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Wen Yin,* Si-Qi Zhang,* Wen-Lin Pang,* Xiao-Jiao Chen, Jing Wen, Jiong Hou, Cui Wang, Li-Yun Song, Zhen-Ming Qiu, Peng-Tao Liang, Jia-Li Yuan, Zhong-Shan Yang, Yao Bian Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Shan Yang; Yao Bian, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China, Tel +86-871-65919932, Email yangzhongshan@ynutcm.edu.cn; 1345538930@qq.comPurpose: Type 2 diabetes mellitus (T2DM) is a complex genetic disease associated with genetic and environmental factors. Previous studies have shown that changes in the gut microbiota may affect the development of host metabolic diseases and promote the progression of T2DM. Tang-ping-san (TPS) decoction can effectively treat T2DM. However, its specific mechanisms must be evaluated.Patients and Methods: In the present study, we established an animal model of T2DM using a high‑fat diet (HFD) with intraperitoneal injection streptozotocin injection.Results: The therapeutic effect of TPS decoction on T2DM in mice was initially evaluated. TPS decoction was found to improve hyperglycemia, hyperlipidemia, insulin resistance, and pathological liver, pancreatic, and colon changes. Moreover, it reduced the pro-inflammatory cytokine levels. Based on 16SrRNA sequencing, TPS decoction reduced the Firmicutes/Bacteroidetes ratio at the phylum level. At the genus level, it increased the relative abundances of Akkermansia, Muribaculaceae, and the Eubacterium coprostanoligenes group and decreased the relative abundance of Fusobacterium, Escherichia coli, Dubosiella, and Helicobacter.Conclusion: TPS decoction improves T2DM and liver function and reduces the risk of hyperglycemia, hyperlipidemia, insulin resistance, pathological organ changes, and inflammatory reactions. The mechanism of TPS decoction in T2DM can be correlated with the reversal of gut microbiota dysfunction and repair of the intestinal mucosal barrier.Keywords: type 2 diabetes mellitus, tang-ping-san decoction, gut microbiota, glycolipid metabolism, insulin resistance

Bo Kou,1,* Yang Yang,2,* Yin-E Bai,3 Yu-Han Shi,4 Rui-Xia Gao,5 Fang-Li Yang,1 Shao-Qiang Zhang,1 Wei Liu6 1Department of Otorhinolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China; 2Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China; 3Department of ENT, Yichuanxian Renmin Hospital, Yan’an 716200, Shaanxi Province, People’s Republic of China; 4Department of Thyroid Breast Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, People’s Republic of China; 5School of Science, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 6Department of Vascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shao-Qiang Zhang; Wei Liu Email entsqzhang@163.com; 821957325@qq.comPurpose: Oridonin, a bioactive diterpenoid derived from Rabdosia rubescens, has been widely reported to exhibit anticancer activity in multiple types of cancer. However, the molecular mechanism of oridonin in human laryngeal carcinoma has not been clearly elucidated. This study investigated the function of oridonin in laryngeal carcinoma to provide a research basis for laryngeal carcinoma therapy.Methods: The proliferation of laryngeal carcinoma Hep-2 and TU212 cells treated with oridonin was determined by MTT assay. The apoptotic induction effect of oridonin on Hep-2 and TU212 cells was analyzed by flow cytometry, Western blot analysis and caspase3 activity assay. In addition, the caspase inhibitor, Z-VAD-fmk, was synergistically treated with oridonin to detect the function of caspase cascade in oridonin-mediated apoptosis. Then, the expressions of endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated-PERK, phosphorylated-eIF2α and CHOP) were measured in Hep-2 and TU212 cells by Western blotting. The cells were treated with 4-PBA (an ER stress inhibitor) or knockdown of CHOP to explore the role of ER stress in oridonin-mediated apoptosis in laryngeal carcinoma. Subsequently, a nude mouse xenograft model was constructed to confirm the function of oridonin in laryngeal carcinoma in vivo.Results: Oridonin was found to significantly inhibit the proliferation of laryngeal carcinoma Hep-2 and TU212 cells in a concentration-dependent manner. Then, we confirmed that oridonin could induce apoptosis in human laryngeal carcinoma cells. The caspase inhibitor, Z-VAD-fmk, could partially reverse the pro-apoptotic effect of oridonin on human laryngeal carcinoma cells. Subsequently, Western blotting analysis demonstrated that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated-PERK, phosphorylated-eIF2α and CHOP) were up-regulated in Hep-2 and TU212 cells exposed to oridonin. In addition, 4-PBA (an ER stress inhibitor) or knockdown of CHOP could antagonize oridonin-induced apoptosis. Oridonin significantly decreased the tumorigenicity of Hep-2 cells in a nude mouse xenograft model.Conclusion: Oridonin-induced apoptosis of human laryngeal carcinoma through the activation of ER stress.Keywords: oridonin, laryngeal carcinoma, ER stress, apoptosis

