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Xu-Lin Wang,1,&ast; Ling-Ling Dai,2,&ast; Yan-Na Li,1 Jian-Wen Zhang,1 Ming-Cui Qu,1 Yao-Yao Zhou,1 Na Xing1 1Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Respiration, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Na Xing, Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, People’s Republic of China, Tel +8613949095172, Email 16427485@qq.comPurpose: This study aimed to compare the efficacy of remimazolam and propofol regarding postoperative anesthesia satisfaction in patients undergoing outpatient gynecological surgery.Patients and Methods: This was a single-center, open-label, non-inferiority, randomized clinical trial. Patients aged ≥ 18 years who underwent outpatient gynecological surgery with sedation were enrolled. Participants were randomly assigned to be sedated with remimazolam or propofol. The primary endpoint was the immediate postoperative anesthesia satisfaction score, evaluated through the Iowa Satisfaction with Anesthesia Scale (ISAS).Results: 168 patients were randomly allocated to either the remimazolam group (n = 84) or the propofol group (n = 84). The mean (standard deviation) ISAS scores immediately after surgery were 1.7 (0.6) for the remimazolam group and 2.0 (0.7) for the propofol group (difference, – 0.2; 97.5% confidence interval [CI]: – 0.5 to – 0.0; p = 0.02), indicating non-inferiority. The length of post-anesthesia care unit (PACU) stay was longer in the remimazolam group than in the propofol group (27.6 [9.1] min vs 22.4 [7.0] min; difference, 5.2 [95% CI: 2.7 to 7.6] min; p < 0.001). High-intensity injection pain was less frequently observed in the remimazolam group than in the propofol group (3.6% vs 45.2%; difference, – 41.7% [95% CI: – 54.2% to – 29.1%]; p < 0.001). The nausea score was higher in the remimazolam group immediately after surgery than in the propofol group. Pain, nausea, sleep quality, anxiety, and depression scores were higher in the remimazolam group than in the propofol group on postoperative day 1. The incidence of adverse events and other secondary endpoints was comparable between the two groups.Conclusion: Remimazolam was non-inferior to propofol regarding postoperative anesthesia satisfaction in patients undergoing outpatient gynecological surgery. Therefore, it should be considered as a new sedation alternative in such procedures.Keywords: remimazolam, propofol, patient satisfaction, outpatient gynecological surgery, sedation

Xin Luo,1,&ast; Hai-Jun Hou,2,&ast; Pei-Shan Chen,1 Xin-Lu Chang,1 Yang Li,1 Li-Xin An,1 Fu-Kun Liu,1 Fu-Shan Xue1,3 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Pain Medicine, Guanganmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 3Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fu-Shan Xue, Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +86-13911177655, Fax +86-0591-88217841, Email xuefushan@aliyun.com; fushanxue@outlook.comObjective: Postoperative pain is a common yet often underestimated complication following esophageal endoscopic submucosal dissection (ESD), with limited strategies for effective management. This prospective, double-blind, randomized controlled trial assessed the effects of adding dexmedetomidine (DEX) to the anesthesia regimen on postoperative pain and early recovery in patients undergoing esophageal ESD.Methods: In total, 60 patients scheduled for elective esophageal ESD under general anesthesia were randomly assigned to the DEX or control group. The DEX group received an intravenous loading dose of DEX at 1 μg/kg for 10 min, followed by a continuous intravenous infusion of 0.6 μg/kg/h, which was stopped 30 min before the end of the procedure. The control group received normal saline as a placebo. The study’s primary outcome was the incidence of moderate-to-severe postoperative pain. Secondary outcomes included postoperative pain scores, hemodynamic parameters, the occurrence of postoperative nausea and vomiting (PONV), patient satisfaction, and lengths of stay in the post-anesthesia care unit (PACU) and hospital.Results: The incidence of moderate-to-severe postoperative pain in the DEX group was significantly lower than that in the control group (absolute difference: − 33.4%; OR: 0.250; 95% CI: 0.085– 0.731, P = 0.01). Pain scores at 1 h postoperatively (0.5[2.0] vs 3.0[1.3], P = 0.003) were significantly lower in the DEX group. Additionally, morphine dosage in the PACU (0[0] vs 1.0[2.0] P = 0.004) was significantly reduced in the DEX group compared with the control group. In the DEX group, the incidence and severity of PONV were significantly decreased and the length of PACU stay was shorter than in the control group (P

YiLin Luo, Xin Yue Bai, Lei Zhang, Qian Qian Hu, Ning Zhang, Jun Zhi Cheng, Ming Zheng Hou, Xiao Long Liu Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of ChinaCorrespondence: Xiao Long Liu, Email liuxiaolong@yau.edu.cnAbstract: Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.Keywords: ferroptosis inducers, small molecules, PROTACs, PDT, SDT, nanomaterials

Huan Xue,1,&ast; Hao-Jie Xing,1,&ast; Bin Wang,1 Chao Fu,1 Yu-Shan Zhang,1 Xi Qiao,1 Chao Guo,1 Xiao-Li Zhang,1 Bin Hu,1 Xin Zhao,1 Li-Jiao Deng,1 Xiao-Chan Zhu,1 Yi Zhang,1 Yun-Feng Liu2 1Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Zhang; Yun-Feng Liu, Tel +86-18835102847 ; +86-18703416169, Email yizhang313@163.com; nectarliu@163.comPurpose: The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.Methods: The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9– 39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R−/− mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.Results: Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9– 39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.Conclusion: Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.Graphical Abstract: Keywords: glucagon-like peptide-1 receptor, cinchonine, drug repurposing, non-alcoholic steatohepatitis, type 2 diabetes mellitus

