Amino acid metabolism of fibroblasts involved in the occurrence and development of pulmonary fibrosis / 药学学报

Pulmonary fibrosis is a common pathological change in many chronic lung diseases, and its pathogenesis and characteristics are mainly caused by repeated lung alveolar injury leading to abnormal activation of fibroblasts and the accumulation of large amounts of extracellular matrix (ECM) deposition. Fibroblasts are not only responsible for constituting the interstitial structure of the lung but are also involved in the post-injury repairment in healthy lung tissue. In contrast, fibroblasts show a typical pro-fibrotic metabolic phenotype after differentiation into myofibroblasts during the development of pulmonary fibrosis. To synthesis large amount of collagen, the myofibroblasts have a strong metabolism characteristic of serine/glycine, glutamine, proline, and arginine. At the same time, the myofibroblast get the ability to resist cell apoptosis. As an important cell type for collagen degradation, fibroblasts reuse the amino acids of collagen to maintain cell metabolism. However, the myofibroblasts cannot degrade the ECM due to the suppression of autophagy activity, thus accelerating the progression of pulmonary fibrosis. This review attempts to summarize how amino acid metabolism of fibroblasts influence the pulmonary fibrosis.

Subcellular localization of macrophage migration inhibitory factor and its diverse biological functions in tumors / 药学学报

Macrophage migration inhibitory factor (MIF) is an enzyme-active pleiotropic cytokine that is expressed in various immune cells and tumor cells. MIF plays diverse roles in inflammation and tumor progression. It acts as a cytokine involved in immune response and inflammatory lesions. Additionally, MIF is closely associated with tumor proliferation, metastasis, and other tumor hallmarks, exerting a multifaceted influence on tumor occurrence and progression. MIF not only functions by being secreted into the extracellular space as a cytokine but can also be localized within the cytoplasm and nucleus, exhibiting diverse biological functions. As MIF in promoting tumor progression becomes increasingly recognized, MIF-based therapeutic strategies have become a hot research topic in oncology. Here, we provide a comprehensive review of MIF with different subcellular localization about their pro-tumoral functions. A better understanding of MIF in tumor biology will bring broader perspectives for the development of novel MIF targeting strategies and give promising direction for future tumor treatments.

Interpretation of guidance on non-clinical safety evaluation for nanomedicines / 药学学报

With the rapid development of nanotechnology, the research and development of nanomedicines have become one of the development directions of drug innovation. Nanomedicines have special physical and chemical properties, such as nanoscale effects and nanostructure effects, so they have special biological properties, which may change the pharmacokinetic profiles such as absorption and tissue distribution of drug molecules, and thus affect their safety and effectiveness. There are many special concerns on the non-clinical safety evaluation of nanomedicines at the basis of ordinary drug because of the particularity of nanomedicines. On August 25, 2021, China issued Guidance on Non-clinical Safety Evaluation for Nanomedicines(interim). This article interprets comprehensively the guidance, focuses on the key points of non-clinical safety evaluation for nanomedicines, and expounds combined with some cases, aiming to provide reference for drug researchers.

TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Percentage of tonsil hypertrophy in orthodontic patients with different sagittal skeletal relationship / 中华口腔医学杂志

Objective: To investigate the prevalence of tonsil hypertrophy in patients with different sagittal skeletal craniofacial patterns, as well as the correlation between tonsil hypertrophy and the type of skeletal pattern. Methods: Lateral cephalograms of patients who visited the Department of Orthodontics Division 1, School of Stomatology, Wuhan University during January to August, 2019 were retrospectively collected. Patients (children: age≥6 and ≤12 year; adults: age≥18 year) were divided into three groups according to the ANB (subspinale-nasion-supramental) angle: the skeletal class Ⅰ group (0°≤ANB≤4°), skeletal class Ⅱ group (ANB>4°) and skeletal class Ⅲ group (ANB<0°). Tonsil hypertrophy was diagnosed with lateral cephalogram by two specifically trained orthodontists independently, according to the Baroni's method. The between-group differences in tonsil hypertrophy prevalence were analyzed using chi-square tests with Bonferroni correction (α=0.017). Results: A total of 1 776 patients (593 children and 1 183 adults) were included, among which 672 (37.8%) were with class Ⅰ, 849 (47.8%) with class Ⅱ, and 255 (14.4%) with class Ⅲ skeletal pattern. The prevalence of tonsil hypertrophy in children was 66.3% (393/593). The proportion of children with tonsil hypertrophy in class Ⅲ group [87.0% (60/69)] were significantly higher than that in class Ⅰ [65.6% (145/221), χ²=11.56, P<0.017] and class Ⅱ [62.0% (188/303), χ²=15.69, P<0.017] groups. The prevalence of tonsil hypertrophy in adults was 23.2% (275/1 183). The proportion of adults with tonsil hypertrophy in class Ⅲ group [42.5% (79/186)] was significantly higher than that in class Ⅰ [19.1% (86/451), χ²=36.50, P<0.017] and class Ⅱ [20.2% (110/546), χ²=35.00, P<0.017] groups. However, there was no significant difference in the prevalence of tonsil hypertrophy between class Ⅰ and class Ⅱ groups for both children (χ²=0.70, P>0.017) and adults (χ²=0.18, P>0.017). Conclusions: The prevalence of tonsil hypertrophy in skeletal class Ⅲ patients was significantly higher than that in patients with skeletal class Ⅰ and Ⅱmalocclusion. Tonsil hypertrophy could be an important risk factor for skeletal class Ⅲ patients.

