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    Editorial Office of Journal of China Pharmaceutical University  Volume 52,2021 Issue 4

    Forward Pharmaceutical Sciences
    Original Articles
    Reviews
    Monograph
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    Forward Pharmaceutical Sciences
    2021,52(4):387-397, DOI: 10.11665/j.issn.1000-5048.20210401
    Abstract:
    Photodynamic therapy, a new type of non-invasive treatment, is based on the principle that the photosensitizer excited by laser can transfer energy to oxygen, which generates cytotoxic singlet oxygen and thus induce tumor cell apoptosis or necrosis. As an oxygen-dependent therapy, the antitumor effect of photodynamic therapy is obviously limited by hypoxia environment of solid tumor tissue. Therefore, reversing and improving the hypoxia of tumor tissue can significantly enhance the efficacy of photodynamic therapy. This review focuses on the progress of tumor oxygenation strategy mediated by nano-delivery system, including direct oxygen delivery strategies, catalytic oxygen production strategies, responsive material in situ oxygen supply strategies and microorganism oxygen supply strategies, aiming to improve the antitumor effect of photodynamic therapy. It provides new ideas and new approaches for further study of oxygen-enchancing nano-delivery system for photodynamic therapy.
    2021,52(4):398-409, DOI: 10.11665/j.issn.1000-5048.20210402
    Abstract:
    Alzheimer''s disease (AD) is the most common cause of senile dementia, accounting for an estimated 60% to 80% of cases, but there are no approved drugs to slow or stop the progressive clinical decline in the past years.Amyloid cascade hypothesis is recognized as the major etiologic basis for AD, however, the failures of several amyloid plaque-targeted programs have led many to dismiss the amyloid beta (Aβ) hypothesis of AD. Several reports show that soluble oligomers of Aβ (AβOs), which appear in brains more than 10 years before the clinical syndrome, are more toxic than Aβ plaque, causing synaptic dysfunction and neuronal apoptosis. Some agents that can effectively inhibit Aβ oligomer formation or block their toxicity made significant efficacy in clinical 2 and 3 trials, with the potential to be approved for the treatment of AD. This article reviews the recent development of AD drugs targeting Aβ oligomers, analyzes their structural characteristics, mechanism of action, preclinical and clinical data, and discusses the future direction of AD treatment, thus providing new strategies for AD drug research.
    2021,52(4):410-421, DOI: 10.11665/j.issn.1000-5048.20210403
    Abstract:
    With the rise of tumor immunotherapy, small molecule modulators targeting the immune system have become a research hotspot. As well-developed and mature targets, immunity protein kinases have attracted more and more attention. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively and modulate the translation of mRNA. Herein we review the structural characteristics, mechanism, signaling transduction pathways and close relationship with tumors of MNKs.Meanwhile, the development process and clinical research progress of the MNKs inhibitors reported by different research institutions are introduced in detail.
    2021,52(4):422-430, DOI: 10.11665/j.issn.1000-5048.20210404
    Abstract:
    Most of the proteomics analysis methods based on tandem mass spectrometry rely on the matching scoring of actual spectrum and theoretical spectrum, the interference of a large number of co-eluting peptides could cause error in the identification and quantification of peptides and proteins. Peptide retention time prediction, as a auxiliary and verification index of the peptide, can transition the chromatographic behavior into stable independent time attributes, and improve the accuracy of the peptide identification. Prediction of peptide chromatographic retention in complex systems is also of great significance for optimizing proteomics determination conditions and improving the detection rate and repeatability of mass spectrometry data in data-independent acquisition. This review focused on the chromatographic retention prediction method of unmodified peptides and modified peptides, summarizes the content, characteristics and limitations of four types of peptide retention time prediction methods based on standardized indexes, peptide molecular models, amino acid residue parameters, and machine learning, as well as their applications in proteomics, with a prospect of their future.
    Original Articles
    2021,52(4):431-437, DOI: 10.11665/j.issn.1000-5048.20210405
    Abstract:
    Using a series of purification methods including silica gel, Sephadex LH-20 and preparative high performance liquid chromatography, secondary metabolites of Myrothecium sp. were purified from the ethyl acetate extract of the solid fermentation product. Based on structure characterization and investigation on the physical and chemical properties a, twelve monomeric compounds were identified as 3''-hydroxyverrucarin A (1), verrucarin A (2), verrucarin L acetate (3), verrucarin J (4), verrucarin K (5), roridin A (6), roridin D (7), roridin H (8), roridin J (9), verrol 4-acetate (10), (3S, 3aS, 6α, 6aR)-dihydrosporothrioride (11) and 4,6-dihydroxy-1(3H)-isobenzofuranone (12). Compounds 1, 5 and 9 -12 were isolated from Myrothecium sp. for the first time.Compounds 2, 3, 4, 7 and 8 exhibited strong inhibitory effects on Candida albicans, with a minimal inhibitory concentration (MIC50) of 0.318, 0.218, 0.047, 0.569 and 0.558 μg/mL, respectively.
