Mefunidone ameliorates lipopolysaccharide-induced acute lung injury through inhibiting MAPK signaling pathway and enhancing Nrf2 pathway.

BACKGROUND AND OBJECTIVE: Acute lung injury (ALI) is a life-threatening disease which has high mortality and lacks effective pharmacological treatments. Excessive inflammation and oxidative stress are the key pathogenesis of ALI. Mefunidone (MFD), a novel small molecule compound, displayed anti-inflammation and anti-oxidative stress effects on streptozocin (STZ) and db/db mice in our previous studies. In this study, we aimed to investigate the effects of MFD on lipopolysaccharide (LPS)-induced ALI and explore the potential molecular mechanisms. METHODS: We investigated the effects of MFD on LPS-induced ALI mouse model and LPS-stimulated immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: MFD could alleviate pulmonary structure disorder and attenuate pulmonary neutrophils infiltration induced by LPS. MFD could also decreased proinflammatory cytokines release and reduce reactive oxygen species (ROS) generation stimulated by LPS. Further, MFD could significantly reduce LPS-induced phosphorylation levels of mitogen-activated protein kinase (MAPK), increase expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and restore the expressions of antioxidant enzymes. CONCLUSION: Our results firstly supported that MFD effectively protected LPS-induced ALI against inflammation and oxidative stress through inhibiting MAPK signaling pathway and activating Nrf2 pathway.

[Progress in the study of new cancer target Cdk5 and its inhibitors].

Cyclin-dependent kinase-5(Cdk5) is a kind of Ser/Thr kinases in the signaling pathway, which regulates the neural development. The recent studies have confirmed that hyperactivation of Cdk5 is closely associated with the evolution, progression and apoptosis of tumors. The Cdk5 inhibitors have been extensively studied in the drug discovery against cancer. The structure features of these inhibitors and molecular mechanisms of their activities have provided clues for the drug development. In the second generation Cdk5 inhibitors, the ATP-binding pocket, a highly conserved site, has been targeted in the drug design in most cases. In addition, a growing number of peptides has been generated by targeting the protein/protein interfaces of Cdk5.

[Research progress of NADPH oxidases and their inhibitors].

NADPH oxidases (NOXs) are the key enzymes of redox signaling in vivo and also the main source of reactive oxygen species (ROS) in the body. ROS plays a role of double-edged sword. On the one hand, ROS, at the level of physiological amount, has the effect of immune defense and also acts as a second messenger involved in the regulation of cellular signaling pathways. On the other hand, excessive ROS can cause oxidative stress, leading to the disorder of cellular functions. Recently, studies showed that ROS plays an important role in acceleration of some pathological reactions such as inflammation, fibrosis and tumor formation. As a major source of ROS, NOX has become a popular target in treating oxidative stress, inflammation, fibrosis and tumor. Herein, the role of NOX in these pathological processes and the research progress of NOX inhibitors are reviewed.

[Research progress of p70 ribosomal protein S6 kinase inhibitors].

p70 ribosomal protein S6 kinase (p70S6K), an important member of AGC family, is a kind of multifunctional Ser/Thr kinases, which plays an important role in mTOR signaling cascade. The p70 ribosomal protein S6 kinase is closely associated with diverse cellular processes such as protein synthesis, mRNA processing, glucose homeostasis, cell growth and apoptosis. Recent studies have highlighted the important role of S6K in cancer, which arose interests of scientific researchers for the design and discovery of anti-cancer agents. Herein, the mechanisms of S6K and available inhibitors are reviewed.

Synthesis and structure-activity relationship of 5-substituent-2(1H)-pyridone derivatives as anti-fibrosis agents.

Pyridone compounds, such as pirfenidone (PFD) and fluorofenidone (AKF-PD), are multi-target anti-fibrotic agents. Using PFD and AKF-PD as the leading compounds, two series of novel (5-substituent)-2(1H)-pyridone compounds were synthesized with the purpose of maintaining multi-targeting property and overcoming the drawbacks of fast metabolism. These derivatives demonstrated good proliferation inhibiting activity against NIH3T3 cells by MTT assay with AKF-PD as the positive control. Compound 5b exhibited a high potent of anti-fibrosis with a IC(50) of 0.08 mmol/L about 34 times of AKF-PD. The SAR of pyridone derivatives as anti-fibrosis agents was also discussed.