Relationship between perivascular space enlargement and cognitive and motor longitudinal changes in patients with Parkinson′s disease / 中华神经科杂志

Objective:To investigate the correlation between basal ganglia (BG) enlarged perivascular space (EPVS; BG-EPVS) and cognitive and motor longitudinal changes in patients with newly diagnosed Parkinson′s disease and its different motor subtypes [tremor dominant (TD), postural instability and gait disorder (PIGD)].Methods:A total of 131 Parkinson′s disease patients from the Parkinson Progression Markers Initiative (PPMI) database were screened and their clinical data were collected at baseline, 1 year and 2 years of follow-up. The number of EPVS in different brain regions was assessed on axial T 2-weighted images by cranial imaging data, and they were divided into two groups according to the degree of EPVS: BG-EPVS- and BG-EPVS+. Parkinson′s disease patients were divided into TD and PIGD groups by Movement Disorder Society Unified Parkinson′s Disease Rating Scale (MDS-UPDRS) score, and the number and clinical data of EPVS were compared between the two groups, and the correlation between the number and degree of BG-EPVS at baseline and longitudinal changes in clinical outcome measures of Parkinson′s disease and its different motor subtypes (TD, PIGD) was analyzed. Results:BG-EPVS was positively correlated with age ( r=0.32, P<0.01), Hoehn & Yahr stage ( r=0.21, P<0.05), serum neurofilament light chain ( r=0.18, P<0.05) and Epworth Sleepiness Scale score ( r=0.20, P<0.05) in all Parkinson′s disease patients. At baseline and 2 years, the number of BG-EPVS was more in the PIGD group than in the TD group (11.0±4.2 vs 9.0±3.8, t=2.18, P=0.03; 16.3±6.7 vs 12.6±4.6 , t=2.71 , P=0.007;after correction).At baseline, more BG-EPVS in patients with Parkinson′s disease and its motor subtypes (TD, PIGD) was significantly associated with baseline motor outcomes ( β=0.66, P=0.01; β=0.64, P=0.008; β=0.91, P=0.009), but not with cognitive outcomes. By linear mixed effects model analysis, BG-EPVS numbers and moderate to severe BG-EPVS were positively correlated with motor outcomes over time in patients with Parkinson′s disease and its motor subtypes (TD, PIGD) ( β=0.51, P=0.008; β=0.59, P=0.025; β=0.80, P=0.038). After dividing BG-EPVS in Parkinson′s disease patients into different degrees, moderate to severe BG-EPVS was positively correlated with motor outcomes over time ( β=3.30, P=0.031). Conclusion:In this longitudinal study, bigger baseline BG-EPVS numbers were found to be positively associated with longitudinal changes in dyskinesia severity in Parkinson′s disease patients, not with cognitive changes, and be able to predict decline in motor function over a 2-year follow-up period.

The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases.

