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Epidemiological studies suggest that consumption of red and processed meat and refined grains are associated with type 2 diabetes and metabolic syndrome and increased inflammatory and fibrinolytic markers. We hypothesised that a diet high in red and processed meat and refined grains (HMD) would increase inflammatory markers and advanced glycation end products (AGEs) compared with a diet high in dairy, whole grains, nuts and legumes (HWD). We performed a randomised crossover study of two four-week interventions in 51 participants without type 2 diabetes (15 men and 36 women aged 35.1 ± 15.6 years; body mass index: 27.7 ± 6.9 kg/m2). No baseline measurements were performed. Plasma fluorescent AGEs, carboxymethyllysine, glucose, insulin, lipids, hs-CRP, interleukin 6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were analysed after four weeks on each diet. IL-6, hs-CRP, AGEs and carboxymethyllysine were not different between diets but PAI-1 was higher after the HMD than after HWD ((median and interquartile range) 158, 81 vs. 121, 53 ng/mL p < 0.001). PAI-1 on the HWD diet was inversely correlated with whole grains intake (p = 0.007). PAI-1 was inversely correlated with insulin sensitivity index (r = −0.45; p = 0.001) and positively correlated with serum total cholesterol (r = 0.35; p = 0.012) and serum triglyceride (r = 0.32; p = 0.021) on HMD. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000519651). Refereed/Peer-reviewed

Plasminogen activators/Plasmin system plays pivotal role in regulating reproductive functions of mammals. Here, we examined the effects of modification of in vitro fertilization medium (IVF medium) with the addition of tissue-type plasminogen activator (t-PA), on bovine embryo development and quality, assessed by quantification of expression of various genes related to metabolism, oxidation, implantation and apoptosis. In addition, plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI) were measured in the spent media. After conventional IVM, 2016 cumulus-oocyte complexes (COCs) were divided into four groups with modified composition of the IVF medium containing t-PA and/or its inhibitor epsilon-aminocaproic acid (control, t-PA, t-PA+ε-ACA, ε-ACA). Presumptive zygotes were cultured for 8 days in synthetic oviductal fluid (SOF) medium; gene expression studies were carried out on morulae and blastocysts. t-PA alone significantly suppressed cleavage and blastocyst formation rates, but this effect was neutralized by the addition of ε-ACA. PAA in the treated group was significantly reduced by ε-ACA, but without total elimination. Significant differences were detected in the expression of genes related to apoptosis and/or cell cycle arrest (BAX, BCL2L1, KAT2B) between embryos produced in t-PA-modified media and controls, giving an overall notion that the inferior developmental competence of treated embryos may be attributed to apoptotic phenomena induced by t-PA. In conclusion, it appears that excessive t-PA content in the IVF media, suppresses blastocyst formation rate, possibly due to induction of apoptotic phenomena.

Aging and obesity exert important effects on disease. Differentiating these effects is difficult, however, because weight gain often accompanies aging. Here, we used a nested design of aged, calorically restricted, and refed rats to measure changes in brain and blood levels of cytokines and gastrointestinal hormones, brain amyloid precursor protein levels, and brain and body weights. By comparing groups and using path analysis, we found divergent influences of chronological aging versus body weight, our main findings being (i) changes in whole brain weight and serum macrophage colony-stimulating factor levels correlated better with body weight than with chronological aging, (ii) a decrease in brain cytokines and brain plasminogen activator inhibitor levels correlated better with chronological aging than with body weight, (iii) serum erythropoietin levels were influenced by both body weight and aging, (iv) serum plasminogen activator inhibitor, serum cytokines, and brain tumor necrosis factor were not influenced by aging or body weight, and (v) brain amyloid precursor protein more closely related to body weight and serum levels of gastrointestinal hormones than to brain weight, chronological aging, or cytokines. These findings show that although aging and body weight interact, their influences are distinct not only among various cytokines and hormones but also between the central nervous system and the peripheral tissue compartments.

The use of prolyl hydroxylase inhibitors such as l-mimosine (L-MIM) and dimethyloxaloylglycine (DMOG) to improve angiogenesis is a new approach for periodontal regeneration. In addition to exhibiting pro-angiogenic effects, prolyl hydroxylase inhibitors can modulate the plasminogen activator system in cells from non-oral tissues. This study assesses the effect of prolyl hydroxylase inhibitors on plasminogen activation by fibroblasts from the periodontium.Gingival and periodontal ligament fibroblasts were incubated with L-MIM and DMOG. To investigate whether prolyl hydroxylase inhibitors modulate the net plasminogen activation, kinetic assays were performed with and without interleukin (IL)-1. Moreover, plasminogen activators and the respective inhibitors were analyzed by casein zymography, immune assays, and quantitative polymerase chain reaction.The kinetic assay showed that L-MIM and DMOG reduced plasminogen activation under basal and IL-1-stimulated conditions. Casein zymography revealed that the effect of L-MIM involves a decrease in urokinase-type plasminogen activator activity. In agreement with these findings, reduced levels of urokinase-type plasminogen activator and elevated levels of plasminogen activator inhibitor 1 were observed.L-MIM and DMOG can reduce plasminogen activation by fibroblasts from the gingiva and the periodontal ligament under basal conditions and in the presence of an inflammatory cytokine.

Transcatheter pulmonary valve (TPV) replacement is an effective therapy of right ventricular outflow tract conduit dysfunction. Acute complications after TPV implantation include infective endocarditis, stent fracture, and device dislocation. We present a novel, life-threatening complication: an acute, noninfectious TPV thrombosis. Within 24 hours after implantation of a Melody system (Medtronic, Inc, Minneapolis, MN), the patient developed an acute TPV thrombosis characterized by severe TPV stenosis on echocardiography and contrast filling defects on computed tomography pulmonary angiography images. Genetic testing revealed heterozygous prothrombin G20210A polymorphism and homozygous 4G/4G polymorphism of the plasminogen-activator-inhibitor. The patient recovered after surgical valve replacement with a pulmonary homograft.

