Plasminogen Activator Activity Research Articles

Anti-angiogenic effects of mangiferin and mechanism of action in metastatic melanoma.

Advanced metastatic melanoma, one of the most aggressive skin malignancies, is currently without reliable therapy. The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone which exerts many pharmacological activities against cancer-inflammation. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we demonstrate that mangiferin interferes with inflammation, lipid and calcium signaling which selectively inhibits multiple NFkB target genes including interleukin-6, tumor necrosis factor, interferon gamma, vascular endothelial growth factor receptor 2, plasminogen activator urokinase, matrix metalloprotease 19, C-C Motif Chemokine Ligand 2 and placental growth factor. This abrogates angiogenic and invasive processes and capillary tube formation of metastatic melanoma cells as well as human placental blood vessel explants in-vitro and blocks angiogenesis characteristic of the chicken egg chorioallantoic membrane assay and in melanoma syngeneic studies in vivo. The results obtained in this research illustrate promising anti-angiogenic effects of the natural glucosylxanthone mangiferin for further (pre)clinical studies in melanoma cancer patients.

Findings of the study of cognitive evoked potentials in persons exposed to radiation

Introduction. After exposure to radiation, an increase in the long-term of cerebrovascular pathology is noted in exposed individuals. Cognitive impairments have a growing importance in the pattern of cerebrovascular diseases which significantly deteriorates social and medical forecast of a patient.The objective of the research is to study cognitive evoked potentials in exposed persons with chronic cerebral ischemia (CCI).Materials and methods. Two groups of patients were examined: the main group consisted of 69 persons exposed to radiation as a result of the “Mayak” PA activity, the comparison group included 110 unexposed residents of the Techa riverside settlements who were diagnosed with chronic cerebral ischemia. The following methods were used in the study: clinical, evaluation method of cognitive evoked potentials (EP), and statistical methods.Results. In the course of clinical examination, it was revealed that the number of people with organic cognitive impairment and syndrome of cognitive decline is statistically significantly higher in the group of the exposed persons with CCI (p < 0.001, p = 0.003, respectfully). It was stated that the studied groups were statistically significantly different in N1 peak latency (ð = 0.030), N2 – P3 inter-peak latency (p = 0.003), N2 – N3 inter-peak latency (p = 0.011).Conclusion. According to the results of clinical examination and study of cognitive EP, cognitive impairments are more expressed in the group of the exposed persons with CCI which is manifested in an increase in the number of patients with syndrome of cognitive decline and organic cognitive impairment in this group; in the change of a latency period of a number of components that characterize both the perception process and the very process of recognition and decision-making.

Secretion by Micromycetes of Proteases with Activity Similar to the Activity of the Hemostatic System Proteins

Proteolytic activity of 8 strains of micromycetes (belonging to different ecological and trophic groups: phyto-, nemato-, myco-, and entomopathogens as well as human pathogens) toward the hemostatic system proteins has been assayed by using the chromogenic peptide substrates. The investigated micromycetes are shown to secrete proteases with a broad substrate specificity. However, there are producers among them exhibiting a pronounced plasmin-like and urokinase activity (Arthrobotrys longa 1, Sarocladium strictum 203) as well as a tPA (tissue plasminogen activator)-like activity (Purpureocillium lilacinum k1). It is found that the most active producer of proteases with fibrinolytic and plasminogen activator activity is S. strictum 203. Plasminogen activator activity of proteinases produced by S. strictum 203 is approximately 50% of the fibrinolytic one, which makes this strain a promising producer of fibrinolytic enzymes.

Examining psychosocial correlates of physical activity and sedentary behavior in youth with and without HIV.

