; Georgieva, G; Slavov, N; Popovski, K; Ivanov, P; Kovacheva, K; Atanasova, M; Blajev, A

    2014-01-01

    Approximately 7-12% of women in reproductive age are affected by PCOS[2] and 40 to 70 percent of them are overweight contributing to the clinical picture of PCOS and increased reproductive and metabolic disorder. In order to investigate the role of PAl-1 as a possible risk factor for the development of PCOS a group of 67 women with polycystic ovarian disease and 70 healthy controls were investigated for levels of PAI-1 and carriage of the promoter polymorphism 675 4G/5G in gene of PAl-1. The results of the DNA analysis showed a high carriage of polymorphism 675 4G/4G in promoter of PAI-1 gene in women with PCOS but not as significant (OR = 1.6645, p = 0.141). Serum levels of PAI-1 were significantly higher in total group of patients compared to controls. The levels of PAI-1 is correlated with carriage of 675 4G/5G polymorphism in the gene for PAI-1 (R = 0.534, p = 0.03) as well as wih BMI, like correlation coefficients were higher in the group with PCOS (0.572, p = 0.04). Data from the disease history showed a higher percentage of women with reproductive problems: 61.5% (early pregnancy loss and infertility) significantly higher in the group with PCOS (70.1% compared to 54.1%). The carriers of polymorphism 4G are at greater risk for early pregnancy loss than those with 5G (61.45% as compared to 36.8%), which confirms that carriage of the polymorphism 4G/5G 675 gene PAI-1 has a specific in multifactorial pathogenesis and expression of PCOS.

  5. Urokinase plasminogen activator (uPA and plasminogen activator inhibitor type-1 (PAI-1 in breast cancer - correlation with traditional prognostic factors

    Directory of Open Access Journals (Sweden)

    Lampelj Maja

    2015-12-01

    Full Text Available Background. Urokinase plasminogen activator (uPA and plasminogen activator inhibitor type-1 (PAI-1 play a key role in tumour invasion and metastasis. High levels of both proteolytic enzymes are associated with poor prognosis in breast cancer patients. The purpose of this study was to evaluate the correlation between traditional prognostic factors and uPA and PAI-1 expression in primary tumour of breast cancer patients.

  6. Increased Umbilical Cord PAI-1 Levels in Placental Insufficiency Are Associated with Fetal Hypoxia and Angiogenesis.

    Science.gov (United States)

    Seferovic, Maxim D; Gupta, Madhulika B

    2016-01-01

    In intrauterine growth restriction (IUGR), a subset of pregnancies undergoes placental vascular dysregulation resulting in restricted blood flow and fetal hypoxemia. Altered transcription of hypoxic regulated plasminogen activator inhibitor 1 (PAI-1) has been associated with pregnancy complications and angiogenic regulation. Here we assessed circulating PAI-1 as an indicator of placental insufficiency. Venous umbilical PAI-1 of hypoxemic (VpO2 20 versus 35 mmHg, p PAI-1 was increased (~10-fold, p PAI-1 levels correlated to blood oxygen (r = -0.68, p PAI-1 levels (r = 0.65, p PAI-1 inhibiting antibody (p PAI-1 as a potential marker of placental insufficiency and identify its close association with pathological hypoxia and angiogenesis in a subset of growth restricted pregnancies.

  7. In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time.

    Science.gov (United States)

    de Lange, Zelda; Rijken, Dingeman C; Hoekstra, Tiny; Conradie, Karin R; Jerling, Johann C; Pieters, Marlien

    2013-01-01

    Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

  8. In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time.

    Directory of Open Access Journals (Sweden)

    Zelda de Lange

    Full Text Available Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT. We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009 but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central obesity was the biggest contributor to PAI-1act variance (12.5%. Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

  9. Diabetic retinopathy, PAI-1 4G/5G and -844G/A polymorphisms, and changes in circulating PAI-1 levels in Tunisian type 2 diabetes patients.

    Science.gov (United States)

    Ezzidi, I; Mtiraoui, N; Chaieb, M; Kacem, M; Mahjoub, T; Almawi, W Y

    2009-06-01

    The association of altered plasminogen activator inhibitor (PAI)-1 levels and PAI-1 polymorphisms (4G/5G and -844G/A) with diabetic retinopathy (DR) was investigated in 856 type 2 diabetes (T2D) patients, of whom 383 presented with (DR group), and 473 presented without (DWR group), retinopathy. PAI-1 4G/5G and -844G/A genotyping were done by PCR-RFLP, and PAI-1 levels were measured by ELISA testing. The genotype distribution of 4G/5G and -844G/A polymorphisms did not deviate from the Hardy-Weinberg equilibrium model among healthy subjects. Higher frequencies of the 4G/4G genotype, and lower frequencies of the -844A allele, -844G/A and -844A/A genotypes, were seen in DR patients, conferring disease susceptibility and protection, respectively. While PAI-1 levels were significantly elevated in the 4G/4G compared with other PAI-1 genotypes, significant differences in PAI-1 levels between DR and DWR patients were seen in the 4G/-844A, 4G/-844G and 5G/-844A haplotype carriers among DR patients. However, comparable distributions of 4G/5G and -844G/A alleles, genotypes and haplotypes, and similar PAI-1 levels, were seen in the proliferative retinopathy (PR) and non-proliferative retinopathy (NPR) patients, indicating that neither PAI-1 variants nor changes in PAI-1 levels were linked to DR severity. Multivariate analyses identified 4G/-844A and 4G/-844G haplotypes as negatively and positively associated, respectively, with DR, but not with DR severity (PR vs NPR) after adjusting for a number of covariates. The present study identifies changes in PAI-1 levels and genetic variations at the PAI-1 locus as risk factors for DR, but not DR severity, that may serve as useful markers of increased DR susceptibility.

  10. p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure.

    Science.gov (United States)

    Tiwari, Nivedita; Marudamuthu, Amarnath S; Tsukasaki, Yoshikazu; Ikebe, Mitsuo; Fu, Jian; Shetty, Sreerama

    2016-03-15

    We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.

  11. A rapid detection method for PAI-1 promoter insertion/deletion polymorphism (4G/5G

    Directory of Open Access Journals (Sweden)

    Annichino-Bizzacchi Joyce M.

    1998-01-01

    Full Text Available Plasminogen activator inhibitor-1 (PAI-1 is an important inhibitor of fibrinolysis, and increased levels of PAI-1 are associated with atheroma and myocardial infarction. A common 4G/5G insertion/deletion polymorphism located in the promoter region of PAI-1 gene has been described associated with PAI-1 activity in plasma levels. Genotyping of this polymorphism is commonly conducted with an allele-specific oligonucleotide melting technique. In the present study, we describe a quick, easy method for genotyping 4G/5G polymorphism in the promoter region of the PAI-1 gene.

  12. The prevalence of 4G/5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in central serous chorioretinopathy and its association with plasma PAI-1 levels.

    Science.gov (United States)

    Sogutlu Sari, Esin; Yazici, Alper; Eser, Betül; Erol, Muhammet Kazim; Kilic, Adil; Ermis, Sitki Samet; Koytak, Arif; Akşit, Hasan; Yakut, Tahsin

    2014-12-01

    Central serous chorioretinopathy (CSCR) is a poorly understood disease and the choroidal circulation abnormality induced by the plasminogen activator inhibitor type 1 (PAI-1) seems to be associated with the pathogenesis. There are many reports indicating that 4 G/5 G polymorphism of the PAI-1 gene is a risk factor for several diseases related to the elevated serum levels of PAI-1. To evaluate the 4 G/5 G polymorphism of the PAI-1 gene and its association with serum levels of PAI-1 in acute CSCR patients. Sixty CSCR patients and 50 healthy control patients were included. The PAI-1 4 G/5 G was genotyped using the polymerase chain reaction-restriction technique. Serum PAI-1 level was measured using enzyme-linked immunosorbent assay. Demographic data consisting of age, sex, body mass index (BMI) as well as genotype disturbances and serum PAI-1 levels were compared between the groups. Statistical significance for differences in the serum PAI-1 levels of each group with different genotypes was also analyzed. The CSCR group consisted of 40 male (66.7%) and 20 female (33.3%) patients with a mean age of 46.7 ± 8.39 years. The control group consisted of 32 male (64%) and 18 female (36%) healthy subjects with a mean age of 45.8 ± 8.39 years. There was no statistically significant difference between the groups in terms of age, sex and BMI. In the CSCR group the genotype frequencies were 4 G/4G: 30% (n = 18), 4G/5 G: 50% (n = 30), 5 G/5G: 20% (n = 12) and in the control group genotype frequencies were 34% (n = 17), 42% (n = 21) and 24% (n = 12), respectively. There was no statistically significant difference in the distribution of genotypes among the groups (chi-squared, p = 0.70). The CSCR group had a significantly higher serum PAI-1 concentration than the control group (p = 0.001). In both groups the mean plasma PAI-1 concentration did not vary significantly among the different genotypes (p > 0.05). Although our results demonstrated that the patients with acute CSCR have

  13. A small molecule PAI-1 functional inhibitor attenuates neointimal hyperplasia and vascular smooth muscle cell survival by promoting PAI-1 cleavage.

    Science.gov (United States)

    Simone, Tessa M; Higgins, Stephen P; Archambeault, Jaclyn; Higgins, Craig E; Ginnan, Roman G; Singer, Harold; Higgins, Paul J

    2015-05-01

    Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo. In contrast to the active full-length serine protease inhibitor (SERPIN), elastase-cleaved PAI-1 (similar to tiplaxtinin) also promoted VSMC apoptosis in vitro and similarly reduced neointimal formation in vivo. The mechanism through which cleaved PAI-1 (CL-PAI-1) stimulates apoptosis appears to involve the TNF-α family member TWEAK (TNF-α weak inducer of apoptosis) and it's cognate receptor, fibroblast growth factor (FGF)-inducible 14 (FN14). CL-PAI-1 sensitizes cells to TWEAK-stimulated apoptosis while full-length PAI-1 did not, presumably due to its ability to down-regulate FN14 in a low density lipoprotein receptor-related protein 1 (LRP1)-dependent mechanism. It appears that prolonged exposure of VSMCs to CL-PAI-1 induces apoptosis by augmenting TWEAK/FN14 pro-apoptotic signaling. This work identifies a critical, anti-stenotic, role for a functionally-inactive (at least with regard to its protease inhibitory function) cleaved SERPIN. Therapies that promote the conversion of full-length to cleaved PAI-1 may have translational implications.

  14. The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis.

    Science.gov (United States)

    Nikolopoulos, Georgios K; Bagos, Pantelis G; Tsangaris, Iraklis; Tsiara, Chrissa G; Kopterides, Petros; Vaiopoulos, Aristides; Kapsimali, Violetta; Bonovas, Stefanos; Tsantes, Argirios E

    2014-07-01

    The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS). Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously. According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The meta-regression analyses showed that the levels of triglycerides (p=0.005), cholesterol (p=0.037) and PAI-1 (p=0.021) in controls were associated with the MI risk conferred by the 4G carriers. The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.

  15. The contribution of different adipose tissue depots to plasma plasminogen activator inhibitor-1 (PAI-1) levels.

    Science.gov (United States)

    Barnard, Sunelle A; Pieters, Marlien; De Lange, Zelda

    2016-11-01

    Increased plasma plasminogen activator inhibitor-1 (PAI-1) level is considered a mechanistic pathway through which obesity contributes to increased cardiovascular disease risk. Abdominal adipose tissue specifically, is a major PAI-1 source with visceral adipose tissue (VAT), an ectopic fat depot, generally considered to produce more PAI-1 than subcutaneous adipose tissue. However, this does not necessarily lead to increased plasma PAI-1 levels. This review provides an overview of studies investigating the association between body fat distribution and plasma PAI-1 levels. It discusses factors that influence this relationship and also considers the contribution of other tissue to plasma PAI-1 levels, placing the relative contribution of adipose tissue into perspective. In conclusion, the relationship between VAT and plasma PAI-1 levels is not fixed but can be modulated by a number of factors such as the size of the subcutaneous adipose tissue depot, ethnicity, possibly genetics and other obesity-related metabolic abnormalities.

  16. Regulation of programmed cell death by plasminogen activator inhibitor type 1 (PAI-1)

    DEFF Research Database (Denmark)

    Lademann, Ulrik Axel; Rømer, Maria Unni Koefoed

    2008-01-01

    PA) observed in tumours; however, several lines of evidence suggest that PAI-1 may contribute directly to the pathology of the disease. PAI-1 has been reported to have an effect on most of the basic cellular processes including cell adhesion, cell migration, cell invasion, and cell proliferation and increasing......Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with poor prognosis in cancer. An explanation to the elevated levels of PAI-1 could be a protective response to the increased proteolytic activity, caused by elevated levels of urokinase- type plasminogen activator (u...... numbers of reports suggest that PAI-1 also can regulate programmed cell death (PCD) in cancer cells and normal cells. A number of reports suggest that PAI-1 can inhibit PCD through its pro-adhesive/anti-proteolytic property whereas other reports suggest that PAI-1 induces PCD through its anti...

  17. PAI-1对鼻咽癌侵袭和转移的影响%Effect of PAI-1 on the Invasion and Metastasis in Nasopharyngeal Carcinoma

    Institute of Scientific and Technical Information of China (English)

    潘国庆; 金树珍; 付红梅; 边莉; 唐慰萍

    2005-01-01

    目的探讨尿激酶激活剂抑制剂-1(PAI-1)对鼻咽癌侵袭和转移的影响.方法以高低不同淋巴道转移能力的鼻咽癌细胞系(CNE-2Z)及其克隆株(CNE-2Z-H5,CNE-2Z-H5-9)作为研究材料;应用逆转录聚合酶反应(RT-PCR)方法检测PAI-1表达水平;应用酶联吸附法(ELISA)测定PAI-1在3种细胞中的蛋白表达量;通过侵袭抑制实验观察PAI-1在鼻咽癌的侵袭和转移过程中的作用.结果 PAI-1在CNE-2Z、CNE-2Z-H5中均有表达,但无显著性差异;PAI-1在CNE-2Z-H5-9中无表达.抗PAI-1抗体对CNE-2Z-H5-9侵袭无影响.结论 PAI-1可能抑制鼻咽癌的侵袭和转移.

  18. UPA and PAI-1 analysis from fixed tissues - new perspectives for a known set of predictive markers.

    Science.gov (United States)

    Malinowsky, K; Böllner, C; Hipp, S; Berg, D; Schmitt, M; Becker, K F

    2010-01-01

    The urokinase-type plasminogen activator (uPA) and its main inhibitor PAI-1 play key roles in tumor-associated processes such as the degradation of the extracellular matrix (ECM), tissue remodeling, cell adhesion and migration. Elevated expression of both molecules is known to correlate with negative outcomes in node negative breast cancer. To date, these molecules are the only prognostic markers to have reached the highest level of evidence (LOE I) in multi-centered clinical trials for prognosis of node negative breast cancer. Unfortunately, the clinical utility of these molecules as markers is limited by the use of enzyme-linked immunoassay (ELISA) tests for their detection. The ELISA relies on the use of fresh or frozen tissue, which are rarely available in routine clinical settings. In this review article, we provide an overview of the clinical relevance of uPA and PAI-1 and present alternative methods for their detection. Common uPA and PAI-1 detection methods discussed in literature include RT-PCR-based assays and classical immunohistochemistry approaches. In recent years, attempts have been made to isolate and analyze proteins of formalin fixed, paraffin embedded (FFPE) tissues. These new methods are of special interest because up to now neither RT-PCR nor immunohistochemistry are recommended for the detection of uPA and PAI-1. Here, we present an approach for the analysis of uPA and PAI-1 directly from FFPE tissues that may eventually overcome the limitations of current assays and make the use of both markers widely available for routine prognosis and therapy decisions for breast cancer patients.

  19. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

    Science.gov (United States)

    Zhang, Wenwen; Xu, Jing; Fang, Hehui; Tang, Lin; Chen, Weiwei; Sun, Qian; Zhang, Qun; Yang, Fang; Sun, Zijia; Cao, Lulu; Wang, Yucai; Guan, Xiaoxiang

    2017-09-12

    Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs-when mixed with TNBC cells-could increase TNBC cell metastatic potency. After treatment with TGF-β to induce endothelial-mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stimulate the expression and secretion of the chemokine, CCL5, from ECs, which then acts in a paracrine fashion on TNBC cells to enhance their migration, invasion, and metastasis. CCL5, in turn, accelerates TNBC cell secretion of PAI-1 and promotes TNBC cell metastasis, thus forming a positive feedback loop. Moreover, this enhanced metastatic ability is reversible and dependent on CCL5 signaling via the chemokine receptor, CCR5. Of importance, key features of this pathway are manifested in patients with TNBC and in The Cancer Genome Atlas database. Taken together, our results suggest that ECs enhance EMT-induced TNBC cell metastasis via PAI-1 and CCL5 signaling and illustrate the potential of developing new PAI-1- and CCL5-targeting therapy for patients with TNBC.-Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. © FASEB.

  20. PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta-analysis.

    Science.gov (United States)

    Wang, Shangqian; Cao, Qiang; Wang, Xiaoxiang; Li, Bingjie; Tang, Min; Yuan, Wanqing; Fang, Jianzheng; Qian, Jian; Qin, Chao; Zhang, Wei

    2013-01-01

    The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results. A meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I(2) test. Overall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03-1.18, I(2) = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06-1.39, I(2) = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04-1.18, I(2) = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09-1.59, I(2) = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04-1.21, I(2) = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05-1.21, I(2) = 25.3%). The results of the present meta-analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer.

  1. Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis.

    LENUS (Irish Health Repository)

    Maher, Vincent M G

    2009-08-01

    Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +\\/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +\\/- 2 ml\\/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +\\/- 8%), triglyceride (45 +\\/- 27%), apolipoprotein B (59 +\\/- 10%) and PAI-1 antigen levels from 10.2 +\\/- 5.2 to 6.0 +\\/- 3.1 ng\\/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +\\/- 1.03 ng\\/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre

  2. Dual Diverse Dynamic Reversible Actions of Ankaferd on EPCR and PAI-1 Inside Vascular Endothelial Cells With and Without LPS

    Directory of Open Access Journals (Sweden)

    Afife Karabıyık

    2012-12-01

    Full Text Available OBJECTIVE: Ankaferd Blood Stopper (ABS comprises a mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum ve Urtica dioica. ABS has been used as a topical haemostatic agent because of its antihaemorrhagic effect. Its haemostatic mechanism of action remains to be investigated. ABS does not affect individual levels of the coagulation factors II, V, VII, VIII, IX, X, XI and XIII. The aim of this study was to investigate the effects of ABS on endothelium and immune response. So, we investigated the possible changes in EPCR and PAI-1 without and with LPS-challenge inside HUVECs. METHODS: 10 μL and 100 μL ABS is given to HUVECs in 5 min., 25 min., and 50 min.,6 hour and 24 hour time periods. 10 μg/ mL LPS has been added for one hour to observe the effects of LPS challenge on HUVECs and then the cells have been treated with ABS for the time period of 5 min., 25 min., 50 min. and 6 hours to observe ABS-effects on HUVECs. Total RNAs were isolated from HUVECs and then EPCR ve PAI-1 mRNA expression levels were investigated. RESULTS: It was microscopically observed that cells arised from the surface and adhered to each other after the ABS application to the HUVECs. Also, after 24 hours cells returned the normal growth and physiology. It suggests that the adhesive cellular functions of ABS may be reversible. 10 µl ABS have negative effect on EPCR and PAI-1 expressions. Moreover the effects increases with 100 µl ABS. EPCR and PAI-1 expression increased by time with LPS and 10 µl ABS. Expressions were very low during the first hour when LPS and 100 µl ABS were given but at the end of 6 hour, EPCR and PAI-1 expression increased similar to LPS and 10 µl ABS experiment. CONCLUSION: In this study, we observed that Ankaferd has dual diverse dynamic reversible actions depend on dose and concentration on EPCR and PAI-1 inside vascular endothelial cells in the model of HUVEC. ABS might have a role on numerous cellular

  3. Modulation of plasminogen activator inhibitor-1 (PAI-1) by the naphthoquinone shikonin.

    Science.gov (United States)

    Han, Tingting; Zhang, Guangping; Yan, Dong; Yang, Hong; Ma, Tonghui; Ye, Zuguang

    2016-09-01

    Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68±2.32μM. This result was further confirmed by urokinase-type plasminogen activator (uPA)-mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956±4.457min to 26.576±2.443min. It also reduced arterial thrombus weight from 0.01±0.001g to 0.006±0.001g (pPAI-1 that could have become a lead drug the treatment of thrombus and fibrosis.

  4. Serum PAI-1 and PAI-1 4G/5G Polymorphism in Hepatitis C Virus-Induced Cirrhosis and Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients.

    Science.gov (United States)

    El Edel, Rawhia H; Essa, Enas Said; Essa, Abdallah S; Hegazy, Sara A; El Rowedy, Dalia I

    2016-11-01

    Association between variable agent-induced hepatocellular carcinoma (HCC) and both PAI-1 4G/5G polymorphism and plasminogen activator inhibitor (PAI-1) levels compared to healthy controls have been reported in earlier studies. We aimed to assess serum PAI-1 and PAI-1 4G/5G polymorphism in hepatitis C virus (HCV)-induced HCC, HCV-induced liver cirrhosis, and viral infection-free apparently healthy control subjects. Forty nine HCC, 52 cirrhosis, and 105 controls were genotyped for PAI-1 4G/5G using an allele-specific polymerase chain reaction analysis. In addition, for 31 HCC, 24 cirrhosis, and 28 controls, serum PAI-1 level was measured by enzyme-linked immunosorbent assay (ELISA). There was no significant difference in PAI-1 4G/5G genotype distribution between cirrhosis and controls (p = 0.33, p = 0.15, and p = 0.38 for the codominant, dominant, and recessive models, respectively) or between HCC and cirrhosis (p = 0.5, p = 0.24, and p = 0.69 for the codominant, dominant, and recessive models, respectively). Serum PAI-1 was significantly higher in cirrhosis than controls and significantly lower in HCC than cirrhosis (p 5G genotypes in controls, cirrhosis, and HCC (p = 0.29, p = 0.28, and p = 0.73 respectively). We documented higher serum PAI-1 in HCV-induced HCC than viral infection-free controls, but interestingly, lower than HCV-induced liver cirrhosis patients. This was not genotype related. Further studies will be needed to clearly elucidate the underlying mechanism.

  5. 4G/5G polymorphism modulates PAI-1 circulating levels in obese women.

    Science.gov (United States)

    Fernandes, Karla S; Sandrim, Valéria C

    2012-05-01

    The increase in plasminogen activator inhibitor type 1 (PAI-1) has been described as a risk factor to thrombosis-related diseases. In addition, it has been demonstrated that the variant 4G of polymorphism 4G/5G located in promoter region of PAI-1 gene is associated with higher PAI-1 levels. We investigate the role of this polymorphism on circulating PAI-1 concentration in a population of 57 obese women (23%, 4G/4G; 49%, 4G/5G and 28%, 5G/5G genotypes). Our results demonstrate a genotype-specific modulation on PAI-1 levels in obese women, thus 5G/5G genotype presented significantly lower levels of plasma PAI-1 when compared to 4G/4G group (46 ± 19 ng/mL vs. 63 ± 13 ng/mL, respectively). Our findings indicate that obese carriers of 4G/4G genotype may have increased risk to develop thrombotic diseases.

  6. Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.

    Science.gov (United States)

    White, Marquitta J; Kodaman, Nuri M; Harder, Reed H; Asselbergs, Folkert W; Vaughan, Douglas E; Brown, Nancy J; Moore, Jason H; Williams, Scott M

    2015-01-01

    Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).

  7. Clinical impact of PAI 1 4G/5G gene polymorphism in colorectal carcinoma patients.

    Science.gov (United States)

    Halamkova, J; Kiss, I; Pavlovsky, Z; Tomasek, J; Jarkovsky, J; Cech, Z; Bednarova, D; Tucek, S; Hanakova, L; Moulis, M; Zavrelova, J; Man, M; Benda, P; Robek, O; Kala, Z; Penka, M

    2013-01-01

    Plasminogen activator ihnibitor (PAI 1) belongs to the plasminogen activator system, which is part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumors. Its plasma level is normally low but 4G/4G homozygotes have higher concentrations of PAI 1. This genotype may be associated with worse prognosis and proximal location of colorectal cancer than 5G/5G homozygotes. In our prospective evaluation we examined plasma level PAI 1 (using photometric microplate method ELISA) pre-surgery and, subsequently, 6-8 weeks later, from 80 patients. For the PAI 1 rs1799889 -675 4G/5G polymorphism test the PCR amplification was used.Analysis of collected data was confirmed that significantly higher plasma levels of PAI 1 were found in patients before starting therapy, which decreased (p=0.004) after initiation of treatment. Patients with higher plasma level PAI 1 before (p=0.013) and after therapy (p=0.004) had significantly shorter survival. We found no relationship between polymorphisms of PAI 1 (-675 4G/5G) in relation to stage, survival or tumor location. PAI 1 is useful as a negative marker of prognosis and could be advantageous when planning adjuvant treatment of patients with colorectal carcinoma. Although opinions on the importance of polymorphisms of PAI 1 in relation to the prognosis are not uniform, it does seem that their role in the prognosis of patients with colorectal cancer is not essential.

  8. 高胆固醇血症大鼠PAI-1活性的变化%Change of PAI-1 Activity in Hypercholesterolemia Rats

    Institute of Scientific and Technical Information of China (English)

    王瑞; 贾汝汉; 刘红艳

    2002-01-01

    为了解纤溶酶原激活物抑制剂-1(PAI-1)在高胆固醇大鼠血及肾皮质的表达及其与肾脏损害的关系,以高脂饮食(含4%胆固醇和1%胆酸钠)诱发高胆固醇血症大鼠,12周后测定血浆及肾皮质PAI-1活性.结果显示,与对照组相比,高脂组血浆及肾皮质PAI-1活性明显升高,系膜基质增多,PAI-1活性与系膜基质呈显著正相关.

  9. The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis.

    Science.gov (United States)

    Lorente, Leonardo; Martín, María M; Borreguero-León, Juan M; Barrios, Ysamar; Solé-Violán, Jordi; Ferreres, José; Labarta, Lorenzo; Díaz, César; Jiménez, Alejandro

    2015-01-01

    Two studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients. An observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality. We included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063-3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221-3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002-1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003-1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes.

  10. In patients with chronic kidney disease (CKD kidney tissues PAI 1 clinical research%CKD患者肾组织中PAI-1的临床研究

    Institute of Scientific and Technical Information of China (English)

    李芊

    2012-01-01

    目的:观察CKD患者肾组织中PAI-1的临床研究.方法:设CKD组32例,对照组12例,取CKD组其肾穿刺标本及正常肾组织,采用免疫组化法检测中PAI-1的表达水平;比较对照组及不同分期的CKD组患者中PAI-1的表达差异,结果:PAI-1在CKD组患者不同分期的肾组织中,其表达明显高于对照组(P<0.05);PAI-1在CKD3肾组织的表达CKD1、2期明显增高(P<0.05).结论:PAI-1在CKD患者肾组织中的表达存在过度的现象,这种现象对于判断CKD患者的肾功能损害程度有很大的帮组,并能有效的防治慢性肾脏疾病.

  11. PAI-1 4G/5G repeat is a target in gastric carcinomas with microsatellite instability.

    Science.gov (United States)

    Palmirotta, Raffaele; Guadagni, Fiorella; Savonarola, Annalisa; Ludovici, Giorgia; Nesi, Gabriella; Palli, Domenico; Falchetti, Mario; Ottini, Laura

    2011-06-01

    The plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of cancer. The 4G/5G promoter polymorphism of PAI-1 is potentially involved in regulating gene transcription. To explore the role of the PAI-1 4G/5G repeat as target of microsatellite instability (MSI), 50 gastric carcinomas (GCs), characterized for MSI, were screened. PAI-1 4G/5G was analysed by direct sequencing. Allelic imbalance was observed in 5 of the 50 (10%) GCs. Specifically, 2 cases (40%) harboured a G deletion and 3 (60%) a G insertion in tumour compared to normal DNA. These five cases were included in the subgroup of 20 GCs (25%) with high level of MSI (MSI-H). A statistically significant association emerged between PAI-1 mutations and MSI-H status (p=0.0073). The frequency of PAI-1 mutations was also evaluated, together with other known target genes, by analysing MSI-H GCs for mutations at selected coding repeats within genes controlling cell growth, apoptosis and DNA repair. Overall, mutation frequency ranged from 56.3% to 5.3%. The frequency of PAI-1 mutations here reported in MSI-H GCs is, accordingly, comparable with values obtained for real targets. The relatively high incidence of PAI-1 mutations is suggestive of a positive pressure towards selection in MSI-H GCs. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  12. Tumor Budding, uPA, and PAI-1 in Colorectal Cancer: Update of a Prospective Study.

    Science.gov (United States)

    Märkl, Bruno; Hardt, Jochen; Franz, Simon; Schaller, Tina; Schenkirsch, Gerhard; Kriening, Bernadette; Hoffmann, Reinhard; Rüth, Stefan

    2017-01-01

    Aims. The prognostic role of the proteases uPA and PAI-1, as well as tumor budding, in colon cancer, has been investigated previously. Methods. We provide 6-year follow-up data and results of the validation set. The initial test set and validation set consisted of 55 colon cancers and 68 colorectal cancers, respectively. Tissue samples were analyzed for uPA and PAI-1 using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Tumor budding was analyzed on cytokeratin-stained slides. Survival analyses were performed using cut-offs that were determined previously. Results. uPA was not prognostic for outcome. PAI-1 showed a trend towards reduced cancer specific survival in PAI-1 high-grade cases (68 versus 83 months; P = 0.091). The combination of high-grade PAI-1 and tumor budding was associated with significantly reduced cancer specific survival (60 versus 83 months; P = 0.021). After pooling the data from both sets, multivariate analyses revealed that the factors pN-stage, V-stage, and a combination of tumor budding and PAI-1 were independently prognostic for the association with distant metastases. Conclusions. A synergistic adverse effect of PAI-1 and tumor budding in uni- and multivariable analyses was found. PAI-1 could serve as a target for anticancer therapy.

  13. Application of long-acting VLHL PAI-1 during sutureless partial nephrectomy in mice reduces bleeding.

    Science.gov (United States)

    Shahrour, Khaled; Keck, Rick; Jankun, Jerzy

    2015-01-01

    PAI-1 prevents lysis of blood clot by inhibiting the urokinase and tPA induced conversion of plasminogen to plasmin. VLHL PAI-1 protein mutant was created to extend half-life over 700 hours. The objective of this paper was to test VLHL PAI-1 effects on bleeding during partial nephrectomy in mice. All animals had a left partial nephrectomy after intravenous infusion of saline or tPA. The animals were divided into four groups. Group 1 was infused with saline and kidney was exposed to saline too; Group 2 was infused with saline and kidney was exposed to PAI-1. Group 3 was infused with tPA and kidney was exposed to saline, while Group 4 was infused with tPA and kidney was exposed to PAI-1. Preweighed gauze containing PAI-1 or saline was then applied to the kidney for 30 minutes. The gauze was afterward weighed and blood loss was measured by subtracting the preweight of gauze from the final weight. We have observed a statistically significant (P ≤ 0.05) reduction of bleeding in PAI-1-treated group in comparison to saline and tPA-treated groups. Based on these results we propose that VLHL PAI-1 can be used therapeutically in limiting the flow of blood from renal wounds.

  14. ACE、PAI-1基因多态性与2型糖尿病血浆PAI-1水平相关%Association of ACE and PAI-1 gene polymorphisms with plasma PAI-1 level in type 2 diabetic patients

    Institute of Scientific and Technical Information of China (English)

    潘时中; 颜晓芳; 林建银; 杨立勇

    2004-01-01

    204例2型糖尿病患者纤溶酶原激活物抑制物1(PAI-1) 值明显高于 60名正常人(P<0.05).血管紧张素Ⅰ转换酶(ACE)基因DD型PAI-1水平明显高于其它两型(均P<0.05),PAI-1基因4G/4G型PAI-1水平较高(P<0.05).Logistic回归表明,ACE基因、PAI-1基因、体重指数、胰岛素敏感指数是血浆PAI-1的危险因素.这些发现提示,ACE基因、PAI-1基因多态性可能影响2型糖尿病患者PAI-1水平.

  15. An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.

    Science.gov (United States)

    Gu, Chunyan; Zhang, Jiandong; Noble, Nancy A; Peng, Xiao-Rong; Huang, Yufeng

    2016-11-01

    While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-β1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.

  16. A low-glycemic-index diet reduces plasma PAI-1 activity in overweight women

    DEFF Research Database (Denmark)

    Jensen, Lotte

    to decrease during weight loss. However, the beneficial effects of healthy diets on PAI-1 levels may not solely depend on weight loss, but other factors may also play a role. For example better glycemic control has been observed in diabetic patients after a low glycemic index (GI) diet compared to a high GI......Introduction An elevated level of plasminogen activator inhibitor-1 (PAI-1) in plasma is a core feature of the metabolic syndrome. Plasma PAI-1 is elevated in obesity and might be responsible for some of the secondary effects of obesity as diabetes and cardiovascular diseases. PAI-1 has been shown...... diet. Still, the relevance of GI in preventing the metabolic syndrome is controversial. Objectives The main purpose of the present study was to investigate the effect of 10 weeks intake of a low glycemic index vs. a high glycemic index high-carbohydrate, low fat ad libitum diet on plasma PAI-1 activity...

  17. PAI-1 secretion of endometrial and endometriotic cells is Smad2/3- and ERK1/2-dependent and influences cell adhesion.

    Science.gov (United States)

    Sui, Cong; Mecha, Ezekiel; Omwandho, Charles Oa; Starzinski-Powitz, Anna; Stammler, Angelika; Tinneberg, Hans-Rudolf; Konrad, Lutz

    2016-01-01

    In the endometrium transforming growth factor-betas (TGF-βs) are involved mainly in menstruation and endometriosis. After binding of the ligands to the high-affinity receptors, TGF-β receptors (TBR1 and TBR2), TGF-βs activate Smad signaling to modulate gene expression and cellular functions. However, recently also Smad-independent pathways have been studied in more details. To evaluate both pathways, we have analyzed TGF-β signaling in human endometrial and endometriotic cells. Although endometrial and endometriotic cells secrete TGF-β1, secretion by stromal cells was higher compared to epithelial cells. In contrast, secretion of TGF-β2 was higher in endometriotic stromal and endometriotic epithelial cells compared to normal endometrial cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-β1 or TGF-β2 increased Smad-dependent secretion of plasminogen activator inhibitor-1 (PAI-1) dramatically in all three cell lines. Of note, endometriotic cells secreted clearly higher levels of PAI-1 compared to endometrial cells. Whereas a TBR1 kinase inhibitor completely blocked the TGF-β1 or TGF-β2-induced PAI-1 secretion, an ERK1/2 inhibitor only partially reduced PAI-1 secretion. This inhibition was not dependent on epidermal growth factor receptor (EGFR) activation by phosphorylation but on kinase activity of the TBR1. Finally, treatment of endometrial and endometriotic cell lines with recombinant PAI-1 showed reduced cell adhesion, especially of the endometrial cells. In summary, our results demonstrate that both Smad-dependent and TBR1-dependent ERK1/2 pathways are necessary for TGF-β-dependent high level secretion of PAI-1, which might increase cellular deadhesion.

  18. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.

    Science.gov (United States)

    Ghosh, Asish K; Rai, Rahul; Park, Kitae E; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D; Vaughan, Douglas E

    2016-11-08

    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.

  19. Highly stable plasminogen activator inhibitor type one (VLHL PAI-1) protects fibrin clots from tissue plasminogen activator-mediated fibrinolysis.

    Science.gov (United States)

    Jankun, Jerzy; Aleem, Ansari M; Selman, Steven H; Skrzypczak-Jankun, Ewa; Lysiak-Szydlowska, Wieslawa; Grafos, Nicholas; Fryer, Hugh J L; Greenfield, Robert S

    2007-11-01

    Plasminogen activator inhibitor-1 (PAI-1) is the major specific inhibitor of tissue-type plasminogen activator (tPA) which mediates fibrin clot lysis through activation of plasminogen. Wild-type-PAI-1 (wPAI-1) is rapidly converted to the latent form (half-life of approximately 2 h) and loses its ability to inhibit tPA. We developed a very long half-life PAI-1 (VLHL PAI-1), a recombinant protein with a half-life >700 h compared with wPAI-1. In this study, VLHL PAI-1 was assessed for its ability to inhibit clot lysis in vitro. Clot formation was initiated in normal plasma supplemented with tPA by the addition of either tissue factor or human recombinant FVIIa. Clot lysis time, monitored turbidimetrically in a microtiter plate reader, was determined at various concentrations of wPAI-1 and VLHL PAI-1. Both wPAI-1 and VLHL PAI-1 caused a significant increase in clot lysis time, although the latter was somewhat less effective at lower concentrations. The VLHL PAI-1, but not wPAI-1, maintained its anti-fibrinolytic activity after preincubation overnight at 37 degrees. These studies demonstrate that VLHL PAI-1 is an effective inhibitor of fibrin clot degradation. Due to the high stability of VLHL PAI-1 compared with wPAI-1, this novel inhibitor of tPA-mediated fibrinolysis may have therapeutic applications for treating surgical and trauma patients when used directly or in conjunction with the procoagulant recombinant FVIIa.

  20. 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly

    NARCIS (Netherlands)

    Hoekstra, T.; Geleijnse, J.M.; Kluft, C.; Giltay, E.J.; Kok, F.J.; Schouten, E.G.

    2003-01-01

    Background and Purpose - Plasminogen activator inhibitor type 1 ( PAI- 1) is the main inhibitor of fibrinolysis, and high levels may increase the risk of cardiovascular disease. The 4G/ 5G polymorphism affects PAI- 1 gene transcription with lower levels of plasma PAI- 1 in the presence of the 5G

  1. 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly

    NARCIS (Netherlands)

    Hoekstra, T.; Geleijnse, J.M.; Kluft, C.; Giltay, E.J.; Kok, F.J.; Schouten, E.G.

    2003-01-01

    Background and Purpose - Plasminogen activator inhibitor type 1 ( PAI- 1) is the main inhibitor of fibrinolysis, and high levels may increase the risk of cardiovascular disease. The 4G/ 5G polymorphism affects PAI- 1 gene transcription with lower levels of plasma PAI- 1 in the presence of the 5G all

  2. 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly

    NARCIS (Netherlands)

    Hoekstra, T.; Geleijnse, J.M.; Kluft, C.; Giltay, E.J.; Kok, F.J.; Schouten, E.G.

    2003-01-01

    Background and Purpose - Plasminogen activator inhibitor type 1 ( PAI- 1) is the main inhibitor of fibrinolysis, and high levels may increase the risk of cardiovascular disease. The 4G/ 5G polymorphism affects PAI- 1 gene transcription with lower levels of plasma PAI- 1 in the presence of the 5G all

  3. 酒大黄对动脉粥样硬化兔模型中NO和PAI-1的表达的干预作用%The intervention effects of Prepared Radix et Rhizoma Rhei with wine on nitrc oxide and expression of plasminogen activator inhibitor type-1 in aorta of atherosclerotic Rabbits

    Institute of Scientific and Technical Information of China (English)

    张海峰; 宋翠荣; 陈俊荣

    2013-01-01

    目的:探讨兔动脉粥样硬化模型中一氧化氮(NO)含量和血浆纤溶酶原激活物抑制物-1(PAI-1)的表达及酒大黄的干预作用.方法:将健康雄性新西兰兔24只随机分为3组(n=8):正常对照组(N组)、AS模型(M组)、酒大黄组(W组).治疗给药12周,全自动生化分析仪检测血清脂蛋白的表达水平,硝酸还原酶法检测家兔血清NO水平,免疫组织化学法检测主动脉组织PAI-1蛋白表达,结果:12周末与模型组相比,酒大黄组血清总胆固醇(TC),低密度脂蛋白(LDL),血清NO含量明显下降(P<0.01或P<0.05),高密度脂蛋白(HDL)明显升高(P<0.01),TG下降不明显.结论:酒大黄干预能抑制AS兔主动脉NO的产生,降低血脂,抑制AS兔PAI-1蛋白表达.有利于延缓动脉粥样硬化进程.

  4. The Association of Plasminogen Activator Inhibitor Type 1 (PAI-1) Level and PAI-1 4G/5G Gene Polymorphism with the Formation and the Grade of Endometrial Cancer.

    Science.gov (United States)

    Yıldırım, Malik Ejder; Karakuş, Savas; Kurtulgan, Hande Küçük; Kılıçgün, Hasan; Erşan, Serpil; Bakır, Sevtap

    2017-08-01

    Plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (Serpine 1), and it inhibits both tissue plasminogen activator and urokinase plasminogen activator which are important in fibrinolysis. We aimed to find whether there is a possible association between PAI-1 level, PAI-1 4G/5G polymorphism, and endometrial cancer. PAI-1 levels in peripheral blood were determined in 82 patients with endometrial carcinoma and 76 female healthy controls using an enzyme-linked immunoassay (ELISA). Then, the genomic DNA was extracted and screened by reverse hybridization procedure (Strip assay) to detect PAI 1 4G/5G polymorphism. The levels of PAI-1 in the patients were higher statistically in comparison to controls (P 5G polymorphism was quite different between patients and controls (P = 0.008), and 4G allelic frequency was significantly higher in the patients of endometrial cancer than in controls (P = 0.026). We found significant difference between Grade 1 and Grade 2+3 patients in terms of the PAI-1 levels (P = 0.047). There was no association between PAI-1 4G/5G polymorphism and the grades of endometrial cancer (P = 0.993). Our data suggest that the level of PAI-1 and PAI-1 4G/5G gene polymorphism are effective in the formation of endometrial cancer. PAI-1 levels are also associated with the grades of endometrial cancer.

  5. Effect of Olmesartan on the Level of Oral Cancer Risk Factor PAI1.

    Science.gov (United States)

    Vassiliou, Stavros; Nkenke, Emeka; Lefantzis, Nikos; Ioannidis, Anastasios; Yapijakis, Christos; Zoga, Margarita; Papakosta, Veronica; Derka, Spyridoula; Nikolaou, Chryssoula; Vairaktaris, Eleftherios

    2016-11-01

    To study if the angiotensin receptor blocker olmesartan reduces levels of plasminogen activator inhibitor 1 (PAI1), a risk factor for oral cancer, in a mouse model and therefore whether it could be used in the treatment of this malignancy. Twelve transgenic PAI1 mice aged 16-20 weeks were divided in two groups each containing six animals. One group was given olmesartan every day for 30 days in drinking water in an amount corresponding to their weight, 0.005 mg/g, while the second group did not receive any medication (control group). Blood samples were obtained from animals of both groups, before and after one month of olmesartan administration and plasma PAI1 levels were measured using enzyme-linked immunosorbent assay. In the olmesartan-treated group, a significant decrease of PAI1 level was found after 1 month of treatment (11.9±8.6 vs. 21.7±7.2 ng/ml, respectively; p=0.028). However, no statistically significant difference was observed in PAI1 levels between the olmesartan-treated and control groups after one month, (p=0.177). Olmesartan did not significantly affect PAI1 levels in this mouse model. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  6. PAI-1基因与血栓性疾病

    Institute of Scientific and Technical Information of China (English)

    路雅茹; 秦勤; 赵炳让

    2002-01-01

    纤溶功能下降是多种血栓性疾病的重要发病机制之一,纤溶酶原激活剂抑制物(plasminogen activator inhibitor PAI)约占纤溶系统抑制物活性的60%,PAI-1是其中最重要的成分。自二十世纪八十年代首次发现PAI-1以来,人们对其血浆水平与多种疾病的关系进行了多方面的研究,普遍认为血浆PAI-1水平升高使纤溶功能下降与多种血栓性疾病有显著的关系。二十世纪九十年代,人们对PAI-1基因及其多态性给予更大的关注,本文将对PAI-1基因多态性对血浆PAI-1水平的影响及与冠心病、脑血管病、外周血管血栓的关系进行综述。

  7. 循环系统疾病、糖尿病与PAI-1

    Institute of Scientific and Technical Information of China (English)

    刘乾文; 高桂华

    2005-01-01

    纤溶酶原激活抑制剂(plasminogen activator inhibitot-1,PAI-1)可阻断纤溶系统使血栓难以溶解。糖耐量异常时血PAI-1水平开始上升。PAI-1在血栓形成过程中起关键作用,血PAI-1水平与发生心血管意外有很强的相关性。PAI-1生成受肿瘤坏死因子(TNF-α)和氧化应激调控,被认为是与代谢综合征、动脉硬化和心肌梗死有关联的分子。PAI-1的表达可被体重减轻、血管紧张素转换酶抑制剂(ACEI)和噻唑烷酮(TZD)衍生物等抑制。

  8. PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2

    DEFF Research Database (Denmark)

    Kozlova, Nina; Jensen, Jan Kristian; Chi, Tabughang Franklin

    2015-01-01

    Plasminogen activator inhibitor-1 (PAI-1) is the major and most specific acting urokinase (uPA) and tissue plasminogen activator (tPA) inhibitor. Apart from its function in the fibrinolytic system, PAI-1 was also found to contribute to processes like tissue remodelling, angiogenesis, and tumour...... progression. However, the role of PAI-1 in those processes remains largely controversial with respect to the influence of PAI-1 on cell signalling pathways. Although PAI-1 does not possess its own cellular receptor, it can be bound to low-density lipoprotein receptor-related protein 1 (LRP1) which...... was proposed to modulate the β-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the β-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that β...

  9. PAI-1反义RNA对内皮细胞中PAI-1和血小板源生长因子的影响(简报) PAI-1反义RNA对内皮细胞中PAI-1和血小板源生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    富路; 梅宇; 李晖

    2001-01-01

    @@纤溶酶原激活物抑制剂-1(PAI-1)可以促进动脉粥样硬化(AS)的发展。本实验构建PAI-1反义RNA重组质粒,将其转导入离体培养的主动脉内皮细胞(EC)中,观察其对PAI-1表达的作用及对血小板源生长因子(PDGF)的影响。   体外培养猪主动脉内皮细胞,免疫组化显示CD31抗体染色阳性。取第1~2代细胞进行实验。在PAI-1基因翻译起始位点第二外显子处设计一对引物,进行PAI-1特异片段扩增。PCR纯化产物与克隆载体pGEM-T连接。ApaⅠ和PstⅠ对pGEM-PAI-1重组质粒和pcDNA3.1(-)质粒进行双酶切。电泳回收目的基因片段和载体片段,T4连接酶连接。转化入感受态细菌,扩增培养,提取目的片段,进行DNA循环测序。pcDNA3.1PAI-1表达质粒与转染试剂FuGene6混合后转染细胞。设立未转染EC作为空白对照。在转染后第3天、第5天和第7天收获转染细胞。用3种方法检测PAI-1表达情况。ELISA检测细胞培养液中PAI-1含量。免疫组化法和Western blot检测细胞中PAI-1蛋白表达。免疫荧光法检测反义RNA对EC中PDGF的作用。

  10. Failure to lyse venous thrombi because of elevated plasminogen activator Inhibitor 1 (PAI-1) and 4G polymorphism of its promotor genome (The PAI-1/4G Syndrome).

    Science.gov (United States)

    Bern, Murray M; McCarthy, Nancy

    2010-10-01

    Plasminogen activator Inhibitor 1 (PAI-1) inhibits plasminogen activators leading to decreased fibrinolysis and increased risk of thromboembolic disease (TED). Shifts in PAI-1 promoter genome from normal 5G>5G to 4G>5G or 4G>4G alleles are associated with overexpression of PAI-1. In this study patients with residual venous thrombi were observed to have increased PAI-1 levels and more frequent shifts to 4G alleles. Of the 26, 20 (76.9%) patients with unresolved thrombus had elevated PAI-1 values. 4G genomic shifts were found in 92.9% patients studied. Normal PAI-1 levels were found in 5 patients with 4G polymorphisms. Thus, PAI-1 is often elevated among patients with residual thrombus, with an unexpectedly high prevalence of the 4G polymorphism of the promoter genome. Patients with persistent thrombus should be considered at risk of having constituently increased PAI-1 due to genomic changes in the PAI-1 promoter genome. Hypotheses are proposed to explain those with normal PAI-1, despite having 4G polymorphisms.

  11. Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes.