Women with previous gestational diabetes mellitus (pGDM) are at high risk for type 2 diabetes and cardiovascular disorders. In this study, we aimed to compare plasma apelin levels between women with and without pGDM, and to investigate the possible association of apelin with cardiometabolic risk factors.Among 252 consecutive Caucasian women with GDM being included in a prospective postpartum follow-up protocol, 141 women eligible for the study protocol were enrolled. Control group consisted of 49 age- and body mass index-matched healthy women without pGDM. Circulating apelin, IL-6 and plasminogen activator inhibitor levels, and carotid intima media thickness (IMT) were measured. To evaluate carbohydrate intolerance, 75-g oral glucose tolerance test was performed. Fasting insulin and lipids were measured, and homeostasis model assessment index was calculated.Plasma apelin levels were reduced in women with pGDM (p 0.001). In multiple regression analysis, apelin was negatively associated with fasting (r (2) 0.090, β -0.273, p = 0.001) and post-load glucose (r (2) 0.061, β -0.187, p = 0.022), serum IL-6 (r (2) 0.082, β -0.234, p = 0.002), and carotid IMT (r (2) 0.057, β -0.168, p = 0.033).Our results suggested that suppressed apelin levels were associated with increased cardiovascular risk in women with pGDM.

Background and Purpose— Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic–ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood–brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood–brain barrier and mitigate neonatal HI brain injury. Methods— Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI). Results— Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood–brain barrier permeability. Conclusions— Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.

The urokinase plasminogen activator system, which is a serine protease family include urokinase-type plasminogen activator (uPA), the uPA receptor and plasminogen activator inhibitors (PAIs). uPA catalyzes the transformation of plasminogen to its active form plasmin, which is able to degrade the extracellular matrix (ECM) and basement membranes, directly or indirectly through activating pro-matrix metalloproteinases (pro-MMPs), promoting cancer cell metastasis and invasion. Both uPA and PAI-1 are poor prognosis markers in primary breast cancer. Evidence has been presented that the uPA system facilitates breast cancer metastasis by several different mechanisms, such as the Ras-ERK pathway and p38 MAPK pathway. This review focuses on uPA system, summarizes their biological effects, highlights the molecular mechanism and pathway, and discusses the role of uPA system in the prevention and treatment of human breast cancers.

BACKGROUND Abdominal aortic aneurysm (AAA) is associated with a prothrombotic diathesis that may increase the risk of cardiovascular events. This diathesis is exacerbated in the short term by open aneurysm repair (OAR) and endovascular aneurysm repair (EVAR). However, the effect of EVAR and OAR on coagulation and fibrinolysis in the medium and long term is poorly understood. The purpose of this study was to investigate the medium-term effects of EVAR and OAR on thrombin generation, neutralization, and fibrinolysis. METHODS Prothrombin fragment (PF)1+2, thrombin antithrombin (TAT) complex, plasminogen activator inhibitor (PAI) activity, and tissue-plasminogen activator (t-PA) antigen were measured in eight age-matched controls (AMCs), 29 patients with AAA immediately before (preoperatively) and 12 months after EVAR (post-EVAR), and in 11 patients at a mean of 16 months after OAR (post-OAR). RESULTS Preoperatively, PF1+2 levels were significantly higher in patients with AAAs than in AMC. PF1+2 levels post-EVAR and post-OAR were significantly lower than preoperative values and similar to AMC. There was no significant difference in TAT, PAI, or t-PA between AMC, AAA preoperatively, and post-EVAR. Post-OAR, PAI activity was significantly higher than in preoperative patients. CONCLUSIONS AAA is associated with increased thrombin generation without upregulation of fibrinolysis. The prothrombotic, hypofibrinolytic diathesis observed in patients with AAA returns toward normal in the medium term after EVAR and OAR, although there is a trend toward decreased fibrinolysis post-OAR.

Abnormal uterine bleeding (AUB) is a substantial cause of ill health in women worldwide. In this study, our aim was to evaluate the effectiveness of endometrial ablation using a modified urologic resectoscope along with tranexamic acid in AUB. Sixty patients were enrolled in this study. All patients underwent resectoscopic surgery. Patients were randomly divided into two groups. Group 1 (n = 30) received 500 mg of tranexamic acid. Group 2 (n = 30) served as the control group and underwent surgery without the administration of tranexamic acid. Total pictorial blood loss assessment chart (PBAC) scores were significantly lower postoperatively (152.14 ± 9.65 versus 6.6 ± 0.90; P < 0.001). When stratified by the administration of tranexamic acid, the number of patients with a postoperative day 1 PBAC score ≤15 was higher in the tranexamic group (19 versus 13), whereas the number of patients with a post operative day 1 PBAC score >15 was lower in the tranexamic group (11 versus 17), but the differences were not statistically significant (P > 0.05). AUB is a complex disease that may need repeated treatments. In expert hands, the treatment rate of resectoscopic surgery seems acceptable. However, some patients may require additional interventions, like repeated surgery, hysterectomy, or a drug therapy in the long run. Introduction of tranexamic acid as a potential adjunct to rollerball endometrial ablation may present an interesting option that requires additional well-designed studies before firm conclusions can be made.

The evidence is mounting that alterations of innate immunity and gut microbiota contribute to chronic liver disease and its complications. Modulation of intestinal microbiota is an emerging therapeutic strategy in hepatology. Probiotics through modulation of intestinal milieu have the potential to affect the course of liver disease. The data concerning the influence of probiotics on various plasma molecules and compounds involved in the pathogenesis of hyperdynamic circulatory state in liver cirrhosis is still not confluent and require further evaluation. In our study twenty patients with compensated and decompensated liver cirrhosis and ten healthy controls received probiotic VSL#3 daily for 28 days. Plasma levels of interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI), macrophage inflammatory protein 3/α (MIP-3 α/CCL20), monocyte chemotactic protein-1α (MCP-1/CCL2), human myeloperoxidase (MPO), nitric oxide (NO), prostaglandins, thromboxane (TXB

Introduction To investigate whether t-PA Alu repeat insertion/deletion (I/D) and PAI-1 4 G/5 G genetic variations are associated with the risk of MI. Methods We conducted a meta-analysis to assess the association between the t-PA I/D and PAI-1 4 G/5 G polymorphisms and risk of MI. We also performed subgroup analyses based on ethnicity (Caucasian, Asian, and African), gender and age. Forty one eligible studies including 12,461 cases and 14,993 controls were identified to evaluate the impact of PAI-1 4 G/5 G polymorphism on MI. Seven studies investigated the relationship between t-PA I/D and MI. Results This meta-analysis revealed that the PAI-1 4 G allele (4 G/4 G and 4 G/5 G genotype) was associated with an increased risk of MI compared with the 5 G allele in the overall population (OR = 1.094, 95% CI = 1.021 - 1.172, p = 0.011). The relative risks of MI for 4 G/4 G genotype was increased when compared to 5 G/5 G genotype and 5 G allele, with odds ratio at 1.157 (95% CI 1.015 - 1.320, p = 0.029) and 1.126 (95% CI = 1.015 - 1.249, p = 0.025). However, the results show that the 4 G/5 G polymorphism risk for MI was not associated with ethnicity stratification as Caucasian, Asian or African population. No substantial differences in the genotype distributions were observed in the MI group and control group along the lines of gender and age. After multivariable analysis t-PA I/D polymorphism showed no consistent association with MI. Conclusions This study suggests that the 4 G/5 G polymorphism of PAI-1 may be a risk factor for MI in overall populations.