The objectives of this study were to examine differences in physical activity behaviors as a function of human immunodeficiency virus (HIV) status and sex, to test differences in physical activity self-efficacy (PASE), body weight satisfaction (BWS), and enjoyment of physical activity as a function of HIV status, and to determine if PASE, BWS, and enjoyment are associated with daily physical activity (daily PA), muscle strengthening activities, and sedentary behavior of youth with and without HIV. A total of 250 HIV positive (HIV+) and HIV negative (HIV-) youth from Botswana aged 12–23 years (Mean = 17.87, SD = 2.24) participated in the study. The HIV+ group (n = 88) was recruited from a previous 12-month antiretroviral therapy (ART) and nutrition intervention study. The HIV- group (n = 162) was randomly selected from public junior and senior (secondary) high schools in and around Gaborone. Participants’ PASE, BWS, enjoyment of physical activity, daily PA, muscle strengthening, body mass index (BMI), and sedentary behavior were obtained using items from the Youth Risk Behavior Surveillance Survey. Multivariate analysis of variance (MANOVA) showed that the HIV- group (M = 1.20, SE = 0.06, CI = 1.08 to 1.32) had significantly higher daily PA than the HIV+ group (M = 0.99, SE = 0.08, CI = 0.82 to 1.15). The HIV- group (M = 0.91, SE = 0.06, CI = 0.79 to 1.03) also reported participating significantly more in muscle strengthening activities than the HIV+ group (M = 0.63, SD = 0.08, CI = 0.47 to 0.78). Multiple regression analyses showed that higher PASE (p < .001) and greater enjoyment of PA (p < .01) were predictive of higher daily PA. HIV- participants had higher PASE but lower BWS compared to HIV+ participants. Sex and age differences were observed in muscle strengthening activities and sedentary behavior. This study supports previous findings on the association of efficacy beliefs to daily PA and muscle strengthening activities. The findings have implications for PA interventions aimed at health promotion and mitigation of the effects of living with HIV/AIDS.

Nomenclature of factor XI and the contact system

Nomenclature of factor XI and the contact system

Transcriptomic Analysis Links Eosinophilic Esophagitis and Atopic Dermatitis.

Background: Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking.Objectives: We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression.Methods: Whole-genome mRNA expression analyses were performed on tissue specimens (biopsies or nasal brushes) from patients with EoE, AD, and AA, and IL-13-stimulated primary human epithelial cells from the esophagus, the skin, and the airways.Results: By human disease expression profiles, EoE evidenced a significantly higher overlap (p = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%). Only 18 genes were found to be commonly dysregulated among the three diseases; these included filaggrin, histamine receptor H1, claudin 1, cathepsin C, plasminogen activator urokinase receptor, and suppressor of cytokine signaling 3. Ontogenetic analysis revealed a common immune/inflammatory response among the three diseases and a different epithelial response (epidermal cell differentiation) between EoE and AA. The overlap between the IL-13–stimulated epithelial cell transcriptome and the respective disease transcriptome was 22, 9, and 5% in EoE, AD, and AA, respectively, indicating a greater involvement of the IL-13 pathway in EoE than AA (p = 0.0007) or AD (p = 0.02).Conclusion: EoE, AD, and AA share a common set of disease-specific transcripts, highlighting common molecular etiology. Their comparative analysis indicates relatively closer relationships between EoE and AD, particularly centered around IL-13–driven pathways. Therefore, these findings provide an increased rationale for shared therapeutic strategies.

2-Hydroxymelatonin mitigates cadmium stress in cucumis sativus seedlings: Modulation of antioxidant enzymes and polyamines.

Cadmium level is continuously increasing in agricultural soils mainly due to anthropogenic activities. Cadmium is one of the most phytotoxic metals in the soils. The present study investigates the possible role of 2-hydroxymelatonin (2-OHMT) in assuagement of Cd-toxicity in cucumber (Cucumis sativus L.) plants. 2-OHMT is an important metabolite produced through interaction of melatonin with oxygenated compounds. Cadmium stress decreased the activity of antioxidant enzymes and polyamines. However, exogenously applied 2-OHMT enhanced plant growth attributes including photosynthetic rate, intercellular CO2 concentration, stomatal conductance and transpiration rate in treated plants. In addition, 2-OHMT induced enhancement of the activity of PAs biosynthesizing enzymes (putrescine, spermidine and spermine) in conjunction with reduction in activity of polyamine oxidase (PAO). 2-OHMT mitigated Cd stress through up-regulation in expression of stress related CS-ERS gene along with the amplified activity of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) in treated seedlings. The improved activity of antioxidant scavengers played central role in reduction of hydrogen peroxide (H2O2), electrolyte leakage (EL) and malondialdehyde (MDA) in plants under Cd stress. Recent findings also advocate the positive correlation between PAs and ethylene, as both possess common precursor. The current study reveals that priming seeds with 2-OHMT reduces Cd-toxicity and makes it possible to cultivate cucumber in Cd-contaminated areas. Future experiments will perhaps help in elucidation of 2-OHMT intervened stress mitigation procedure in C.sativus crop. Furthermore, research with reference to potential of 2-OHMT for stress alleviation in other horticultural and agronomic crops will assist in enhancement of crop productivity.