    2021,52(4):438-446, DOI: 10.11665/j.issn.1000-5048.20210406
    Abstract:
    Nowadays, there is still no mature gene delivery system for safe and effective transfection on primary dendritic cells (DC). Herein, we constructed a liposome-based gene delivery system for primary DCs and optimized the preparation method to improve the transfection efficiency of siRNA on primary DCs. In this study, different methods, including co-incubation method, ethanol injection method, and protamine compound method, were used to prepare liposome/siRNA complexes based on different cationic lipids. Moreover, particle size, zeta potential, siRNA loading capacity, safety, stability, uptake efficiency and gene silencing efficiency of various liposome/siRNA complexes were detected to screen the optimal cationic lipid as well as its preparation method. We demonstrated that the OA2/siRNA delivery system prepared by the co-incubation method exhibited the best safety, uptake efficiency and gene silencing effect, compared to other siRNA delivery systems including the commercial Lipo2000. In summary, we provide a safe and effective gene delivery vector for primary DC cells through simple preparation method, which could also offer a gene delivery platform for other immune cells.
    2021,52(4):447-454, DOI: 10.11665/j.issn.1000-5048.20210407
    Abstract:
    The aim of this study was to study the synthesis of two folate conjugates and their application in the preparation of folate targeted liposome, and to investigate their targeting effect in hepatocellular carcinoma HepG2 cell line in vitro. In this study, Folate-PEG-Cholesteryl hemisuccinate(Folate-PEG2000-CHEMS and Folate-PEG4000-CHEMS)were synthesized by linking folate and cholesterol succinate with two kinds of PEG materials. Structures of Folate-PEG2000-CHEMS and Folate-PEG4000-CHEMS were characterized by 1H NMR and ultra-high resolution mass spectrometry. Calcein was selected as the model drug, and calcein liposomes FA-PEG2000-L and FA-PEG4000-L were prepared by film dispersion method using Folate-PEG2000-CHEMS and Folate-PEG4000-CHEMS, respectively. The particle size and Zeta potential of FA-PEG2000-L and FA-PEG4000-L were measured by laser particle size analyzer. The drug delivery effect of FA-PEG2000-L and FA-PEG4000-L was evaluated by cellular uptake experiment in HepG2 cell line in vitro. Flow cytometry and laser confocal scanning microscope were used to determine fluorescence in HepG2 cells in vitro. The results showed that the average particle size of calcein liposome was (205.8 ± 10.2) nm, and the Zeta potential of calcein liposome was -(1.19 ± 0.31) mV.There was no significant difference in particle size and Zeta potential between FA-PEG2000-L and FA-PEG4000-L. The fluorescence intensity of FA-PEG4000-L liposome group was about 3.6 and 3.1 times higher than that of non-targeted liposome group and FA-PEG2000-L liposome group, with statistically significant difference (P < 0.01). The drug delivery efficiency of FA-PEG4000-L group in HepG2 cells was higher than that in FA-PEG2000-L and non-targeted groups, and the results indicated that Folate-PEG4000-CHEMS can promote the uptake of liposome by HepG2 cells in vitro. All in all, Folate-PEG4000-CHEMS could be applied in the preparation of folate targeted liposome, which could promote the uptake of liposome by HepG2 cells.
    2021,52(4):455-462, DOI: 10.11665/j.issn.1000-5048.20210408
    Abstract:
    To investigate the effects of intratracheal instillation of PM2.5 suspension on bleomycin (BLM)-induced pulmonary fibrosis in mice and the intervention of neotuberostemonine (NTS), the BLM dose (1.5 or 3.0 U/kg) and PM2.5 frequency (1 or 2 times per week) were studied by factorial experiment design. After intratracheal instillation of BLM (1.5 or 3.0 U/kg) on day 0, PM2.5 (5 mg/kg) was intratracheally injected to mice once or twice a week from day 1 to day 21, and the mice in the treatment group were given 30 mg/kg NTS by gavage once a day from day 8 to day 21. The degree of pulmonary fibrosis was evaluated by lung coefficient, hydroxyproline (HYP) content, HE staining and Masson staining lung sections as well as their semi-quantitative index (HE inflammatory score and collagen volume fraction, CVF). The results showed that the HE scores increased significantly in mice singly given PM2.5 once a week, the HYP content and HE score increased in mice singly given PM2.5 twice a week, but their CVF values did not significantly increase. However, the CVF values increased significantly in mice treated with PM2.5 and BLM co-infusion. These results suggested that PM2.5 (administered singly) could significantly increase BLM-induced collagen deposition and greatly aggravate pulmonary fibrosis although it mainly caused pulmonary inflammation rather than pulmonary fibrosis. NTS could significantly reduce the CVF value and α-SMA protein level of the model mice. It can be concluded that PM2.5 has great influence on patients with respiratory diseases, while NTS can improve pulmonary fibrosis induced by the combination of PM2.5 and BLM.
