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Advances in small molecule inhibitors of PD-1/PD-L1 immune checkpoint pathway

Jiping TIAN ; Jian ZHANG ; Jinpei ZHOU ; Huibin ZHANG

Journal of China Pharmaceutical University.2019;50(1):1-10. doi:10.11665/j.issn.1000-5048.20190101

Studies have found that a variety of tumors continue to activate PD-1(programmed cell death protein 1, PD-1)/PD-L1(programmed cell death-ligand 1)signaling pathway by up-regulating PD-L1 expression in tumor cells and microenvironment. The dysfunction of T cells leads to the occurrence of tumor immune escape. Several PD-1/PD-L1 monoclonal antibodies have been marketed to achieve significant clinical efficacy. However, because of the high production cost, the harsh conditions for storage and transportation, and the potential immunogenicity of monoclonal antibody, the seeking for PD-1/PD-L1 small molecule inhibitors has become a hot spot in the development of new drugs. In this paper, the biological mechanisms of PD-1/PD-L1 was introduced in detail. Based on the structural classification, the research progress of PD-1/PD-L1 small molecule inhibitors was reviewed, with a prospect of the development of small molecule inhibitors.

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Strategies of nano drug delivery system applied in anti-angiogenic therapy

Shan YANG ; Cheng XU ; Jing YAO

Journal of China Pharmaceutical University.2019;50(1):11-18. doi:10.11665/j.issn.1000-5048.20190102

Anti-angiogenic therapy has a wide range of applications in the treatment of tumor. Nano drug delivery system can contribute to higher efficacy and lower toxicity in anti-angiogenic therapy. This article reviews the application of nano drug delivery system in anti-angiogenic therapy and introduces the strategies to improve its treatment efficiency with varieties of nanoparticles, providing reference for the development of anti-angiogenic therapy.

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Chemistry of steroidal saponins as natural resource compounds

Weisheng TIAN

Journal of China Pharmaceutical University.2019;50(1):19-32. doi:10.11665/j.issn.1000-5048.20190103

This article briefly summarizes our group′s systematic studies on the resource chemistry of steroidal sapogenins. Steroidal sapogenins are an important class of natural compounds, which could be utilized to synthesize various steroidal drugs. In order to achieve their efficient, clean and atom-economical utilization, our research group systematically investigated the oxidative degradation reaction of steroidal sapogenins. By employing 30% H2O2 as the oxidant, pseudo-sapogenins and sapogenins could be oxidized to the corresponding pregnenolone, pregnane-3β, 16, 20-triol, steroidal 22-lactone, as well as a series of bifunctional reagents with chiral methyl group. These oxidative degradation products have been applied to the synthesis of steroidal drugs, biologically active natural steroidal molecules and non-steroid functional chiral molecules. Furthermore, we explored the bromination-ring opening, amination-ring opening and bromolactonization reactions of the spiroketal moiety, which provides new strategies and methods in the utilization of their intact skeleton to the efficient syntheses of active components of traditional Chinese medicines with the cholesterol skeleton, as well as biologically active steroidal natural products.

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Progress in the analysis of adulterated additives in traditional Chinese medicines and health care products

Xiaofang HOU ; Yingdi SHI ; Sicen WANG

Journal of China Pharmaceutical University.2019;50(1):33-40. doi:10.11665/j.issn.1000-5048.20190103

In recent years, cases of illegal addition of chemical substances into the TCMs and health-care products happened regularly. Therefore, it is particularly important to develop fast, sensitive and accurate analysis methods for detection of the adulterated chemical substances. Through literature survey of relevant papers published in 2016-2017, this article summarizes the application of various analytical techniques for adulterated chemical substances to the TCMs and health-care products with useful information for the further development of new methods and technologies in this field.

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Chemical constituents extracted from Dictamnus dasycarpus and their α-glucosidase inhibitory activity

Xiaojun YANG ; Fengfeng AI ; Junbing LIN ; Jiangjiang TANG

Journal of China Pharmaceutical University.2019;50(1):41-45. doi:10.11665/j.issn.1000-5048.20190105

Five compounds were isolated from the petroleum ether extract of Dictamnus dasycarpus using various chromatographic techniques, such as column chromatography over silica gel and Sephadex LH-20. Their structures were elucidated by spectroscopic data(IR, MS, NMR), which were identified as docosanol(1), ethyl 2, 2-dibenzhydryl-3, 3-di-phenylpropionate(2), limonin(3), obacunone(4)and dictamnine(5). Compound 2 was a new compound and compound 1 was isolated from this plant for the first time. PNPG method was used to determine α-glucosidase inhibitory activity of these compounds. The results indicated that compounds 3- 5 possessed stronger inhibitory activities than the positive control of acarbose, which provided a theoretical basis for further development and utilization of Dictamnus dasycarpus.