Identification of potential hub genes associated with the pathogenesis and prognosis of pancreatic duct adenocarcinoma using bioinformatics meta-analysis of multi-platform datasets.

Pancreatic duct adenocarcinoma (PDAC) is a highly malignant type of cancer with a low five-year survival rate. Gene alterations are crucial to the molecular pathogenesis of PDAC. Therefore, the present study analyzed gene expression profiles to reveal genes involved in the tumorigenesis of PDAC. A total of eight gene expression profiles (GSE15471, GSE16515, GSE41368, GSE62165, GSE62452, GSE71729, GSE71989 and GSE91035) and a PDAC dataset were acquired from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database, respectively. Differentially expressed genes (DEGs) were screened using functional annotation, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network construction. A Cox proportional hazards model was then constructed and used to analyze the data. A total of 136 DEGs (67 up- and 69 downregulated genes) were identified between PDAC tissues and normal tissues. The ‘extracellular matrix-related’ genes were the most enriched in the GO term analysis. ‘Pancreatic secretion’, ‘phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-Akt) signaling pathway’, ‘protein digestion and absorption’ and ‘ECM-receptor interaction’ were the most enriched categories in KEGG pathway analysis. Following PPI network construction, the 10 most significant genes [albumin, epidermal growth factor, matrix metalloproteinase (MMP) 9, epidermal growth factor receptor, fibronectin 1, MMP1, plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase 1, plasminogen activator urokinase (PLAU) and PLAU receptor) exhibiting a high degree of connectivity, were identified as the hub genes likely to be associated with the pathogenesis of PDAC. In addition, a prognostic predictive system for PDAC, composed of five genes (laminin subunit γ 2, laminin subunit β 3, serpin family B member 5, amphiregulin and secreted frizzled related protein 4), was constructed. This was validated in the GSE62452 dataset (using 66 PDAC samples with outcome data) and TCGA PDAC dataset (using 146 PDAC samples with outcome data). In conclusion, the present study revealed potential hub genes involved in PDAC progression, providing directive significance for individualized clinical decision-making and molecular-targeting therapy in patients with PDAC.

Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system

Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonstrate that PFD reduces proliferation, 2D- and 3D-migration as well as colony formation of the non-small-cell lung carcinoma (NSCLC) cells. On a molecular level, we show that PFD on the one hand interacts with plasminogen activator inhibitor-1 (PAI-1; Kd of 46.2±11.3nM) and affects its inhibitory potency, but on the other hand it also increases PAI-1 expression; in both cases consequently leading to the reduction of urokinase (uPA) activity. Finally, we report that the effect of PFD on 2D-migration of NSCLC cells depends on PAI-1 expression and thus on the activity of the uPA system whereas the PFD-induced changes in cancer cell proliferation, 3D-migration and colony formation are PAI-1 independent. To conclude, a direct interference of PFD with the uPA-PAI-1 system may deregulate pericellular proteolytic activity and thereby influence the stability of the tumor blood vessels and the matrix architecture within tumor stroma.

