Research advances on dihydrofolate reductase inhibitors in the treatment of tumors and bacterial infections / 药学学报

Dihydrofolate reductase (DHFR) is a well-known key target in the treatment of tumors, bacterial infections, and parasitic infections; and it plays a critical role in the biosynthesis of cellular DNA. DHFR inhibitors interfere with one-carbon metabolism by inhibiting substrate binding to DHFR, thereby inhibiting cell proliferation. Research on DHFR inhibitors has continued since the 1940s. To date, a variety of DHFR inhibitors have come into the market, primarily used for anti-tumor, antibacterial, antiparasitic, and anti-inflammatory therapy. This review summarizes the research progress of DHFR inhibitors with antitumor or antibacterial effects in recent years based on the classification of single-target and dual-target and looks forward to the opportunities and challenges faced by the work in this field.

Advances in anti-tumor research of HDAC inhibitors and combination with PI3K inhibitors / 药学学报

Histone deacetylase (HDAC) is usually abnormally overexpressed, which mainly leads to the transcriptional repression of tumor suppressor genes. Histone deacetylase inhibitors (HDIs) exert anti-tumor biological effects by regulating nucleosome structure, inhibiting HDAC activity, and controlling the expression of tumor suppressor genes. There are currently 5 drugs on the market, but only for peripheral T-cell lymphoma and cutaneous T-cell lymphoma. In solid tumors, most of the HDAC inhibitors used have failed to achieve effective therapeutic effects. Phosphoinositide 3-kinase (PI3K) is the starting node of the PI3K-AKT-mTOR signaling pathway, which plays a very important role in the proliferation, migration, invasion, and differentiation of tumor cells. The abnormal activation of PI3K is closely related to the occurrence and development of tumors, and the combined use of HDAC and PI3K inhibitors and HDAC/PI3K dual-target inhibitors show synergistic anticancer activity. This article introduces the anti-tumor clinical and preclinical research progress of representative HDAC inhibitors and PI3K inhibitors, as well as HDAC/PI3K dual-target inhibitors.

Research Advances of Genetics, Diagnosis and Treatment of T-cell Prolymphocytic Leukemia--Review / 中国实验血液学杂志

T-cell prolymphocytic leukemia (T-PLL) is a rare but highly aggressive and malignant mature T-lymphoid tumor. The diagnosis of T-PLL mainly depend on genetic characteristics, clinical manifestations, cell morphology and immunophenotype. At present, clinical treatment is mainly aimed at improving the response rate and prolonging the remission period. With the development of new molecular biology technologies, researchers have gained a deeper understanding of the pathogenesis and related genetics of T-PLL, targeted drugs, including HDAC inhibitors, JAK/STAT inhibitors, AKT inhibitors and BCL-2 inhibitors, are also under evolution and providing the new opportunities to improve the efficacy of therapy. In this review, the advances in genetics and treatment of T-PLL were summarized briefly.

Research Progress on Chemical Constituents and Pharmacological Effects of Asari Radix et Rhizoma / 中国实验方剂学杂志

Asari Radix et Rhizoma （ARR） is a traditional Chinese medicine for relieving exterior syndrome， and its roots and stems contain rich chemical components， including volatile oils （terpenoids， aromatics and aliphatics）， lignans， flavonoids， etc. Clinically， it has been traditionally used for the treatment of diseases such as phlegm and cough， anemofrigid cold， rheumatic arthralgia due to its ability to spread cold. Modern pharmacological studies have shown that ARR played beneficial roles in analgesic， anti-inflammatory， antitussive， antiasthmatic， antiviral， antibacterial， sedative， antioxidative， and antidepressant responses， antihypertension， as well as tumor suppression. The current studies on the chemical composition of ARR mainly focused on volatile components， and little information is available for the occurrence and pharmacological effects of non-volatile components. In addition， there is a lack of clear classification of chemical components and the distribution of chemical components in medicinal parts and the origin of species. Therefore， in this study， the authors reviewed a large number of literature on the chemical compositions and pharmacological effects of ARR， and hoping to provide a reference for further pharmacological research and the new drug development of ARR.

