Study on the modification and anti-tumor activity of silybin derivatives for CDK4/6 targeted / 药学学报

By using computer-aided drug design, the activities group model which CDK4/6 inhibitors on the market were introduced to silybin C-7, and a series of silybin derivatives were designed and synthesized, and the structure was confirmed by MS, 13C NMR and 1H NMR. The in vitro antitumor activity evaluation of the target compound was carried out by MTT method, and the in vitro anti-tumor activity was carried out in human hepatocellular carcinoma cells (HepG-2). Experimental results show that all compounds are higher than the activity of the parent silybin, of which compound I1 has a certain inhibitory effect on human HepG-2 cells, which is worth further study.

Bioinformatics analysis of the association between long non-coding RNA ubiquitin-specific peptidase 30 antisense RNA 1 (lncRNA USP30-AS1) and immune cell infiltration in ovarian serous cystadenocarcinoma / 细胞与分子免疫学杂志

Objective To investigate the expression of long non-coding RNA ubiquitin-specific peptidase 30 antisense RNA 1 (lncRNA USP30-AS1) and its relationship with immune infiltration in ovarian serous cystadenocarcinoma (OSC), and to determine its prognostic role in OSC. Methods The Cancer Genome Atlas (TCGA) database was utilized to retrieve the expression of USP30-AS1 and clinical information of 384 OSC patients. Wilcoxon rank-sum test was employed to compare the expression of USP30-AS1 between OSC and normal ovarian tissues. Logistic regression analysis was conducted to assess the relationship between clinical pathological features and USP30-AS1. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were performed to investigate enrichment pathways and functions and quantify the degree of immune cell infiltration in USP30-AS1. Based on the expression level of long non-coding RNA (lncRNA) USP30-AS1, the samples were divided into high and low expression groups according to the expression mean. Log-rank tests, univariate and multivariate proportional hazards model (Cox) were used to compare prognostic differences between different USP30-AS1 expression groups. The impact of lncRNA USP30-AS1 expression on other genomic analyses was also analyzed. Results High expression of USP30-AS1 was significantly associated with the International Federation of Gynecology and Obstetrics (FIGO) stage of the tumor. Multivariate survival analysis indicated that USP30-AS1 expression level served as an independent prognostic marker for OSC. GSEA data showed that high expression of USP30-AS1 might activate programmed death 1 (PD-1) signaling pathway, cytotoxic T lymphocyte-associated protein 4 (CTLA4) pathway, B-cell receptor signaling pathway, cell apoptosis, fibroblast growth factor receptor (FGFR) signaling pathway, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. The expression of USP30-AS1 was negatively correlated with immune cell infiltration, including B cells, CD4+ T cells, dendritic cells, CD8+ T cells, and neutrophils. Conclusion USP30-AS1 may be used as a prognostic molecular marker for OSC.

Nano-vesicles derived from M1 macrophages affect the development of mouse endometriosis by polarizing M2 macrophages to M1 phenotype / 细胞与分子免疫学杂志

Objective To explore whether nano-vesicles derived from M1 macrophages (M1-NVs) can reprogram M2 macrophages into M1 phenotype and further affect the development of endometriosis (EMS). Methods Extracellular vesicles (EVs) were isolated from macrophage culture supernatant by differential centrifugation. Immunofluorescence cytochemistry was used to detect the expression of vimentin, CD31 and F4/80 to identify endometrial stromal cells (EMS-ESCs), HUVECs and polarized peritoneal macrophages of EMS patients. M1-NVs were prepared by filtering cell suspension through (5, 1, 0.4, 0.22)μm polycarbonate membrane filters after syringe aspiration at 0-4 DegreesCelsius. Flow cytometry was used to analyze the polarization of RAW264.7 mouse peritoneal macrophages in vitro, and reverse transcription PCR (RT-qPCR) was employed to detect mRNA expression of VEGF, CD86, interleukin-6 (IL-6), IL-1β, tumor necrosis factor α (TNF-α), arginase 1 (Arg1), CD163, CD206, and IL-10. PKH67-labeled M1-NVs were co-cultured with EMS-ESCs, HUVECs and macrophages. And tubule formation experiments were conducted to assess the impact of M1-NVs on the tubule formation of HUVECs. TranswellTM invasion and migration assays were employed to evaluate changes in the migration and invasion abilities of EMS-ESCs. Results By monitoring the contents of NVs, it was found that NVs contained much more protein and other bioactive particles than the same amount of EVs; immunofluorescence staining results showed that PKH67 labeled M1-NVs were internalized by EMS-ESCs, HUVECs and macrophages when co-cultured. The results of flow cytometry and RT-qPCR multi-target analysis showed that after treatment with different concentrations of M1-NVs or M0-NVs, 20 μg/mL of M1-NVs could effectively reprogram M2 macrophages into M1 macrophages compared with M0-NVs. TransewellTM results showed that compared with the blank group and M0-NVs group, the number of EMS-ESCs migrating from the upper chamber to the lower chamber after M1-NV treatment was significantly reduced, while the number of EMS-ESCs treated with M2NVs increased significantly. The invasion situation was similar to the migration situation, indicating that M1-NVs directly or indirectly inhibited invasion, migration and tubule formation of EMS-ESCs in vitro. Conclusion M1-NVs reprogrammes M2 macrophages into M1 macrophages by internalization of primary cells and macrophages, thereby inhibiting invasion, migration and angiogenesis of EMS-ESCs, and further hindering the occurrence and development of EMS.