Rheumatoid arthritis (RA) is associated with increased mortality due to cardiovascular disease (CVD). Abnormalities in coagulation have been linked with CVD in general and RA population. The aim of our study is to determine whether particular single nucleotide polymorphisms thought to be involved in the regulation of coagulation are over-represented in patients with RA compared to controls. We compared the frequency of atherothrombotic polymorphisms (Factor V Leiden, fibrinogen G455A, prothrombin G20210A and plasminogen activator inhibitor 4G5G) in 322 RA patients [231 females, mean age 61.5 ± 12, median disease duration 10 years (IQR = 14)] with 441 local controls. No significant differences were observed in genotype or allele frequencies either between RA and controls or between the disease subgroups studied. Whereas these polymorphisms may be of importance at the level of individual patients, they are unlikely to be clinically important on a population basis.

Tuberculosis (TB) is associated with excessive production and bioactivation of transforming growth factor bets (TGF-β) in situ. Here, modification of expression of components of plasminogen/plasmin pathway in human monocytes (MN) by inhibitors of TGF-β signalling was examined. Smad3 siRNA effectively inhibited TGF-β-induced urokinase plasminogen activator receptor (uPAR). Agents known to interfere with TGF-β signalling, including the Smad inhibitors SIS3 and erythromycin derivatives, and ALK5 receptor inhibitor (SB 431542) in inhibition of uPAR expression in response to Mycobacterium tuberculosis (MTB) were examined. Inhibition by SIS3 only inhibited uPAR mRNA significantly. SIS3 may prove to be an effective adjunct to TB therapy.

Background We developed 90%-hepatectomized mice that were the fatal model, and analyzed the gene expression profiles using a complementary DNA (cDNA) microarray to clarify the mechanisms of hepatic failure after excessive hepatectomy. Materials and Methods Ribonucleic acid (RNA)s from the remnant hepatic tissue of 70%- and 90%-hepatectomized mice were labeled with fluorescent dyes, and hybridized to the Riken set of 39,168 full-length enriched mouse cDNA arrays. The gene expression profiles in 90%- and 70%-hepatectomized mice were analyzed by scanning date for fluorescent dye signals. Results The down-regulated genes in 90%-hepatectomized mice were genes activating extracellular matrix (ECM) remodeling (matrix metalloproteinases, laminins, and integrins), genes related to cytokines (tumor necrosis factorα converting enzyme, and Janus kinase 3) that were related to the priming, genes related to growth factor (heparin-binding epidermal growth factor-like growth factor and others), and genes promoting cell cycle progression (cyclin D1, D2, and E2) that were related to the progression of hepatocytes. The up-regulated genes were genes inhibiting ECM remodeling [plasminogen activator inhibitors (PAIs)]. Conclusions Hepatic failure after hepatectomy was characterized by the inhibition of hepatic cell cycle priming and progression both induced by ECM remodeling in liver regeneration. Particularly, the overexpression of PAIs was thought to play the major role in the first step of inhibition of ECM remodeling.

The levels of urokinase plasminogen activator (uPA) system in tumor tissues are implicated as prognostic biomarkers in a wide range of malignancies. However, their possible impact on the risk and prognosis of oral cancer and the susceptibility of environmental carcinogens to oral cancer remains poorly investigated. The genetic polymorphisms of uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 253 patients with oral cancer and 344 healthy controls. There was no significant effect of uPA system genes on the susceptibility of oral cancer; however, the impact of uPA system gene polymorphisms on the susceptibility of betel nut and tobacco consumptions to oral cancer was revealed, except for that of uPAR gene polymorphism on tobacco consumption. Patients with oral cancer with at least one 5G allele of PAI-1 gene have a low risk for the development of clinical stage III or IV (p ≤ 0.05) and lymph node metastasis (p ≤ 0.05) compared with those with 4G/4G homozygotes. Our results suggest that the combination of uPA system gene polymorphisms and environmental carcinogens was related to the risk of oral cancer, and the genetic polymorphism of PAI-1 was associated with a low risk to the clinicopathological development of oral cancer.

This work aims at studying the possible alteration of renal renin secretion after human ischemic stroke and correlating it to the post stroke neurological and renal function alterations using angiotensin II type 1(AT1) receptor blocker (ARB), candesartan, and beta 1 adrenoreceptor blocker atenolol, which inhibits renin secretion, in Wistar rats subjected to middle cerebral artery occlusion. Methods . This study comprised 21 patients with cerebral ischemic stroke. Seventeen normal persons were used for comparison. Recumbent and standing plasma renin activity (PRA), reflex plasma renin sensitivity, plasminogen activator inhibitor and creatinine clearance (Ccr) were estimated at admission and two weeks later. Moreover, 60 male Wistar rats were divided into two groups SHAM and ischemic. Each of the two groups was further subdivided into three subgroups, non-treated, atenolol treated, and candesartan treated. In all rats, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), neurobehavioral evaluation, Ccr, PRA, and infarct size were measured. Results . Together with the significant deterioration of the neurological score, focal cerebral ischemia in rats resulted in increased PRA and decreased glomerular filtration rate (GFR). In ischemic stroke patients, GFR was significantly decreased at admission and two weeks later, PRA increased at admission and two weeks later while plasma renin reflex secretion sensitivity had decreased significantly at admission relative to controls, but it increased significantly 2 weeks later. Atenolol caused significant improvement of the neurobehavioral score and renal function and decrease infarct size of rats subjected to focal cerebral ischemia whereas candesartan caused significant improvement of the neurobehavioral score and decreased infarct size with no significant change in GFR. Neither atenolol nor candesartan caused significant change in MAP, SBP, DBP, PP and HR Conclusion . (1) Ischemic stroke seems to be associated with a postischemic increase of the plasma renin secretion, which may increase the infarct size in the brain and may induce acute renal insufficiency. (2) This study confirms that Atenolol and ARBs could benefit ischemic stroke patients without altering blood pressure.