Synthesis and biological evaluation of phosphoinositide 3-kinase (PI3K) inhibitors based on a quinoxaline scaffold / 药学学报

Based on the structure of inhibitors XL765 and WR23, the quinoxaline scaffold was selected as an attractive structure for drug design. In this protocol, the 2-position of quinoxaline was modified with a substituted phenoxy fragment. Meanwhile, the linking chain at the 3-position was changed to a sulfonyl hydrazine or was removed. A series of substituent groups were added at the 6-position of the quinoxaline scaffold. Twenty-two quinoline derivatives were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR, and ESI-MS. All compounds were screened for anti-tumor activity in vitro in A549, MCF-7, HCT-116 and HepG2 cancer cells. The results showed that P6b was effective, P6e and P6f had better activity against HCT116 (IC50 = 3.24, 4.78 and 4.50 μmol·L-1), and P6d had strong inhibitory effect on MCF-7 (IC50 = 0.228 7 μmol·L-1).

Pien Tze Huang promotes HepG2 apoptosis via regulating ANXA1/VEGF signaling pathway / 中国药理学通报

Aim To explore the effect of Pien Tze Huang (PZH) on inhibiting HepG2 cells via regulating ANXA1/VEGF signaling pathway and the underlying mechanism. Methods HepG2 cells were treated with different concentrations (1, 1 0, 100 mg • L ~ l ) of PZH. MTT assay and colony formation assay were used to calculate cell viability and cell survival. Western blot was used to determine the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-9, and ANXA1/VEGF signaling pathway protein, such as ANXA1, VEGF, VEGFR, NF-KB P 5 0 . Results Compared with normal group, different concentrations of PZH inhibited HepG2 cells in a dose-dependent manner, inhibited the colony formation, promoted the expression of apoptotic expression, promoted the expression of ANXA1 protein, inhibited the expression of VEGF, VEGFR, and N F - K B P 5 0 as well. Conclusions PZH can inhibit the activity of HepG2 cells in vitro. Its main mechanism is related to the promotion of apoptotic protein in HepG2 cells, the promotion of cell ANXA1 protein, and the inhibition of VEGF/VEGF receptor and NF-KB signaling pathway.

Establishment and optimization of an enzyme-cell based high-throughput screening platform for IDO1 inhibitors / 药学学报

In this study, we used the tumor immunotherapy protein indoleamine 2,3-dioxygenase 1 (IDO1) as the target, and proposed an enzyme-cell-based tertiary IDO1 inhibitor high throughput screening platform. Firstly, the recombinant human IDO1 protein was expressed by genetic engineering and efficient IDO enzymatic screening system was established. Secondly, A172 cells stimulated with interferon-γ (IFNγ) or constructed plasmid which could highly express human IDO1 protein in HEK293 cells with transient transfection were used to construct the specific IDO1 cell based screening system. Finally, the effect of the compound on kynurenine and tryptophan in mouse plasma was determined by LC/MS/MS method on C57 mice, which could further verify the inhibitory effect of the selected compounds on IDO1 in vivo. The established and optimized enzyme-cell based screening model in this study can efficiently and effectively obtain IDO1 inhibitors in vitro, which lays a good foundation for the rapid development of clinical drugs. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.