Advances in bacterial adsorption and transport of aromatic compounds / 生物工程学报

Aromatic compounds are a class of organic compounds with benzene ring(s). Aromatic compounds are hardly decomposed due to its stable structure and can be accumulated in the food cycle, posing a great threat to the ecological environment and human health. Bacteria have a strong catabolic ability to degrade various refractory organic contaminants (e.g., polycyclic aromatic hydrocarbons, PAHs). The adsorption and transportation are prerequisites for the catabolism of aromatic compounds by bacteria. While remarkable progress has been made in understanding the metabolism of aromatic compounds in bacterial degraders, the systems responsible for the uptake and transport of aromatic compounds are poorly understood. Here we summarize the effect of cell-surface hydrophobicity, biofilm formation, and bacterial chemotaxis on the bacterial adsorption of aromatic compounds. Besides, the effects of outer membrane transport systems (such as FadL family, TonB-dependent receptors, and OmpW family), and inner membrane transport systems (such as major facilitator superfamily (MFS) transporter and ATP-binding cassette (ABC) transporter) involved in the membrane transport of these compounds are summarized. Moreover, the mechanism of transmembrane transport is also discussed. This review may serve as a reference for the prevention and remediation of aromatic pollutants.

Abuse of Pharmaceutical Drugs and Its Prevention / 法医学杂志

Abuse of pharmaceutical drugs is a major public health and social problem worldwide. Mostly abused drugs mainly include opioids such as morphine, tramadol, methadone and fentanyl, sedative-hypnotics such as benzodiazepines and non-benzodiazepines, and central stimulants such as Ritalin (methylphenidate), Adderall (amphetamine and dextroamphetamine) and modafinil. Abuse of pharmaceutical drugs not only causes direct damage to multiple systems of the body, but also significantly increases risks of mental and physical diseases, imposing a heavy burden on individuals, families and society. Therefore, the prevention and control of pharmaceutical drug abuse are of vital importance. The Chinese government has taken strict administration measures for pharmaceutical drugs with abuse risk. However, confronting endless new drugs and changing abuse trends, it is necessary to further strengthen management and prevention of pharmaceutical drugs, monitor the trend of abuse, establish rapid response mechanisms, popularize relevant knowledge, and develop specific therapeutic drugs and intervention means, in order to promote prevention and treatment of pharmaceutical drug abuse.

Targeting PDGF receptor inhibitors: synthesis and biological evaluation of oleanolic acid analogs / 药学学报

The computer-aided design was used to simulate the docking of PDGF receptor with known active compounds, and the active groups that can bind to key sites were identified by analyzing the key amino acid residue fragments that exerted active effects on the target proteins. The natural product oleanolic acid was used as the parent, and the active group was introduced into the 2-position, and the C-28 carboxyl group was esterified and amidated. A series of oleanolic acid analogues targeting PDGF receptor inhibitors were designed and synthesized. Their structures were confirmed by MS and NMR. Through MTT assay, SGC-7901 and A549 cells were selected for preliminary in vitro anti-tumor activity screening. PDGF receptor protein inhibition test was performed on I3 and Ⅱ5 by FPIA. The activity tests showed that I3 and Ⅱ5, compared with the positive control drug, had stronger inhibition. FPIA test showed that Ⅱ5 and PDGF receptor protein had good binding ability. The newly synthesized oleanolic acid analogues have significantly higher antitumor activity than the parent compound and deserve further study.