Zhuo-Yue Li,1,2 Yi-Fan Yin,1,2 Yang Guo,1,2 Hui Li,1,2 Mei-Qi Xu,1,2 Man Liu,1,2 Jing-Ru Wang,1,2 Zhen-Han Feng,1,2 Xiao-Chuan Duan,1,2 Shuang Zhang,1,2 Shuai-Qiang Zhang,1,2 Guang-Xue Wang,2 Ai Liao,2 Shu-Min Wang,3 Xuan Zhang1,2 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 3Department of Ultrasound, Peking University Third Hospital, Peking University, Beijing 100191, People’s Republic of ChinaCorrespondence: Xuan ZhangDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing 100191, People’s Republic of ChinaTel/Fax +86-10-82805765Email xuanzhang@bjmu.edu.cnShu-Min WangDepartment of Ultrasound, Peking University Third Hospital, Peking University, Xueyuan Road 38, Beijing 100191, People’s Republic of ChinaEmail shuminwang2014@163.comIntroduction: Because tumor-associated inflammation is a hallmark of cancer treatment, in the present study, sorafenib mesoporous silica nanomatrix (MSNM@SFN) co-administrated with flufenamic acid (FFA, a non-steroidal anti–inflammatory drug (NSAID)) was investigated to enhance the anti-tumor activity of MSNM@SFN.Methods: Metastatic breast tumor 4T1/luc cells and hepatocellular carcinoma HepG2 cells were selected as cell models. The effects of FFA in vitro on cell migration, PGE2 secretion, and AKR1C1 and AKR1C3 levels in 4T1/luc and HepG2 cells were investigated. The in vivo anti-tumor activity of MSNM@SFN co-administrating with FFA (MSNM@SFN+FFA) was evaluated in a 4T1/luc metastatic tumor model, HepG2 tumor-bearing nude mice model, and HepG2 orthotopic tumor-bearing nude mice model, respectively.Results: The results indicated that FFA could markedly decrease cell migration, PGE2 secretion, and AKR1C1 and AKR1C3 levels in both 4T1/luc and HepG2 cells. The enhanced anti-tumor activity of MSNM@SFN+FFA compared with that of MSNM@SFN was confirmed in the 4T1/luc metastatic tumor model, HepG2 tumor-bearing nude mice model, and HepG2 orthotopic tumor-bearing nude mice model in vivo, respectively.Discussion: MSNM@SFN co-administrating with FFA (MSNM@SFN+FFA) developed in this study is an alternative strategy for improving the therapeutic efficacy of MSNM@SFN via co-administration with NSAIDs.Keywords: sorafenib mesoporous silica nanomatrix, MSNM@SFN, flufenamic acid, FFA, PGE2, AKR1C1, AKR1C3, 4T1/luc, HepG2

Jie Gao,1,2,* An-Jing Kang,3,* Shuai Lin,1,* Zhi-Jun Dai,1 Shu-Qun Zhang,1 Di Liu,1 Yang Zhao,1 Peng-Tao Yang,1 Meng Wang,1 Xi-Jing Wang11Department of Oncology, 2Department of Nephrology, 3Department of Pathology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China *These authors contributed equally to this workPurpose: Previous studies have suggested associations between MDM2 (mouse double minute 2 homolog) polymorphisms and cancer risk. The aim of this study was to evaluate the relationship between the MDM2 rs 2279744 polymorphism and the susceptibility of breast cancer.Methods: We searched PubMed, Web of Knowledge, Embase, and the Chinese National Knowledge Infrastructure (CNKI) database for case–control studies published up to October 2013 that investigated MDM2 rs 2279744 polymorphism and breast cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of these associations.Results: A total of 19 studies were identified for the meta-analysis, including 9,788 cases and 11,195 controls. The variant heterozygote (TG) was associated with breast cancer risk in the overall population (TG vs TT: OR =1.10, 95% CI =1.04–1.17, P=0.001, P=0.23 for heterogeneity test). In the subgroup analyses by ethnicity, a significantly increased risk was observed among Asians (G vs T: OR =1.12, 95% CI =1.02–1.23, P=0.02, Phet=0.04; GG vs TT: OR =1.29, 95% CI =1.06–1.56, P=0.01, Phet=0.04; TG vs TT: OR =1.36, 95% CI =1.15–1.60, P=0.0004, Phet=0.45; dominant model TG+GG vs TT: OR =1.21, 95% CI =1.03–1.41, P=0.02, Phet=0.07). However, among Caucasians, rs 2279744 was associated with breast cancer risk in only one genotype (TG vs TT: OR =1.09, 95% CI =1.00–1.18, P=0.04, Phet=0.37). No publication bias was found in the present study.Conclusion: This meta-analysis provides evidence for the association between the MDM2 rs 2279744 polymorphism and breast cancer susceptibility. The results suggest that the MDM2 rs 2279744 polymorphism plays an important role in breast cancer, especially in Asians.Keywords: breast cancer, MDM2, single nucleotide polymorphism, susceptibility, meta-analysis