BACKGROUND: Ethanol intoxication is a common contributor to traumatic injury. It is unknown whether ethanol consumption contributes to the coagulation differences seen between men and women after trauma. Our aim was to examine the combined effect of ethanol intoxication and gender on coagulation. METHODS: Fifty-eight healthy subjects participated and chose to enter into a control group (CG; n = 20; 10 men and 10 women) or drinking group (DG; n = 38; 20 men and 18 women). Venous blood samples for thrombelastography, plasminogen activator inhibitor, thrombin-antithrombin complex, and tissue plasminogen activator were drawn at the beginning of the study. Subjects then interacted in a social atmosphere for at least 2 hours, eating and consuming alcoholic (DG) or nonalcoholic (CG) beverages. After 2 hours, blood alcohol level was determined and blood was drawn for a second set of coagulation studies. RESULTS: Demographics were similar between groups except for age (36.7 years CG vs. 29.9 years DG; p = 0.009). All baseline thrombelastography measurements were similar between the CG and DG. Blood alcohol levels in the DG were similar between genders at the end of study. At the end of study, a decreased rate of fibrin formation, decreased clot strength, and a decreased rate of fibrin cross-linking was seen in men but not in women. Fibrinolysis was inhibited in drinkers compared with controls. CONCLUSIONS: Consumption of commonly ingested quantities of alcohol correlated with the development of a hypocoagulable state in men but had no effect on coagulation status in women. This phenomenon may contribute to differences in post-trauma coagulation status previously noted between genders. Language: en

Inactivators of plasminogen activator inhibitor-1 (PAI-1) have been identified as possible treatments for a range of conditions, including atherosclerosis, venous thrombosis, and obesity. We describe the synthesis and inhibitory activity of a novel series of compounds based on bis-arylsulfonamide and aryl sulfonimide motifs that show potent and specific activity towards PAI-1. Inhibitors containing short linking units between the sulfonyl moieties and a 3,4-dihydroxy aryl substitution pattern showed the most potent inhibitory activity, and retained high specificity for PAI-1 over the structurally-related serpin anti-thrombin III (ATIII).

The influence of hGH and IGF-I levels on lipid-, lipoprotein metabolism and fibrinolysis were studied in 23 patients with active acromegaly (14 women and 9 men, mean age 49.8 +/- 2.1 years) compared to a sex, BMI and age-matched control group. Mean Lp(a) levels were significantly higher in acromegalics than in controls (469.8 +/- 140.1; n = 23 vs. 162.7 +/- 64.9 mg/l; n = 111; p < 0.01). We found elevated apolipoprotein A-I and Apo E-concentrations in acromegalic patients compared to controls (apo A-I: 1.79 +/- 0.06 vs. 1.46 +/- 0.04 g/l; p < 0.01; apo E: 98.35 +/- 6.4 vs. 72.53 +/- 3.38 mg/l; p < 0.05). 30% of the acromegalics showed increased plasminogen activator inhibitor activity (PAI) while 66% had increased tissue-type plasminogen activator (t-PA) concentrations. There was a correlation between hGH and Lp(a) (r = 0.414; p = 0.05), between hGH and PAI (r = -0.59; p < 0.005) and IGF-I and t-PA activity (r = -0.44; p < 0.05). In a subgroup of nine acromegalics Lp(a) was reduced by 32.2 +/- 6.7% (p < 0.05) after a six-month octreotide therapy and HDL2-cholesterol-concentration increased from 0.17 +/- 0.04 to 0.24 +/- 0.04 mmol/l (p < 0.05). In conclusion, our results demonstrate that elevated Lp(a)-concentrations and changes in fibrinolysis contribute to the cardiovascular complications and should therefore be controlled in acromegalic patients.

Contact lens wear (CLW) has been shown to cause an elevation in tear fluid (TF) plasmin levels. This study investigated whether the proteolytic activity assayed by a caseinolytic technique was also bound by CLs and whether certain bacterial species contribute to the production of plasmin. CLs worn by patients with corneal disease showed proteolytic activity in five out of nine cases when examined on casein agar. Histological and electron microscopic examination of the lenses revealed bacterial adherence and growth on both surfaces of the CLs. Strains of Staph. epidermidis, Staph. aureus, Pseudomonas aeruginosa and Branhamella catarrhalis, isolated from eyes with external infections, were cultured on a modified milk casein agar and examined for their proteolytic activity. Neither cultures of Branhamella catarrhalis nor Staph. aureus showed proteolytic activity when examined by direct caseinolytic assay. The proteolytic activity shown by Staph. epidermidis or Pseudomonas aeruginosa was not affected by a proteinase inhibitor aprotinin. However, when exogenous plasminogen was added into the casein agar, Staph. aureus was shown to produce caseinolytic activity. This activity was interpreted to be due to plasminogen activator (PA) activity. It was inhibited by aprotinin. Examination of culture fluids of the bacterial species mentioned above did not show caseinolytic activity. Culture fluid of Staph. aureus contained PA activity. The present study confirms the ability of certain bacterial species to adhere to CLs. Moreover, proteases such as plasmin and bacterial enzymes are present in TF during CL wear and may even adhere to the surface of CLs. Hence, bacterial growth probably contributes to the production of proteases on the ocular surface during CL wear.

Summary. Plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI), against t-PA (t-PAI) or u-PA (u-PAI), in spermatozoa and seminal plasma as well as testosterone in the blood of Friesland, Chios, and Karagouniki rams all showed a seasonal variation with the highest values during the corresponding breeding season of the ewes (Autumn-Winter). The seasonal variation of PAA and PAI in spermatozoa or seminal plasma as well as blood testosterone was different among the three breeds studied. Increased spermatozoal PAA was observed in November and May in Friesland rams, in October and November in Chios rams, and in October in Karagouniki rams. Spermatozoal t-PAI was increased in December and June in Friesland rams, in November and December in Chios rams, and in November in Karagouniki rams. Spermatozoal u-PAI was increased in December in Friesland rams, in October and December in Chios rams, and in November and December in Karagouniki rams. Plasminogen activator activity and PAI in seminal plasma also showed similar seasonal variations. Plasminogen activator activity and PAI in spermatozoa and seminal plasma showed a positive correlation with blood testosterone. The results of the present study support our previous findings on the possible role of spermatozoal PAA and PAI in the fertilizing ability of spermatozoa.

