Showing papers by "Jian Luo published in 2015"

Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops

Abstract: Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca(2+)/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.

In vivo selection for spine-derived highly metastatic lung cancer cells is associated with increased migration, inflammation and decreased adhesion.

Abstract: // Xiaopan Cai 1,* , Jian Luo 2,*,** , Xinghai Yang 1,* , Huayun Deng 2 , Jishen Zhang 1 , Shichang Li 3 , Haifeng Wei 1 , Cheng Yang 1 , Leqin Xu 1 , Rongrong Jin 2 , Zhenxi Li 1 , Wang Zhou 1 , JianDong Ding 1 , Jianjun Chu 4 , Lianshun Jia 1 , Qi Jia 1 , Chengjun Tan 5 , Mingyao Liu 1,6,** and Jianru Xiao 1,** 1 East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, P. R. China 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, P. R. China 3 The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, P. R. China 4 Department of Orthopedics, Binhu Hospital, The First People’s Hospital of Hefei City, Hefei, P. R. China 5 Department of General Surgery, The Fifth People’s Hospital of Qinghai Province, Qinghai, P. R. China 6 Center for Cancer and Stem Cell Biology, Alkek Institute of Biosciences and Technology, Texas AM bone metastasis; spine metastasis; A549 Received : February 02, 2015 Accepted : May 29, 2015 Published : June 10, 2015 Abstract We developed a murine spine metastasis model by screening five metastatic non-small cell lung cancer cell lines (PC-9, A549, NCI-H1299, NCI-H460, H2030). A549 cells displayed the highest tendency towards spine metastases. After three rounds of selection in vivo , we isolated a clone named A549L6, which induced spine metastasis in 80% of injected mice. The parameters of the A549L6 cell spinal metastatic mouse models were consistent with clinical spine metastasis features. All the spinal metastatic mice developed symptoms of nerve compression after 40 days. A549L6 cells had increased migration, invasiveness and decreased adhesion compared to the original A549L0 cells. In contrast, there was no significant differences in cell proliferation, apoptosis and sensitivity to chemotherapeutic agents such as cisplatin. Comparative transcriptomic analysis and Real-time PCR analysis showed that expression of signaling molecules regulating several tumor properties including migration (MYL9), metastasis (CEACAM6, VEGFC, CX3CL1, CST1, CCL5, S100A9, IGF1, NOTCH3), adhesion (FN1, CEACAM1) and inflammation (TRAF2, NFκB2 and RelB) were altered in A549L6 cells. We suggest that migration, adhesion and inflammation related genes contribute to spine metastatic capacity.

A Novel TGR5 Activator WB403 Promotes GLP-1 Secretion and Preserves Pancreatic β-Cells in Type 2 Diabetic Mice.

Abstract: The G protein-coupled receptor TGR5 is a membrane receptor for bile acids. Its agonism increases energy expenditure and controls blood glucose through secretion of glucagon-like peptide-1 in enteroendocrine cells. In this study, we explored the therapeutic potential of WB403, a small compound activating TGR5 which was identified by combining TGR5 targeted luciferase assay and active GLP-1 assay, in treating type 2 diabetes. After confirmation of TGR5 and GLP-1 stimulating activities in various cell systems, WB403 was examined in oral glucose tolerance test, and tested on different mouse models of type 2 diabetes for glycemic control and pancreatic β-cell protection effect. As a result, WB403 exhibited a moderate TGR5 activation effect while promoting GLP-1 secretion efficiently. Interestingly, gallbladder filling effect, which was reported for some known TGR5 agonists, was not detected in this novel compound. In vivo results showed that WB403 significantly improved glucose tolerance and decreased fasting blood glucose, postprandial blood glucose and HbA1c in type 2 diabetic mice. Further analysis revealed that WB403 increased pancreatic β-cells and restored the normal distribution pattern of α-cell and β-cell in islets. These findings demonstrated that TGR5 activator WB403 effectively promoted GLP-1 release, improved hyperglycemia and preserved the mass and function of pancreatic β-cells, whereas it did not show a significant side effect on gallbladder. It may represent a promising approach for future type 2 diabetes mellitus drug development.

DSEP: A Tool Implementing Novel Method to Predict Side Effects of Drugs.

Abstract: Drug side effects, or adverse drug reactions, have become a focus of public health concern. Anticipating side effects before the drugs are granted marketing authorization for clinical use can help reduce health threats. An increasing need for methods and tools that facilitate side-effect prediction still remains. Here, we present DSEP, which is a tool that is able to analyze chemistry files to predict side effects of drugs that are under development and have not been included into any database. Meanwhile, DSEP provides three computational methods, one of which is a novel method proposed by us. The method can obtain higher AUC(0.8927) and AUPR(0.4143) scores than previous work. The advantage characteristic and method made DSEP a useful tool to predict potential side effects for a given drug or compound. We use DSEP to conduct uncharacterized drugs' side-effect prediction and confirm interesting results.