Daytime Dynamics of the Photosynthetic Apparatus’ Structural and Functional Parameters in Wild Halophytes

Dynamics of the photosynthetic apparatus' (PA) structural and functional parameters during the day was investigated in euhalophyte Salicorniaperennans Willd., crynohalophyte Limoniumgmelinii (Willd.) O. Kuntze, and glycohalophyte Artemisiasantonica L. The greatest PA activity judging from the rate of СО2 consumption/release by the leaves was observed in the morning. In salt-accumulating (S. perennans) and salt-eliminating (A. santonica) species, the rate of photosynthesis was greater than in L. gmelinii plants possessing the systems of salt excretion. In A. santonica and S. perennans, the content of green pigments decreased during the day, while it remained permanent in L. gmelinii. During the day, the ratio between plastid lipids and pigments increased in A. santonica and S. perennans. In chloroplast lipids from S. perennans, a decrease in the relative content of monogalactosyldiacylglycerol (MGDG) was compensated for by a rise in relative content of digalactosyldiacylglycerol (DGDG), with the contribution of sulfoquinovosyldiacylglycerol (SQDG) and phosphatidylglycerol (PG) remaining the same. In the chloroplasts from L. gmelinii, the proportion of neutral lipids MGDG and DGDG did not change in contrast to the level of anionic lipids SQDG and PG. In A. santonica, we detected changes in both neutral and anionic lipids. A high proportion of unsaturated FA (UFA) (over 70%) in the total pool of FA was mainly accounted for by α-linolenic acid. It was found that the proportion of saturated FA tended to increase in the evening. All the revealed structural and functional reorganizations of PA associated with fluctuation of pigment-lipid resources of thylakoid membranes were adaptive and aimed at optimization of photosynthesis under specific environmental conditions.

Urokinase receptor and tissue plasminogen activator as immediate-early genes in pentylenetetrazole-induced seizures in the mouse brain.

Epileptogenesis progressively leads to the rearrangement of normal neuronal networks into more excitable ones and can be viewed as a form of neuroplasticity, the molecular mechanisms of which still remain obscure. Here, we studied pentylenetetrazole seizure-induced regulation of genes for plasminogen activator system in the mouse brain. We found that expression of tissue plasminogen activator (tPA) and urokinase receptor (uPAR) mRNA was strongly increased in the mouse cerebral cortex, hippocampus, striatum and amygdala as early as 3hr after pentylenetetrazole seizures. Such early activity-induced expression of uPAR in the central nervous system has not been demonstrated before. uPAR mRNA accumulation was followed by elevation of uPAR protein, indicating a complete transcription-translation process. Both tPA gene induction and uPAR gene induction were independent of the protein synthesis, suggesting that they are regulated by neural activity as immediate-early genes. In contrast to tPA and uPAR genes, the expression of which returned to the basal level 6hr following seizures, urokinase and plasminogen activator inhibitor-1 gene expression showed a delayed activation only at 3days after seizures. In conclusion, our results suggest an important sensitivity of the brain plasminogen activator system to seizure activity which raises the question of its role in activity-dependent neural tissue remodeling in pathological and normal conditions.

The Effects of a Novel Series of KTTKS Analogues on Cytotoxicity and Proteolytic Activity.

KTTKS is a matrikine that originates from the proteolytic hydrolysis of collagen. This peptide stimulates ECM production and types I and III collagen expression in vitro. A more stable form of KTTKS is pal-KTTKS, known as Matrixyl® or palmitoyl pentapeptide-3. A series of novel pentapeptides, analogues of KTTKS with the general formula X-KTTKS-OH(NH2), where X = acetyl, lipoyl, palmitoyl residues, was designed and synthesized. Their effect on amidolytic activity of urokinase, thrombin, trypsin, plasmin, t-PA, and kallikrein were tested. Cytotoxic tests on fibroblasts, as well as collagen and DNA biosynthesis tests for selected peptides, were also carried out. The test results showed that the most active plasmin inhibitors were palmitoyl peptides, whether in acid or amide form. No biological effects of lysine modification to arginine in the synthesized peptides were found. None of the synthesized peptides was not cytotoxic on fibroblasts, and three of them showed cell growth. These three compounds showed no concentration-activity relationship in the collagen and DNA biosynthesis assays.