After a single injection of serum gonadotrophin (PMSG) at the dose of 15 IU/kg, i.m. into rams testosterone in the plasma of blood showed a significant rise between 4th and 7th day post-injection. At the same time (4th-7th day) the plasminogen activator activity (PAA) in seminal plasma was found to be increased, but the plasminogen activator inhibition (PAI) expressed against t-PA (anti-t-PA) showed an increase between 32nd and 46th day. In spermatozoa a marked increase of PAA was revealed between 32nd and 46th day post-injection, while an increase of PAI (anti-t-PA) was exhibited on the 74th day. Plasmin inhibition (PI) in seminal plasma and spermatozoa showed no change compared to controls. A positive correlation has been found between increased concentrations of testosterone and PAA or PAI (anti-t-PA) in spermatozoa and seminal plasma. The induced increase of PAA in spermatozoa under the effect of testosterone might be of physiological importance, since PAA is localized to sperm membranes and might participate in the whole process of fertilization.

Summary Genetic association studies have implicated functional DNA polymorphisms in genes encoding factors related to angiogenesis, inflammation and thrombosis with increased risk for oral squamous cell carcinoma (OSCC). This study examines possible interactions between nine such genotype polymorphisms and their combinatory effect in assessing the OSCC risk in a European population. OSCC cases ( N = 162) and healthy controls ( N = 168) of comparable age, gender, and ethnicity (Greeks and Germans) were studied. Multivariate logistic regression models were constructed in order to assess the contribution of homozygous or heterozygous variant genotypes of polymorphisms MMP-1 (− 1607 1G/2G ), MMP-3 (− 1171 5A/6A ), MMP-9 (− 1562C/T ), TIMP-2 (− 418C/G ), VEGF ( +936C/T ), GPI-α ( +807C/T ), PAI-1 ( 4G/5G ), ACE ( intron 16D/I ) and TAFI ( +325C/T ) upon overall, early and advanced stages of OSCC. Four out of nine polymorphisms affecting PAI-1 , MMP-9 , TIMP-2 and ACE expression contributed significantly in OSCC prediction in the various logistic regression models. Based on these findings and previous reports, possible interactions of the implicated factors leading to OSCC development, as well as an algorithm of risk estimation are discussed.

The impact of heart failure with preserved left ventricular ejection fraction (LVEF) on activated hemostasis is still unclear. We sought to compare the activation of hemostasis in patients with heart failure with preserved LVEF, with impaired LVEF, and in healthy controls. Biomarkers of coagulation and fibrinolysis (D-dimer, tPA and PAI-1) were determined in outpatients with chronic stable (NYHA I-III), optimally managed heart failure with preserved LVEF (n = 46) and with impaired LVEF (n = 52), and in healthy age- and gender-matched controls (n = 14). In comparison to healthy controls, patients with heart failure and preserved LVEF had increased median D-dimer levels (606 [330-1222] microg/L versus 174 [86-249] microg/L; P < 0.001), and median PAI-1 (20 [15.3-33.1] microg versus 6.2[3.4-8.9] microg/L; P < 0.001) and tPA antigen concentrations (9.6 [8.1-13.3] versus 3.6 [2.2-5.0] microg/L; P < 0.001). However, unlike tPA and PAI antigens, D-dimer levels in preserved LVEF did not reach values as high as in impaired LVEF (917 [454-1185] microg/L; P = 0.013). Moreover, in patients with impaired LVEF, but not in those with preserved LVEF, age and NT-proBNP emerged as independent predictors of log-transformed D-dimer levels. Heart failure with preserved LVEF is associated with a procoagulant state as determined by increased levels of D-dimer, tPA and PAI-1 antigens. D-dimer levels are significantly higher in patients with impaired LVEF, while tPA and PAI-1 levels are increased regardless of LVEF.

Deep venous thrombosis (DVT) after major orthopaedic surgery is a substantial concern. We asked whether the single or combined presence of thrombophilic genetic polymorphisms might further increase the already high risk for venous thrombosis and pulmonary embolism (PE) after THA. We therefore compared the prevalence of factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, and plasminogen activator inhibitor 4G/5G polymorphisms between 50 patients with symptomatic DVT within 3 weeks after elective THA and an asymptomatic control group of 85 patients. We found no major difference for the presence of a single mutation between the groups. Factor V Leiden and homozygous MTHFR C667T mutations were of borderline significance with odds ratios (95% confidence intervals) of 3.73 (0.89-15.63) and 2.93 (0.92-9.29), respectively. Patients with homozygous or combined heterozygous status of MTHFR C677T and A1298C mutation had a higher frequency of DVT after elective THA (odds ratio, 2.86; 95% confidence interval, 1.32-6.35) than those with wild-type. The presence of a single mutation may not further increase the already high risk for symptomatic DVT after THA, whereas combinations of mutations of distinct polymorphisms might be important. However, prospective studies with a larger number of patients are needed before we would recommend preoperative screening.Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Background: Plasminogen activators (PAs) and their regulatory counterparts, PA inhibitors (PAIs), play a role in normal differentiation processes and various pathophysiologic conditions of the epidermis. Normal desquamation of corneocytes from the skin3s surface may, in part, be regulated by the balanced activities of tissue-type PA (tPA) and PAI-2. Salicylic acid (SA) is commonly used to remove the hyperkeratotic tissue of corns, calluses, and verrucae, and it may disrupt intercellular adhesion structures; however, its exact mechanism of keratolytic action is poorly defined. We sought to determine the effects of SA by comparing the levels of PA and PAI messenger RNA (mRNA) in normal skin, untreated corns, and SA-treated corns. Methods: Untreated and SA-treated human corn tissue samples were obtained from patients electing surgery to repair bony defects that underlay their lesions. Histopathologic examination of corns was performed by staining the tissue sections with hematoxylin and eosin and by light microscopy. Polymerase chain reaction was used to compare mRNA expression of PAs and PAIs in normal skin, untreated corns, and SA-treated corns. Results: We demonstrated lower tPA and higher PAI-2 mRNA levels in corn tissue compared with normal skin. In corn tissue treated with SA, the expression of tPA mRNA increased and of PAI-2 mRNA decreased to the levels found in normal skin. Conclusion: An altered balance in tPA and PAI-2 levels contributes to the induction of hyperkeratotic corn tissue and suggests that the keratolytic action of SA is associated with its ability to stimulate proteinase-meditated desquamation processes. (J Am Podiatr Med Assoc 98(5): 345–352, 2008)