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Isolation and identification of antitumor constituents from Trichosanthes tricuspidata

Yongmei ZHOU ; Cheng TANG ; Sifang ZHANG

Journal of China Pharmaceutical University.2019;50(1):46-52. doi:10.11665/j.issn.1000-5048.20190106

Ten compounds were isolated and purified from the dichloromethane fraction of Trichosanthes tricuspidata roots by silica gel and ODS column chromatographies. Their chemical structures were identified on the basis of their physical and chemical properties as well as the spectral data. These isolated compounds were elucidated as khekadaengoside O(1), a new hexanorcucurbitane glycoside, together with nine known compounds, including khekadaengoside C-E, K(2-5), cucurbitacin J-2-O-β-glucopyranoside(6), cucurbitacin K-2-O-β-glucopyranoside(7), cucurbitacin B, J, K(8-10). In addition, the anti-tumor activity of compounds 1-10 were evaluated in hepatocellular carcinoma BEL-7402 cell line. Among them, compounds 8-10 showed potent antitumor activity.

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Preparation and in vitro evaluation of pregabalin controlled porosity osmotic pump tablets

Ling ZHU ; Chao QIN ; Jinlian WU ; Yuhong CHEN ; Lifang YIN

Journal of China Pharmaceutical University.2019;50(1):53-58. doi:10.11665/j.issn.1000-5048.20190107

In this study, pregabalin controlled porosity osmotic pump tablets which are taken once a day were prepared. Single-factor tests were carried out to investigate the influence of excipients and manufacturing process. The formulation was optimized through orthogonal experiment on three levels of three significant factors including the amount of sodium citrate, and polyethylene glycol 400 and coating weight gain. On the basis of the results of the single-factor tests and the orthogonal experiment, optimal formulation and manufacturing process were obtained. The final tablet formulation contained pregabalin(82. 5 mg), microcrystalline cellulose(40%), sodium citrate(27. 5%), magnesium stearate(0. 5%)and 5% povidone K30 solution as the tablet binder; the coating formulation consisted of cellulose acetrate and 60% of polyethylene glycol 400 as a porogen; the coating weight gain was 3%. In vitro drug release kinetic study suggested that the drug release from controlled porosity osmotic pump tablets was mainly driven by osmotic pressure, which was barely affected by the pH of the release medium. The drug release behavior of the tablets within 12 hours complied with zero-order release rule and the linear correlation coefficient was 0. 991 6. The obtained porosity osmotic pump tablets could effectively slow the drug release rate, reduce concentration fluctuation and improve the safety and convenience for the patients, hence with broad prospects.

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Analysis of transcriptome sequencing and related genes of flavonoid biosynthesis from Anoectochilus roxburghii

Fuxian ZOU ; Wen XU ; Zehao HUANG ; Xun ZHANG ; Shuyun CHEN ; Yu LIN ; Wei XU

Journal of China Pharmaceutical University.2019;50(1):66-74. doi:10.11665/j.issn.1000-5048.20190109

Transcriptome sequencing was performed for the first time on Anoectochilus roxburghii(AR)in different harvesting periods using RNA-seq high-throughput sequencing technique, and the results were verified and analyzed by Q-PCR and HPLC. A total of 51, 370 genes were obtained by transcriptome sequencing and annotated to the database of Nr, GO, Swiss-Prot, KEGG and KOG. The species that were sequenced according to the homology sequence were the same as AR monocotyledon plants. Through comparison of AR transcriptome in different periods, it was found that the differences were mainly in flavonoid biosynthesis-related genes. The expression levels of flavonoid biosynthesis-related genes(trans-cinnamate 4-monooxygenase, caffeoyl-CoA O-methyltransferase, chalcone synthase, flavonol synthase, shikimate O-hydroxycinnamoyltransferase and flavonoid 3′, 5′-hydroxylase)were verified by Q-PCR, and the results were consistent with those of transcriptome sequencing. The contents of 6 flavonoids(rutin, isoquercitrin, narcissin, quercetin, kaempferol and isorhamnrtin)were determined by HPLC. The results showed that the expression of flavonoid synthetic gene in AR increased with the growth time, and the variation trend of flavonoid compound content and gene expression were basically consistent. Combined with transcriptome data, the biosynthetic pathway of flavonoid content in AR was plotted. This study provides important genetic resources for the key genes of flavonoid synthesis in AR and the biosynthesis of flavonoids, as well as the basis for the development of its medicinal value.