    Science.gov (United States)

    Rebalka, Irena A; Raleigh, Matthew J; D'Souza, Donna M; Coleman, Samantha K; Rebalka, Alexandra N; Hawke, Thomas J

    2015-07-01

    Diabetes impairs the ability to heal cutaneous wounds, leading to hospitalization, amputations, and death. Patients with diabetes experience elevated levels of plasminogen activator inhibitor 1 (PAI-1), regardless of their glycemic control. It has been demonstrated that PAI-1-deficient mice exhibit improved cutaneous wound healing, and that PAI-1 inhibition improves skeletal muscle repair in mice with type 1 diabetes mellitus, leading us to hypothesize that pharmacologically mediated reductions in PAI-1 using PAI-039 would normalize cutaneous wound healing in streptozotocin (STZ)-induced diabetic (STZ-diabetic) mice. To simulate the human condition of variations in wound care, wounds were aggravated or minimally handled postinjury. Following cutaneous injury, PAI-039 was orally administered twice daily for 10 days. Compared with nondiabetic mice, wounds in STZ-diabetic mice healed more slowly. Wound site aggravation exacerbated this deficit. PAI-1 inhibition had no effect on dermal collagen levels or wound bed size. PAI-039 treatment failed to improve angiogenesis in the wounds of STZ-diabetic mice and blunted angiogenesis in the wounds of nondiabetic mice. Importantly, PAI-039 treatment significantly improved epidermal cellular migration and wound re-epithelialization compared with vehicle-treated STZ-diabetic mice. These findings support the use of PAI-039 as a novel therapeutic agent to improve diabetic wound closure and demonstrate the primary mechanism of its action to be related to epidermal closure.

  12. PAI- 1 4G/5G Polymorphism in patients with SAS%睡眠呼吸暂停综合征患者PAI-1 4G/5G基因多态性分析

    Institute of Scientific and Technical Information of China (English)

    徐霞; 王言森; 高辉

    2001-01-01

    目的研究睡眠呼吸暂停综合症(SAS)患者纤溶酶原激活物抑制物-1(PAI-1)活性(PAI-1:A)及含量(PAI-1:Ag)与PAI-1 4G/5G基因多态性的关系.方法依据睡眠呼吸监测的结果,将实验对象分为2组,正常对照组与SAS组,分别测定其血浆PAI-1:A和PA1-1:Ag、PA1-1 4G/5G基因多态性(RFLP),并用SPSS软件包进行统计学分析.结果SAS患者4G/4G+4G/5G基因型出现频率显著高于对照组.4G/4G基因型PA1-1:A和PAI-1:Ag的水平最高,其次为4G/5G基因型,5G/5G基因型PAI-1:A和PAI-1:Ag的水平最低,经统计学检验差异显著.结论 PAI-1的基因型与PA1-1:A及PAI-1:Ag水平之间关系密切.SAS患者具有较高的4G/4G、4G/5G基因频率,血浆PAI-1:A及PAI-1:Ag水平亦较高,所以我们认为SAS患者罹患心血管疾病的危险性更高,但SAS与心血管疾病的相互关系尚待进一步研究.

  13. PAI-1、t-PA/PAI-1比值与急性血管事件的相关性研究%To research the correlation between the marks of t-PA, PAI-1 and acute vascular infaction events

    Institute of Scientific and Technical Information of China (English)

    钟远; 杨庆良; 李蔚; 金俊

    2006-01-01

    目的 了解血浆t-PA、PAI-1和t-PA/PAI-1比值在急性血管事件中的变化和意义.方法 对于健康对照组、陈旧性和急性血管事件组分别采用ELISA法检测t-PA和PAI-1活性,计算t-PA/PAI-1比值.结果 急性血管事件组血浆t-PA、PAI-1明显增高、t-PA/PAI-1比值明显降低,与其它两组相比P<0.01;陈旧性血管事件组血浆PAI-1增高,与对照组相比P<0.05;t-PA升高和t-PA/PAI-1比值降低,与对照组相比无显著差异.结论 血浆t-PA和PAI-1水平与血管内皮稳定性密切相关.PAI-1增高和t-PA/PAI-1比值降低的程度在急性血管事件发生中起着重要的作用.监测PAI-1和t-PA/PAI-1比值这两项指标,在心脑血管事件的预防和治疗方面具有重要意义.

  14. The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: Relation to prognosis

    DEFF Research Database (Denmark)

    Pappot, Helle; Pedersen, Anders N; Brünner, Nils

    2006-01-01

    In a lung cancer population comprising tumor tissue from 99 pulmonary adenocarcinoma patients, the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival was studied. The study included patient material previously investigated....... The amounts of uPA-PAI-1 complex measured in pulmonary adenocarcinoma tissue were within the same range as previously reported in breast cancer tissue (0.11-5.74 ng/mg protein). uPA and PAI-1 levels were weakly correlated to the uPA-PAI-1 complex, r = 0.52 and r = 0.47, respectively, and no relation was found...... these interactions and the clinical importance of the tissue levels of uPA, PAI-1 and uPA-PAI-1 complex, the results suggest further exploratory studies of the components in pulmonary adenocarcinomas and other cancers....

  15. The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma

    DEFF Research Database (Denmark)

    Pappot, Helle; Pedersen, Anders N.; Brünner, Nils

    2006-01-01

    In a lung cancer population comprising tumor tissue from 99 pulmonary adenocarcinoma patients, the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival was studied. The study included patient material previously investigated....... The amounts of uPA-PAI-1 complex measured in pulmonary adenocarcinoma tissue were within the same range as previously reported in breast cancer tissue (0.11-5.74 ng/mg protein). uPA and PAI-1 levels were weakly correlated to the uPA-PAI-1 complex, r = 0.52 and r = 0.47, respectively, and no relation was found...... these interactions and the clinical importance of the tissue levels of uPA, PAI-1 and uPA-PAI-1 complex, the results suggest further exploratory studies of the components in pulmonary adenocarcinomas and other cancers....

  16. HIF-2alpha-dependent PAI-1 induction contributes to angiogenesis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Geis, Theresa, E-mail: geis@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Döring, Claudia, E-mail: C.Doering@em.uni-frankfurt.de [Dr. Senckenberg Institute of Pathology, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Popp, Rüdiger, E-mail: popp@vrc.uni-frankfurt.de [Institute for Vascular Signalling, Centre for Molecular Medicine, Faculty of Medicine Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt am Main (Germany); Grossmann, Nina, E-mail: grossmann@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Fleming, Ingrid, E-mail: fleming@vrc.uni-frankfurt.de [Institute for Vascular Signalling, Centre for Molecular Medicine, Faculty of Medicine Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt am Main (Germany); Hansmann, Martin-Leo, E-mail: m.l.hansmann@em.uni-frankfurt.de [Dr. Senckenberg Institute of Pathology, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Dehne, Nathalie, E-mail: dehne@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Brüne, Bernhard, E-mail: b.bruene@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany)

    2015-02-01

    Hypoxia promotes progression of hepatocellular carcinoma (HCC), not only affecting tumor cell proliferation and invasion, but also angiogenesis and thus, increasing the risk of metastasis. Hypoxia inducible factors (HIF)-1α and -2α cause adaptation of tumors to hypoxia, still with uncertainties towards the angiogenic switch. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies as an in vitro tumor model mimicking the cancer microenvironment. The naturally occuring oxygen and nutrient gradients within the cocultures allow us to question the role of distinct HIF isoforms in regulating HCC angiogenesis. In cocultures with a HIF-2α knockdown, angiogenesis was attenuated, while the knockdown of HIF-1α was without effect. Microarray analysis identified plasminogen activator inhibitor 1 (PAI-1) as a HIF-2α target gene in HepG2 cells. The knockdown of PAI-1 in HepG2 cells also lowered angiogenesis. Blocking plasmin, the downstream target of PAI-1, with aprotinin in HIF-2α knockdown (k/d) cells proved a cause–effect relation and restored angiogenesis, with no effect on control cocultures. Suggestively, HIF-2α increases PAI-1 to lower concentrations of active plasmin, thereby supporting angiogenesis. We conclude that the HIF-2α target gene PAI-1 favors the angiogenic switch in HCC. - Highlights: • HepG2 were cocultured with stem cells to mimic a cancer microenvironment in vitro. • A knockdown of HIF-2α reduces angiogenesis. • PAI-1 was identified as a HIF-2α target gene in HCC by microarray analysis. • HIF-2α induces the angiogenic switch via inhibition of plasmin.

  17. 4G5G-Polymorphismus des PAI-1-Genes und Restenoserisiko nach koronarer Stentimplantation

    OpenAIRE

    Lahn, Christina

    2005-01-01

    In dieser Studie wurde der 4G5G-Polymorphismus des PAI-1 von 1850 Patienten mit koronarer Stentimplantation, bei denen nach 6 Monaten eine angiographische Kontrolluntersuchung erfolgte und das klinische Follow-up über 1 Jahr erhoben wurde, evaluiert. Untersucht wurde, ob der Insertions-Deletions-Polymorphismus in der Promotorregion des PAI-1-Genes einen Einfluss auf die Instent-Restenose hat. Die 4G-Allel-Frequenz betrug 0,56. 32,5 % der für das 4G-Allel homozygoten Patienten entwickelten ein...

  18. Isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations.

    Science.gov (United States)

    Cinemre, Hakan; Bilir, Cemil; Akdemir, Nermin

    2010-12-01

    Isolated renal vein thrombosis is very rare without the presence of nephrotic syndrome. It is more common in the newborns and infants. Whereas major risk factors in adults are the procoagulant states such as protein C or S deficiency, factor V Leiden mutation, primary or secondary antiphospholipid syndrome, severe hypothyroidism, and trauma. Here, we report a case of isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations. It should be noted that the presence of MTHFR-1298 and PAI-1 4G gene mutations together might be one of the examples of genetic mutation combinations that increase the likelihood of a thrombotic event.

  19. Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City

    Science.gov (United States)

    Barajas-Castañeda, Luis Miguel; Cortés-Gutiérrez, Evelin; García-Rodríguez, Francisco Mario; Campos-Rodríguez, Rafael; Lara-Padilla, Eleazar; Enríquez-Rincón, Fernando; Figueroa-Arredondo, Paula

    2016-01-01

    Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p < 0.05). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (p < 0.05). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern. PMID:27975070

  20. Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City

    Directory of Open Access Journals (Sweden)

    Luis Miguel Barajas-Castañeda

    2016-01-01

    Full Text Available Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118 primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%. In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45% was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p<0.05. At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24% than tumors without metastasis (p<0.05. We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern.

  1. The plasminogen activator inhibitor-1 (PAI-1) gene -844 A/G and -675 4G/5G promoter polymorphism significantly influences plasma PAI-1 levels in women with polycystic ovary syndrome.

    Science.gov (United States)

    Lin, Sun; Huiya, Zhang; Bo, Liu; Wei, Wei; Yongmei, Guan

    2009-12-01

    Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with increased PAI-1 levels, have been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). We investigated a possible influence of the promoter polymorphism (-844 A/G and -675 4G/5G) in the PAI-1 gene on plasma PAI-1 levels in 126 PCOS patients and 97 healthy controls. Levels of total testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), fasting plasma glucose (FPG), fasting insulin, and PAI-1 were measured, and body mass index (BMI), waist-to-hip ratio (WHR), LH/FSH ratio, and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. PAI-1 -675 4G/5G and -844 A/G gene polymorphisms were also performed. Total testosterone, fasting insulin, and PAI-1 levels; BMI, LH/FSH, and HOMA-IR were significantly higher in PCOS patients than controls (P 5G or 5G/5G genotype. The plasma PAI-1 levels of the combination of the PAI-1 -844 A/A and -675 4G/4G or 4G/5G genotypes, or the coadunation of 4G/4G and -844 non-G/G (A/A + A/G) genotypes were significantly high in PCOS women compared with controls. A trend to a positive interaction between PAI-1 -675 4G/5G and -844 A/G gene polymorphism may elevate plasma PAI-1 levels and hypofibrinolysis, which is probably an important hereditary risk factor in PCOS.

  2. The Association of the Metabolic Syndrome with PAI-1 and t-PA Levels

    Directory of Open Access Journals (Sweden)

    Christopher S. Coffey

    2011-01-01

    Full Text Available Background. We used a random sample (n=2,495 from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND study population to examine the association of the metabolic syndrome (Met S with plasminogen activator inhibitor type 1 (PAI-1 and tissue plasminogen activator (t-PA antigen levels. Results. The overall prevalence of the Met S was 18%, was dependent on age and gender, and was positively associated with higher antigen levels of both PAI-1 and t-PA. These significant effects were maintained after adjustment for age, gender, BMI, elevated C-reactive protein, smoking status, urinary albumin excretion, and insulin levels. We found no significant interactions between the Met S and other covariates on PAI-1 and t-PA levels. Conclusions. Our study demonstrates that those with the Met S have significantly higher levels of PAI-1 and t-PA antigen, factors known to increase the risk of cardiovascular disease.

  3. The association between PAI-1 -675 4G/5G polymorphism and type 2 diabetes mellitus.

    Science.gov (United States)

    Chen, L; Li, S-Y; Liu, M

    2017-08-15

    In this study, we aimed to analyze the association between plasminogen activator inhibitor 1 (PAI-1) -675 4G/5G polymorphism and type 2 diabetes mellitus (T2DM) risk. We included in 187 T2DM patients and 186 heathy controls between 2014 and 2017 from Tianjin Gong An Hospital, China. All patients and controls were ethnically Chinese Han population. The primers and polymerase chain reaction (PCR) conditions were performed. Results from this case-control study suggested that PAI-1 -675 4G/5G polymorphism was not associated with T2DM risk in four genetic models. Additionally, PAI-1 -675 4G/5G polymorphism was not associated with clinical and laboratory characteristics, such as age, gender, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, and HbA1c. In conclusion, this case-control study suggested that PAI-1 -675 4G/5G polymorphism was not associated with T2DM risk in this population.

  4. Evaluating PAI-1 as a biomarker for stress in diving: human serum total PAI-1 is unaltered after 2 h dry exposures to 280 kPa hyperbaric air.

    Science.gov (United States)

    Eftedal, Ingrid; Fredriksen, Hallvard Aglen; Hjelde, Astrid; Møllerløkken, Andreas

    2015-06-01

    Plasminogen activator inhibitor (PAI-1) is induced in the vasculature and secreted into the vascular lumen in response to inflammation and oxidative stress. We have previously reported a fivefold increase in plasma PAI-1 from rats exposed to 708 kPa hyperbaric air. In the current study we assess the potential of human serum total PAI-1 as a biomarker for stress in compressed air diving. Eleven recreational divers, nine males and two females, completed four 2 h hyperbaric air exposures to 280 kPa in a pressure chamber over a period of 2 weeks. The air pressure corresponds to a diving depth of 18 m in water. Serum was collected before the study and again 3 h 30 min after completion of each hyperbaric exposure. All samples were taken in the afternoon to minimize the contribution of circadian variation. The analysis revealed no change in serum total PAI-1 after hyperbaric exposures within the group of divers (P = 0.064), but significant interindividual differences persisted throughout the study (P PAI-1. In conclusion, compressed air exposure to 280 kPa does not affect serum total PAI-1, and significant interindividual variation in PAI-1 levels may limit its usefulness as a biomarker. This does, however, not give a complete answer regarding PAI-1 in physiologically stressful dives. Further studies with different exposures and timing are needed for that.

  5. PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2

    DEFF Research Database (Denmark)

    Kozlova, Nina; Jensen, Jan Kristian; Chi, Tabughang Franklin

    2015-01-01

    of β-catenin abolished this effect. Together, the data of the current study show that PAI-1 can promote cell migration via LRP1-dependent activation of the β-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels....

  6. Low plasminogen activator inhibitor-1 levels in thyroid carcinoma: uPA/PAI-1 paradox in cancer proggression

    Directory of Open Access Journals (Sweden)

    Bekir Ucan

    2017-06-01

    Conclusions: Serum PAI-1 levels were lower in patients with papillary thyroid carcinoma. Our results might support the thesis of PAI-1 is expected to suppress cancer progression due to its ability to inhibit urokinase plasminogen activator activity. [J Contemp Med 2017; 7(2.000: 121-125

  7. Fibrinolysis inhibitors in plaque stability: a morphological association of PAI-1 and TAFI in advanced carotid plaque.

    Science.gov (United States)

    Jönsson Rylander, A-C; Lindgren, A; Deinum, J; Bergström, G M L; Böttcher, G; Kalies, I; Wåhlander, K

    2017-01-30

    Essentials Fibrinolysis inhibitors are localized in advanced atheroma by immunohistology of endarterectomies. Neovascular endothelium/neocapillaries show thrombin-activatable fibrinolysis inhibitor (TAFI). Macrophage areas show free plasminogen activator inhibitor (PAI-1), notably in the vulnerable part. Free PAI-1 and TAFI stabilize active plaque area by inhibition of fibrinolysis and inflammation.

  8. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

    Science.gov (United States)

    Huang, Jie; Sabater-Lleal, Maria; Asselbergs, Folkert W.; Tregouet, David; Shin, So-Youn; Ding, Jingzhong; Baumert, Jens; Oudot-Mellakh, Tiphaine; Folkersen, Lasse; Johnson, Andrew D.; Smith, Nicholas L.; Williams, Scott M.; Ikram, Mohammad A.; Kleber, Marcus E.; Becker, Diane M.; Truong, Vinh; Mychaleckyj, Josyf C.; Tang, Weihong; Yang, Qiong; Sennblad, Bengt; Moore, Jason H.; Williams, Frances M. K.; Dehghan, Abbas; Silbernagel, Günther; Schrijvers, Elisabeth M. C.; Smith, Shelly; Karakas, Mahir; Tofler, Geoffrey H.; Silveira, Angela; Navis, Gerjan J.; Lohman, Kurt; Chen, Ming-Huei; Peters, Annette; Goel, Anuj; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Lundmark, Per; Psaty, Bruce M.; Strawbridge, Rona J.; Boehm, Bernhard O.; Carter, Angela M.; Meisinger, Christa; Peden, John F.; Bis, Joshua C.; McKnight, Barbara; Öhrvik, John; Taylor, Kent; Franzosi, Maria Grazia; Seedorf, Udo; Collins, Rory; Franco-Cereceda, Anders; Syvänen, Ann-Christine; Goodall, Alison H.; Yanek, Lisa R.; Cushman, Mary; Müller-Nurasyid, Martina; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Kooner, Jaspal S.; Hofman, Albert; Danesh, John; Clarke, Robert; Meigs, James B.; Kathiresan, Sekar; Reilly, Muredach P.; Klopp, Norman; Harris, Tamara B.; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Watkins, Hugh; Spector, Timothy D.; Becker, Lewis C.; Tracy, Russell P.; März, Winfried; Uitterlinden, Andre G.; Eriksson, Per; Cambien, Francois; Morange, Pierre-Emmanuel; Koenig, Wolfgang; Soranzo, Nicole; van der Harst, Pim; Liu, Yongmei

    2012-01-01

    We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. PMID:22990020

  9. Global fibrinolytic activity, PAI-1 level, and 4G/5G polymorphism in Thai children with arterial ischemic stroke.

    Science.gov (United States)

    Natesirinilkul, Rungrote; Sasanakul, Werasak; Chuansumrit, Ampaiwan; Kadegasem, Praguywan; Visudtibhan, Anannit; Wongwerawattanakoon, Pakawan; Sirachainan, Nongnuch

    2014-01-01

    Prolonged euglobulin clot lysis time (ECLT) and increased level of plasminogen activator inhibitor-1 (PAI-1) were reported to be risk factors of arterial ischemic stroke (AIS) by some studies; however, these findings were not supported by other studies. The objective of this study was to determine the association of ECLT, PAI-1 level, and polymorphisms of 4G and 5G of PAI-1 gene to the development of AIS in Thai children. This study included patients aged 1-18 years old. Diagnosis of AIS was confirmed by imaging study. The control group was age- and sex-matched healthy subjects. Demographic data were recorded, and blood was tested for ECLT, PAI-1 level, lipid profiles, fasting blood sugar (FBS), and 4G and 5G polymorphisms of PAI-1 gene. There were 70 subjects participating in this study, consisting of 30 patients and 40 controls. Demographic data, lipid profiles, and FBS were similar between the 2 groups. Furthermore, ECLT and PAI-1 level did not differ between patient and control groups; however, both showed significant correlation (r = .352, P = .006). The 4G/5G polymorphism was the most common genotype in both patient and control groups (69.0% vs. 80.0%). However, 4G and 5G polymorphisms of PAI-1 gene did not correlate with PAI-1 level in this study (P = .797). The PAI-1 level and 4G/5G polymorphism may not be a risk factor of AIS in this population. It was also found that the 4G/5G polymorphism was the most common PAI-1 genotype in this study. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  10. Degree of obesity influences the relationship of PAI-1 with body fat distribution and metabolic variables in African women.

    Science.gov (United States)

    Barnard, Sunelle A; Pieters, Marlien; Nienaber-Rousseau, Cornelie; Kruger, Herculina S

    2016-10-01

    Although the relationship of plasminogen activator inhibitor-1 (PAI-1) with obesity has been well established, the relationship of PAI-1 with different body fat distribution patterns is less clear particularly in non-white ethnicities. We investigated the cross-sectional association of PAI-1act with body fat % and two different body fat distribution patterns, namely sarcopenic obesity (SO) and visceral (VAT) compared to subcutaneous (SCAT) abdominal obesity, in 246 healthy African women by creating sub-groups according to different body fat distribution patterns. The PAI-1act level of the SO group did not differ significantly from that of the excessive % body fat, non-sarcopenic group (p=0.8). The relationship of PAI-1act, with body fat %, insulin, triglycerides and appendicular skeletal mass (ASM) was influenced by body fat distribution patterns and degree of obesity. PAI-1act was higher (1.65 vs 0.16U/ml; p=0.001) in women with a proportionally higher abdominal VAT compared to higher abdominal SCAT compartment in the total study population, but not in the centrally obese sub-group (1.72 vs 0.83U/ml; p=0.5). Multiple regression models indicated that body fat % per se did not contribute significantly to PAI-1act variance in women with increased fat mass. Fat distribution patterns and degree of obesity influenced the association of PAI-1act with insulin, triglycerides, ASM and body fat % in African women. In centrally obese women, abdominal VAT no longer contributed more to plasma PAI-1act, than abdominal SCAT. Inflammation and endothelial dysfunction contributed more to PAI-1act variance in obese African women than did body fat % per se. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. P38MAPK介导Ghrelin对肿瘤坏死因子-α诱导的HepG2细胞纤溶酶原激活物抑制剂-1分泌的影响%Ghrelin inhibit PAI-1 secretion induced by tumor necrosis factor-αvia p38MAPK in HepG2 cells

    Institute of Scientific and Technical Information of China (English)

    丁丽颖; 赵宏; 宗志红; 李健; 刘国良

    2008-01-01

    Objective To investigate the effect of ghrelin on PAI-1 secretion in HepG2 cells induced by TNF-αand the effect of p-38 MAPK.Methods HepG2 cells were cultured.The concentration of TNF-α used to treat the HepG2 cells wag selected.The effect of ghrelin on PAI-1 secretion induced by TNF-α was detected by ELISA,the p-38 MAPK expression was investigated by Western blot.Results The concentration of PAI-1 was increased when cells were exposed to different concentration of TNF-α.The p-p38 MAPK expression was increased when the cells were exposed to TNF-α,ghrelin could inhibit the increase of PAI-1 secretioN induced by TNF-α.The expression of p-p38 MAPK was decreased when the cells were pretreated with ghrelin.Conclusion PAI-1 secretion were increased after TNF-α in-creasing.Ghrelin could inhibit PAI-1 secretion via p38 MAPK.%目的 探讨Ghrelin对TNF-α诱导的HepG2细胞PAI-1分泌的影响及p38MAPK的作用.方法 HepG2细胞培养,加入TNF-α,ELISA法测定上清PAI-1的含量;免疫印迹法检测磷酸化p38的表达.Ghrelin预处理1 h,检测TNF-α变化.结果 TNF-α浓度依赖地增高PAI-1分泌;Ghrelin组PAI-1减少;TNF-α组p-p38增加,Ghrelin组较TNF-α组减少.结论 TNF-α可能通过p-p38介导HepG2 PAI-1的表达;Ghrelin可能通过抑制p-38通路抑制PAI-1的表达.

  12. The change of PAI-1 and TNF-α in old patients with metabolic syndrome and the effect of metformin%PAI-1和TNF-α在老年代谢综合征患者中的变化及二甲双胍对其影响

    Institute of Scientific and Technical Information of China (English)

    邓满香; 刘慧霞; 张骥; 杨幼波

    2012-01-01

    Objective To explore the correlation of PAI-1 and TNF-α and the pathophysiology of the metabolic syndrome (MS) and coronary heart disease,and explore the role of metformin in the MS.Methods Sixty cases of old patients with the MS were chosen.These patients were divided into two groups at random.One group interfered with living style and metformin,the other group only interfered with living style.The activity of PAI-1 was detected by chromogenic substrate method,and the level of TNF-α was detected by ELISA assay.Results (1) The levels of PAI-1 and TNF-α in the MS patients [(0.95 ± 0.05) AU/ml,(24.81 ± 3.87)ng/ml] were significantly higher than in normal old people[(0.66 ± 0.10)AU/ml,(10.76 ±2.00) ng/ml] (P <0.001) ;(2)The levels of PAI-1 and TNF-α in the MS patients with CHD [(0.96 ± 0.05) AU/ml,(26.12 ± 2.83) ng/ml] were significantly higher than those in the patients without CHD [(0.94 ± 0.03) AU/ml,(23.71 ± 4.27) ng/ml] (P < 0.05) ;(3)The activity of PAI-1 and the level of TNF-α in the metformin group was decreased significantly [△ was (0.20 ± 0.17)AU/ml,(4.42 ± 0.85ng/ml),P <0.01],and metformin can improve the components of the MS.Conclusions The old patients with MS is prone to develop cardiac vascular disease.PAI-1 and TNF-α participate in pathophysiology of the MS and its complication.Metformin can inhibit the expression of PAI-1 and TNF-α to suppress the components of the MS,and block the complication of the MS.%目的 探讨纤溶酶原激活物抑制剂-1(PAI-1)及肿瘤坏死因子-α(TNF-α)与代谢综合征(Metabolic syndrome,MS)及并发冠心病发病的关系,并探讨二甲双胍对PAI-1、TNF-α及MS的影响.方法 老年MS患者60例,分成两组各30例:二甲双胍组予生活方式及二甲双胍干预治疗,生活干预组仅予生活方式干预.另选择同期健康体检者30例为对照组,发色底物法检测血浆PAI-1水平,ELISA法检测TNF-α水平.结果 (1)老年MS患者血PAI-1活性、TNF-α水平[(0

  13. t-PA,PAI-1检测在脑梗死患者中的应用%The Application of t-PA, PAI-1 in the Detection of Patients with Cerebral Infarction

    Institute of Scientific and Technical Information of China (English)

    李光荣; 温先勇; 熊文娟

    2009-01-01

    目的:探讨组织型纤溶酶原激活物(t-PA)和纤溶酶原激活抑制物(PAI-1)含量及t-PA/ PAI-1比值在脑梗死患者中的临床意义.方法:用酶联免疫发色底物法分别测定53例脑梗死患者和30例健康对照组血浆t-PA、PAI-1含量. 结果:脑梗死患者血浆中t-PA、PAI-1及t-PA/ PAI-1比值与正常对照组比较均有显著性差异(P<0.01).结论:检测患者血t-PA、PAI-1水平及t-PA/ PAI-1比值对脑梗死患者的诊断和治疗有重要意义.

  14. 肾病综合征患者血和尿中PAI-1的变化及其临床意义%Alterations of Plasma and Uric PAI-1 in Nephrotic Syndrome Patients

    Institute of Scientific and Technical Information of China (English)

    陈晓晴; 江明华; 温怀凯

    2007-01-01

    目的 探讨肾病综合征患者血、尿PAI-1浓度的改变及其与疾病的关系.方法 分为正常对照组、肾病综合征组,采集激素治疗前后血浆和尿液标本用ELISA法检测PAI-1的含量,速率散射比浊法测定尿清蛋白,常规生化方法检测肾功能.结果 肾病综合征组血、尿PAI-1含量升高(P<0.05),血浆和尿液中PAI-1与尿清蛋白浓度无明显相关性(r=0.247,0.234,P>0.05),尿液PAI-1和血肌酐值呈正相关(r=0.37,P<0.05).激素治疗后比治疗前PAI-1水平降低.结论 PAI-1在肾病综合征的发生发展中起重要作用.

  15. Development of a plasminogen activator inhibitor (PAI-1) assay and comparison of plasma PAI-1 activity in hyperlipidemic/dyslipidemic dogs with either hyperadrenocorticism or diabetes mellitus, and healthy dogs.

    Science.gov (United States)

    Wong, Cheryl J; Koch, Michael; Behling-Kelly, Erica L

    2016-11-08

    Thrombosis is a serious complication of many canine diseases and may be related to decreased fibrinolytic potential. Plasminogen activator inhibitor-1 (PAI-1) is the key regulator of fibrinolysis with increased levels demonstrated in states of pro-thrombosis and abnormal lipid metabolism. Our objective was to develop and validate a canine PAI-1 activity assay and test whether dogs with hyperadrenocorticism or diabetes mellitus that are hyperlipidemic/dyslipidemic have increased plasma PAI-1 activity. Functionally active PAI-1 in the plasma sample was incubated with recombinant tissue plasminogen activator (tPA), allowing the formation of a 1:1 stoichiometric inactive complex. Residual unbound tPA was then reacted with excess plasminogen in the presence of a colorimetric plasmin substrate. Plasmin production is quantified by computing the area under the curve of time (x) vs optical density (y) plot and converted to tPA IU/mL by comparison to a calibration curve of tPA standards. PAI-1 activity was determined by calculating the proportion of exogeneous tPA suppressed by PAI-1 in plasma. Assay verification included assessment of linearity, specificity, precision, sensitivity, and stability. PAI-1 activity was increased in hyperlipidemic compared to healthy dogs, but there was no significant difference between dogs with hyperadrenocorticism and diabetes mellitus. A near significant decrease in activity was detected in thawed plasma stored for 20h at 4°C. Our successfully validated assay offers a new tool for investigating fibrinolysis in dogs. Investigation of PAI-1 activity in dogs with other diseases associated with an increased risk of thrombosis would be valuable. Future studies of PAI-1 activity should consider its lability.

  16. PAI-1启动子区4G/5G多态性和PAI-1抗原含量与2型糖尿病肾病的相关性研究

    Institute of Scientific and Technical Information of China (English)

    王玲; 刘艳; 郭晖

    2007-01-01

    目的 观察PAI-1启动子区4G/5G多态性与PAI-1抗原含量在不同人群中的差异,探讨糖尿病肾病( DN)的发病机制及危险因素.方法 检测2型糖尿病(T2DM)患者、DN患者、健康者血浆PA I-1抗原水平和 PAI-1基因多态性、HbA1C、FBG、血脂、UAER水平.结果 (1)T2DM患者血浆PAI-1抗原含量、HbA1C、TG 水平明显升高,以DN患者升高最显著 ,与其他各组比较有统计学意义(P<0.05).(2)PAI-1基因启动区4G/5G多态性可影响血浆PAI-1抗原水平,4G纯合子的血浆PAI-1抗原水平显著高于5G纯合子,差异显著( P<0.05).(3)DN患者4G等位基因频率和4G/4G基因型频率显著增高(P<0.05) .[ HT6H〗结论 (1) PAI-1基因启动区4G/5G多态性可影响血浆PAI-1抗原水平及TG 水平. (2)DN患者血浆PAI-1抗原含量、TG水平明显升高,HbA1c、TG、PAI-1抗原含量与早期DN的发生有关,属DN的独立危险因素.(3) 中国北方汉族人中T2DM PAI -1基因启动子区4G纯合子携带者发生DN的危险性增加.

  17. Relationship between post-SARS osteonecrosis and PAI-1 4G/5G gene polymorphisms.

    Science.gov (United States)

    Sun, Wei; Li, Zirong; Shi, Zhengcai; Wang, Bailiang; Gao, Fuqiang; Yang, Yurun; Guo, Wanshou

    2014-05-01

    To explore the correlation between post-severe acute respiratory symptom (SARS) patients with osteonecrosis, investigate the etiology of post-SARS osteonecrosis and select the sensitive molecular symbols for early diagnosis and distinguish the high-risk population. The studied subjects were divided into two groups. Sixty-two post-SARS patients with osteonecrosis were one group, and 52 age- and sex-matched healthy people were as normal controlled group. Empty stomach blood samples from cubital veins were collected from both groups. Plasminogen activator inhibitor (PAI) by means of enzyme-linked immunosorbent assay and PAI-1 4G/5G polymorphism was detected by polymerase chain reaction and solid phase oligonucleotide assay. The blood agents of post-SARS patients changed obviously with 15.64 ± 13.85 U/ml while the control group 7.96 ± 4.27 U/ml; 4G/4G genotype for the PAI-1 polymorphism detected in post-SARS group was more than that of the control group, but had no statistical significance. The plasma PAI activity was related to homozygote 4G/4G genotype. This reveals that homozygote 4G/4G genotype may be a susceptible gene mark to Chinese osteonecrosis patients. Plasminogen activator inhibitor-1 is sensitive blood symbol for screening high-risk susceptible population; 4G/4G PAI-1 genotype may be an etiological factor in osteonecrosis.

  18. Sedentary subjects have higher PAI-1 and lipoproteins levels than highly trained athletes

    Directory of Open Access Journals (Sweden)

    Lira Fabio S

    2010-01-01

    Full Text Available Abstract Physical exercise protects against the development of cardiovascular disease, partly by lowering plasmatic total cholesterol, LDL-cholesterol and increased HDL-cholesterol levels. In addition, it is now established that reduction plasmatic adiponectin and increased C-reactive protein (CRP and plasminogen activator inhibitor-1 (PAI-1 levels play a role in the maintenance of an inflammatory state and in the development of cardiovascular disease. This study aimed to examine plasma lipid profile and inflammatory markers levels in individual with sedentary lifestyle and/or highly trained athletes at rest. Methods: Fourteen male subjects (sedentary lifestyle n = 7 and highly trained athletes n = 7 were recruited. Blood samples were collected after an overnight fast (~12 h. The plasmatic lipid profile (Triglycerides, HDL-cholesterol, LDL-cholesterol, total cholesterol, LDL-oxidized and total cholesterol/HDL-c ratio, glucose, adiponectin, C - reactive protein and PAI-1 levels were determined. Results: Total cholesterol, LDL-cholesterol, TG and PAI-1 levels were lower in highly trained athletes group in relation to sedentary subjects (p

  19. Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

    Science.gov (United States)

    Kim, Jung Oh; Han, Soo Hong; Lee, Yeon Ho; Ahn, Tae Keun; Lim, Jae Joon; Chung, Young Sun; Shin, Dong Eun; Lee, Woo Sik; Han, In Bo; Kim, Nam Keun

    2016-12-09

    Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms -844A > G, -675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 -675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene-environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

  20. Plasminogen Activator Inhibitor -1 (PAI-1) Predicts Negative Alterations in Whole Body Insulin Sensitivity in Chronic HIV Infection.

    Science.gov (United States)

    Wirunsawanya, Kamonkiat; Belyea, Loni; Shikuma, Cecilia; Watanabe, Richard; Kohorn, Lindsay; Shiramizu, Bruce; Mitchell, Brooks; Souza, Scott A; Keating, Sheila; Norris, Philip J; Ndhlovu, Lishomwa; Chow, Dominic

    2017-03-21

    Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be a potential predictor of the development of insulin resistance and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism including insulin resistance and diabetes mellitus, we postulated PAI-1 could be one of multifactorial pathogenic roles in the development of insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines including PAI-1 and whole body insulin sensitivity with two-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = -.435 , p = .001) and a negative correlation with PAI-1 at baseline and Matsuda Index at two years (r = -.377 , p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at two-year follow-up (β = -.397, p = .002). Our longitudinal study suggests PAI-1 is an independent predictor of insulin resistance among chronic HIV-infected individuals.

  1. Association of PAI-1 4G/5G and -844G/A gene polymorphisms and changes in PAI-1/tissue plasminogen activator levels in myocardial infarction: a case-control study.

    Science.gov (United States)

    Abboud, Nesrine; Ghazouani, Lakhdar; Saidi, Sarra; Ben-Hadj-Khalifa, Sonia; Addad, Fawzi; Almawi, Wassim Y; Mahjoub, Touhami

    2010-02-01

    Myocardial infarction (MI) is induced by acquired and inherited risk factors, including the plasminogen activator inhibitor-1 (PAI-1) -844G/A and -675G/A (4G/5G) gene variants. The aim of this study was to investigate the association between PAI-1-844G/A and 4G/5G polymorphisms and changes in PAI-1 and tissue plasminogen activator (tPA) levels in MI in a Tunisian population. This was a case-control study involving 305 patients with MI and 328 unrelated healthy controls. PAI-1 genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP) (-844G/A) or by polymerase chain reaction-allele specific amplification. PAI-1 and tPA levels were assayed by serological assays. In contrast to tPA levels, mean plasma PAI-1 antigen levels were higher in cases than in control subjects. The elevation in PAI-1 levels was more pronounced in -844A and 4G allele carriers. Significantly higher frequencies of (mutant) 4G and -844A alleles and 4G/4G and -844A/-844A genotypes, and corresponding lower frequencies of (wild-type) 5G and -844G alleles and 5G/5G and -844G/-844G genotypes were seen in patients than in controls. Increased prevalence of 4G/-844A and decreased prevalence of 5G/-844G haplotypes were seen in patients than in controls, thereby conferring a susceptibility and protective nature to these haplotypes, respectively. Regression analysis confirmed the independent association of 4G/4G and -844A/A with MI, after controlling for a number of covariates. This study indicated that the risk of MI was notably high in 4G and -844A carriers with elevated plasma PAI-1 and were associated with reduced tPA levels.

  2. 胰腺癌患者血浆PAI-1测定的临床意义%Determination of the Plasma PAI-1 and Its Clinical Significance in Pancreatic Cancer Patients

    Institute of Scientific and Technical Information of China (English)

    钱璞; 卢志贤; 杨春香

    2012-01-01

    Objective To investigate the concentration change of plasma plasminogen activator inhibitor-1 ( PAI-1) in patients with pancreatic cancer and its applicative value in the diagnosis. Methods The level of PAI-1 was measured (by ELISA) in 50 cases of pancreatic cancer and SO cases of normal healthy people served as control, and compare the differences between the two groups. Re-sults The level of PAI-1 in pancreatic cancer patients(20.49 ± 8. 74 ng/ml) was significantly higher than the control group (P < 0.01) , the concentration of PAI-1 in thelV stage was higher than Ⅰ , Ⅱ and Ⅲ stage of pancreatic cancer. Conclusion The concentration of plasma PAI-1has some relationships with the development of pancreatic cancer, and can be used as a laboratory indicator in the diagnosis of such malignant tumor.%目的:探讨血浆纤溶酶原激活物抑制剂1(PAI-1)在胰腺癌患者中的浓度变化,并探讨在胰腺癌诊断中的应用价值.方法:收集胰腺癌患者50例,以及正常健康人50例,用ELISA检测胰腺癌患者及正常对照组血浆PAI-1的含量,并比较其差异.结果:胰腺癌组血浆PAI-1的含量(20.49±8.74)ng/ml明显高于正常对照组(P<0.01),且PAI-1浓度在胰腺癌Ⅳ期的含量与Ⅰ、Ⅱ、Ⅲ期比较均有不同程度升高(P<0.05).结论:血浆中PAI-1的浓度升高与胰腺癌的发生有一定的联系,可作为诊断该类恶性肿瘤的实验室指标.

  3. PAI-1 -675 4G/5G polymorphism as a prognostic biomarker in breast cancer.

    Science.gov (United States)

    Lei, Haixin; Hemminki, Kari; Johansson, Robert; Altieri, Andrea; Enquist, Kerstin; Henriksson, Roger; Lenner, Per; Försti, Asta

    2008-05-01

    Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor prognosis in breast cancer. We examined whether genetic variation in the genes of the uPA system affect breast cancer susceptibility and prognosis. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in six genes of the uPA system in 959 Swedish breast cancer patients with detailed clinical data and up to 15 years of follow-up together with 952 matched controls. We used the unconditional logistic regression models to evaluate the associations between genotypes and breast cancer risk and tumor characteristics. The Kaplan-Meier method was used to estimate the survival probabilities; the log-rank test was used to test differences between subgroups. None of the SNPs conferred an increased breast cancer risk, but correlation with some traditional prognostic factors was observed for several SNPs. Most importantly, we identified the -675 4G/5G SNP in the PAI-1 gene as a promising prognostic biomarker for breast cancer. Compared to the 4G/4G and 4G/5G genotypes 5G/5G homozygosity correlated significantly with worse survival (RR 2.04, 95% CI 1.45-2.86, P5G/5G homozygotes were also the group with worse survival among lymph node negative cases. Our finding suggests that genotyping PAI-1 -675 4G/5G may help in clinical prognosis of breast cancer.

  4. [Implication of PAI-1 4G/5G polymorphism in recurrent implantation failure after IVF].

    Science.gov (United States)

    Ivanov, P; Ivanov, P; Gacheva, Sv; Konova, E; Komsa-Penkova, R

    2014-01-01

    During implantation, an accurate balance of coagulation, fibrin deposition and fibrinolysis is mandatory for trophoblastic invasion. Inhibition of fibrinolysis after increased activity of plasminogen activator inhibitors such as PAI-1 could impair properdeep trophoblastic invasion. This study investigated correlation between increased PAI-1 levels due to gene polymorphism (PL) 4G/5G and recurrent implantation failure after IVF procedure. Sixty one women with two or more unsuccessful IVF procedure after good quality embryo transfer and 97 health women with at least one normal delivery were investigated for carrier status for PL 4G/5G (genotype 4G/4G) and serum levels of anti-cardiolipin (ACA) and anti-beta2-glycoprotein antibody level (IgG and IgM type). The prevalence of genotype 4G/4G in women with RIF was about two times higher compared to controls although the difference did not rich significance (respectively 41% and 26.8%, OR 1.9, 95%CI 0.91-3.96, p=0.09). The prevalence of polymorphism was similar after exclusion of for women with elevated levels of ACA (respectively 42.1% and 26.8%, OR 1.99, 95%CI 0.94-4.21, p=0.075). PL 4G/5G could be possible risk factor forimpaired embryo implantation. The causative hypofibrinolysis due to increased PAI-1 levels should be interpreted in context of multifactor complexity of recurrent implantation failure development. A discussion remains for fraction heparin application and endometrial receptivity modulation in very early pregnancy wastage.

  5. Elevated Cytokines, Thrombin and PAI-1 in Severe HCPS Patients Due to Sin Nombre Virus

    Directory of Open Access Journals (Sweden)

    Virginie Bondu

    2015-02-01

    Full Text Available Sin Nombre Hantavirus (SNV, Bunyaviridae Hantavirus is a Category A pathogen that causes Hantavirus Cardiopulmonary Syndrome (HCPS with case fatality ratios generally ranging from 30% to 50%. HCPS is characterized by vascular leakage due to dysregulation of the endothelial barrier function. The loss of vascular integrity results in non-cardiogenic pulmonary edema, shock, multi-organ failure and death. Using Electric Cell-substrate Impedance Sensing (ECIS measurements, we found that plasma samples drawn from University of New Mexico Hospital patients with serologically-confirmed HCPS, induce loss of cell-cell adhesion in confluent epithelial and endothelial cell monolayers grown in ECIS cultureware. We show that the loss of cell-cell adhesion is sensitive to both thrombin and plasmin inhibitors in mild cases, and to thrombin only inhibition in severe cases, suggesting an increasing prothrombotic state with disease severity. A proteomic profile (2D gel electrophoresis and mass spectrometry of HCPS plasma samples in our cohort revealed robust antifibrinolytic activity among terminal case patients. The prothrombotic activity is highlighted by acute ≥30 to >100 fold increases in active plasminogen activator inhibitor (PAI-1 which, preceded death of the subjects within 48 h. Taken together, this suggests that PAI-1 might be a response to the severe pathology as it is expected to reduce plasmin activity and possibly thrombin activity in the terminal patients.

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

    Directory of Open Access Journals (Sweden)

    Merih Ozgen

    2012-11-01

    Full Text Available 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.

  7. Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

    Directory of Open Access Journals (Sweden)

    Saba Saleem

    Full Text Available In the present study we determined the association of angiotensin converting enzyme (ACE and plasminogen activator inhibitor-1 (PAI-1 gene polymorphisms with diabetic retinopathy (DR and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR for ACE Insertion/Deletion (ID polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR 1.870 [95% confidence interval (CI = 1.04-3.36] and its sub-clinical class non-proliferative DR (NPDR (p = 0.006, OR 2.250 [95% CI = 1.098-4.620], while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR.

  8. 尿激酶型纤溶酶原激活物抑制剂1参与非小细胞肺癌的侵袭与转移%PAI-1 involve in invasion and metastasis of non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    刘明; 周承志; 欧阳铭

    2015-01-01

    目的:探讨尿激酶型纤溶酶原激活物抑制剂1(PAI-1)的表达与非小细胞肺癌(NSCLC)的浸润转移的关系。方法应用免疫组化的方法,观察68例 NSCLC 患者标本中 PAI-1在肺癌组织中的表达及细胞定位,分析其与肺癌病理类型、分期、转移的关系。检测 PAI-1在 NSCLC 细胞系中的表达,分析其与转移相关分子基质金属蛋白酶9的关系,观察细胞因子复合物 Cytomix(TGF-β1+IL-1β+IFN-γ)刺激 A549细胞后 PAI-1的变化及 PAI-1 siRNA 转染对其侵袭能力的影响。结果在 NSCLC 组织标本中,PAI-1的表达主要分布于细胞胞浆,部分可为细胞膜或细胞核,表达可见于肿瘤细胞、间质成纤维细胞、血管内皮细胞及部分巨噬细胞,阳性表达率分别为64.7%、44.1%、25.0%、22.1%(P <0.01)。PAI-1高表达多见于Ⅱ~Ⅲ期、有远处转移的肺癌患者。PAI-1在不同 NSCLC 细胞系具有不同的表达水平,且与转移相关蛋白基质金属蛋白酶9的表达一致。Cytomix 刺激可导致 PAI-1表达的上调,使A549细胞转分化为具有侵袭性的梭形细胞,而给予 PAI-1 siRNA 能抑制该表型的出现。结论 PAI-1在肺癌组织中高表达,提示其在肿瘤发生过程中发挥一定的作用,其不同的表达模式提示其不同的功能需要,PAI-1的表达与转移密切相关。%Objective To investigate the expression and clinical significance of plasminogen activator inhibitor-1 (PAI-1 )in non-small cell lung cancer (NSCLC).Methods Immunohistochemistry was applied to evaluate the expression of PAI-1 protein in 68 paraffin-embedded specimens with NSCLC, the correlations of their expression to the clinicopathologic characteristics of patients were analyzed.The expression and correlations of PAI-1 and matrix metalloprotein-9,and the role of PAI-1 in cell invasion were investigated in NSCLC cell lines by cytomix (transforming growth factor-β1 + interleukin-1β+interferon-γ)stimulation and PAI-1 si

  9. Fiber Intake and PAI-1 in type 2 diabetes: Look AHEAD Trial Findings at Baseline and Year 1

    Science.gov (United States)

    Belalcazar, L. Maria; Anderson, Andrea M.; Lang, Wei; Schwenke, Dawn C.; Haffner, Steven M.; Yatsuya, Hiroshi; Rushing, Julia; Vitolins, Mara Z.; Reeves, Rebecca; Pi-Sunyer, F. Xavier; Tracy, Russell P.; Ballantyne, Christie M.