Preparation and evaluation of new cyanoacrylate nanosphere with alcoxyle side group for gene delivery / 国际药学研究杂志

Objective To prepare a new(alcoxyle cyanoacrylate)-based nanosphere for brain targeting gene delivery and evaluate its physicochemical properties,capability of delivery of transforming growth factor beta 2(TGF-β2)antisense oligonucle?otides(ASON),and its potential use on tumor cell suppression in vitro.Methods The cationic nanospheres(NS)were prepared by emulsion polymerization method with DEAE-dextran as cationic stabilizer.The ASON were adsorbed by charge interaction,and poly?sorbate-80 was used as brain-targeting modification.The morphology was observed by transmission electron microscopy(TEM).The average particle size and Zeta potential were determined by dynamic light scattering(DLS). The ultraviolet spectrophotometry was used to determine the entrapment efficiency and drug loading.Agarose gel electrophoresis was used to analyze the optimal loading ratio of ASON-NS,and also the protection of ASON in DNaseⅠand serum containing environment.The release rate of ASON was deter?mined by dialysis.The cytotoxicity on L929 cells and the anti-tumor activity on A172 cells were evaluated by MTS.Results The TEM showed a typical round nanospheres morphology,and no adhesion was detected.The particle size was(79.04±4.33)nm,the disper?sion coefficient was 0.04 ± 0.03,the Zeta potential was(33.60 ± 0.60)mV. The encapsulation efficiency of ASON-NS was(83.14 ± 1.90)%,and the drug loading of ASON-NS was(11.59±0.56)%.The NS provided ASON protection against the Dnase I and serum containing environment. The NS-ASON could effectively deliver ASON into A172 cells and show anti-tumor activity. Besides,little L929 cytotoxicity was detected.Conclusion A new cyanoacrylate nanosphere with alcoxyle side group for brain targeting gene deliv?ery was prepared successfully. It had good ASON loading and delivery capability,providing new carrier materials for nucleic acid drugs.

Synthesis and anti-tumor activity of derivatives of ursolic acid in vitro / 药学学报

A series of ursolic acid derivatives were synthesized by the introduction of 4-chloroindole compounds at A ring and esterification and amidation at C-28 position, which structures were characterized by 1H NMR, MS and etc. The cytotoxic activity of derivatives was evaluated against HepG2 and SGC7901 cells in vitro by MTT assay, in which paclitaxel and adriamycin were used as a positive control. The results indicated that all of derivatives can inhibit cell proliferation in HepG2 and SGC7901 cells with a better activity than ursolic acid. Especially, the compounds 6 and 12 showed significant antitumor activity comparable to the paclitaxel. The compounds are worthy to be studied further.

Advances in study of Survivin inhibitors / 药学学报

Survivin, a member of the inhibitor of apoptosis proteins family, is considered to be an important target of anticancer treatment for its key role in the control of cell division and cell apoptosis. Currently, only a few Survivin inhibitors have been developed, and most of them reduce Survivin level by interacting with other biomolecules instead of directly interacting with Survivin protein. This review summarizes the structure of Survivin protein, the mechanism of action and research progress of Survivin inhibitors, which may has a great significance in the study of selective Survivin inhibitors in the future.

Synthesis and anti-tumor activity of oleanolic acid derivatives / 药学学报

Thirteen novel oleanolic acid (OA) derivatives were designed and synthesized with modification at positions of C-3, C-12 and C-28 of OA. Their structures were confirmed by MS, 1H NMR and elemental analysis. Their in vitro cytotoxicities against various cancer cell lines (SGC7901, MCF-7 and A549) were evaluated by MTT assay. The results indicated that the tested derivatives were found to have stronger cell growth inhibitory activity than OA. Among them, compounds II2 and II3 showed more potent cytotoxicity on MCF-7 and A549 tumor cells than gefitinib (positive control). They are worthy to be studied further.