5949Interleukin-6 and growth differentiation factor-15 in hypertensive heart failure

Abstract Background Hypertension is the leading cause for the development of heart failure (HF). Increased hemodynamic load, including mechanical stretch and neurohumoral factors, is able to trigger hypertrophic growth of cardiac myocytes. Although hypertensive HF is prevalent, there is no useful biomarker to identify HF due to chronic hypertension. Aims To identify plasma markers associated with incidence of hypertensive HF. Methods Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4469 individuals from the Malmö Diet and Cancer study. Protein levels were compared to stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVM) in response to 1, 4, 12, 24 or 48 hours of cyclic mechanical stretch. Association between plasma proteins level and HF incidence and hypertension was studied using respectively Cox proportional hazards model and binary logistic regressions. Results After Bonferroni correction, 44 circulating proteins were significantly differentially expressed in individuals who developed HF during follow-up versus controls (P&lt;3.4E-4). Out of these, 5 proteins (Interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF15), Interleukin-1 Receptor-Like-1 (ST2), Plasminogen Activator Urokinase Receptor (U-PAR), Transforming Growth Factor-α (TGF-α)), corresponding mRNA levels were upregulated by mechanical stretch in NRVM at all time points (P&lt;0.05). Similar upregulation for the 5 proteins was shown in hypertensive versus normotensive individuals (P≤8.05E-4). In a model with all 5 proteins entered simultaneously, GDF15 and IL-6 were predictive of incident HF after adjustment for age, sex and NT-BNP levels (205 events; hazard ratio [HR] per SD increment of protein: HR=1.29, CI=1.05–1.58, P=0.013 and HR=1.16, CI=1.02–1.33, P=0.028). Using the same model, IL-6 but not GDF15 associated with hypertension (Odds ratio [OR] per SD increment of IL-6: OR=1.18, CI=1.09–1.27, P=3.3E-5). In hypertensive individuals GDF15 and IL-6 were individually predictive of future HF after adjustment for age, sex, NT-BNP levels, smoking, BMI and diabetes (183 events; HR=1.36, CI=1.16–1.60, P=1.64E-4 and HR=1.21, CI=1.05–1.40, P=0.008). Furthermore, in these hypertensive individuals, GDF15 and IL-6 were predictive of HF in a model with IL-6, GDF15, ST2 and TGF-α entered simultaneously after adjustment for age, sex and NT-BNP levels (176 events; HR=1.36, CI=1.13–1.64, P=0.001 and HR=1.16, CI=1.01–1.34, P=0.041). Conclusions Circulating levels of IL-6 and GDF15 might be used as NT-BNP independent biomarkers for HF development in hypertensive patients. Acknowledgement/Funding Påhlsson, Crafoord, Lundström, Åke Wiberg, Royal Physiographic Society and the Swedish Foundation for Strategic Research for IRC15-0067

Fiber-Reinforced Silk Composite for Enhanced Urokinase Production Using High-Density Perfusion Culture and Bioactive Molecule Supplementation.

Urokinase plasminogen activator (uPA) has been extensively used as a thrombolytic drug in cases of myocardial infarction, thromboembolism, and ischemic brain stroke. Media optimization and high-density perfusion culture are the decisive factors that facilitate enhanced urokinase production in a conditioned medium. In this study, we have aimed for a high-density perfusion culture of HT1080, a human fibrosarcoma cell line, by formulating optimal media for enhanced urokinase productivity. Four scaffold variants were fabricated from silk fibroin and microfibers of Bombyx mori (BM) and Antheraea assamensis (AA) and physico-chemically characterized. Field emission scanning electron microscopy studies revealed a heterogeneous distribution of pores with interconnected networks supporting cell infiltration, attachment, and long-term viability. AA-based fiber-reinforced scaffolds (ASAF) demonstrated superior mechanical strength, integral stability, and increased cell proliferation as compared to pure silk scaffolds. Media formulation was accomplished by limiting serum concentration (2% FBS) and supplementing with 20 μg/mL arginine and 20 ng/mL TGF-β1 to retain the stationary phase of cells and augment the urokinase production. A perfusion bioreactor culture of HT1080-laden scaffolds in the presence of formulated media was performed for improving the production of urokinase, with a maximum activity of 432 U/L. Also, gene expression analysis revealed that the individual silk scaffolds have different effects on regulating the expression of plasminogen activator urokinase and plasminogen activator urokinase receptor. In brief, our results suggest that a perfusion bioreactor culture of HT1080-laden ASAF scaffolds in formulated media promotes an increased urokinase production, such that it can be further used as a novel 3D matrix platform for industrial production of the lifesaving uPA drug.