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Pharmacokinetics and absolute bioavailability of isoschaftoside in rat by LC-MS/MS

Feng LIANG ; Duo LI ; Rongbin WANG ; Chang SHU ; Li DING

Journal of China Pharmaceutical University.2019;50(1):75-80. doi:10.11665/j.issn.1000-5048.20190110

The aim of this study was to develop a highly sensitive and specific LC-MS/MS method to explore the pharmacokinetic properties and absolute bioavailability of isoschaftoside in rats. Blood sampling was performed at different time points after intragastric administration of isoschaftoside(1. 5, 3. 0, 6. 0 mg/kg)and 0. 5 mg/kg by intravenous injection. Isoschaftoside was analyzed by a validated LC-MS/MS method in plasma; the pharmacokinetic parameters and absolute bioavailability were evaluated by software DAS 3. 0. The results showed that the linear concentration ranges of isoschaftoside was 1. 0- 500. 0 ng/mL(r=0. 997 6). The precision, accuracy, matrix effect, sensitivity, dilution reliability and stability met the requirements of biological sample analysis. For ig administration of isoschaftoside(1. 5, 3. 0, 6. 0 mg/kg), the pharmacokinetic parameter cmax was(109. 34±22. 87), (259. 84±95. 35)and(499. 26±288. 09)ng/mL; AUC0-t was(310. 57±46. 18), (552. 67±207. 14)and(1 075. 03±371. 19)h ·ng/mL; t1/2 was(2. 36±0. 22), (2. 91±0. 19)and(3. 04±0. 86)h; tmax was(1. 03±0. 25), (1. 18±0. 17)and(1. 5±0. 43)h; MRT0-t was(11. 33±1. 53), (11. 27±1. 09)and(8. 29±0. 76)h, respectively. For iv administration of isoschaftoside(0. 5 mg/kg), the pharmacokinetic parameter AUC0-t was(1 536±421. 3)h ·ng/mL; t1/2 was(2. 57±0. 46)h; MRT0-t was(9. 55±2. 37)h. Furthermore, the absolute bioavailability was 6. 73%, 5. 99%, 5. 80%, respectively. The LC-MS/MS analysis method established in this study was accurate and sensitive, so it can be applied to the pharmacokinetic study of isoschaftoside.

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Comparative investigation of in vitro antitumor activity of Ganoderma lucidum spore oil

Xuehan PENG ; Wenmin XIE ; Ji LI ; YU Feng

Journal of China Pharmaceutical University.2019;50(1):81-86. doi:10.11665/j.issn.1000-5048.20190111

To investigate the antitumor activity induced by Ganoderma lucidum spore oil on different tumor cells. Human hepatoma cells(HepG2), human non-small cells lung cancer cells(A549)and human colon cancer cells(HCT116)were selected and tested. Cell viability was determined by MTT assay. Western blot analysis was performed to measure the expression of NF-κB and Caspase-3 activity in order to elucidate the mechanism of apoptotic activity caused by Ganoderma lucidum spore oil and to screen out the most sensitive cancer cell lines to Ganoderma lucidum spore oil. MTT assay demonstrated that Ganoderma lucidum spore oil had a strong inhibitory effect on the growth of three cancer cell lines. Among these cells, A549 cells were most sensitive to Ganoderma lucidum spore oil, followed by HepG2 cells and then by HCT116 cells. The results of Western blot showed that Ganoderma lucidum spore oil could promote the activation of NF-κB pathway, and that the activation of NF-κB signaling pathway in cancer cells treated by Ganoderma lucidum spore oil was stronger in A549 cells, HepG2 cells, HCT116 cells respectively. The detection of Caspase-3 activity showed that ganoderma spore oil could activate Caspase-3 dependent apoptosis pathways, which was more important in A549 cells, HepG2 cells and HCT116 cells. This study found that Ganoderma lucidum spore oil had inhibitory effects on A549, HepG2 and HCT116 cells growth and that its antitumor activity was in time-dose dependence. The mechanism may be related to the activation of NF-κB pathway and the Caspase-3 apoptotic pathway, which could accelerate apoptosis and necrosis of tumor cells. Among the three kinds of cancer cells, A549 cells was most sensitive to Ganoderma lucidum spore oil, followed by the HepG2 cells, and then by HCT116 cells.

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