    2021,52(4):463-471, DOI: 10.11665/j.issn.1000-5048.20210409
    Abstract:
    To investigate the effects of sanguinarine (Sang) combined with cisplatin (Cis) in accelerating the apoptosis of bladder cancer EJ cells, CCK-8 method was used to detect the proliferation of bladder cancer EJ cells treated with different concentrations of Sang with the IC50 values calculated. Annexin V FITC/PI method was used to detect cell apoptosis in the control group, Sang group, Cis group and the combination group. Flow cytometer was used to detect cell cycle arrested. Western blot was used to detect the influence of Bcl-2 expression in the control group, Sang group, Cis group and the combination group. Nude mouse subcutaneous tumor model was constructed to verify that the combination group could accelerate the apoptosis of bladder cancer EJ cells and reduce the side-effects on mice. The safety of the Sang was evaluated by HE staining of vital organs in mice. In vitro, Sang could significantly inhibit the proliferation of EJ cells. Compared with the control group, the number of apoptosis EJ cells in the combination group was significantly increased (P < 0.05), and more cells were arrested in G2/M phase. The expression of Bcl-2 was significantly down-regulated in the combination group (P <0.001). In vivo, compared with the control group, the tumor growth was significantly slower, and a large number of apoptotic cells were inspected (P < 0.05) of the combination group. The side effects of cisplatin were reduced in the combination group. Sang has high biosafety and little side effect. Combined Sang and Cis can increase cell cycle G2/M block, down-regulate Bcl-2 expression, promote cell apoptosis and inhibit tumor growth.
    2021,52(4):472-479, DOI: 10.11665/j.issn.1000-5048.20210410
    Abstract:
    B7-H3 is an immune checkpoint molecule overexpressed on the surface of a variety of tumors, and is is an ideal target for tumor immunotherapy. In this study, nitrolated T cell epitope designed in the early stage of the laboratory was used to construct an epitope vaccine that can target immune checkpoint B7-H3. The vaccine can significantly inhibit tumor growth in the CT26 colon cancer model, and has a significant synergistic effect with the PD-L1 protein vaccine. B7-H3 vaccine can increase the proportion of CD4+ T cells in splenic T lymphocytes and the proportion of CD8+ T cells in tumor-infiltrating T lymphocytes, while reducing the proportion of suppressor Treg cells in tumor-infiltrating CD4+ T lymphocytes, which effectively improves tumor immunosuppressive microenvironment. Research results suggest that the B7-H3 epitope vaccine can be used as an effective tumor vaccine candidate molecule.
    2021,52(4):480-486, DOI: 10.11665/j.issn.1000-5048.20210411
    Abstract:
    In this study, the effects and mechanisms of miR-23b in the AD cell model were explored. Aβ25-35 was used to induce neuronal injury model, and cell viabilities were detected by MTT assay. The effect of miR-23b on the apoptotic levels of Aβ25-35-induced SH-SY5Y cells was analyzed using Annexin V-FITC/PI detection kit. The effect of miR-23b on the mitochondrial membrane potential of Aβ25-35-induced SH-SY5Y cells was examined using JC-1 fluorescent probe. The levels of cell apoptosis-related proteins and autophagy-related proteins were detected by Western blot. The results showed that miR-23b could alleviate the apoptosis and the abnormal mitochondrial membrane potential in SH-SY5Y cells induced by Aβ25-35.This study suggested that miR-23b may attenuate Aβ25-35-induced neuronal apoptosis by regulating apoptosis and autophagy-related pathway.
    2021,52(4):487-495, DOI: 10.11665/j.issn.1000-5048.20210412
    Abstract:
    Finding stable expression sites on the chromosomes of Chinese hamster ovary (CHO) cells is an effective method to solve the problem of unstable expression of CHO cells in long-term culture. Our group used lentiviral transfection to integrate the tracer gene (Zsgreen1) into the chromosome of CHO cells and found multiple potential stable expression sites. This study verified the ability of one of the sites located in the 148052-148157 bp region on chromosome NW_003614241.1 to stably express exogenous proteins.The expression of Zsgreen1 gene was first observed, and CRISPR/Cas9 technology was then used to integrate the enhanced green fluorescent protein (EGFP) gene into this site. Three strains of EGFP gene integrated cells were obtained. After 60 generations of suspension culture, the fluorescence intensity of the cells had no significant changes, which proved that this site can stably express the EGFP gene. The same method was used to construct recombinant CHO cell lines expressing the human serum albumin (HSA) gene, and was verified by Western blot that this site could express and secrete HSA. It shows that the above-mentioned sites can be integrated and can stably express exogenous proteins.
    Reviews
    2021,52(4):496-504, DOI: 10.11665/j.issn.1000-5048.20210413
    Abstract:
    Adoptive cellular immunotherapy has been widely recognized in recent years due to its remarkable results, especially the success of CD19-specific chimeric antigen receptor (CAR) autologous T cell therapy for malignant hematoma. Previous studies have found the existence of tumor immune microenvironment, heterogeneous targets, and immunosuppressive receptors in solid tumors, which has led to the shortcomings of CAR-T treatment of solid tumors. This article proposes the methods to improve CAR-T cells to increase T cell infiltration, co-expression of cytokines and enzymes and modification of related receptors in order to enhance the anti-solid tumor activity of CAR-T, laying a theoretical foundation for the follow-up CAR-T cell treatment of solid tumors.