Expression and clinical significance of BAK and cFLIP in endometriosis / 实用医学杂志

Objective To explore the association of expression of apoptosis-associated gene BAK and cFLIP with the biological behaviors in endometriosis. Methods The expression of BAK and cFLIP protein gene in eutopic and ectopic tissue samples from 40 cases with pathologically confirmed ovarian endometriosis and 40 cases with pathologically confirmed normal endometrium was detected by immunohistochemical method. Results ①The expression of BAK and cFLIP protein gene was found in three groups of different endometrial tissue. ②The expression of BAK protein gene was increased gradually in ectopic endometrial , eutopic endometrium and normal tissue and there was significantly difference between every two groups ,while cFLIP was contrary expressed (P 0.05). ④The expression of BAK protein gene in severe group (Ⅲ-Ⅳ period) is lower than mild group both in eutopic or ectopic endometrial tissues,while cFLIP was contrary expressed (P < 0.05). ⑤The expression of BAK and cFLIP was negatively correlated with each other in ectopic endometrium (r=-0.389,P< 0.05). Conclusion BAK and cFLIP was negatively expressed in EMS, which may take a part in the endometrial apoptosis and disorderly proliferation. BAK and cFLIP may play an important role in the the diagnosis and treatment of endometriosis.

Study on the expression of human tissue kallikrein gene 6 in cervical cancer tissues / 中国医师进修杂志

Objective To study the expression and significance of human tissue kallikrein gene 6(KLK6) in cervical cancer tissues.Methods With glyceraldehyde 3-phosphate dehydrogenase (GAPDH)as reference,the expression of KLK6 in 80 cases of cervical cancer tissues (40 cases with metastasis and 40cases without metastasis) and 40 cases of normal cervical tissues was determined by Taqman probe real-time quantitative reverse transcription-polymerase chain reaction,and analyzed the relationship between cervical cancer occurring and KLK6 expression with clinical data and pathological dats.Results The expression of KLK6 in normal cervical tissues[(1.06 ± 0.40) × 10-3] was lower than that in cervical cancer tissues without and with metastasis[(4.41 ± 1.70) × 10-3,(32.22 ± 6.70) × 10-3],and there was significant difference (P＜0.01).The expression of KLK6 in Ⅰ a,Ⅰ b,Ⅱ a stage of cervical cancer tissues with metastasis was (30.42 ± 5.00) × 10-3,(31.64 ± 1.30) × 10-3,(33.02 ± 8.00) × 10-3,and there was no significant difference among them (P ＞ 0.05).The expression of KLK6 in Ⅰ a,Ⅰ b,Ⅱ a stage of cervical cancer tissues without metastasis was (4.12 ± 1.10) × 10-3,(4.35 ± 1.30) × 10-3,(4.82 ± 1.90) × 10-3,and there was no significant difference among them (P＞0.05).There was significant difference in the expreesion of KLK6 in Ⅰ a,Ⅰ b,Ⅱ a stage between cervical cancer tissues with metastasis and cervical cancer tissues without metastasis (P ＜0.01).Conclusion KLK6 can stimulate the cervical cancer cell proliferation,and participate in the progresses of cervical cancer metastasis.

Synthesis and anti-tumor activity of oleanolic acid derivatives / 药学学报

Structural modifications were performed with natural product of oleanolic acid to search for novel anticancer drugs. Ten oleanolic acid derivatives were designed and obtained by the reaction of oxidation, acylation or hydrolyzation, etc. The cytotoxic activity of derivatives was evaluated against HeLa, HepG2 and BGC-823 cells in vitro by MTT assay, gefitinib and etoposide used as a positive control. The results showed that compound 5a was particularly active to inhibit HepG2 cells growth, and anti-tumor activity of compound 7 on HeLa cells was significantly stronger than oleanolic acid. They are worthy to be studied further.

Synthesis and anti-tumor activity of ursolic acid derivatives / 药学学报

Structure of natural product-ursolic acid was modified for increasing its antitumor activity. Ursolic acid was acylated, esterified, hydrolized or oxidized to obtain target pentacyclic triterpenoid compounds with different substitutes. Sixteen derivatives of ursolic acid were designed and synthesized including eleven new compounds. Anti-tumor activities of ursolic acid and these derivatives against HeLa, SKOV3 and BGC-823 cells in vitro were investigated by MTT assay. The results indicated that compounds 7a and 8a were found to have stronger cell growth inhibitory than ursolic acid on HeLa cells and SKOV3 cells separately, and are worth to be intensively studied further.