Background & Aims: Although ischemic colitis (IC) usually occurs in old people with concomitant illnesses, an increasing frequency of this disease among young people has been reported. Inherited risk factors have been suggested to play an important role in the pathogenesis of IC. The aim of this study was to investigate the prevalence and possible role of mutations associated with cardiovascular morbidity in young patients with IC. Methods: Patients younger than 55 years old with nonocclusive colon ischemia who were conservatively treated were included in the study. The diagnosis of definite IC was based on established clinical, endoscopic, and histologic criteria. Twelve polymorphisms of thrombophilic and vasoactive genes were evaluated in a group of 19 young patients with IC compared with 52 matched healthy controls (HC) by using commercially available kit. Results: The frequency of the 506 Q allele of the factor V (FV) 506 RQ (Leiden) mutation was significantly higher in patients with IC than in HC (P = .005). The allele frequency of the mutant 4G allele of plasminogen activator inhibitor (PAI) polymorphism was significantly higher in patients with IC compared with HC (P = .006). The frequencies of the genotypes and mutant alleles of the other 10 polymorphisms were not statistically different in the 2 groups (P > .05). Conclusions: Our results suggest that FV R506Q and PAI-1 gene polymorphisms might be associated with the development of IC in young patients without other serious illness. Genetic predisposition might play an important role in the pathogenesis of IC in young patients.

Three patients with congenital, nephrogenic diabetes insipidus (NDI) from two unrelated families were tested for haemostatic and fibrinolytic responses to DDAVP infusion and venous occlusion. None of the three patients showed a response of factor VIII:C, vWF:Ag or t-PA to DDAVP, a V2-agonist. However, the baseline levels of these factors in the patients' plasma were normal and during venous occlusion a rise in t-PA antigen and t-PA activity was observed in all patients. One patient showed a definite response of the t-PA antigen level to exercise. It is concluded that (extrarenal) V2-receptor-mediated responses are absent in these patients, but that baseline homeostasis and the response to venous occlusion and physical exertion are intact. Presumably, these depend on other mechanisms. This observation denies a central role for vasopressin receptors in the on-demand regulation of clotting and clot dissolving properties of the blood.

Recent advancements in cancer research have led to some major breakthroughs; however, the impact on overall cancer-related death rate remains unacceptable, suggesting that further insight into tumor markers and development of targeted therapies is urgently needed. The urokinase plasminogen activator (uPA) system represents a family of serine proteases that are involved in the degradation of basement membrane and the extracellular matrix, leading to tumor cell invasion and metastasis. In this review, we have provided an overview of emerging data, from basic research as well as clinical studies, highlighting the evolving role of uPA/uPAR system in tumor progression. It is currently believed that the expression and activation of uPA plays an important role in tumorigenicity, and high endogenous levels of uPA and uPAR are associated with advanced metastatic cancers. The endogenous inhibitors of this system, PAI-1 and PAI-2, regulate uPA-uPAR activity by either direct inhibition or affecting cell surface expression and internalization. PAI-1's role in cancers is rather unusual; on one hand, it inhibits uPA-uPAR leading to inhibition of invasion and metastasis and on the other it has been reported to facilitate tumor growth and angiogenesis. Individual components of uPA/uPAR system are reported to be differentially expressed in cancer tissues compared to normal tissues and, thus, have the potential to be developed as prognostic and/or therapeutic targets. Therefore, this system represents a highly attractive target that warrants further in-depth studies. Such studies are likely to contribute towards the development of molecularly-driven targeted therapies in the near future.

Introduction: Atrial fibrosis has been shown to concur with the persistence of atrial fibrillation (AF) and is only incompletely reversible, thus counteracting attempts to restore and maintain sinus rhythm (SR). Besides the angiotensin system, the matrix metalloproteinases (MMP) play a major role in the pathogenesis of fibrosis. Thus, the present study investigated changes of the MMP system during the development of human AF. Methods and Results: Right atrial appendages of 146 patients were excised during heart surgery and grouped according to rhythm (SR vs AF) and AF duration. Hydroxyproline as a surrogate for collagen content and morphometrically determined collagen content increased significantly from SR (14.3 ± 7.7%) to chronic permanent AF (CAF) of 6–24 months (21.2 ± 9.2%, P = 0.02), and CAF of > 60 months (25.3 ± 4.7%, P < 0.01). From SR to paroxysmal and chronic persistent AF (CPAF) and to CAF MMP-2 and MMP-9 activity rose, while their mRNA and protein levels were not altered significantly. Plasminogen activator inhibitor (PAI), an inhibitor of a potent activator of many MMPs, was significantly decreased with increasing duration of AF. In parallel, the mRNA levels of the tissue inhibitors of MMPs TIMP-1 and -2 decreased significantly. Conclusion: Human atrial fibrogenesis is enhanced with increasing duration of AF: a longer AF duration is associated with elevated atrial interstitial MMP activity, but decreased PAI and TIMP expression.