    2014-01-01

    Plasminogen Activator Inhibitor 1 (PAI-1) is elevated in obese individuals with type 2 diabetes (T2DM) and may contribute, independently of traditional factors, to increased cardiovascular disease (CVD) risk. Fiber intake may decrease PAI-1 levels. We examined the associations of fiber intake and its changes with PAI-1, before and during an intensive lifestyle intervention for weight loss (ILI) in 1,701 Look AHEAD participants with dietary, fitness and PAI-1 data at baseline and 1-year. Look AHEAD was a randomized CVD trial in 5,145 overweight/obese subjects with T2DM, comparing ILI (goal of ≥7% reduction in baseline weight) with a control arm of diabetes support and education (DSE). ILI participants were encouraged to consume vegetables, fruits and grain products low in sugar and fat. At baseline, median fiber intake was 17.9 g/d. Each 8.3 g/day higher fiber intake was associated with a 9.2% lower PAI-1 level (p=0.008); this association persisted after weight and fitness adjustments (p=0.03). Higher baseline intake of fruit (p=0.019) and high-fiber grain and cereal (p=0.029) were related to lower PAI-1 levels. Although successful in improving weight and physical fitness at 1-year, ILI in Look AHEAD resulted in small increases in fiber intake (4.1g/day, compared with -2.35 g/day with DSE), which were not related to PAI-1 change (p=0.34). Only 31.3% of ILI participants (39.8% of women; 19.1% of men) met daily fiber intake recommendations. Increasing fiber intake in overweight/obese individuals with diabetes interested in weight loss is challenging. Future studies evaluating changes in fiber consumption during weight loss interventions are warranted. PMID:25131348

  10. Increased PAI-1 plasma levels and risk of death from dengue: no association with the 4G/5G promoter polymorphism

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    ten Cate H

    2005-11-01

    Full Text Available Abstract Background Dengue virus infected patients have high plasminogen activator inhibitor type I (PAI-1 plasma concentrations. Whether the insertion/deletion (4G/5G polymorphism in the promotor region of the PAI-1 gene is associated with increased PAI-1 plasma concentrations and with death from dengue is unknown. We, therefore, investigated the relationship between the 4G/5G polymorphism and PAI-1 plasma concentrations in dengue patients and risk of death from dengue. Methods A total of 194 patients admitted to the Dr. Kariadi Hospital in Semarang, Indonesia, with clinical suspected severe dengue virus infection were enrolled. Blood samples were obtained on day of admission, days 1, 2 and 7 after admission and at a 1-month follow-up visit. Plasma concentrations of PAI-1 were measured using a sandwich ELISA kit. The PAI-1 4G/5G polymorphism was typed by allele-specific PCR analysis. Results Concentrations of PAI-1 on admission and peak values of PAI-1 during admission were higher than the values measured in healthy controls. Survival was significantly worse in patients with PAI-1 concentrations in the highest tertile (at admission: OR 4.7 [95% CI 0.9–23.8], peak value during admission: OR 6.3 [95%CI 1.3–30.8]. No association was found between the PAI-1 4G/5G polymorphism, and PAI-1 plasma concentrations, dengue disease severity and mortality from dengue. Conclusion These data suggest that the 4G/5G polymorphism has no significant influence on PAI-1 concentrations in dengue virus infected patients and is not associated with the risk of death from dengue. Other factors contributing to the variability of PAI-1 plasma concentrations in patients with dengue need to be explored.

  11. The Effect of PAI-1 4G/5G Polymorphism and Clinical Factors on Coronary Artery Occlusion in Myocardial Infarction.

    Science.gov (United States)

    Parpugga, Tajinder Kumar; Tatarunas, Vacis; Skipskis, Vilius; Kupstyte, Nora; Zaliaduonyte-Peksiene, Diana; Lesauskaite, Vaiva

    2015-01-01

    Data on the impact of PAI-1-675 4G/5G genotype for fibrinolysis during myocardial infarction are inconsistent. The aim of our study was to evaluate the association of clinical and genetic (PAI-1-675 4G/5G polymorphism) factors with coronary artery occlusion in patients with myocardial infarction. PAI-1-675 4G/5G detection was achieved by using Sanger sequencing in a sample of patients hospitalized for stent implantation due to myocardial infarction. We categorized the patients into two groups: patients with coronary artery occlusion and patients without coronary artery occlusion according to angiographic evaluation. We identified n = 122 (32.4%) 4G/4G, n = 186 (49.5%) 4G/5G, and n = 68 (18.1%) 5G/5G PAI-1 genotype carriers. Univariate and multivariate analysis showed that only the 4G/5G genotype was associated with coronary artery occlusion (OR: 1.656 and 95% CI: 1.009-2.718, p = 0.046). Our results showed that carriers of PAI-1 4G/5G genotype with myocardial infarction have increased odds of coronary artery occlusion more than 1.6 times in comparison to the carriers of homozygous genotypes.

  12. TGF-β induces p53/Smads complex formation in the PAI-1 promoter to activate transcription

    Science.gov (United States)

    Kawarada, Yuki; Inoue, Yasumichi; Kawasaki, Fumihiro; Fukuura, Keishi; Sato, Koichi; Tanaka, Takahito; Itoh, Yuka; Hayashi, Hidetoshi

    2016-01-01

    Transforming growth factor β (TGF-β) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-β is still unknown, and it is unclear whether inhibition of TGF-β signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-β signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-β-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-β in several cell lines. Our results suggest that p53 enhances TGF-β-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-β is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-β-targeting therapies for cancer. PMID:27759037

  13. ZEB1 Promotes invasiveness of colorectal carcinoma cells through the opposing regulation of uPA and PAI-1

    DEFF Research Database (Denmark)

    Sánchez-Tilló, Ester; de Barrios, Oriol; Siles, Laura

    2013-01-01

    a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer...... DESIGN: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (-/-) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level. RESULTS: ZEB1 regulates uPA and PAI-1 in opposite......PURPOSE: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (β-catenin/TCF4). Tumor invasiveness...

  14. PAI-1 4G/5G polymorphism and coronary artery disease risk: a meta-analysis

    Science.gov (United States)

    Liang, Zhongshu; Jiang, Weihong; Ouyang, Mao; Yang, Kan

    2015-01-01

    Many epidemiologic studies have investigated the plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G polymorphism and this association with coronary artery disease (CAD). But definite conclusions can not be drawn. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 10 August 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. A total of 53 studies including 20921 CAD cases and 18434 controls were included. Significantly elevated CAD risk was found in overall analysis (OR = 1.13, 95% CI: 1.05-1.21, P = 0.0009). In the subgroup analysis by races, significantly increased risk was found in Caucasians (OR = 1.11, 95% CI: 1.03-1.20, P = 0.005) and Asians (OR = 1.20, 95% CI: 1.01-1.42, P = 0.04). In the subgroup analysis by gender, significant association was found in males (OR = 1.15, 95% CI: 1.06-1.25, P = 0.0008), but was not found in females (OR = 1.05, 95% CI: 0.92-1.20, P = 0.47). In the subgroup analysis by age, young populations showed increased CAD risk (OR = 1.19, 95% CI: 1.02-1.37, P = 0.02), but old populations did not show this association (OR = 1.01, 95% CI: 0.82-1.24, P = 0.93). This meta-analysis provides the evidence that PAI-1 4G/5G polymorphism may contribute to the CAD development. PMID:25932140

  15. PAI-1 4G/5G polymorphism and coronary artery disease risk: a meta-analysis.

    Science.gov (United States)

    Liang, Zhongshu; Jiang, Weihong; Ouyang, Mao; Yang, Kan

    2015-01-01

    Many epidemiologic studies have investigated the plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G polymorphism and this association with coronary artery disease (CAD). But definite conclusions can not be drawn. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 10 August 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. A total of 53 studies including 20921 CAD cases and 18434 controls were included. Significantly elevated CAD risk was found in overall analysis (OR = 1.13, 95% CI: 1.05-1.21, P = 0.0009). In the subgroup analysis by races, significantly increased risk was found in Caucasians (OR = 1.11, 95% CI: 1.03-1.20, P = 0.005) and Asians (OR = 1.20, 95% CI: 1.01-1.42, P = 0.04). In the subgroup analysis by gender, significant association was found in males (OR = 1.15, 95% CI: 1.06-1.25, P = 0.0008), but was not found in females (OR = 1.05, 95% CI: 0.92-1.20, P = 0.47). In the subgroup analysis by age, young populations showed increased CAD risk (OR = 1.19, 95% CI: 1.02-1.37, P = 0.02), but old populations did not show this association (OR = 1.01, 95% CI: 0.82-1.24, P = 0.93). This meta-analysis provides the evidence that PAI-1 4G/5G polymorphism may contribute to the CAD development.

  16. The Role of PAI-1 4G/5G Promoter Polymorphism and Its Levels in the Development of Ischemic Stroke in Young Indian Population.

    Science.gov (United States)

    Akhter, Mohammad Suhail; Biswas, Arijit; Abdullah, Saleh Mohammed; Behari, Madhuri; Saxena, Renu

    2017-01-01

    The plasminogen activator inhibitor-1 (PAI-1) gene has been found to be associated with the pathogenesis and progression of vascular diseases including stroke. A 4G/5G, PAI-1 gene polymorphism has been found to be associated with the plasma PAI-1 levels in different ethnic populations but results are still controversial. The aim of this study was to determine the potential association of 4G/5G polymorphism and plasma PAI-1 levels in the development of ischemic stroke (IS) in young Asian Indians. One hundred patients with IS and an equal number of age- and sex-matched controls were studied. The 4G/5G polymorphism was genotyped in the study population through allele-specific polymerase chain reaction. Plasma PAI-1 levels were evaluated using a commercial kit. The PAI-1 levels were significantly higher in patients when compared to the controls ( P = .03). The variant 4G allele for the PAI-I 4G/5G polymorphism showed both genotypic ( P = .0013, χ(2) = 10.303; odds ratio [OR] = 3.75) as well as allelic association ( P = .0004, χ(2) = 12.273; OR = 1.99) with IS. The homozygous variant 4G/4G also was found to be associated with the higher PAI-1 levels (0.005). The variant allele 4G of PAI-1 4G/5G polymorphism and higher plasma PAI-1 levels were found to be significantly associated with IS in young Asian Indians.

  17. Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population.

    Science.gov (United States)

    Shammaa, Dina M R; Sabbagh, Amira S; Taher, Ali T; Zaatari, Ghazi S; Mahfouz, Rami A R

    2008-09-01

    Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. Increased plasma PAI-1 levels play an essential role in the pathogenesis of cardiovascular risk and other diseases associated with thrombosis. The 4G/5G polymorphism of the PAI-1 promoter region has been extensively studied in different populations. We studied 160 healthy unrelated Lebanese individuals using a reverse hybridization PCR assay to detect the 5G/5G, 4G/5G and, 4G/4G genotypes of the PAI-1 gene and the frequencies of the 4G and 5G alleles. We found that 4G/5G genotype was the most prevalent (45.6%) followed by 5G/5G (36.9%) and 4G/4G (17.5%). The frequencies of the 4G and 5G alleles were calculated to be 0.403 and 0.597, respectively. Compared to other ethnic communities, the Lebanese population was found to harbour a relatively high prevalence of the rare 4G allele. This, in turn, may predispose this population to develop cardiovascular diseases and other thrombotic clinical conditions. This study aids to enhance our understanding of the genetic features of the Lebanese population.

  18. Inhibition of PAI-1 release from human endothelial cells by Angelica keiskei Koidzumi (Ashitaba chalcones is structure-dependent

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    Naoki Ohkura

    2015-12-01

    Full Text Available Angelica keiskei Koidzumi (Ashitaba is a traditional herbal medicine and it is also regarded in Japan as a health food that might have antithrombotic properties. Ashitaba exudate suppresses lipopolysaccharide (LPS-induced plasma plasminogen activator inhibitor 1 (PAI-1, a risk factor for thrombotic diseases in mice. Xanthoangelol (XA and 4-hydroxyderricin (4-HD comprise > 95% of total chalcones from Ashitaba exudates that also contain trace amounts of other chalcone subtypes. The present study aimed to determine the effects of Ashitaba chalcones including xanthoangelols B (XB, D (XD, E (XE, F (XF and XA as well as 4-HD on PAI-1 levels in the medium of stimulated human EA.hy926 endothelial cells. Xanthoangelol (10 and #61549;M inhibited PAI-1 production at a rate of 77.1%, whereas the inhibition rates of XB, XD, XE and 4-HD were not significant. Xanthoangelol F was highly cytotoxic and thus its ability to inhibit PAI-1 production could not be evaluated. The side hydrocarbon chain of XA played an important role in the excretion of inhibitory activity. Small modifications of the hydrocarbon chain or small functional groups on the A ring measurably influenced the inhibitory activity of xanthoangelols. These findings warrant future research towards an understanding of the mechanism of antithrombotic action of Ashitaba as herbal medicine or antithrombotic health food. [J Intercult Ethnopharmacol 2015; 4(4.000: 355-357

  19. PAI-1 gene: pharmacogenetic association of 4G/4G genotype with bleeding after cardiac surgery--pilot study.

    Science.gov (United States)

    Sirgo, Gonzalo; Morales, Pablo; Rello, Jordi

    2009-05-01

    To investigate whether the 4G/4G genotype of the PAI-1 gene is associated with bleeding after cardiac surgery and whether it may influence the use of antifibrinolytic drugs. After a case-control association study to compare the distribution of genotypes of the 4G/5G polymorphism of the PAI-1 gene (4G/4G, 4G/5G and 5G/5G) between cardiac surgery patients (n = 260) and nonhospitalized age-matched controls (n = 111), we have evaluated the possible association of genotype homozygous 4G/4G (considered procoagulant) in two cohorts of cardiac surgery patients (treated with aprotinin or tranexamic acid) with postoperative bleeding and transfusion requirements. Chest tube output was measured at 6 h and 24 h and then total blood output. Genotypes were typed using restriction fragment length polymorphism analysis. The PAI-1 4G/4G genotype was not associated with bleeding except in the subgroup of patients treated with aprotinin in whom blood loss was significantly lower than in nonhomozygous 4G/4G patients at 6 h and 24 h [mean 135.9 ml (SD 101.8 ml) vs. mean 227.6 ml (SD 218.2 ml), P bleeding in the general patient population. The 4G/4G genotype of the PAI-1 gene was associated with less bleeding after cardiac surgery only in the subgroup of patients treated with aprotinin.

  20. The -844 G>A PAI-1 Polymorphism Is Associated with Acute Coronary Syndrome in Mexican Population

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    Ilian Janet García-González

    2015-01-01

    Full Text Available Background. Acute coronary syndrome (ACS has an important impact in public health with high morbidity and mortality. Prothrombotic and proinflammatory states are involved in the pathogenesis of the disease. Plasminogen activator inhibitor-1 (PAI-1 is the major inhibitor of the fibrinolysis and also is part of immune response. The -844 G>A gene polymorphism is related to increased PAI-1 protein levels. The aim of the study is to evaluate the association of -844 G>A PAI-1 polymorphism with ACS. Methods. A total of 646 individuals were recruited from Western Mexico: 350 unrelated healthy subjects and 296 patients with diagnosis of ACS. Results. The most important risk factor in our population was hypertension, followed by smoking. The genetic distribution showed an association of the A allele (OR=1.27, P=0.04 and AA genotype (OR=1.86, P=0.02 with ACS. The recessive model displayed similar results (OR=1.76, P=0.02. As additional finding, we observed significant differences in the genetic distribution of ACS dyslipidemic patients (OR=1.99, P=0.04. The A allele and AA genotype of -844 polymorphism of PAI-1 gene are risk factors for ACS. The AA genotype might be associated with the development of dyslipidemia in ACS patients.

  1. Relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss

    NARCIS (Netherlands)

    Kockx, M.; Leenen, R.; Seidell, J.; Princen, H.M.G.; Kooistra, T.

    1999-01-01

    This study was aimed at evaluating the relationship between visceral fat accumulation and plasma plasminogen activator inhibitor-1 (PAI-1) levels in healthy, obese men and women undergoing weight loss therapy. The subjects, 25 men and 25 premenopausal women, aged between 26 and 49 years, with an

  2. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

    NARCIS (Netherlands)

    Huang, Jie; Sabater-Lleal, Maria; Asselbergs, Folkert W.; Tregouet, David; Shin, So-Youn; Ding, Jingzhong; Baumert, Jens; Oudot-Mellakh, Tiphaine; Folkersen, Lasse; Johnson, Andrew D.; Smith, Nicholas L.; Williams, Scott M.; Ikram, Mohammad A.; Kleber, Marcus E.; Becker, Diane M.; Vinh Truong, [No Value; Mychaleckyj, Josyf C.; Tang, Weihong; Yang, Qiong; Sennblad, Bengt; Moore, Jason H.; Williams, Frances M. K.; Dehghan, Abbas; Silbernagel, Guenther; Schrijvers, Elisabeth M. C.; Smith, Shelly; Karakas, Mahir; Tofler, Geoffrey H.; Silveira, Angela; Navis, Gerjan J.; Lohman, Kurt; Chen, Ming-Huei; Peters, Annette; Goel, Anuj; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Lundmark, Per; Psaty, Bruce M.; Strawbridge, Rona J.; Boehm, Bernhard O.; Carter, Angela M.; Meisinger, Christa; Peden, John F.; Bis, Joshua C.; McKnight, Barbara; Ohrvik, John; Taylor, Kent; Franzosi, Maria Grazia; Seedorf, Udo; Collins, Rory; Franco-Cereceda, Anders; Syvaenen, Ann-Christine; Goodall, Alison H.; Yanek, Lisa R.; Cushman, Mary; Mueller-Nurasyid, Martina; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Kooner, Jaspal S.; Hofman, Albert; Danesh, John; Clarke, Robert; Meigs, James B.; Kathiresan, Sekar; Reilly, Muredach P.; Klopp, Norman; Harris, Tamara B.; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Watkins, Hugh; Spector, Timothy D.; Becker, Lewis C.; Tracy, Russell P.; Maerz, Winfried; Uitterlinden, Andre G.; Eriksson, Per; Cambien, Francois; Morange, Pierre-Emmanuel; Koenig, Wolfgang; Soranzo, Nicole; van der Harst, Pim; Liu, Yongmei; O'Donnell, Christopher J.; Hamsten, Anders

    2012-01-01

    We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19

  3. Influence of PAI-1 gene promoter-675 (4G/5G) polymorphism on fibrinolytic activity after cardiac surgery employing cardiopulmonary bypass.

    Science.gov (United States)

    Ozolina, Agnese; Strike, Eva; Jaunalksne, Inta; Serova, Jelena; Romanova, Tatjana; Zake, Liene Nikitina; Sabelnikovs, Olegs; Vanags, Indulis

    2012-01-01

    The plasminogen activator inhibitor type-1 (PAI-1) gene promoter contains 675 (4G/5G) polymorphism. The aim of this study was evaluate the effect of the PAI-1 promoter-675 (4G/5G) polymorphism on the concentrations of PAI-1 and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex and bleeding volume after on-pump cardiac surgery. A total of 90 patients were included in the study at Pauls Stradins Clinical University Hospital. Seven patients were excluded due to surgical bleeding. Eighty-three patients were classified according to the PAI-1 genotype: 21 patients had the 4G/4G genotype; 42, the 4G/5G genotype; and 20, the 5G/5G genotype. The following fibrinolysis parameters were recorded: the PAI-1 level preoperatively, D-dimer level at 0, 6, and 24 hours after surgery, and t-PA/PAI-1 complex level 24 hours postoperatively. A postoperative bleeding volume was registered in mL 24 hours after surgery. The patients with the 5G/5G genotype had significantly lower preoperative PAI-1 levels (17 [SD, 10.8] vs. 24 ng/mL [SD, 9.6], P=0.04), higher D-dimer levels at 6 hours (371 [SD, 226] vs. 232 ng/mL [SD, 185], P=0.03) and 24 hours (326 [SD, 207] vs. 209 ng/mL [SD, 160], P=0.04), and greater postoperative blood loss (568 [SD, 192] vs. 432 mL [168], P=0.02) compared with the 4G/4G carriers. There were no significant differences in the levels of the t-PA/PAI-1 complex comparing different genotype groups. The carriers of the 5G/5G genotype showed the lower preoperative PAI-1 levels, greater chest tube blood loss, and higher D-dimer levels indicating that the 5G/5G carriers may have enhanced fibrinolysis.

  4. Optimized immunohistochemistry in combination with image analysis: a reliable alternative to quantitative ELISA determination of uPA and PAI-1 for routine risk group discrimination in breast cancer.

    Science.gov (United States)

    Lang, D S; Heilenkötter, U; Schumm, W; Behrens, O; Simon, R; Vollmer, E; Goldmann, T

    2013-10-01

    The determination of the invasion markers urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) has further improved the possibilities for individualized therapy of breast cancer. To date, quantitative measurement by ELISA, that needs large amounts of fresh, frozen material, is the only standardized procedure for diagnostic purposes. Therefore, the aim of this study was the establishment of a reliable alternative method based on immunohistochemistry (IHC) and image analysis requiring only small amounts of fixed tumor tissue. Protein expression of uPA and PAI-1 was analyzed in HOPE-fixed tumor samples using tissue microarrays (TMAs) and semiquantitative image analysis. The results of both methods were significantly correlated and risk assessment showed an overall concordance of 78% (83/107; high- and low-risk) and of 94% (74/79) regarding only high-risk patients. The data demonstrate that optimized IHC in combination with image analysis can provide adequate clinical significance compared to ELISA-derived determination of uPA and PAI-1.

  5. PAI-1 promoter 4G/5G polymorphism (rs1799768) contributes to tumor susceptibility: Evidence from meta-analysis.

    Science.gov (United States)

    Xu, Xin; Xie, Yanqi; Lin, Yiwei; Xu, Xianglai; Zhu, Yi; Mao, Yeqing; Hu, Zhenghui; Wu, Jian; Chen, Hong; Zheng, Xiangyi; Qin, Jie; Xie, Liping

    2012-12-01

    Plasminogen activator inhibitor-1 (PAI-1), belonging to the urokinase plasminogen activation (uPA) system, is involved in cancer development and progression. The PAI-1 promoter 4G/5G polymorphism was shown to contribute to genetic susceptibility to cancer, although the results were inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The electronic databases PubMed, Scopus, Web of Science and Chinese National Knowledge Infrastructure (CNKI) were searched; data were extracted and analyzed independently by two reviewers. Ultimately, 21 eligible case-control studies with a total of 8,415 cancer cases and 9,208 controls were included. The overall odds ratio (OR) with its 95% confidence interval (CI) showed a statistically significant association between the PAI-1 promoter 4G/5G polymorphism and cancer risk (4G/4G vs. 5G/5G: OR=1.25, 95% CI=1.07-1.47, P(heterogeneity)=0.001; 4G/4G vs. 4G/5G+5G/5G: OR=1.10, 95% CI=1.03-1.17, P(heterogeneity)=0.194; 4G/4G+4G/5G vs. 5G/5G: OR=1.17, 95% CI=1.01-1.35, P(heterogeneity)=0.041). In further subgroup analyses, the increased risk of cancer was observed in a subgroup of Caucasians with regards to endometrial cancer. Our meta-analysis suggests that the PAI-1 4G/5G polymorphism most likely contributes to susceptibility to cancer, particularly in Caucasians. Furthermore, the 4G allele may be associated with an increased risk of endometrial cancer.

  6. Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms.

    Directory of Open Access Journals (Sweden)

    G R Scott Budinger

    Full Text Available BACKGROUND: Exposure of human populations to ambient particulate matter (PM air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism. METHODS AND PRINCIPAL FINDINGS: Adult, male C57BL/6 and IL-6 knock out (IL-6(-/- mice were exposed to either concentrated ambient PM less than 2.5 µm (CAPs or filtered air 8 hours daily for 3 days or were exposed to either urban particulate matter or PBS via intratracheal instillation and examined 24 hours later. Exposure to CAPs or urban PM resulted in the IL-6 dependent activation of coagulation in the lung and systemically. PAI-1 mRNA and protein levels were higher in the lung and adipose tissue of mice treated with CAPs or PM compared with filtered air or PBS controls. The increase in PAI-1 was similar in wild-type and IL-6(-/- mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation. CONCLUSIONS: Mice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state.

  7. Prognostic significance of tPA/PAI-1 complex in patients with heart failure and preserved ejection fraction.

    Science.gov (United States)

    Winter, Max-Paul; Kleber, Marcus E; Koller, Lorenz; Sulzgruber, Patrick; Scharnagl, Hubert; Delgado, Graciela; Goliasch, Georg; März, Winfried; Niessner, Alexander

    2017-02-28

    Heart failure with preserved ejection fraction (HFpEF) represents a major epidemic, clinical and public health problem with rising patient numbers every year. Traditional markers for heart failure have been shown to be of limited sensitivity in patients with HFpEF, as those do not reflect pathophysiology of the disease properly. Dysregulation of haemostasis is thought to be central for the initiation and progression of HFpEF. For this reason, we aimed to assess markers of fibrinolytic activity as potential biomarkers for risk assessment in patients with HFpEF. We evaluated blood coagulation parameters in 370 patients with HFpEF included in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. Within an observation period of 9.7 years, 40 percent of these patients died from any cause. tPA/PAI-1 complex significantly predicted all-cause mortality with a hazard ratio (HR) of 1.24 (95 % confidence interval [CI] 1.04-1.47) per increase of 1 SD and cardiovascular mortality with a HR 1.26 (95 % CI 1.02-1.56) per increase of 1 SD. Both associations remained significant after adjustment for cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and frequent HFpEF- related comorbidities. Importantly, tPA/PAI-1 complex had additional prognostic value above and beyond NT-proBNP as indicated by integrated discrimination improvement (0.0157, p=0.017). In conclusion, the concentration of tPA/PAI-1 complex is an independent predictor of mortality from all causes and from cardiovascular causes in patients with HFpEF. The concomitant measurement of tPA/PAI-1 complex might be useful in clinical practice to add prognostic value to traditional markers of heart failure.

  8. Evaluation of 12-Lipoxygenase (12-LOX and Plasminogen Activator Inhibitor 1 (PAI-1 as Prognostic Markers in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Tomasz Gondek

    2014-01-01

    Full Text Available In carcinoma of prostate, a causative role of platelet 12-lipoxygenase (12-LOX and plasminogen activator inhibitor 1 (PAI-1 for tumor progression has been firmly established in tumor and/or adjacent tissue. Our goal was to investigate if 12-LOX and/or PAI-1 in patient’s plasma could be used to predict outcome of the disease. The study comprised 149 patients (age 70±9 divided into two groups: a study group with carcinoma confirmed by positive biopsy of prostate (n=116 and a reference group (n=33 with benign prostatic hyperplasia (BPH. The following parameters were determined by the laboratory test in plasma or platelet-rich plasma: protein level of 12-LOX, PAI-1, thromboglobulin (TGB, prostate specific antigen (PSA, C-reactive protein (CRP, hemoglobin (HGB, and hematocrit (HCT, as well as red (RBC and white blood cells (WBC, number of platelets (PLT, international normalized ratio of blood clotting (INR, and activated partial thromboplastin time (APTT. The only difference of significance was noticed in the concentration of 12-LOX in platelet rich plasma, which was lower in cancer than in BPH group. Standardization to TGB and platelet count increases the sensitivity of the test that might be used as a biomarker to assess risk for prostate cancer in periodically monitored patients.

  9. The role of TPA I/D and PAI-1 4G/5G polymorphisms in multiple sclerosis.

    Science.gov (United States)

    Zivković, Maja; Starčević Čizmarević, Nada; Lovrečić, Luca; Klupka-Sarić, Inge; Stanković, Aleksandra; Gašparović, Iva; Lavtar, Polona; Dinčić, Evica; Stojković, Ljiljana; Rudolf, Gorazd; Jazbec, Saša Sega; Perković, Olivio; Sinanović, Osman; Sepčić, Juraj; Kapović, Miljenko; Peterlin, Borut; Ristić, Smiljana

    2014-01-01

    Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63-0.99, P = 0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01-1.66, P = 0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06-1.82, P = 0.017). We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS.

  10. Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the Gaza Strip.

    Science.gov (United States)

    Al Sallout, Rami J; Sharif, Fadel A

    2010-01-01

    This study was conducted to investigate the correlation between spontaneous recurrent miscarriage (RM) and common polymorphisms in angiotensin-converting enzyme (ACE), plasminogen activator inhibitor 1 (PAI-1) and endothelium-derived nitric oxide synthase 3 (NOS3) genes among women experiencing RM in the Gaza Strip. The presence of these genetic profiles was determined for 100 women who had had at least 3 constitutive abortions and 100 controls without any history of abortion using molecular biological techniques. The ACE D/D polymorphism was present in 49% of the study population and in 54% of the controls (p = 0.479). Similarly, there was no significant difference detected in the distribution of polymorphisms for PAI-1, with the 4G/4G genotype present in the study group and in controls (p = 1.00). NOS3 4a/4a was present in 4% of the study group and in none of the 100 controls (p = 0.123). In this study, we also discovered a new variant in the NOS3 gene which was named 4c allele and was encountered in 1 patient and in 1 control subject. There was no significant association between ACE I/D, PAI-1 4G/5G and NOS3 4a/4b and the occurrence of first-trimester RM. In-depth investigation of the association of NOS3 4a/4a with RM is strongly recommended. Copyright 2010 S. Karger AG, Basel.

  11. 肾病综合征、过敏性紫癜患儿尿液PAI-1含量的检测及意义

    Institute of Scientific and Technical Information of China (English)

    陈晓晴; 江明华; 陶洪群; 温怀凯

    2006-01-01

    目的 探讨肾病综合征、过敏性紫癜患儿尿液PAI-1含量的改变及其与疾病的关系.方法 用ELISA法检测尿液PAI-1含量,速率散射比浊法测定尿微量蛋白,常规生化方法检测肾功能.结果 NS组尿液PAI-1含量升高(P<0.05),PAI-1与尿微量蛋白无明显相关性(P值均>0.05),和血肌酐值呈正相关;HSPN组尿液PAI-1升高,但无统计学意义(P>0.05);HSP无肾炎组尿液PAI-1无明显变化.结论 尿液中PAI-1含量可成为反映肾脏局部血管损害的一项指标,该指标对过敏性紫癜意义不大.

  12. PAI-1与妊娠期糖尿病及胰岛素抵抗关系的研究

    Institute of Scientific and Technical Information of China (English)

    吴艳; 丛林

    2009-01-01

    分别测定40例GDM孕妇和40例正常妊娠妇女身高,体重,FBG,FINS;计算指数,胰岛素抵抗指数.应用ELISA法检测研究对象血浆PAI-1水平,免疫组化PV-9000法检测对应脂肪组织PAI-1表达情况.结果:GDM组血浆PAI-1明显高于正常妊娠组(P<0.01);GDM组肥胖孕妇血浆PAI-1均值400.89±45.69ng/ml,明显高于非肥胖孕妇(P<0.01);血浆PAI-1与胰岛素抵抗呈正相关(P<0.001);PAI-1在GDM组脂肪组织中阳性表达率为37.5%,明显高于正常妊娠组的阳性表达率17.5%(P<0.05);GDM组肥胖孕妇与非肥胖孕妇中脂肪组织PAI-1表达无显著差异性.结论:在GDM孕妇的血浆和脂肪组织中都存在PAI-1升高现象,PAI-1与胰岛素抵抗有明显相关性.

  13. Impact of guideline-based use of uPA/PAI-1 on patient outcome in intermediate-risk early breast cancer.

    Science.gov (United States)

    Kolben, Thomas; Augustin, D; Armbrust, R; Kolben, T M; Degenhardt, T; Burgmann, M; Goess, C; Ditsch, N; Kates, R; Harbeck, N; Wuerstlein, R

    2016-01-01

    The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5 % of patients with low uPA/PAI-1, i.e., 38.8 % of the total patient collective. Median follow-up was 52.5 months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99 %. Five-year overall survival including all causes of death was 95 %. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5 years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center.

  14. Increased Serum PAI-1 Levels in Subjects with Metabolic Syndrome and Long-Term Adverse Mental Symptoms: A Population-Based Study

    Directory of Open Access Journals (Sweden)

    Anne Huotari

    2010-01-01

    Full Text Available Depression is an independent risk factor for cardiovascular diseases and is associated with metabolic syndrome (MetS. Levels of plasminogen activator inhibitor-1 (PAI-1, an inhibitor of tissue-type and urokinase-type plasminogen activators, are associated with MetS. To clarify the role of PAI-1 in subjects with long-term adverse mental symptomatology (LMS; including depression and MetS, we measured circulating PAI-1 levels in controls (n=111, in subjects with MetS and free of mental symptoms (n=42, and in subjects with both MetS and long-term mental symptoms (n=70. PAI-1 increased linearly across the three groups in men. In logistic regression analysis, men with PAI-1 levels above the median had a 3.4-fold increased likelihood of suffering from the comorbidity of long-term adverse mental symptoms and MetS, while no such associations were detected in women. In conclusion, our results suggest that in men high PAI-1 levels are independently associated with long-term mental symptomatology.

  15. Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle.

    Science.gov (United States)

    Scheer, Frank A J L; Shea, Steven A

    2014-01-23

    Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. Plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a key circulating prothrombotic factor that rises in the morning in humans. We tested whether this morning peak in PAI-1 is caused by the internal circadian system or by behaviors that typically occur in the morning, such as altered posture and physical activity. Twelve healthy adults underwent a 2-week protocol that enabled the distinction of endogenous circadian effects from behavioral and environmental effects. The results demonstrated a robust circadian rhythm in circulating PAI-1 with a peak corresponding to ∼6:30 am. This rhythm in PAI-1 was 8-times larger than changes in PAI-1 induced by standardized behavioral stressors, including head-up tilt and 15-minute cycle exercise. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events.

  16. The Role of TPA I/D and PAI-1 4G/5G Polymorphisms in Multiple Sclerosis

    Science.gov (United States)

    Živković, Maja; Starčević Čizmarević, Nada; Lovrečić, Luca; Klupka-Sarić, Inge; Stanković, Aleksandra; Gašparović, Iva; Dinčić, Evica; Stojković, Ljiljana; Rudolf, Gorazd; Šega Jazbec, Saša; Perković, Olivio; Sinanović, Osman; Sepčić, Juraj; Kapović, Miljenko; Peterlin, Borut

    2014-01-01

    Background. Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). Methods. The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. Results. TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63–0.99, P = 0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01–1.66, P = 0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06–1.82, P = 0.017). Conclusions. We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS. PMID:24825926

  17. Prognostic value of the PAI-1 4G/5G polymorphism in invasive ductal carcinoma of the breast.

    Science.gov (United States)

    Yagmurdur, M C; Atac, F B; Tutar, N U; Verdi, H; Isiklar, I; Ozdemir, B H; Ozbek, N; Karakayali, H; Haberal, M

    2008-01-01

    The study group was derived from the archive materials of 55 invasive ductal breast cancer (IDC) patients who had undergone breast-preserving surgery (partial mastectomy/ axillary dissection). All patients included in the study had clinically T(1)-2, N0-M0 invasive ductal carcinoma. Genomic DNA species were extracted from paraffin-embedded blocks, and plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Patient demographics, axillary metastasis status, metastatic lymph nodi/total dissected lymph nodes from axilla, histopathologic characteristics of tumors, local recurrences, and survival ratio were assessed. PAI-1 4G/5G genotype frequencies were 4G/4G (64%), 4G/5G (31%), and 5G/5G (5%) in the patient group. According to the results based on frequencies, the demographics were not different. Five-year local recurrence rate of 4G/5G patients was the lowest (2/17, 12%) (P = 0.02). Also five-year distant metastases ratio of 4G/5G patients was the highest (18%) (P = 0.01). Five- and 10-year disease-free survival rates for the 4G/4G, 4G/5G, and 5G/5G groups were 97% and 94%, 82% and 77%, and 100% and 94%, respectively (P = 0.004). The results of this study indicate that the 4G allele in the PAI 1 gene had a negative impact on local recurrence and disease-free survival of patients with clinical T(1)-2N0M0 IDC.

  18. The Role of TPA I/D and PAI-1 4G/5G Polymorphisms in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Maja Živković

    2014-01-01

    Full Text Available Background. Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA and its inhibitor (PAI-1 are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS. Methods. The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. Results. TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63–0.99, P=0.037 and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01–1.66, P=0.038. A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06–1.82, P=0.017. Conclusions. We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS.

  19. Moderate rest intervals are superior to short intervals for improving PAI-1 following exhaustive exercise in recreational weightlifters.

    Science.gov (United States)

    Rossi, Fabrício Eduardo; Gerosa-Neto, Jose; Diniz, Tiego Aparecido; Freitas, Ismael F; Lira, Fabio Santos; Cholewa, Jason Michael

    2016-12-01

    This study investigated the influence of short and moderate recovery intervals on lipid profiles and plasminogen activator inhibitor-1 (PAI-1) following exhaustive strength exercise in recreational weightlifters. Seven subjects performed two conditions in a randomized order: short, 90% of one maximum repetition (1RM) and 30-sec rest allowed between sets; moderate, 90% of 1RM and 90-sec rest allowed between sets. Total cholesterol (Chol), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triacylglycerol (TAG), Chol/HDL-c ratio and PAI-1 concentrations were assessed at baseline, immediately postexercise, and 15- and 30-min postexercise (post-15 and post-30). The LDL-c concentrations decreased and HDL-c concentrations increased in both conditions but without significant differences (LDL-c: 30 sec: pre, 82.0±19.5 mg/dL, immediately, 73.9±16.4 mg/dL, 90 sec: pre, 75.9±30.8 mg/dL, immediately, 66.2±35.5 mg/dL, P=0.423; HDL-c: 30 sec: pre, 53.5±9.2 mg/dL, immediately, 61.4±11.4 mg/dL; 90 sec: pre, 55.8±11.1 mg/dL, immediately, 84.9±27.8, mg/dL; P=0.146). On the other hand, PAI-1 had a tendency to decrease only in the 90-sec condition (pre, 7,754.9±2,927.7 pg/mL; immediately, 5,313.1±4,637.4 pg/mL; P=0.085). There was a positive correlation between PAI-1 and Chol (30 sec: r=0.83, 90 sec: r=0.91; PPAI-1 and fat-free mass in both conditions (30 sec post-15: r=0.79, post-30: r=081, PPAI-1 and TAG only in 30 sec (r=0.87, PPAI-1 concentration in recreational weightlifters.

  20. Association between PAI-1 4G/5G polymorphism and diabetic nephropathy: a meta-analysis in the Chinese population.

    Science.gov (United States)

    Gao, Wen-Feng; Guo, Ying-Bo; Bai, Yu; Ding, Xin-Yu; Yan, Yong-Ji; Wu, Zhen-Qi

    2016-09-01

    Although a number of studies have been conducted on the association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and diabetic nephropathy (DN) in Chinese population, this association remains elusive and controversial. To further assess the effects of PAI-1 4G/5G polymorphism on the risk of DN, a meta-analysis was performed in the Chinese population. Relevant studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine through November, 2015. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the associations. This meta-analysis identified nine studies, including 777 DN cases, 413 healthy controls, and 523 DM controls. In the total analyses, a significantly elevated risk of DN was associated with variants of PAI-1 4G/5G when compared with the healthy group (4G vs. 5G, OR 2.46, 95 % CI 1.45-4.16; 4G/4G vs. 5G/5G, OR 4.32, 95 % CI 1.79-10.39; 4G/4G vs. 4G/5G +5G/5G, OR 2.96, 95 % CI 1.59-5.53; 4G/4G +4G/5G vs. 5G/5G, OR 2.78, 95 % CI 1.34-5.75) and DM group (4G vs. 5G, OR 1.93, 95 % CI 1.28-2.92; 4G/4G vs. 5G/5G, OR 2.99, 95 % CI 1.44-6.21; 4G/4G vs. 4G/5G +5G/5G, OR 2.84, 95 % CI 1.77-4.54). In the subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. This meta-analysis showed that the PAI-1 4G/4G variant, 4G allele might be risk alleles for DN susceptibility in the Chinese population, and further studies in other ethic groups are required for definite conclusions.

  1. Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function

    Science.gov (United States)

    Kim, Dong Young; Oh, Sam S.; Torgerson, Dara R.; Pino-Yanes, Maria; Hu, Donglei; Sen, Saunak; Huntsman, Scott; Eng, Celeste; Farber, Harold J.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose R.; Serebrisky, Denise; Thyne, Shannon M.; Borrell, Luisa N.; Williams, L. Keoki; DuPont, William; Seibold, Max A.; Burchard, Esteban G.; Avila, Pedro C.; Kumar, Rajesh

    2016-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk. Methods We included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function. Results RSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted. Conclusions A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population. PMID:27556405

  2. Binding of upstream stimulatory factor 1 to the E-box regulates the 4G/5G polymorphism-dependent plasminogen activator inhibitor 1 expression in mast cells.

    Science.gov (United States)

    Ma, Zhongcai; Jhun, Bongsook; Jung, Sandy Y; Oh, Chad K

    2008-04-01

    Plasminogen activator inhibitor (PAI)-1 is a key regulator of the fibrinolytic system. PAI-1 levels are markedly elevated in the asthmatic airways. The 4G/5G polymorphism of the PAI-1 gene is associated with allergic asthma. To characterize the mechanisms of the 4G/5G-dependent PAI-1 expression in mast cells (MCs), a major source of PAI-1 and key effector cells in asthma. Transcription of PAI-1 was assessed by transiently transfecting human MC line (HMC-1) cells with the luciferase-tagged PAI-1 promoters containing the 4G or 5G allele (4G-PAI-1 or 5G-PAI-1 promoter). Upstream stimulatory factor (USF)-1 and the E-box interactions were studied by electrophoretic mobility shift assays and supershift assays. Expression of USF-1 was determined by Western blot analysis. The 4G-PAI-1 promoter has higher promoter activity than the 5G-PAI-1 promoter in stimulated HMC-1 cells, and the E-box adjacent to the 4G/5G site (E-4G/5G) regulates the genotype-specific PAI-1 transcription. USF-1 binds to the E-4G with greater affinity than to the E-5G. USF-1 level is increased in HMC-1 cells after stimulation, and elevated USF-1 enhances PAI-1 transcription. Overexpression of wild-type USF-1 or dominant-negative USF remedies the 4G/5G-dependent PAI-1 transcription. Binding of USF-1 to the E-4G/5G regulates the 4G/5G polymorphism-dependent PAI-1 expression in MCs.

  3. Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population.

    Science.gov (United States)

    Wang, Yongjie; Long, Jianhong; Wang, Xiaoyan; Sun, Yang

    2014-10-28

    A keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk. A total of 242 Chinese keloid patients and 207 controls were enrolled in this study. Polymerase chain reaction-restriction technique was used to determine PAI-1 promoter polymorphism (-675 4G/5G and -844 A/G) distribution. Plasma PAI-1 levels were detected using enzyme-linked immunosorbent assay (ELISA). There was a statistically significant difference in the distribution of PAI-1 -675 4G/5G polymorphism between keloid patients and healthy controls. 4G/4G carriers were more likely to develop keloid. In contrast, the -844 A/G polymorphism distribution did not vary significantly between keloid patients and controls. The keloid patients group had a significantly higher plasma PAI-1 level than the control group. In the -675 4G/4G carrier population, the plasma PAI-1 levels were significant higher in keloid patients compared with controls. Our study provides evidence that PAI-1 promoter polymorphism -675 4G/5G and plasma PAI-1 level are associated with keloid risk. PAI-1 -675 4G/5G polymorphism may be an important hereditary factor responsible for keloid development in the Chinese Han population.

  4. Inhibitory Effects of Fenofibrate on Plasminogen Activator Inhibitor-1 Expression in Human Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    DONG Chunxia; HU Yu; WANG Huafang; SUN Chunyan; WANG Yadan; HE Wenjuan; ZHANG Xiaoping

    2006-01-01

    The effects of fenofibrate on plasminogen activator inhibitor-1 (PAI-1) expression in human umbilical endothelial cell-derived transformed cell line-ECV 304 cells were investigated. ECV 304 cells were incubated with different concentrations of fenofibrate (0, 10, 50, 100 μmol/L) for 24 h. PAI-1 mRNA and protein was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Westernblot respectively. PAI-1 antigenic content of endothelial cells was measured by using ELISA. Fenofibrate could inhibit the PAI-1 mRNA and protein expression and reduce PAI-1 antigenic content dependently. After treatment with fenofibrate (10 μmol/L), the expression levels of PAI-1 mRNA and protein were 0.65±0.05 and 0.96±0.11 respectively, significantly lower than in the control group (0.78±0.03 and 1.21±0.15, respectively, P<0.05). PAI-1 antigenie contents (24.52±8.39) in ECV304 cells treated with 10 μmol/L fenofibrate were significantly lower than those in the control group (6.98±5.12, P<0.05). It was concluded that fenofibrate inhibited the expression of PAI-1 mRNA in ECV304 cells, and reduce the protein expression and the antigenic content of PAI-1, suggesting that fenofibrate may have an antiatherosclerotic effect on endothelial cells by PAI-1 pathway.

  5. Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism in Indian venous thrombosis patients: A case-control study.

    Science.gov (United States)

    Prabhudesai, Aniket; Shetty, Shrimati; Ghosh, Kanjaksha; Kulkarni, Bipin

    2017-09-01

    The role of PAI-1 4G/5G polymorphism in venous thrombosis has been contradictory. PAI-1 4G/4G genotype is associated with elevated levels of PAI-1 resulting in a hypofibrinolytic state and a higher thrombotic risk. In this study, the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of PAI-1 gene in Indian patients with different types of venous thrombosis was investigated for its role in development of thrombosis. A total of 87 portal vein thrombosis (PVT), 71 Budd-Chiari syndrome (BCS), 156 cerebral vein thrombosis (CVT), and 163 deep vein thrombosis (DVT) patients were studied alongside 251 healthy controls for the PAI-1 4G/5G polymorphism by allele-specific PCR. Frequency of 4G/4G genotype was higher in all groups in comparison with controls. 4G/4G was associated with PVT risk (OR=2.51, 95% CI=1.29-4.96, P=.0075), BCS risk (OR=5.98, 95% CI=2.68-13.42, P<.0001), and DVT risk (OR=1.75, 95% CI=0.98-3.02, P=.0225). This is the first case-control study from India establishing PAI-1 4G/4G as a strong risk factor for abdominal thrombosis (PVT and BCS). Statistically significant association was not found between 4G/4G genotype and CVT risk. PAI-1 4G/4G is a strong risk factor for venous thrombosis in Indian patients and should be included in laboratory testing panel of thrombophilia. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Relationship between uPA/PAI-1 and clinical pathology factors in breast cancer tissues%乳腺癌组织uPA和PAI-1表达与临床病理因素相关性的探讨

    Institute of Scientific and Technical Information of China (English)

    王丽; 宋兰英; 刘运江

    2009-01-01

    目的:探讨尿激酶型纤溶酶原激活物(uPA)、纤溶酶原激活物抑制因子-1(PAI-1)在乳腺癌组织中的表达及其临床意义.方法:免疫组化SP法检测乳腺癌组织及良性乳腺疾病组织中uPA、PAI-1的表达,结合临床病理因素、骨髓微转移状况及随访结果对数据进行统计处理.结果:50例乳腺癌患者癌组织中uPA、PAI-1表达阳性率分别为92.0%和82.0%.与良性乳腺疾病相比,癌组织中两者表达增强,P值均为0.001.癌组织中uPA、PAI-1表达随肿瘤的增大而增高;淋巴结转移阳性者表达强度高;临床分期晚者表达强度高;组织学分级高者表达强度高.ER、PR表达阴性组uPA、PAI-1表达强度较阳性组高,P值均<0.05;c-erbB-2蛋白过表达组uPA、PAI-1表达强度高,P值分别为0.021和0.014; uPA、PAI-1表达强度高者易发生骨髓微转移,且易发生远处转移.uPA与PAI-1的表达呈正相关,r=0.664, P=0.000.结论:乳腺癌组织uPA、PAI-1高表达者发生骨髓微转移及远处转移机会高、预后差,uPA、PAI-1检测可以作为判断乳腺癌预后的指标之一.uPA与PAI-1两者之间存在协同作用.

  7. The 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency, which triggers fetal hemodynamic centralization.

    Science.gov (United States)

    Souza, P C P; Alves, J A G; Maia, S M; Araujo Júnior, E; Santana, E F M; Silva Costa, F Da

    2015-01-01

    To describe a case report of 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency. Case report. Department of Public Health, State University of Ceará (UECE), Fortaleza-CE, Brazil. Hereditary hypofibrinolysis, which is mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency. We report a case of a low risk pregnancy, which separately presented placental insufficiency and fetal centralization at the beginning of the third trimester, without any other clinical manifestations during pregnancy. However, immediately after childbirth, the patient had a deep vein thrombosis of a lower limb. The anatomopathological examination of the placenta showed old and recent placental infarcts. Homozygosity for the 4G allele of PAI-1 gene was subsequently diagnosed as the sole probable causal factor.

  8. 辛伐他汀对慢性血栓栓塞性肺动脉高压患者血浆PAI-1的影响%Effects of simvastatin to PAI- 1 activity in chronic thromboembolic pulmonary hypertension patients

    Institute of Scientific and Technical Information of China (English)

    侯鲁静; 王枫岭

    2011-01-01

    Objective To investigate the effects of simvastatin to plasminogen activator inhibitor - 1 (PAI - 1 ) activity in chronic thromboembolic pulmonary hypertension ( CTEPH ) patients. Methods After 7、14 and 21 days continously use of different dosage of simvastatin, plasma PAI- 1 level were dected using chromogenic assay kit. Results Plasma level of PAI- lincrease significantly in CTEPH group compared with that in control group; Simvastatin decrease plasma levels of PAl - 1 in CTEPH group in a dose dependent manner (P < 0. 05 ). Conclusions Simvastatin can decrease plasma levels of PAl - 1 in CTEPH patients.%目的 探讨辛伐他汀对慢性血栓栓塞性肺动脉高压(chronic thromboembolic pulmonary hypertension,CTEPH)患者血浆纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)活性的影响.方法 CTEPH患者分别服用10、20、40mg/天辛伐他汀7、14、21d后,用PAI-1发色底物法检测血浆PAI-1活性.结果 与对照组相比,CTEPH组血浆PAI-1水平明显增高;辛伐他汀呈剂量依赖性降低CTEPH患者血浆PAI-1水平.结论 辛伐他汀可降低CTEPH患者血浆PAI-1水平.