The effects of different stimulators on the activation of human lymphocytes / 药学学报

The research aims to study the effects of different stimulants on the activation of human lymphocytes. Human peripheral blood mononuclear cells were prepared by density centrifugation. The blood's sample was provided by National Institutes for Food and Drug Control and approved by its Ethics Committee. The expressions of CD69 in CD3+CD4+ and CD3+CD8+ human T cells were detected by flow cytometry after administrated with CD3/CD28 antibody, phytohaemagglutinin (PHA), Staphylococcus auresus enterooxin B (SEB), interleukin (IL27) and PMA plus ionomycin for 24 h. The proliferation of lymphocyte was detected by CellTiter-Glo kit. The secreted IFNγ in supernatant of medium was examined by ELISA kit. The proliferation of lymphocytes had no change after exposed of CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin for 24 h. However, the CD69 expressions in CD3+CD4+ and CD3+CD8+ T cells and IFNγ productions were significantly increased by CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin at 24 h, indicating that CD3+CD4+ and CD3+CD8+ T cells were activated under above-mentioned stimulated condition. CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin were valid stimulants for T cell activation.

Influence of different prompt measures on the quality of cardiopulmonary resuscitation chest compressions in the first year standardized training of residents in Chinese medicine hospitals / 中国中西医结合急救杂志

Objective To investigate the influence of different prompt measures on the quality of cardiopulmonary resuscitation (CPR) chest compressions in the standardized training of residents in Chinese medicine hospitals. Methods There were 84 participants who were the first year standardized training residents recruited from Guangdong Provincial Hospital of Chinese medicine during July to August 2016, and eleven of them were excluded because of incomplete chest compression data collected from the feedback system. Finally, 73 participants being volunteers were enrolled. They were divided randomly into phone metronome group (n = 16), music metronome group (n = 15), depth display group (n = 22), and blank control group (n = 20). In phone metronome group, a mobile phone metronome was applied in the duration of CPR, with a frequency of 110 beats per minute, beat 2/4; in the music metronome group, it was accompanied by the music Staying Alive during the compression period, with frequency of 107 beats per minute, beat 4/4; in depth display group, a model electronic displayer was used in the duration of the compressions to feedback the real time compression depth and its rebound situation in CPR; there was no any intervention measure in blank control group. Each participant performed 5 cycles of CPR on a manikin. A chest compression feedback device was placed on the pressing point, on which the participants places the hand for CPR. The chest compression fraction 1 (CCF1), compression depth, compression rate, too slow frequency, too fast frequency, too shallow frequency, the total times of compressions, the correct times of compressions, correct rate, and the rate of compression retention were record as preliminary evaluation data by using the dual sensor and the pressure sensor built in the chest compression feedback device. At the same time, the correct compression ratio, correct ventilation ratio, the chest compression fraction 2 (CCF2) displayed on the human electronic displayer of the manikin were used as the review criteria. The quality of chest compression among the four groups of volunteers was compared. Results The compression rate and the too fast frequency in the depth display group were significantly higher than those in the music metronome group [compression rate (bpm): 140.59±17.90 vs. 124.27±21.43, the too fast frequency (times): 134.18±49.88 vs. 95.40±53.76, both P < 0.05], and the total compression times in depth display group were significantly higher than either in music metronome group or in blank control group (times: 152.73±27.05 vs. 135.60±10.38, 144.60±12.56, all P < 0.05), the rate of compression retention in depth display group was significantly higher than that in blank control group [37.50% (4.75%, 88.25%) vs. 12.00% (2.75%, 47.00%)]. Consistency detection of two sets of feedback systems for chest compression showed that the chest compression ratio in music metronome group evaluated by the chest compression feedback device was obviously lower than that assessed by the analog human electronic displayer [(53.60±9.87)% vs. (58.20±28.17)%], and it was suggested that the chest compression ratio in depth display group evaluated by the chest compression feedback device be markedly higher than that assessed by the analog human electronic displayer [(56.32±7.77)% vs. (43.86±27.63)%, P < 0.05], and it was shown that the correct rates of chest compression assessed by the chest compression feedback device were significantly lower than those evaluated by the analog human electronic displayer in metronome, music, depth and blank control groups [phone metronome group: 0.00% (0.00%, 60.75%) vs. 38.50% (24.25%, 92.00%), music metronome group: 0.00% (0.00%, 7.00%) vs. 60.00% (32.00%, 89.00%), depth display group: 0.00% (0.00%, 0.25%) vs. 34.00% (20.75%, 68.25%), blank control group: 0.00% (0.00%, 1.75%) vs. 61.50% (30.75%, 84.25%), all P < 0.05], suggesting that the consistency of this two feedback systems be poor and their degrees of reliability low. Conclusion The effects of intervention measures on the quality of chest compressions vary from person to person, and the quality of chest compressions can be really elevated only by systematic training and repeated practice.