    Monograph
    2021,52(4):505-512, DOI: 10.11665/j.issn.1000-5048.20210414
    Abstract:
    This paper aims to explore the feasibility of establishing a representative work screening method based on the academic recognition of the paper. Through comparative analysis of the strong and weak points of representative method, h-index core method, the subjective selection results by faculty applying for higher professional titles, and the academic recognition method established in this research (Q1 Journal-Percentile in Subject Area-Category Normalized Citation Impact, Q1-PSA-CNCI), representative works were introduced into the Z-index to form the Zh, Zr and Zq-index, and the correlations between the indicators were analyzed. Compared with other methods, the number of representative works obtained by the Q1-PSA-CNCI method is more reasonable. There was significant correlation among the indicators (P < 0.05), with no significant difference in the Zq-index among faculty evaluated for different professional titles (P > 0.05). Studies have shown that the Q1-PSA-CNCI method could help to screen representative works and was more reasonable than the number of representative works selected based on the other two methods, so Zq-index could be used as an indicator for representative work evaluation to provide reference for the qualitative evaluation of papers. It is more reasonable to improve the review process with the participation of "small peers".
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    Available online:July 17, 2021, DOI:
    Abstract:
    Duchene muscular dystrophy (DMD) is a serious progressive muscular dystrophy. Recently, reports about abnormal lipid in DMD patients have increased but little attention has been paid to liver lipid. This research aims to explore the effect of dystrophin gene defect on liver lipid synthesis. 7-year-old mdx male mice were used as a DMD model. The condition of liver function, liver lipid accumulation and liver lipid synthesis were determined through liver tissue morphology examination, blood biochemical examination, and detection of hepatic gene and protein expression. The results showed that lipid droplets in liver of mdx mice increased significantly. The contents of TC and TG in liver, ALT and AST in serum increased. The gene and protein expression of hepatic lipid synthesis-related enzymes such as ACC, FASN, SREBP-1c were up-regulated. These results showed accumulation of liver lipid in mdx mice.
    Available online:July 09, 2021, DOI:
    Abstract:
    As a key component of glutamatergic system, metabotropic glutamate receptor 5 (mGluR5) has been implicated in broad regulation of physiological processes such as synaptic transmission, synaptic plasticity and synaptic excitation/inhibition bal-ance. Over the past few decades, mGluR5 has been found closely related to multiple neurological and psychiatric disorders, thus mGluR5 is of considerable interest as a drug target in the treatment of these neurological and psychiatric disorders.This review summarizes the structure and distribution of mGluR5, its normal physi-ological function, its pathylogical roles in related central nervous system (CNS) diseases, as well as the current status of its drug development, in order to provide reference for further investigation.
    Available online:June 25, 2021, DOI:
    Abstract:
    MLL1 is a member of the "SET" histone methyltransferases family. MLL1 methyltransferase complex, consisting of MLL1, WDR5, RbBP5, Ash2L and DYP-30, regulates methylation level of histone H3 lysine 4 and is essential for development of human hematopoietic system and selfrenewal of blood cells. MLL1 fusion protein is an oncogenic protein caused by the translocation of MLL1 gene and has been found in some patients with leukemia. The complete MLL1 enzyme complex is required to perform histone demethylation effect. Therefore, targeting the protein-protein interaction of MLL1-WDR5 has become a potential strategy for treatment of leukemia induced by MLL1 fusion protein. This review systematically summarized the biological mechanism, structural information and inhibitors of MLL1-WDR5 protein-protein interaction, and made a perspective base on the reported data. These may provide a reference for further studies of this field.
    Available online:June 21, 2021, DOI:
    Abstract:
    This study aimed to investigate the effects of 60% ethanol elution fraction (ESMW) from Simiao pills on the hepatic lipid accumulation and its mechanism. TG kit, BODIPY fluorescence staining, QPCR, WB, oil red O staining, and AMPKα knockdown were used to detect the ability of ESMW to improve hepatic lipid accumulation in hepatocytes stimulated with free fatty acid. Furthermore, the effects of ESMW on the oral glucose tolerance, serum biochemical indexes, TG content in liver tissue, the expressions of mRNA and protein related to lipid metabolism in liver tissue were studied in high fat diet fed mice to verify the mechanism of ESMW fraction on hepatic lipid metabolism. The results showed that ESMW inhibited lipid accumulation induced by free fatty acids by regulating AMPK signaling pathway; The ESMW significantly improved the lipid metabolism of mice fed high fat diet, and the effect was related to AMPK signaling pathway.
    Available online:June 03, 2021, DOI:
    Abstract:
    Pancreatic cancer stroma plays a critical role in tumor progression, invasion, metastasis and resistance. Targeting tumor cell alone could not meet the demand for prolonging patients’ survival. Growing studies put emphasis on developing combined regimens between tageting pancreatic cancer stroma and chemotherapy, radiotherapy and immunotherapy. Great challenges are brought owing to the complicated stroma components, crosstalking siganal pathways and abnormal aniogenesis of pancreatic cancer, meanwhile providing relative opportunities. In this review, recent advances in theraputic strategies of targeting pancreatic cancer stroma were overviewed and analyzed from the aspects of extracellular matrix, cancer associated fibroblasts and vessels to provide novel ideas for targeting pancreatic cancer therapy.
