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Purpose: To investigate the anti-asthmatic effect of laurotetanine on allergic asthma rat model. Methods: Laurotetanine was extracted from the roots of Litsea cubeba (Lour.) Pers. Asthma was induced in rats by ovalbumin injection. Laurotetanine (20, 40, or 60 mg/kg) was administered orally to the rats for 21 days. Inflammatory cells and cytokines released by T-cell subsets Th1 and Th2 in the bronchoalveolar lavage fluid were determined. Serum immunoglobulin E (IgE) and histamine, in addition to expression of mucin 5AC (MUC-5AC), nuclear factor-kappa B (NF-κB), and an inhibitor of NF-κB (IκB) in lung tissues were also evaluated. Results: Laurotetanine treatment (20, 40, 60 mg/kg) significantly reduced inflammatory cells, including eosinophils, neutrophils, lymphocytes, and macrophages in treated rats compared with control animals (p < 0.01). Inflammatory cytokines, viz, interleukin (IL) -4, IL-6, IL-13 were also significantly (p < 0.01) decreased by laurotetanine treatment (20, 40, 60 mg/kg), whereas interferon gamma (IFN-κ) was increased (p < 0.01). Serum IgE and histamine were significantly reduced (p < 0.01) by laurotetanine (20, 40, 60 mg/kg). Furthermore, MUC5AC expression in lung tissues was significantly (p < 0.01) downregulated by laurotetanine (20, 40, and 60 mg/kg, but NF-κB and IκB were significantly (p < 0.01) upregulated by laurotetanine (20, 40, and 60 mg/kg). Conclusion: Laurotetanine exerts an anti-asthmatic effect in rats by inhibition of IgE, histamine, and inflammatory reactions via down-regulating MUC5AC and NF-κB signaling pathways. This finding justifies the need for further development of laurotetanine as a potential anti-asthmatic drug. [ABSTRACT FROM AUTHOR]

Objective: This study was performed to evaluate the comparative efficacy and safety of axitinib and sorafenib in the therapy of metastatic renal cell carcinoma. Materials and methods: Eligible studies were searched from PubMed, Embase, and Future Medicine databases. The pooled hazard ratios and relative risk ratios (RRs) were calculated by using Stata 12.0 software. Results: A total of 1,011 patients qualified to participate in this Phase III study that included randomized controlled trials. Meta-analysis results showed that axitinib was more highly and significantly associated with a survival benefit in the independently assessed progression-free survival in comparison to sorafenib. The values of RR of the objective response rate and disease control rate were also significantly different. Results of the analysis of adverse events concerning hypertension and hypothyroidism demonstrated that the values of RR were significantly higher in the axitinib group and lower risks were established in the patients treated with axitinib. Conclusion: Therefore, axitinib was a better treatment option for metastatic renal cell carcinoma treatment than sorafenib, especially after failure of prior systemic therapies. This analysis revealed that axitinib had higher risks of hypertension and hypothyroidism and lower risks of rash and palmar-plantar erythrodysesthesia. [ABSTRACT FROM AUTHOR]

