Endometriosis, an oestrogen-dependent disorder, is related to inflammation, p38 Mitogen activated protein kinases (p38 MAPK) can be activated by sex hormone and inflammatory factors, which plays an important role in many cellular reactions such as apoptosis, proliferation, inflammation and stresses, etc. Many studies showed that p38 MAPK was participated directly in regulating the pathogenesis of endometriosis. The special regulatory action of p38 MAPK on sex hormone and inflammation may help us to understand the intricate endometriosis pathological hypothesis. p38 MAPK inhibitors play a key role in the the study of endometriosis, and show great promise for the future. Blocking and regulating the expression of p38 MAPK on the signal transduction pathway level may hope to be a new strategy to prevent and treat endometriosis.
Animals ; Anti-Inflammatory Agents, Non-Steroidal ; pharmacology ; therapeutic use ; Endometriosis ; drug therapy ; metabolism ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Female ; Humans ; Imidazoles ; pharmacology ; Inflammation ; drug therapy ; metabolism ; Pyrazoles ; therapeutic use ; Pyridines ; pharmacology ; therapeutic use ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism ; pharmacology

BACKGROUNDGrowing preclinical evidence shows that zoledronic acid (ZOL) exhibits direct antitumor activity in various cancer cell lines. However, the cytotoxic effects of ZOL on human hepatocellular carcinoma (HCC) cells have not been established. In the present study, we investigated the effect of ZOL on HCC both in vitro and in vivo.

METHODSCytotoxicity and cell cycles were assessed with Sulforhodamine B colorimetric assay and flow cytometry. Expression levels of cell cycle phase-linked proteins were examined. The effect of ZOL on HCC in vivo was explored based on H22-subcutaneous injection (s.c.) and H22-intraperitoneal injection (i.p.) mice model.

RESULTSZOL inhibited the growth of SK-HEP-1 and H22 cells and induced S-phase arrest through downregulating cdc2 protein and upregulating cyclin A. It inhibited the growth of s.c tumors, and increased the survival of both H22-s.c. and H22-i.p. mice in vivo.

CONCLUSIONZOL inhibits growth of HCC cells in vitro and in vivo.

Animals ; Carcinoma, Hepatocellular ; drug therapy ; pathology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Diphosphonates ; pharmacology ; therapeutic use ; Female ; Humans ; Imidazoles ; pharmacology ; therapeutic use ; Liver Neoplasms ; drug therapy ; pathology ; Mice ; Xenograft Model Antitumor Assays

OBJECTIVETo observe the effect and mechanisim of zoledronate sodium on periprosthetic osteolysis in rat induced by polyethylene particles.

METHODSTotal 30 adult male SD rats, weighting from 250 to 300 g, were selected and randomly divided into three groups: blank control group, model control group and zoledronate sodium group respectively, 10 animals for each group. No treatment was performed in the blank control group. In model control group and zoledronate sodium group, the modle of periprosthetic osteolysis in rats were made by implanting polyethylene particles and titanium rods into their right femurs. After operation, rats in zoledronate sodium group were administered with zoledronate sodium (0.1 mg/kg each week) through subcutaneous injection for 8 weeks, then the blood was obtained and all experimental animals were sacrificed to get the right femur specimens. The femur BMD, IL-1β, IL-6, TNF-α, serum TRACP5b and CTX-I were detected.

RESULTSCompared with the model control group, the femur BMD was increased, while IL-1β, IL-6 and TNF-α were all decreased in zoledronate sodium group; the serum TRACP5b and CTX-I level were both reduced in zoledronate sodium group.

CONCLUSIONThe zoledronate sodium could effectively inhibit periprosthetic osteolysis in rats induced by polyethylene particles, which might be realized by inhibiting the activity of osteoclasts and the expression of IL-1β, IL-6 and TNF-α. It provides a new method to treat periprosthetic osteolysis of the artificial joint prosthesis.