Buyang Huanwutang Alleviated Oxidative Stress Following Cerebral Ischemia/Reperfusion in Rats by Formyl Peptide Receptor 2 / 中国实验方剂学杂志

Objective:To investigate the role of formyl peptide receptor 2 （FPR2） in the inhibitory effects of Buyang Huanwutang （BYHWT） on the oxidative stress and its protective effects on cerebral ischemia-reperfusion in rats. Method:Forty-eight male SD rats were randomly divided into sham group， model group， BYHWT group and BYHWT combined with FPR2 inhibitor （Boc-2） group. In the sham group， only the vessels were isolated. In other groups， the middle cerebral artery occlusion （MCAO） model was constructed using the modified Longa method and reperfused after 2 h of ischemia. BYHWT （16 g·kg^-1） was given by gavaged twice daily after reperfusion in BYHWT group and BYHWT+Boc-2 group. Boc-2 （0.4 mg·kg^-1） was injected intraperitoneally 30 min before surgery. Equal volume of saline were given instead in sham and model group. After 24 h of reperfusion， Fluoro-Jade C （FJC） staining was performed to observe the changes in the number of FJC-positive cells. Western blot was performed to detect the expression of apoptosis-related B-cell lymphoma-2 (Bcl-2)， Bcl-2 associated X (Bax)， and cleaved aspartic acid cysteine proteolytic enzyme-3（Caspase-3）. Besides， superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione （GSH）， and nitric oxide （NO） was measured. The mean fluorescence intensity of nicotinamide adenine dinucleotide phosphate Ⅱ（NADPH） oxidase 2 （NOX2） was examined by immunofluorescence. Result:Compared with sham group， the model group showed increased number of FJC-positive cells （<italic>P</italic><0.01）， decreased Bcl-2 expression （<italic>P</italic><0.01）， increased Bax and cleaved Caspase-3 expression （<italic>P</italic><0.01）， increased NO and MDA content （<italic>P</italic><0.05，<italic>P</italic><0.01）， decreased GSH and SOD activities （<italic>P</italic><0.05，<italic>P</italic><0.01）， and increased NOX2 expression （<italic>P</italic><0.01）. Compared with model group， there were decreased FJC-positive cells （<italic>P</italic><0.01）， up-regulated Bcl-2 expression （<italic>P</italic><0.01） with down-regulated cleaved Caspase-3 and Bax （<italic>P</italic><0.05，<italic>P</italic><0.01）， decreased NO and MDA （<italic>P</italic><0.05，<italic>P</italic><0.01） with increased GSH and SOD （<italic>P</italic><0.01）， and decreased NOX2 expression （<italic>P</italic><0.01） in the BYHWT group. All the above effects were partially blocked by Boc-2. Conclusion:BYHWT can reduce oxidative stress injury and inhibit apoptosis in cerebral ischemia/reperfusion rats， which may be related with the down-regulation of NOX2 expression by FPR2.

TRIB3 promotes lung cancer cell survival and inhibits apoptosis through NRF2 activation / 药学学报

The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2- antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.

The upregulation mechanism of OCT4 signaling by ID1 in colorectal cancer / 药学学报

Inhibitor of DNA binding 1 (ID1) has an aberrantly high expression in multiple cancer tissues, including colon cancer, lung cancer, breast cancer, and so on, which is closely related to cancer aggressiveness and poor clinical outcomes in cancer patients. It has been reported that ID1 maintains colorectal cancer cells (CRCs) stemness traits and contributes to the CRC drug resistance. While, the biological molecular mechanisms have not been fully elucidated. In this research, we found that ID1 upregulates octamer binding transcription factor (OCT4) protein level as well as OCT4 signaling pathway via Western blot, gene set enrichment analysis (GSEA), dual-luciferase reporter assay, and real-time PCR. Through the in vitro sphere formation assay, we found that overexpression of OCT4 reverses the inhibitory effect of knocking down ID1 on CRC sphere formation ability. With the help of JASPAR and GEPIA database, we predicted a novel transcriptional repressor—forkhead box D3 (FOXD3) of OCT4. Finally, by using co-immunoprecipitation (Co-IP), confocal and real-time PCR, we demonstrated that ID1 interacts with FOXD3 to inhibit its transcriptional repression activity and therefore to upregulate OCT4 transcription and OCT4 signaling pathway. In conclusion, this study provides a new theoretical basis for the regulation mechanism of colon cancer stem cells, and the newly found protein-protein interaction of ID1-FOXD3 provides a potential drug target for the therapy of CRC.