Research progress of indoleamine 2,3-dioxygenase 1 in tumor immunotherapy / 药学学报

IDO1 (indoleamine 2,3-dioxygenase 1) is one of the most significant checkpoint in tumor immunology. Numerous studies indicates that IDO1 is abnormally expressed in breast cancer, colorectal cancer, liver cancer and other tumor tissues, participating in tumor immune escape through multiple pathways. This review is prepared to elucidate the biological function of IDO1, highlight its pivotal role in tumor evasion, and summarize IDO1 inhibitors in the clinical trials.

Antitumor activity of a novel PARP1/2 inhibitor YHP-743 / 药学学报

Poly(ADP-ribose) polymerase (PARP)-1 and PARP2 function as ADP-ribosylases involved in DNA repair. PARP1/2 is highly expressed in cancers and emerged as an attractive target for antitumor drug. In this study, we investigated the antitumor activity of a novel PARP1/2 inhibitor YHP-743 in vitro and in vivo. The results showed that YHP-743 had potent enzymatic inhibitory activity against PARP1 and PARP2 to down-regulate the PAR level. YHP-743 not only inhibited breast cancer cells with genes deficiency of homologous recombination repair, but also potentiated chemotherapy agent's cytotoxicity, such as temozolomide, topotecan, cisplatin and doxorubicin. YHP-743 elicited good antitumor activity in combination with temo-zolomide in vivo.

Optimize dropping process of Ginkgo biloba dropping pills by using design space approach / 中国中药杂志

In this paper, a design space approach was applied to optimize the dropping process of Ginkgo biloba dropping pills. Firstly, potential critical process parameters and potential process critical quality attributes were determined through literature research and pre-experiments. Secondly, experiments were carried out according to Box-Behnken design. Then the critical process parameters and critical quality attributes were determined based on the experimental results. Thirdly, second-order polynomial models were used to describe the quantitative relationships between critical process parameters and critical quality attributes. Finally, a probability-based design space was calculated and verified. The verification results showed that efficient production of Ginkgo biloba dropping pills can be guaranteed by operating within the design space parameters. The recommended operation ranges for the critical dropping process parameters of Ginkgo biloba dropping pills were as follows: dropping distance of 5.5-6.7 cm, and dropping speed of 59-60 drops per minute, providing a reference for industrial production of Ginkgo biloba dropping pills.

The effect of triptolide derivative LB-1 on imiquimod-induced psoriasiform inflammation of BALB/c mice / 药学学报

The aim of present study was to explore the effect of triptolide derivative LB-1 on imiquimod (IMQ) induced psoriasiform inflammation in BALB/c mice, and to investigate the immune mechanism of LB-1 in the prevention and treatment of psoriasis. In the present study, topical application of IMQ for seven days induced the psoriasiform inflammation in BALB/c mice. This is a promising mouse model of psoriasis for the natural immune reaction compared to those induced by xenograft, trangenic or gene knockout. psoriasis area and severity index (PASI) score, hematoxylin-eosin (HE) staining and flowcytometry were employed to investigate the changes of psoriasiform inflammation, histopathological response and percentage of T cells, respectively. The result showed that LB-1 significantly attenuated the psoriasiform inflammation. Com-pared with model group, PASI score were decreased in the LB-1 group. In the isolated immunocytes of spleen, LB-1 decreased percentage of CD8+ (P +/CD8+ T cells at the dosage of 2 mg·kg-1 (P + T cells and CD3+ T cells at the dosage of 4 mg·kg-1. In conclusion, the present study demonstrated that LB-1 attenuated psoriasiform inflammation induced by imiquimod in BALB/c mice. The mechanism of LB-1 action may be related to change percentage of CD4+ T, CD8+ T cells in the spleen. These results provide a basis for LB-1 or other triptolide derivative in the intervention of psoriasis in the future.