Animals ; Bone Density ; drug effects ; Collagen Type I ; analysis ; Cytokines ; analysis ; Diphosphonates ; therapeutic use ; Imidazoles ; therapeutic use ; Joint Prosthesis ; Male ; Osteolysis ; drug therapy ; Peptides ; analysis ; Polyethylene ; pharmacology ; Rats ; Rats, Sprague-Dawley

Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs.
AC133 Antigen/genetics/metabolism ; Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromones/pharmacology/therapeutic use ; Colorectal Neoplasms/drug therapy/metabolism/pathology ; Humans ; Imidazoles/pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Morpholines/pharmacology/therapeutic use ; Neoplastic Stem Cells/cytology/drug effects/metabolism ; Paclitaxel/pharmacology/therapeutic use ; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors/metabolism ; Quinolines/pharmacology/therapeutic use ; SOXB1 Transcription Factors/genetics/metabolism ; Signal Transduction/*drug effects ; Sirolimus/pharmacology/therapeutic use ; TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Xenograft Model Antitumor Assays

OBJECTIVETo observe the effect of intra-articular injection of SB203580, a selective p38 mitogen-activated protein kinase inhibitor, on the expression of matrix metalloproteinase (MMP)-3, MMP-13 in a rat model of osteoarthritis (OA) and to explore the relationship between the MMP-3/MMP-13 expressions and the severity of OA.

METHODSFourty SD rats underwent unilateral anterior cruciate ligament transection (ACLT) and then randomly divided into four groups, with 10 rats in each group. Group A received 0.1 ml intra-articular injection of SB203580 at a high concentration of 100 micromol/L (once a week) immediately after surgery, and group B were treated under the same condition using SB203580 with a low concentration of 10 micromol/ L Group C received 0.1 ml intra-articular normal saline, and group D were not injected as controls after ACLT. All rats were sacrificed seven weeks after the surgery. Macroscopic and immunohistochemical studies were performed on the cartilage. Protein expressions of MMP-3 and MMP-13 were determined by Western blot. RESULTS Cartilage degradation was significantly milder in group A and group B than in the control groups, as shown by morphological studies (P < 0. 05) and immunohistochemical studies (P < 0. 05). The protein expressions of MMP-3 and MMP-13 in cartilage were significantly lower in groups A and B than in groups C and D (P < 0.01).

CONCLUSIONSB203580 can inhibit the expressions of MMP-3 and MMP-13 and thus protect the cartilage.

Animals ; Cartilage, Articular ; drug effects ; enzymology ; Imidazoles ; administration & dosage ; pharmacology ; therapeutic use ; Injections, Intra-Articular ; Matrix Metalloproteinase 13 ; metabolism ; Matrix Metalloproteinase 3 ; metabolism ; Matrix Metalloproteinases, Secreted ; metabolism ; Osteoarthritis ; drug therapy ; enzymology ; Protein Kinase Inhibitors ; administration & dosage ; pharmacology ; therapeutic use ; Pyridines ; administration & dosage ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors

BACKGROUNDThe microemboli produced during spontaneous plaque rupture and ulceration and during coronary intervention will reduce coronary reserve and cause cardiac dysfunction. It is though that inflammation caused by the microinfarction induced by the microembolization may play an essential role. It is known that the activation of p38 mitogen-activated protein kinases (MAPK) in both infected and non-infected inflammation in myocardium may cause a contractile dysfunction. But the relation between the activation of p38 MAPK and microembolization is still unknown.

METHODSSprague-Dawley rats were randomly divided into three groups: Sham group, coronary microembolization (CME) group and SB203580 group (n = 10 per group). CME rats were produced by injection of 42 µm microspheres into the left ventricle with occlusion of the ascending aorta. SB203580, a p38 MAPK inhibitor, was injected into the femoral vein after the injection of microspheres to make the SB203580 group. Left ventricular ejection fraction (LVEF) was determined by echocardiography. The protein concentration of P38 MAPK in the myocardium was assessed by Western blotting. The relative expression of mRNA for tumor necrosis factor (TNF)-α was assessed by the technique of semi-quantitative polymerase chain reaction amplification.