Utilization of hospital service and its influencing factors among patients with occupational pneumoconiosis / 中国职业医学

OBJECTIVE: To analyze the utilization of hospital service and its related influencing factors among patients with occupational pneumoconiosis. METHODS: A total of 178 patients with occupational pneumoconiosis were selected as the study subjects using the convenience sampling method. The utilization of hospital service and health-related quality of life of patients with pneumoconiosis and its complications were investigated using the Questionnaire on Pneumoconiosis Patients′ Medical Consultation Behavior and its Influencing Factors and the European Quality of Life Inventory.RESULTS: The one-year hospitalization rate of patients with pneumoconiosis was 57.3%(102/178), and 88.2% of the patients were hospitalized once a year. The median number of hospitalization time in a year was 20.0 days. Visual health scale(VAS) score was(58±15) points. The multiple logistic regression analysis results showed that the utilization of hospital service among patients with employment injury insurance and fund reimbursement provided by the local governmentwere higher than those without employment injury insurancea nd without fund reimbursement provided by the local government(all P<0.05). The utilization of hospital service of patients with problems in usual activities and those unable to perform usual activities were higher than those without any problems(P<0.05). The utilization hospital service of patients with VAS scores <60 was higher than those with VAS scores of 60-<75(P<0.05). CONCLUSION: The patients with pneumoconiosis have a relatively overall high level of utilization of hospital service. The employment injury insurance, fund reimbursement provided by the local government, VAS score, and status of physical health are important influencing factors of utilization of hospital service.

TRIB3‒GSK-3

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3

Comparison of radiological and clinicopathological features of craniofacial fibro-osseous lesions / 中华病理学杂志

To investigate the clinicopathological and radiological features of benign fibro-osseous lesion (BFOL). Sixty-five cases of craniofacial BFOL, eight cases of peripheral ossifying fibroma (POF) and one case of low-grade central osteosarcoma diagnosed at Sichuan Provincial People's Hospital between January 2010 and March 2019 were collected. The clinicopathologic features, hematoxylin-eosin and immunohistochemical (IHC) staining and radiographic features were analyzed. MDM2 gene amplification was detected by FISH in difficult borderline cases. This cohort of BFOLs included 50 cases of fibrous dysplasia (FD), 12 cases of ossifying fibroma (OF), and three cases of juvenile psammomatoid ossifying fibroma (JPOF). The average ages of patients with FD,OF and JPOF were 31.7, 39.2 and 26.0 years respectively. The male to female ratio was 1.0∶1.8.The average age of POF was 47.0 years, with male to female ratio of 1∶7. Patient of low-grade central osteosarcoma was a 48-year-old man. Twenty-seven cases of FD were located in the jaw, and 23 cases were in other craniofacial bones. Nine cases of OF were located in the jaw, and three cases were in the nasal cavity. Two cases of JPOF were in the nasal sinus, and one was in the jaw. All POF were located in the gingiva, and low-grade central osteosarcoma was located in the mandible. The imaging features of FD were luffa-like or ground-glass like signal shadows with poorly defined borders with expansion. OF had clear borders or sclerosing margins. Both JOF and low-grade central osteosarcoma were expansile intraosseously and with focally invasive nodular masses with ground-glass like signal shadows; and POF showed soft tissue mass with bone formation. Histological features of BFOLs showed mixed fibrous and irregular osteoid lesions. FD had no clear relationship with the host bone and no osteoblasts surrounded the bone trabeculae. Osteoblasts rimming was found in OF, and the boundaries of the host bone were clear. JPOF and low-grade central osteosarcoma infiltrated the host bone focally, and the latter showed mild cellular atypia. MDM2 amplification was detected in low-grade central osteosarcoma. BFOLs are a group of fibro-osseous lesions with similar morphology in the head and neck and face, but their clinical features and prognosis are different; and their imaging and histological characteristics are also slightly different. Attentions should be given to the combination of clinical, imaging and pathologic features of BFOLs, especially the differential diagnosis between BFOLs and low-grade central osteosarcoma. Molecular detection could be used to assist the diagnosis in difficult cases.

Serum level of ceruloplasmin in patients with different liver diseases in Jilin, China / 临床肝胆病杂志