Evaluation of the gastrointestinal decompression after gastrectomy: a prospective randomized controlled trial / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the value of using nasogastric tube for patients after gastrectomy.</p><p><b>METHODS</b>One hundred and eight patients undergone gastrectomy were divided randomizely into nasogastric decompression group(n=53) and non-nasogastric decompression group (n=55). Gastrointestinal function and postoperative complications were compared between the two groups.</p><p><b>RESULTS</b>Between nasogastric decompression group and non-nasogastric decompression group, no significant differences in postoperative complications (20.8% vs 23.6%, P=0.719), postoperative time of flatus [(3.2+/-0.9) d vs (3.0+/-0.7) d, P=0.192], recovery time of drinking [(5.9+/-3.4) d vs (5.1+/-1.6) d, P=0.143], eating time of fluid food [(7.8+/-3.6) d vs (6.8+/-1.8) d, P=0.085] and eating time of semi-fluid food [(9.8+/-3.5) d vs (8.8+/-1.9) d, P=0.081] were found. While the recovery time of bowl sound [(1.8+/-0.7) d vs (2.2+/-0.9) d, (P=0.013)] and hospital stay [(10.2+/-2.1) d vs (11.7+/-4.3) d, (P=0.021)] were shorter in non-nasogastric decompression group.</p><p><b>CONCLUSION</b>It is not necessary to use nasogastric decompression for patients after gastrectomy.</p>

Clinical value of routine haematoxylin-eosin stain in diagnosing submucosal lymphatic vessel infiltration in early gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the value of routine haematoxylin-eosin(HE) stain for submucosal lymphatic vessel infiltration in early gastric cancer.</p><p><b>METHODS</b>Four thousand four hundred and twenty early gastric cancer patients underwent D2 operation. Submucosal lymphatic vessel was detected by routine HE stain. The results were compared with pathological lymph node metastasis.</p><p><b>RESULTS</b>In early gastric cancer, the sensitivity, specificity, accuracy, positive predicting value (PPV), and negative predicting value (NPV) of routine HE stain for submucosal lymphatic vessel infiltration were 54.5%, 82.0%, 78.9%, 27.4%, and 93.5% respectively. In early gastric cancer limited in mucosa, these indexes were 14.5%, 98.0%, 95.8%, 15.8%, and 97.8% respectively. In early gastric cancer infiltrated to submucosa, they were 60.3%, 57.8%, 58.3%, 28.1%, and 84.2% respectively. There were significant differences of submucosal lymphatic vessel infiltration with lymph node metastasis (P< 0.001), but no significant difference with survival rate. The 5-year survival rates of submucosal lymphatic vessel infiltration positive and negative group were 84.4% and 87.3%, median survival time was 6998 d and 7237 d, and mean survival time was 6163.9 d and 6042.6 d respectively (P=0.2495).</p><p><b>CONCLUSION</b>The accuracy of routine HE stain is too low, thus it is not suitable for diagnosing submucosal lymphatic vessel infiltration in early gastric cancer.</p>

Clinical effect of intraoperative peritoneal hyperthermic chemotherapy for advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the clinical effect of intraoperative peritoneal hyperthermic chemotherapy (IPHC) for advanced gastric cancer (AGC).</p><p><b>METHODS</b>A total of 118 AGC patients with serosal invasion were enrolled in this study from 1998 to 2001. Among these cases, 96 patients without macroscopic peritoneal metastases were selected for prophylactic study, including 42 cases with IPHC and 54 cases without IPHC as control. Other 22 patients with macroscopic peritoneal metastases were selected for therapeutic study, including 10 cases with IPHC and 12 without IPHC. Postoperative survival rate and peritoneal recurrence were compared.</p><p><b>RESULTS</b>For prophylactic study, the 1, 2 and 4 years survival rates were 85.7%, 81.0% and 63.9% respectively in the patients with IPHC,significantly higher than 77.3%, 61.0% and 50.8% in the patients without IPHC. Cox ratio hazard model revealed that IPHC procedure was an independent prognostic factor. More patients in the control group suffered from peritoneal recurrence than those in IPHC group (34.7% vs 10.3%). For therapeutic study,the median survival period of the patients with IPHC was 10 months, higher than 5 months in the patients without IPHC. The overall 1, 2, 4 year survival rates were 76.9%, 69.2%, 55.2% respectively in all cases with IPHC, higher than 66.2%, 49.7%, 41.4% in the cases without IPHC.</p><p><b>CONCLUSION</b>IPHC procedure can improve the prognosis of AGC patients with serosal invasion, reduce the risk for peritoneal recurrence, and is an independent prognostic factor.</p>