RESULTSLVEF was depressed at three hours up to 12 hours in the CME group. Increased p38 MAPK activity and TNF-α mRNA expression were observed in the CME group. The administration of SB203580 partly inhibited p38 MAPK activity, but did not fully depress the TNF-α expression, and partly preserved cardiac contractile function.

CONCLUSIONSp38 MAPK is significantly activated by CME and the inhibition of p38 MAPK can partly depress the TNF-α expression and preserve cardiac contractile function.

Animals ; Blotting, Western ; Coronary Disease ; drug therapy ; etiology ; metabolism ; Echocardiography ; Embolism ; complications ; Imidazoles ; pharmacology ; therapeutic use ; Immunohistochemistry ; Microcirculation ; drug effects ; Myocardial Contraction ; drug effects ; physiology ; Myocardium ; metabolism ; Pyridines ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha ; genetics ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism

Angiogenesis is considered to be an integral process to the growth and spread of solid tumors. Anti-angiogenesis therapy recently has been found to be one of the most promising anti-cancer therapeutic strategies. In this study, we provide several lines of evidences showing that KR-31831, a new benzopyran derivative, has anti-angiogenic activities. KR-31831 inhibited the proliferation, migration, invasion and tube formation of bovine aortic endothelial cells (BAECs), and suppressed the release of matrix metalloproteinase-2 (MMP-2) of BAECs. KR-31831 also inhibited in vivo angiogenesis in mouse Matrigel plug assay. Furthermore, the mRNA expressions of basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-2 (FGFR-2), and vascular endothelial growth factor receptor-2 (VEGFR-2) were decreased by KR-31831. Taken together, these results suggest that KR-31831 acts as a novel angiogenesis inhibitor and might be useful for treating hypervascularized cancers.
Vascular Endothelial Growth Factor Receptor-2/metabolism ; Receptor, Fibroblast Growth Factor, Type 2/metabolism ; Neovascularization, Physiologic/drug effects ; Neovascularization, Pathologic/*drug therapy ; Models, Biological ; Mice, Inbred C57BL ; Mice ; Matrix Metalloproteinase 2/metabolism ; Male ; Ischemia/drug therapy ; Imidazoles/*pharmacology/therapeutic use ; Fibroblast Growth Factor 2/metabolism ; Endothelial Cells/drug effects ; Cells, Cultured ; Cell Movement/drug effects ; Cattle ; Benzopyrans/*pharmacology/therapeutic use ; Animals ; Angiogenesis Inhibitors/*pharmacology/therapeutic use

PURPOSE: Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to exhibit antitumor effects in various cancers apart from nasopharyngeal cancer (NPC). NPC exhibits high invasiveness, as well as metastatic potential, and patients continue to suffer from residual, recurrent, or metastatic disease even after chemoradiation therapy. Therefore, new treatment strategies are needed for NPC. In this study, we investigated the efficacy and molecular mechanisms of TA in NPC treatment. MATERIALS AND METHODS: TA-induced cell death was detected by cell viability assay in the NPC cell lines, HNE1 and HONE1. Wound healing assay, invasion assay, and Western blot analysis were used to evaluate the antitumor effects of TA in NPC cell lines. RESULTS: Treatment with TA suppressed the migration and invasion of HNE1 and HONE1 cells. Hepatocyte growth factor enhanced the proliferation, migration, and invasion abilities of NPC cells. This enhancement was successfully inhibited by TA treatment. Treatment with TA increased phosphorylation of p38, and the inhibition of p38 with SB203580 reversed the cytotoxic, anti-invasive, and anti-migratory effects of TA treatment in NPC cell lines. Moreover, inhibition of p38 also reversed the decrease in expression of Slug that was induced by TA treatment. CONCLUSION: In conclusion, the activation of p38 plays a role in mediating TA-induced cytotoxicity and inhibition of invasion and migration via down-regulation of Slug.
Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cell Proliferation/*drug effects ; Cell Survival/*drug effects ; Down-Regulation ; Gastropoda ; Gene Expression Regulation, Neoplastic/drug effects ; Hepatocyte Growth Factor/metabolism/*pharmacology ; Humans ; Imidazoles ; MAP Kinase Signaling System/drug effects ; Nasopharyngeal Neoplasms/*drug therapy/metabolism/pathology ; Neoplasm Invasiveness/*prevention & control ; Phosphorylation/drug effects ; Pyridines ; ortho-Aminobenzoates/*pharmacology/therapeutic use

OBJECTIVETo assess the role of p38 mitogen-activated protein kinases (p38MAPK) in the protective effect of remifentanil preconditioning (RPC) on hepatic ischemia-reperfusion injury in rats.