  9. Genetic polymorphisms of PAI-1 and PAR-1 are associated with acute normal tissue toxicity in Chinese rectal cancer patients treated with pelvic radiotherapy.

    Science.gov (United States)

    Zhang, Hui; Wang, Mengyun; Shi, Tingyan; Shen, Lijun; Zhu, Ji; Sun, Menghong; Deng, Yun; Liang, Liping; Li, Guichao; Wu, Yongxin; Fan, Ming; Wei, Qingyi; Zhang, Zhen

    2015-01-01

    Plasminogen activator inhibitor type 1 (PAI-1) and protease-activated receptor-1 (PAR-1) are crucial mediators of the intestinal microenvironment and are involved in radiation-induced acute and chronic injury. To evaluate whether genetic polymorphisms of PAI-1 and PAR-1 were predictors of radiation-induced injury in patients with rectal cancer, we retrospectively evaluated 356 rectal cancer patients who had received pelvic radiotherapy and analyzed the association of genetic polymorphisms of PAI-1 and PAR-1 with acute toxicities after radiotherapy. Acute adverse events were scored, including dermatitis, fecal incontinence (anal toxicity), hematological toxicity, diarrhea, and vomiting. The patients were grouped into grade ≥2 and grade 0-1 toxicity groups to analyze the acute toxicities. Genotyping of six single nucleotide polymorphisms (SNPs) of PAI-1 and PAR-1 was performed using TaqMan assays. A logistic regression model was used to estimate the odds ratios and 95% confidence intervals. Of the 356 individuals, 264 (72.5%) had grade ≥2 total toxicities; within this group, there were 65 (18.3%) individuals who reached grade ≥3 toxicities. There were 19.5% (69/354) and 36.9% (130/352) patients that developed grade ≥2 toxicities for diarrhea and fecal incontinence, respectively. The variant genotype GG of rs1050955 in PAI-1 was found to be negatively associated with the risk of diarrhea and incontinence (PPAI-1 were associated with an increased risk of incontinence. The CT genotype of PAR-1 rs32934 was associated with an increased risk of total toxicity compared with the CC allele. Our results demonstrated that SNPs in the PAI-1 and PAR-1 genes were associated with acute injury in rectal cancer patients treated with pelvic irradiation. These SNPs may be useful biomarkers for predicting acute radiotoxicity in patients with rectal cancer if validated in future studies.

  10. 高血压病患者血浆PAI-1、t-PA及t-PA/PAI-1水平的变化%Plasma plasminogen activator inhibiter-1, tissue-type plasminogen activator and tissue-type plasminogen activator/plasminogen activator inhibiter-1 in hypertensive patients

    Institute of Scientific and Technical Information of China (English)

    马岩; 徐秀英

    2008-01-01

    目的 通过对原发性高血压患者血浆纤溶酶原活化物抑制剂1(PAI-1)、组织型纤溶酶原活化物(t-PA)含量及t-PA/PAI-1比值的测定,亍解高血压患者纤溶功能的情况.方法 未用药物干预过的轻至中度原发性高血压患者(高血压组)64例,正常对照组42例,采用酶联免疫吸附双抗体夹心法测定两组血浆PAI-1、t-PA含量并计算t-PA/PAI-1.结果 正常组PAI-1含量明星低于高血压组,(13.5±5.0)μg/L vs(53.0±22.6)μg/L(P<0.01);正常组t-PA/PAI-1明显高于高血压组,(0.83±0.52)μg/L vs (0.25±0.13)μg/L(P<0.01).结论 高血压患者的纤溶功能减退.

  11. Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: Modulation by cross-sex hormone administration

    NARCIS (Netherlands)

    Giltay, E.J.; Elbers, J.M.H.; Gooren, L.J.G.; Emeis, J.J.; Kooistra, T.; Asscheman, H.; Stehouwer, C.D.A.

    1998-01-01

    Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance s

  12. Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: Modulation by cross-sex hormone administration

    NARCIS (Netherlands)

    Giltay, E.J.; Elbers, J.M.H.; Gooren, L.J.G.; Emeis, J.J.; Kooistra, T.; Asscheman, H.; Stehouwer, C.D.A.

    1998-01-01

    Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance s

  13. Concomitant Administration of Different Doses of Simvastatin with Ivabradine Influence on PAI-1 and Heart Rate in Normo- and Hypercholesterolaemic Rats

    Directory of Open Access Journals (Sweden)

    Jacek Owczarek

    2012-01-01

    Full Text Available Ivabradine is a novel heart rate lowering agent that inhibits If ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg×kg−1 bw with ivabradine (10 mg×kg−1 bw during a 4-week period. Ivabradine exacerbated the decrease of PAI-1 in normocholesterolemic animals receiving simvastatin at a dose of 1 mg/kg bw and was not observed to have any significant influence on the PAI-1 values in rats receiving 20 mg×kg−1 bw simvastatin. Ivabradine, coadministered with simvastatin given at a dose of 20 mg×kg−1 bw, significantly slowed the heart rate in normocholesterolaemic and hypercholesterolaemic groups as compared to the group receiving ivabradine alone. Conclusion. The administration of ivabradine to normocholesterolaemic and hypercholesterolaemic rats receiving simvastatin significantly exacerbated the slowing of heart rate with no effect on blood pressure. The administration of ivabradine has been shown to demonstrate different effects on PAI-1 values depending on lipid disorders.

  14. Elevated circulating PAI-1 levels are related to lung function decline, systemic inflammation, and small airway obstruction in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Wang H

    2016-09-01

    Full Text Available Hao Wang,1,2,* Ting Yang,1,2,* Diandian Li,1,2 Yanqiu Wu,1,2 Xue Zhang,1,2 Caishuang Pang,1,2 Junlong Zhang,3 Binwu Ying,3 Tao Wang,1,2 Fuqiang Wen1,2 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: Plasminogen activator inhibitor-1 (PAI-1 and soluble urokinase-type plasminogen activator receptor (suPAR participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO in COPD. Methods: Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1, Matrix metalloproteinase-9 (MMP-9, and C-reactive protein (CRP were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. Results: First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007. Then, the

  15. PAI-1基因4G/5G多态性与肥胖型多囊卵巢综合征的相关性研究*%Correlations between 4G/5G Polymorphism in Plasminogen Activator Inhibitor-1(PAI-1)Gene and Obese Polycystic Ovarian Syndrome

    Institute of Scientific and Technical Information of China (English)

    庄朝辉; 沈宗姬; 黄亚珍; 徐文新

    2013-01-01

    Objective:To investigate the prevalence of 4G/5G polymorphism of plasminogen activator inhibitor-1(PAI-1)gene in obese polycystic ovary syndrome(PCOS)and their relationships between insulin sensitivity and plasma fibrinolysis function,to find a new way to prevent obesity and insulin resistance of obese PCOS.Method:135 patients and 124 controls were selected.Body mass index(BMI)and waist-to-hip(WHR) ratio were determined.Based on the BMI,the PCOS patients were divided into two groups:74 patients without obesity and 61 patients with obesity.Blood samples were obtained for DNA analysis.PAI-1 plasma levels,fasting insulin and fasting glucose were measured by the ELISA in all subjects.The 4G/5G polymorphic site of the PAI-1 gene promoter region was amplified by the polymerase chain reaction(PCR).We evaluate insulin resistance with Homa-IR and measure insulin sensitivityindex(ISI).Result:Comparison of the clinical data:BMI,WHR,fasting insulin,Homa-IR in patients with obesity were significant greater than those in patients without obesity,the difference was statistically significant between the groups(P<0.05);The PCOS group had significantly higher 4G/4G than the control group,whereas there were significantly less 5G/5G.PCOS women have higher levels of PAI-1 compared with the control group(P<0.05).There was no statistical difference of genotype distribution between patients with obesity and patients without obesity, whereas there was a statistically significant difference in the PAI-1 levels among the groups(P<0.05).Conclusion:The presence of the 4G allele in PAI-1 promoter region of the gene further increases the PAI-1 levels.PAI-1 gene polymorphism 4G genetype may be correlated with PCOS in Chinese women.PAI-1 gene polymorphism 4G genetype may be not correlated with obesity of PCOS in Chinese women.Anti-PAI-1 study may be a new way to prevent obesity and insulin resistance of obese PCOS.%  目的:通过研究肥胖型多囊卵巢综合征(PCOS)纤

  16. PAI-1 4G/5G gene polymorphism is associated with angiographic patency in ST-elevation myocardial infarction patients treated with thrombolytic therapy.

    Science.gov (United States)

    Ozkan, Bugra; Cagliyan, Caglar E; Elbasan, Zafer; Uysal, Onur K; Kalkan, Gulhan Y; Bozkurt, Mehmet; Tekin, Kamuran; Bozdogan, Sevcan T; Ozalp, Ozge; Duran, Mustafa; Sahin, Durmus Y; Cayli, Murat

    2012-09-01

    In this study, we examined the relationship between PAI-1 4G/5G polymorphism and patency of the infarct-related artery after thrombolysis in patients with ST-elevation myocardial infarction (STEMI). Acute STEMI patients who received thrombolytic therapy within first 12 h were included in our study. The PAI-1 4G/5G promoter region insertion/deletion polymorphism was studied from venous blood samples. Patients with the PAI-1 4G/5G gene polymorphism were included in group 1 and the others were included in group 2. Coronary angiography was performed in all patients in the first 24 h after receiving thrombolytic therapy. Thrombolysis in myocardial infarction (TIMI) 0-1 flow in the infarct-related artery was considered as 'no flow', TIMI 2 flow as 'slow flow', and TIMI 3 flow as 'normal flow'. A total of 61 patients were included in our study. Thirty patients (49.2%) were positive for the PAI-1 4G/5G gene polymorphism, whereas 31 of them (50.8%) were in the control group. There were significantly more patients with 'no flow' (14 vs. 6; P=0.02) and less patients with 'normal flow' (8 vs. 19; P=0.02) in group 1. In addition, time to thrombolytic therapy (TTT) was maximum in the 'no flow' group and minimum in the 'normal flow' group (P=0.005). In the logistic regression analysis, TTT (odds ratio: 0.9898; 95% confidence interval: 0.982-0.997; P=0.004) and the PAI-1 4G/5G gene polymorphism (odds ratio: 4.621; 95% confidence interval: 1.399-15.268; P5G gene polymorphism and TTT are associated independently with 'no flow' after thrombolysis in patients with STEMI.

  17. The PAI-1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women.

    Science.gov (United States)

    Said, J M; Tsui, R; Borg, A J; Higgins, J R; Moses, E K; Walker, S P; Monagle, P T; Brennecke, S P

    2012-05-01

    Plasminogen activator inhibitor type 1 (PAI-1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. We aimed to assess the impact of the 4G PAI-1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI-1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre-eclampsia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty-nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI-1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81-2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53-1.31, P = 0.44) or with the individual pregnancy complications. The PAI-1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women. © 2012 International Society on Thrombosis

  18. 代谢综合征大血管病变与PAI-1、hs-CRP水平及心脑血管危险因素相关性研究%The association of macroangiopathy with levels of PAI-1 and C-reactive protein and cerebro-cardiovascular risk factors in metabolic syndrome

    Institute of Scientific and Technical Information of China (English)

    周善存; 罗进才; 王少波; 梁志丽; 张煜; 邓黎

    2010-01-01

    Objective To explore the changes in levels of plasminogen activator inhibitor-1 (PAI-1) and C-reactive protein (CRP) in patients with metabolic syndrome and their significance.Methods Levels of hs - CRP, PAI-1 and blood glucose, lipids, and FFA were determined in 77 patients with metabolic syndrome(40 with macroangiopathy and 37 with no complications)and 30 healthy subjects and then were compared. Results Levels of he - CRP and PAI- 1 were significnatly higher in the group with macroangiopathy than in the group with no complications and the control group(P<0.01).Conclusions Levels of hs - CRP and PAI-1 are closely related with macroangiopathy in metabolic syndrome. the diagnosis, treatment and prevention of metabolic syndrome with macorangiopathy.%目的 研究代谢综合征大血管病变患者血浆纤溶酶原激活物抑制物-1(PAI-1)、血清超敏C反应蛋白(hs-CRP)水平变化和意义.方法 检测77例代谢综合征患者(其中大血管病变患者40例,无并发症患者37例)PAI-1、hs-CRP及血糖、血脂、游离脂肪酸(FFA)等生化指标水平,与30例健康对照组比较,并进行各指标之间的相关分析.结果 代谢综合征大血管病变组患者PAI-1、hs-CRP水平明显高于正常对照组及无并发症组,且差异有统计学意义(P<0.01).结论 PAI-1、hs-CRP水平与代谢综合征大血管病变有密切关系,PAI-1、hs-CRP水平检测对代谢综合征大血管并发症的诊断、预防和治疗具有很好的价值.

  19. The High Affinity Binding Site on Plasminogen Activator Inhibitor-1 (PAI-1) for the Low Density Lipoprotein Receptor-related Protein (LRP1) Is Composed of Four Basic Residues.

    Science.gov (United States)

    Gettins, Peter G W; Dolmer, Klavs

    2016-01-08

    Plasminogen activator inhibitor 1 (PAI-1) is a serpin inhibitor of the plasminogen activators urokinase-type plasminogen activator (uPA) and tissue plasminogen activator, which binds tightly to the clearance and signaling receptor low density lipoprotein receptor-related protein 1 (LRP1) in both proteinase-complexed and uncomplexed forms. Binding sites for PAI-1 within LRP1 have been localized to CR clusters II and IV. Within cluster II, there is a strong preference for the triple CR domain fragment CR456. Previous mutagenesis studies to identify the binding site on PAI-1 for LRP1 have given conflicting results or implied small binding contributions incompatible with the high affinity PAI-1/LRP1 interaction. Using a highly sensitive solution fluorescence assay, we have examined binding of CR456 to arginine and lysine variants of PAI-1 and definitively identified the binding site as composed of four basic residues, Lys-69, Arg-76, Lys-80, and Lys-88. These are highly conserved among mammalian PAI-1s. Individual mutations result in a 13-800-fold increase in Kd values. We present evidence that binding involves engagement of CR4 by Lys-88, CR5 by Arg-76 and Lys-80, and CR6 by Lys-69, with the strongest interactions to CR5 and CR6. Collectively, the individual binding contributions account quantitatively for the overall PAI-1/LRP1 affinity. We propose that the greater efficiency of PAI-1·uPA complex binding and clearance by LRP1, compared with PAI-1 alone, is due solely to simultaneous binding of the uPA moiety in the complex to its receptor, thereby making binding of the PAI-1 moiety to LRP1 a two-dimensional surface-localized association.

  20. The Association between PAI-1 Gene Promoter Polymorphism and Serum Serpin E1, MDA, and Hs-CRP Levels in Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Ansar Karimian

    2016-09-01

    Full Text Available Background: Coronary Artery Disease (CAD is caused by atherosclerosis. Studies have shown that a number of factors, including cellular binding molecules such as Plasminogen Activator Inhibitor-1 (PAI-1, lipid peroxidation, inflammation, and hemostasis, are closely related to development and progression of CAD. Objectives: The present case-control study aimed to evaluate the association between Plasminogen Activator Inhibitor-1 (PAI-1 4G/5G polymorphism and oxidative stress markers and Coronary Artery Disease (CAD. Patients and Methods: Blood was drawn and DNA was extracted from 90 subjects (46 patients with angiographically diagnosed CAD and 44 age- and sex-matched healthy controls. The 4G/5G polymorphism of PAI-1 was detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP analysis. Besides, the risk factors, serpin E1, Malondialdehyde (MDA, high-sensitivity C-Reactive Protein (hs-CRP, and lipid profile serum levels were measured by standard methods and were compared between the two study groups using independent samples t-test, one-way ANOVA, and Mann-Whitney U test as appropriated. Results: Results: The frequency of 4G/4G genotype of PAI-1 gene was higher in the CAD patients than in the controls (28/46 (60.87% vs. 8/44 (18.18%, P < 0.01. Additionally, the serpin E1 plasma level was significantly higher in the CAD group carrying the 4G allele compared to those homozygous for the 5G allele (P = 0.016. Besides, a significant difference was found between the 4G/4G and 5G/5G subjects of the CAD group regarding plasma High-Density Lipoprotein (HDL (P < 0.01. Also, significant differences were observed among the three genotypes of both groups concerning the plasma levels of cholesterol, triglyceride, and Low-Density Lipoprotein (LDL. However, no significant correlation was found between PAI-1 gene polymorphism and MDA serum level, hs-CRP, and risk of CAD. Conclusion: The findings of this study suggested that 4G/4G PAI

  1. 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study.

    Science.gov (United States)

    Madách, Krisztina; Aladzsity, István; Szilágyi, Agnes; Fust, George; Gál, János; Pénzes, István; Prohászka, Zoltán

    2010-01-01

    Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis. We enrolled 208 Caucasian patients with severe sepsis due to pneumonia admitted to an intensive care unit (ICU). Patients were followed up until ICU discharge or death. Clinical data were collected prospectively and the PAI-1 4G/5G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. Patients were stratified according to the occurrence of multiple organ dysfunction syndrome, septic shock or death. We found that carriers of the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome (odds ratio [OR] 95% confidence interval [CI] = 1.335 - 5.604; p = 0.006) and a 2.57-fold higher risk for septic shock (OR 95%CI = 1.180 - 5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture also supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome (adjusted odds ratio [aOR] = 2.957; 95%CI = 1.306 -6.698; p = 0.009) and septic shock (aOR = 2.603; 95%CI = 1.137 - 5.959; p = 0.024). However, genotype and allele analyses have not shown any significant difference regarding mortality in models non-adjusted or adjusted for acute physiology and chronic health evaluation (APACHE) II. Patients bearing the 4G allele had higher disseminated intravascular coagulation (DIC) score at admission (p = 0.007) than 5G/5G carriers. Moreover, in 4G allele carriers the length of ICU stay of non-survivors was longer

  2. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To evaluate the different roles of thrombophiliain patients with and without viral etiology. The thrombophilicgenetic factors (THRGFs), PAI-1 4G-4G, MTHFR677TT, V Leiden 506Q and prothrombin 20210A,were studied as risk factors in 1079 patients with livercirrhosis (LC), enrolled from January 2000 to January2014.METHODS: All Caucasian LC patients consecutivelyobserved in a seven year period were included; thepresence of portal vein thrombosis (PVT) and BuddChiari syndrome (BCS) was registered. The differencesbetween the proportions of each THRGF with regardto the presence or absence of viral etiology and thefrequencies of the THRGF genotypes with those predictedin a population by the Hardy-Weinberg equilibriumwere registered.RESULTS: Four hundred and seventeen/one thousandand seventy-six patients (38.6%) showed thrombophilia:217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leidenfactor and 41 prothrombin G20210 A, 84 with morethan 1 THRGF; 350 presented with no viral liver cirrhosis(NVLC) and 729 with, called viral liver cirrhosis (VLC),of whom 56 patients were hepatitis C virus + hepatitisB virus. PAI-1 4G-4G, MTHFR C677TT, the presence ofat least one TRHGF and the presence of 〉 1 THRGF,were statistically more frequent in patients with NVLC vspatients with VLC: All χ 2 〉 3.85 and P 〈 0.05. Patientswith PVT and/or BCS with at least one TRHGF were189/352 (53.7%). The Hardy-Weinberg of PAI-1 andMTHFR 677 genotypes deviated from that expectedfrom a population in equilibrium in patients with NVLC(respectively χ 2 = 39.3; P 〈 0.000 and χ 2 = 27.94; P 〈0.05), whereas the equilibrium was respected in VLC.CONCLUSION: MTHFR 677TT was nearly twofold andPAI-1 4G-4G more than threefold more frequently foundin NVLC vs patients with VLC; the Hardy-Weinbergequilibrium of these two polymorphisms confirms thisdata in NVLC. We suggest that PAI-1 4G-4G and MTHFR677TT could be considered as factors of fibrosis andthrombosis

  3. Relationship of metabolic syndrome and its components with -844 G/A and HindIII C/G PAI-1 gene polymorphisms in Mexican children

    Directory of Open Access Journals (Sweden)

    De la Cruz-Mosso Ulises

    2012-03-01

    Full Text Available Abstract Background Several association studies have shown that -844 G/A and HindIII C/G PAI-1 polymorphisms are related with increase of PAI-1 levels, obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, which are components of metabolic syndrome. The aim of this study was to analyze the allele and genotype frequencies of these polymorphisms in PAI-1 gene and its association with metabolic syndrome and its components in a sample of Mexican mestizo children. Methods This study included 100 children with an age range between 6-11 years divided in two groups: a 48 children diagnosed with metabolic syndrome and b 52 children metabolically healthy without any clinical and biochemical alteration. Metabolic syndrome was defined as the presence of three or more of the following criteria: fasting glucose levels ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, HDL-cholesterol th percentile, systolic blood pressure (SBP and diastolic blood pressure (DBP ≥ 95th percentile and insulin resistance HOMA-IR ≥ 2.4. The -844 G/A and HindIII C/G PAI-1 polymorphisms were analyzed by PCR-RFLP. Results For the -844 G/A polymorphism, the G/A genotype (OR = 2.79; 95% CI, 1.11-7.08; p = 0.015 and the A allele (OR = 2.2; 95% CI, 1.10-4.43; p = 0.015 were associated with metabolic syndrome. The -844 G/A and A/A genotypes were associated with increase in plasma triglycerides levels (OR = 2.6; 95% CI, 1.16 to 6.04; p = 0.02, decrease in plasma HDL-cholesterol levels (OR = 2.4; 95% CI, 1.06 to 5.42; p = 0.03 and obesity (OR = 2.6; 95% CI, 1.17-5.92; p = 0.01. The C/G and G/G genotypes of the HindIII C/G polymorphism contributed to a significant increase in plasma total cholesterol levels (179 vs. 165 mg/dL; p = 0.02 in comparison with C/C genotype. Conclusions The -844 G/A PAI-1 polymorphism is related with the risk of developing metabolic syndrome, obesity and atherogenic dyslipidemia, and the HindIII C/G PAI-1 polymorphism was associated with the

  4. 不同糖耐量人群的PAI-1、C-RP水平及其与体脂等的关系%Relationship of PAI-1 and C-RP levels with body fat in NGT,IGT and T2DM

    Institute of Scientific and Technical Information of China (English)

    韩瑞红; 冯凭; 张德利

    2007-01-01

    对50例NGT,69例IGT,46例T2DM患者研究显示:(1)T2DM与IGT、NGT相比,C-RP和PAI水平升高,IGT与NGT相比也如此.(2)BMI≥25与BMI<25相比,PAI-1和C-RP均升高,见于NGT,IGT和T2DM组.(3)PAI-1与C-RP水平的升高随血糖异常从NGT到IGT再到T2DM而逐渐加重,且与体脂正相关.

  5. Up-Regulation of PAI-1 and Down-Regulation of uPA Are Involved in Suppression of Invasiveness and Motility of Hepatocellular Carcinoma Cells by a Natural Compound Berberine.

    Science.gov (United States)

    Wang, Xuanbin; Wang, Ning; Li, Hongliang; Liu, Ming; Cao, Fengjun; Yu, Xianjun; Zhang, Jingxuan; Tan, Yan; Xiang, Longchao; Feng, Yibin

    2016-04-16

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and its prognosis remains poor due to the high risk of tumor recurrence and metastasis. Berberine (BBR) is a natural compound derived from some medicinal plants, and accumulating evidence has shown its potent anti-tumor activity with diverse action on tumor cells, including inducing cancer cell death and blocking cell cycle and migration. Molecular targets of berberine involved in its inhibitory effect on the invasiveness remains not yet clear. In this study, we identified that berberine exhibits a potent inhibition on the invasion and migration of HCC cells. This was accompanied by a dose-dependent down-regulation of expression of Cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 in berberine-treated HCC cells. Furthermore, berberine inactivated p38 and Erk1/2 signaling pathway in HCC cells. Primarily, this may be attributed to the up-regulation of plasminogen activator inhibitor-1 (PAI-1), a tumor suppressor that can antagonize uPA receptor and down-regulation of uPA. Blockade of uPA receptor-associated pathways leads to reduced invasiveness and motility of berberine-treated HCC cells. In conclusion, our findings identified for the first time that inactivation of uPA receptor by up-regulation of PAI-1 and down-regulation of uPA is involved in the inhibitory effect of berberine on HCC cell invasion and migration.

  6. 胰岛素对人Hep G2细胞合成PAI-1的刺激作用

    Institute of Scientific and Technical Information of China (English)

    潘建新; 程树群; 张遂一; 翁小鸽

    2000-01-01

    @@ 血浆纤溶酶原激活剂抑制物(PAI-1)活性水平升高可出现在冠心病、外周血管栓塞、手术后等情况,PAI活性升高可预测心肌梗塞的复发.PAI-1是血浆中t PA的主要生理抑制剂,由内皮细胞、肝细胞合成[1].近年研究显示血浆胰岛素水平与PAI水平相关.本实验观察胰岛素对体外培养肝癌细胞系Hep G2合成PAI的作用,报道如下.

  7. PAI-1 -675 4G/5G polymorphism in association with diabetes and diabetic complications susceptibility: a meta-analysis study.

    Science.gov (United States)

    Xu, Kuanfeng; Liu, Xiaoyun; Yang, Fan; Cui, Dai; Shi, Yun; Shen, Chong; Tang, Wei; Yang, Tao

    2013-01-01

    A meta-analysis was performed to assess the association between the PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg's and Egger's test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes (REM OR 1.07, 95% CI 0.96, 1.20), DN (REM OR 1.10, 95% CI 0.98, 1.25), DR (REM OR 1.09, 95% CI 0.97, 1.22) or diabetic CAD risk (REM OR 1.07, 95% CI 0.81, 1.42), and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies.

  8. Fructose rich diet-induced high plasminogen activator inhibitor-1 (PAI-1) production in the adult female rat: protective effect of progesterone.

    Science.gov (United States)

    Castrogiovanni, Daniel; Alzamendi, Ana; Ongaro, Luisina; Giovambattista, Andrés; Gaillard, Rolf C; Spinedi, Eduardo

    2012-08-01

    The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4-FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production.

  9. Unmanipulated Native Fat Exposed To High-energy Diet, But Not Autologous Grafted Fat By Itself, May Lead To Overexpression Of Ki67 And Pai-1

    OpenAIRE

    Claro, Francisco; Morari, Joseane; Moreira, Luciana R; Sarian, Luís O Z; Pinto, Glauce A; Licio A Velloso; Pinto-Neto, Aarão M

    2016-01-01

    Background: Although its unclear oncological risk, which led to more than 20 years of prohibition of its use, fat grafting to the breast is widely used nowadays even for aesthetic purposes. Thus, we proposed an experimental model in rats to analyze the inflammatory activity, cellular proliferation and levels of Plasminogen Activator Inhibitor (PAI-1) in grafted fat, and in native fat exposed to high-energy diet in order to study the oncological potential of fat tissue. Methods: Samples of gra...

  10. PAI-1 4G/5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients.

    Science.gov (United States)

    Fernandez-Cadenas, I; Del Rio-Espinola, A; Rubiera, M; Mendioroz, M; Domingues-Montanari, S; Cuadrado, E; Hernandez-Guillamon, M; Rosell, A; Ribo, M; Alvarez-Sabin, J; Molina, C A; Montaner, J

    2010-04-01

    Despite t-PA proven benefits related to vessel reopening, up to 13% of stroke patients suffer reocclusions after t-PA. We aimed to analyze whether a functional polymorphism in a fibrinolysis inhibitor gene [plasminogen activator inhibitor-1 (PAI-1)] might be associated with reocclusion rates after stroke thrombolytic therapy. 165 patients with ischemic stroke who received t-PA 4G/5G polymorphism determination was performed by sequencing. PAI-1 mRNA was studied by real-time PCR analysis. National institutes of health stroke scale (NIHSS) was serially measured since patients arrival to assess the neurological outcome, and modified ranking scale (mRS) at 3rd month was used to evaluate functional outcome following stroke. PAI-1 4G/4G patients had higher reocclusion rates (4G/4G = 12.5% versus other genotypes = 2.7%, p = 0.025). . In a logistic regression, the 4G/4G genotype was the only factor associated with reocclusion (OR = 15.16 95%, CI = 1.4-163.4, p = 0.025). 4G/4G genotype was also associated with poor functional outcome at 3rd month (4G/4G = 4 versus others genotypes = 3, p = 0.017) and with mRNA levels at 12 h post stroke symptoms onset (4G/4G patients = 2.01% versus other genotypes = 0.68%, p = 0.034). PAI-1 4G/4G genotype is associated with reocclusion rates and poor functional outcome among stroke patients treated with t-PA.

  11. A comparison among HER2, TP53, PAI-1, angiogenesis, and proliferation activity as prognostic variables in tumours from 408 patients diagnosed with early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Alsner, Jan; Ege Olsen, Karen;

    2008-01-01

    BACKGROUND: The prognostic potential of HER2, TP53 mutations, PAI-1 protein levels, angiogenesis and proliferation were investigated in tumours from 408 patients with early breast cancer followed >10 years. One hundred and sixty seven patients (41%) died from breast cancer. MATERIALS AND METHODS...... receptor (p prognosis. In multivariate analysis, metastatic nodes (1-3 positive: RR 1.56 95% CI 1.02-2.38; >3 positive: RR 3.70 95% CI 2.54-5.38), HER2+ (RR 1.91, 95% CI 1.35-2.70), mutated TP53 (RR 1.70, 95% CI 1.21-2.38), PAI-1 (RR 1.04, 95% CI 1.......01-1.07) and grade 3 (RR 1.96, 95% CI 1.83-3.22) were independent markers of poor outcome. CONCLUSION: Compared to PAI-1 protein levels, Chalkley counts and MIB-1, HER2+ and mutations of TP53 were the strongest independent markers of poor prognosis irrespective of nodal status....

  12. Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children.

    Science.gov (United States)

    de la Cruz-Mosso, Ulises; Muñoz-Valle, José Francisco; Salgado-Bernabé, Aralia Berenice; Castro-Alarcón, Natividad; Salgado-Goytia, Lorenzo; Sánchez-Corona, José; Flores-Martínez, Silvia Esperanza; Parra-Rojas, Isela

    2013-01-01

    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. 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, state of Guerrero, 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. 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. The -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  13. The -675 4G/5G polymorphism at the Plasminogen Activator Inhibitor 1 (PAI-1) gene modulates plasma Plasminogen Activator Inhibitor 1 concentrations in response to dietary fat consumption.

    Science.gov (United States)

    Pérez-Martínez, P; Adarraga-Cansino, M D; Fernández de la Puebla, R A; Blanco-Molina, A; Delgado-Lista, J; Marín, C; Ordovás, J M; López-Miranda, J; Pérez-Jiménez, F

    2008-04-01

    The objective of the study was to determine whether Plasminogen Activator Inhibitor Type 1 (PAI-1) -675 4G/5G polymorphism is associated with the response of functional plasma PAI-1 concentrations to changes in the amount and quality of dietary fat in healthy subjects. PAI-1 is the major inhibitor of fibrinolysis, and a lower level of fibrinolytic activity could be implicated in an increased risk of IHD. Fifty-nine healthy Spanish volunteers (ten 4G/4G homozygotes, twenty-eight heterozygotes 4G/5G and twenty-one 5G/5G homozygotes) consumed three diets for periods of 4 weeks each: a SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate-rich diet (30 % fat, 55 % carbohydrate) and a MUFA-rich diet (38 % fat, 22 % MUFA) according to a randomized crossover design. At the end of each dietary period plasma lipid and functional plasma PAI-1 concentrations were determined. Subjects carrying the 4G allele (4G/4G and 4G/5G) showed a significant decrease in PAI-1 concentrations after the MUFA diet, compared with the SFA-rich and carbohydrate-rich diets (genotype x diet interaction: P = 0.028). 5G/5G homozygotes had the lowest plasma PAI-1 concentrations compared with 4G/4G and 4G/5G subjects (genotype: P = 0.002), without any changes as a result of the amount and the quality of the dietary fat. In summary, no differences in plasma PAI-1 concentration response were found after changes in dietary fat intake in 5G/5G homozygotes, although these subjects displayed the lowest concentrations of PAI-1. On the other hand, carriers of the 4G allele are more likely to hyper-respond to the presence of MUFA in the diet because of a greater decrease in PAI-1 concentrations.

  14. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis.

    Science.gov (United States)

    Pasta, Linda; Pasta, Francesca

    2015-12-18

    To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014. All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered. Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ (2) > 3.85 and P 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing the inflammation response, and causing the hepatic fibrosis and augmented intrahepatic vascular resistance typical of LC. PAI-1 4G-4G and MTHFR 677TT screening of LC patients could be useful, mainly in those with NVLC, to identify patients in which new drug therapies based on the attenuation of the hepatic stellate cells activation or other mechanisms could be more easily evaluated.

  15. Hormonal Regulation of Expression of Tissue Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 in Cultured Rat Granulosa Cells

    Institute of Scientific and Technical Information of China (English)

    刘以训; 彭晓蓉; 刘奎

    1994-01-01

    In the present study, gonadotropin and gonadotropin-releasing hormone (GnRH) regulation of tPA and PAI-1 expression in PMSG-primed granulosa cells has been investigated, (i) Addition of go-nadotropins (FSH and LH) and GnRH agonist (GnRHa) or PMA to the culture increases tPA activity) FSH (or LH) plus GnRHa (or PMA) in the culture further enhances the enzyme production to such an extent that a more obvious effect than the additive effect caused by these hormones used alone has been observed; (ii) in contrast, FSH and LH decrease PAI-1 activity, whereas GnRHa and PMA alone markedly increase PAI-1 mRNA level and PAI-1 activity. Because FSH and LH stimulate tPA production and have no significant effect on PAI-1 mRNA induction, the observed inhibition of PAI-1 activity by gonadotropins may be due to the occurrence of neutralization of PA and PAI-1 proteins in the conditioned media by the formation of complexes between PA and PAI-1 ; (iii) increases in PAI-1 mRNA level and activity by GnRH and PMA are complet

  16. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population.

    Science.gov (United States)

    Kurzawińska, Grażyna; Barlik, Magdalena; Drews, Krzysztof; Różycka, Agata; Seremak-Mrozikiewicz, Agnieszka; Ożarowski, Marcin; Klejewski, Andrzej; Czerny, Bogusław; Wolski, Hubert

    2016-01-01

    Recurrent miscarriage (RM) is one of the most common obstetric complications. Numerous studies have suggested that genetic variants leading to an impaired balance between coagulation and fibrinolysis may contribute to elevated risk of pregnancy loss. The aim of the study was to investigate a possible association between angiotensin-converting enzyme (ACE, rs1799752) I/D and plasminogen activator inhibitor type 1 (PAI-1, rs1799768) 4G/5G polymorphisms with RM among Polish women. DNA was extracted from peripheral blood samples of 152 women with a history of ≥ 2 consecutive pregnancy losses before 22 weeks of gestation, and 180 healthy controls with at least 1 live birth at term and no history of pregnancy loss. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to identify the polymorphisms. No statistically significant differences were found in genotype and allele frequencies of the studied polymorphisms. The most relevant difference between the study group and controls was found for the ID genotype distribution of the ACE gene (52.6 vs. 46.7%, OR = 1.27, p = 0.28). The analysis of genotype coexistence revealed a higher incidence of the combination of the ACE II and the PAI-1 4G/4G genotypes in the control group (10.0 vs.5.9% in control group; p = 0.17). The obtained results suggest no apparent association between the ACE I/D, PAI-1 4G/5G polymorphisms and increased RM susceptibility in the analyzed Polish population.

  17. The 4G/4G genotype of the PAI-1 (serpine-1) 4G/5G polymorphism is associated with decreased lung allograft utilization.

    Science.gov (United States)

    Sapru, A; Zaroff, J G; Pawlikowska, L; Liu, K D; Khush, K K; Baxter-Lowe, L A; Hayden, V; Menza, R L; Convery, M; Lo, V; Poon, A; Kim, H; Young, W L; Kukreja, J; Matthay, M A

    2012-07-01

    Widespread thrombi are found among donor lungs rejected for transplantation. The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene impacts transcription and the 4G allele is associated with increased PAI-1 levels. We hypothesized that the 4G/4G genotype would be associated with decreased lung graft utilization, potentially because of worse oxygenation in the donor. We genotyped donors managed by the California Transplant Donor Network from 2001 to 2008 for the 4G/5G polymorphism in the PAI-1 gene. Non-Hispanic donors from 2001 to 2005 defined the discovery cohort (n = 519), whereas donors from 2006 to 2008 defined the validation cohort (n = 369). We found, that the odds of successful lung utilization among Non-Hispanic white donors were lower among donors with the 4G/4G genotype compared to those without this genotype in both the discovery (OR = 0.55, 95% CI = 0.3-0.9, p = 0.02) and validation (OR = 0.5, 95% CI = 0.3-0.9, p = 0.03) cohorts. This relationship was independent of age, gender, cause of death, drug use and history of smoking. Donors with the 4G/4G genotype also had a lower PaO2/FiO2 ratio (p = 0.03) and fewer donors with the 4G/4G genotype achieved the threshold PaO2/FiO2 ratio ≥ 300 (p = 0.05). These findings suggest a role for impaired fibrinolysis resulting in worse gas exchange and decreased donor utilization. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  18. Concomitant Administration of Different Doses of Simvastatin with Ivabradine Influence on PAI-1 and Heart Rate in Normo- and Hypercholesterolaemic Rats

    OpenAIRE

    Jacek Owczarek; Magdalena Jasińska-Stroschein; Daria Orszulak-Michalak

    2012-01-01

    Ivabradine is a novel heart rate lowering agent that inhibits If ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg × kg−1 bw) with ivabradine (10 mg × kg−1 bw) d...

  19. Polymorphism of the PAI-1gene (4G/5G) may be linked with Polycystic Ovary Syndrome and associated pregnancy disorders in South Indian Women.

    Science.gov (United States)

    Mary, Maniraja Jesintha; Saravanan, Lakshmanan; Deecaraman, Munuswamy; Vijayalakshmi, Melantharu; Umashankar, Vetrivel; Sailaja, Jaigopal

    2017-01-01

    Polycystic Ovary syndrome (PCOS) is the most common endocrine disorder affecting 5 - 10% of all women of reproductive age group. The present research was carried out to study the impact of Plasminogen Activator Inhibitor (PAI-1) 4G/5G polymorphism (rs1799889) in PCOS, and the risk of developing PCOS in South Indian Population. The study was carried out in 60 subjects of South Indian population (30 PCOS and 30 Non PCOS) recruited from ARC Research and Fertility Centre, Chennai, India. Genotype and Allelic frequencies were compared by Fisher exact test, Hardy Weinberg equilibrium. p5G), and 5.88% carried wild type homozygous (5G/5G), the allelic difference was highly significant with 4G (62.5%), and 5G (37.5%). P value is highly significant and recorded at p=0.0164. The positive correlation between PAI-1 4G/5G polymorphism and PCOS risk was not observed in this study, however, the correlation between Recurrent Pregnancy Loss (RPL) and Implantation failures were observed in PCOS cases.

  20. Serum tetranectin is an independent prognostic marker in colorectal cancer and weakly correlated with plasma suPAR, plasma PAI-1 and serum CEA

    DEFF Research Database (Denmark)

    Høgdall, Claus K; Christensen, Ib J; Stephens, Ross W

    2002-01-01

    Soluble tetranectin (TN) was measured preoperatively in serum from 567 patients with primary colorectal cancer and levels were tested for association with prognosis. The prognostic significance of TN was also compared to that of plasminogen-activator inhibitor-1 (PAI-1), urokinase plasminogen...... activator (uPAR) and carcinoembryonic antigen (CEA). Significantly shorter survival was found for patients with TN levels below a cut-off point of 7.5 mg/l compared to patients with levels above, as illustrated by Kaplan-Meier curves. By Cox analyses, log TN, log soluble uPAR as well as log CEA were found...... to have an independent prognostic value for survival (log TN: HR = 0.47, 95% CI: 0.29-0.76); log soluble uPAR: HR = 1.65, 95% CI: 1.18-2.31; log CEA: HR = 1.I1, 95% CI: 1.03-1.20). Based on the multivariate model, a patient with a combination of low levels of TN and PAI-1 and elevated levels of soluble u...

  1. The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients.

    Science.gov (United States)

    Güngör, Yahya; Kayataş, Mansur; Yıldız, Gürsel; Özdemir, Öztürk; Candan, Ferhan

    2011-01-01

    In this study, we investigated the relationship between early arteriovenous fistula (AVF) thrombosis with angiotensin-converting enzyme (ACE) gene and thrombophilic factor gene polymorphisms. Thirty-five patients who suffered from three or more fistula thrombosis episodes in the early period after AVF operation and 33 control patients with no history of thrombosis for at least 3 years were enrolled in this study. Factor V G1691A Leiden, factor V H1299R (R2), prothrombin G20210A, factor XIIIV34L, β-fibrinogen-455 G-A, glycoprotein IIIa L33P human platelet antigens (HPA-1), methylenetetrahydrofolate reductase C677T, and methylenetetrahydrofolate reductase A1298C gene polymorphisms were similar in both groups (p > 0.05). Plasminogen activator inhibitor 1 (PAI-1) 4G/5G genotype in the study group and 4G/4G genotype in the control group were significantly higher (p = 0.014). No significant difference was detected in terms of the 5G/5G genotype. With regard to the ACE gene polymorphism, the control group showed more ID genotype (19/33, 57.6%), whereas the study group showed more DD genotype (17/35, 48.6%). II genotype was similar in both groups (x(2) = 7.40, p = 0.025). The rate of ACE inhibitor-angiotensin II receptor blockers use was 5/35 in the study group (14.3%) and 5/33 in the control group (15.2%). Individuals with PAI-1 4G/5G genotype showed 5.03 times more risk of thrombosis when compared with 4G/4G and 5G/5G genotypes [p = 0.008, OR = 5.03, 95% confidence interval (1.44:17.64)]. Individuals with ACE DD genotype showed 4.25 times more risk of thrombosis when compared with II and ID [p = 0.008, OR = 4.25, 95% confidence interval (1.404:12.83)]. PAI-1 4G/5G and ACE DD genotypes are associated with increased risk for early AVF thrombosis.

  2. Irradiation-induced regulation of plasminogen activator inhibitor type-1 and vascular endothelial growth factor in six human squamous cell carcinoma lines of the head and neck; Bestrahlungsinduzierte Regulation des Plasminogenaktivator-Inhibitor Typ 1 (PAI-1) und des vaskulaeren endothelialen Wachstumsfaktors (VEGF) in sechs Plattenepithelkarzinomzelllinien der Kopf-Hals-Region

    Energy Technology Data Exchange (ETDEWEB)

    Artman, Meri Tuuli

    2014-01-29

    Radiation therapy is frequently used to treat squamous cell carcinoma of the head and neck (SCCHN), although, it can be unsuccessful due to radiation resistance of the tumor. Currently, there are no established predictive markers for radiation resistance in SCCHN. The aim of this work was to investigate PAI-1 and VEGF secretion as markers for radiation resistance in six human SCCHN cell lines. The cell lines differed in their basal secretion levels and in their in vitro radiation sensitivity. PAI-1 and VEGF levels increased after irradiation in a dose-dependent manner. A significant correlation was detected between radiation-induced PAI-1 and VEGF secretion, which suggests that irradiation-induced secretion of PAI-1 and VEGF are partially regulated by related mechanisms. However, neither basal levels nor radiation-induced PAI-1 and VEGF secretion correlated with radiation resistance. Therefore, PAI-1 and VEGF are most likely not predictive markers for radiation resistance in SCCHN.

  3. 电针对OLETF大鼠sICAM-1、sVCAM-1及PAI-1表达的影响%Effect of Electroacupuncture on Plasma Levels of sICAM-1, sVCAM-1 and PAI-1 in OLETF Rats

    Institute of Scientific and Technical Information of China (English)

    蓝丹纯; 易玮; 许能贵; 孙健; 陈婧; 李知行; 张弘弢

    2016-01-01

    目的:探讨电针对自发性胰岛素抵抗模型大鼠血浆中细胞间黏附分子(sICAM-1)及血管间黏附分子(sVCAM-1)、纤溶酶原激活物抑制物-1(PAI-1)的影响.方法:以8只雄性LETO大鼠(Long-Evans Tokushima rats)作为空白组,将16只雄性OLETF大鼠(Otsuka Long-Evans Tokushima Fatty rats)随机分为两组,即电针组及模型组,每组8只.空白组及模型组进行正常饲养,不给予其他处理.电针组针刺双侧内关、三阴交、足三里及肾俞,并予双侧足三里及三阴交加电.1次/d,每次20 min,持续4周.治疗结束后,禁食12 h,次晨眼眶静脉窦采血.检测各组大鼠空腹血糖(FPG)、空腹胰岛素(FINS)、sICAM-1及sVCAM-1、PAI-1.HE染色观察主动脉病理变化.结果:模型组的FPG、FINS、HOMA-IR、C-P及sICAM-1、sVCAM-1、PAI-1水平相比空白组显著升高(P<0.01).电针组的FPG、FINS和HOMA-IR与空白组相比,差异无统计学意义(P>0.05).电针组的FPG、FINS、C-P及sICAM-1、sVCAM-1及PAI-1水平较模型组显著降低(P<0.01).HOMA-IR与大鼠血浆sICAM-1、sVCAM-1及PAI-1均成正相关关系.光镜显示,电针干预能总体病理损伤有不同程度的改善.结论:电针能改善胰岛素抵抗水平,控制血浆中过高的sICAM-1、sVCAM-1及PAI-1水平,对糖尿病血管并发症的防治有良性作用.

  4. Relationship Between Scavenger Receptors and uPA:PAI-1 and uPA Receptors in Breast Cancer

    Science.gov (United States)

    1998-10-01

    Cell Surface Expression of LRP Methods: Confluent cell layers of tumor-derived mammary epithelial cells and a human fibrosarcoma cell line ...could be co-immunoprecipitated together. The human fibrosarcoma cells , HT1080 , were used in this procedure to optimize our co- immunoprecipitation... fibrosarcoma cell line , HT1080 . 100" M MDA-MB-231 E0 184-B5 90 0 NRK 80 70 60t M 50- " 40- LO~ 30- 20- 10-

  5. Common TNF-alpha, IL-1 beta, PAI-1, uPA, CD14 and TLR4 polymorphisms are not associated with disease severity or outcome from Gram negative sepsis

    DEFF Research Database (Denmark)

    Jessen, Kirstine Marie; Lindboe, Sarah Bjerre; Petersen, Anncatrine Luisa

    2007-01-01

    consecutive adult patients with culture proven Gram negative bacteremia admitted to a Danish hospital between 2000 and 2002. Analysis for commonly described SNPs of tumor necrosis-alpha, (TNF-alpha), interleukin-1 beta (IL-1 beta), plasminogen activator-1 (PAI-1), urokinase plasminogen activator (uPA), CD14...

  6. Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population.

    Science.gov (United States)

    D'Amico, Mario; Pasta, Francesca; Pasta, Linda

    2015-08-15

    The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and Prothrombin 20210A, were studied as risk factors in 865 Caucasian patients with liver cirrhosis, consecutively enrolled from June 2008 to January 2014. A total of 582 HCV, 80 HBV, 94 alcohol, (82 with more than one etiologic factor) and 191 cryptogenic patients with liver cirrhosis had been consecutively enrolled; 243 patients showed portal vein thrombosis (PVT). At least one of the above THRGFs was present in 339/865 patients (39.2%). PAI-1 4G-4G and MTHFR 677TT were the most frequent THRGFs, statistically significant in patients with alcohol, cryptogenic liver cirrhosis, and PVT: respectively 24 and 28, 50 and 73, and 65 and 83 (all chi-square tests>3.84, and p values4G-4G and MTHFR 677TT, as dependent variable, confirmed the independent significant relationship of these THRGFs with alcohol, cryptogenic liver cirrhosis and PVT. PAI 1 and MTHFR 677 genotypes, deviated from those expected in populations in Hardy-Weinberg equilibrium (all p values4G-4G and MTHFR 677TT in patients with alcohol, cryptogenic liver cirrhosis, and PVT, in a Caucasian population. In conclusion, thrombo and fibro-genetic mechanisms of PAI-1 4G-4G and MTHFR 677TT, could have a role in the development of liver cirrhosis, mainly in patients without HCV and HBV, and PVT. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. A comparison among HER2, TP53, PAI-1, angiogenesis, and proliferation activity as prognostic variables in tumours from 408 patients diagnosed with early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Alsner, Jan; Olsen, Karen Ege

    2008-01-01

    BACKGROUND: The prognostic potential of HER2, TP53 mutations, PAI-1 protein levels, angiogenesis and proliferation were investigated in tumours from 408 patients with early breast cancer followed >10 years. One hundred and sixty seven patients (41%) died from breast cancer. MATERIALS AND METHODS:...