The corpus luteum (CL) offers the opportunity to study high proliferative processes during its development and degradation processes during its regression. We examined the mRNA expression of matrix metalloproteases (MMP)-1, MMP-2, MMP-9, MMP-14, MMP-19, tissue inhibitor of MMP (TIMP)-1, TIMP-2, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), uPA-receptor (uPAR), PA-inhibitors (PAI)-1, PAI-2 in follicles 20 h after GnRH application, CLs during days 1–2, 3–4, 5–7 and 8–12 of the oestrous cycle as well as after induced luteolysis. Cows in the mid-luteal phase were injected with Cloprostenol and the CLs were collected at 0.5, 2, 4, 12, 24, 48 and 64 h after PGF2α injection. Real-time RT-PCR determined mRNA expressions. Expression from 20 h after GnRH to day 12: MMP-1, MMP-2, MMP-14 and tPA showed a clear expression, but no regulation. TIMP-1 and uPAR mRNA increased when compared with the follicular phase. TIMP-2, MMP-9, MMP-19 and uPA increased from the follicular phase to days 8–12. PAI-1 and PAI-2 expression increased from days 1–7 and decreased to days 8–12. Induced luteolysis: MMP-1, MMP-2, MMP-9, MMP-14, MMP-19 and TIMP-1 all increased at different time points and intensities, whereas TIMP-2 was constantly decreased from 24 to 64 h. The plasminogen activator system and their inhibitors were up-regulated from 2 to 64 h, tPA was already increased after 0.5 h. Immunohistochemistry for MMP-1, MMP-2, MMP-14: an increased staining for MMP-1 and MMP-14 was seen in large luteal cells beginning 24 h after PGF2α application. MMP-2 showed a strong increase in staining in endothelial cells at 48 h.

Objective Chronic inflammation in periodontal disease is associated with increased plasminogen activation and elevated levels of chemokines. It is unknown whether chemokines can regulate the activation of plasminogen via modulation of plasminogen activators (PA) and the corresponding plasminogen activator inhibitors (PAI) in periodontal tissue. Design To establish a link between chemokines and activation of plasminogen, human periodontal ligament fibroblasts (PDL) and gingival fibroblasts (GF) were incubated with IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and platelet factor-4, either alone or in the presence of the inflammatory mediators TGF-β and IL-1. The potential of the cell lysates to activate plasminogen was based on kinetic studies with the substrate casein. Casein zymography was performed to determine the molecular sizes of the PA. Total PAI-1 in the cell-conditioned medium was quantified by immunoassay. Results We report that the chemokines did not affect activation of plasminogen by PDL and GF. Even in the presence of TGF-β which suppressed, and IL-1 which stimulated plasminogen activation, the chemokines had no direct effect. Inhibition of PA and plasmin, but not of matrix metalloproteinases and cysteine proteinases prevented caseinolysis. The plasminogen activation capacity of the cell lysates was represented by a single band with features of uPA. The immunoassay showed that the release of PAI-1 in PDL and GF remained unaffected by the chemokines, also when stimulated with TGF-β. Conclusions These results suggest that plasminogen activation by PDL and GF is not directly affected by the chemokines even in the presence of the inflammatory mediators TGF-β and IL-1.

Human thyroid cells in culture take up and organify 125I when cultured in TSH (acting through cAMP) and insulin. They also secrete urokinase (uPA) and tissue-type (tPA) plasminogen activators (5–100 IU/106cells/day). TSH and insulin both decreased secreted PA activity (PAA), uPA and tPA protein and their mRNAs. Autocrine fibroblast growth factor increased secreted PAA and inhibited thyroid cell 125I uptake. Epidermal growth factor (EGF) and the protein kinase C (PKC) activator, TPA significantly increased PAA and inhibited thyroid differentiated function, (TPA > EGF). For TPA, effects were rapid, increased PAA secretion and decreased 125I uptake being seen at 4 h whereas for EGF, a 24 h incubation was required. qRT-PCR showed significantly increased mRNA expression of uPA with lesser effects on tPA. Aprotinin, which inhibits PAA, increased 125I uptake but did not abrogate the effects of TPA and EGF. The MEKK inhibitor, PD98059 partially reversed the effects of EGF and TPA on PAA, and largely reversed the effects of EGF but not TPA on differentiated function. PKC inhibitors bisindoylmaleimide 1, and the specific PKCβ inhibitor, LY379196 completely reversed the effects of TPA on 125I uptake and PAA whereas EGF effects were unaffected. TPA inhibited follicle formation and this effect was blocked by LY379196 but not PD98059. We conclude that in thyroid cells, MAPK activation inversely correlates with 125I uptake and directly correlates with PA expression, in contrast to the effects of cAMP. TPA effects on iodide metabolism, dissolution of follicles and uPA synthesis are mediated predominantly through PKCβ whereas EGF exerts its effects through MAPK but not PKCβ. J. Cell. Physiol. 212:643–654, 2007. © 2007 Wiley-Liss, Inc.

International audience; Lactation performance is dependent on both the genetic characteristics and the environmental conditions surrounding lactating cows. However, individual variations can still be observed within a given breed under similar environmental conditions. The role of the environment between birth and lactation could be better appreciated in cloned cows, which are presumed to be genetically identical, but differences in lactation performance between cloned and noncloned cows first need to be clearly evaluated. Conflicting results have been described in the literature, so our aim was to clarify this situation. Nine cloned Prim' Holstein cows were produced by the transfer of nuclei from a single fibroblast cell line after cell fusion with enucleated oocytes. The cloned cows and 9 noncloned counterparts were raised under similar conditions. Milk production and composition were recorded monthly from calving until 200 d in milk. At 67 d in milk, biopsies were sampled from the rear quarter of the udder, their mammary epithelial cell content was evaluated, and mammary cell renewal, RNA, and DNA were then analyzed in relevant samples. The results showed that milk production did not differ significantly between cloned and noncloned cows, but milk protein and fat contents were less variable in cloned cows. Furthermore, milk fat yield and contents were lower in cloned cows during early lactation. At around 67 DIM, milk fat and protein yields, as well as milk fat, protein, and lactose contents, were also lower in cloned cows. These lower yields could be linked to the higher apoptotic rate observed in cloned cows. Apoptosis is triggered by insulin-like factor growth binding protein 5 (IGFBP5) and plasminogen activator inhibitor (PAI), which both interact with CSN1S2. During our experiments, CSN1S2 transcript levels were lower in the mammary gland of cloned cows. The mammary cell apoptotic rate observed in cloned cows may have been related to the higher levels of DNA (cytosine-5-)-methyltransferase 1 (DNMT1) transcripts, coding for products that maintain the epigenetic status of cells. We conclude, therefore, that milk production in cloned cows differs slightly from that of noncloned cows. These differences may be due, in part, to a higher incidence of subclinical mastitis. They were associated with differences in cell apoptosis and linked to variations in DNMT1 mRNA. However, milk protein and fat contents were more similar among cloned cows than among noncloned cows.