    Available online:June 01, 2021, DOI:
    Abstract:
    To establish a rapid method for the determination of dezocine and pethidine in hair samples by UPLC-MS/MS. After cleaned hair was extracted by grinding with methanol and ultrasonic, the final solution was analyzed by UPLC-MS/MS. The targets were gradient eluted on a Waters ACQUITY BEH C18 (2.1 mm × 100 mm, 1.7 μm) column with 0.1% formic acid-water and methanol as mobile phase at a flow rate of 0.4 mL/min. The ESI+ ion source and multiple reaction monitoring(MRM)were used to select the qualitative and quantitative ion pairs of dezocine and pethidine. Dezocine and pethidine showed good linearity in the range of 0.01~8 ng/mg, and the limit of detection was 0.005 ng/mg, LOQs were 0.01 ng/mg; the accuracy, precision, matrix effect, extraction recovery, and stability all met the requirements. The established method is simple, rapid, and accurate for the qualitative and quantitative determination of dezocine and pethidine in hair, which can be applied to the abuse of dezocine and/or pethidine.
    Available online:May 31, 2021, DOI:
    Abstract:
    The purpose of this article is to express the UDP-glucose 4-epimerase from Acinetobacter baumannii AB0057 and characterize its enzymatic properties as well as analyzing its structure and function. The epimerase gene was constructed into pET-28a expression vector and heterologously expressed in BL21(DE3). Enzyme activity was assayed using high performance liquid chromatography. The structure and key residues were analyzed by phylogenetic analysis, sequence alignment, homology modeling and molecular docking. Results indicated that the recombinant enzyme Gne1 was expressed at a molecular weight of 38.9 kDa, with an optimum temperature of 44 °C and an optimum pH of 6.0 . Michaelis-Menten parameters KM and kcat were 1.227±0.0824 mmol/L and (82.64±3.562) 10-3·min-1. The N-terminal structural domain bound to NAD, while the C-terminal structural domain bound to substrate, and the catalytic key sites were S125 and Y150. The paper verified the epimerase activity of Gne1, explained its sequence and structural features, revealed its binding mode with substrates and cofactors, and analyzed key residues. It provides a basis for protein engineering to improve the epimerase activity and then use biological enzymatic method to synthesize rare functional sugars.
    Available online:May 31, 2021, DOI:
    Abstract:
    Poly-adenosine diphosphate ribose polymerases (PARPs) use the nicotinamide adenine dinucleotide (NAD+) as substrate to regulate various kinds of cell responses by transferring single or chains of ADP-ribose subunits to themselves or other target proteins. Wherein, mono-(ADP-ribosyl) transferase (MART) enzymes catalyze single ADP-ribose. Similar to PARP1/2, most MARTs are highly expressed in cancers. Some MARTs including PARP7, PARP9, PARP10 and PARP14 have been proved to be closely related to the occurrence and progression of cancers, they might be potential targets for detection and treatment of these cancers. This review will focus on the MARTs that are highly expressed in cancers to summary their potential value in cancer therapy and the research progress of their inhibitors.
    Available online:May 11, 2021, DOI:
    Abstract:
    A deuterated internal standard quantitative analysis method based on liquid-liquid extraction-ultra performance liquid chromatography-tandem mass spectrometry (LLE-UPLC-MS/MS) for simultaneous determination of 10 illicit drugs in wastewater was established. Wastewater samples were concentrated by liquid-liquid extraction with dichloromethane: ethyl acetate (1:1, v:v), and separated by a linear gradient of 0.1% formic acid-5mM ammonium formate aqueous solution and acetonitrile on a C18 column. The samples were then detected by ESI positive ion mode and multiple reaction monitoring mode (MRM) for quantitative analysis. All analytes had a good linear relationship (r≥0.9957) within the range of their respective standard curves, the limit of quantification was 1 ng/L (except amphetamine at 2. 5 ng/L); the relative recovery rate ranged from 96.36 to 106.43%, and the intra- and inter-day precisions were less than 4.70 %. This method is accurate, reliable and reproducible, and is suitable for the quantitative determination of 10 illicit drugs in wastewater. It is also suitable for wastewater with complex matrixes that affect solid phase extraction and enrichment. It provides a new analytical method for real-time monitoring of drug abuse.
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    2016,47(3):259-266, DOI: 10.11665/j.issn.1000-5048.20160302
    [Abstract] (3376) [HTML] (0) [PDF 1.56 M] (40343)
    Abstract:
    Hedgehog pathway regulates the physiological process of tumor cells, including proliferation, cycle, invasion and metastasis, and maintains tumorigenesis and development. With abnomal activation of Hedgehog pathway, most tumors response poorly to chemotherapy, which is mediated by Hedgehog pathway through activation of target gene and crosstalk with other pathways. Herein, Hedgehog pathway has been an important target for reversing resistance. In this study, the Hedgehog pathway and role of Hedgehog-mediated resistance in recent years are reviewed.