  8. Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

    Directory of Open Access Journals (Sweden)

    Cusi Kenneth

    2010-02-01

    Full Text Available Abstract Background CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects. Methods 40 non-diabetic subjects (age = 38 ± 3 yr, BMI = 28 ± 1 kg/m2, FPG = 95 ± 1 mg/dl, HbA1c = 5.3 ± 0.1% were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1 and vascular (VCAM-1 adhesion molecules-1, E-selectin (sE-S, myeloperoxidase (MPO and total plasminogen inhibitor-1 (tPAI-1. Insulin sensitivity was measured by a hyperglycemic clamp (M/I. Results Lipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01. Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 ± 10 vs. 186 ± 25 ng/ml, VCAM-1 (1066 ± 67 vs. 1204 ± 65 ng/ml and sE-S (20 ± 1 vs. 24 ± 1 ng/ml between 13-35% and by ≥ 2-fold plasma levels of myeloperoxidase (7.5 ± 0.9 to 15 ± 25 ng/ml, an inflammatory marker of future CVD, and tPAI-1 (9.7 ± 0.6 to 22.5 ± 1.5 ng/ml, an indicator of a prothrombotic state (all p ≤ 0.01. The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects. Conclusions An increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.

  9. Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

    Directory of Open Access Journals (Sweden)

    Gupta Arvind

    2010-03-01

    Full Text Available Abstract Background To determine association of nine single nucleotide polymorphisms (SNPs in ADP ribosyltransferase-1 (ADPRT1, aldo-keto reductase family 1 member B1 (AKR1B1, receptor for advanced glycation end-products (RAGE, glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2, and plasminogen activator inhibitor-1 (PAI-1 genes with chronic renal insufficiency (CRI among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS, and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set. Methods Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl constituted the cases (n = 196, and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225. Allelic and genotypic constitution of 10 polymorphisms (SNPs from five genes namely- ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes. Results Single nucleotide polymorphisms -429 T>C in RAGE and rs7725 C>T SNP in 3' UTR in GFPT2 gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in GFPT2 was a perfect target for predicted miRNA (hsa miR-378 suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor TGF-β1 (investigated using the same sample set and reported elsewhere and GFPT2 genotype was observed. Conclusions

  10. Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs.

    Science.gov (United States)

    Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J; Hong, Nancy J; Dominici, Fernando P; Carretero, Oscar A; Garvin, Jeffrey L

    2016-02-01

    Angiotensin II (Ang II) causes nitric oxide synthase (NOS) to become a source of superoxide (O2 (-)) via a protein kinase C (PKC)-dependent process in endothelial cells. Ang II stimulates both NO and O2 (-) production in thick ascending limbs. We hypothesized that Ang II causes O2 (-) production by NOS in thick ascending limbs via a PKC-dependent mechanism. NO production was measured in isolated rat thick ascending limbs using DAF-FM, whereas O2 (-) was measured in thick ascending limb suspensions using the lucigenin assay. Consistent stimulation of NO was observed with 1 nmol/L Ang II (P thick ascending limbs via a PKC- and NADPH oxidase-dependent process; and (2) the effect of Ang II is not due to limited substrate.

  11. Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells.

    Science.gov (United States)

    Ko, Benjamin; Mistry, Abinash; Hanson, Lauren; Mallick, Rickta; Hoover, Robert S

    2015-04-01

    Angiotensin II (ANG II) increases thiazide-sensitive sodium-chloride cotransporter (NCC) activity both acutely and chronically. ANG II has been implicated as a switch that turns WNK4 from an inhibitor of NCC into an activator of NCC, and ANG II's effect on NCC appears to require WNK4. Chronically, ANG II stimulation of NCC results in an increase in total and phosphorylated NCC, but the role of NCC phosphorylation in acute ANG II actions is unclear. Here, using a mammalian cell model with robust native NCC activity, we corroborate the role that ANG II plays in WNK4 regulation and clarify the role of Ste20-related proline alanine-rich kinase (SPAK)-induced NCC phosphorylation in ANG II action. ANG II was noted to have a biphasic effect on NCC, with a peak increase in NCC activity in the physiologic range of 10(-11) M ANG II. This effect was apparent as early as 15 min and remained sustained through 120 min. These changes correlated with significant increases in NCC surface protein expression. Knockdown of WNK4 expression sharply attenuated the effect of ANG II. SPAK knockdown did not affect ANG II action at early time points (15 and 30 min), but it did attenuate the response at 60 min. Correspondingly, NCC phosphorylation did not increase at 15 or 30 min, but increased significantly at 60 min. We therefore conclude that within minutes of an increase in ANG II, NCC is rapidly trafficked to the cell surface in a phosphorylation-independent but WNK4-dependent manner. Then, after 60 min, ANG II induces SPAK-dependent phosphorylation of NCC.

  12. Circulating Levels of PAI-1 and SERPINE1 4G/4G Polymorphism Are Predictive of Poor Prognosis in HCC Patients Undergoing TACE

    Directory of Open Access Journals (Sweden)

    Rosa Divella

    2015-08-01

    Full Text Available Although several molecular markers have been proposed as prognostic of disease progression in Hepatocellular carcinoma (HCC, predictive markers of response to treatment are still unsatisfactory. Here, we propose a genetic polymorphism as a potential predictive factor of poor prognosis in HCC patients treated with transcatheter arterial chemoembolization (TACE. In particular, we show that the guanosine insertion/deletion polymorphism in the promoter region of SERPINE1 gene at the −675 bp position, named 4G/4G, predicts poor prognosis in a cohort of 75 patients with HCC undergoing TACE. By a combination of ELISA and SERPINE1 promoter study, we found that the presence of elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1 in patients with 4G/4G genotype is significantly associated with reduced overall survival compared to patients with 5G/5G or 4G/5G genotype in HCC patients after TACE. Our analysis provided evidence that variation in SERPINE1 gene plays a role in defining the outcome in patients treated with TACE. In addition to a poor disease outcome, the 4G/4G variant represents an unfavorable predictive factor for response to chemotherapy as well.

  13. Circulating Levels of PAI-1 and SERPINE1 4G/4G Polymorphism Are Predictive of Poor Prognosis in HCC Patients Undergoing TACE1

    Science.gov (United States)

    Divella, Rosa; Daniele, Antonella; Abbate, Ines; Savino, Eufemia; Casamassima, Porzia; Sciortino, Giancarlo; Simone, Giovanni; Gadaleta-Caldarola, Gennaro; Fazio, Vito; Gadaleta, Cosimo Damiano; Sabbà, Carlo; Mazzocca, Antonio

    2015-01-01

    Although several molecular markers have been proposed as prognostic of disease progression in Hepatocellular carcinoma (HCC), predictive markers of response to treatment are still unsatisfactory. Here, we propose a genetic polymorphism as a potential predictive factor of poor prognosis in HCC patients treated with transcatheter arterial chemoembolization (TACE). In particular, we show that the guanosine insertion/deletion polymorphism in the promoter region of SERPINE1 gene at the − 675 bp position, named 4G/4G, predicts poor prognosis in a cohort of 75 patients with HCC undergoing TACE. By a combination of ELISA and SERPINE1 promoter study, we found that the presence of elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) in patients with 4G/4G genotype is significantly associated with reduced overall survival compared to patients with 5G/5G or 4G/5G genotype in HCC patients after TACE. Our analysis provided evidence that variation in SERPINE1 gene plays a role in defining the outcome in patients treated with TACE. In addition to a poor disease outcome, the 4G/4G variant represents an unfavorable predictive factor for response to chemotherapy as well. PMID:26310373

  14. The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study.

    Science.gov (United States)

    Kim, Jin Ju; Choi, Young Min; Lee, Sung Ki; Yang, Kwang Moon; Paik, Eun Chan; Jeong, Hyeon Jeong; Jun, Jong Kwan; Han, Ae Ra; Hong, Min A

    2014-12-01

    Thrombophilia has been postulated to be a contributor to the pathophysiology of recurrent pregnancy loss (RPL). We investigated the role of the plasminogen activator inhibitor type 1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D polymorphisms in Korean patients with RPL. Genotyping was performed using the TaqMan assay in 227 RPL patients and 304 controls. The genotype distributions of both polymorphisms in the RPL group did not differ from those of controls. Because the frequency of being homozygous for ACE D/D and the PAI-I 4G/4G combination has been reported to be significantly higher in RPL patients, this was also analyzed. However, no significant difference was noted; 3.1% of RPL patients had both ACE D/D and PAI-I 4G/4G, as did 4.9% of controls (P = 0.791). The current study suggests that both polymorphisms, either alone or in combination, are not major determinants of the development of RPL in Korean women. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Circulating Levels of PAI-1 and SERPINE1 4G/4G Polymorphism Are Predictive of Poor Prognosis in HCC Patients Undergoing TACE.

    Science.gov (United States)

    Divella, Rosa; Daniele, Antonella; Abbate, Ines; Savino, Eufemia; Casamassima, Porzia; Sciortino, Giancarlo; Simone, Giovanni; Gadaleta-Caldarola, Gennaro; Fazio, Vito; Gadaleta, Cosimo Damiano; Sabbà, Carlo; Mazzocca, Antonio

    2015-08-01

    Although several molecular markers have been proposed as prognostic of disease progression in Hepatocellular carcinoma (HCC), predictive markers of response to treatment are still unsatisfactory. Here, we propose a genetic polymorphism as a potential predictive factor of poor prognosis in HCC patients treated with transcatheter arterial chemoembolization (TACE). In particular, we show that the guanosine insertion/deletion polymorphism in the promoter region of SERPINE1 gene at the -675 bp position, named 4G/4G, predicts poor prognosis in a cohort of 75 patients with HCC undergoing TACE. By a combination of ELISA and SERPINE1 promoter study, we found that the presence of elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) in patients with 4G/4G genotype is significantly associated with reduced overall survival compared to patients with 5G/5G or 4G/5G genotype in HCC patients after TACE. Our analysis provided evidence that variation in SERPINE1 gene plays a role in defining the outcome in patients treated with TACE. In addition to a poor disease outcome, the 4G/4G variant represents an unfavorable predictive factor for response to chemotherapy as well. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes.

    Science.gov (United States)

    Sundgren, N C; Giraud, G D; Stork, P J S; Maylie, J G; Thornburg, K L

    2003-05-01

    Rat and sheep cardiac myocytes become binucleate as they complete the 'terminal differentiation' process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2'-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.

  17. Activation of peroxisome proliferator-activated receptor α in human endothelial cells increases plasminogen activator inhibitor type-1 expression

    Institute of Scientific and Technical Information of China (English)

    叶平; 胡晓晖; 刘永学; 赵亚力

    2003-01-01

    Objective To investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism.Methods Human umbilical vein endothelial cells (HUVECs) were obtained from normal fetus, and cultured conventionally. Then the HUVEC were exposed to fatty acids and prostaglandin J2 in varying concentrations with fresh media. RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs. Transient co-transfection of PAI-1 promoter and PPARα gene or PPARγ gene to ECV304 was performed.Results PPARα, PPARδ and PPARγ mRNA in HUVECs were detected by RT-PCR. Treatment of HUVECs with PPARα and PPARγ activators-linolenic acid, linoleic acid, oleic acid and prostaglandin J2, but not with stearic acid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner. Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARα DNA in HUVECs through a transient gene transfection assay, although the mRNA expression of the 3 subtypes of PPAR with their activators were not changed compared with controls.Conclusions HUVECs express PPARs. PPARs activators may increase PAI-1 expression in endothelial cells (EC). Although PPARs expression was not enhanced after being stimulated by their activators in EC, the functionally active PPARα is probably involved in regulating PAI-1 expression in EC.

  18. Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells.

    Science.gov (United States)

    Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Taguchi, Ayumi; Takahashi, Juri; Kojima, Satoko; Yamashita, Aki; Tomio, Kensuke; Nagamatsu, Takeshi; Wada-Hiraike, Osamu; Oda, Katsutoshi; Osuga, Yutaka; Fujii, Tomoyuki

    2016-02-01

    The plasminogen activator (PA) system consists of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR). PAI-1 inhibits the activation of uPA (which converts plasminogen to plasmin), and is involved in cancer invasion and metastasis, by remodeling the extracellular matrix (ECM) through regulating plasmin. Cancer stem cells (CSCs) are a small subset of cells within tumors, and are thought to be involved in tumor recurrence and metastasis. Considering these facts, we investigated the relationship between PAI-1 and cervical CSCs. We used ALDH1 as a marker of cervical CSCs. First, we demonstrated that culturing ALDH1-high cells and ALDH-low cells on collagen IV-coted plates increased their expression of active PAI-1 (ELISA), and these increases were suggested to be at mRNA expression levels (RT-qPCR). Secondly, we demonstrated PAI-1 was indeed involved in the ECM maintenance. With gelatin zymography assays, we found that ALDH1-high cells and ALDH-low cells expressed pro-matrix metalloproteinase-2 (pro-MMP-2) irrespective of their coatings. With gelatinase/collagenase assay kit, we confirmed that collagenase activity was increased when ALDH1-low cells were exposed to TM5275, a small molecule inhibitor of PAI-1. Putting the data together, we hypothesized that cancer cells adhered to basal membrane secrete abundant PAI-1, on the other hand, cancer cells (especially CSCs rather than non-CSCs) distant from basal membrane secrete less PAI-1, which makes the ECM surrounding CSCs more susceptible to degradation. Our study could be an explanation of conflicting reports, where some researchers found negative impacts of PAI-1 expression on clinical outcomes and others not, by considering the concept of CSCs.

  19. Relation between plasminogen activator inhibitor-1 and the PAI-1 gene locus 4G/5G polymorphism and their effect on the incidence of coronary heart disease%冠心病发病与血浆纤溶酶原激活物抑制剂-1及其基因4G/5G多态性的关系

    Institute of Scientific and Technical Information of China (English)

    王艳苓; 付研; 王旭东; 刘复强; 钱筠; 樊峥; 祁雅惠; 杨凌

    2003-01-01

    目的探讨冠心病患者血浆纤溶酶原激活物抑制剂-1(PAI-1)水平和活性(PAI:A)的升高与PAI-1基因4G/5G多态性的关系及其对发病的影响.方法 122例冠心病患者与172例健康对照者,同时做PAI-1基因型分析并测定PAI-1、PAI∶A.结果 PAI-1基因型分布在冠心病组4G/4G型最多( 47.2%),对照组中以4G/5G型最多( 49.4%);PAI-1与PAI∶A在4G/4G、5G/5G、4G/5G 3种基因型组间比较差异有显著性意义,其中以4G/4G基因型组PAI-1及PAI∶A最高.结论血浆PAI-1增高,是冠心病发病的危险因素.冠心病组4G/4G基因型频率是PAI-1增高的重要影响因素,PAI-1基因4G/5G多态性可能部分地决定了冠心病发病的倾向性.

  20. 4G/5G Sequence Polymorphism and Plasma Activity of the Promotor of Plasminogen Activator Inhibitor-1 Gene in Cerebral Infarction%脑梗死患者PAI-1基因启动子区域4G/5G多态性与血浆活性关系的研究

    Institute of Scientific and Technical Information of China (English)

    陈懿建; 张立群; 陈方平

    2008-01-01

    目的 探讨纤溶酶原激活物抑制剂-1(PAI-1)基因启动子区域的4G/5G多态性在脑梗死(CI)发病中的作用,并分析PAI-1基因4G/5G多态性与PAI-1活性的关系.方法 随机收集130例CI患者,100例健康人作对照.等位基因特异性引物PCR分析PAI-1多态性基因型(4G/4G、4G/5G和5G/5G).底物发色法测定血浆PAI-1活性,酶法测定血清三酰甘油(TG)、总胆固醇(TC)、血糖(Glu).结果 PAI-1基因型分布频率及4G和5G等位基因分布频率在CI组和健康对照组差异无统计学意义(P>0.05);CI组的PAI-1活性与对照组比较差异有统计学意义(P<0.01);PAI-1 4G/5G基因型多态性与PAI-1活性水平有关,3种基因型PAI-1活性间差异有统计学意义(P<0.01).结论 PAI-1基因4G/5G多态性与其血浆活性水平相关;4G等位基因者PAI-1活性水平增高,导致机体纤溶活性降低,从而增加CI的发病风险;PAI-1活性水平在CI发生过程中起重要的作用.

  1. [Changes of focal and brainstem neurologic signs in patients with traumatic brain injury and their dependence on the -675 4G/5G polymorphism in the PAI-1 gene].

    Science.gov (United States)

    Potapov, O; Kmyta, O

    2014-09-01

    Regressive course of neurological signs and symptoms is an important factor of evaluating the clinical course and treatment efficacy of traumatic brain injury. This article presents changes evaluation of focal and brainstem symptoms in 200 patients with traumatic brain injury, and determines the association between these changes and the -675 4G/5G polymorphism in the PAI-1 gene. We have found a connection between 4G/4G and 4G/5G genotypes for the studied polymorphism and the changes of focal and brainstem symptoms in patients with traumatic brain injury. Thus, we have demonstrated that the clinical course of traumatic brain injury is influenced by the -675 4G/5G polymorphism in the PAI-1 gene.

  2. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Victor Villar

    2013-01-01

    Full Text Available Purpose. To determine whether Ski-interacting protein (SKIP regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA, matrix metalloproteinase-9 (MMP-9, and uPA Inhibitor (PAI-1 in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

  3. Do serum angiopoietin-1, angiopoietin-2, and their receptor Tie-2 and 4G/5G variant of PAI-1 gene have a role in the pathogenesis of preeclampsia?

    Science.gov (United States)

    Kamal, Manal; El-Khayat, Waleed

    2011-10-01

    To evaluate whether serum angiogenesis markers such as angiopoietins (Ang-1, Ang-2) and their receptor (Tie-2) are altered in women with preeclampsia. We also performed genotyping to determine if the 4G/5G genotypes of -675 PAI-1 gene may play a role in the pathogenesis of preeclampsia. Sixty-eight pregnant women with preeclampsia were compared to 35 normotensive pregnant women and 24 normotensive nonpregnant women in a cross-sectional study. Using enzyme-linked immunosorbent assay, levels of serum Ang-1 and Ang-2, and Tie-2 were measured. A single base pair insertion/deletion 4G/5G polymorphism of the PAI-1 gene was determined by polymerase chain reaction. Serum levels of Ang-1 and Tie-2 were significantly different among the study groups (P = 0.001 and P = 0.025, respectively) being lower in the preeclamptic group. Positive significant correlation was found between Ang-2 and Tie-2, (r = 0.26, P = 0.024). The frequency of the genotypes (4G/5G, 4G/4G, and 5G/5G) differed among the groups (P = 0.001). Also, the mean of systolic and diastolic blood pressures differed significantly according to the PAI-1 genotype being higher in those bearing the 4G allele; P = 0.04 and P = 0.023, respectively. Sera Ang-1 and Ang-2, and Tie-2 as well as variants of 4G/5G of PAI-1 polymorphism have positive implications in the pathogenesis of preeclampsia.

  4. Suppression of angiotensin II stimulated responses in aortic vascular smooth muscle cells of experimental cirrhotic rats

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    Functional responses to angiotensin II(AT-II) were determined in aortic vascular smooth muscle cells (VSMCs) from experimental cirrhotic rats.Our data showed that AT-II-stimulated extracellular acidification rate (ECAR),which was measured by Cytosesor microphysiometry,was significantly reduced in the aortic VSMCs from the cirrhotic rats as compared to those from the control animals.The ability of AT-II to promote formation of inositol phosphates,the second messenger produced by the activation of Gq-coupled receptors,was also considerably suppressed in the cirrhotic VSMCs.Furthermore,the maximal p42/44 MAPK phosphorylation stimulated by AT-II was significantly reduced in the cirrhotic VSMCs in contrast to that in the normal VSMCs.Taken together,our data clearly demonstrated that the functional responses to AT-II was severely suppressed in aortic VSMCs in cirrhosis,indicating the impairment of general Gq-coupled receptor signaling and subsequent biological function in the cirrhotic VSMCs.

  5. Common TNF-α, IL-1β, PAI-1, uPA, CD14 and TLR4 polymorphisms are not associated with disease severity or outcome from Gram negative sepsis

    Directory of Open Access Journals (Sweden)

    Eugen-Olsen Jesper

    2007-09-01

    Full Text Available Abstract Background Several studies have investigated single nucleotide polymorphisms (SNPs in candidate genes associated with sepsis and septic shock with conflicting results. Only few studies have combined the analysis of multiple SNPs in the same population. Methods Clinical data and DNA from consecutive adult patients with culture proven Gram negative bacteremia admitted to a Danish hospital between 2000 and 2002. Analysis for commonly described SNPs of tumor necrosis-α, (TNF-α, interleukin-1β (IL-1β, plasminogen activator-1 (PAI-1, urokinase plasminogen activator (uPA, CD14 and toll-like receptor 4 (TLR4 was done. Results Of 319 adults, 74% had sepsis, 19% had severe sepsis and 7% were in septic shock. No correlation between severity or outcome of sepsis was observed for the analyzed SNPs of TNF-α, IL-1β, PAI-1, uPA, CD14 or TLR-4. In multivariate Cox proportional hazard regression analysis, increasing age, polymicrobial infection and haemoglobin levels were associated with in-hospital mortality. Conclusion We did not find any association between TNF-α, IL-1β, PAI-1, uPA, CD14 and TLR4 polymorphisms and outcome of Gram negative sepsis. Other host factors appear to be more important than the genotypes studied here in determining the severity and outcome of Gram negative sepsis.

  6. Pioglitazone suppresses advanced glycation end product-induced expression of plasminogen activator inhibitor-1 in vascular smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    Xiaochen Yuan; Naifeng Liu

    2011-01-01

    Advanced glycation end products (AGEs) play an important role in vascular complications of diabetes, including fibrinolytic abnormalities.Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARΥ) agonist, has recently been shown to reduce circulating plasminogen activator inhibitor-1 (PAI-1) levels in diabetes mellitus. In the present study, we investigated the effects of pioglitazone on the expression of local PAI-1 in rat vascular smooth muscle cells (VSMCs) induced by AGEs and the underlying mechanism. The result showed that AGEs could enhance the PAI-1 expression by 5.1-fold in mRNA and 2.7-fold in protein level, as evaluated by real-time RT-PCR and Western blotting,respectively. Pioglitazone was found to down-regulate the AGE-stimulated PAI-1 expression in VSMCs. However, these inhibitory effects were partially attenuated by the PPARΥ antagonist, GW9662. Furthermore, we found that AGEs induced a rapid increase in phosphorylation and activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2). The ERK kinase inhibitor, UO126, partially prevented the induction of PAI-1 by AGEs. Moreover, pioglitazone was also found to inhibit the phosphorylation of ERKi/2. Taken together, it was concluded that pioglitazone could inhibit AGE-induced PAI-1 expression, which was mediated by the ERK1/2 and PPARΥ pathways. Our findings suggestedpioglitazone had a therapeutic potential in improving fibrinolytic activity, and consequently preventing thromboembolic complications of diabetes and cardiovascular disease.

  7. Hormonal control of plasminogen activator inhibitor-1 gene expression and production in human adipose tissue: stimulation by glucocorticoids and inhibition by catecholamines.

    Science.gov (United States)

    Halleux, C M; Declerck, P J; Tran, S L; Detry, R; Brichard, S M

    1999-11-01

    Plasma levels of type 1 plasminogen activator inhibitor (PAI-1), a risk factor for cardiovascular disease, are elevated in obese subjects, especially those with omental fat accumulation. We investigated the hormonal control of PAI-1 gene expression and secretion in cultured human adipose tissue. We more particularly focused on the effects of glucocorticoids, insulin, cAMP, and catecholamines in explants from the omental region. The addition of dexamethasone to the culture medium increased PAI-1 secretion in a time-dependent manner for up to 24 h. The stimulation by the glucocorticoid was preceded by a 2-fold rise in PAI-1 messenger ribonucleic acid levels between 4-8 h of culture. The effectiveness of the glucocorticoid was concentration dependent, with a half-maximal effect within a physiological range. This stimulation was also observed in sc fat, but dexamethasone-stimulated as well as basal PAI-1 secretion rates were always higher in omental fat. Unlike dexamethasone, 24-h insulin did not modify PAI-1 secretion while accelerating glucose consumption. In contrast, 24-h cAMP inhibited PAI-1 gene expression and protein production under basal conditions and in the presence of dexamethasone. This inhibition was already detectable after 1 h and was maximal after 4 h at the level of gene expression. It occurred in both omental and sc adipose tissues. Importantly, epinephrine dose dependently inhibited PAI-1 parameters, an effect that was reproduced by isoproterenol. Dexamethasone- and cAMP-induced changes in PAI-1 messenger ribonucleic acid abundance were similar in explants and isolated fat cells. In isolated stromal-vascular cells, only dexamethasone was effective. In conclusion, we provide evidence for a reciprocal regulation of PAI-1 by dexamethasone (positive effector) and cAMP/catecholamines (negative effectors) in cultured human adipose tissue. The stimulation by glucocorticoids could contribute to enhanced production of PAI-1 by adipose tissue and high plasma

  8. PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies.

    Science.gov (United States)

    Pasta, Linda; Pasta, Francesca; D'Amico, Mario

    2016-03-01

    There are no univocal opinions on the role of genetic thrombophilia on splanchnic vein thrombosis (SVT). We defined genetic thrombophilia the presence of one of these thrombophilic genetic factors (THRGFs): PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and prothrombin 20210A. To evaluate the frequencies of these THRGFs in SVT patients, we analyzed individual data of 482 Caucasian patients, recruited from 2000 to 2014 in three prospective studies. SVT was defined as the presence of thrombosis of portal (PVT), mesenteric (MVT), splenic (SPVT), cava (CT), and hepatic vein (Budd Chiari syndrome, BCS). Pre-hepatic SVT (pre-HSVT) was defined as PVT with or without MVT/SPVT, without BCS. Post-hepatic SVT (post-HSVT) was BCS with or without PVT/MVT/SPVT. We compared 350 patients with liver cirrhosis (LC), 47 hepatocellular carcinoma (HCC), 37 myeloproliferative neoplasm (MPN), 38 associated disease (AD), 10 without any associated disease (WAD), vs 150 healthy controls (HC); 437 patients showed pre-HSVT and 45 post-HSVT. Thrombophilia was present in 294/482 (60.9%) patients: 189/350 LC (54.0%), 31/47 (66.0%) HCC, 29/39 (74.4%) MPN, 35/38 AD (92.1%), and 10/10 (100%) WAD, and 54/150 (36.0%) in HC. In the total group, we found 175 PAI-1 4G-4G, 130 MTHFR 677TT, 42V Leiden 506Q, and 27 prothrombin 20210A; 75 patients showed presence of >1 TRHGF; the more frequent association was PAI-1 4G-4G/MTHFR 677TT, in 36 patients. PAI-1 4G-4G and MTHFR 677TT were significantly more frequent in patients with SVT (P values 4G-4G and MTHFR 677TT distributions deviated significantly from that expected from a population in Hardy-Weinberg equilibrium. Thrombophilia was significantly less frequent in patients with pre-HSVT (250/437, 57.2%) than in patients with post-HSVT (44/45, 97.8%). Our study shows the significant prevalence of PAI-1 4G-4G and MTHFR 677TT in SVT, mainly in post-HSVT.

  9. Gene expression of fibrinolytic factors urokinase plasminogen activator and plasminogen activator inhibitor-1 in rabbit temporo-mandibular joint cartilage with disc displacement

    Institute of Scientific and Technical Information of China (English)

    ZHAN Jing; GU Zhi-yuan; WU Li-qun; ZHANG Yin-kai; HU Ji-an

    2005-01-01

    Background The urokinase plasminogen activator system is believed to play an important role in degradation of the extracellular matrix associated with cartilage and bone destruction; however its precise roles in temporomandibular disorders have not yet been clarified. The aims of this study were to investigate the gene expression of fibrinolytic factors urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the articular cartilage of rabbit temporomandibular joint (TMJ) with disc displacement (DD) and to probe the relationship between fibrinolytic activity and cartilage remodeling. Methods Disc displacement of right joints was performed in 36 of 78 rabbits under investigation. The animals were sacrificed at 4 days and 1, 2, 4, 8 and 12 weeks after surgery, respectively. The right joints of these animals were harvested and processed for the examination of mRNA expression of uPA and PAI-1 in articular cartilage using in situ hybridization techniques. Results The expression of uPA and PAI-1 was co-expressed weakly in the chondrocytes from transitive zone to hypertrophic zone and mineralized zone, while no hybridizing signals were shown in proliferative zone and superficial zone in control rabbits. The most striking was the up-regulation of uPA and PAI-1 mRNA in 4-day rabbits postoperatively at the onset of cartilage degeneration. The strongest hybridizing signals for uPA and PAI-1 were seen in 2-week rabbits postoperatively. After 2 weeks, the expression of uPA and PAI-1 began to decrease and reached nearly normal level at 12 weeks. Conclusions The expression of the uPA/PAI-1 system coincides with the pathological changes in condylar cartilage after DD. The uPA/PAI-1 system may be one of the essential mediators in articular cartilage remodeling.

  10. Role of connective growth factor in plasminogen activator inhibitor-1 and fibronectin expression induced by transforming growth factor β1 in renal tubular cells

    Institute of Scientific and Technical Information of China (English)

    张春; 孟宪芳; 朱忠华; 杨晓; 邓安国

    2004-01-01

    Background Connective tissue growth factor (CTGF) contributes greatly to renal tubulointerstitial fibrosis, which is the final event leading to end-stage renal failure. This study was designed to investigate the effects of CTGF antisense oligodeoxynucleotides (ODNs) on the expressions of plasminogen activator inhibitor-1 (PAI-1) and fibronectin in renal tubular cells induced by transforming growth factor β1 (TGF-β1) in addition to the role of CTGF in the accumulation and degradation of renal extracellular matrix (ECM).Methods A human proximal tubular epithelial cell line (HKC) was cultured in vitro. Cationic lipid-mediated CTGF antisense ODNs were transfected into HKC cells. After HKC cells were stimulated with TGF-β1 (5 μg/L), the mRNA levels of PAI-1 and fibronectin were measured by RT-PCR. Intracellular PAI-1 protein synthesis was assessed by flow cytometry. The secreted PAI-1 and fibronectin in the medium were determined by Western blot and ELISA, respectively.Results TGF-β1 was found to induce tubular CTGF, PAI-1, and fibronectin mRNA expression. PAI-1 and fibronectin mRNA expression induced by TGF-β1 was significantly inhibited by CTGF antisense ODNs. CTGF antisense ODNs also inhibited intracellular PAI-1 protein synthesis and lowered the levels of PAI-1 and fibronectin protein secreted into the medium.Conclusions CTGF may play a crucial role in the accumulation and degradation of excessive ECM during tubulointerstitial fibrosis, and transfecting CTGF antisense ODNs may be an effective way to prevent renal fibrosis.

  11. Coordinated Regulation of Tissue Type Plasminogen Activator and Plasminogen Activator Inhibitor Type-1 Gene Expression in Hypophysectomized Rat Ovaries During GnRHa-Induced Ovulation

    Institute of Scientific and Technical Information of China (English)

    刘以训; 刘奎; 彭晓蓉; T.Ny

    1994-01-01

    In this study we have demonstrated that both granulosa and theca-interstitial cells of hy-pophysectomized rat ovaries are capable of synthesizing tPA and PAI-1.Injection of a GnRH agonist canmarkedly induce these gene expressions in the ovary in a cell-specific and time-coordinated manner,so that asurge of tPA mRNA and its activity in both granulosa and theca-interstitial cells was obtained just prior toovulation.Theca-interstitial cells make PAI-1 become the most active in the ovary.Both the amount PAI-1mRNA and its activity in the cells reach the maximum level 6 h before the tPA peak.By contrast,granulosacells produce only a little amount of PAI-1 (most increase tPA activity),and both PAI-1 mRNA and activityin the cells reach the maximum after ovulation.The coordinated regulation of tPA and PAI-1 in the ovarymay fine-tune the peak of tPA activity which may be important for the regulation of the ovulatory process.The changes of tPA and PAI-1 in the ovarian cells of hypophysectomized rats during GnRHa-induced ovula-tion are similar to that in intact rats during hCG-induced ovulation,suggesting that the ovulatory process canbe modulated by different regulatory signals mediated by influencing the coordinated expression of both tPAand PAI-1.

  12. Synergistic and multidimensional regulation of plasminogen activator inhibitor type 1 expression by transforming growth factor type β and epidermal growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaoling; Thalacker, F.W.; Nilsen-Hamilton, Marit

    2012-04-06

    The major physiological inhibitor of plasminogen activator, type I plasminogen activator inhibitor (PAI-1), controls blood clotting and tissue remodeling events that involve cell migration. Transforming growth factor type β (TGFβ) and epidermal growth factor (EGF) interact synergistically to increase PAI-1 mRNA and protein levels in human HepG2 and mink Mv1Lu cells. Other growth factors that activate tyrosine kinase receptors can substitute for EGF. EGF and TGFβ regulate PAI-1 by synergistically activating transcription, which is further amplified by a decrease in the rate of mRNA degradation, the latter being regulated only by EGF. The combined effect of transcriptional activation and mRNA stabilization results in a rapid 2-order of magnitude increase in the level of PAI-1. TGFβ also increases the sensitivity of the cells to EGF, thereby recruiting the cooperation of EGF at lower than normally effective concentrations. The contribution of EGF to the regulation of PAI-1 involves the MAPK pathway, and the synergistic interface with the TGFβ pathway is downstream of MEK1/2 and involves phosphorylation of neither ERK1/2 nor Smad2/3. Synergism requires the presence of both Smad and AP-1 recognition sites in the promoter. This work demonstrates the existence of a multidimensional cellular mechanism by which EGF and TGFβ are able to promote large and rapid changes in PAI-1 expression.

  13. UROKINASE-TYPE PLASMINOGEN ACTIVATOR, ITS RECEPTOR AND INHIBITOR EXPRESSION IN HEPATOCELLULAR CARCINOMA RELATION TO CANCER INVASIVENESS AND PROGNOSIS

    Institute of Scientific and Technical Information of China (English)

    Zheng Qi; Tang Zhaoyou; Wu Zhiquan; Shi Daren; Tang Huibin; Zhu Yunsong; Song Houyan

    1998-01-01

    Objective:To study the relevance of uPA, uPAR and PAI-1 to hepatocellular carcinoma (HCC). Methods:The expression at protein level of uPA, uPAR and PAI-1was determined in 48 cases of HCC and 12 cases of benign tumors of liver (as control) by immunohistochemistry.Results: When compared to cancer-adjacent liver tissue and the control, positive rate of immune staining for uPA,uPAR and PAI-1 on cell membrane were significantly higher in HCC cells (P<0.05). Positive staining of uPA and uPAR was seen in 16 of 22 and 19 of 22 cases of HCC with invasion, respectively (P<0.01 and P<0.001). In 8 of 8cases with cancer embolus, and in 6 of 6 cases with lymph node metastasis was the expression of positive uPAR.Compared with 2 of 17 cases without recurrence, uPAR was positive in 15 of 17 recurrent cases (P<0.01). In 36cases who survived, 17 was positive uPAR and 15 positive PAI-1, while in 12 cases who died 2 years after surgery, 12were positive for uPAR and 9 positive PAI-1, respectively (P<0.01 and P<0.05). In 15 positive cases for all three parameters, 11 had cancer invasion and 7 died within 2 years, while in negative cases, 2 had invasion and none died within 2 years (P<0.05). Conclusion: Expression of.uPA, uPAR and PAI-1 is increased in HCC, uPA and uPAR may contribute significantly to HCC invasion and metastasis. uPAR and PAI-1 are associated with poor prognosis of HCC.

  14. Adiposidade corporal, mas não resistência insulínica, associa-se ao polimorfismo -675 4G/5G no gene PAI-1 em uma amostra de crianças mexicanas

    Directory of Open Access Journals (Sweden)

    Ulises de la Cruz-Mosso

    2013-10-01

    Full Text Available 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.

  15. Thrombophilic Genetic Factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A in Noncirrhotic Portal Vein Thrombosis and Budd-Chiari Syndrome in a Caucasian Population

    Directory of Open Access Journals (Sweden)

    Mario D’Amico

    2013-01-01

    Full Text Available Thrombophilic genetic factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A were studied as risk factors in 235 Caucasian subjects: 85 patients with abdominal thrombosis (54 with portal vein thrombosis (PVT and 31 with Budd-Chiari syndrome (BCS without liver cirrhosis or hepatocellular carcinoma and 150 blood bank donors. Seventy-five patients with PVT/BCS showed associated disease or particular clinical status (46 PVT/29 BCS: 37 myeloproliferative neoplasm (20 PVT/17 BCS, 12 abdominal surgery (10 PVT/2 BCS, 10 contraception or pregnancy (6 PVT/4 BCS, 7 abdominal acute disease (6 PVT/1 BCS, and 9 chronic disease (4 PVT/5 BCS; ten patients did not present any association (8 PVT/2 BCS. PAI-14G-4G, MTHFR677TT, and V Leiden 506Q were significantly frequent (OR 95% CI and χ2 test with P value in abdominal thrombosis; in these patients PAI-14G-4G and MTHFR677TT distributions deviated from that expected from a population in the Hardy-Weinberg equilibrium (PAI-1: χ2=13.8, P<0.001; MTHFR677: χ2=7.1, P<0.01, whereas the equilibrium was respected in healthy controls. V Leiden Q506 and Prothrombin 20210A were in the Hardy-Weinberg equilibrium both in patients with abdominal thrombosis and healthy controls. Our study shows an important role of PAI-14G-4G and MTHFR677TT in abdominal thrombosis without liver cirrhosis or hepatocellular carcinoma.

  16. Expression and prognostic value of plasminogen activator inhibitor type 1 in node-negative breast cancer%淋巴结阴性乳腺癌PAI-Ⅰ表达及预后价值

    Institute of Scientific and Technical Information of China (English)

    Bin Wang; Ning Wang; Chunyan Xue; Bin Jiang; Yajie Wang

    2008-01-01

    Objective:To investigate the expressions of plasminogen activator inhibitor type 1(PAI-1),C-erbB-2,VEGF and Ki-67 by immunohistostaining and then to evaluate the prognostic value of PAJ-1 in node-negative breast cancer,Methods:The study included a retrospective series of 62 female patients with axillary lymph node-negative breast cencer.Expressions of PAI-1,C-erbB-2,VEGF and Ki-67 were determined by immunohistostaining on formalin-fixed paraffin-embedded tissue sections from these patients after a median follow-up of 69 months(range 22-117 months).Correlations with well known clinicopathologic factors were assessed and multivariate survival analyses were performed.Results:High PAI-1 level was positively associated with high histologic grade of the tumors.Disease-free survival(DFS)was significantly shorter for the patients with moderate to intensive expression of PAI-1 lban for those with negative(X2=25.46,P<0.001:X2=23.07,P<0.001)to mild expression(X2=19.75,P<0.001:X2=17.40.P<0.001).Although on univariate analysis of the prognostic factors,tumor size,location of primary tumor and age as well as expressions of PAI-1,VEGF and Ki-67 were all significantly prognostic factors for DFS(P<0.05),PAI-1 was the only independent prognostic factor on multivariate analysis(P<0.0001;hazard ratio[HR].4.041:95% confidence intewal[CI],1.928-8.468).Conclusion:These results of the current study indicate that intermediate or high expression of PAI-1 represents a strong and independent unfavorable prognostic factor for the development of recurrence or metastases in axillary node-negative breast cancer.

  17. Altered expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in high-risk soft tissue sarcomas.

    Science.gov (United States)

    Benassi, M S; Ponticelli, F; Azzoni, E; Gamberi, G; Pazzaglia, L; Chiechi, A; Conti, A; Spessotto, P; Scapolan, M; Pignotti, E; Bacchini, P; Picci, P

    2007-09-01

    In recent years, classification of soft-tissue sarcomas (STS) has improved with cytogenetic analyses, but their clinical behavior is still not easily predictable. The aim of this study was to detect alterations in the urokinase-type plasminogen system, involved in tumor growth and invasion, by comparing mRNA levels of its components with those of paired normal tissues, and relating them with patient clinical course. Real-time PCR was performed on human STS cell lines and tissues from highly malignant STS, including leiomyosarcomas and malignant fibrous histiocytomas, to evaluate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of gene products was also performed. Median mRNA values of all genes studied were higher in tumors than in paired normal tissues. In agreement with data on STS cell lines, significant up-regulation for uPA and PAI-1 genes compared to reference values was seen. Moreover, different levels of expression were related to histotype and metastatic phenotype. There was accordance between uPA mRNA and protein expression, while immunodetection of PAI-1 product was weak and scattered. Clearly, the controversial role of PAI-1 protein requires further biological analyses, but evident involvement of uPA/PAI-1 gene overexpression in STS malignancy may highlight a molecular defect useful in discriminating STS high-risk patients.

  18. Urokinase, urokinase receptor, and plasminogen activator inhibitor-1 expression on podocytes in immunoglobulin A glomerulonephritis

    OpenAIRE

    Lee, Ji-Hye; Oh, Mee-Hye; Park, Jae-seok; Na, Gyoung-Jae; Gil, Hye-Wook; Yang, Jong-Oh; Lee, Eun-Young; Hong, Sae-Yong

    2014-01-01

    Background/Aims The purpose of this study was to investigate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1 on podocytes in immunoglobulin A (IgA) glomerulonephritis (GN). Methods Renal biopsy specimens from 52 IgA GN patients were deparaffinized and subjected to immunohistochemical staining for uPA, PAI-1, and uPAR. The biopsies were classified into three groups according to the expression of uPA and uPAR on podo...

  19. Tenecteplase (TNK-tPA - ein neues Fibrinolytikum mit herausragenden Eigenschaften: Einzelbolusgabe, hohe Fibrinspezifität, PAI-1-Resistenz, körpergewichtsadaptierte Dosierung und geringe Blutungsrate für Hochrisikopatienten

    Directory of Open Access Journals (Sweden)

    Huber K

    2002-01-01

    Full Text Available Mit Tenecteplase (TNK-tPA; METALYSE® in Kombination mit dem niedermolekularen Heparin Enoxaparin (LOVENOX® wurde ein vorläufiger Endpunkt in der Weiterentwicklung neuer Fibrinolytika erreicht. Die einfache Applikationsweise (als Einzelbolus in Kombination mit den Eigenschaften einer hohen Fibrinselektivität, einer Resistenz gegenüber dem natürlichen Inhibitor PAI-1 sowie eine verhältnismäßig geringe Blutungskomplikationsrate bei Hochrisikopatienten könnten dazu beitragen Tenecteplase (+ Enoxaparin als neuen "Goldstandard" der medikamentösen Reperfusionstherapie des akuten STEMI zu etablieren. Tenecteplase würde sich potentiell als Fibrinolytikum der ersten Wahl überall dort anbieten, wo die Etablierung einer prähospitalen Fibrinolysetherapie angezeigt ist. Die Kombinationstherapie (halbe Dosis Tenecteplase mit GP IIb/IIIa-Rezeptorblockern (Volldosis gehört noch nicht zum klinischen Standardrepertoire der medikamentösen Reperfusionstherapie und sollte vorerst wissenschaftlichen Untersuchungen vorbehalten sein (Stichwort "facilitated PCI". Auch die Frage, ob eine frühe medikamentöse Reperfusion (mittels Fibrinolytikum, GP IIb/IIIa-Blocker oder Kombinationstherapie mit einer unmittelbar nachfolgenden koronaren Intervention verknüpft werden soll, muß erst in prospektiven Studien untersucht werden und erfordert neben den erhöhten Kosten auch ein hohes Maß an Kooperation und Organisation.

  20. PAI-1基因多态性与不孕患者子宫内膜发育不良的遗传易感性研究%Association of genetic polyrnorphism in plasminogen activator inhibitor-1 gene with endometrial hypoplasia in infertile women

    Institute of Scientific and Technical Information of China (English)

    孙静华; 管立学; 蔺冬菊; 代培凤; 潘力; 牟倩

    2008-01-01

    Objective To investigate the relationship between the plasminogen activator inhibitor(PAI-1) poly-morphisms and endometrial hypoplasia in infertile women. Methods The study was conducted in 105 primary infertile patients with endometrial hypoplasia diagnosed by pathology and the thickness of endometrium by B-mode ultrasound and 85 controls who were not pregnant and had normal fertility. The - 675 4G/5G polymorphism in the PAI-1 gene was de-tected by polymerase chain reaction-restriction fragment length polymerphim analysis. Results The frequencies of 4G/ 4G genotype and 4G allele of the PAI-1 gene were higher in the patient group (48.6% and 66.2%) than in the normal controls(22.4% and 47.1%)(P<0.01).The PAI-1 4G/4G genotype was significantly associated with endometrial hypoplasia in the infertile patients (OR=4.9,95% CI:2.10-10.12). Conclusion The present findings suggest that the 4G/5G polymorphism of the PAI-1 gene was associated with endometrial hypoplasia in infertile patients.%目的 探讨纤溶酶原激活剂抑制物-1(plasminogen activator inhibitor-1,PAI-1)基因多态性与不孕患者的子宫内膜发育的相关性.方法 选取经B超测量子宫内膜厚度及子宫内膜病理学检查诊断为子宫内膜发育不良不孕患者105例,有正常生育的健康非妊娠妇女85名,应用聚合酶链反应-限制性片段长度多态性分析技术检测PAI-1基因-675位4G/5G多态性.结果 患者组PAI-1基因4G/4G基因频率(48.6%)和4G等位基因频率(66.2%)显著高于对照组(22.4%和47.1%)(P<0.01)差异有统计学意义,与5G/5G基因型比较4G/4G型患者发生子宫内膜反应不良致不孕的相对风险率的比数比(odds ratio,OR)为4.9,95%的可信区间为2.10-10.12.结论 PAI-1基因4G/5G多态性与不孕患者的子宫内膜发育不良密切相关.

  1. Phosphatidylcholine is a major source of phosphatidic acid and diacylglycerol in angiotensin II-stimulated vascular smooth-muscle cells.

    Science.gov (United States)

    Lassègue, B; Alexander, R W; Clark, M; Akers, M; Griendling, K K

    1993-06-01

    In cultured vascular smooth-muscle cells, angiotensin II produces a sustained formation of diacylglycerol (DG) and phosphatidic acid (PtdOH). Since the fatty acid composition of these molecules is likely to determine their efficacy as second messengers, it is important to ascertain the phospholipid precursors and the biochemical pathways from which they are produced. Our experiments suggest that phospholipase D (PLD)-mediated phosphatidylcholine (PtdCho) hydrolysis is the major source of both DG and PtdOH during the late signalling phase. First, in cells labelled with [3H]myristate, which preferentially labels PtdCho, formation of [3H]PtdOH precedes formation of [3H]DG. Second, in contrast with phospholipase C (PLC) activation, DG mass accumulation is dependent on extracellular Ca2+. Similarly, DG mass accumulation is not attenuated by protein kinase C activation, which we have previously shown to inhibit the phosphoinositide-specific PLC. Third, the fatty acid composition of late-phase DG and PtdOH more closely resembles that of PtdCho than that of phosphatidylinositol. Finally, in cells labelled for a short time with [3H]glycerol, the radioactivity incorporated into [3H]DG and PtdOH was greater than that incorporated into PtdIns, but not into PtdCho. We found no evidence that synthesis de novo or phosphatidylethanolamine breakdown contributes to sustained DG and PtdOH formation. Thus, in angiotensin II-stimulated cultured vascular smooth-muscle cells, PLD-mediated PtdCho hydrolysis is the major source of sustained DG and PtdOH, whereas phosphoinositide breakdown is a minor contributor. Furthermore, PtdOH phosphohydrolase, which determines the relative levels of DG and PtdOH, appears to be regulated by protein kinase C. These results have important implications for the role of these second messengers in growth and contraction.