Induction of Urokinase Activity by Retinoic Acid in Two Cell Lines of Neuronal Origin.

Retinoic acid is one of the most well-known agents able to induce differentiation in several types of tumours. Unfortunately, most of the tumours are refractive to the differentiation cues. The aim of this investigation was to analyse the effects of prolonged treatment with retinoic acid on two cell lines of neural origin refractive to differentiation. Cells were also treated with retinoic acid in combination with a poly(ADP-ribosyl) polymerase (PARP) inhibitor because PARP1 is a known chromatin modulator and can influence the process of differentiation. The main methods comprised tumour cell line culturing and treatment; analysis of RNA and protein expression after cell treatment; as well as analysis of urokinase activity, migration, and proliferation. Both cell lines continued to proliferate under the prolonged treatment and showed increase in urokinase plasminogen activator activity. Analysis of gene expression and cell phenotype revealed different mechanisms, which only in neuroblastoma H4 cells could indicate the process of epithelial-mesenchymal transition. The data collected indicate that the activity of the urokinase plasminogen activator, although belonging to an extracellular protease, does not necessary lead to epithelial-mesenchymal reprogramming and increase in cell migration but can have different outcomes depending on the intracellular milieu.

Serum plasminogen activator urokinase receptor predicts elevated risk of acute respiratory distress syndrome in patients with sepsis and is positively associated with disease severity, inflammation and mortality.

The present study aimed to evaluate the predictive value of serum soluble urokinase plasminogen activator receptor (suPAR) regarding the risk of acute respiratory distress syndrome (ARDS) in sepsis patients, and investigate its correlation/association with disease severity, inflammation and mortality in sepsis patients with ARDS. A total of 57 sepsis patients with ARDS and 58 sepsis patients without ARDS were recruited for the present case-control study. Laboratory tests, acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score were evaluated, and mortality during hospitalization was recorded. Blood samples were collected and serum suPAR was detected by ELISA. Furthermore, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17, as well as C-reactive protein (CRP) were detected. The results indicated that the serum levels of suPAR in sepsis patients with ARDS were higher than those in sepsis patients without ARDS. Receiver operating characteristics (ROC) curve analysis indicated that it was possible to distinguish sepsis patients with ARDS from sepsis patients without ARDS based on their serum suPAR levels, and multivariate logistic regression analysis suggested that serum suPAR levels were an independent predictor of the risk of ARDS in sepsis patients. In sepsis patients with ARDS, serum suPAR levels were positively correlated with the APACHE II score, SOFA score and the levels of CRP, TNF-α, IL-1β and IL-8. In addition, serum suPAR levels were lower in survivors compared with those in non-survivors, and ROC curve analysis suggested that serum suPAR was able to predict the probability of mortality. In conclusion, serum suPAR independently predicted an elevated risk of ARDS in patients with sepsis, and was correlated/associated with greater disease severity, higher inflammation and increased mortality in patients with sepsis and ARDS.

Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor.

Breast cancer cells experience a range of shear stresses in the tumor microenvironment (TME). However most current in vitro three-dimensional (3D) models fail to systematically probe the effects of this biophysical stimuli on cancer cell metastasis, proliferation, and chemoresistance. To investigate the roles of shear stress within the mammary and lung pleural effusion TME, a bioreactor capable of applying shear stress to cells within a 3D extracellular matrix was designed and characterized. Breast cancer cells were encapsulated within an interpenetrating networkhydrogel and subjected to shear stress of 5.4 dynes cm-2 for 72 hr. Finite element modeling assessed shear stress profiles within the bioreactor. Cells exposed to shear stress had significantly higher cellular area and significantly lower circularity, indicating a motile phenotype. Stimulated cells were more proliferative than static controls and showed higher rates of chemoresistance to the anti-neoplastic drug paclitaxel. Fluid shear stress-induced significant upregulation of the PLAU gene and elevated urokinase activity was confirmed through zymography and activity assay. Overall, these results indicate that pulsatile shear stress promotes breast cancer cell proliferation, invasive potential, chemoresistance, and PLAU signaling.