Xin Liu,1,&ast; Miao Tang,2,&ast; Tian-Yi He,1 Shuang Zhao,1 Hui-Zhou Li,1 Zhao Li,1 Yue-Xian Guo,3 Xiu-Li Wang1 1Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiu-Li Wang, Department of Anesthesiology, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-13313019968, Email wangxl311@126.comObjective: This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms.Methods: Morris Water Maze (MWM) test was used to evaluate the mice’s spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1β, IL-4, and IL-10.Results: PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527.Conclusion: Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.Keywords: resveratrol, paclitaxel, SIRT1/PGC-1α, microglia, M2 polarization

He-xiang Zong, Sheng-qian Xu, Jian-xiong Wang, Yi-ran Chu, Ke-ming Chen, Cong Wang, Wan-qiu Tong, Xi-le Wang Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Sheng-qian Xu, Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, No. 218, Ji-xi Road, Hefei, Anhui, 230022, People’s Republic of China, Tel +86 551 62922261, Fax +86 551 62923040, Email xsqian-1112@163.comPurpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have generally been viewed as first-line therapy for axial spondyloarthritis (axSpA). Imrecoxib is a selective COX-2 inhibitor developed independently in China. At present, only one single-center RCT trial has shown that imrecoxib is equally effective as celecoxib in treating axSpA. Based on real-world data, our study aims to explore the efficiency of imrecoxib and TNF inhibitor (TNFi) combined with imrecoxib in treating axSpA.Patients and Methods: A total of 163 patients with axSpA who had more than two follow-up records in 6 months and treated with imrecoxib/celecoxib/TNFi combined with imrecoxib/TNFi combined with celecoxib from the First Affiliated Hospital of Anhui Medical University SpA Real World Database (AHSpA) were selected for analysis of our study. The linear mixed model was used to compare efficacy indexes before and after treatment and between different groups, adjust baseline measurement value and follow-up time. The Kaplan–Meier survival analysis was used to identify the differences in cumulative clinical remission rates between groups with different treatment at the follow-up period.Results: Results showed that after treatment ASDAScrp was slightly improved in imrecoxib group and celecoxib group within 6 months (p < 0.05). CRP, ESR, BASDAI, ASDAScrp, BASFI, occiput to wall distance and finger floor distance all significantly improved in TNFi combined with imrecoxib group and TNFi combined with celecoxib group within 6 months (all p < 0.05). According to the Kaplan–Meier survival curve and Log rank test analysis, the clinical remission rate was not significantly different between different treatment during 24-month follow-up (all p > 0.05).Conclusion: ASDAScrp improved slightly within 6 months after treatment with imrecoxib, and TNFi combined with imrecoxib significantly improved multiple effect indexes in axSpA patients. The efficacy of imrecoxib and celecoxib in the treatment of axSpA is equivalent. Also, they have the same efficacy after being combined with TNFi.Keywords: axial spondyloarthritis, imrecoxib, celecoxib, TNF inhibitor

Xi-Qian Zhang,&ast; Li-Jia Zhang,&ast; Xiu-Lan Zhu, Hong Xu, Yan-Qun Luo, Li Yao, Qian-Wen Huang, Ying-Qi Nong, Wen-Juan Liu, Feng-Hua Liu Reproductive Medical Center, Guangdong Women and Children Hospital, Guangzhou, 511442, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng-Hua LiuDepartment of Reproductive Medical Center, Guangdong Women and Children Hospital, No. 521 Xingnan Road, Panyu District, Guangzhou, 511442, Guangdong Province, People’s Republic of ChinaTel +86 20-3915 1861Fax +86 20-3915 1617Email liufenghua377@21cn.comObjective: To compare the use and clinical efficacy of three different follicle-stimulating hormones (FSHs) for follicle growth and development in long-protocol controlled ovarian hyperstimulation (COH).Methods: A total of 540 gonadotropin-releasing hormone (GnRH) agonists’ long protocol treatment cycles at our hospital between January 2015 and May 2020 and met the inclusion criteria were retrospectively analyzed. The cycles were divided into three groups based on their indexes (groups A, B, and C). Each of the groups received a different type of FSH during treatment. A cross-group comparison was then undertaken to evaluate the growth and development of the three largest follicles and the patients’ pregnancy-related indexes between the normal-response and high-response populations.Results: In the normal-response populations, the number of high-quality embryos obtained in groups A and B was significantly higher than in group C, and the FSH dosage was significantly lower than in group C (P < 0.05). There were more follicles with a diameter of 16– 18 mm found in group A than in group C on the day of hCG injection (hCG day) (P < 0.05), but there were no significant differences in the groups in other indicators. In the high-response populations, the number of oocytes retrieved and high-quality embryos obtained in group A were significantly higher than in group C (P < 0.05), and the total dosage and duration of FSH stimulation in group C were significantly higher than groups A and B (P < 0.05).Conclusion: Three different types of FSH led to comparable growth rates of the three largest follicles and clinical pregnancy rates per fresh cycle in long-protocol COH treatment.Keywords: follicle-stimulating hormone, follicle growth rate, high-quality embryos, Gn stimulation duration, follicle distribution on hCG day

