Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Abiraterone is commonly used as a targeted drug for the treatment of prostate cancer， which commonly causes adverse drug reactions （ADR）， including abnormal liver function， fatigue， nausea and edema， etc. This study reports a 78-year-old man with a history of hepatitis B and liver cirrhosis after prostate cancer resection who was admitted to the First Affiliated Hospital of Henan University of Chinese Medicine. The patient received abiraterone treatment 1 month before admission and developed gastrointestinal symptoms 3 weeks after the treatment and worsened at 4th week with yellowing of the skin， sclera and urine. Unfortunately， the patient died after 5 weeks of abiraterone treatment （1 week after admission）. Based on test and examination results， the patient was diagnosed with acute-on-chronic liver failure （ACLF）. This paper analyzes the patient’s medical history and the relevant treatment in detail. It is evaluated that ACLF and abiraterone are “probably” related based on Naranjo ADR Probability Scale， suggesting abiraterone may induce severe ADR of liver failure in patients with chronic liver diseases such as cirrhosis. These patients should be monitored dynamically for changes in liver function and treated prophylactically with liver-protective drugs if necessary.

Objective:To investigate the status of satisfaction of postgraduates majoring in public health with the teaching material of The prevention and control of chronic non- communicable disease, so as to provide the basis for promoting the teaching and optimizing the reprint of the teaching material. Methods:An online survey was conducted among 180 public health postgraduates of Batch 2018 to Batch 2020 from China CDC who took the selective course of "prevention and control of chronic non-communicable diseases". The survey content included the overall satisfaction of the respondents with the teaching material and such four levels of satisfaction as primary indicators at the content level, thinking level, motivation level and arrangement level and 20 secondary indicators. The statistical analysis was made by SPSS 25.0.Results:The effective response rate was 90.56% (163/180), and the overall satisfaction of postgraduates with the teaching material was 88.96%. The satisfaction of "scientificity", "comprehensiveness", "internal coordination" and "hierarchy" at the content level, "systematic thinking" and "quality education" at the thinking level, "deepening the understanding and application of relevant knowledge in the field of chronic disease prevention and control" and "the content is convenient for self-study and helps guide the construction of new knowledge" at the motivation level, and "accurate words, fluent language and easy to read and understand" and "firm binding, good paper quality and clear printing" at the arrangement level of the teaching material was more than 90.00%. Only the satisfaction of "the critical thinking" at the thinking level and "stimulating learning enthusiasm" at the motivation level was less than 85.00%.Conclusion:The teaching material of The prevention and control of chronic non- communicable disease meets the learning needs of postgraduates majoring in public health, and students have high overall satisfaction evaluation on the teaching material. It is necessary to further optimize the two aspects of "the critical thinking" and "stimulating learning enthusiasm" in the revision of the teaching material.

Objective:To explore the potential mechanism of Bianketong tablet （BKT） in the treatment of constipation-predominant irritable bowel syndrome （C-IBS） based on network pharmacology and bioinformatics. Method:The BKT-meridian network was constructed for analyzing the combined effect of the nine Chinese herbs in BKT. The active components and targets of BKT were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and then screened according to the oral bioavailability （OB） and drug likeness （DL） criteria. Following the acquisition of C-IBS target set from GeneCards， Online Mendelian Inheritance in Man （OMIM）， Drugbank and DisGeNet， the protein-protein interaction （PPI） network was constructed. Cytoscape 3.7.2 was utilized for network visualization. The screened key targets were subjected to gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis using DAVID platform. The C-IBS mouse model was established via intragastric administration of ice water， and the key targets of BKT against C-IBS were verified by enzyme linked immunosorbent assay （ELISA） and immunohistochemistry. Result:The large intestinal meridian was the main site where BKT acted. There were 70 potential active components in BKT， which acted on 227 intersection targets. Through T helper cell 17（Th17） differentiation， Toll-like receptor （TLR）， tumor necrosis factor and other signaling pathways， BKT participated in inflammatory response， immune regulation， intestinal nerve regulation， hormonal regulation， and oxidative stress response， thus exerting the therapeutic effects against C-IBS. As reveled by in vivo experiments， BKT significantly improved the small intestinal propulsion rate， up-regulated the expression of vasoactive intestinal peptide （VIP） in serum and colon tissue of C-IBS mice， and down-regulated the expression of nuclear transcription factor-κB （NF-κB）， interleukin（IL）-6， and TLR2 in serum and colon tissue， which confirmed the reliability of integration analysis. Conclusion:BKT inhibits C-IBS via multiple components， multiple targets， and multiple pathways. This study has provided ideas for further clinical research and experimental verification of BKT in the treatment of C-IBS.

Objective:To investigate the protective effects of neferine on lipopolysaccharide ( LPS)-induced human umbilical vein endothelial cells ( HUVECs) injury. Methods:The optimum inducing concentration of LPS was screened out through pretests and used for the model establishment of HUVECs damage. CCK8 was used to detect the influence of neferine at different concentrations on LPS-induced human umbilical vein endothelial cells ( HUVECs) injury. Nitric oxide ( NO) content was measured by the Griess Reagent method. The nitric-oxide synthase (NOS) activity was assessed by the commercially available kits. Results:The inhibitory rate of HU-VECs was 54. 50% detected by CCK8, which induced by LPS at the concentration of 100 μg·ml-1(P<0. 01). Neferine at the con-centrations of 0. 3-5. 0μmol·L-1 could increase the cell viability in a concentration-dependent manner, while it inhibited the cell pro-liferation at the concentration of 10 μmol·L-1(P<0.05). Neferine could reverse the situation, and the NO release was increased and the tNOS/iNOS activity was increased induced by LPS (P<0. 05). The results shown by the inverted microscope suggested that the floating dead cells were decreased, the cell shape was basically sound and tightly packed with the concentration increase of neferine (0. 3-5. 0μmol·L-1) in a concentration-dependent manner. Conclusion:The results show that neferine has protective effects on HU-VECs injury induced by LPS, and the mechanism may be related with the decrease of intracellular levels of NO and NOS activity.