Clinical observation of Xuanfeitongfu method in cluster treatment of severe pneumonia / 实用医学杂志

Objective To observe the clinical efficacy of Xuanfeitongfu method in treatment of severe pneumonia and to explore its clinical value in the management of severe pneumonia. Methods Totally,62 patients with severe pneumonia were randomly divided into the control group (n = 30) and the treatment group (n = 32). The control group was given cluster treatment,including oxygen cure,anti-infection and nutrition support and maintaining a stable internal environment and etc. The treatment group was treated with Tongfu decoction orally(one dose a day,a total of 5 days)on a basis of cluster treatment. The comparison was conducted in the 2 groups in the levels of C reaction protein,calcitonin,the change of blood gas analysis,the time of mechanical ventilation and the mortality of severe pneumonia in ICU at baseline and 3,5 days after treatment. Results The level of C-reactive protein,calcitonin,the change of blood gas analysis were statistically significant (P < 0.05). The time of mechanical ventilation and the mortality were better in the treatment group (P < 0.05). Conclusion Xuanfeitongfu method can effectively improve oxygenation ,assist the anti-infection effect ,reduce the time of mechanical ventilation and ICU retention time ,ultimately improve the outcome of severe pneumonia.

Establishment of a glioma orthotopic xenograft model based on imaging technology / 药学学报

Orthotopic xenograft model of human brain cancer cells is a good preclinical model for evaluation of antitumor compounds. In the present study, an orthotopic xenograft model of U87MG-mCherry-luc was established in Balb/c nude mice and the tumor growth was monitored via imaging technology including magnetic resonance imaging (MRI), in vivo imaging (IVI) and micro-CT. Furthermore, the model was evaluated with a positive drug temozolomide. Our data suggest that integrated imaging technology including MRI, IVI and micro-CT in orthotopic xenograft model can be used to facilitate monitoring of cancer progression and evaluate antitumor activity of drugs against glioma.

Olaparib potentiates the antitumor effect of Taxol on 4T1 breast cancer / 药学学报

Poly (ADP-ribose) polymerase 1/2(PARP1/2) can catalyze the poly (ADP ribose) (PAR) substrate protein modification and play an important role in the regulation of DNA damage repair, cell death and transcriptional activity. The PARP inhibitor olaparib (AZD2281) can be used as a sensitizer of radiotherapy and chemotherapy in the cancer treatment. Through establishment of biological fluorescent labeled 4T1 ectopic breast tumor model, we found that olaparib exhibited a poor effect on 4T1 breast cancer alone. However, in the combination with Taxol, olaparib significantly increased the anti-tumor effect of Taxol, and reduced the PAR levels of the tumor tissues. Importantly, olaparib did not amplify the toxicity of chemotherapy drugs. This study suggests that olaparib is a representative of the PARP inhibitor that can enhance Taxol 's antitumor effect in the 4T1 ectopic breast tumor model, which sets the foundation for future study of the mechanism of olaparib action.

