Effect of chinese traditional herb Epimedium grandiflorum C.Morren and its extract Icariin on osteoarthritis via suppressing NF-kB pathway.

Osteoarthritis (OA), which is also called degenerative arthritis, is the leading cause of disabilities in the old people. The Chinese traditional herb Epimedium grandiflorum had long been found to attenuate osteoarthritis process, but the detailed mechanism was not clear. To study the mechanisms of E. grandiflorum in the treatment of osteoarthritis, rabbit osteoarthritis model combined with D-galactose was used. After different treatments for 10 weeks, cartilage sections were analyzed by immunohistochemistry for uPA, uPAR and PAI expression level. E. grandiflorum could significantly attenuate OA condition and decrease uPA, uPAR and PAI expression. The extract of E. grandiflorum, icariin also had a similar effect when compared with E. grandiflorum treatment alone. Rabbit chondrocytes were further isolated to be stimulated by TNFα combined with different reagents treatment. Here, icariin treatment significantly reduced nuclear factor kappa B NF-B (P65) activity, decreased uPA expression level and increased IBα protein level. The results indicated that E. grandiflorum and its extract icariin could attenuate OA condition, reduce the expression of uPA and uPAR and increase PAI in experimental rabbit model and this effect may be conducted by suppressing NF-kB activity by increasing IkBα level.

Relation of serum vascular endothelial growth factor as an angiogenesis biomarker with nitric oxide & urokinase-type plasminogen activator in breast cancer patients.

BACKGROUND & OBJECTIVE: The primary mediator of angiogenesis is vascular endothelial growth factor (VEGF). It is well documented that angiogenic activity in human cancer depends on nitric oxide (NO) levels in tissues. Additionally, urokinase type plasminogen activator (u-PA) plays a role in cell adhesion and migration. Serum VEGF and its relationship between NO and u-PA concentrations are poorly reported in breast cancer patients. The aim of this study was to investigate the relationship between serum levels of VEGF and NO and u-PA in patients with breast cancer. METHODS: Serum concentrations of VEGF, NO and u-PA were measured in groups of pre-operative breast cancer patients without metastasis (n=20), post-operative breast cancer patients without metastasis (four wk after the operation, n=20), breast cancer patients with metastasis (n=23), patients with benign breast disease (n=11) and healthy female controls (n=20). RESULTS: There was no difference in serum concentrations of VEGF, NO and u-PA between controls and patients with benign breast disease. Serum VEGF, NO and u-PA concentrations were significantly higher in pre-operative breast cancer patients than in controls and in patients with benign breast diseases (P<0.01). Post-operative breast cancer patients without metastasis had significantly lower serum VEGF and u-PA concentrations than the pre-operative patients (P<0.01). In breast cancer patients with metastasis, serum VEGF, and u-PA were significantly higher than post-operative nonmetastatic patients (P<0.01). Serum VEGF concentrations were positively correlated with serum uPA in all of the patients groups (r=0.886, P<0.01). Serum VEGF levels were positively correlated with serum NO levels in breast cancer patients with metastasis (r= 0.386, P<0.05). INTERPRETATION & CONCLUSION: Our results demonstrated that the angiogenic activity was increased in patients with breast cancer. Elevated VEGF levels as an angiogenesis marker may be associated with uPA. VEGF, NO and uPA seem to be associated with the angiogenetic and metastatic process of breast cancer.

Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines

The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (c-Met), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time- and dose- dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.

A study of the interaction between Helicobacter pylori and components of the human fibrinolytic system

The interaction of plasminogen, tissue plasminogen activator (t-PA) and urokinase with a clinical strain of Helicobacter pylori was studied. Plasminogen bound to the surface of H. pylori cells in a concentration-dependent manner and could be activated to the enzymatic form, plasmin, by t-PA. Affinity chromatography assays revealed a plasminogen-binding protein of 58.9 kDa in water extracts of surface proteins. Surface-associated plasmin activity, detected with the chromogenic substrate CBS 00.65, was observed only when plasminogen and an exogenous activator were added to the cell suspension. The two physiologic plasminogen activators, t-PA and urokinase, were also shown to bind to and remain active on the surface of bacterial cells. epsilon-Aminocaproic acid caused partial inhibition of t-PA binding, suggesting that the kringle 2 structure of this activator is involved in the interaction with surface receptors. The activation of plasminogen by t-PA, but not urokinase, strongly depended on the presence of cells and a 25-fold enhancer effect on the initial velocity of activation by t-PA compared to urokinase was established. Furthermore, a relationship between cell concentration and the initial velocity of activation was demonstrated. These findings support the concept that plasminogen activation by t-PA on the bacterial surface is a surface-dependent reaction which offers catalytic advantages

Plasminogen activation and breast cancer

Plasminogen activation is a widespread cellular mechanism for localized extracellular proteolysis that is postulated to participate in many diverse physiological and pathological phenomena. The present review in intended as an introduction to the subject, and is by no means comprehensive, except for the section on breast cancer. Seral extensive reviews are available that should be consulted by intersted readers (1-6).