  2. 纤溶酶原激活物抑制剂在子宫内膜癌中表达及其意义的初步研究%Preliminary study on expression and significance of plasminogen activator inhibitor-1 in endometrial carcinoma

    Institute of Scientific and Technical Information of China (English)

    黄帅; 郑明飞; 张思辰; 王少为

    2014-01-01

    Objective To research the relationship between the expression of PAI-1 and the clinical characteristics of the endometrial carcinoma.Methods We detected the level of the serum PAI-1 by ELISA in the patients with endometrial carcinoma,the patients with endometrial hyperplasia and the patients with normal endometrium.The expression of PAI-1 in endometrial carcinoma and normal endometrial tissues was observed by immunohistochemistry.Results The concentration of serum PAI-1 in patients with endometrial carcinoma was 18.64 ± 6.22 μtg/L,significantly higher than those of patients with endometrial hyperplasia (6.94 ± 2.87) μg/L and patients with normal endometrium (6.68 ± 2.13)μg/L (P=0.00).The expression rate of PAI-1 was 68.2% (15/22) in endometrial carcinoma tissue,and 8.3% (2/24) in normal endometrial tissue (P=0.00).Compared with the early endometrial carcinoma,the expression rate of PAI-1 in the advanced endometrial carcinoma was significantly higher (6/6 w 9/16,P=0.03).Conclusions The expression level of PAI-1 may be related to the stage of the endometrial carcinoma.%目的 研究纤溶酶原激活物抑制剂(PAI-1)在子宫内膜癌中表达情况及与临床特征之间的关系. 方法 采用酶联免疫吸附试验(ELISA)测定子宫内膜癌患者、子宫内膜增生患者与正常子宫内膜者的血清PAI-1水平;通过免疫组化检测PAI-1在子宫内膜癌及正常子宫内膜组织中的表达情况. 结果 内膜癌组患者血清中PAI-1含量为(18.64±6.22)μg/L,明显高于内膜增生组(6.94±2.87)μg/L及正常对照组(6.68±2.13)μg/L(均P=0.00);PAI-1在子宫内膜癌组织中的表达率为68.2%(15/22),正常子宫内膜组织的表达率8.3%(2/24),差异有统计学意义(P=0.00).与早期子宫内膜癌相比,晚期子宫内膜癌中PAI-1的表达率明显升高(6/6对比9/16,P=0.03). 结论 PAI-1表达水平可能与子宫内膜癌进展情况相关.

  3. Fish-oil esters of plant sterols differ from vegetable-oil sterol esters in triglycerides lowering, carotenoid bioavailability and impact on plasminogen activator inhibitor-1 (PAI-1 concentrations in hypercholesterolemic subjects

    Directory of Open Access Journals (Sweden)

    Chan Yen-Ming

    2007-10-01

    Full Text Available Abstract Background Consumption of plant sterol (PS esters lower low-density lipoprotein (LDL-cholesterol levels by suppressing intestinal absorption of cholesterol. Commercially available PS are mainly esterified to omega-6 fatty acid (FA, such as sunflower oil (SO FA. Emerging trends include using other sources such as olive oil (OO or omega-3 FA from fish oil (FO, known to exert potent hypotriglyceridemic effects. Our objective was to compare the actions of different FA esterified to PS on blood lipids, carotenoid bioavailability as well as inflammatory and coagulation markers. Methods Twenty-one moderately overweight, hypercholesterolemic subjects consumed experimental isoenergetic diets enriched with OO (70% of fat, each lasting 28-day and separated by 4-week washout periods, using a randomized crossover design. Diets were supplemented with three PS esters preparations, PS-FO, PS-SO, or PS-OO. All PS treatments contained an equivalent of 1.7 PS g/d, and the PS-FO provided a total of 5.4 g/d FO FA (eicosapentaenoic and docosahexaenoic acids. Results There were no differences between PS-containing diet effects on total cholesterol, LDL-cholesterol, or high-density lipoprotein (HDL-cholesterol levels. However, PS-FO consumption resulted in markedly lower (P Conclusion Our findings suggest that, in hypercholesterolemic subjects consuming an OO-based diet, PS-FO results in lowered blood triglyceride and PAI-1 concentrations, and higher fat-soluble vitamin levels in comparison to the vegetable oil FA esters of PS (PS-SO and PS-OO. Thus, PS-FO may offer hyperlipidemic subjects a more comprehensive lipid lowering approach while reducing the potential risk of decreased plasma carotenoid concentrations.

  4. EXPRESSION AND ROLE OF PLASMINOGEN SYSTEM IN PROCESS OF RESTENOSIS

    Institute of Scientific and Technical Information of China (English)

    ZHAO Hai-guang; LU Xin-wu; HUANG Ying; JIANG Mi-er

    2005-01-01

    Objective To study the expression and role of plasminogen system in the process of restenosis.Methods We established a double-injury model of atherosclerotic restenosis in rabbit iliac artery mimicking human arterial restenosis. The time course of tissue plaminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) was investigated by immunohistochemistry. The mRNA expression of uPA and uPAR were detected after vascular procedures by in situ hybridization. Results In uninjured arteries, the weak expression of tPA and PAI-1 was detected in intimal and endothelial cells. The expression of tPA, uPA, uPAR and PAI-1 was significantly induced after double-injury, but after double-injury 14d, the expression of tPA restore to preinjury levels. The expression of uPA and uPAR in intimal was higher than that of media and maintain high levels in intimal within 42d and 56d. Conclusion Whereas t-PA is primarily involved in clot dissolution and play a limited role in the process of restenosis, in plasminogen system, uPA and uPAR play a prominent role in the process of restenosis.

  5. Panaxquin quefolium diolsaponins dose-dependently inhibits the proliferation of vascular smooth muscle cells by downregulating proto-oncogene expression

    Directory of Open Access Journals (Sweden)

    Zhihao Wang

    2013-01-01

    Conclusions: Our study demonstrates that PQDS may reduce AngII-stimulated VSMC proliferation by suppressing the expression of proto-oncogenes. These results may provide insights for the development of novel traditional Chinese medicines to prevent atherosclerosis.

  6. mRNA expression of genes involved in inflammation and haemostasis in equine fibroblast-like synoviocytes following exposure to lipopolysaccharide, fibrinogen and thrombin

    DEFF Research Database (Denmark)

    Andreassen, Stine Mandrup; Berg, Lise Charlotte; Nielsen, Søren Saxmose;

    2015-01-01

    ) and protease activator receptor 1 (PAR-1) was assessed using quantitative real time reverse transcriptase PCR. Results: LPS caused a significant increase in mRNA expression of SAA, IL-6, MCP-1 and uPA, and a decrease in TF, PAI-1 and PAR-1 when compared to non-treated cells. Treatment with thrombin resulted...

  7. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases

    DEFF Research Database (Denmark)

    Illemann, Martin; Bird, Nigel; Majeed, Ali;

    2009-01-01

    Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase-type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor-1 (PAI-1......). To compare the expression patterns of uPA, uPAR and PAI-1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI-1 in primarily stromal cells at the invasive front. In 5 of the 14......, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI-1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings...

  8. Angiotensin II stimulates thick ascending limb NO production via AT(2) receptors and Akt1-dependent nitric-oxide synthase 3 (NOS3) activation.

    Science.gov (United States)

    Herrera, Marcela; Garvin, Jeffrey L

    2010-05-14

    Angiotensin II (Ang II) acutely stimulates thick ascending limb (TAL) NO via an unknown mechanism. In endothelial cells, activation of Ang II type 2 receptor (AT(2)) stimulates NO. Akt1 activates NOS3 by direct phosphorylation. We hypothesized that Ang II stimulates TAL NO production via AT(2)-mediated Akt1 activation, which phosphorylates NOS3 at serine 1177. We measured NO production by fluorescence microscopy. In isolated TALs, Ang II (100 nm) increased NO production by 1.1 +/- 0.2 fluorescence units/min (p NOS3 at serine 1177 by 130% (p NOS3 phosphorylation. We concluded that Ang II enhances TAL NO production via activation of AT(2) and Akt1-dependent phosphorylation of NOS3 at serines 1177 and 633.

  9. Angiotensin II Stimulates Thick Ascending Limb NO Production via AT2 Receptors and Akt1-dependent Nitric-oxide Synthase 3 (NOS3) Activation*

    Science.gov (United States)

    Herrera, Marcela; Garvin, Jeffrey L.

    2010-01-01

    Angiotensin II (Ang II) acutely stimulates thick ascending limb (TAL) NO via an unknown mechanism. In endothelial cells, activation of Ang II type 2 receptor (AT2) stimulates NO. Akt1 activates NOS3 by direct phosphorylation. We hypothesized that Ang II stimulates TAL NO production via AT2-mediated Akt1 activation, which phosphorylates NOS3 at serine 1177. We measured NO production by fluorescence microscopy. In isolated TALs, Ang II (100 nm) increased NO production by 1.1 ± 0.2 fluorescence units/min (p NOS3 at serine 1177 by 130% (p NOS3 phosphorylation. We concluded that Ang II enhances TAL NO production via activation of AT2 and Akt1-dependent phosphorylation of NOS3 at serines 1177 and 633. PMID:20299462

  10. mRNA expression of genes involved in inflammation and haemostasis in equine fibroblast-like synoviocytes following exposure to lipopolysaccharide, fibrinogen and thrombin

    DEFF Research Database (Denmark)

    Andreassen, Stine Mandrup; Berg, Lise Charlotte; Nielsen, Søren Saxmose;

    2015-01-01

    to lipopolysaccharide (LPS), fibrinogen and thrombin. Synovial membranes were collected from metacarpo-phalangeal joints of 6 skeletally mature horses euthanized for non-orthopaedic reasons. Passage 4 fibroblast-like synoviocytes were left non-treated or treated with either 0.1 μ g/ml LPS, 5 mg/ml fibrinogen or 5 U...... in increased mRNA expression of SAA, IL-6, MCP-1 and PAI-1, and a decreased PAR-1 expression compared to non-treated cells. The fibrinogen-treated synoviocytes showed significantly increased mRNA expression of IL-6, MCP-1, TF and PAI-1, and decreased PAR-1 expression compared to non-treated cells. Conclusion......: LPS, fibrinogen and thrombin induced an increased gene expression of inflammatory markers in isolated equine fibroblast-like synoviocytes. LPS caused changes in gene expression promoting increased fibrinolysis, while fibrinogen and thrombin changed the gene expression resulting potentially in reduced...

  11. Estrogen receptor alpha augments changes in hemostatic gene expression in HepG2 cells treated with estradiol and phytoestrogens.

    Science.gov (United States)

    Kelly, Lynne A; Seidlova-Wuttke, Dana; Wuttke, Wolfgang; O'Leary, John J; Norris, Lucy A

    2014-01-15

    Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in post-menopausal women are unknown. The aim of this study was to determine the effect of the phytoestrogens, genistein, daidzein and equol on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen. HepG2 cells and Hep89 cells (expressing estrogen receptor alpha (ERα)) were incubated for 24 h with 50 nM 17β-estradiol, genistein, daidzein or equol. Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), Factor VII, fibrinogen γ, protein C and protein S mRNA expression were determined using TaqMan PCR. Genistein and equol increased tPA and PAI-1 expression in Hep89 cells with fold changes greater than those observed for estradiol. In HepG2 cells (which do not express ERα), PAI-1 and tPA expression were unchanged. Increased expression of Factor VII was observed in phytoestrogen treated Hep89 cells but not in similarly treated HepG2s. Prothrombin gene expression was increased in equol and daidzein treated HepG2 cells in the absence of the classical estrogen receptors. These data suggest that phytoestrogens can regulate the expression of coagulation and fibrinolytic genes in a human hepatocyte cell line; an effect which is augmented by ERα.

  12. Construction,expression and characterization of tissue-type plasminogen activator mutants

    Institute of Scientific and Technical Information of China (English)

    刘士辉; 黄培堂; 黄翠芬

    1995-01-01

    Three tissue-type plasminogen activator(t-PA)mutants were constructed by recombinant andsite-directed mutagenesis techniques.They are del(296—302)with deletion of PAI-1 binding site,N117Q/N184Qwith deglycosylation of K1 and K2 domains,and their combination mutant designated as GGI.Then these threemutants were suocessfully transiently expressed in COS-7 ceils,and GGI was further stably expressed in CHOcells.The biological characterization of the expression products indicated that del(296—302)and GGIpossessed the resistance to inhibition by PAI-1.In addition,the specific activity of GGI was increased byabout 46,the plasma half-life was prolonged by about one fold,while its affinity for fibrin was not affected.

  13. Leucocyte expression of genes implicated in the plasminogen activation cascade is modulated by yoghurt peptides.

    Science.gov (United States)

    Theodorou, Georgios; Politis, Ioannis

    2016-08-01

    The urokinase-plasminogen activator (u-PA), its receptor (u-PAR) and the inhibitors of u-PA (PAI-1 and PAI-2) provide a multi-molecular system in leucocytes that exerts pleiotropic functions influencing the development of inflammatory and immune responses. The objective of the present study was to examine the ability of water soluble extracts (WSE) obtained from traditional Greek yoghurt made from bovine or ovine milk to modulate the expression of u-PA, u-PAR, PAI-1 and PAI-2 in ovine monocytes and neutrophils. WSE were obtained from 8 commercial traditional type Greek yoghurts made from ovine or bovine milk. WSE upregulated the expression of all 4 u-PA related genes in monocytes but the upregulation was much higher in the PAI-1 (10-fold) than in u-PA and u-PAR (3-4 fold) thus, shifting the system towards inhibition. In line with this observation, WSE reduced total and membrane-bound u-PA activity in monocytes. In neutrophils, WSE caused small (50-60%) but significant (P yoghurts made from bovine or ovine milk were essentially equally effective in affecting the u-PA system except for the u-PAR gene in ovine neutrophils that was affected (reduced) by the ovine and not the bovine WSE. In conclusion, peptides present in WSE modulated the expression of u-PA related genes but the effect was much more prominent in monocytes than in neutrophils.

  14. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue

    DEFF Research Database (Denmark)

    Usher, Pernille Autzen; Thomsen, Ole Frøkjær; Iversen, Peter

    2005-01-01

    RNAs was predominantly seen in cells identified as macrophages, which in most of the carcinomas (approximately 90%) were located in the interstitial tissue between the tumor cell islands, while in most of the benign hyperplasias they were located in the lumen of the glands and were in only a few cases (approximately 30......%) found in the interstitial tissue. uPAR immunoreactivity correlated with the mRNA expression and was, in addition, found in neutrophils. PAI-1 mRNA was detected in 13 of the 16 carcinomas and in 8 of the 9 benign hyperplasias, located in scattered fibroblast-like cells in both groups, in some vascular...... structures and in a few macrophages located in the interstitial tissue of both malignant and benign lesions. A similar expression pattern was found for PAI-1 immunoreactivity. In 8 of the 16 carcinomas, all 3 components were present, and in several areas colocalization was observed in stromal cells in close...

  15. Regulation of p53-mediated changes in the uPA-fibrinolytic system and in lung injury by loss of surfactant protein-C expression in alveolar epithelial cells.

    Science.gov (United States)

    Puthusseri, Bijesh; Marudamuthu, Amarnath S; Tiwari, Nivedita; Fu, Jian; Idell, Steven; Shetty, Sreerama

    2017-04-06

    Pulmonary surfactant protein-C (SP-C) expression by type II alveolar epithelial cells (AECs) is markedly reduced in diverse types of lung injuries and is often associated with AEC apoptosis. It is unclear whether loss of SP-C contributes to the increased p53 and urokinase-type plasminogen activator (uPA) system cross talk and apoptosis of AECs. We therefore inhibited SP-C expression in human and murine AECs using lentivirus vector expressing shRNA and tested p53 and downstream changes in uPA-fibrinolytic system. Inhibition of SP-C expression in AECs induced p53 and activated caspase-3, indicating AEC apoptosis. We also found that bleomycin or cigarette smoke exposure failed to inhibit SP-C expression or apoptosis in AECs in p53- and plasminogen activator inhibitor-1 (PAI-1)-deficient mice. Depletion of SP-C expression by lentiviral SP-C shRNA in PAI-1-deficient mice failed to induce p53 or apoptosis in AECs, while it increased both AEC p53 and apoptosis in wild type or uPA-deficient mice. SP-C inhibition in AECs also increased in CXCL1 and CXCL2, and their receptor CXCR2 as well as ICAM-1 expression, indicative of a pro-inflammatory response. Overexpression of p53-binding 3'UTR sequences in AECs inhibited PAI-1 induction while maintaining uPA and uPAR protein and mRNA expression. Further, caveolin-1 expression and phosphorylation were increased in AECs indicating an intricate link between caveolin-1 and Src kinase-mediated cell signalling and AEC apoptosis due to loss of SP-C expression through p53 and uPA system-mediated cross-talk. The role of uPA, PAI-1 and p53 in the regulation of AEC apoptosis after injury was also determined in knock out mice.

  16. Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline.

    Science.gov (United States)

    Tsai, Chung-Hung; Lee, Shiuan-Shinn; Chang, Yu-Chao

    2015-10-01

    Oral submucous fibrosis (OSF) is regarded as a pre-cancerous condition with fibrosis in oral subepithelial connective tissue. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal buccal mucosa tissues and OSF specimens and further explore the potential mechanisms that may lead to the induction of HIF-1α expression. Twenty-five OSF specimens and six normal buccal mucosa were examined by immunohistochemistry. The expression of HIF-1α from fibroblasts cultured from OSF and normal buccal mucosa was measured by Western blot. Arecoline, a major areca nut alkaloid, was challenged to normal buccal mucosa fibroblasts (BMFs) to elucidate whether HIF-1α expression could affect by arecoline. In addition, the effects of arecoline on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia. HIF-1α expression was significantly higher in OSF specimens and expressed mainly by fibroblasts, epithelial cells, and inflammatory cells. Fibroblasts derived from OSF were found to exhibit higher HIF-1α protein expression than BMFs (P Arecoline was found to upregulate HIF-1α protein in a dose-dependent manner (P arecoline-induced PAI-1 protein expression than normoxic conditions (P < 0.05). These results suggest that HIF-1α expression is significantly upregulated in OSF tissues from areca quid chewers, implying a potential role as a biomarker for local tissue hypoxia. The activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in oral submucosa leading to fibrosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Nicotine Treatment Induces Expression of Matrix Metalloproteinases in Human Osteoblastic Saos-2 Cells

    Institute of Scientific and Technical Information of China (English)

    Tomoko KATONO; Takayuki KAWATO; Natsuko TANABE; Naoto SUZUKI; Kazuhiro YAMANAKA; Hitoshi OKA; Masafumi MOTOHASHI; Masao MAENO

    2006-01-01

    Tobacco smoking is an important risk factor for the development of severe periodontitis.Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs),tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1(PAI- 1), α7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3,and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the α7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13,thereby tipping the balance between bone matrix formation and resorption toward the latter process.

  18. Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-κB activities in cardiac microvascular endothelial cells.

    Science.gov (United States)

    Ni, Xiao-Qing; Zhu, Jian-Hua; Yao, Ning-Hua; Qian, Juan; Yang, Xiang-Jun

    2013-01-01

    The aim of this study was to investigate the possible proinflammatory signaling pathways involved in statin inhibition of glucose-induced plasminogen activator inhibitor-1 (PAI-1) expression in cardiac microvascular endothelial cells (CMECs). Primary rat CMECs were grown in the presence of 5.7 or 23 mmol/L glucose. PAI-1 mRNA and protein expression levels were measured by realtime polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay, respectively. A pull-down assay was performed to determine RhoA activity. IκBα protein expression was measured by Western blotting, nuclear factor (NF)-κB activation was detected by electrophoretic mobility shift assay and its transcription activity was determined by a dual luciferase reporter gene assay. PAI-1 mRNA and protein expression levels were both increased with high glucose concentrations, but they were significantly suppressed by simvastatin and atorvastatin treatment (P statins (P statins may occur partly by regulating the RhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularly beneficial for patients with metabolic syndrome.

  19. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis

    Science.gov (United States)

    Bae, Chang-Hwan; Jin, Young-Woo; Lee, Seung-Sook

    2017-01-01

    Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

  20. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis

    Directory of Open Access Journals (Sweden)

    Jong-Geol Lee

    2017-01-01

    Full Text Available Purpose. Radiation-induced lung fibrosis (RILF is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI- 1 and fibronectin (FN and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

  1. Correlation with Platelet Parameters and Genetic Markers of Thrombophilia Panel (Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, β-Fibrinogen, Factor XIIIA (V34L), Glycoprotein IIIa (L33P)) in Ischemic Strokes.

    Science.gov (United States)

    Tasdemir, Sener; Erdem, Haktan Bagis; Sahin, Ibrahim; Ozel, Lutfi; Ozdemir, Gokhan; Eroz, Recep; Tatar, Abdulgani

    2016-06-01

    An important type of arterial thrombosis, ischemic stroke is associated with increased mortality risk, severe disability and life quality impairment. In this study, we analyzed mean platelet volume, platelet count values and genetic thrombophilia markers of patients who have ischemic stroke history and searched the relationship with genetic predisposition of ischemic strokes and platelet parameters. A retrospective, clinical trial was performed by reviewing the ischemic stroke history (except cryptogenic events) of 599 patients and 100 controls. The results of the genetic thrombophilia panel were used to classify the study group and control group into low and high risk for thrombophilia groups. The high-risk group included patients homozygous/heterozygous for Factor II g.20210G>A or Factor V Leiden mutations with/without any other polymorphism. The low-risk group included patients heterozygous or homozygous for MTHFR (C677T, A1298C), PAI-1, β-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms or negative in terms of both mutations and polymorphisms. The results of study showed us that high-risk group mutations are important risk factors for ischemic stroke but low-risk group polymorphisms are not significant. According to platelet parameters, although there was a significant difference between MPV and PLT values of ischemic stroke and control group, thrombophilia mutations and polymorphisms have not a significant effect on MPV and PLT values in ischemic stroke patients.

  2. Interferons Induce STAT1-Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease.

    Science.gov (United States)

    Strandin, Tomas; Hepojoki, Jussi; Laine, Outi; Mäkelä, Satu; Klingström, Jonas; Lundkvist, Åke; Julkunen, Ilkka; Mustonen, Jukka; Vaheri, Antti

    2016-05-15

    Hantaviruses are zoonotic viruses that show various degrees of vasculopathy in humans. In this study, we analyzed the regulation of 2 fibrinolytic parameters, tissue plasminogen activator (tPA) and its physiological inhibitor, plasminogen activator inhibitor 1 (PAI-1), in Puumala hantavirus (PUUV)-infected patients and in human microvascular endothelial cells. We detected strong upregulation of tPA in the acute phase of illness and in PUUV-infected macaques and found the tPA level to positively correlate with disease severity. The median levels of PAI-1 during the acute stage did not differ from those during the recovery phase. In concordance, hantaviruses induced tPA but not PAI-1 in microvascular endothelial cells, and the induction was demonstrated to be dependent on type I interferon. Importantly, type I and II interferons directly upregulated tPA through signal transducer and activator of transcription 1 (STAT1), which regulated tPA gene expression via a STAT1-responsive enhancer element. These results suggest that tPA may be a general factor in the immunological response to viruses.

  3. Periodontitis is characterized by elevated PAI-1 activity

    NARCIS (Netherlands)

    Bizzarro, S.; van der Velden, U.; ten Heggeler, J. M. A. G.; Leivadaros, E.; Hoek, F. J.; Gerdes, V. E. A.; Bakker, S. J. L.; Gans, R. O. B.; ten Cate, H.; Loos, B. G.

    2007-01-01

    Objectives: Periodontitis is a chronic infectious disease and has been associated with cardiovascular diseases (CVD). We investigated whether plasma levels of markers of a prothrombotic state were elevated in patients with periodontitis in comparison with healthy controls. Materials and methods: Unt

  4. Prothrombotic Effect of Anti-beta-2 Glycoprotein-1 Antibodies on the Expression of Tissue Factor, Thrombomodulin, and Plasminogen Activator Inhibitor-1 in Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Rikarni Rikarni

    2015-03-01

    Full Text Available Aim: to analyse the effects of immunoglobulin (IgG and IgM anti-beta-2 glycoprotein-1 (anti-β2GP1 on the expression of tissue factor (TF, thrombomodulin (TM, and plasminogen activator inhibitor-1(PAI-1 of endothelial cells in the messenger RNA level. Methods: laboratory experimental study in human umbilical vein endothelial cells (HUVEC was done at Cipto Mangunkusumo Hospital/Faculty of Medicine, Universitas Indonesia. Samples are purified IgG anti-β2GP1 from six  antiphospholipid syndrome (APS patients serum and IgM anti-β2GP1 from six APS patients serum. For controls, purified IgG from six normal human serum (IgM-NHS and purified IgM from six normal human serum (IgM-NHS were used. HUVEC were treated with purified IgG anti-β2GP1, IgM anti-β2GP1, IgG-NHS, IgM-NHS for four hours of incubation. We measured TF, TM, and PAI-1 of HUVEC in mRNA relative expression levels (before and after treatment by real time reverse transcription polymerase chain reaction. Results: the mean value of TF, TM, and PAI-1 mRNA levels in HUVEC after treated with IgG anti-β2GP1 compared to Ig-NHS were 3.14 (0.93-, 0.31 (0.13-, 5.33 (2.75-fold respectively. In other hand, after treated with IgM anti-β2GP1 compared to IgM-NHS, mRNA levels of TF, TM, and PAI-1 were 4.33 (1.98-, 0.33 (0.22-, 5.47 (2.64-fold respectively. Before and after treatment with IgG anti-β2GP1 showed significant differences of TF mRNA levels {1.09 (0.76 versus 3.14 (0.93, p=0.003}, TM mRNA levels {0.91 (0.11 versus 0.31(0.13, p=0.001}, and PAI-1 mRNA levels 0.93 (0.13 versus 5.33 (2.75, p=0.013}. Before and after treatment with IgM anti-β2GP1 showed significant differences of TF mRNA levels {1.03 (0.11 versus 4.33 (1.98, p=0.008}, TM mRNA levels {0.93 (0.08 versus 0.33 (0.22, p=0.003}, and PAI-1 mRNA levels {1.02 (0.10 versus 5.47 (2.64, p=0.01}. Conclusion: IgG anti-β2GP1 and IgM anti-β2GP1 increased TF and PAI-1 mRNA levels. However, IgG anti-β2GP1 and IgM anti-β2GP1 decreased TM m

  5. ANGIOTENSIN II DECREASES NOS3 EXPRESSION VIA NITRIC OXIDE AND SUPEROXIDE IN THE THICK ASCENDING LIMB

    OpenAIRE

    Ramseyer, Vanesa D.; Garvin, Jeffrey L.

    2008-01-01

    Nitric oxide (NO) produced by NO synthase type 3 (NOS3) in medullary thick ascending limbs (mTHALs) inhibits Cl− reabsorption. Acutely, angiotensin II stimulates THAL NO production. In endothelial cells NO inhibits NOS3 expression. Therefore, we hypothesized that angiotensin II decreases NOS3 expression via NO in mTHALs. After 24 hrs, 10 and 100 nmol/L angiotensin II decreased NOS3 expression by 23 ± 9% (n=6, p

  6. Expression

    Directory of Open Access Journals (Sweden)

    Wang-Xia Wang

    2014-02-01

    Full Text Available The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs, sharing a 5′ AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR-103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively. In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS. In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs. Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.

  7. Effects of urokinase type plasminogen activator and plasminogen activator inhibitor-1 expressions on the formation of aneurysm of perimembranous ventricular septal defect%尿激酶型纤溶酶原激活物及其抑制物表达在膜周型室间隔缺损自发闭合中的作用

    Institute of Scientific and Technical Information of China (English)

    钱娟; 李本尚; 殷敏智; 沈萍; 孙锟

    2015-01-01

    0.05).结论 uPA及抑制物系统在VSA形成过程中起重要作用,参与瘤体的形成和纤维增殖过程.%Objective The exact mechanisms of defect closure in patients with perimembranous ventricular septal defect (PMVSD) remain unknown.We hypothesized that the expression of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) may mediate extracellular matrix (ECM) remodeling in aneurysms.Method Seven normal heart tricuspid septal leaflet and 33 aneurysms were collected in Shanghai Renji Hospital and Shanghai Children's Medical Center from January 2008 to June 2010.Immunohistochemical expression of uPA and PAI-1 in 4 normal heart valvular tissues and 15 aneurysms was detected with immunohistochemical methods.The expression of uPA and PAI-1 mRNA in 3 normal heart valvular tissues and 7 aneurysms was studied by real time fluorescent PCR;the protein expression of uPA and PAI-1 in 4 normal heart valvular tissues and 11 aneurysms was tested with Western blotting.Result The surface of the aneurysms were completely covered by endothelial cells.Two types of granulation tissue,myxoid and fibrous,were associated with the aneurismal formation.uPA were recognized predominantly in valvar interstitial cells (VICs) which located mainly in regions adjacent to the endothelium and smooth muscle cells of blood vessels.PAI-1 was found in both VICs which located mainly in granulation tissue and endothelial cells.Nine aneurysms expressed a higher uPA activity than 4 normal valvular tissues ((74.6 ± 11.8) % vs.(49.5 ± 7.4) %;t =3.87,P =0.003) and six aneurysms expressed a low uPA activity ((10.3±3.1)% vs.(49.5±7.4)%;t=11.78,P=0.000) andahighPAI-1 activity ((55.2±1.7) % vs.(50.8 ± 3.8) %;t =2.55,P =0.034) using immunohistochemical methods.uPA / PAI-1 ratio of protein expression tested by Western blot was 0.88 ± 0.22 in four normal heart vavular tissues;five aneurysms expressed high uPA activity and low PAI-1 activity and uPA/PAI

  8. Effects of Bicyclol on Expression of NF-κB and PAM in Rats with Uniliteral Ureteral Obstruction%双环醇对UU0模型大鼠肾间质核转录因子κB和纤溶酶原激活物抑制剂-1表达的影响

    Institute of Scientific and Technical Information of China (English)

    刘艳红; 韩子明

    2011-01-01

    目的:通过双环醇干预单侧输尿管梗阻( uniliteral ureteral obstruction,UUO)模型大鼠,动态观察核转录因子-κB(nuclear factor-κB,NF-κB)、纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)和PAW mRNA在梗阻侧肾组织间质中的表达,探讨双环醇延缓肾间质纤维化的可能机制.方法:采用UUO致肾间质纤维化大鼠模型,将81只大鼠随机分假手术组、模型组、治疗组.治疗组于术后第1天开始给予双环醇200mg·kg-1灌胃;假手术组和模型组给予等量生理盐水灌胃.在术后7,14,21d每组各取9只大鼠处死,取梗阻侧肾组织行HE及Mason染色,观察肾脏病理学变化.用免疫组化方法检测肾组织NF-κB,PAI-1蛋白的表达.RT-PCR法检测各组肾组织PAI-1 mRNA的表达水平.结果:模型组7,14,21d肾间质纤维化的相对面积分别为(13.03±0.66)%,(25.76±1.47)%,(53.16±2.45)%,治疗组分别为(9.63±0.58)%,(16.84±0.83)%,(33.59±1.61)%,治疗组较模型组肾间质纤维化的相对面积明显降低(P<0.05).7,14,21d模型组肾组织NF-κB的表达分别为(11.73±0.42)%,(22.56±0.69)%,(36.27±1.14)%,而治疗组分别为(5.67±0.42)%,(10.79±0.37)%,(26.62±0.23)%;模型组肾组织PAI-1蛋白的表达分别为(7.29±0.23)%,(12.32±0.20)%,(18.36±0.19)%,治疗组分别为(4.26±0.14)%,(7.69±0.13)%,(13.35±0.21)%;肾组织PAI-1 mRNA在模型组的表达分别为(1.17±0.10) ,(2.29±0.07) ,(3.33±0.10),而治疗组的表达分别为(0.32±0.03),(1.18±0.05),(2.06±0.40),治疗组肾组织NF-κB,PAI-1蛋白和mRNA的表达均较模型组减少(P均<0.05).结论:双环醇能够减轻UU0所致的肾间质损伤及纤维化的程度.其作用机制可能是通过下调NF-κB,PAI-1的表达,从而抑制肾间质纤维化.%Objective: To observe the expression of nuclear factor-κB (NF-κB) and plasminogen activator inhibitor-1 (PAI-1) of the renal interstitial in rat unilateral ureteral obstruction (UUO) model and the renoprotective effect

  9. Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

    OpenAIRE

    Li, X.; M Shams; Zhu, J; Khalig, A; Wilkes, M; Whittle, M; Barnes, N; Ahmed, A.

    1998-01-01

    Angiotensin II (ANG II) is a potent vasoconstrictor and growth promoter. Quantitative receptor autoradiography using the nonselective radioligand [125I]ANG II and subtype-selective competing compounds demonstrated the presence of both ANG II receptor (AT)1 and AT2 receptor recognition sites. In addition, a relatively small population of apparently non-AT1/non-AT2 sites was identified that may represent a novel high affinity ANG II recognition site in human placenta. Using placental membrane p...

  10. Inflammatory Gene Expression Upon TGF-β1-Induced p38 Activation in Primary Dupuytren's Disease Fibroblasts

    Science.gov (United States)

    Bujak, Maro; Ratkaj, Ivana; Markova-Car, Elitza; Jurišić, Davor; Horvatić, Anita; Vučinić, Srđan; Lerga, Jonatan; Baus-Lončar, Mirela; Pavelić, Krešimir; Kraljević Pavelić, Sandra

    2015-01-01

    Objectives: Inflammation is an underlying mechanism behind fibrotic processes and differentiation of cells into myofibroblasts. Presented study therefore provides new data on activation of autoimmune and inflammatory immune response genes that accompany activation of p38 and cell differentiation in primary cells derived from Dupuytren's disease (DD) patients. Methods: Primary non-Dupuytren's disease cells (ND) were isolated from macroscopically unaffected palmar fascia adjacent to diseased tissue obtained from patients diagnosed with the last stage of DD and cultured in vitro. Gene expression, collagen gel contraction assay and analysis of secreted proteins were performed in ND cells treated with TGF-β1 and/or inhibitor of p38 phosphorylation. Results: During differentiation of ND fibroblasts, increased expression of immune response genes PAI-1, TIMP-1, CCL11, and IL-6 was found. These changes were accompanied by increased cell contractility and activation of p38 and its target kinase MK2. Inhibition of p38 phosphorylation reversed these processes in vitro. Conclusions: TGF-β1 induced p38 phosphorylation in ND cells grown from macroscopically unaffected palmar fascia adjacent to diseased tissue from DD patients. This was accompanied by activation of the cytokine genes CCL-11 and IL-6 and secretion of extracellular matrix regulatory proteins PAI-1 and TIMP-1. A combined approach directed toward inflammation and p38 MAPK-mediated processes in DD might be considered for improving management of DD patients and prevention of recurrence. PMID:26697433

  11. Inflammatory gene expression upon TGF-β1- induced p38 activation in primary Dupuytren’s disease fibroblasts

    Directory of Open Access Journals (Sweden)

    Maro eBujak

    2015-12-01

    Full Text Available Objectives: Inflammation is an underlying mechanism behind fibrotic processes and differentiation of cells into myofibroblasts. Presented study therefore provides new data on activation of autoimmune and inflammatory immune response genes that accompany activation of p38 and cell differentiation in primary cells derived from Dupuytren's disease (DD patients. Methods: Primary non-Dupuytren's disease cells (ND were isolated from macroscopically unaffected palmar fascia adjacent to diseased tissue obtained from patients diagnosed with the last stage of DD and cultured in vitro. Gene expression, collagen gel contraction assay and analysis of secreted proteins were performed in ND cells treated with TGF-β1 and/or inhibitor of p38 phosphorylation.Results: During differentiation of ND fibroblasts, increased expression of immune response genes PAI-1, TIMP-1, CCL11 and IL-6 was found. These changes were accompanied by increased cell contractility and activation of p38 and its target kinase MK2. Inhibition of p38 phosphorylation reversed these processes in vitro.Conclusions: TGF-β1 induced p38 phosphorylation in ND cells grown from macroscopically unaffected palmar fascia adjacent to diseased tissue from DD patients. This was accompanied by activation of the cytokine genes CCL-11 and IL-6 and secretion of extracellular matrix regulatory proteins PAI-1 and TIMP-1. A combined approach directed towards inflammation and p38 MAPK-mediated processes in DD might be considered for improving management of DD patients and prevention of recurrence.

  12. Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia.

    Directory of Open Access Journals (Sweden)

    Kamlesh K Gupta

    Full Text Available Sepsis-induced acute kidney injury (AKI contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1 and vitronectin (Vn are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/- or expressing a PAI-1-mutant (PAI-1R101A/Q123K in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity.

  13. Effect of Puumala hantavirus infection on Human Umbilical Vein Endothelial Cell hemostatic function: platelet interactions, increased tissue factor expression and fibrinolysis regulator release

    Directory of Open Access Journals (Sweden)

    Marco eGoeijenbier

    2015-03-01

    Full Text Available Puumala virus (PUUV infection causes over 5000 cases of hemorrhagic fever in Europe annually and can influence the hemostatic balance extensively. Infection might lead to hemorrhage, while a recent study showed an increased risk of myocardial infarction during or shortly after PUUV infection. The mechanism by which this hantavirus influences the coagulation system remains unknown. Therefore we aimed to elucidate mechanisms explaining alterations seen in primary and secondary hemostasis during PUUV infection. By using low passage PUUV isolates to infect primary human umbilical vein endothelial cells (HUVECs we were able to show alterations in the regulation of primary- and secondary hemostasis and in the release of fibrinolysis regulators. Our main finding was an activation of secondary hemostasis due to increased tissue factor expression leading to increased thrombin generation in a functional assay. Furthermore, we showed that during infection platelets adhered to HUVECs and subsequently specifically to PUUV virus particles. Infection of HUVECs with PUUV did not result in increased von Willebrand factor while they produced more plasminogen activator inhibitor type-1 (PAI-1 compared to controls. The PAI-1 produced in this model formed complexes with vitronectin. This is the first report that reveals a potential mechanism behind the pro-coagulant changes in PUUV patients, which could be the result of increased thrombin generation due to an increased tissue factor expression on endothelial cells during infection. Furthermore, we provide insight into the contribution of endothelial cell responses regarding hemostasis in PUUV pathogenesis.

  14. mRNA expression of adipocytokines and glucocorticoid-related genes are associated with downregulation of E-cadherin mRNA in colorectal adenocarcinomas.

    Science.gov (United States)

    Størkson, Ragnhild H; Aamodt, Rolf; Vetvik, Katja Kannisto; Pietilainen, Kirsi; Bukholm, Geir; Jonsdottir, Kristin; Vollan, Hilde S; Sonerud, Tonje; Lüders, Torben; Jacobsen, Morten B; Bukholm, Ida R K

    2012-08-01

    There is a consistently reported relationship between the incidence of colon cancer and obesity. It is thought that adipose tissue, particularly visceral fat, which secretes systemic factors that alter immunological, metabolic and endocrine milieu and promotes insulin resistance by producing adipocytokines, is important in cancer progression. Systemic high concentrations of adipocytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and glucocorticoid metabolism-related genes have been associated with gastrointestinal cancer. However, limited information exists about the expression of these cytokines within tumour tissue. mRNA expression of TNF-α, IL-6,IL-8, IL-10, IL-1RN, glucocorticoid receptor alpha (GR-α), 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), plasminogen activator inhibitor-1 (PAI-1), Slug, vimentin, Snail and E-cadherin was analysed in paired samples of tumour tissue and normal mucosa in 60 surgical patients for Dukes B and C colorectal adenocarcinomas using quantitative reverse transcription PCR and microarray technology. The mRNA expression level of analysed genes was compared between tumour tissue and normal mucosa from the same patients, and a correlation to mRNA expression of E-cadherin in the same tissue samples was also performed. A highly significant difference in mRNA expression level of several of the analysed genes was observed between tumour tissue and the normal intestinal mucosa. Inverse correlation between mRNA expression of 11βHSD1, IL-6, GR-α and PAI-1 on one hand and mRNA expression of E-cadherin on the other hand was observed. Results show that the adipocytokines and glucocorticoid metabolism-related genes are overexpressed in colorectal adenocarcinomas, and expression of these genes is associated with the downregulation of E-cadherin mRNA, connecting these genes to carcinogenesis and progression of colorectal cancer.

  15. Inhibitory effects of harpagoside on TNF-α-induced pro-inflammatory adipokine expression through PPAR-γ activation in 3T3-L1 adipocytes.

    Science.gov (United States)

    Kim, Tae Kon; Park, Kyoung Sik

    2015-12-01

    Obesity is closely associated with increased production of pro-inflammatory adipokines, including interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, and adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, which contribute to chronic and low-grade inflammation in adipose tissue. Harpagoside, a major iridoid glycoside present in devil's claw, has been reported to show anti-inflammatory activities by suppression of lipopolysaccharide (LPS)-induced production of inflammatory cytokines in murine macrophages. The present study is aimed to investigate the effects of harpagoside on both tumor necrosis factor (TNF)-α-induced inflammatory adipokine expression and its underlying signaling pathways in differentiated 3T3-L1 cells. Harpagoside significantly inhibited TNF-α-induced mRNA synthesis and protein production of the atherogenic adipokines including IL-6, PAI-1, and MCP-1. Further investigation of the molecular mechanism revealed that pretreatment with harpagoside activated peroxisome proliferator-activated receptor (PPAR)-γ. These findings suggest that the clinical application of medicinal plants which contain harpagoside may lead to a partial prevention of obesity-induced atherosclerosis by attenuating inflammatory responses.

  16. Transforming growth factor-beta modulates plasminogen activator activity and plasminogen activator inhibitor type-1 expression in human keratinocytes in vitro.

    Science.gov (United States)

    Wikner, N E; Elder, J T; Persichitte, K A; Mink, P; Clark, R A

    1990-11-01

    Transforming growth factor beta (TGF-beta) is a multifunctional mediator with effects on cellular growth, differentiation, and extracellular matrix (ECM) metabolism. Because TGF-beta stimulates fibronectin expression in cultured human keratinocytes, we wished to determine whether it might also affect ECM degradation through the plasminogen activator (PA)-plasminogen activator inhibitor (PAI) system. Immunofluorescence of human keratinocytes using a monospecific antiserum to type 1 PAI (PAI-1) showed enhanced cellular and ECM staining when they were cultured in the presence of TGF-beta. The antiserum also identified an Mr 50,000 protein in conditioned media that was markedly enhanced by TGF-beta. A corresponding stimulation of PAI-1 mRNA was demonstrated by quantitative RNA blot analysis. Total plasminogen activating activity of conditioned medium was markedly decreased by TGF-beta. Zymography showed this to be at least partially due to decreased secreted urokinase activity. TGF-beta may play an important role in stabilizing the provisional matrix synthesized by keratinocytes in healing wounds.

  17. Effects of Modified Qing'e Pill () on expression of adiponectin, bone morphogenetic protein 2 and coagulation-related factors in patients with nontraumatic osteonecrosis of femoral head.

    Science.gov (United States)

    Li, Cheng-Gang; Shen, Lin; Yang, Yan-Ping; Xu, Xiao-Juan; Shuai, Bo; Ma, Chen

    2017-03-01

    To observe the regulation of Chinese herbal medicine, Modifified Qing'e Pill (, MQEP), on the expression of adiponectin, bone morphogenetic protein 2 (BMP2), osteoprotegerin (OPG) and other potentially relevant risk factors in patients with nontraumatic osteonecrosis of the femoral head (ONFH). A total of 96 patients with nontraumatic ONFH were unequal randomly divided into treatment group (60 cases) and control group (36 cases). The treatment group were treated with MQEP while the control group were treated with simulated pills. Both groups were given caltrate D. Six months were taken as a treatment course. Patients were followed up every 2 months. The levels of plasma adiponectin, BMP2, OPG, von Willebrand factor (vWF), von Willebrand factor cleaving protease (vWF-cp), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), C-reactive protein (CRP), blood rheology, bone mineral density (BMD) of the femoral head and Harris Hip Score were measured before and after treatment. After 6 months of treatment, compared with the control group, patients in the treatment group had signifificantly higher adiponectin and BMP2 levels (Padiponectin showed a positive association with BMP2 (r=0.231, P=0.003) and a negative association with PAI-1 (r=-0.159, Padiponectin, regulating bone metabolism and improving the hypercoagulation state, which may provide an experimental base for its clinical effects.

  18. The 4G/4G plasminogen activator inhibitor-1 genotype is associated with frequent recurrence of acute otitis media.

    NARCIS (Netherlands)

    Emonts, M.; Wiertsema, S.P.; Veenhoven, R.H.; Houwing-Duistermaat, J.J.; Walraven, V.; Groot, R. de; Hermans, P.W.M.; Sanders, E.A.M.

    2007-01-01

    OBJECTIVES: Plasminogen activator inhibitor-1 counterregulates cell migration, adhesion, and tissue repair. The PAI1 4G/5G promoter polymorphism has an effect on expression levels of PAI1. After a first acute otitis media episode, children are at increased risk for a next episode. Because the PAI1 4

  19. Epigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa

    DEFF Research Database (Denmark)

    Gao, Shan; Nielsen, Boye Schnack; Krogdahl, Annelise

    2010-01-01

    cells in oral carcinomas by immunohistochemistry, we found that PAI-1 was expressed in 18 of the 20 patients, mainly by cancer cells. Two showed PAI-1 positive stromal cells surrounding the tumor areas and five showed PAI-1 positive cells in tumor-adjacent normal epithelium. By real-time RT-PCR analysis...

  20. The 4G/4G plasminogen activator inhibitor-1 genotype is associated with frequent recurrence of acute otitis media.

    NARCIS (Netherlands)

    Emonts, M.; Wiertsema, S.P.; Veenhoven, R.H.; Houwing-Duistermaat, J.J.; Walraven, V.; Groot, R. de; Hermans, P.W.M.; Sanders, E.A.M.

    2007-01-01

    OBJECTIVES: Plasminogen activator inhibitor-1 counterregulates cell migration, adhesion, and tissue repair. The PAI1 4G/5G promoter polymorphism has an effect on expression levels of PAI1. After a first acute otitis media episode, children are at increased risk for a next episode. Because the PAI1 4

  1. Gain-of-function of mutant p53: mutant p53 enhances cancer progression by inhibiting KLF17 expression in invasive breast carcinoma cells.

    Science.gov (United States)

    Ali, Amjad; Shah, Abdus Saboor; Ahmad, Ayaz

    2014-11-01

    Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal-transition (EMT). However, its expression is downregulated in metastatic breast cancer that contains p53 mutations. Here, we show that mutant-p53 plays a key role to suppress KLF17 and thereby enhances cancer progression, which defines novel gain-of-function (GOF) of mutant-p53. Mutant-p53 interacts with KLF17 and antagonizes KLF17 mediated EMT genes transcription. Depletion of KLF17 promotes cell viability, decreases apoptosis and induces drug resistance in metastatic breast cancer cells. KLF17 suppresses cell migration and invasion by decreasing CD44, PAI-1 and Cyclin-D1 expressions. Taken together, our results show that KLF17 is important for the suppression of metastasis and could be a potential therapeutic target during chemotherapy.

  2. Local Transient Unfolding of Native State PAI-1 Associated with Serpin Metastability

    DEFF Research Database (Denmark)

    Trelle, Morten B; Madsen, Jeppe Buur; Andreasen, Peter A.;

    2014-01-01

    The metastability of the native fold makes serpin (serine protease inhibitor) proteins prone to pathological conformational change, often by insertion of an extra β-strand into the central β-sheet A. How this insertion is made possible is a hitherto unresolved question. By the use of advanced hyd...

  3. Interventional effect of flunarizine on the expression of cyclooxygenase-2 and plasminogen activator inhibitor type-1 during experimental Cerebral ischemia/reperfusion in gerbils

    Institute of Scientific and Technical Information of China (English)

    Wensheng Zhou; Zhiping Hu; Yan Hong

    2006-01-01

    BACKGROUND:Some researches suggest that induced cyclooxygenase-2 (COX-2) can cause brain injury through a series of ways at the phase of cerebral ischemia/hypoxia.Plasminogen activator inhibitor type-1(PAI-1)is a kind of inhibitor of serine stretch protein enzyme and is able to protect cell surface and microvascular basement membrane from degradation of protease and also protect contact surface among cells so as to maintain integrality of tissue structure.However,correlation of protective effect of flunarizine on brain with COX-2 and PAI-1 should be studied further.OBJECTIVE:To observe the effect of flunadzine on expressions of COX-2 and PAI-1 protein in forebrain and degree of brain injury among gerbils after cerebral ischemia.DESIGN:A randomized controlled animal study.SEITING:Department of Neurology,the Second Xiangya Hospital of Central South University;Department of Neurology,Mawangdui Hospital of Hunan Province.MATERIALS:A total of 40 healthy gerbils,of both genders,aged 9 months,weighing(90±10)g,were selected in this study.Anti-COX-2 multi-antibody,anti-PAI-1 multi-antibody,SABC immunohistochemical kit and DAB kit were provided by Wuhan Boster Biological Engineering Co.,Ltd.;and flunarizine capsule was provided by Xi'an Yangsen Pharmaceutical Company(batch number:041018726,dosage:5 mg/pill).METHODS:The experiment was Carried out in Laboratory of Mental Disease,Hunan Provincial Gedatdcs Institute affiliated by Hunan Provincial Mawangdui Hospital from January 2004 to March 2005.① All gerbils were randomly divided into cerebral ischemia group,flunarizine intervention group,sham operation group and normal control group with 10 in each group.Gerbils in normal control group were only cut off their heads.Gerbils in sham operation group were only dissected their bilateral common carotid arteries and sacdficad 1 day later.Gerbils in cerebral ischemia group and flunanzine intervention group were anesthetized,centrally cut open skin of neck,bluntly dissected

  4. Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis.