The concept of enzyme immobilization via an inhibitor-derived peptide was developed. This method of immobilization was shown to be advantageous over physical adsorption and covalent bonding in retaining the enzymatic activity. Moreover, the surface-immobilized enzyme exhibited resistance against its inhibitor due to the occupation of an inhibitor binding site on the enzyme.

BC-11 is an easily synthesized simple thiouronium-substituted phenylboronic acid, which has been shown to be cytotoxic on triple negative MDA-MB231 breast cancer cells by inducing a perturbation of cell cycle when administered at a concentration equal to its ED50 at 72 h (117 μM). Exposure of cells to BC-11, either pre-absorbed with a soluble preparation of the N-terminal fragment of urokinase-plasminogen activator (uPa), or in co-treatment with two different EGFR inhibitors, indicated that: (i) BC-11 acts via binding to the N-terminus of the enzyme where uPa- and EGF receptor-recognizing sites are present, thereby abrogating the growth-sustaining effect resulting from receptor binding, and (ii) the co-presence of the EGFR inhibitor PD153035 potentiates BC-11’s cytotoxicity. Exposure of cells to a higher concentration of BC-11 corresponding to its ED75 at 72 h (250 μM) caused additional impairment of mitochondrial activity, the production of reactive oxygen species and promotion of apoptosis. Therefore, BC-11 treatment appears to show potential for the development of this class of compounds in the prevention and/or therapy of “aggressive” breast carcinoma.

Evidence of severe hepatobiliary morbidity associated with Opisthorchis viverrini liver fluke infection including cholangiocarcinoma (CCA) is scarce in Laos although O. viverrini infection is highly prevalent. We assessed hepatobiliary morbidity using abdominal ultrasonography (US) in O. viverrini adult patients in Saravan province, Southern Laos. A random sample of 431 O. viverrini patients from 10 villages underwent abdominal US. Mild, moderate and markedly advanced periductal fibrosis was diagnosed in 7.0%, 66.5%, and 17.0% of patients, respectively. Normal liver parenchyma was seen in only 9.5% of patients. Presence of gall stones (13.2%), sludge (1.4%), gall wall thickening (1.2%), bile duct dilatation (1.6%), fatty liver (12.0%), kidney stones (8.6%) and cysts (7.9%) were diagnosed in considerable frequencies. In five patients (1.2%) hepatobiliary lesions suggesting CCA were diagnosed. Tumour markers, i.e. Interleukin-6, plasminogen activator inhibitor and carbohydrate antigen 19-9 were within normal range. The number of CCA suspected liver masses and hepatobiliary morbidity diagnosed among clinically asymptomatic adult patients in O. viverrini endemic area presents a major public health concern in Laos. However, definitive diagnosis of Opisthorchis-related severe sequelae including CCA is urgently needed to gauge the burden of this deadly disease in Laos.

To elucidate some of the links between homocysteine and vascular disease, we have evaluated the effect of the amino acid on the formation (by kinetics studies), structure (by electron microscopy) and lysis of the fibrin network, using tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). We have studied whether homocysteine could alter the activity of the components involved in fibrinolysis (by amidolytic and thrombolytic methods). The results showed that homocysteine-associated networks were more compact and branched than controls (52 +/- 6 vs 44 +/- 5 fibers/field, P = 0.008), and were formed by shorter and thicker fibers. This clot proved to be more resistant to fibrinolysis with u-PA than control [lysis time 50%: 257 +/- 16 (homocysteine) vs 187 +/- 6 min (control); P < 0.004], but there were no differences with t-PA. Homocysteine did not affect the biological activities of plasmin, or plasminogen activation by t-PA and u-PA. Defective fibrinolysis with u-PA was therefore associated with homocysteine-fibrin structural alterations rather than the homocysteine effect on the biological activities of the fibrinolytic components evaluated. Results suggest that hyperhomocysteinemic patients could produce tight clots, were more resistant to lysis, and generated a procoagulant environment in situ. We believe that our findings may contribute to understanding the mechanisms involved in the homocysteine harmful effect.

Anthocyanins, present in various fruits and vegetables as natural colorant, have been well characterized to be involved in various bioactive properties and are wildly used for their antioxidant properties. Furthermore, recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of anthocyanin. Berry extract contains high amounts of anthocyanins and is commonly used in diet or in some therapeutic applications. In this study, we first observed that cyanidin 3-rutinoside and cyanidin 3-glucoside (extracted from Morus alba L.) exerted a dose-dependent inhibitory effect on the migration and invasion, of highly metastatic A549 human lung carcinoma cells in absence of cytotoxicity. The results showed that cyanidin 3-glucoside and cyanidin 3-rutinoside treatments could decrease the expressions of matrix matalloprotinase-2 (MMP-2) and urokinase-plasminogen activator (u-PA) in a dose-dependent manner and enhance the expression of tissue inhibitor of matrix matalloprotinase-2 (TIMP-2) and plasminogen activator inhibitor (PAI). Further analysis with semi-quantitative RT-PCR showed that these alterations were all on the transcriptional level. Further, a treatment of cyanidin 3-rutinoside and cyanidin 3-glucoside also resulted in an inhibition on the activation of c-Jun and NF-kappaB. Together, these result suggested that anthocyanins could decrease the in vitro invasiveness of cancer cells and therefore, may be of great value in developing a potential cancer therapy.

Episodes of psychological and physical stress may elicit thrombotic cardiac events, such as myocardial infarction. These events are triggered when there are concurrent hemodynamic, hemostatic, and endothelial abnormalities. Hemodynamic, hemostatic, and endothelial reactions of 72 (15 women, 57 men) coronary artery disease patients to psychological and physical stress were examined. Blood pressure, electrocardiography, and impedance cardiography were recorded during rest, mental arithmetic, and exercise. Blood was collected, via catheter, at rest and after each task. Mental arithmetic elicited increases in blood pressure, heart rate, cardiac output, and cardiac contractility, but no consistent changes in hemostatic and endothelial markers. In contrast, exercise, in addition to increasing blood pressure, heart rate, cardiac output, cardiac contractility, and lowering peripheral resistance, elicited increases in plasma viscosity, hematocrit, platelets, and tissue plasminogen activator together with a decrease in plasminogen activator inhibitor. This pattern of hemodynamic, hemostatic, and endothelial reactions suggests that acute psychological and physical stress influence the thrombotic system differently in these high risk patients. Future research is needed to investigate how these stress responses are prospectively related to acute cardiac events.