Yun-Hong Wang,1 Tong Qu,2 Xue-Lian Wang,3 Rong-Ping Yang3 1Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, People’s Republic of China; 2Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China; 3Department of Pharmacy College, Southwest University, Chongqing, 400715, People’s Republic of ChinaCorrespondence: Rong-Ping YangDepartment of Pharmacy College, Southwest University, No. 2 of Tiansheng Street, Beibei District, Chongqing, 400715, People’s Republic of ChinaTel +86 023-68251225Fax +86 023-68251225Email yangrongping1119@163.comObjective: This study aims to investigate the preparation of sustained-release microcapsules of salvianolic acid.Methods: The stability of salvianolic acid microcapsules was improved, and the time of action was prolonged in the present study. This was prepared using the spray-drying method, with chitosan as the carrier. In the preparation process, the prescription and process were optimized by L9 (34) using an orthogonal design, with yield and drug loading as indexes, in order to obtain optimum conditions.Results: The optimal process and prescription for the preparation of salvianolic acid microcapsules were found to be as follows: mass concentration of chitosan, 1.5%; mass ratio of salvianolic acid to chitosan, 1:3; inlet air temperature, 190°C; and peristaltic pump speed, 300 mL·h-1. The surface of the microcapsules was round, the drug loading was 25.99% ± 2.14%, the yield was 51.88% ± 2.84%, the entrapment efficiency was 86.21% ± 2.89%, and the average particle size was 105.6 ± 2.56 nm. The microcapsules in vitro had certain sustained release characteristics. The internally fitted first-order release model equation was ln(1-Q) = − 0.236 t + 4.591 7, r = 0.920. In addition, the results of differential scanning calorimetry show that the properties of salvianolic acid were not changed by the microcapsules.Conclusion: Sustained-release microcapsules of salvianolic acid can be successfully prepared by adopting marine polysaccharide as a carrier.Keywords: salvianolic acid sustained-release microcapsule, marine polysaccharides, chitosan, Salvia miltiorrhiza, salvianolic acid B

Hua-Feng Yin,1,2 Chun-Ming Yin,3 Ting Ouyang,4 Shu-Ding Sun,1 Wei-Guo Chen,1 Xiao-Lin Yang,5 Xin He,6 Chun-Feng Zhang1 1School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, People’s Republic of China; 2Jiangxi QingFeng Pharmaceutical Co., Ltd, Ganzhou, 341000, Jiangxi, People’s Republic of China; 3Emergency Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People’s Republic of China; 4School of Chinese Materia Medical, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 6School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of ChinaCorrespondence: Xin HeSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of ChinaTel +852-54445989Email xhe06@qub.ac.ukChun-Feng ZhangSchool of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of ChinaTel +86-25-86185129Email zhangchunfeng67@163.comPurpose: The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA.Methods: We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model.Results: The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model.Conclusion: Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.Keywords: insoluble herbal drug, nanoparticle-based drug delivery system, intestinal permeability, pharmacokinetics, anticancer efficacy

Jing-Fang Shi,1,2 Ping Wu,2 Xiao-Li Cheng,2 Xiao-Yi Wei,2 Zi-Hua Jiang3 1Guangdong Provincial Key Laboratory for Crop Germplasm Resources Preservation and Utilization, Agro-Biological Gene Research Center, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, People’s Republic of China; 2Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People’s Republic of China; 3Department of Chemistry, Lakehead University, Thunder Bay, Ontario P7B 5E1, CanadaCorrespondence: Zi-Hua JiangDepartment of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario P7B 5E1, CanadaTel +1-807-766-7171Email zjiang@lakeheadu.caXiao-Yi WeiKey Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou 510650, People’s Republic of ChinaTel +86-20-37252538Email wxy@scbg.ac.cnBackground: Annonaceous acetogenins (ACGs) are secondary metabolites produced by the Annonaceae family and display potent anticancer activity against various cancer cell lines. Squamocin and bullatacin are two examples of ACGs that show promising antitumor activity; however, preclinical data are not sufficient partly due to their being highly lipophilic and poorly soluble in water. These compounds also display high toxicity to normal cells. Due to these disadvantageous properties, the therapeutic potential of squamocin and bullatacin as antitumor agents has not been fully evaluated.Methods: In order to enhance their water solubility and potentially improve their cancer targeting, squamocin and bullatacin were conjugated to a glucose or galactose to yield glycosylated derivatives by direct glycosylation or the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction (the click reaction). The synthesized compounds were evaluated for their anticancer property against HeLa, A549 and HepG2 cancer cell lines using MTT assay.Results: Nine glycosyl derivatives were synthesized and structurally characterized. Most of them show comparable in vitro cytotoxicity against HeLa, A549 and HepG2 cancer cell lines as their parent compounds squamocin and bullatacin. It appears that the type of sugar residue (glucose or galactose), the position at which the sugar residue is attached, and whether or not a linking spacer is present do not affect the potency of these derivatives much. The solubility of galactosylated squamocin 13 in phosphate buffer saline (PBS, pH = 7) is greatly improved (1.37 mg/mL) in comparison to squamocin (not detected in PBS).Conclusion: The conjugation of a glucose or galactose to squamocin and bullatacin yields glycosyl derivatives with similar level of anticancer activity in tested cell lines. Further studies are needed to demonstrate whether or not these compounds show reduced toxicity to normal cells and their therapeutic potential as antitumor agents.Keywords: annonaceous acetogenins, squamocin, bullatacin, glycosylated, cytotoxicity, anticancer, solubility