Background: Infected bone defect poses a great challenge for orthopedists because it is difficult to cure. Tissue-engineered bone based on the human mesenchymal stem cells (hMSCs), has currently taken a promising treatment protocol in clinical practice. In a previous study, a porous hydroxyapatite/fibronectin/alginate (PHA/FN/ALG) composite scaffold displayed favorable biological properties as a novel scaffold, which was considered better than single-material scaffolds. In addition, Wnt11 has been demonstrated to play an important role in the development of osteoblasts, but until recently, its role in the osteogenic differentiation of hMSCs in infectious environment remained unclear. Methods: In this study, we constructed a PHA/FN/ALG composite scaffold with layer-by-layer technology. Furthermore, we also constructed Wnt11-silenced (RNAi) and -overexpressing hMSCs by lentiviral transduction. The gene transduction efficacy was confirmed by quantitative PCR assay and Western blot analysis. Tissue-engineered bone was constructed with hMSCs and PHA/FN/ALG composite scaffolds, and then was implanted into an infected bone defect model for evaluating the osteogenic capacity by quantitative PCR, gross observation, micro-CT and histology analysis. Results: All those cells showed similar adhesion abilities and proliferation capacities in scaffolds. After tissue-engineered bone implantation, there were high levels of systemic inflammatory factors in vivo, which significantly declined three days after antibiotic therapy. One or two months after implantation, the results of osteogenic-related gene analyses, gross observation, micro-CT and histology consistently showed that the Wnt11 over-expression hMSC group displayed the strongest osteogenesis capacity, whereas the Wnt11-RNAi hMSC group displayed inferior osteogenesis capacity, when compared with the other cell-containing groups. However, the blank control group and the only composite scaffold without cell implantation group both showed extremely weak osteogenesis capacity. Conclusion: Our results revealed that the Wnt11 gene plays an important role in hMSCs for enhancing the osteogenesis in an infectious environment. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (5): 408–413 Background Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, have anticancer effects in vitro and in vivo. Epidermal growth factor’s mechanism of cancer formation involves the activation of Ras. Materials and methods These four cardiac hormones were evaluated for their ability to inhibit mitogen (epidermal growth factor) activation of Ras. Results Epidermal growth factor increased the activation of Ras by 68%, 85% and 90% at its 1, 2 and 5 ng mL−1 concentrations. Vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide inhibited 5 ng mL−1 epidermal growth factor’s stimulation of Ras by 73%, 79%, 33% and 45%, respectively, at their 1 μM concentrations. Their effects on epidermal growth factor’s activation of Ras were specific with addition of the cardiac hormones’ respective antibodies (5 μM) blocking 95%, 93%, 100% and 100% ( P < 0·001 for each) of their ability to inhibit epidermal growth factor’s stimulation of Ras. Conclusions Four cardiac hormones specifically inhibit epidermal growth factor’s activation of Ras. This investigation would suggest that these cardiac hormones’ anticancer effects involve the inhibition of mitogens such as epidermal growth factor’s ability to activate Ras as well as inhibiting unstimulated basal activity of Ras. [ABSTRACT FROM AUTHOR]

AbstractAim:Insulin-like growth factor-1 (IGF-1) is an important hypertrophic and cell cycle progression factor for a number of cell types. It has been proven that IGF-1 is involved in the regulation of thyroid proliferation and cell cycle progression; however, the exact mechanism of this regulation has not been fully elucidated. In the present study, we investigated the effect of IGF-1 on the expression of cyclin D1, an important cell cycle regulatory protein, and a signaling pathway involved in IGF-1's effect on cyclinD1 expression in FRTL thyroid cells.Methods:FRTL thyroid cells were treated with IGF-1 or vector control for 24 h. As appropriate to individual experiments, a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and/or a nuclear factor-κB (NF-κB) inhibitor, BAY11-7082, were added 1 h prior to IGF-1 treatment. Western blotting was used to detect cyclin D1 protein expression. Immunofluorescence was performed to analyze the expression of IκBα, an NF-κB inhibitory protein. Cell cycle analysis was performed by fluorescence activated cell sorting (FACS).Results:IGF-1 increased the cyclin D1 expression in thyroid cells. This increase was blocked by pretreatment with LY294002 or BAY11-7082. Further studies showed that IGF-1 specifically induced NF-κB activity. Treatment with IGF-1 could accelerate cell cycle progression from G0/G1 to S phase, whereas this progression was inhibited by the presence of LY294002 or BAY11-7082.Conclusion:In summary, the results of the present study show that in FRTL cells, IGF-1 promotes cell cycle progression via an upregulation of cyclin D1 expression, at least partially through the PI3K/NF-κB signaling pathway.Acta Pharmacologica Sinica (2009) 30: 113–119; doi: 10.1038/aps.2008.8; published online 8th December 2008 [ABSTRACT FROM AUTHOR]