Targeting aminopeptidase N (APN/CD13) with cyclic-imide peptidomimetics derivative CIP-13F inhibits the growth of human ovarian carcinoma cells.

Aminopeptidase N (APN/CD13) is an essential peptidase involved in the process of tumor growth, metastasis and angiogenesis. Inhibition of APN/CD13 may be an effective strategy for cancer treatment. CIP-13F is a cyclic-imide peptidomimetics compound designed to fit the active pockets S1 and S'1 of APN/CD13 that act in tumor proliferation. Our aim in this study was to evaluate the efficacy of CIP-13F as a candidate compound for cancer treatment. The experiments were performed on the human ovarian carcinoma (OVCA) ES-2 and HRA cell lines, which have high and low levels of APN/CD13 respectively. CIP-13F significantly blocked APN/CD13 activity on the surface of ES-2 cells as measured by quantitating the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. CIP-13F effectively inhibited ES-2 cell growth and migration without significant cytotoxic effect. In contrast, CIP-13F did not significantly inhibit HRA cell growth, indicating that CIP-13F may inhibit ES-2 cell growth via suppression of APN/CD13. The suppression of APN/CD13 was also observed by using the assays of flow cytometry and Western blot analysis. Further, the inhibitory effects of CIP-13F on APN/CD13 and on ES-2 proliferation were supported by the induction of ES-2 apoptosis. CIP-13F-treated ES-2 cells resulted apoptotic characteristics, such as induction of externalization of phosphatidylserine and DNA laddering fragment. The activation of caspase-3 and poly ADP-ribose polymerase (PARP) was also enhanced. The inhibitory effects of CIP-13F on APN/CD13 expression and on ES-2 proliferation were confirmed in mice bearing ES-2 xenografts. CIP-13F delayed the growth of ES-2 xenografts in mice after 2 weeks of vena caudalis injection. These results suggest that CIP-13F has a high inhibitory effect on the growth of OVCA cells via decreasing the activity and expression of APN/CD13.

Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion through suppressing matrix metalloproteinase activity.

Matrix metalloproteinase (MMP)-2 and MMP-9 have been associated with the ability of tumor cells to metastasize because of their capacity to degrade type IV collagen, the main component of basement membrane, and to their elevated expression in malignant tumors. (S)-methyl 6-(benzyloxycarbonylamino)-2-(2-((S)-2,6-dioxo-3-(3,4,5-trimethoxybenzamido) piperidin-1-yl) acetamido) hexanoate (CH1104I) is a galloyl cyclic-imide derivative designed to fit and extend into the S1' active pocket of MMP-2 and MMP-9. We aimed to evaluate the efficacy of CH1104I as a candidate compound for antiinvasion and antimetastasis of tumor cells. CH1104I significantly blocked gelatinase activity as evidenced by a decrease in the degradation of succinylated gelatin. Gelatin zymography analysis showed that the compound (7-210 micromol/l) inhibited the activity of MMP-2 and MMP-9 produced by human ovarian carcinoma SKOV3 cells. Inhibition of MMP-2 and MMP-9 expression was also observed using the assays of immunocytochemical staining and western blot analysis. The results showed that CH1104I suppressed the expression of zymogens and active MMP-2 and MMP-9. The effects of CH1104I on the invasion and migration of SKOV3 cells were then measured. Both the trans-well motility assay and wound scratch assay indicated that CH1104I was very effective for the antiinvasion and antimigration of SKOV3 cells. Furthermore, the Lewis lung carcinoma model was used to evaluate the efficacy of CH1104I in vivo. A significant inhibition of pulmonary metastasis of carcinoma cells was observed in CH1104I-administrated mice (25-100 mg/kg). These results suggest that CH1104I is a potential MMP-2 and MMP-9 inhibitor that may effectively suppress tumor invasion and metastasis.