Hao-Zhen Zheng, Xiao Shen, Ying-Ying He, Xiang-Li Yan, Sheng-Xin Wang, Ai-Ming Yu, Li-Sheng Wang College of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 51006, Guangdong, People’s Republic of ChinaCorrespondence: Li-Sheng Wang Tel +86 20-39358290Email wlis68@126.comObjective: The aim of our research was to analyze and compare the pharmacokinetics of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in the blood and brain tissue of normal and cerebral ischemia-reperfusion injury rats by HPLC-MS/MS method.Methods: The blood and brain tissue samples of normal and middle cerebral artery occlusion (MCAO) rats were compared. The blood and brain tissue samples were collected by using microdialysis technique. The concentrations of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in blood and brain tissues were determined by the HPLC-MS/MS internal standard method.Results: Compared with the normal group, the model group after the administration of the Huangqi Guizhi Wuwu Decoction showed that Cmax blood, AUC0-t blood, and AUC0-inf blood of paeoniflorin were increased, CLblood, t1/2 brain, and Vbrain of paeoniflorin were decreased; Cmaxblood, AUC0-tblood, AUC0-infblood, and average residence time (MRTbrain) of calycosin-7-o-β-d-6-glucoside were decreased and the CLblood and Cmax brain of calycosin-7-o-β-d-6-glucoside were increased; Cmax blood of calycosin was decreased, Vblood and Vbrain of calycosin were increased; Cmax blood, AUC0-t blood, AUC0-inf blood, and MRTbrain of 6-gingerol were decreased, CLblood of 6-gingerol was increased.Conclusion: This method is simple, rapid, and sensitive. It is suitable for the pharmacokinetic study of Huangqi Guizhi Wuwu Decoction in the blood and brain tissue of rats. Cerebral ischemia-reperfusion injury increased the content of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in the blood, affecting the clearance rate of paeoniflorin in the brain, the detention time of calycosin-7-o-β-d-6-glucoside and the 6-gingerol in the brain. In normal and cerebral ischemia-reperfusion rats, the content of paeoniflorin and 6-gingerol in the blood was higher than that in brain tissue, while the content of calycosin, calycosin-7-o-β-d-6-glucoside in the brain tissue was higher than that in blood, suggesting that calycosin and calycosin-7-o-β-d-6-glucoside have brain targeting properties.Keywords: Huangqi Guizhi Wuwu Decoction, microdialysis, paeoniflorin, calycosin-7-o-β-d-6-glucoside, calycosin, 6-gingerol, pharmacokinetics

Qian Li,1,2,* Kai Wang,3,* Hai-Yan Shi,2 Yue-E Wu,1 Yue Zhou,1 Min Kan,1 Yi Zheng,1 Guo-Xiang Hao,1 Xin-Mei Yang,2 Yi-Lei Yang,2 Le-Qun Su,2 Xiao-Ling Wang,4 Evelyne Jacqz-Aigrain,5,6 Jun Zhou,7,* Wei Zhao1,2,* 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Respiratory Disease, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 5Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, AP-HP, Paris, France; 6University Paris Diderot, Sorbonne Paris-Cité, Paris, France; 7Clinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun ZhouClinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, 16766 Jing Shi Street, Jinan 250014, People’s Republic of ChinaTel/Fax +86 531 8237 3200Email zhoujun_jn@163.comWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 Culture West Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei@hotmail.comBackground: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients.Methods: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient’s clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.Results: Fifty patients (age range: 0.7–10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient’s weight was also found to be significantly corrected with montelukast clearance (p

Fang Li,1,* Xin Zheng,2,* YongChu Bao,3 Ting Chen,3 Jia Zeng,1 XiaoLi Xu,4 Chao Yan,5 LingLin Feng1 1NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, and Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai, China; 2Harro Hoefliger Shanghai Representative Office, Shanghai, China; 3Zhitong Laboratories Co., Ltd, Shanghai, China; 4Traditional Chinese Medicine Testing Department, Chongqing Institute for Food and Drug Control, Chongqing, China; 5Schoolof Pharmacy, Shanghai Jiao Tong University, Shanghai, China *These authors contributed equally to this work Purpose: Fenofibrate and statin combination therapy is highly recommended by the current clinical guidelines for treatment of mixed dyslipidemia. In this study, an innovative delayed-release preparation of fenofibrate was designed to reduce the risk of muscle toxicity, caused by simultaneous administration of this combination therapy, by altering the pharmacokinetic profile of fenofibrate, as well as to improve the oral bioavailability of the modified-release formulation.Methods: Micronized fenofibrate was used to prepare drug-loaded cores via a powder layering process before multiparticulate pellet coating. Different coating formulations (Eudragit® RS PO/E100, Eudragit® RS PO/RL PO, Eudragit® NE30D/HPMC, and EC/HPMC) were screened, and their in vitro release was compared with the commercial sustained-release pellets Lipilfen®. Two optimized formulations were evaluated in beagle dogs using two commercial preparations of fenofibrate (the immediate-release preparation Lipanthyl® and the sustained-release pellets Lipilfen®) as references.Results: The in vivo release of fenofibrate from R1 and R2 selected from in vitro tests exhibited a lag phase, and then rapid and complete drug release. The relative bioavailabilities of R1 and R2 were 100.4% and 201.1%, respectively, which were higher than that of Lipilfen® (67.2%).Conclusion: The modified fenofibrate pellets developed showed enhanced bioavailability and delayed-release properties. They have the potential to improve safety and compliance when co-administrated with statins. This is the first report of a delayed-release fenofibrate preparation. Keywords: fenofibrate, modified-release pellets, coated multiparticulate pellet, pharmacokinetics, in vivo studies