Recepteur d'origine nantais (RON) belongs to a subfamily of receptor tyrosine kinases (RTK) with unique expression patterns and biological activities. RON is activated by a serum-derived growth factor macrophage stimulating protein (MSP). The RON gene transcription is essential for embryonic development and critical in regulating certain physiological processes. Recent studies have indicated that altered RON expression contributes significantly to cancer progression and malignancy. In primary tumors, such as colon and breast cancers, overexpression of RON exists in large numbers and is often accompanied by the generation of different splicing variants. These RON variants direct a unique program that controls cell transformation, growth, migration, and invasion, indicating that altered RON expression has the ability to regulate motile/invasive phenotypes. These activities were also seen in transgenic mice, in which targeted expression of RON in lung epithelial cells resulted in numerous tumors with pathological features of human bronchioloalveolar carcinoma. Thus, abnormal RON activation is a pathogenic factor that transduces oncogenic signals leading to uncontrolled cell growth and subsequent malignant transformation. Considering these facts, RON and its variants can be considered as potential targets for therapeutic intervention. Experiments using small interfering RNA and neutralizing monoclonal antibodies demonstrated that suppressing RON expression and activation decreases cancer cell proliferation, increases apoptotic death, prevents tumor formation in nude mice, and reduces malignant phenotypes. Thus, blocking RON expression and activation has clinical significance in reversing malignant phenotypes and controlling tumor growth. [ABSTRACT FROM AUTHOR]

Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss--mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8+ and CD4+ T cells were essential to the optimal antitumor effect of this combination treatment in an IFN-γ--dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte--associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the dose-response relationship of green tea polyphenol in an animal model of lung cancer. Methods: The effects of epigallocatechin-3-gallate (EGCG) on the inhibition of xenograft tumor growth, the accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), and apoptosis based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were evaluated in non-small cell lung cancer (NSCLC) cell lines, namely, H1155, H661, and A427 (a human lung carcinoma-derived cell line). The dose-dependent effects of EGCG on H1155 xenograft tumor growth, as well as the levels of EGCG in plasma and tissue, were also determined in male nude mice. Results: EGCG inhibited the growth of NSCLC-derived cell lines (H1155) over a 45-day period. There was a significant reduction (57 %) in tumor weight in EGCG-fed (0.5 %) animals compared with the control group (p < 0.05). Linear regression analysis revealed a dose-dependent reduction in tumor size. MTT assay results revealed inhibition of H1155 cell growth (25 %, p < 0.05) after 24 h treatment with EGCG. The addition of superoxide dismutase (5 U/mL) and catalase (30 U/mL) reduced the inhibitory effect of EGCG. Mice administered 30 mg/kg EGCG via intraperitoneal injection exhibited the least amount of oxidative stress. Conclusion: The results demonstrate the concentration-dependent inhibitory effects of EGCG on lung cancer cells, including H1155 cells, both in vitro and in vivo. The induction of reactive oxygen species, oxidative DNA damage, and apoptosis were evident following EGCG treatment. [ABSTRACT FROM AUTHOR]

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure−activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors. [ABSTRACT FROM AUTHOR]

Insulin’s ability to contribute to cancer formation and proliferation is mediated in part by converting inactive GDPRas to the active form of Ras, i.e., GTP-Ras. Four endogenous cardiac hormones, i.e., vessel dilator, atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP) and kaliuretic peptide, which eliminate up to 80% of human pancreatic adenocarcinomas, 2/3rds of human breast cancers and up to 86% of human small-cell lung cancers in athymic mice were evaluated for the ability to decrease insulin’s conversion of GDP-Ras to GTPRas. Vessel dilator, ANP, kaliuretic peptide and LANP decreased the activation of unstimulated Ras 95%, 90%, 90% and 83%, respectively. Dose-response experiments revealed that 1 µM of regular human insulin caused a 100% conversion of GDP-Ras to GTP-Ras. Vessel dilator, LANP, ANP and kaliuretic peptide, each at 1 µM, inhibited 88%, 94%, 56%, and 47%, respectively, of insulin’s (1 µM) activation of Ras. The addition of antibodies (5 µM) to vessel dilator, LANP, ANP and kaliuretic peptide allowed 75%, 50%, 70%, and 96% of insulin’s activation of Ras with the respective cardiac hormones present, suggesting that their effects were specific. This study indicates that four cardiac hormones inhibit insulin’s activation of Ras as another mechanism of their anticancer effects, i.e., blocking mitogenic stimulation of Ras. [ABSTRACT FROM AUTHOR]