Nuciferine is a major aporphine alkaloid in the leaves of Nelumbo nueifera. It has great effects such as lipid-lowering,anti-oxidation,antimicrobial activitity and anti-cancer. The review focused on its pharmacological effects and pharmacokinetic characters reported in recent years,which can be helpful to the further researches on nuciferine.

Objective To investigate the situation of dog rabies and analyze it's relationship with human rabies. Methods In Guizhou, Guangxi and Hunan provinces which suffered from rabies most heavily, one or two cities were selected respectively from regions with high-, middle-, low-incidence rate of human rabies as investigation spots where Dogs' brain specimens were collected and detected with both direct immunofluorescence assay (IFA) and RT-PCR. Results A total of 2887 specimens were collected and 66 of these were positive for IFA and RT-PCR. Therefore, the rate of positive specimens was 2.3 %. However, there was not a close relationship in the incidence rate of dog rabies and human rabies. Conclusion Dog's infection situation of rabies contributed to the severe epidemic of human rabies.

OBJECTIVETo study the effects of celecoxib on the cell proliferation and expression of vascular endothelial growth factor (VEGF) in human nasopharyngeal carcinoma line.

METHODS3-[ 4,5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) test was used to investigate the cell proliferation. Flow cytometry (FCM) was used to analyze the cell cycle arrest. Immunocytochemistry technique was to observe the expression of VEGF.

RESULTSCelecoxib inhibited the growth of nasopharyngeal carcinoma line, the cell number of G0/G1 phase increased from 62.13% to 91.35%, and the cell number of G2/M and S phase decreased from 21.59% to 3.56% and from 16.28% to 5.01%, respectively, cell cycle progression was arrested at G1/S phase. Celecoxib decreased the positive expression of VEGF in HNE-1 cells.

CONCLUSIONSCelecoxib inhibited the proliferation of nasopharyngeal carcinoma significantly and the expression of VEGF.

Celecoxib ; Cell Line, Tumor ; drug effects ; metabolism ; Cell Proliferation ; drug effects ; Humans ; Nasopharyngeal Neoplasms ; metabolism ; pathology ; Pyrazoles ; pharmacology ; Sulfonamides ; pharmacology ; Vascular Endothelial Growth Factor A ; metabolism

AIMTo investigate the effects of Nrf2 (Nuclear-E2 related factor) on gamma-glutamylcysteine synthase (gamma-GCS) in lung of guinea pigs with bronchial asthma.

METHODS20 adult male guinea pigs were randomly divided into two groups (n = 10): control group (C group) and asthmatic group (A group), asthmatic model was established by ovalbumin intraperitoneal and ovalbumin inhalation. The reactive oxygen piece (ROS), reduced glutathione (GSH), oxidant glutathione (GSSG) and total GSH in lung tissue were examined respectively. Inflammatory cell infiltration and index of remodeling of bronchiole were detected. In situ hybridization detected the gamma-GCS heavy subunit (gamma-GCS h) mRNA in lung tissue. Immunohistochemistry detected the expression of Nrf2 protein and gamma-GCS protein in lung tissue. RT-PCR measured the expression of Nrf2 mRNA in lung tissue. The activity of gamma-GCS was measured by coupled enzyme assay.

RESULTS(1) The number of eosinophils and lymphocytes in bronchiole of A group were significantly higher than that of C group (P < 0.05), the remodeling of bronchiole in A group was definite. (2) ROS (U/mg pro), GSSG (micromol/g pro) and total GSH in lung tissue of A group were significantly higher than that of C group (P < 0.01). The GSH/GSSG in lung tissue of A group was much lower than that of C group (P < 0.01), GSH in lung tissue showed no difference between A group and C group. (3) Immunohistochemistry indicated that Nrf2 protein and gamma-GCS protein were more positively expressed in A group than that in C group (P < 0.01). In situ hybridization discovered that the expression of gamma-GCS-h mRNA in lung tissue of A group was more positive than that of C group. (4) RT-PCR showed that the expression of Nrf2 mRNA was no difference between A group and C group (P > 0.05). (5) The activity of gamma-GCS of A group was (28 +/- 8)U which was significantly higher than that of C group (9 +/- 2)U (P < 0.01). (6) Linear correlation analysis indicated that in lung tissue of guinea pig with asthma there existed strongly positive relationship among ROS, GSSG and the expression of Nrf2, gamma-GCS mRNA, gamma-GCS protein, the activity of gamma-GCS, there existed strongly negative relationship among GSH/GSSG and the expression of Nrf2, gamma-GCS mRNA, gamma-GCS protein, the activity of gamma-GCS.

CONCLUSIONThere existed oxidative stress in lung of guinea pigs with bronchial asthma, which possibly positively regulated gamma-GCS via up regulating transcription factor Nrf2.

Animals ; Asthma ; metabolism ; Glutamate-Cysteine Ligase ; metabolism ; Guinea Pigs ; Lung ; metabolism ; Male ; NF-E2-Related Factor 2 ; metabolism ; Oxidative Stress ; RNA, Messenger ; genetics