"Application of ""layered cooperation"" teaching in clinical teaching in intensive care unit" / 中华医学教育探索杂志

Objective To observe the application effect of layered cooperation teaching in clinical teaching in intensive care unit (ICU).Methods The master graduate students who practiced in ICU of Fangcun branch of Guangzhou Provincial Hospital of Traditional Chinese Medicine form September 2013 to July 2014 were divided into two groups according to the rotation cycle.Diagnostic test was conducted to all the above students.The new teaching group (21 people) was determined according to the diagnostic test results and students' majoring to frm study group and the layered cooperation teaching was adopted,while the traditional teaching was used in the traditional clinical education group (19 cases).In the end of the rotation training,a theoretical examination was conducted among the two groups of students,and the questionnaire of teachers' teaching quality was issued.The related data were processed by SPSS 17.0,and the data between groups were compared by t test.Results The examination result in the layered cooperation teaching group (78.35 ± 3.13) were better than those in the traditional clinical education group (70.21 ± 4.58) and the difference was statistically significant (P=0.041).Survey results showed that the new teaching group students' evaluation to teaching content,teaching methods and teaching effectiveness was higher than traditional teaching group,and the score difference was statistically significant (P＜0.05).Conclusion The layered cooperation teaching in the clinical teaching in intensive care unit (ICU) to mobilize the students' subjective initiative,so that students of different knowledge structure can be integrated into the clinical practice of ICU,and enhance their ability of clinical analysis of ICU disease.

A novel HIF-1 inhibitor--manassantin A derivative LXY6099 inhibits tumor growth / 药学学报

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor on hypoxia responses in mammalian tissues. HIF-1 plays as a positive factor in solid tumor and leads to hypoxia-driven responses that enhance its downstream gene expression for tumor growth and survival. LXY6099 was obtained by the structural modification and optimization of manassantin A (MA) as a high potent HIF-1 inhibitor. Antitumor activity of LXY6099 was observed in this study. LXY6099 with an IC50 value of 2.46 x 10(-10) mol x L(-1) showed more sensitive inhibition activity to HIF-1 than that of MA detected by reporter gene assay (> 100 folds). It showed strong inhibition on the growth of human solid tumor cell lines. Furthermore, LXY6099 exhibited significant antitumor activity against established human tumor xenografts in nu/nu mice with treatment of MX-1 breast cancer. Thus, LXY6099 as a novel HIF-1 inhibitor could be further developed into anti-cancer agents.

Research progress of hypoxia-inducible factor 1 inhibitors against tumors / 药学学报

Hypoxia occurs in chronic and acute vascular diseases and tumor formation. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducible factor 1 (HIF-1). Tumor hypoxia mediated by HIF-1 would facilitate the likelihood of resistance to chemotherapy and radiotherapy, proliferation, metastasis and the invasive potential; all of which culminate in a decrease in patient survival. And HIF-1 alpha subunit decides the activity of HIF-1, which is regulated by oxygen. So understanding the role of HIF in signal pathway, drug resistance mechanism and its feature is crucial for developing novel anticancer therapies. In recent years, more attentions have focused on HIF-1 alpha inhibitors. It is expected that development of more potent and selective HIF inhibitors will provide an effective treatment of cancer and other HIF-related diseases. So we will focus on the biological characteristics and mechanism of HIF-1 to review currently studied HIF-1 inhibitors.

Development of a novel screening assay for inhibitors targeting HIF-1alpha and P300 interaction / 药学学报

Hypoxia is a general characteristic of most solid malignancies and intimately related to cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor-1alpha (HIF-1alpha) that elicits transcriptional activity through recruitment P300 coactivator. Targeting the interaction of HIF- alpha and P300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, a screening assay was developed for inhibitors targeting the interaction between HIF-1alpha and P300. The nucleotide sequence of human HIF-1alpha and P300 were cloned into pBIND and pACT vectors, named pBIND-HIF1alpha and pACT-P300. The interaction of HIF-1alpha and P300 was identified in HEK293 cell using mammalian two-hybrid system. And compound chetomin decreased their interaction in this mammalian two-hybrid system. We further verified HIF-1 inhibition effect of chetomin in U251-HRE cells. Therefore, we established a screening assay combined HIF-1alpha and P300 mammalian two-hybrid system and U251-HRE reporter assay for HIF-1 selective inhibitors.