Yue Huang, Xiao-Lin Yang, Yi-Hua Ni, Zheng-Min Xu Department of Otolaryngology-Head and Neck Surgery, Children’s Hospital of Fudan University, Shanghai, China Background: Geraniol is a monoterpene alcohol that has anti-fungal, anti-cancer and anti-nociceptive properties, but its anti-allergic rhinitis (AR) property is unclear.Methods: In this study, the anti-inflammatory role and its possible mechanisms of geraniol in human mast cell line (HMC-1) cells stimulated by inflammatory trigger phorbol 12-myristate 13-acetate plus A23187 (PMACI), as well as in ovalbumin (OVA)-induced AR mice models were investigated.Results: PMACI results in a significant increase in the production of proinflammatory cytokines, such as TNF-α, IL-1β, MCP-1, IL-6 and as well as histamine. Geraniol was found to inhibit both TNF-α, IL-1β and IL-6 protein and mRNA expressions at concentrations of 40, 80, 160 μM. In OVA-induced AR models, geraniol treatment was able to suppress AR biomarkers (OVA-specific IgE and IL-1β as well as histamine) and nasal rub scores. Interestingly, p38, a member of the mitogen-activated protein kinase (MAPK) signaling family, was found to be increasingly hypophosphorylated as geraniol dose was increased. Similar decreases in the nuclear level of p65, a member of the nuclear factor kappa B (NF-κB) signaling pathway, were also observed.Conclusion: Our data highlights that the anti-inflammatory properties of geraniol on AR-related markers in activated HCM-1 cells and OVA-induced AR models may be mediated through the regulation of the MAPK/NF-κB signaling pathway. Keywords: geraniol, HMC-1, allergic rhinitis, PMACI

Meilin Liu, Xiaolong Chen, Henan Liu, Yu Di Department of Ophthalmology, Shengjing Affiliated Hospital, China Medical University, Shenyang, Liaoning, People’s Republic of China Aim: The aim of the study was to investigate the signal transduction mechanism of Hedgehog–vascular endothelial growth factor in oxygen-induced retinopathy (OIR) and the effects of cyclopamine on OIR. Methods: An OIR model was established in C57BL/6J mice exposed to hyperoxia. Two hundred mice were randomly divided into a control group, an OIR group, an OIR-control group (treated with isometric phosphate-buffered saline by intravitreal injection), and a cyclopamine group (treated with cyclopamine by intravitreal injection), with 50 mice in each group. The retinal vascular morphology was observed using adenosine diphosphatase and number counting using hematoxylin and eosin-stained image. Quantitative real-time quantitative polymerase chain reaction was used to detect mRNA expression. Protein location and expression were evaluated using immunohistochemistry and Western blot. Results: The OIR group and OIR-control group demonstrated large-area pathological neovascularization and nonperfused area when compared with the control group (both P

Juan Wang, Handong Wang, Kangjian Sun, Xiaoliang Wang, Hao Pan, Jianhong Zhu, Xiangjun Ji, Xiang Li Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China Background: Chrysin, an active natural bioflavonoid, has been proven to protect against carcinogenesis. However, the role of chrysin in glioblastoma and the potential molecular mechanisms remain to be elucidated. In our previous study, we found that nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is highly expressed in a variety of glioblastoma cell lines associated with the mitogen-activated protein kinase (MAPK) pathway. The aim of this study was to evaluate the antitumor effects of chrysin in glioblastoma cells and how chrysin is related to the MAPK/Nrf2 signaling pathway.Methods: A Cell Counting Kit-8 assay and a plate colony formation assay were performed to evaluate cell proliferation. Cell migration ability was tested by a wound-healing assay. Transwell migration and Matrigel invasion assay were used to test the migration and invasion potential of cells. Nrf2 was knocked down by shRNA transfection. Protein expression was determined by Western blotting and immunofluorescence staining. The in vivo anticancer effect was measured using tumor xenografts in nude mice.Results: Chrysin inhibited the proliferation, migration, and invasion capacity of glioblastoma cells in dose- and time-dependent manners. Mechanistically, chrysin deactivated the Nrf2 signaling pathway by decreasing the translocation of Nrf2 into the nucleus and suppressing the expression of hemeoxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1, meanwhile, Nrf2 shRNA attenuated the anticancer activity of chrysin. Furthermore, chrysin downregulated the protein expression of p-extracellular signal-regulated kinase 1 and 2 (ERK1/2), but did not significantly affect p-JNK and p-P38 expression levels. However, the downregulated level of Nrf2 and the antitumor effect of chrysin in glioblastoma cell lines were partially abrogated by the ERK1/2 signaling inhibitor (U0126). Finally, chrysin inhibited tumor growth in U87 xenografts.Conclusion: Our results show that chrysin exerts anticancer activity in glioblastoma cell lines possibly via the ERK/Nrf2 signaling pathway and indicate the potential application of chrysin as a natural sensitizer in chemotherapy. Keywords: chrysin, glioblastoma, nuclear factor erythroid 2-related factor 2, Nrf2, extracellular signal-regulated kinase, ERK

Wenjie Guo,1,* Sihan Liu,2,* Xiaoli Zhang,1,* Yating Chen,1 Ruolan Qian,1 Ziyuan Zou,2 Xin Chen,1 Peng Luo1 1Department of Respiratory Medicine, Zhujiang Hospital, 2Department of Respiratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Non-small-cell lung cancer (NSCLC) is a common disease threatening the health of humankind. It has a low survival rate and a poor prognosis. Under normal circumstances, tumor infiltrating lymphocytes (TILs) play the main role in the antitumor process, but studies in recent years have found that NSCLC is capable of releasing various immunosuppressive ­factors, inducing the TILs to exhibit high expression of immune inhibitory receptors and relevant immunosuppressive factors. They can not only activate their own signal pathways but also block those of TILs, which causes inefficiency of tumor destruction. Researchers have now developed targeted drugs that specifically bind to immunosuppression receptors. By blocking signal transmission of immune inhibitory receptors, restraint on T lymphocytes can be released to recover antitumor role. Further research and understanding of the immunosuppression signal pathways of NSCLC are of significant importance to promote the development of immune-targeted drugs and the formulation of new treatment plans. This paper summarizes the immunosuppressive mechanisms of multiple important and newly discovered immune inhibitory receptors on T lymphocytes and immunosuppressive factors released by NSCLC cells, and their influence on patients’ survival rate and prognosis. Further laboratory and clinical studies on immune-targeted drugs for primary NSCLC are needed to provide more evidence. Keywords: NSCLC, TIL, immune inhibitory receptors, immune-targeted drugs