    2010,41(5):385-394, DOI:
    [Abstract] (5541) [HTML] (0) [PDF 1.18 M] (9878)
    Abstract:
    Prostaglandins is a kind of endogenous compounds with extensive physiological activities,and more than twenty kinds of natural prostaglandins have been found,while about two thousand prostanoid have been synthetized.These compounds have been developed as therapic agents,which are used in alimentary system,cardiovascular system, genital system and anti-glaucoma.Numerous types of prostaglandin receptors exist in organism,belonging to G-protein-coupled receptor superfamily,mediate multiple physiological and pathological processes,such as asthma,pain and inflammation.This review summarizes the properties of each type of prostaglandin receptor,and the clinical applications and research progress of drugs targeting their corresponding prostaglandin receptors.
    2010,41(2):97-103, DOI:
    [Abstract] (5510) [HTML] (0) [PDF 539.59 K] (9707)
    Abstract:
    Mechanism studies in the gene regulation in the eukaryotic cells is one of the momentous areas in molecular biology.Regulation at transcription level is a complex progress with multiple steps with the presence of the gene functions.There exist ubiquitous occurrence of transcription factors in mammalian tissues and biodiversity in the factors.These transcription factors are found to relate closely to various carcinogeneses,including cell proliferation,apoptosis,invasion and angiogenesis.Understanding of transcription factors and their action mechanisms,through the activation and inhibition of transcription factors, would potentially lead to the discovery of new entities in the targeting treatment and prevention of the cancer diseases.
    2012,43(5):475-480, DOI:
    [Abstract] (3791) [HTML] (0) [PDF 947.09 K] (9516)
    Abstract:
    New solid forms with modified physicochemical and biopharmaceutical properties can be obtained by introducing different guest molecules to form cocrystals or salts.This approach appears to be an advantageous alternative for pharmaceutical research and development.Inspired by the newly released Guidance for Industry:Regulatory Classification of Pharmaceutical Cocrystals,we reviewed the differences between cocrystals and salts in their definition,structure,characterization,regulatory issues and physicochemical properties such as solubility,stability as well as bioavailability.In addition,some newly developed techniques for characterizing cocrystals or salts are also introduced.
    2018,49(2):136-146, DOI: 10.11665/j.issn.1000-5048.20180202
    [Abstract] (1522) [HTML] (0) [PDF 2.90 M] (9388)
    Abstract:
    Fullerene is an effective free radical scavenger and antioxidant. The fullerene derivatives obtained by chemical modification of fullerene have good water solubility and biological activities. Fullerene and its derivatives have many advantages in cell protection and antioxidant properties, antibacterial activity, antiviral activity, photodynamic activity, drug delivery and anti-tumor activities, playing an important role in the field of medicine. In recent years, great progress has been made in this field. In this review, we summarized the latest research progress and applications of fullerene and its derivatives in medicine field at home and abroad from four aspects of regulating tumor microenvironment, drug delivery, photodynamic therapy and anti-oxidative stress. At last, the future development and application of fullerene and its derivatives in the domain of medicine are prospected.
    2010,41(1):55-59, DOI:
    [Abstract] (5053) [HTML] (0) [PDF 969.51 K] (9218)
    Abstract:
    Aim:To study pharmacokinetics of aconitine,mesaconitine and hypaconitine in rats after single oral administration of decoctions composed with Radix Aconiti Lateralis.Methods:Four groups of rats were orally administered four decoctions including decoction a(Sini decoction),decoction b(decoction composed with Radix Aconiti Lateralis),decoction c(decoction composed with Radix Aconiti Laterali and Radix et Rhizoma Glycyrrhizae Praeparata Cum Melle) and decoction d(decoction composed with Radix Aconiti Laterali and Rhizoma Zingiberis),respectively.Quantitative analysis of aconitine,mesaconitine and hypaconitine in rat plasma was achieved using a liquid chromatography-electrospray ionization/tandem mass spectrometry method.Pharmacokinetic parameters were estimated using DAS 2.0.Results:Pharmacokinetic parameters of aconitine,mesaconitine and hypaconitine were different after oral administration of four decoctions according to Radix Aconiti Laterali combined with different herbal medicines.Multiple peaks were observed in plasma concentration-time curve after oral administration of the decoction of herb couple Radix Aconiti Laterali and Radix et Rhizoma Glycyrrhizae Praeparata Cum Melle,and the results showed a delay in tmax and a prolonger in MRT0-t compared with the decoction of Radix Aconiti Lateralis.When Radix Aconiti Lateralis was combined with Radix et Rhizoma Glycyrrhizae Praeparata Cum Melle and Rhizoma Zingiberis at the same time in Sini decoction,tmaxwas delayed too but MRT0-t was shorten than that of the group of Radix Aconiti Lateralis.Conclusion:The pharmacokinetic parameters of the three compounds obtained in this work shows that the pharmacokinetics of aconitine,mesaconitine and hypaconitine were influenced diversely when Radix Aconiti Laterali was combined with different herbal medicines.