    Science.gov (United States)

    Swarbreck, Scott B; Secor, Dan; Ellis, Christopher G; Sharpe, Michael D; Wilson, John X; Tyml, Karel

    2015-06-01

    The microcirculation during sepsis fails due to capillary plugging involving microthrombosis. We demonstrated that intravenous injection of ascorbate reduces this plugging, but the mechanism of this beneficial effect remains unclear. We hypothesize that ascorbate inhibits the release of the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and platelets during sepsis. Microvascular endothelial cells and platelets were isolated from mice. Cells were cultured and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα), or thrombin (agents of sepsis), with/without ascorbate for 1-24 h. PAI-1 mRNA was determined by quantitative PCR. PAI-1 protein release into the culture medium was measured by ELISA. In platelets, PAI-1 release was measured after LPS, TNFα, or thrombin stimulation, with/without ascorbate. In endothelial cells, LPS and TNFα increased PAI-1 mRNA after 6-24 h, but no increase in PAI-1 release was observed; ascorbate did not affect these responses. In platelets, thrombin, but not LPS or TNFα, increased PAI-1 release; ascorbate inhibited this increase at low extracellular pH. In unstimulated endothelial cells and platelets, PAI-1 is released into the extracellular space. Thrombin increases this release from platelets; ascorbate inhibits it pH-dependently. The data suggest that ascorbate promotes fibrinolysis in the microvasculature under acidotic conditions in sepsis.

  5. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.

    Science.gov (United States)

    Ma, Li-Jun; Mao, Su-Li; Taylor, Kevin L; Kanjanabuch, Talerngsak; Guan, YouFei; Zhang, YaHua; Brown, Nancy J; Swift, Larry L; McGuinness, Owen P; Wasserman, David H; Vaughan, Douglas E; Fogo, Agnes B

    2004-02-01

    Increased plasminogen activator inhibitor 1 (PAI-1) has been linked to not only thrombosis and fibrosis but also to obesity and insulin resistance. Increased PAI-1 levels have been presumed to be consequent to obesity. We investigated the interrelationships of PAI-1, obesity, and insulin resistance in a high-fat/high-carbohydrate (HF) diet-induced obesity model in wild-type (WT) and PAI-1-deficient mice (PAI-1(-/-)). Obesity and insulin resistance developing in WT mice on an HF diet were completely prevented in mice lacking PAI-1. PAI-1(-/-) mice on an HF diet had increased resting metabolic rates and total energy expenditure compared with WT mice, along with a marked increase in uncoupling protein 3 mRNA expression in skeletal muscle, likely mechanisms contributing to the prevention of obesity. In addition, insulin sensitivity was enhanced significantly in PAI-1(-/-) mice on an HF diet, as shown by euglycemic-hyperinsulinemic clamp studies. Peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin mRNA, key control molecules in lipid metabolism and insulin sensitivity, were maintained in response to an HF diet in white adipose tissue in PAI-1(-/-) mice, contrasting with downregulation in WT mice. This maintenance of PPAR-gamma and adiponectin may also contribute to the observed maintenance of body weight and insulin sensitivity in PAI-1(-/-) mice. Treatment in WT mice on an HF diet with the angiotensin type 1 receptor antagonist to downregulate PAI-1 indeed inhibited PAI-1 increases and ameliorated diet-induced obesity, hyperglycemia, and hyperinsulinemia. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro. Our data suggest that PAI-1 may not merely increase in response to obesity and insulin resistance, but may have a direct causal role in obesity and insulin resistance. Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment.

  6. Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking.

    Directory of Open Access Journals (Sweden)

    Anna E Daniel

    Full Text Available Plasminogen activator inhibitor-1 (PAI-1, a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact.We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus.Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall.

  7. MICROARRAY ANALYSIS OF DIFFERENT GENE EXPRESSION OF HUMAN CERVICAL CANCER SUBCLONE CELL LINES

    Institute of Scientific and Technical Information of China (English)

    Chen Wei; Li Xu; Wang Xiang

    2006-01-01

    Objective To examine the differentially expressed invasion-related genes in two anchorage-independent uterine cervical carcinoma cell lines derived from the same patient using a cDNA array. Methods Two human uterine cervical carcinoma subclonal cell lines CS03 and CS07 derived from a single donor line CS1213 were established by limited dilution procedure. The two cDNA samples retro-transcribed from total RNA derived from CS03 and CS07 cells were screened by a cDNA microarray carrying 234 human cell-cycle related genes and 1011 human signal transduction and membrane receptor -associated genes, scanned with a ScanArray 3000 laser scanner. Results The cDNA microarray analysis showed that 12 genes in CS03 were up-regulated compared to CS07, and 24 genes in CS07 were up-regulated. The function of a number of differentially expressed genes was consistently associated with cell-cycle, cell proliferation, migration, apoptosis, signal transduction and tumor metastasis, including p34cdc2, TSC22, plasminogen activator inhibitor I (PAI-1)and desmosome associated protein(Pinin). Conclusion Multiple genes are differentially expressed in uterine cervical carcinoma cell lines even came from the same patient. It is suggested that these genes are involved in the different phenotypic characteristics and development of cervical carcinoma.

  8. Quercetin Impacts Expression of Metabolism- and Obesity-Associated Genes in SGBS Adipocytes.

    Science.gov (United States)

    Leiherer, Andreas; Stoemmer, Kathrin; Muendlein, Axel; Saely, Christoph H; Kinz, Elena; Brandtner, Eva M; Fraunberger, Peter; Drexel, Heinz

    2016-05-12

    Obesity is characterized by the rapid expansion of visceral adipose tissue, resulting in a hypoxic environment in adipose tissue which leads to a profound change of gene expression in adipocytes. As a consequence, there is a dysregulation of metabolism and adipokine secretion in adipose tissue leading to the development of systemic inflammation and finally resulting in the onset of metabolic diseases. The flavonoid quercetin as well as other secondary plant metabolites also referred to as phytochemicals have anti-oxidant, anti-inflammatory, and anti-diabetic effects known to be protective in view of obesity-related-diseases. Nevertheless, its underlying molecular mechanism is still obscure and thus the focus of this study was to explore the influence of quercetin on human SGBS (Simpson Golabi Behmel Syndrome) adipocytes' gene expression. We revealed for the first time that quercetin significantly changed expression of adipokine (Angptl4, adipsin, irisin and PAI-1) and glycolysis-involved (ENO2, PFKP and PFKFB4) genes, and that this effect not only antagonized but in part even overcompensated the effect mediated by hypoxia in adipocytes. Thus, these results are explained by the recently proposed hypothesis that the protective effect of quercetin is not solely due to its free radical-scavenging activity but also to a direct effect on mitochondrial processes, and they demonstrate that quercetin might have the potential to counteract the development of obesity-associated complications.

  9. Effects of Nebivolol on Endothelial Gene Expression during Oxidative Stress in Human Umbilical Vein Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Ulisse Garbin

    2008-01-01

    Full Text Available The endothelium plays a key role in the development of atherogenesis and its inflammatory and proliferative status influences the progression of atherosclerosis. The aim of this study is to compare the effects of two beta blockers such as nebivolol and atenolol on gene expression in human umbilical vein endothelial cells (HUVECs following an oxidant stimulus. HUVECs were incubated with nebivolol or atenolol (10 micromol/L for 24 hours and oxidative stress was induced by the addition of oxidized (ox-LDL. Ox-LDL upregulated adhesion molecules (ICAM-1, ICAM-2, ICAM-3, E-selectin, and P-selectin; proteins linked to inflammation (IL-6 and TNFalpha, thrombotic state (tissue factor, PAI-1 and uPA, hypertension such as endothelin-1 (ET-1, and vascular remodeling such as metalloproteinases (MMP-2, MMP-9 and protease inhibitor (TIMP-1. The exposure of HUVECs to nebivolol, but not to atenolol, reduced these genes upregulated by oxidative stress both in terms of protein and RNA expression. The known antioxidant properties of the third generation beta blocker nebivolol seem to account to the observed differences seen when compared to atenolol and support the specific potential protective role of this beta blocker on the expression of a number of genes involved in the initiation and progression of atherosclerosis.

  10. Quercetin Impacts Expression of Metabolism- and Obesity-Associated Genes in SGBS Adipocytes

    Directory of Open Access Journals (Sweden)

    Andreas Leiherer

    2016-05-01

    Full Text Available Obesity is characterized by the rapid expansion of visceral adipose tissue, resulting in a hypoxic environment in adipose tissue which leads to a profound change of gene expression in adipocytes. As a consequence, there is a dysregulation of metabolism and adipokine secretion in adipose tissue leading to the development of systemic inflammation and finally resulting in the onset of metabolic diseases. The flavonoid quercetin as well as other secondary plant metabolites also referred to as phytochemicals have anti-oxidant, anti-inflammatory, and anti-diabetic effects known to be protective in view of obesity-related-diseases. Nevertheless, its underlying molecular mechanism is still obscure and thus the focus of this study was to explore the influence of quercetin on human SGBS (Simpson Golabi Behmel Syndrome adipocytes’ gene expression. We revealed for the first time that quercetin significantly changed expression of adipokine (Angptl4, adipsin, irisin and PAI-1 and glycolysis-involved (ENO2, PFKP and PFKFB4 genes, and that this effect not only antagonized but in part even overcompensated the effect mediated by hypoxia in adipocytes. Thus, these results are explained by the recently proposed hypothesis that the protective effect of quercetin is not solely due to its free radical-scavenging activity but also to a direct effect on mitochondrial processes, and they demonstrate that quercetin might have the potential to counteract the development of obesity-associated complications.

  11. Plasminogen activator inhibitor type 1 interacts with alpha3 subunit of proteasome and modulates its activity.

    Science.gov (United States)

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S

    2011-02-25

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting.

  12. Plasminogen Activator Inhibitor Type 1 Interacts with α3 Subunit of Proteasome and Modulates Its Activity*

    Science.gov (United States)

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S.

    2011-01-01

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting. PMID:21135093

  13. miR-34a Modulates Angiotensin II-Induced Myocardial Hypertrophy by Direct Inhibition of ATG9A Expression and Autophagic Activity

    Science.gov (United States)

    Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3′-UTR, but not to the mutated 3′-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  14. Constriction velocities of renal afferent and efferent arterioles of mice are not related to SMB expression.

    Science.gov (United States)

    Patzak, Andreas; Petzhold, Daria; Wronski, Thomas; Martinka, Peter; Babu, Gopal J; Periasamy, Muthu; Haase, Hannelore; Morano, Ingo

    2005-12-01

    Constriction of renal arterioles contributes significantly to the control of perfusion and glomerular filtration. Afferent but not efferent arterioles express smooth muscle myosin heavy chain B (SMB) (with a 5'-insert of seven amino acids). The aim of the present study was to investigate (1) the constriction characteristics of afferent and efferent arterioles under physiologic load and (2) whether expression of SMB may causally contribute to these constriction characteristics. We compared constriction parameters [constriction amplitude, maximal rate of constriction velocity ("dc/dt(max)"), and time to half-maximal constriction (t(1/2)) of in vitro perfused renal afferent and efferent arterioles of wild-type (smb(+/+)] and homozygous SMB knockout [smb(-/-)] mice upon stimulation with angiotensin II (Ang II) (10(-8) mol/L) and potassium chloride (KCl) (100 mmol/L). SMB expression was investigated by double-labeling immunofluorescence. Contraction amplitude and dc/dt(max) of mouse afferent arterioles upon Ang II stimulation were significantly greater compared to efferent arterioles. However, constriction amplitudes, dc/dt(max), and t(1/2) of afferent as well as efferent arterioles upon Ang II stimulation were similar in smb(+/+) and smb(-/-) mice. Constriction amplitudes upon KCl stimulation of afferent arterioles were similar in both smb(+/+) and smb(-/-) mice. Furthermore, KCl-induced dc/dt(max) and t(1/2) of afferent arterioles were similar in both smb(+/+) and smb(-/-) mice. SMB expression could be detected in afferent but not efferent arterioles in smb(+/+) mice. No SMB expression in either arteriole could be observed in smb(-/-) mice. Our results suggest that the presence of different alternatively 5'-spliced smooth muscle-myosin heavy chain (SM-MHC) isoforms does not dominate the different contractile features of physiologically loaded renal afferent or efferent arterioles.

  15. Arabidopsis PAI gene arrangements, cytosine methylation and expression.

    OpenAIRE

    Melquist, S.; Luff, B; Bender, J.

    1999-01-01

    Previous analysis of the PAI tryptophan biosynthetic gene family in Arabidopsis thaliana revealed that the Wassilewskija (WS) ecotype has four PAI genes at three unlinked sites: a tail-to-tail inverted repeat at one locus (PAI1-PAI4) plus singlet genes at two other loci (PAI2 and PAI3). The four WS PAI genes are densely cytosine methylated over their regions of DNA identity. In contrast, the Columbia (Col) ecotype has three singlet PAI genes at the analogous loci (PAI1, PAI2, and PAI3) and no...

  16. Expression of. Arabidopsis tryptophan biosynthetic pathway genes: effect of the 5’ coding region of phosphoribosylanthranilate isomerase gene

    Institute of Scientific and Technical Information of China (English)

    何奕昆; 刘新仿; 李家洋

    1999-01-01

    There are three non-allelic isogenes encoding phosphoribosylanthranilate isomerase (PAI) in Arabidopsis thaliana. The expression plasmids were constructed by fusion of the GUS reporter gene to the three PAI promoters with or without the 5’ region encoding PAI N-terminal polypeptides and transferred into Arabidopsis plants by Agrobacterium tumefaciens. Analysis of GUS activity revealed that the PAI 5’ coding region was necessary for high expression of GUS activity. GUS activity in transgenic plants transformed with the expression plasmids containing the 5’ coding region of PAI1 or PAI3 was 60—100-fold higher than that without the corresponding 5’ region. However, the effect of 5’ coding region of PAI2 gene on the GUS activity was very small (only about 1 time difference). The GUS histochemical staining showed a similar result as revealed by GUS activity assay. It was expressed in the mesophyll cells and guard cells, but not in the epidermic cells, indicating that the N-terminal polypeptides encoded by t

  17. Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.

    Science.gov (United States)

    Botla, Sandeep K; Savant, Soniya; Jandaghi, Pouria; Bauer, Andrea S; Mücke, Oliver; Moskalev, Evgeny A; Neoptolemos, John P; Costello, Eithne; Greenhalf, William; Scarpa, Aldo; Gaida, Matthias M; Büchler, Markus W; Strobel, Oliver; Hackert, Thilo; Giese, Nathalia A; Augustin, Hellmut G; Hoheisel, Jörg D

    2016-07-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.

  18. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases

    Directory of Open Access Journals (Sweden)

    Yao Ye

    2017-07-01

    Full Text Available Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1. PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA and urokinase-type plasminogen activator (uPA. In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL, preeclampsia, intrauterine growth restriction (IUGR, gestational diabetes mellitus (GDM in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS. In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

  19. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases.

    Science.gov (United States)

    Ye, Yao; Vattai, Aurelia; Zhang, Xi; Zhu, Junyan; Thaler, Christian J; Mahner, Sven; Jeschke, Udo; von Schönfeldt, Viktoria

    2017-07-29

    Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

  20. Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

    Directory of Open Access Journals (Sweden)

    Jeon Hyejin

    2012-06-01

    Full Text Available Abstract Background Plasminogen activator inhibitor type 1 (PAI-1 is the primary inhibitor of urokinase type plasminogen activators (uPA and tissue type plasminogen activators (tPA, which mediate fibrinolysis. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis. However, little is known about the role of PAI-1 in the central nervous system. Methods In this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model. Phagocytic activity was measured by uptake of zymosan particles. Results The levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP 1/Janus kinase (JAK/signal transducer and activator of transcription (STAT1 axis. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner. Conclusion Our results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. This may have important implications in the regulation of brain microglial activities in health and disease.

  1. Relationship of plasminogen activator inhibitor 1 gene 4G/5G polymorphisms to hypertension in Korean women.

    Science.gov (United States)

    Kim, Kyu-nam; Kim, Kwang-min; Kim, Bom-taeck; Joo, Nam-seok; Cho, Doo-yeoun; Lee, Duck-joo

    2012-04-01

    Hypertension (HTN) is a major determinant of various cardiovascular events. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) modulate this risk. A deletion/insertion polymorphism within the PAI-1 loci (4G/4G, 4G/5G, 5G/5G) affects the expression of this gene. The present study investigated the association between PAI-1 loci polymorphisms and HTN in Korean women. Korean women (n = 1312) were enrolled in this study to evaluate the association between PAI-1 4G/5G gene polymorphisms and HTN as well as other metabolic risk factors. PAI-1 loci polymorphisms were investigated using polymerase chain reaction amplification and single-strand conformation polymorphism analysis. The three genotype groups differed with respect to systolic blood pressure (P = 0.043), and diastolic blood pressure (P = 0.009) but not with respect to age, body mass index, total cholesterol, low or high density lipoprotein cholesterol, triglycerides, or fasting blood glucose. Carriers of the PAI-1 4G allele had more hypertension significantly (PAI-1 4G/5G vs. PAI-1 5G/5G, P = 0.032; PAI-1 4G/4G vs. PAI-1 5G/5G, P = 0.034). When stratified according to PAI-1 4G/5G polymorphism, there was no significant difference in all metabolic parameters among PAI-1 genotype groups in patients with HTN as well as subjects with normal blood pressure. The estimated odds ratio of the 4G/4G genotype and 4G/5G for HTN was 1.7 (P = 0.005), and 1.6 (P = 0.015), respectively. These findings might indicate that PAI-1 loci polymorphisms independently contribute to HTN and that gene-environmental interaction may be not associated in Korean women.

  2. Sulforaphane inhibits TNF-α-induced adhesion molecule expression through the Rho A/ROCK/NF-κB signaling pathway.

    Science.gov (United States)

    Hung, Chi-Nan; Huang, Hui-Pei; Wang, Chau-Jong; Liu, Kai-Li; Lii, Chong-Kuei

    2014-10-01

    Endothelial dysfunction is an early indicator of cardiovascular diseases. Increased stimulation of tumor necrosis factor-α (TNF-α) triggers the inflammatory mediator secretion of endothelial cells, leading to atherosclerotic risk. In this study, we investigated whether sulforaphane (SFN) affected the expression of intracellular adhesion molecule-1 (ICAM-1) in TNF-α-induced ECV 304 endothelial cells. Our data showed that SFN attenuated TNF-α-induced expression of ICAM-1 in ECV 304 cells. Pretreatment of ECV 304 cells with SFN inhibited dose-dependently the secretion of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-8. SFN inhibited TNF-α-induced nuclear factor-κB (NF-κB) DNA binding activity. Furthermore, SFN decreased TNF-α-mediated phosphorylation of IκB kinase (IKK) and IκBα, Rho A, ROCK, ERK1/2, and plasminogen activator inhibitor-1 (PAI-1) levels. Collectively, SFN inhibited the NF-κB DNA binding activity and downregulated the TNF-α-mediated induction of ICAM-1 in endothelial cells by inhibiting the Rho A/ROCK/NF-κB signaling pathway, suggesting the beneficial effects of SFN on suppression of inflammation within the atherosclerotic lesion.

  3. Ärge eales tehke liblikale pai. (1) / Eerik Purje ; fotod: V. Sarapuu; Vaike Külvet

    Index Scriptorium Estoniae

    Purje, Eerik, 1927-

    2004-01-01

    28. mail 2004 toimus Torontos Tartu College'i saalis lugemisteater "Ilutuli", kus esitati Urve Karuksi luuleloomingut. Lisaks autorile etles 8 inimest, muusikalisi vahepalu mängisid 3 flötisti, vaadata sai Hilda Truupere maale

  4. Ärge eales tehke liblikale pai. (1) / Eerik Purje ; fotod: V. Sarapuu; Vaike Külvet

    Index Scriptorium Estoniae

    Purje, Eerik, 1927-

    2004-01-01

    28. mail 2004 toimus Torontos Tartu College'i saalis lugemisteater "Ilutuli", kus esitati Urve Karuksi luuleloomingut. Lisaks autorile etles 8 inimest, muusikalisi vahepalu mängisid 3 flötisti, vaadata sai Hilda Truupere maale

  5. Lack of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism and osteoarthritis.

    Science.gov (United States)

    Bayram, Banu; Sayin, Emrah; Erkasap, Nilüfer; Onlü, Harun; Ozkurt, Mete; Sahin, Fezan; Türkoğlu, Züleyha

    2012-01-01

    This study was conducted in Turkish osteoarthritis patients to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and to examine the role of this polymorphism in osteoarthritis development. Genomic DNA obtained from 200 persons (140 patients with osteoarthritis and 60 healthy controls) was used in the study. DNA was amplified by polymerase chain reaction using 4G allele- and 5G allele-specific primers. Polymerase chain reaction products were assessed with CCD camera by being exposed to 2% agarose gel electrophoresis. No statistically significant difference between the groups with respect to genotype distribution was found (P > 0.05) in the study. The 4G allele frequency was indicated as 44% and 5G allele was as 56% in patients, whereas this was 45-55% in the control group. This study has established that 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene do not play a role in the development of osteoarthritis in the Turkish population.

  6. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice

    DEFF Research Database (Denmark)

    Almholt, Kasper; Nielsen, Boye Schnack; Frandsen, Thomas Leth;

    2003-01-01

    of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth...... limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency....

  7. Circadian fluctuations in circulating plasminogen activator inhibitor-1 are independent of feeding cycles in mice.

    Science.gov (United States)

    Oishi, Katsutaka; Ohkura, Naoki; Yasumoto, Yuki; Yamamoto, Saori

    2017-01-01

    To evaluate the involvement of the day-night feeding cycle in the circadian regulation of circulating plasminogen activator inhibitor-1 (PAI-1) concentrations, mice were fed with a diet for eight hours during either daytime (DF) or nighttime (NF) for one week. The reversed feeding cycle did not affect the circadian phases of plasma PAI-1 levels as well as the nocturnal wheel-running activity, although the phase of Pai-1 mRNA expression was significantly advanced for 8.6 hours in the livers of DF, compared with NF mice. The day-night feeding cycle is not a critical Zeitgeber for circadian rhythm of circulating PAI-1.

  8. E2F1-mediated transcriptional inhibition of the plasminogen activator inhibitor type 1 gene

    DEFF Research Database (Denmark)

    Koziczak, M; Müller, H; Helin, K;

    2001-01-01

    -sensitive retinoblastoma protein (pRB), a shift to a permissive temperature induced PAI-1 mRNA expression. In U2OS cells stably expressing an E2F1-estrogen receptor chimeric protein that could be activated by tamoxifen, PAI-1 gene transcription was markedly reduced by tamoxifen even in the presence of cycloheximide...

  9. Interfering with TGFβ-induced Smad3 nuclear accumulation differentially affects TGFβ-dependent gene expression

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    Dittmer Jürgen

    2003-03-01

    Full Text Available Abstract Background Transforming growth factor-β (TGFβ plays an important role in late-stage carcinogenesis by stimulating invasive behavior of cancer cells, promoting neo-angiogenesis and by helping cancer cells to escape surveillance by the immune system. It also supports colonization of the bone by metastatic breast cancer cells by increasing expression of osteolytic parathyroid hormone-related protein (PTHrP. Interfering with TGFβ signalling may thus weaken the malignant properties of cancer cells. We investigated to what extent two inhibitors, SB-202190 and SB-203580, interfere with TGFβ-signalling in invasive MDA-MB-231 breast cancer cells. These compounds, formerly used as p38-MAPK-specific inhibitors, were recently also demonstrated to inhibit TGFβ type I receptor kinase. Results Our results show that these inhibitors delay the onset of TGFβ-induced nuclear accumulation of Smad3 and reduces its amplitude. This effect was accompanied by a strong reduction in TGFβ-responsivess of the slow-responder genes pthrp, pai-1 and upa, while the reactivity of the fast-responder gene smad7 to TGFβ remained almost unchanged. Neither was the TGFβ response of the fast-responder ese-1/esx gene, whose expression we found to be strongly downregulated by TGFβ, affected by the inhibitors. Conclusion The data show that SB-202190 and SB-203580 suppress TGFβ-dependent activation of genes that are important for the acquisition of invasive behavior, while having no effect on the expression of the natural TGFβ inhibitor Smad7. This suggests that these compounds are potent inhibitors of malignant behavior of cancer cells.

  10. Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells

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    Lee Seung-Hyo

    2011-04-01

    Full Text Available Abstract Background Many studies have found that smoking reduces lung function, but the relationship between cigarette smoke and allergic asthma has not been clearly elucidated, particularly the role of mast cells. This study aimed to investigate the effects of smoke exposure on allergic asthma and its association with mast cells. Methods BALB/c mice were sensitized and challenged by OVA to induce asthma, and bone marrow-derived mast cells (BMMCs were stimulated with antigen/antibody reaction. Mice or BMMCs were exposed to cigarette smoke or CSE solution for 1 mo or 6 h, respectively. The recruitment of inflammatory cells into BAL fluid or lung tissues was determined by Diff-Quik or H&E staining, collagen deposition by Sircol assay, penh values by a whole-body plethysmography, co-localization of tryptase and Smad3 by immunohistochemistry, IgE and TGF-β level by ELISA, expressions of Smads proteins, activities of signaling molecules, or TGF-β mRNA by immunoblotting and RT-PCR. Results Cigarette smoke enhanced OVA-specific IgE levels, penh values, recruitment of inflammatory cells including mast cells, expressions of smad family, TGF-β mRNA and proteins, and cytokines, phosphorylations of Smad2 and 3, and MAP kinases, co-localization of tryptase and Smad3, and collagen deposition more than those of BAL cells and lung tissues of OVA-induced allergic mice. CSE solution pretreatment enhanced expressions of TGF-β, Smad3, activities of MAP kinases, NF-κB/AP-1 or PAI-1 more than those of activated-BMMCs. Conclusions The data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-β/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling.

  11. Plasminogen activator inhibitor-1 in cigarette smoke exposure and influenza A virus infection-induced lung injury.

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    Yashodhar P Bhandary

    Full Text Available Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE, which contributes to chronic obstructive pulmonary disease (COPD. Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT mice with passive CSE (PCSE, p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1. Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3'UTR sequences of PAI-1 mRNA likewise suppressed CS-induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE.

  12. JNK suppression is essential for 17β-Estradiol inhibits prostaglandin E2-Induced uPA and MMP-9 expressions and cell migration in human LoVo colon cancer cells

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    Chen Wei-Kung

    2011-08-01

    Full Text Available Abstract Background Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol treatment is sufficient to inhibit prostaglandin E2 (PGE2-induced cellular motility in human colon cancer cells. Methods We analyzed the protein expression of urokinase plasminogen activator (uPA, tissue plasminogen activator (tPA, matrix metallopeptidases (MMPs, plasminogen activator inhibitor-1 (PAI-1 and tissue inhibitor of metalloproteinases (TIMPs, and the cellular motility in PGE2-stimulated human LoVo cells. 17β-Estradiol and the inhibitors including LY294002 (Akt activation inhibitor, U0126 (ERK1/2 inhibitor, SB203580 (p38 MAPK inhibitor, SP600125 (JNK1/2 inhibitor, QNZ (NFκB inhibitor and ICI 182 780 were further used to explore the inhibitory effects of 17β-estradiol on PGE2-induced LoVo cell motility. Student's t-test was used to analyze the difference between the two groups. Results Upregulation of urokinase plasminogen activator (uPA, tissue plasminogen activator (tPA and matrix metallopeptidases (MMPs is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. After administration of inhibitors including LY294002, U0126, SB203580, SP600125 or QNZ, we found that PGE2 treatment up-regulated uPA and MMP-9 expression via JNK1/2 signaling pathway, thus promoting cellular motility in human LoVo cancer cells. However, PGE2 treatment showed no effects on regulating expression of tPA, MMP-2, plasminogen activator inhibitor-1 (PAI-1, tissue inhibitor of metalloproteinase-1, -2, -3 and -4 (TIMP-1, -2, -3 and -4. We further observed that 17β-estradiol treatment inhibited PGE2-induced uPA, MMP-9 and cellular motility by suppressing activation of JNK1/2 in human LoVo cancer cells. Conclusions Collectively, these results suggest that 17β-estradiol treatment significantly inhibits PGE2-induced motility

  13. Different effects of lipopolysaccharide on plasminogen activator inhibitor-1 production in aortic media in vivo and in culture

    NARCIS (Netherlands)

    Leeuwen, R.T.J. van; Quax, P.H.A.; Tippins, J.R.; Antoniw, J.W.; Andreotti, F.; Maseri, A.; Kluft, C.; Sperti, G.

    1996-01-01

    Background: Lipopolysaccharide (endotoxin) has been shown to increase the expression of plasminogen activator inhibitor type-1 (PAI-1) in the vessel wall. Endotoxin is known to increase PAI-1 production in endothelial cells, but its action on smooth muscle cells (SMCs) is presently not clear. In thi

  14. Role of Connective Tissue Growth Factor in Extracellular Matrix Degradation in Renal Tubular Epithelial Cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG Chun; ZHU Zhonghua; LIU Jianshe; YANG Xiao; FU Ling; DENG Anguo

    2007-01-01

    In order to investigate the effects of connective tissue growth factor (CTGF) antisense oligodeoxynucleotide (ODN) on plasminogen activator inhibitor-1 (PAI-1) expression in renal tubular cells induced by transforming growth factor β1 (TGF-β1) and to explore the role of CTGF in the degradation of renal extracellular matrix (ECM), a human proximal tubular epithelial cell line (HKC) was cultured in vitro. Cationic lipid-mediated CTGF antisense ODN was transfected into HKC. After HKC were stimulated with TGF-β1 (5 μg/L), the mRNA level of PAI-1 was detected by RT-PCR. Intracellular PAI-1 protein synthesis was assessed by flow cytometry. The secreted PAI-1 in the media was determined by Western blot. The results showed that TGF-β1 could induce tubular CTGF and PAI-1 mRNA expression. The PAI-1 mRNA expression induced by TGF-β1 was significantly inhibited by CTGF antisense ODN. CTGF antisense ODN also inhibited intracellular PAI-1 protein synthesis and lowered the levels of PAI-1 protein secreted into the media. It was concluded that CTGF might play a crucial role in the degradation of excessive ECM during tubulointerstitial fibrosis, and blocking the biological effect of CTGF may be a novel way in preventing renal fibrosis.

  15. Enhancing the function of CD34(+ cells by targeting plasminogen activator inhibitor-1.

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    Sugata Hazra

    Full Text Available Previously, we showed that transient inhibition of TGF- β1 resulted in correction of key aspects of diabetes-induced CD34(+ cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1, a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34(+ cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34(+ cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO reduced PAI-1 mRNA in diabetic (p<0.01 and non-diabetic (p=0.05 CD34(+ cells. To reduce PAI-1 in human CD34(+ cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34(+ cell proliferation and migration in vitro, likely through increased PI3(K activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+ cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.

  16. Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue[S

    Science.gov (United States)

    Xu, X. Julia; Gauthier, Marie-Soleil; Hess, Donald T.; Apovian, Caroline M.; Cacicedo, Jose M.; Gokce, Noyan; Farb, Melissa; Valentine, Rudy J.; Ruderman, Neil B.

    2012-01-01

    We previously reported that adenosine monophosphate-activated protein kinase (AMPK) activity is lower in adipose tissue of morbidly obese individuals who are insulin resistant than in comparably obese people who are insulin sensitive. However, the number of patients and parameters studied were small. Here, we compared abdominal subcutaneous, epiploic, and omental fat from 16 morbidly obese individuals classified as insulin sensitive or insulin resistant based on the homeostatic model assessment of insulin resistance. We confirmed that AMPK activity is diminished in the insulin resistant group. A custom PCR array revealed increases in mRNA levels of a wide variety of genes associated with inflammation and decreases in PGC-1α and Nampt in omental fat of the insulin resistant group. In contrast, subcutaneous abdominal fat of the same patients showed increases in PTP-1b, VEGFa, IFNγ, PAI-1, and NOS-2 not observed in omental fat. Only angiotensinogen and CD4+ mRNA levels were increased in both depots. Surprisingly, TNFα was only increased in epiploic fat, which otherwise showed very few changes. Protein carbonyl levels, a measure of oxidative stress, were increased in all depots. Thus, adipose tissues of markedly obese insulin resistant individuals uniformly show decreased AMPK activity and increased oxidative stress compared with insulin sensitive patients. However, most changes in gene expression appear to be depot-specific. PMID:22323564

  17. Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

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    Jingjing Zhao

    2013-09-01

    Full Text Available Background: C-reactive protein (CRP participates in development of inflammatory diseases. Hepatocytes are a major contributor of circulating CRP. Although angiotensin II (Ang II is known to evoke inflammatory response, it remains unknown whether Ang II induces CRP expression in hepatocytes. The present study observed effect of Ang II on CRP expression and the related signal pathway in hepatocytes. Methods: mRNA and protein expressions in human hepatocytes were determined with RT-PCR and Western blot respectively. Reactive oxygen species (ROS was measured using a fluorescence probe. CRP in liver and serum of rats was determined by immunohistochemistry and ELISA respectively. Results: Ang II induced mRNA and protein expression of CRP in hepatocytes and increased CRP production in liver and CRP level in serum. Losartan reduced Ang II- induced CRP expression in hepatocytes. Losartan and thenoyltrifluoroacetone decreased Ang II-stimulated ROS production. N-acetylcysteine antagonized Ang II-induced CRP expression. Losartan and N-acetylcysteine inhibited Ang II-activated ERK1/2. Unlike ERK1/2, only losartan inhibited Ang II-activated JNK. Furthermore, pyrrolidine dithiocarbamate abolished Ang II-induced CRP expression. Conclusion: Ang II has ability to induce CRP expression in hepatocytes in vitro and in vivo through AT1 receptor followed by ROS, MAPK and NF-κB signal pathway.

  18. Quinoa extract enriched in 20-hydroxyecdysone protects mice from diet-induced obesity and modulates adipokines expression.

    Science.gov (United States)

    Foucault, Anne-Sophie; Mathé, Véronique; Lafont, René; Even, Patrick; Dioh, Waly; Veillet, Stanislas; Tomé, Daniel; Huneau, Jean-François; Hermier, Dominique; Quignard-Boulangé, Annie

    2012-02-01

    Besides their well-known effect in the molting control in insects, ecdysteroids are steroid hormones that display potential pharmacologic and metabolic properties in mammals. The most common ecdysteroid, 20-hydroxyecdysone (20E) is found in many plants such as quinoa. The aim of the present study was to investigate the ability of quinoa extract (Q) enriched in 20E supplementation to prevent the onset of diet-induced obesity and to regulate the expression of adipocyte-specific genes in mice. Mice were fed a standard low-fat (LF) or a high-fat (HF) diet with or without supplementation by 20E-enriched Q or pure 20E for 3 weeks. Supplementation with Q reduced adipose tissue development in HF mice without modification of their body weight gain. This adipose tissue-specific effect was mainly associated with a reduced adipocyte size and a decrease in the expression of several genes involved in lipid storage, including lipoprotein lipase and phosphoenolpyruvate carboxykinase. Furthermore, Q-treated mice exhibited marked attenuation of mRNA levels of several inflammation markers (monocyte chemotactic protein-1, CD68) and insulin resistance (osteopontin, plasminogen activator inhibitor-1 (PAI-1)) as compared to HF mice. Q supplementation also reversed the effects of HF-induced downregulation of the uncoupling protein(s) (UCP(s)) mRNA levels in muscle. Similar results were obtained in mice fed a HF diet supplemented with similar amounts of pure 20E, suggesting that the latter accounted for most of the Q effects. Our study indicates that Q has an antiobesity activity in vivo and could be used as a nutritional supplement for the prevention and treatment of obesity and obesity-associated disorders.

  19. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway.

    Science.gov (United States)

    Jo, Hee Kyung; Kim, Go Woon; Jeong, Kyung Ju; Kim, Do Yeon; Chung, Sung Hyun

    2014-01-01

    Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca(2+)-calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenol-treated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.

  20. Post-weaning diet affects faecal microbial composition but not selected adipose gene expression in the cat (Felis catus.

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    Emma N Bermingham

    Full Text Available The effects of pre- (i.e., gestation and during lactation and post-weaning diet on the composition of faecal bacterial communities and adipose expression of key genes in the glucose and insulin pathways were investigated in the cat. Queens were maintained on a moderate protein:fat:carbohydrate kibbled ("Diet A"; 35:20:28% DM; n  =  4 or high protein:fat:carbohydrate canned ("Diet B"; 45:37:2% DM; n = 3 diet throughout pregnancy and lactation. Offspring were weaned onto these diets in a nested design (n  =  5 per treatment. Faecal samples were collected at wk 8 and 17 of age. DNA was isolated from faeces and bacterial 16S rRNA gene amplicons were analysed by pyrosequencing. RNA was extracted from blood (wk 18 and adipose tissue and ovarian/testicular tissues (wk 24 and gene expression levels determined using RT-qPCR. Differences (P<0.05 in composition of faecal bacteria were observed between pregnant queens fed Diet A or B. However, pre-weaning diet had little effect on faecal bacterial composition in weaned kittens. In contrast, post-weaning diet altered bacterial population profiles in the kittens. Increased (P<0.05 abundance of Firmicutes (77% vs 52% of total reads and Actinobacteria (0.8% vs 0.2% of total reads, and decreased (P<0.05 abundance of Fusobacteria (1.6% vs 18.4% of total reads were observed for kittens fed the Diet A compared to those fed Diet B post-weaning. Feeding Diet B pre-weaning increased (P<0.05 the expression levels of INRS, LEPT, PAI-1 and tended to increase GLUT1, while the expression levels of IRS-1 in blood increased in kittens fed Diet A pre-weaning. Post-weaning diet had no effect on expression levels of target genes. Correlations between the expression levels of genes involved in glucose and insulin pathways and faecal Bacteriodetes and Firmicutes phyla were identified. The reasons for why post-weaning diet affects microbial populations and not gene expression levels are of interest.

  1. The construction and expression of chimeric urokinase-type plasminogen activator genes containing kringle domains of human plasminogen.

    Science.gov (United States)

    Boutaud, A; Castellino, F J

    1993-06-01

    A series of chimeric urokinase-type plasminogen activator (uPA) genes, which contain combinations of kringle domains of human plasminogen (HPg) in place of the uPA kringle (KuPA), has been constructed and expressed. Some of the resulting recombinant (r) variant uPA chimeras contain modules that potentially mediate the macroscopic binding of HPg to its activation effectors, fibrin(ogen) and 6-aminohexanoic acid (EACA). Such binding sites are not possessed by KuPA, but are present in certain of the HPg kringles, viz., kringle 1 (K1HPg), kringle 4 (K4HPg), and kringle 5 (K5HPg). The recombinant (r) chimeras constructed included molecules with replacements of KuPA with K1HPg (r-[KuPA-->K1HPg]uPA), and with KuPA replaced by double kringle combinations of K1HPgK4HPg (r-[KuPA-->K1HPgK4HPg]uPA), K2HPgK3HPg (r-[KuPA-->K2HPgK3HPg]uPA), and K4HPgK5HPg (r-[KuPA-->K4HPgK5HPg]uPA). All of these variant genes, along with their wild-type (wt) r-uPA counterparts, were expressed in human kidney 293 cells. In cases wherein EACA-binding kringles from HPg have been placed in uPA, this property has been retained in the chimeric molecule and employed as an essential part of the purification procedures for the variants. The steady state amidolytic activity of two-chain (tc) wtr-uPA toward the chromogenic substrate, H-D-pyroglutamyl-Gly-L-Arg-p-nitroanilide (S2444), is characterized by a kcat/KM (pH 7.4, 37 degrees C) of 120 s-1 mM-1. This value ranges from 92 s-1 mM-1 (tcr-[KuPA-->K1HPg]uPA) to 166 s-1 mM-1 (tcr-[KuPA-->K1HPgK4HPg]uPA) for each of the variants, demonstrating that the catalytic efficiency of the active site is altered only in a small way by changes in the noncatalytic domain of uPA. Small differences are also observed in the abilities of these tcr variants to interact with the fast-acting plasma inhibitor of uPA, viz., plasminogen activator inhibitor-1 (PAI-1). The second-order rate constant for the interaction of PAI-1 with tcr-uPA, 0.46 x 10(7) M-1s-1 (pH 7.4, 10 degrees

  2. PGF2alpha induced differential expression of genes involved in turnover of extracellular matrix in rat decidual cells

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    Callegari Eduardo A

    2005-01-01

    Full Text Available Abstract In the rat, the decidual tissue is an important component for maternal recognition of pregnancy. Decidualization can be induced by either the implantation of the blastocyst or by artificial stimuli. The process of decidua formation or decidualization, is characterized by growth and differentiation of endometrial stromal cells. Prostaglandin F2alpha (PGF2α has been shown to be involved in inhibition of implantation, alteration of embryo development, induction of luteal regression, and the mediation of pregnancy loss induced by microorganism infections. In order to establish a direct role for PGF2α in decidual function, we have evaluated its effects on the expression of an extensive array of genes using primary decidual cell culture. Upon treatment with PGF2α sixty genes were significantly down-regulated whereas only six genes were up-regulated (from a total of 1176 genes studied. Interestingly, the majority of the genes inhibited by PGF2α are either directly or indirectly involved in the turnover of the extracellular matrix (ECM. Genes such as gelatinase A (MMP2, cathepsin L, tissue inhibitor metalloproteinases 2 (TIMP2 and 3 (TIMP3, plasminogen activator inhibitor1 (PAI1, tissue type plasminogen activator (tPA, urokinase plasminogen activator (tPA, endothelin 1, calponin, carboxypeptidase D and calponin acidic were down regulated. The opposite effect was observed for prostromelysin 53 kDa (proMMP3, plasma proteinase I alpha and alpha 1 antiproteinase, all of which were significantly up-regulated by PGF2α. The results strongly suggest that the abortificient role of elevated levels of PGF2α after implantation is due, in large part, to inhibition of genes involved in the normal turnover of the extracellular matrix necessary for decidual formation.

  3. 11beta-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women.

    Science.gov (United States)

    Ayachi, S Ei; Paulmyer-Lacroix, O; Verdier, M; Alessi, M-C; Dutour, A; Grino, M

    2006-03-01

    Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients. We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction. Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated. Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid. Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.

  4. The expression and clinical significance of plasmin associated proteins in plasma and bone marrow in the patient with acute leukemia%急性白血病患者血浆和骨髓中纤溶酶相关蛋白的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    刘家华; 钟明; 徐军发; 温才国; 周君纯; 陈小芳

    2007-01-01

    目的 观察纤溶酶相关蛋白t-PA、u-PA、su-PAR、PAI-1、PAI-2在急性白血病中的表达并探讨其临床意义.方法 选择25例急性白血病患者作为研究组,22例非白血病患者为对照组.采用ELISA法检测血浆和骨髓液中t-PA、u-PA、su-PAR、PAI-1、PAI-2的水平.结果 研究组血浆和骨髓液u-PA、su-PAR、PAI-1、PAI-2均高于健康对照组;研究组血浆t-PA高于对照组,而骨髓液中t-PA指标与对照组比较差异无统计学意义(P>0.05).两组血液及骨髓液中PAI-1、PAI-2均无差异.治疗后研究组血液和骨髓液中u-PA、su-PAR、PAI-1、PAI-2均有所降低(P<0.05).将患者按治疗效果不同分为CR、PR、NR三组,预后越差者,u-PA、su-PAR、PAI-1、PAI-2越高.结论 急性白血病患者存在纤溶酶系统表达紊乱.检测u-PA、su-PAR、PAI-1、PAI-2对于急性白血病的诊断、疗效及预后判断具有重要意义.

  5. Early Pregnancy Plasminogen Activator Inhibitor-1 Levels in ...

    African Journals Online (AJOL)

    2017-05-22

    May 22, 2017 ... mother and fetus, include changes in the expression of the coagulation ... inhibitor-1 (PAI-1) in normal pregnancy and preeclampsia and determined its relationship .... The continuous variables (age, body mass index [BMI],.

  6. Distal hinge of plasminogen activator inhibitor-1 involves its latency transition and specificities toward serine proteases

    Directory of Open Access Journals (Sweden)

    Shaltiel Shmuel

    2003-07-01

    Full Text Available Abstract Background The plasminogen activator inhibitor-1 (PAI-1 spontaneously converts from an inhibitory into a latent form. Specificity of PAI-1 is mainly determined by its reactive site (Arg346-Met347, which interacts with serine residue of tissue-type plasminogen activator (tPA with concomitant formation of SDS-stable complex. Other sites may also play roles in determining the specificity of PAI-1 toward serine proteases. Results To understand more about the role of distal hinge for PAI-1 specificities towards serine proteases and for its conformational transition, wild type PAI-1 and its mutants were expressed in baculovirus system. WtPAI-1 was found to be about 12 fold more active than the fibrosarcoma PAI-1. Single site mutants within the Asp355-Arg356-Pro357 segment of PAI-1 yield guanidine activatable inhibitors (a that can still form SDS stable complexes with tPA and urokinase plasminogen activator (uPA, and (b that have inhibition rate constants towards plasminogen activators which resemble those of the fibrosarcoma inhibitor. More importantly, latency conversion rate of these mutants was found to be ~3–4 fold faster than that of wtPAI-1. We also tested if Glu351 is important for serine protease specificity. The functional stability of wtPAI-1, Glu351Ala, Glu351Arg was about 18 ± 5, 90 ± 8 and 14 ± 3 minutes, respectively, which correlated well with both their corresponding specific activities (84 ± 15 U/ug, 112 ± 18 U/ug and 68 ± 9 U/ug, respectively and amount of SDS-stable complex formed with tPA after denatured by Guanidine-HCl and dialyzed against 50 mM sodium acetate at 4°C. The second-order rate constants of inhibition for uPA, plasmin and thrombin by Glu351Ala and Glu351Arg were increased about 2–10 folds compared to wtPAI-1, but there was no change for tPA. Conclusion The Asp355-Pro357 segment and Glu351 in distal hinge are involved in maintaining the inhibitory conformation of PAI-1. Glu351 is a specificity

  7. Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport.

    Science.gov (United States)

    Komlosi, Peter; Fuson, Amanda L; Fintha, Attila; Peti-Peterdi, János; Rosivall, Laszlo; Warnock, David G; Bell, Phillip Darwin

    2003-08-01

    Angiotensin (Ang) II directly stimulates epithelial sodium channel activity in the rabbit cortical collecting duct. Because Ang I and converting enzyme analogues might be present in the distal nephron, this raises the possibility of intraluminal generation of Ang II. Conversion of Ang I to Ang II was monitored by Ang II-dependent changes in intracellular sodium concentration as a reflection of sodium transport across the apical membrane. This involved imaging-based fluorescence microscopy with sodium-binding benzofuran isophthalate in isolated, perfused, cortical collecting-duct segments from rabbit kidney. Principal and intercalated cells were differentiated by rhodamine-conjugated peanut lectin. Control principal cell intracellular sodium concentration, during perfusion with 25 mmol/L NaCl and zero sodium in the bath plus monensin (10(-5) mol/L) averaged 5.8+/-0.14 mmol/L (n=156). The increase in intracellular sodium concentration, when luminal NaCl was increased from 25 to 150 mmol/L, was elevated by 3.5-fold in the presence of intraluminal Ang I (10(-6) mol/L). Also, the effects of Ang I on sodium transport were not significantly different from the effects of Ang II (10(-9) mol/L). Ang I was used in micromolar concentrations to ensure that there was sufficient substrate available for conversion to Ang II. Inhibition of the angiotensin-converting enzyme with captopril reduced the stimulatory effect of Ang I. These results suggest that intraluminal conversion of Ang I to Ang II can occur in the cortical collecting duct, resulting in enhanced apical sodium entry.

  8. Vasopressin and angiotensin II stimulate oxygen uptake in the perfused rat hindlimb

    DEFF Research Database (Denmark)

    Colquhoun, E Q; Hettiarachchi, M; Ye, J M;

    1988-01-01

    uptake and pressure were not inhibited by either phentolamine, propranolol or a combination of the two, but were completely inhibited by the vasodilator, nitroprusside. Nitroprusside also inhibited flow-induced increases in hindlimb oxygen uptake and perfusion pressure. The findings indicate a key role...

  9. Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element.