Manni Wang,* Xuelei Ma,* Linghong Guo, Fan Xia State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Background: The aim of the present review is to systematically evaluate the efficacy and safety of pembrolizumab by analyzing survival outcomes and at the same time, to present evidence for future clinical applications of anti-programmed cell death protein 1 (anti-PD-1) antibodies by analyzing the efficacy and safety of pembrolizumab.Methods: A comprehensive literature search of PubMed, Medline, and Embase was performed for all relevant clinical trials. In this study, adverse events of any grades and grades ≥3 were summarized and calculated for event rates. For controlled trials, odd ratios (ORs) were calculated to determine the role of pembrolizumab in adverse events. The Kaplan–Meier survival curves were extracted for hazard ratio (HR) calculation and survival outcomes were measured by progression-free survival (PFS).Results: A total of 3,953 patients were included in safety analyses. The results indicated that the overall incidence of any treatment emergent adverse events was 74.3% (95% confidence interval [CI]: 0.671–0.805). The efficacy analysis involving 915 patients with advanced melanoma suggested that 10 mg/kg of pembrolizumab every 3 weeks could improve patients’ PFS (HR =0.73, 95% CI: 0.64–0.83).Conclusion: Pembrolizumab is a promising therapeutic option that could bring better survival outcomes but, at the same time, leads to higher frequency of some adverse events. Keywords: pembrolizumab, safety, efficacy, meta-analysis

Fayong Ke,1,2,* Zheng Wang,1,2,* Xiaoling Song,1,2 Qiang Ma,1,2 Yunping Hu,2 Lin Jiang,2 Yijian Zhang,2 Yingbin Liu,1,2 Yong Zhang,1 Wei Gong1,2 1Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Institute of Biliary Disease Research, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Cholangiocarcinoma (CCA) is the most common biliary tract malignancy in the world with high resistance to current chemotherapies and extremely poor prognosis. The main objective of this study was to investigate the inhibitory effects of cryptotanshinone (CTS), a natural compound isolated from Salvia miltiorrhiza Bunge, on CCA both in vitro and in vivo and to explore the underlying mechanisms of CTS-induced apoptosis and cell cycle arrest. Methods: The anti-tumor activity of CTS on HCCC-9810 and RBE cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and Hoechst 33342 staining assays. The efficacy of CTS in vivo was evaluated using a HCCC-9810 xenograft model in athymic nude mice. The expression of key proteins involved in cell apoptosis and signaling pathway in vitro was analyzed by Western blot analysis. Results: CTS induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in HCCC-9810 and RBE cells in a dose-dependent manner. Intraperitoneal injection of CTS (0, 10, or 25 mg/kg) for 4 weeks significantly inhibited the growth of HCCC-9810 xenografts in athymic nude mice. CTS treatment induced S-phase arrest with a decrease of cyclin A1 and an increase of cyclin D1 protein level. Bcl-2 expression was downregulated remarkably, while Bax expression was increased after apoptosis occurred. Additionally, the activation of JAK2/STAT3 and PI3K/Akt/NFκB was significantly inhibited in CTS-treated CCA cells. Conclusion: CTS induced CCA cell apoptosis by suppressing both the JAK2/STAT3 and PI3K/Akt/NFκB signaling pathways and altering the expression of Bcl-2/Bax family, which was regulated by these two signaling pathways. CTS may serve as a potential therapeutic agent for CCA. Keywords: cholangiocarcinoma, cryptotanshinone, apoptosis, JAK2/STAT3, PI3K/Akt/NFκB

Fei Sun,1 Bing Xu,1,2 Yi Zhang,1 Shengyun Dai,1 Chan Yang,1 Xianglong Cui,1 Xinyuan Shi,1,2 Yanjiang Qiao1,2 1Research Center of Traditional Chinese Medicine Information Engineering, School of Chinese Materia Medica, Beijing University of Chinese Medicine, 2Key Laboratory of Manufacture Process Control and Quality Evaluation of Chinese Medicine, Beijing, People’s Republic of China Abstract: The quality of Chinese herbal medicine tablets suffers from batch-to-batch variability due to a lack of manufacturing process understanding. In this paper, the Panax notoginseng saponins (PNS) immediate release tablet was taken as the research subject. By defining the dissolution of five active pharmaceutical ingredients and the tablet tensile strength as critical quality attributes (CQAs), influences of both the manipulated process parameters introduced by an orthogonal experiment design and the intermediate granules’ properties on the CQAs were fully investigated by different chemometric methods, such as the partial least squares, the orthogonal projection to latent structures, and the multiblock partial least squares (MBPLS). By analyzing the loadings plots and variable importance in the projection indexes, the granule particle sizes and the minimal punch tip separation distance in tableting were identified as critical process parameters. Additionally, the MBPLS model suggested that the lubrication time in the final blending was also important in predicting tablet quality attributes. From the calculated block importance in the projection indexes, the tableting unit was confirmed to be the critical process unit of the manufacturing line. The results demonstrated that the combinatorial use of different multivariate modeling methods could help in understanding the complex process relationships as a whole. The output of this study can then be used to define a control strategy to improve the quality of the PNS immediate release tablet. Keywords: Panax notoginseng saponins, PNS immediate release tablet, pharmaceutical process understanding, partial least squares, orthogonal projections to latent structures, multiblock partial least squares, quality by design