    2013,44(2):97-104, DOI: 10.11665/j.issn.1000-5048.20130201
    [Abstract] (2257) [HTML] (0) [PDF 1.03 M] (8070)
    Abstract:
    Modern pharmaceutics has undergone a rapid development in recent years.For the significance of reducing adverse drug reaction,improving drug efficiency and ensuring safety of drugs,novel drug delivery system (DDS) shows expansive foreground.The latest advances on modern pharmaceutics including organic drug DDS,inorganic drug DDS and biopharmaceutics DDS,are reviewed in this paper.
    2016,47(3):267-274, DOI: 10.11665/j.issn.1000-5048.20160303
    [Abstract] (2370) [HTML] (0) [PDF 1.07 M] (8047)
    Abstract:
    Genotoxic or potentially genotoxic impurities seriously threaten people′s health, therefore, it is necessary to identify and quantify these impurities in pharmaceutical materials even at trace levels. Due to the special requirements on the sensitivity, selectivity, analyte stability and matrix effect, development of analytical methods is a challenge for the determination of genotoxic impurities. This paper reviews the recent advances in analytical methods for trace levels of commonly encountered genotoxic or potentially genotoxic impurities, including alkyl halides, alkyl sulfonates, hydrazines, epoxides and acyl halides, which would be helpful to control these impurities.
    2011,42(2):97-106, DOI:
    [Abstract] (6425) [HTML] (0) [PDF 1.12 M] (7594)
    Abstract:
    Diabetes mellitus,an epidemic metabolic disorder characterized by high blood glucose level associated with various microvascular complications,is one of the main causes of human suffering across the globe.With the advance of the pathogenesis of diabetic research,the study of anti-diabetic drugs has transformed from the traditional drugs to the current products with new targets and new mechanism.Some of these drugs are already marketed or still in clinical trials,e.g. GLP-1 activator,DPP-4 inhibitor,GPR119 activator,SGLT-2 inhibitor,11β-HSD1 inhibitor,PTP1B inhibitor and so on.In this article,the new antidiabetic drugs mentioned above are reviewed with regard to the therapeutic targets and mechanism.
    2012,43(1):9-15, DOI:
    [Abstract] (2963) [HTML] (0) [PDF 1.31 M] (7460)
    Abstract:
    Targeted delivery system have been the important research fields in pharmaceutics,but the complicated physiological conditions hinder the targeting efficacy.The scientists took many strategies in designing the drug carriers to face the situation,including the intelligent delivery system and adaptive delivery system,which can navigate drug carriers through the blood hurdles,target to the specific cell,even the organelle.The review introduced these advances.
    2016,47(2):125-133, DOI: 10.11665/j.issn.1000-5048.20160201
    [Abstract] (2013) [HTML] (0) [PDF 1.73 M] (7366)
    Abstract:
    With the rapid development of nanotechnology and in-depth understanding of tumor microenvironment, stimuli-responsive smart drug delivery nanosystem based on tumor microenvironment(TME)has received extensive attention. TME-responsive smart delivery nanosystem can transport antitumor drug in circulation stably, after arriving in tumor tissue or targeted cells, the structure of nanocarriers changes under the stimuli of TME. Improved drug concentrations in targeted site significantly increase the antitumor efficiency and reduce the side effects of drugs. The stimulating factors in the TME include pH, redox potential, enzyme, reactive oxygen species(ROS), adenosine-5′-triphosphate(ATP)and so on. This review mainly gives a comprehensive overview in the latest research and new development in TME-responsive smart drug delivery nanosystems for efficient tumor therapy, mainly based on pH response type, enzyme response, reduction response, ROS response, and ATP response smart drug delivery nanosystems. Moreover, research directions in the future are pointed out in this review.
    2012,43(2):107-112, DOI:
    [Abstract] (3775) [HTML] (0) [PDF 1.10 M] (7203)
    Abstract:
    In recent years,some new anticancer strategies have been found with a growing understanding of the underlying biology of cancer.For example,molecular targeting cancer therapy,which is based on the oncogene addiction phenomenon,had proved to be a successful strategy in some specific cancer types.A more recent example came from synthetic lethality which is now showing great promise as a new direction of anticancer drug discovery.Previous research has shown that PARP-1 and BRCA have a relationship of synthetic lethality.We herein describe the rationale of this synthetic lethality and the potential applications of this interaction in anticancer therapy.
    2012,43(6):567-572, DOI:
    [Abstract] (1919) [HTML] (0) [PDF 1.38 M] (7061)
    Abstract:
    Mesoporous silica nanoparticles(MSNs) is a new inorganic material which has attracted extensive attention as drug nanocarriers in recent years.In this review,we summarized the current investigations about the preparation,biocompatibility,drug loading and drug delivery applications of MSNs.
    2010,41(1):1-10, DOI:
    [Abstract] (7235) [HTML] (0) [PDF 1.09 M] (7034)
    Abstract:
    Tumor microenvironment plays a crucial role in neoplastic evolution process as it may provide functional interactions between neoplastic and non-neoplastic cells involved in tumor invasion,metastasis and angiogenesis,which implies that it can be regarded as a novel target for the antitumor therapy of polysaccharides. This review focuses on the protumor variations existing in tumor microenvironment,such as growth factors,immunosuppressive factors,proteases,glycoproteins,etc.,which may offer possible mechanisms of polysaccharides on the regulation of their corresponding functions.