    Directory of Open Access Journals (Sweden)

    Frederick M Stanley

    Full Text Available Plasminogen activator inhibitor type 1 (PAI-1 is a multifunctional protein that has important roles in inflammation and wound healing. Its aberrant regulation may contribute to many disease processes such as heart disease. The PAI-1 promoter is responsive to multiple inputs including cytokines, growth factors, steroids and oxidative stress. The statin drugs, atorvastatin, mevastatin and rosuvastatin, increased basal and stimulated expression of the PAI-1 promoter 3-fold. A statin-responsive, nuclear hormone response element was previously identified in the PAI-1 promoter, but it was incompletely characterized. We characterized this direct repeat (DR of AGGTCA with a 3-nucleotide spacer at -269/-255 using deletion and directed mutagenesis. Deletion or mutation of this element increased basal transcription from the promoter suggesting that it repressed PAI-1 transcription in the unliganded state. The half-site spacing and the ligand specificity suggested that this might be a pregnane X receptor (PXR responsive element. Computational molecular docking showed that atorvastatin, mevastatin and rosuvastatin were structurally compatible with the PXR ligand-binding pocket in its agonist conformation. Experiments with Gal4 DNA binding domain fusion proteins showed that Gal4-PXR was activated by statins while other DR + 3 binding nuclear receptor fusions were not. Overexpression of PXR further enhanced PAI-1 transcription in response to statins. Finally, ChIP experiments using Halo-tagged PXR and RXR demonstrated that both components of the PXR-RXR heterodimer bound to this region of the PAI-1 promoter.

  10. Effect of ascorbate on fibrinolytic factors in septic mouse skeletal muscle.

    Science.gov (United States)

    Swarbreck, Scott; Secor, Dan; Li, Fuyan; Gross, Peter L; Ellis, Christopher G; Sharpe, Michael D; Wilson, John X; Tyml, Karel

    2014-10-01

    Plugging of the capillary bed in tissues correlates with organ failure during sepsis. In septic mouse skeletal muscle, we showed that blood in capillaries becomes hypercoagulable and that ascorbate injection inhibits capillary plugging. In the present study, we hypothesized that ascorbate promotes fibrinolysis, reversing this plugging. Sepsis in mice was induced by fecal injection into peritoneum. Mice were injected intravenously with a bolus of streptokinase (fibrinolytic agent) or ascorbate at 5-6 h. Both agents reversed capillary plugging in muscle at 7 h. Sepsis increased mRNA expression of urokinase plasminogen activator (u-PA) (profibrinolytic) and plasminogen activator inhibitor 1 (PAI-1) (antifibrinolytic) in muscle and liver homogenates at 7 h. Ascorbate did not affect u-PA mRNA in either tissue, but it inhibited PAI-1 mRNA in muscle, suggesting enhanced fibrinolysis in this tissue. However, ascorbate did not affect increased PAI-1 mRNA in the liver (dominant source of soluble PAI-1 in systemic blood). Consistently, ascorbate affected neither elevated PAI-1 protein/enzymatic activity in septic liver nor lowered plasmin antiplasmin level in septic blood. Furthermore, hypocoagulability of septic blood revealed by thrombelastography and thrombin-induced PAI-1 release from isolated platelets (ex-vivo model of sepsis) were not affected by ascorbate. Based on the PAI-1 protein data, the present study does not support the hypothesis that ascorbate promotes fibrinolysis in sepsis.

  11. Peritoneal Fluid Reduces Angiogenesis-Related MicroRNA Expression in Cell Cultures of Endometrial and Endometriotic Tissues from Women with Endometriosis

    Science.gov (United States)

    Braza-Boïls, Aitana; Gilabert-Estellés, Juan; Ramón, Luis A.; Gilabert, Juan; Marí-Alexandre, Josep; Chirivella, Melitina; España, Francisco; Estellés, Amparo

    2013-01-01

    Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent gynecological diseases. It has been suggested that modifications of both endometrial and peritoneal factors could be implicated in this disease. Endometriosis is a multifactorial disease in which angiogenesis and proteolysis are dysregulated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the protein expression and may be the main regulators of angiogenesis. Our hypothesis is that peritoneal fluid from women with endometriosis could modify the expression of several miRNAs that regulate angiogenesis and proteolysis in the endometriosis development. The objective of this study has been to evaluate the influence of endometriotic peritoneal fluid on the expression of six miRNAs related to angiogenesis, as well as several angiogenic and proteolytic factors in endometrial and endometriotic cell cultures from women with endometriosis compared with women without endometriosis. Methods Endometrial and endometriotic cells were cultured and treated with endometriotic and control peritoneal fluid pools. We have studied the expression of six miRNAs (miR-16, -17-5p, -20a, -125a, -221, and -222) by RT-PCR and protein and mRNA levels of vascular endothelial growth factor-A, thrombospondin-1, urokinase plasminogen activator and plasminogen activator inhibitor-1 by ELISA and qRT-PCR respectively. Results Control and endometriotic peritoneal fluid pools induced a significant reduction of all miRNAs levels in endometrial and endometriotic cell cultures. Moreover, both peritoneal fluids induced a significant increase in VEGF-A, uPA and PAI-1 protein levels in all cell cultures without significant increase in mRNA levels. Endometrial cell cultures from patients treated with endometriotic peritoneal fluid showed lower expression of miRNAs and higher expression of VEGF-A protein levels than cultures from controls. In conclusion, this “in vitro” study indicates that

  12. Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1

    DEFF Research Database (Denmark)

    Schmitt, Manfred; Harbeck, Nadia; Brünner, Nils;

    2011-01-01

    and III breast cancer therapy trials (Chemo-N0, NNBC-3 and Plan B), and introduces ongoing clinical trials targeting uPA in advanced cancers of the breast and pancreas, employing synthetic small-size drugs to counteract uPA activity (WX-UK1, Mesupron(®)). The therapeutic effect of a uPA-derived small...

  13. Venus Express

    Science.gov (United States)

    Svedhem, L. H.

    2006-08-01

    After a launch from the Baikonur cosmodrome, Kazakhstan, 9 November 2005 and a five-month cruise, the Venus Express spacecraft reached Venus on 11 April 2006. The spacecraft has now reached its final operational, 24 hour polar orbit, with apocentre altitude of 66000km and pericentre altitude of 250 km. During the first weeks of routine operation the spacecraft has already sent back a wealth of exiting information. Venus is thus again, after having been the `"forgotten planet" for more than a decade, target for intense studies to better understand the many problems not answered by the more than twenty US and Soviet probes launched in the previous decades. The objective of the Venus Express mission is to carry out a comprehensive study of the atmosphere of Venus, the plasma environment and its interaction with the solar wind, and to study certain aspects of the surface of the planet. A well optimised payload composed of two multi channel spectrometers, an IR-Vis-UV imaging spectrometer, a wide angle camera, a multi-sensor energetic particle instrument, a magnetometer, and a radio science experiment, allows all elements of the objectives to be addressed at a sufficient depth. Venus Express has been developed in record time, less than four years, using an efficient concept of re-using elements of recently developed spacecraft, mainly Mars Express and Rosetta. Significant savings for both the space and ground segments have been possible by using existing teams in industry, in ESA and in several of the science institutes involved. The first data has shown a highly dynamic atmosphere, including close-ups of the southern polar double vortex, indeed topics of high interest and among the top priority objectives. The high resolution spectrometers are finding several minor species at various depths of the atmosphere. Venus Express is the first mission fully exploiting the Infrared spectral windows, in order to map the atmosphere in three dimensions. The first data returned

  14. Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1

    Directory of Open Access Journals (Sweden)

    Lihu Gong

    2016-03-01

    Full Text Available Thrombosis is a leading cause of death worldwide [1]. Recombinant tissue-type plasminogen activator (tPA is the FDA-approved thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism. tPA is a multi-domain serine protease of the trypsin-family [2] and catalyses the critical step in fibrinolysis [3], converting the zymogen plasminogen to the active serine protease plasmin, which degrades the fibrin network of thrombi and blood clots. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1 [4] (Fig. 1. Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort [5]. Tenecteplase (TNK-tPA is a newer generation of tPA variant showing slower inhibition by PAI-1 [6]. Extensive studies to understand the molecular interactions between tPA and PAI-1 have been carried out [7–18], however, the precise details at atomic resolution remain unknown. We report the crystal structure of tPA·PAI-1 complex here. The methods required to achieve these data include: (1 recombinant expression and purification of a PAI-1 variant (14-1B containing four mutations (N150H, K154T, Q319L, and M354I, and a tPA serine protease domain (tPA-SPD variant with three mutations (C122A, N173Q, and S195A, in the chymotrypsin numbering [19]; (2 formation of a tPA-SPD·PAI-1 Michaëlis complex in vitro [19]; and (3 solving the three-dimensional structure for this complex by X-ray crystallography [deposited in the PDB database as 5BRR]. The data explain the specificity of PAI-1 for tPA and uPA [19,20], and provide structural basis to design newer generation of PAI-1-resistant tPA variants as thrombolytic agents [19].

  15. Influence of plasminogen activator inhibitor-1 (SERPINE1) 4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection.

    Science.gov (United States)

    Divella, Rosa; Mazzocca, Antonio; Gadaleta, Cosimo; Simone, Giovanni; Paradiso, Angelo; Quaranta, Michele; Daniele, Antonella

    2012-01-01

    Hepatocarcinogenesis is heavily influenced by chronic hepatitis B (HBV) and C (HCV) infection. Elevated levels of plasminogen activator inhibitor-1 (SERPINE1/PAI-1) have been reported in patients with hepatocellular carcinoma (HCC) associated with viral infection. The gene encoding SERPINE1 is highly polymorphic and the frequently associated 4/5 guanosine (4G/5G) polymorphism in the gene promoter may influence its expression. Here, we investigated the distribution of genotypes and the frequency of alleles of the 4G/5G polymorphism in patients with HCC, the influence of the 4G/5G polymorphism on plasma SERPINE1 levels and its association with viral infection. A total of 75 patients with HCC were enrolled: 32 (42.6%) were HBV(+)/HCV(+), 11 (14.6%) were only HCV(+), and 32 (42.6%) were negative for both viruses. A control group of healthy donors was also enrolled (n=50). SERPINE1 plasma concentrations were determined by ELISA and the detection of the promoter 4G/5G polymorphism was performed by an allele-specific PCR analysis. We found that the frequency of both the 4G/4G genotype (p=0.02) and the 4G allele (p=0.006) were significantly higher in patients with HCC compared to the control group, and particularly higher in patients with HCC co-infected with HBV(+)/HCV(+) than in those with no viral infection. We also found that patients with the 4G/4G genotype had significantly higher plasma SERPINE1 protein levels when compared with patients with the 4G/5G or 5G/5G genotype (p5G SERPINE1 polymorphism with a higher level of SERPINE1 protein in patients with HCC with HBV(+)/HCV(+) than those without infection, suggest the presence of two distinct pathogenic mechanisms in hepatocarcinogenesis, depending on the etiology.

  16. Expressing Curiosity

    Institute of Scientific and Technical Information of China (English)

    段育付

    2009-01-01

    好奇是人的天性,它有时有助于人们发现或发明新事物。但是在日常交往中,对他人的一些新奇事物或情况则不宜表现出过分的好奇,否则会引起对方的反感。那么,如何用英语表达你的好奇心呢?让我们走进本期话题:Expressing curiosity

  17. A pilot trial assessing urinary gene expression profiling with an mRNA array for diabetic nephropathy.

    Directory of Open Access Journals (Sweden)

    Min Zheng

    Full Text Available BACKGROUND: The initiation and progression of diabetic nephropathy (DN is complex. Quantification of mRNA expression in urinary sediment has emerged as a novel strategy for studying renal diseases. Considering the numerous molecules involved in DN development, a high-throughput platform with parallel detection of multiple mRNAs is needed. In this study, we constructed a self-assembling mRNA array to analyze urinary mRNAs in DN patients with aims to reveal its potential in searching novel biomarkers. METHODS: mRNA array containing 88 genes were fabricated and its performance was evaluated. A pilot study with 9 subjects including 6 DN patients and 3 normal controls were studied with the array. DN patients were assigned into two groups according to their estimate glomerular rate (eGFR: DNI group (eGFR>60 ml/min/1.73 m(2, n = 3 and DNII group (eGFR<60 ml/min/1.73 m(2, n = 3. Urinary cell pellet was collected from each study participant. Relative abundance of these target mRNAs from urinary pellet was quantified with the array. RESULTS: The array we fabricated displayed high sensitivity and specificity. Moreover, the Cts of Positive PCR Controls in our experiments were 24±0.5 which indicated high repeatability of the array. A total of 29 mRNAs were significantly increased in DN patients compared with controls (p<0.05. Among these genes, α-actinin4, CDH2, ACE, FAT1, synaptopodin, COL4α, twist, NOTCH3 mRNA expression were 15-fold higher than those in normal controls. In contrast, urinary TIMP-1 mRNA was significantly decreased in DN patients (p<0.05. It was shown that CTGF, MCP-1, PAI-1, ACE, CDH1, CDH2 mRNA varied significantly among the 3 study groups, and their mRNA levels increased with DN progression (p<0.05. CONCLUSION: Our pilot study demonstrated that mRNA array might serve as a high-throughput and sensitive tool for detecting mRNA expression in urinary sediment. Thus, this primary study indicated that mRNA array probably could be a

  18. p38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells.

    Science.gov (United States)

    Hsu, Hsi-Hsien; Liu, Chung-Jung; Shen, Chia-Yao; Chen, Yi-Jyun; Chen, Li-Mien; Kuo, Wu-Hsien; Lin, Yueh-Min; Chen, Ray-Jade; Tsai, Chang-Hai; Tsai, Fuu-Jen; Huang, Chih-Yang

    2012-11-01

    Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E(2)) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E(2) to explore whether E(2) down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E(2) treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E(2) significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E(2) treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E(2) -downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E(2) /ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E(2) treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E(2) treatment simultaneously impaired cell migration by

  19. Clathrin-dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to COX-2 protein expression in rat aortic vascular smooth muscle cells.

    Science.gov (United States)

    Morinelli, Thomas A; Walker, Linda P; Velez, Juan Carlos Q; Ullian, Michael E

    2015-02-05

    The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT1A receptor activation. Certain effects initiated by AT1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by β-arrestin-dependent receptor internalization and NF-κB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT1A receptor mediates NF-κB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2׳s effects on AT1 receptor/GFP internalization in HEK-293 cells and p65 NF-κB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT1A receptor (44.7% ± 3.1% Control vs. 13.2% ± 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-κB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFα signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through β-arrestin mediated internalization of G protein-coupled receptors, such as AT1A receptors.

  20. Clinicopathological significance of plasminogen activator inhibitor-1 promoter 4G/5G polymorphism in breast cancer: a meta-analysis.

    Science.gov (United States)

    Lee, Ju-Han; Kim, Younghye; Choi, Jung-Woo; Kim, Young-Sik

    2013-01-01

    Plasminogen activator inhibitor type 1 (PAI-1) is associated with poor prognosis in breast cancer. Transcriptional expression of the PAI-1 can be controlled by PAI-1 promoter 4G/5G polymorphism. However, the significance of PAI-1 promoter 4G/5G polymorphism in breast cancer patients is contentious. To address this controversy, we conducted a meta-analysis for the relationships between PAI-1 promoter polymorphism and clinicopathological characteristics of breast cancer. Relevant published studies were identified using a search of PubMed, Embase, and the ISI Web of Science. The effect sizes of PAI-1 promoter 4G/5G polymorphism on breast cancer risk, lymph node metastasis, histologic grade, and overall survival were calculated by odds ratio (OR) or hazard ratio. The effect sizes were combined using a random-effects model. Individuals with 4G/4G genotype had a higher risk of breast cancer than those with the combined 4G/5G and 5G/5G genotypes (OR = 1.388; p = 0.031). Breast cancer patients with the 5G/5G genotype displayed lymph node metastasis more than patients with either the combined other genotypes (OR = 1.495; p = 0.027) or with the 4G/4G genotype (OR = 1.623; p = 0.018). However, the PAI-1 promoter 4G/5G polymorphism was not associated with histological grade or overall survival. PAI-1 promoter 4G/5G polymorphism is associated with a relatively increased risk of breast cancer development and lymph node metastasis. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  1. Plasminogen activator inhibitor I 4G/5G polymorphism in neonatal respiratory distress syndrome.

    Science.gov (United States)

    Armangil, Didem; Yurdakök, Murat; Okur, Hamza; Gürgey, Aytemiz

    2011-08-01

    Fibrin monomers inhibit surfactant function. 4G/5G insertion/deletion polymorphism plays an important role in the regulation of plasminogen activator inhibitor 1 (PAI-1) gene expression. To examine the genotype distribution of PAI-1 polymorphism in 60 infants with respiratory distress syndrome (RDS) and 53 controls, an allele-specific polymerase chain reaction (PCR) was used. The proportion of 4G/4G, 4G/5G, and 5G/5G genotypes did not differ statistically between the RDS and control groups (P > .05). Having PAI-1 4G/4G genotype polymorphism appears to increase the risk of RDS (odds ratio [OR] =1.5; 95% confidence interval [CI], 0.5-4.3), although it was not statistically significant. No relation was found between the PAI-1 4G/5G polymorphisms and RDS, but there was an increased risk associated with the 4G variant of the PAI-1 gene. We believe that our findings of increased 4G allele of the PAI-1 gene in infants with RDS would also help to clarify the pathogenesis of RDS.

  2. IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

    Directory of Open Access Journals (Sweden)

    Toshifumi Tezuka

    Full Text Available Plasminogen activator inhibitor (PAI-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp. IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

  3. IMD-4690, a Novel Specific Inhibitor for Plasminogen Activator Inhibitor-1, Reduces Allergic Airway Remodeling in a Mouse Model of Chronic Asthma via Regulating Angiogenesis and Remodeling-Related Mediators

    Science.gov (United States)

    Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

    2015-01-01

    Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling. PMID:25785861

  4. Clinicopathological significance of plasminogen activator inhibitor-1 gene polymorphism in breast cancer patients from North West of Iran

    Directory of Open Access Journals (Sweden)

    M Younesi

    2016-06-01

    Full Text Available Introduction: A common polymorphism 4G/5G in the promoter region of the Plasminogen activator inhibitor-1 (PAI-1 gene has been reported to influence the expression levels of PAI-1. According to the evidence, progression of breast cancer can be associated with elevated levels of PAI-1, it seems that evaluation of a possible correlation between the polymorphism and clinical status of breast cancer patients is reasonable. Methods: This descriptive-analytical study included 160 unrelated patients from North West of Iran. According to established clinical criteria, these paitients were diagnosed with breast cancer. Based on previous study, PAI-1 4G/5G had been determined. In order to investigate the association of this polymorphism with clinicopathological features Fisher’s exact tests and SPSS software was used with a significance level of 0.05. Results: All declared features of breast cancer regarding PAI-1 4G/5G polymorphism were investigated. Results indicated that PAI-1 4G/5G polymorphism positive correlation with several traditional prognostic factors, including tumor size, lymph node metastases and tumor stage. Conclusion: Data showed that the patients with 5G/5G genotype are more susceptible to the development of breast cancer, while the paitients with 4G/4G and 4G/5G genotypes show lower sensitivity to the breast cancer. Therefore, the 4G allele likely has a protective role against the development of breast cancer in this cohort.

  5. Bone Morphogenetic Protein (BMP-7 expression is decreased in human hypertensive nephrosclerosis

    Directory of Open Access Journals (Sweden)

    Cohen Clemens D

    2010-11-01

    Full Text Available Abstract Background Bone Morphogenetic Protein (BMP-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described. Methods BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8 expression was quantified in proximal tubular cells (HK-2. Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-β induced epithelial-to-mesenchymal transition (EMT, expression of TGF-β receptor type I (TGF-βRI and phosphorylated Smad 2 (pSmad 2 as well as on TNF-α induced apoptosis of proximal tubular cells. Results BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml were able to reverse TNF-α-induced apoptosis and TGF-β-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-βRI. In addition, BMP-7 was able to reverse TGF-β-induced phosphorylation of Smad 2. Conclusions The findings suggest a protective role for BMP-7 by counteracting the TGF-β and TNF-α-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease.

  6. Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H{sub 2}O{sub 2} in HL-1 mouse cardiac muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Rao, F. [Department of Cardiology, Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou (China); Research Center of Medical Sciences, Guangdong General Hospital, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China); Deng, C.Y. [Research Center of Medical Sciences, Guangdong General Hospital, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China); Zhang, Q.H.; Xue, Y.M. [Department of Cardiology, Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China); Xiao, D.Z.; Kuang, S.J.; Lin, Q.X.; Shan, Z.X.; Liu, X.Y.; Zhu, J.N. [Research Center of Medical Sciences, Guangdong General Hospital, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China); Yu, X.Y. [Department of Cardiology, Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou (China); Research Center of Medical Sciences, Guangdong General Hospital, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China); Wu, S.L. [Department of Cardiology, Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou (China); Guangdong Academy of Medical Sciences, Guangzhou (China)

    2013-09-06

    Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H{sub 2}O{sub 2}), but not angiotensin II, stimulated MIF expression in HL-1 cells. H{sub 2}O{sub 2}-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H{sub 2}O{sub 2}-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.

  7. Express web application development

    CERN Document Server

    Yaapa, Hage

    2013-01-01

    Express Web Application Development is a practical introduction to learning about Express. Each chapter introduces you to a different area of Express, using screenshots and examples to get you up and running as quickly as possible.If you are looking to use Express to build your next web application, ""Express Web Application Development"" will help you get started and take you right through to Express' advanced features. You will need to have an intermediate knowledge of JavaScript to get the most out of this book.

  8. After Effects expressions

    CERN Document Server

    Geduld, Marcus

    2013-01-01

    Put the power of Expressions to work in your animations with controls and efficiencies impossible to achieve with traditional keyframing techniques. No programming skills are required. Foundation concepts and skills orient the new designer and serve as a handy reference to the experienced one. Basics of creating expressions, variables, commands, and expression helpers precede the leap into javascript and math essentials for more advanced expressions that include randomness, physical simularions and 3D. Full color illustrations display the scripts and the resulti

  9. Extrachromosomal inducible expression

    NARCIS (Netherlands)

    Veltman, Douwe M; Van Haastert, Peter J M

    2013-01-01

    Inducible expression systems are very convenient for proteins that induce strong side effects such as retardation of growth or development and are essential for the expression of toxic proteins. In this chapter we describe the doxycycline-inducible expression system, optimized for the controlled exp

  10. High-level inducible Smad4-reexpression in the cervical cancer cell line C4-II is associated with a gene expression profile that predicts a preferential role of Smad4 in extracellular matrix composition

    Directory of Open Access Journals (Sweden)

    Schwarz Elisabeth

    2007-11-01

    Full Text Available Abstract Background Smad4 is a tumour suppressor frequently inactivated in pancreatic and colorectal cancers. We have recently reported loss of Smad4 in every fourth carcinoma of the uterine cervix. Smad4 transmits signals from the TGF-β superfamily of cytokines and functions as a versatile transcriptional co-modulator. The prevailing view suggests that the tumour suppressor function of Smad4 primarily resides in its capability to mediate TGF-β growth inhibitory responses. However, accumulating evidence indicates, that the acquisition of TGF-β resistance and loss of Smad4 may be independent events in the carcinogenic process. Through inducible reexpression of Smad4 in cervical cancer cells we wished to shed more light on this issue and to identify target genes implicated in Smad4 dependent tumor suppression. Methods Smad4-deficient human C4-II cervical carcinoma cells were used to establish inducible Smad4 reexpression using the commercial Tet-on™ system (Clontech. The impact of Smad4 reexpression on cell growth was analysed in vitro and in vivo. Transcriptional responses were assessed through profiling on cDNA macroarrays (Clontech and validated through Northern blotting. Results Clones were obtained that express Smad4 at widely varying levels from approximately physiological to 50-fold overexpression. Smad4-mediated tumour suppression in vivo was apparent at physiological expression levels as well as in Smad4 overexpressing clones. Smad4 reexpression in a dose-dependent manner was associated with transcriptional induction of the extracellular matrix-associated genes, BigH3, fibronectin and PAI-1, in response to TGF-β. Smad4-dependent regulation of these secreted Smad4 targets is not restricted to cervical carcinoma cells and was confirmed in pancreatic carcinoma cells reexpressing Smad4 after retroviral transduction and in a stable Smad4 knockdown model. On the other hand, the classical cell cycle-associated TGF-β target genes, c-myc, p

  11. Transgenic expression of an altered angiotensin type I AT1 receptor resulting in marked modulation of vascular type I collagen.

    Science.gov (United States)

    Yu, Jun; Taylor, Linda; Rich, Celeste; Toselli, Paul; Stone, Philip; Green, Daniel; Warburton, Rod; Hill, Nicholas; Goldstein, Ronald; Polgar, Peter

    2012-05-01

    The angiotensin II (AngII) type I receptor (AT1) was modified by replacing its third intracellular loop and C-terminal tail with the corresponding regions from the bradykinin B2 receptor. Transgenic mice were produced that overexpress this mutated receptor (AB3T). Considerably less collagen content in the intact aorta and in primary aortic smooth muscle cells (aSMCs) cultures was observed in the transgenic mice. On the other hand, elastin content remained unchanged as measured by Western blot, and insoluble amino acid quantitation. The contraction of isolated aortas also remained unaltered. The aSMCs derived from the transgenic mice showed a reduction in AngII responsive type I collagen production. In aSMCs from transgenic mice, the cascade of Akt to the mammalian target rapamycin (mTOR) to p70 S6 kinase (p70S6K) was not AngII activated, while in the aSMCs from wild-type (WT) mice the cascade was AngII activated. Angiotensin activation of Smad2 and Stat3 was also reduced in the AB3T aSMCs. However, no change in the effect of transforming growth factor β (TGFβ) on type I collagen production was observed. Also, the activation of ERK and JNK and G-protein linked signaling remained unaltered in response to AngII. Akt and PI3K activation inhibitors blocked AngII-stimulated type I collagen expression in WT aSMCs, whereas ERK inhibitor had no such effect. Our results point to an Akt/mTOR/p70S6K regulation of collagen production by AngII with participation of Smad2 and Stat3 cascades in this process.

  12. 纤溶酶原激活物抑制因子-1对肝星状细胞活化及细胞外基质合成的影响%The effect of Plasminogen activator inhibitor type-1 on HSC and synthesis of extrocellar matrix

    Institute of Scientific and Technical Information of China (English)

    焦黎; 武希润; 王琦

    2011-01-01

    Objective To study the effect of plasminogen activator inhibitor type-1 (PAI-1) on the activation of hepatic stellate cells(LX-2) and extrocellar matrix. Methods The effect of PAI-1 on LX-2 proliferation was detected by Methyl thiazolyl tetrazolium(MTT). After incubation with PAI-1 for 12 h, the level of hyaluronic acid(HA) and transforming growth factor-β1 (TGFβ1) in LX-2 supernatant were detected with ELISA, and the level of smooth muscle α-actin (α-SMA),matrix metalloproteinase-2(MMP-2),tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator(PLAU)and PAI-1 in LX-2 were detected by immunocytochemistry and the level of PAI-1 mRNA, TGFβ1 mRNA were investigated by reverse transcription polymerase chain reaction (RT-PCR). Results After incubation with PAI-1 for 12 h, the level of HA and TGFβ1 in the LX-2 supernatant increased significantly(t = 5. 474, t′= 5. 785, P<0. 01 ). The protein expression of α-SMA, TIMP-1 and PAI-1 in LX-2 in the PAI-1 treatment group increased remarkally when compared to normal group as well (t = 5.438,9.511,4. 857, P<0.01 ). The protein expression of MMP-2 and PLAU remain unchanged (t= 0. 473,0. 581 ,P>0.05), while the level of PAI-1mRNA and TGFβ1mRNA in LX-2 increased significantly (t = 4. 683, t′ = 4. 135, P<0. 01 ). There was a positive correlation between PAI-1 mRNA and TGFβ1mRNA(r = 0. 827,P<0. 05). Conclusion PAI-1 may accelerate the formation and development of hepatic fibrosis and cirrhosis through activating LX-2, upregulating TGFβ1 mRNA and protein and promoting synthesis of extrocellar matrix.%目的 探讨外源性纤溶酶原激活物抑制因子-1(PAI-1)对人肝星状细胞(LX-2)活化及细胞外基质合成的影响.方法 采用四甲基偶氮唑盐法(MTT)检测培养液中加入PAI-1后LX-2细胞的增殖变化,确定PAI-1的最佳干预浓度.将LX-2培养液中加入PAI-1培养12 h,ELISA法检测细胞上清液中转化生长因子(TGFβ1)、透明质酸(HA)的变

  13. The insulin-like growth factors I and II stimulate proliferation of different types of Schwann cells

    DEFF Research Database (Denmark)

    Sondell, M; Svenningsen, Åsa Fex; Kanje, M

    1997-01-01

    A combination of immunocytochemistry for glial specific antigens and bromodeoxyuridine (BrdU) and teasing was used to identify proliferating cells in cultured rat sciatic nerve segments. The nerve segments were exposed to insulin, or the insulin-like growth factors IGF-I and IGF-II. Teasing...

  14. Insulin-like growth factor II stimulates production of inositol trisphosphate in proximal tubular basolateral membranes from canine kidney.

    OpenAIRE

    Rogers, S A; Hammerman, M R

    1988-01-01

    To determine whether insulin-like growth factor II (IGF-II) activates phospholipase C in the basolateral membrane of the renal proximal tubular cell, we incubated basolateral membranes isolated from canine kidney with rat IGF-II (rIGF-II) and measured levels of inositol trisphosphate (Ins-P3) in suspensions and of diacylglycerol extractable from the membranes. Incubation with rIGF-II increased levels of Ins-P3 and diacylglycerol in a concentration-dependent manner. Significant enhancement of ...

  15. Holistic facial expression classification

    Science.gov (United States)

    Ghent, John; McDonald, J.

    2005-06-01

    This paper details a procedure for classifying facial expressions. This is a growing and relatively new type of problem within computer vision. One of the fundamental problems when classifying facial expressions in previous approaches is the lack of a consistent method of measuring expression. This paper solves this problem by the computation of the Facial Expression Shape Model (FESM). This statistical model of facial expression is based on an anatomical analysis of facial expression called the Facial Action Coding System (FACS). We use the term Action Unit (AU) to describe a movement of one or more muscles of the face and all expressions can be described using the AU's described by FACS. The shape model is calculated by marking the face with 122 landmark points. We use Principal Component Analysis (PCA) to analyse how the landmark points move with respect to each other and to lower the dimensionality of the problem. Using the FESM in conjunction with Support Vector Machines (SVM) we classify facial expressions. SVMs are a powerful machine learning technique based on optimisation theory. This project is largely concerned with statistical models, machine learning techniques and psychological tools used in the classification of facial expression. This holistic approach to expression classification provides a means for a level of interaction with a computer that is a significant step forward in human-computer interaction.

  16. Novel mechanism of intra‑renal angiotensin II-induced sodium/proton exchanger 3 expression by losartan in spontaneously hypertensive rats.

    Science.gov (United States)

    Fan, Xiaoqin; Liu, Kaishan; Cui, Wei; Huang, Jiongmei; Wang, Weina; Gao, Yuan

    2014-11-01

    The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar‑kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid‑inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II‑SGK1‑NHE3 of intra‑renal tissue.

  17. Angiotensin II-induced protein kinase D activates the ATF/CREB family of transcription factors and promotes StAR mRNA expression.

    Science.gov (United States)

    Olala, Lawrence O; Choudhary, Vivek; Johnson, Maribeth H; Bollag, Wendy B

    2014-07-01

    Aldosterone synthesis is initiated upon the transport of cholesterol from the outer to the inner mitochondrial membrane, where the cholesterol is hydrolyzed to pregnenolone. This process is the rate-limiting step in acute aldosterone production and is mediated by the steroidogenic acute regulatory (StAR) protein. We have previously shown that angiotensin II (AngII) activation of the serine/threonine protein kinase D (PKD) promotes acute aldosterone production in bovine adrenal glomerulosa cells, but the mechanism remains unclear. Thus, the purpose of this study was to determine the downstream signaling effectors of AngII-stimulated PKD activity. Our results demonstrate that overexpression of the constitutively active serine-to-glutamate PKD mutant enhances, whereas the dominant-negative serine-to-alanine PKD mutant inhibits, AngII-induced StAR mRNA expression relative to the vector control. PKD has been shown to phosphorylate members of the activating transcription factor (ATF)/cAMP response element binding protein (CREB) family of leucine zipper transcription factors, which have been shown previously to bind the StAR proximal promoter and induce StAR mRNA expression. In primary glomerulosa cells, AngII induces ATF-2 and CREB phosphorylation in a time-dependent manner. Furthermore, overexpression of the constitutively active PKD mutant enhances the AngII-elicited phosphorylation of ATF-2 and CREB, and the dominant-negative mutant inhibits this response. Furthermore, the constitutively active PKD mutant increases the binding of phosphorylated CREB to the StAR promoter. Thus, these data provide insight into the previously reported role of PKD in AngII-induced acute aldosterone production, providing a mechanism by which PKD may be mediating steroidogenesis in primary bovine adrenal glomerulosa cells.

  18. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    Science.gov (United States)

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2014-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

  19. Regular expressions cookbook

    CERN Document Server

    Goyvaerts, Jan

    2009-01-01

    This cookbook provides more than 100 recipes to help you crunch data and manipulate text with regular expressions. Every programmer can find uses for regular expressions, but their power doesn't come worry-free. Even seasoned users often suffer from poor performance, false positives, false negatives, or perplexing bugs. Regular Expressions Cookbook offers step-by-step instructions for some of the most common tasks involving this tool, with recipes for C#, Java, JavaScript, Perl, PHP, Python, Ruby, and VB.NET. With this book, you will: Understand the basics of regular expressions through a

  20. Regular Expression Pocket Reference

    CERN Document Server

    Stubblebine, Tony

    2007-01-01

    This handy little book offers programmers a complete overview of the syntax and semantics of regular expressions that are at the heart of every text-processing application. Ideal as a quick reference, Regular Expression Pocket Reference covers the regular expression APIs for Perl 5.8, Ruby (including some upcoming 1.9 features), Java, PHP, .NET and C#, Python, vi, JavaScript, and the PCRE regular expression libraries. This concise and easy-to-use reference puts a very powerful tool for manipulating text and data right at your fingertips. Composed of a mixture of symbols and text, regular exp

  1. The Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Skottrup, Peter; Pedersen, Katrine Egelund; Christensen, Anni

    2002-01-01

    spectrometry and monosaccharide composition analysis and compared to that of natural and recombinant PAI-1 from other sources. These results contribute to a structural basis for previous observations of a different functional importance of the N-linked glycosylation at each of the 2 sequences.......Plasminogen activator inhibitor type-1 (PAI-1) has three potential sites for N-linked glycosylation, including Asn209Tyr210Thr211, Asn265Met266Thr267, and Asn329Glu330Ser331. Using a HEK293 expression system, we have made mutants with Asp or Gln substitutions of the Asn residue in each...... of these sequences. Analyses of these mutants for the content of N-acetyl glucosamine showed that Asn209 and Asn265, but not Asn329, are glycosylated, in agreement with previous suggestions made on the basis of X-ray crystal structure analysis of PAI-1 expressed in CHO cells (Xue et al. (1998) Structure 6, 627...

  2. The Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Skottrup, Peter; Pedersen, Katrine Egelund; Christensen, Anni

    spectrometry and monosaccharide composition analysis and compared to that of natural and recombinant PAI-1 from other sources. These results contribute to a structural basis for previous observations of a different functional importance of the N-linked glycosylation at each of the 2 sequences.......Plasminogen activator inhibitor type-1 (PAI-1) has three potential sites for N-linked glycosylation, including Asn209Tyr210Thr211, Asn265Met266Thr267, and Asn329Glu330Ser331. Using a HEK293 expression system, we have made mutants with Asp or Gln substitutions of the Asn residue in each...... of these sequences. Analyses of these mutants for the content of N-acetyl glucosamine showed that Asn209 and Asn265, but not Asn329, are glycosylated, in agreement with previous suggestions made on the basis of X-ray crystal structure analysis of PAI-1 expressed in CHO cells (Xue et al. (1998) Structure 6, 627...

  3. Darwin and Emotion Expression

    Science.gov (United States)

    Hess, Ursula; Thibault, Pascal

    2009-01-01

    In his book "The Expression of the Emotions in Man and Animals," Charles Darwin (1872/1965) defended the argument that emotion expressions are evolved and adaptive (at least at some point in the past) and serve an important communicative function. The ideas he developed in his book had an important impact on the field and spawned rich domains of…

  4. Facial expression and sarcasm.

    Science.gov (United States)

    Rockwell, P

    2001-08-01

    This study examined facial expression in the presentation of sarcasm. 60 responses (sarcastic responses = 30, nonsarcastic responses = 30) from 40 different speakers were coded by two trained coders. Expressions in three facial areas--eyebrow, eyes, and mouth--were evaluated. Only movement in the mouth area significantly differentiated ratings of sarcasm from nonsarcasm.

  5. Darwin and Emotion Expression

    Science.gov (United States)

    Hess, Ursula; Thibault, Pascal

    2009-01-01

    In his book "The Expression of the Emotions in Man and Animals," Charles Darwin (1872/1965) defended the argument that emotion expressions are evolved and adaptive (at least at some point in the past) and serve an important communicative function. The ideas he developed in his book had an important impact on the field and spawned rich domains of…

  6. Pleiotrophin expression during odontogenesis.

    Science.gov (United States)

    Erlandsen, Heidi; Ames, Jennifer E; Tamkenath, Amena; Mamaeva, Olga; Stidham, Katherine; Wilson, Mary E; Perez-Pinera, Pablo; Deuel, Thomas F; Macdougall, Mary

    2012-05-01

    Pleiotrophin (PTN) is an extracellular matrix-associated growth factor and chemokine expressed in mesodermal and ectodermal cells. It plays an important role in osteoblast recruitment and differentiation. There is limited information currently available about PTN expression during odontoblast differentiation and tooth formation, and thus the authors aimed to establish the spatiotemporal expression pattern of PTN during mouse odontogenesis. Immortalized mouse dental pulp (MD10-D3, MD10-A11) and odontoblast-like (M06-G3) and ameloblast-like (EOE-3M) cell lines were grown and samples prepared for immunocytochemistry, Western blot, and conventional and quantitative PCR analysis. Effects of BMP2, BMP4, and BMP7 treatment on PTN expression in odontoblast-like M06-G3 cells were tested by quantitative PCR. Finally, immunohistochemistry of sectioned mice mandibles and maxillaries at developmental stages E16, E18, P1, P6, P10, and P28 was performed. The experiments showed that PTN, at both the mRNA and protein level, was expressed in all tested epithelial and mesenchymal dental cell lines and that the level of PTN mRNA was influenced differentially by the bone morphogenetic proteins. The authors observed initial expression of PTN in the inner enamel epithelium with prolonged expression in the ameloblasts and odontoblasts throughout their stages of maturation and strong expression in the terminally differentiated and enamel matrix-secreting ameloblasts and odontoblasts of the adult mouse incisors and molars.

  7. The Tomato Expression Atlas.

    Science.gov (United States)

    Fernandez-Pozo, Noe; Zheng, Yi; Snyder, Stephen I; Nicolas, Philippe; Shinozaki, Yoshihito; Fei, Zhangjun; Catala, Carmen; Giovannoni, James J; Rose, Jocelyn K C; Mueller, Lukas A

    2017-08-01

    With the development of new high-throughput DNA sequencing technologies and decreasing costs, large gene expression datasets are being generated at an accelerating rate, but can be complex to visualize. New, more interactive and intuitive tools are needed to visualize the spatiotemporal context of expression data and help elucidate gene function. Using tomato fruit as a model, we have developed the Tomato Expression Atlas to facilitate effective data analysis, allowing the simultaneous visualization of groups of genes at a cell/tissue level of resolution within an organ, enhancing hypothesis development and testing in addition to candidate gene identification. This atlas can be adapted to different types of expression data from diverse multicellular species. The Tomato Expression Atlas is available at http://tea.solgenomics.net/ . Source code is available at https://github.com/solgenomics/Tea . jr286@cornell.edu or lam87@cornell.edu. Supplementary data are available at Bioinformatics online.

  8. Regulation of melanopsin expression.

    Science.gov (United States)

    Hannibal, Jens

    2006-01-01

    Circadian rhythms in mammals are adjusted daily to the environmental day/night cycle by photic input via the retinohypothalamic tract (RHT). Retinal ganglion cells (RGCs) of the RHT constitute a separate light-detecting system in the mammalian retina used for irradiance detection and for transmission to the circadian system and other non-imaging forming processes in the brain. The RGCs of the RHT are intrinsically photosensitive due to the expression of melanopsin, an opsin-like photopigment. This notion is based on anatomical and functional data and on studies of mice lacking melanopsin. Furthermore, heterologous expression of melanopsin in non-neuronal mammalian cell lines was found sufficient to render these cells photosensitive. Even though solid evidence regarding the function of melanopsin exists, little is known about the regulation of melanopsin gene expression. Studies in albino Wistar rats showed that the expression of melanopsin is diurnal at both the mRNA and protein levels. The diurnal changes in melanopsin expression seem, however, to be overridden by prolonged exposure to light or darkness. Significant increase in melanopsin expression was observed from the first day in constant darkness and the expression continued to increase during prolonged exposure in constant darkness. Prolonged exposure to constant light, on the other hand, decreased melanopsin expression to an almost undetectable level after 5 days of constant light. The induction of melanopsin by darkness was even more pronounced if darkness was preceded by light suppression for 5 days. These observations show that dual mechanisms regulate melanopsin gene expression and that the intrinsic light-responsive RGCs in the albino Wistar rat adapt their expression of melanopsin to environmental light and darkness.

  9. EXPRESS Rack Mockup

    Science.gov (United States)

    2002-01-01

    The EXPRESS Rack is a standardized payload rack system that transports, stores, and supports experiments aboard the International Space Station (ISS). EXPRESS stands for EXpedite the PRocessing of Experiments to the Space Station, reflecting the fact that this system was developed specifically to maximize the Station's research capabilities. The EXPRESS Rack system supports science payloads in several disciplines, including biology, chemistry, physics, ecology, and medicine. With the EXPRESS Rack, getting experiments to space has never been easier or more affordable. With its standardized hardware interfaces and streamlined approach, the EXPRESS Rack enables quick, simple integration of multiple payloads aboard the ISS. The system is comprised of elements that remain on the ISS, as well as elements that travel back and forth between the ISS and Earth via the Space Shuttle. The Racks stay on orbit continually, while experiments are exchanged in and out of the EXPRESS Racks as needed, remaining on the ISS for three months to several years, depending on the experiment's time requirements. A refrigerator-sized Rack can be divided into segments, as large as half of an entire rack or as small as a bread box. Payloads within EXPRESS Racks can operate independently of each other, allowing for differences in temperature, power levels, and schedules. Experiments contained within EXPRESS Racks may be controlled by the ISS crew or remotely by the Payload Rack Officer at the Payload Operations Center at the Marshall Space Flight Center (MSFC). The EXPRESS Rack system was developed by MSFC and built by the Boeing Co. in Huntsville, Alabama. Eight EXPRESS Racks are being built for use on the ISS.

  10. EXPRESS Pallet Payload Interface Requirements

    Science.gov (United States)

    Holt, Alan C.

    2004-01-01

    A viewgraph presentation describing the EXPRESS Pallet Space Station payload interface requirements is shown. The topics include: 1) External Payload Sites; 2) EXPRESS Pallet with Six Payload Envelopes; 3) EXPRESS Pallet in Payload Bay Representative Layout; 4) EXPRESS Pallet Installation SSRMS positions pallet for PAS mating on S3 truss; 5) EXPRESS Pallet Major Components; 6) EXPRESS Pallet Adapter; 7) EXPRESS Pallet Center Location Payload Envelope; 8) Envelope Restriction for EXPRESS Pallet Corner Payload Locations; 9) EXPRESS Pallet-PAS Truss Configuration; and 10) EXPRESS Pallet Payload Services and Specifications.

  11. 4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study.

    Science.gov (United States)

    Pooyan, Honari; Ahmad, Ebrahimi; Azadeh, Rakhshan

    2015-01-01

    Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients.

  12. Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.

    Science.gov (United States)

    Jacobsen, J Steven; Comery, Thomas A; Martone, Robert L; Elokdah, Hassan; Crandall, David L; Oganesian, Aram; Aschmies, Suzan; Kirksey, Yolanda; Gonzales, Cathleen; Xu, Jane; Zhou, Hua; Atchison, Kevin; Wagner, Erik; Zaleska, Margaret M; Das, Indranil; Arias, Robert L; Bard, Jonathan; Riddell, David; Gardell, Stephen J; Abou-Gharbia, Magid; Robichaud, Albert; Magolda, Ronald; Vlasuk, George P; Bjornsson, Thorir; Reinhart, Peter H; Pangalos, Menelas N

    2008-06-24

    The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.

  13. Polymorphisms in the genes related to angiogenesis are associated with uterine cervical cancer.

    Science.gov (United States)

    Ramos-Flores, Christian; Romero-Gutiérrez, Teresa; Delgado-Enciso, Iván; Maldonado, Gabriela Enríquez; Plascencia, Víctor Montaño; Vazquez-Vuelvas, Oscar F; Quintero-Ramos, Antonio; Mejía, Roberto Chaparro; Espinoza-Gomez, Francisco; Baltazar-Rodriguez, Luz M; Valdez-Velazquez, Laura L

    2013-09-01

    The expression of plasminogen activator inhibitor type 1 (PAI-1), vascular endothelial growth factor (VEGF), and transforming growth factor β1 (TGF-β1) participates in the angiogenesis of several cancer types. The goal of this study was to investigate polymorphisms in genes related to angiogenesis (PAI-1-675 4G/5G, VEGF C936T, and TGF-β1 G-800A) to evaluate the risk for developing uterine cervical cancer (UCC). In a case-control study, 100 healthy subjects and 100 patients with UCC from Mexico were included. We determined the genetic profile of the polymorphic markers, which were evaluated by polymerase chain reaction using a sequence-specific primer. There was no statistical difference in the allele distribution from the intergroup comparisons of PAI-1 675 4G/5G and VEGF C936T data; however, a significant difference was observed within TGF-β1 G-800A. The linkage disequilibrium analysis revealed that PAI-1 -675 4G and TGF-β1 -800A pair-haplotype was in strong linkage disequilibrium with a significantly increased risk (odds ratio, 3.44; 95% confidence interval, 1.66-7.25) to UCC. The polymorphisms in the genes related to angiogenesis -675 4G/5G PAI-1 and G-800A TGF-β1, segregated solely or combined, might contribute to the increased susceptibility to UCC in a Mexican population.

  14. Expert Oracle application express

    CERN Document Server

    Scott, John Edward

    2011-01-01

    Expert Oracle Application Express brings you groundbreaking insights into developing with Oracle's enterprise-level, rapid-development tool from some of the best practitioners in the field today. Oracle Application Express (APEX) is an entirely web-based development framework that is built into every edition of Oracle Database. The framework rests upon Oracle's powerful PL/SQL language, enabling power users and developers to rapidly develop applications that easily scale to hundreds, even thousands of concurrent users. The 13 authors of Expert Oracle Application Express build their careers aro

  15. Structural basis of specific inhibition of tissue-type plasminogen activator by plasminogen activators inhibitor-1

    Science.gov (United States)

    Gong, Lihu; Liu, Min; Zeng, Tu; Shi, Xiaoli; Yuan, Cai; Andreasen, Peter A.; Huang, Mingdong

    2016-01-01

    Thrombosis is a leading cause of death worldwide [1]. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug for ischemic strokes, myocardial infarction and pulmonary embolism. tPA is a multi-domain serine protease of the trypsin-family [2] and catalyses the critical step in fibrinolysis [3], converting the zymogen plasminogen to the active serine protease plasmin, which degrades the fibrin network of thrombi and blood clots. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1) [4] (Fig. 1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort [5]. Tenecteplase (TNK-tPA) is a newer generation of tPA variant showing slower inhibition by PAI-1 [6]. Extensive studies to understand the molecular interactions between tPA and PAI-1 have been carried out [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], however, the precise details at atomic resolution remain unknown. We report the crystal structure of tPA·PAI-1 complex here. The methods required to achieve these data include: (1) recombinant expression and purification of a PAI-1 variant (14-1B) containing four mutations (N150H, K154T, Q319L, and M354I), and a tPA serine protease domain (tPA-SPD) variant with three mutations (C122A, N173Q, and S195A, in the chymotrypsin numbering) [19]; (2) formation of a tPA-SPD·PAI-1 Michaëlis complex in vitro [19]; and (3) solving the three-dimensional structure for this complex by X-ray crystallography [deposited in the PDB database as 5BRR]. The data explain the specificity of PAI-1 for tPA and uPA [19], [20], and provide structural basis to design newer generation of PAI-1-resistant tPA variants as thrombolytic agents [19]. PMID:26909366

  16. Materiality for Musical Expressions

    DEFF Research Database (Denmark)

    Lindell, Rikard; Tahiroğlu, Koray; Riis, Morten S.

    2016-01-01

    Nordic univer