Jiapeng Li,1,2 Yang Liu,2 Jingru Zhang,1,2 Xiaotong Yu,1,2 Xiaoling Wang,1 Libo Zhao11Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, 2Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Background: The intestinal cytochrome P450 3A (CYP 3A) and P-glycoprotein (P-gp) present a barrier to the oral absorption of saquinavir (SQV). Resveratrol (RESV) has been indicated to have modulatory effects on P-gp and CYP 3A. Therefore, this study was to investigate the effects of RESV on P-gp and CYP 3A activities in vitro and in vivo on oral SQV pharmacokinetics in rats.Methods: In vitro, intestinal microsomes were used to evaluate RESV effect on CYP 3A-mediated metabolism of SQV; MDR1-expressing Madin–Darby canine kidney (MDCKII-MDR1) cells were employed to assess the impact of RESV on P-gp-mediated efflux of SQV. In vivo effects were studied using 10 rats randomly assigned to receive oral SQV (30 mg/kg) with or without RESV (20 mg/kg). Serial blood samples were obtained over the following 24 h. Concentrations of SQV in samples were ascertained using high-performance liquid chromatography-tandem mass spectrometry analysis.Results: RESV (1–100 µM) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1–100 µM) reduced the accumulation of SQV in MDCKII-MDR1 cells in a concentration-dependent manner. A double peaking phenomenon was observed in the plasma SQV profiles in rats. The first peak of plasma SQV concentration was increased, but the second peak was reduced by coadministration with RESV. The mean AUC0–∞ of SQV was slightly decreased, with no statistical significance probably due to the high individual variation.Conclusion: RESV can alter the plasma SQV concentration profiles, shorten the Tmax of SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats. Keywords: resveratrol, saquinavir, P-glycoprotein, CYP 3A, pharmacokinetic

Yixuan Zeng,1,2,* Wenyuan Guo,1,* Guangqing Xu,3 Qinmei Wang,4 Luyang Feng,1,2 Simei Long,1 Fengyin Liang,1 Yi Huang,1 Xilin Lu,1 Shichang Li,5 Jiebin Zhou,5 Jean-Marc Burgunder,6 Jiyan Pang,5 Zhong Pei1,2 1Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, 2Guangzhou Center, Chinese Huntington’s Disease Network, 3Department of Rehabilitation, The First Affiliated Hospital, 4Key laboratory on Assisted Circulation, Ministry of Health, Department of Cardiovascular Medicine of the First Affiliated Hospital, 5School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 6Swiss Huntington’s Disease Center, Department of Neurology, University of Bern, Bern, Switzerland *These authors contributed equally to this work Abstract: Huntington’s disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington’s disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson’s and Alzheimer’s diseases. To identify potential neuroprotective molecules for Huntington’s disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington’s disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington’s disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results. Keywords: Huntington’s disease, mutant Huntingtin, xyloketal derivatives, Caenorhabditis elegans, protein misfolding, molecular target

Xiao-Liang Fan,1,* Guo-Ping Cai,2,* Liu-Long Zhu,1 Guo-Ming Ding1 1Department of Orthopaedics, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, 2Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the relevant studies and conducted a meta-analysis to assess the efficacy of ifosfamide-based chemotherapy in patients with osteosarcoma.Methods: A systematic literature search on PubMed, Embase, and Web of Science databases was performed. Eligible studies were clinical trials of patients with osteosarcoma who received ifosfamide-based chemotherapy. Hazard ratios (HRs) were pooled to compare event-free survival (EFS) and overall survival (OS). Risk ratios (RRs) were pooled to compare good histologic response rates and adverse event incidence. Meta-analysis was performed using a fixed-effects model or a random-effects model according to heterogeneity.Results: A total of seven randomized controlled trials were included in this meta-analysis. Pooled results showed that ifosfamide-based chemotherapy significantly improved EFS (HR=0.72, 95% confidence interval [CI]: 0.63, 0.82; P=0.000) and OS (HR=0.83, 95% CI: 0.70, 0.99; P=0.034); furthermore, this form of chemotherapy increased good histologic response rate (RR=1.27, 95% CI: 1.10, 1.46; P=0.001). In addition, patients in the ifosfamide group exhibited a significantly higher incidence of fever (RR=2.23, 95% CI: 1.42, 3.50; P=0.000) and required more frequent platelet transfusion (RR=1.92, 95% CI: 1.23, 3.01; P=0.004).Conclusion: This meta-analysis confirmed that ifosfamide-based chemotherapy can significantly improve EFS and OS; this chemotherapy can also increase good histologic response rate in patients with osteosarcoma. However, evidence may be limited by potential biases and confounders. Thus, large-scale well-designed randomized controlled trials are needed to verify current findings. Keywords: ifosfamide, osteosarcoma, chemotherapy, meta-analysis

Jin-Yang Shen,1,* Xiao-Lin Yang,2,* Zhong-Lin Yang,1 Jun-Ping Kou,1 Fei Li11State Key Laboratory of Natural Medicines, China Pharmaceutical University, 2Key Laboratory of Pharmaceutical and Biological Marine Resources Research and Development of Jiangsu Province, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workPurpose: This present study investigated the absorption kinetics of echinacoside (ECH) in situ and in vitro and its oral bioavailability in rats. Additional aim was to find an agent(s) to promote ECH absorption and oral bioavailability among two efflux proteins and three absorption promoters.Methods: ECH absorption behaviors were investigated by everted gut sac model in vitro and single-pass intestinal perfusion model in situ. Pharmacokinetics study was performed to investigate the influences of verapamil and clove oil on ECH bioavailability in vivo. All samples were measured at different time intervals by high performance liquid chromatography.Results: The results showed that the effective permeability coefficient (Peff) and apparent permeability coefficient of ECH were 0.83×10-6–3.23×10-6 cm/s and 2.99×10-6–9.86×10-6 cm/s, respectively. The Peff among duodenum, jejunum, and ileum were not statistically different, but they were higher than colon (P