    2017,48(1):110-116, DOI: 10.11665/j.issn.1000-5048.20170117
    [Abstract] (1040) [HTML] (0) [PDF 1.00 M] (6807)
    Abstract:
    Autophagy is a conserved self-defense mechanism of organism, degrading the necrotic organelles and excess protein into small molecules for recycling. Autophagy plays a role in both physiological and pathological condition, influencing the expression of intracellular substance through multiple signaling pathways. Although it has been demonstrated that Ras/Raf/MEK/ERK signaling pathway was not only extensively involved in the regulation of cell growth, proliferation, differentiation and apoptosis, but was also implicated in autophagy and autophagic cell death, though its detailed mechanisms involved in regulation of autophagy has not been fully elucidated yet. This review focused on the advances of autophagy induced by Ras/Raf/MEK/ERK signaling pathway, to better understand the role of Ras/Raf/MEK/ERK signaling pathway in regulation of autophagy.
    2010,41(1):91-96, DOI:
    [Abstract] (2574) [HTML] (0) [PDF 1.01 M] (6413)
    Abstract:
    Pharmacometrics,developed from the conventional pharmacokinetics,is the science of applying mathematical and statistical methods to characterize,understand,and predict a drug′s pharmacokinetic,pharmacodynamic,and biomarker-outcome behaviors.Pharmacometrics has been widely valued for its utility of modeling and simulation in drug research and development,therapeutic drug monitoring and individualized therapy.This paper reviewed the advances of pharmacometrics employed in new drug research and development and therapeutic drug monitoring both at home and abroad.
    2017,48(3):361-370, DOI: 10.11665/j.issn.1000-5048.20170318
    [Abstract] (1252) [HTML] (0) [PDF 2.19 M] (6136)
    Abstract:
    Indoleamine 2, 3-dioxygenase 1(IDO1)is the rate-limiting enzyme which catalyses the metabolism of L-tryptophan(L-Trp)in the kynurenine pathway. It is overexpressed in many tumor cells and antigen presenting cells. This enzyme inhibits local immune response and supports tumor cells to evade immune surveillance by depleting L-Trp and producing kynurenine metabolites, thus, it is an important target for cancer immunotherapy. There are several IDO1 inhibitors with different scarfold under investigation, three of which have already entered clinical stage. The role of IDO1 in tumor immune tolerance and the research progress on IDO1 inhibitors in recent years are summarized in this paper.
    2010,41(4):317-320, DOI:
    [Abstract] (6477) [HTML] (0) [PDF 466.63 K] (5717)
    Abstract:
    This paper deals with the development of a practical process for lapatinib tosylate monohydrate(〖STHZ〗1〖STBZ〗),a molecule-targeted antitumor agent.The target product 1 was synthesized from commercially available 6-iodoquinazolin-4-one(3 in a five-step process with an overall yield of 48% via chlorination(88% yield),palladium carbon catalyzed Suzuki coupling with 5-formyl-2-furylboronic acid(96% yield),reductive amination with 2-(methylsulfone)ethylamine(94% yield),salt formation with p-toluenesulfonic acid monohydrate(87% yield),and final crystallization from THF-water (8∶2) (70% yield).The intermediates and the target product were characterized by melting points,1H NMR,13C NMR,and ESI-MS.During our optimized process,chromatography,large excess of chlorinating agent and halogenated solvent that are unfriendly to the environment were all removed;expensive and difficult-to-handle homogeneous catalyst was successfully substituted with heterogeneous catalyst palladium carbon which could be recovered easily.In conclusion,this streamlined synthetic process of lapatinib tosylate monohydrate(1) highlights excellent yield in almost every procedure,ease of operation,robustness,as well as green chemistry,and thus should be amenable to large-scale production.
    2015,46(3):279-288, DOI: 10.11665/j.issn.1000-5048.20150304
    [Abstract] (2055) [HTML] (0) [PDF 1.15 M] (5676)
    Abstract:
    The successes of therapeutic monoclonal antibodies(mAbs)in clinical practice has drawn more attention to mAbs development. Compared to chemical drugs with small molecules, mAbs have larger molecular weight; besides, they show much higher selectivity and specificity. As a result, new pharmacokinetic(PK)and pharmacokinetic/pharmacodynamic(PK/PD)models have been proposed to guide mAbs development. This article summarizes the unique PK characteristics of mAbs and introduces the models used in PK investigation of mAbs, such as target-mediated drug disposition(TMDD)model and physiologically based pharmacokinetic(PBPK)model. In addition, four different categories of PK/PD models for mAbs in immuno-toxicotherapy, target-cell elimination, alteration of cellular function and drug targeting are also reviewed in the present article.
  • 中国药科大学学报
  • 主    编:王广基
  • 常务副主编:尤启冬
  • 副主编:孔令义 吴晓明 张奕华
  • 主    办:中国药科大学
  • 地    址:江苏省南京市童家巷24号
  • 电    话:025-83271566
  • 传    真:025-83271279
  • E-mail:xuebao@cpu.edu.cn
  • 刊    号:ISSN 1000-5048  
                    CN 32-1157/R
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