Nonsteroidal anti-inflammatory drugs (NSAID) are effective in suppressing the formation of colorectal tumors. However, the mechanisms underlying the antineoplastic effects of NSAIDs remain unclear. The effects of NSAIDs are incomplete, and resistance to NSAIDs is often developed. Growing evidence has indicated that the chemopreventive activity of NSAIDs is mediated by induction of apoptosis. Our previous studies showed that second mitochondria-derived activator of caspase (SMAC

The anticoagulant pentasaccharide fondaparinux was synthesized using an improved and optimized synthetic strategy including a convergent [3+2] coupling approach, orthogonal protecting groups and various glycosyl donors. The new methods of glycosylation were also used for controlling the stereochemical configuration and improving the yield of the glycosylation. In addition, HPLC and NMR methods to monitor the process of total synthesis of fondaparinux were employed. This work provides a comprehensive elaboration for the synthesis and analysis of fondaparinux based on related literature, as well as abundant information for the synthesis of heparin-like oligosaccharides.

Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFα, IL-1β and IL-6 secretions. Also, Western blotting analysis indicated that NF-κB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS-stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-κB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

A chemical investigation of the roots of Cynanchum stauntonii has resulted in the characterization of a new hydroperoxide with a 13,14 : 14,15-disecopregnane-type skeleton, named stauntonine (1), together with three related compounds, anhydrohirundigenin (2), anhydrohirundigenin monothevetoside (3), and glaucogenin-C mono- D-thevetoside (4). Their structures were established by spectroscopic methods, including X-ray crystallographic diffraction analysis of stauntonine that confirmed its relative stereochemistry. The compound 1 showed dose-dependent relaxation on aortic rings with endothelium contracted by phenylepherine or KCl.

Yuanhu Zhitong prescription (YZP) is a typical and relatively simple traditional Chinese medicine (TCM), widely used in the clinical treatment of headache, gastralgia, and dysmenorrhea. However, the underlying molecular mechanism of action of YZP is not clear. In this study, based on the previous chemical and metabolite analysis, a complex approach including the prediction of the structure of metabolite, high-throughput in silico screening, and network reconstruction and analysis was developed to obtain a computational drug-target network for YZP. This was followed by a functional and pathway analysis by ClueGO to determine some of the pharmacologic activities. Further, two new pharmacologic actions, antidepressant and antianxiety, of YZP were validated by animal experiments using zebrafish and mice models. The forced swimming test and the tail suspension test demonstrated that YZP at the doses of 4 mg/kg and 8 mg/kg had better antidepressive activity when compared with the control group. The anxiolytic activity experiment showed that YZP at the doses of 100 mg/L, 150 mg/L, and 200 mg/L had significant decrease in diving compared to controls. These results not only shed light on the better understanding of the molecular mechanisms of YZP for curing diseases, but also provide some evidence for exploring the classic TCM formulas for new clinical application.

Ebselen is a synthetic organoselenium radical scavenger compound that possesses glutathione peroxidase-like activity and its own unique bioactivity by reacting with thiols, hydroperoxides and peroxynitrites. Owing to its high affinity toward several essential reactions, ebselen protects cellular components from oxidative and free radical damage, and it has been employed as a useful tool for studying redox-related mechanisms. Based on numerous in vitro and in vivo research, mechanisms are proposed to understand the biomedical and molecular actions of ebselen in health and disease, and it is currently under clinical trials for the prevention and treatment of various human disorders. Based on these outstanding discoveries, this review summarizes the current understanding of the biochemical and molecular characteristics, pharmacological applications and future directions of ebselen.

Background. Qingyihuaji formula (QYHJ) is a widely used herbal formula that has shown promising antitumor effect in the treatment of pancreatic cancer in the Cancer Hospital, Fudan University, Shanghai, China. Objective. This research was conducted to study whether Ski acts as a therapeutic target of QYHJ formula in the treatment of SW1990 pancreatic cancer. Methods. The expression changes of Ski mRNA and protein in SW1990 pancreatic cancer subcutaneously transplanted tumor treated with QYHJ were detected by real-time polymerase chain reaction and Western blot. Then, we established a stable transfection SW1990 cell with low expression of Ski through lentivirus-mediated RNA interference (RNAi) technique. The responses to QYHJ treatment on a subcutaneously transplanted tumor with different Ski expression statuses were evaluated. Finally, the effect of Ski downregulation on SW1990 cell biological behavior was also evaluated. Results. Expression of Ski mRNA and protein in SW1990 subcutaneously transplanted tumor decreased dramatically after the treatment with QYHJ. Stable transfection cells with low expression of Ski (SW1990/Ski RNAi) were created, and negative vector-transfected cells (SW1990/con RNAi) were used as controls. The tumor weight inhibitory rates of QYHJ on subcutaneously transplanted tumors formed by SW1990 or SW1990/con RNAi were 29.6% and 32.2%, respectively, whereas they were 16.0% to 17.8% when the tumors were formed by SW1990/Ski RNAi. Ski downregulation sensitized the response of SW1990 cells to TGF-b1-induced growth inhibition in vitro. Flow cytometric analyses revealed that the percentage of cells in the G1 phase increased from 40.4% to 62.9% when Ski was downregulated. The subcutaneously transplanted tumors formed by SW1990/Ski RNAi grew much more slowly than those formed by parental and control vector-transfected cells. Conclusion. Ski acts as therapeutic target of QYHJ in the treatment of SW1990 pancreatic cancer cells, and its expression status mediates different responses to QYHJ treatment.