Sheng-Long Li,1,* Fang-Yan Jing,1–3,* Li-Li Ma,2,3 Li-Li Guo,2,3 Feng Na,2,3 Sheng-Li An,4 Yan Ye,5 Jun-Ming Yang,1 Ming Bao,1 Dong Kang,1 Xiao-Lan Sun,1 Yong-Jian Deng2,3 1Department of Anorectal Surgery, 2Department of Pathology, Nanfang Hospital, 3Department of Pathology, School of Basic Medical Sciences, 4Department of Biostatistics, Southern Medical University, 5Department of General Surgery, Xintang Hospital, Zengcheng, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: The etiology and pathogenesis of hemorrhoids is unclear, although hemorrhoids are a worldwide disease in men and women, with peak prevalence at 45–65 years of age. Hemorrhoidal cushions as the anal venous plexi are normal anatomical structures from infancy. This study attempts to reveal the angiodysplasia and other pathological changes in association with different degrees of symptomatic hemorrhoids.Materials and methods: A total of 281 patients with internal hemorrhoids from degree I to IV underwent hemorrhoidectomy. The vascular changes were analyzed by microscopic assessment and software analysis, with Masson’s trichrome, CD34, and smooth muscle actin.Results: The hemorrhoidal tissues exhibited abnormal vessels in the mucosae and submucosae that we termed them as myofibrotic malformation vessels (MMVs). MMVs are not ascribed to arteries or veins because they exhibit enlarged and tortuous lumens with smooth muscle dysplasia and fibrotic deposition in the walls without overlying mucosal ulceration. The muscularis mucosae also showed smooth muscle dysplasia and fibrosis, even if it were interrupted by the intruding MMVs. The statistical data indicated that the severity of all the changes correlate positively with the progression of hemorrhoids (P

Guanghong Yang,1 Zhiwei Zhou,2 Yanli Cen,1 Xiaolin Gui,1 Qibing Zeng,1 Yunxia Ao,1 Qian Li,1 Shiran Wang,1 Jun Li,1 Aihua Zhang1 1Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, 2Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and posttranscriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury. Keywords: Fas/FasL pathway, mitochondrial pathway, liver injury

Anyuan Zhong,1* Xiaolu Xiong,2* Minhua Shi,1 Huajun Xu3 1Department of Respiratory Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, 2Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, 3Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contribute equally to this work Background: Pemetrexed is currently recommended as the second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether pemetrexed-based doublet therapy improves treatment efficacy and safety. Thus, this meta-analysis was performed to resolve this controversial question. Methods: Electronic databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles before April 2015. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) were used to analyze the overall response rate (ORR) and grade ≥3 toxicities. Subgroup analysis, sensitivity analysis, and publication bias were also evaluated. Results: A total of 2,519 patients from ten randomized controlled trials were included. Compared to pemetrexed alone, PFS and ORR significantly improved in the pemetrexed-based doublet group (HR, 0.86; 95% CI [confidence interval], 0.75–0.99; P=0.038; and OR, 1.98; 95% CI, 1.25–3.12; P=0.003, respectively). However, no statistically significant differences in OS were observed between groups (HR, 0.92; 95% CI, 0.83–1.02; P=0.132). In addition, subgroup analyses indicated that improved OS was only observed in nonsquamous NSCLC patients who received the combination of pemetrexed and erlotinib. An increasing incidence of grade ≥3 neutropenia and thrombocytopenia was observed in the pemetrexed-based doublet group. Conclusion: Among patients with advanced NSCLC, pemetrexed-based doublet treatment tended to be associated with improved PFS, ORR, and increased toxicity, but not OS. Keywords: non-small-cell lung cancer, pemetrexed, second-line, meta-analysis

Fang Yang,1 Ka-Hing Wong,2 Yufeng Yang,3 Xiaoling Li,1 Jie Jiang,1 Wenjie Zheng,1 Hualian Wu,1 Tianfeng Chen1 1Department of Chemistry, Jinan University, Guangzhou, People’s Republic of China; 2Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, People’s Republic of China; 3Institute of Hydrobiology, College of Life Science and Technology, Jinan University, Guangzhou, People’s Republic of China Abstract: Tellurium-containing phycocyanin (Te-PC) and allophycocyanin (Te-APC), two organic tellurium (Te) species, were purified from tellurium-enriched Spirulina platensis by a fast protein liquid chromatographic method. It was found that the incorporation of Te into the peptides enhanced the antioxidant activities of both phycobiliproteins. With fractionation by ammonium sulfate precipitation and hydroxylapatite chromatography, Te-PC and Te-APC could be effectively separated with high purity, and Te concentrations were 611.1 and 625.3 µg g-1 protein in Te-PC and Te-APC, respectively. The subunits in the proteins were identified by using MALDI-TOF-TOF mass spectrometry. Te incorporation enhanced the antioxidant activities of both phycobiliproteins, as examined by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid assay. Moreover, Te-PC and Te-APC showed dose-dependent protection on erythrocytes against the water-soluble free radical initiator 2,2'-azo(2-asmidinopropane)dihydrochloride-induced hemolysis. In the hepatoprotective model, apoptotic cell death and nuclear condensation induced by tert-butyl hydroperoxide in HepG2 cells was significantly attenuated by Te-PC and Te-APC. Taken together, these results suggest that Te-PC and Te-APC are promising Te-containing proteins with application potential for treatment of diseases related to oxidative stress. Keywords: tellurium, phycocyanin, allophycocyanin, purification, antioxidant activity