MicroRNA-193a-3p suppresses the colorectal cancer cell proliferation and progression through downregulating the PLAU expression.

BackgroundColorectal cancer (CRC) is one of the leading causes of cancer-related death in China. Dysregulation of microRNAs (miRNAs) is involved in cancer development and progression. Our previous study showed an inverse relationship between miR-193a-3p expression and the prognosis of CRC. However, the exact biological functions of miR-193a-3p in CRC are still poorly understood. This study aimed to explore the role and mechanism of miR-193a-3p in CRC.MethodsReal-time PCR and Western blotting were used to examine the expression levels of RNA and protein, respectively. A dual luciferase assay was performed to validate predicted targets of miR-193a-3p. Loss and gain-of-function studies were carried out to reveal the effects and potential mechanism of the miR-193a-3p in the proliferation, metastasis and angiogenesis of CRC cells.ResultsThe expression levels of miR-193a-3p in human CRC cell lines were significantly decreased compared with that in normal colonic epithelium cell line. Furthermore, plasminogen activator urokinase (PLAU) was validated as a direct target gene of miR-193a-3p. Over-expression of miR-193a-3p inhibited proliferation, migration and angiogenesis of HT-29 cell, whereas forced expression of PLAU could rescue the inhibitory effects.ConclusionmiR-193a-3p might inhibit CRC cell growth, migration and angiogenesis partly through targeting PLAU. MiR-193a-3p/PLAU axis might provide a potent therapeutic opportunity for aggressive CRC.

Synthesis and Antibacterial Activities of Novel Hg(II) and Zn(II) Complexes of Bis(Thiosemicarbazone) Acenaphthenequinone Loaded to MWCNTs

This paper describes a series of new polyamides containing bis(thiosemicarbazone) acenaphthenequinone (PA), bis(thiosemicarbazone) acenaphthenequinone zinc (Z-PA), and bis(thiosemicarbazone) acenaphthenequinone mercury (H-PA) complexes loaded onto MWCNTs synthesized via a chemical precipitation method in methanol followed by antimicrobial activity studies on the novel functionalized MWCNTs complexes. These complexes are characterized by FT-IR spectroscopy, powder X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The antibacterial activity of free PA, Z-PA, and H-PA complexes loaded onto MWCNTs are studied against gram-positive and gram-negative bacteria. The results indicate that the HPA/MWCNT complex is the most effective growth inhibitor against Listeria monocytogenes and Pseudomonas aeruginosa, exhibiting the potential for the use as an antibacterial agent.

Induction of cell fusion/apoptosis in anaplastic thyroid carcinoma in orthotopic mouse model by urokinase-specific oncolytic Sendai virus.

This study was designed to assess the therapeutic effect of urokinase-targeted recombinant oncolytic Sendai virus, termed "BioKnife," on anaplastic thyroid carcinoma (ATC). Urokinase activity was investigated in human ATC cell lines, and BioKnife cytotoxicity against the cell lines was evaluated in vitro. Orthotopic mouse models of ATC were treated with three intratumoral injections of BioKnife, control virus, or phosphate-buffered saline (PBS) and were observed daily until >20% weight loss occurred. All three ATC cell lines showed a high level of urokinase activity. BioKnife induced urokinase-dependent cell fusion and cytotoxicity in all cell lines. Orthotopic models treated with BioKnife showed significantly prolonged survival compared with models treated with control virus or PBS (BioKnife 41.6 ± 15.0, control virus 17.0 ± 2.9, PBS 17.7 ± 6.3 days). BioKnife exerted therapeutic effects in orthotopic ATC mouse models. Thus, BioKnife represents a possible treatment option for ATC.