METHODSNinety-six male SD rats were randomly assigned into sham-operated group, ischemia-reperfusion group (I/R group), RPC group, and SB (an inhibitor of p38 MAPK) +RPC group. The rats were sacrificed at the end of reperfusion, and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured. HE staining was used to observe the hepatic histopathological changes, and Western blotting was employed to examine p38MAPK and pp38MAPK protein expression. TUNEL staining was used to examine cell apoptosis in the liver tissues.

RESULTSCompared with sham-operated group, I/R group showed significantly increased serum levels of AST, ALT, TNF-α and IL-1β with obvious histopathological changes and cell apoptosis in the liver. RPC significantly decresed the elevated serum levels of AST, ALT, TNF-α and IL-1β and lessened hepatic histopathological changes, and caused reduced p38MAPK phosphorylation and hepatic cell apoptosis index. The protective effects of RPC were abolished by SB 203580 pretreatment.

CONCLUSIONRPC attenuates the production of inflammatory factors by activating p38MAPK signal pathway to improve hepatic ischemia-reperfusion injury, and these effects can be blocked by SB203580, a p38MAPK inhibitor.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Imidazoles ; pharmacology ; Interleukin-1beta ; blood ; Ischemia ; physiopathology ; Ischemic Preconditioning ; methods ; Liver ; blood supply ; MAP Kinase Signaling System ; Male ; Piperidines ; therapeutic use ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid ; agonists ; Reperfusion Injury ; prevention & control ; Tumor Necrosis Factor-alpha ; blood ; p38 Mitogen-Activated Protein Kinases ; metabolism

Binding of viruses to cell surface molecules is an essential step in viral infection. In vitro studies suggested that the alpha v beta3 integrin receptor is the epithelial cell receptor for Hantaan virus (HTNV). Whether beta3 is in vivo the only or central cellular receptor for HTNV infection is not known. To investigate the role of beta3 integrin for cellular entry of HTNV, we established an HTNV infection model in newborn murine pups. Infected pups died at an average age of 14.2 +/- 1.1 days with high levels of viral antigen detected in their brain, lung, and kidney. Pre-injection of blocking monoclonal antibodies (mAb) specific for either beta3 or av prolonged survival significantly to a maximal average survival of 19.7 +/- 1.5 days (P<0.01) and 18.4 +/- 0.9 days (P<0.01), respectively. XT-199, a chemical blocker of the alpha v beta3 receptor also prolonged survival to 19.5 +/- 1.3 days (P<0.01). In contrast to these receptor blockades, anti-HTNV antibody was not only able to prolong survival, but 20% of infected pups achieved long-term survival. An anti-murine beta1 antibody comparatively prolonged survival (19.0 +/- 1.2 days), suggesting that HTNV infection is partly mediated through integrin beta1 receptors as well as through beta3 receptors in vivo. Our data demonstrate that the beta3 receptor is important for HTNV infection in vivo, but also suggest that HTNV may utilize additional receptors beyond beta3 for cellular entry within an organism.
Animals ; Animals, Newborn ; Antibodies, Monoclonal/therapeutic use ; Antigens, CD29/metabolism ; Hantaan virus/*metabolism/pathogenicity ; Hemorrhagic Fever with Renal Syndrome/mortality/*virology ; Imidazoles/pharmacology ; Integrin alphaV/metabolism ; Integrin alphaVbeta3/antagonists & inhibitors ; Integrin beta3/*metabolism ; Mice ; Receptors, Virus/*metabolism ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.