ObjectiveTo investigate the serum level of ceruloplasmin in patients with different stages and etiologies of liver diseases. MethodsA total of 1077 patients with liver diseases who were hospitalized in Department of Hepatology, The First Hospital of Jilin University, from January 2012 to January 2018 were enrolled, and the serum level of ceruloplasmin was analyzed for the patients with different liver diseases. The Kruskal-Wallis H test was used to compare the level of ceruloplasmin between the patients with virus-related liver diseases with different liver functional states, and a Spearman correlation analysis was used to investigate the correlation of ceruloplasmin with other biomarkers. ResultsIn the Wilson’s disease group, 97.6% (41/42) of the patients had a serum ceruloplasmin level of ＜0.2 g/L and 881% (37/42) had a level of ＜0.1 g/L. In the non-Wilson’s disease group, 24.3% (251/1035) of the patients had a ceruloplasmin level of ＜0.2 g/L and 0.2% had a level of ＜0.1 g/L. There was a significant difference in the serum level of ceruloplasmin between the patients with virus-related liver diseases with different liver functional states, and the patients with chronic viral hepatitis, severe viral hepatitis, and viral hepatitis cirrhosis had a significantly lower level than those with acute viral hepatitis and virus-related liver cancer (P=0005, P＜0.001, P=0.001, P=0.027, P＜0.001, and P=0.001). In the patients without Wilson’s disease, serum ceruloplasmin was positively correlated with albumin and prealbumin (r=0.068 and 0.091, both P＜0.05) and was negatively correlated with prothrombin time (r=-0.297, P＜0.05). ConclusionCeruloplasmin often decreases significantly in patients with Wilson’s disease, with a slight reduction in patients with other types of liver diseases. For these patients, it should be determined whether the reduction in ceruloplasmin is caused by hepatocyte injury or the presence of Wilson’s disease.

Joint effect of school and family on domestic second-hand smoke exposure in middle school students / 中国学校卫生

Objective@#To observe the joint effect of school and family tobacco control on middle school students, and to explore its effectiveness in reducing second-hand smoke exposure in middle school students’ families, as so asto provide a new way of thinking for controlling smoking among middle school sudents.@*Methods@#A questionnaire survey was conducted on the study of 2 125 primary and high school students in four middle schools in the Dongcheng District of Beijing by means of a stratified group sampling method. Personal information of students, tobacco control environment around the family, school and surrounding ares, as well as the knowledge, attitude and behavior of students related to tobacco control was collected.@*Results@#The exposure rate of second-hand smoke in the families of middle and high school students in Dongcheng District of Beijing was 33.41%. Smoking by at least one parent was positively correlated with second-hand smoke exposure in the student’s home (OR=22.88, P<0.05). Among the students who saw the "clear no-smoking label" on campus, the exposure rate (4.92%) when the smoking restriction was set on the home was lower than that of those who did not have a regulation in the home (58.94%) (χ2=452.57, P<0.01). The results of Logistic regression showed that there was a combination of family smoking restrictions and second-hand smoke exposure in middle and high school students who had seen the smoking ban on campus (OR=0.08) and had the school’s tobacco control education (OR=0.08).@*Conclusion@#The joint tobacco control measures between school and family can effectively reduce the exposure rate of second-hand smoke in middle school students’ families, which is better than the effect of tobacco control alone.

Advances and applications of lysine acetylation / 药学学报

Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.

TRIM25 enhances EGFR stability and signaling activity to promote lung cancer progression / 药学学报

Mutation and amplification of epidermal growth factor receptor (EGFR), one of the most important driver gene, are both reported to participate in the regulation of lung cancer development and progression. Here we investigated the effect and molecular mechanism of tripartite motif 25 (TRIM25) in the regulation of development of lung cancer. CCK-8 and Transwell assays were used to explore the tumor-promoting effect of TRIM25. Results showed that knockdown of TRIM25 significantly inhibited cell proliferation (34% inhibition rate) and invasion (42% inhibition rate). Gene set enrichment analysis (GSEA), Western blot and immunohistochemistry were adopted to detect the effect of TRIM25 on EGFR expression and its downstream signal activity. The results explained that TRIM25 not only up-regulated the expression level of EGFR, but also promoted EGFR signal activation. Co-immunoprecipitation, real-time PCR and cycloheximide (CHX) inhibit protein degradation assays were employed to explore the molecular mechanism of TRIM25 in regulating EGFR stability. Preliminary exploration results indicate that TRIM25 increases the expression level of EGFR and activates its downstream signaling activity through promoting K63-linked ubiquitination of EGFR. Restoration of EGFR expression rescues the phenotype of TRIM25 depletion. In A549 cells, overexpression of EGFR increased cell proliferation rate 1.5-fold and invasion rate 1.6-fold compared with knockdown of TRIM25 cells. Similarly, in H1975 cells, cell proliferation rate was enhanced 2-fold and invasion rate was improved 1.7-fold. These data suggest that TRIM25 promotes lung cancer development via maintaining EGFR stability and continuous EGFR signaling activation. The human lung cancer tissues were obtained from lung cancer patients at Cancer Hospital Chinese Academy of Medical Sciences. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Cancer Hospital Chinese Academy of Medical Sciences.

Expression and Clinical Significance of Late Endosomal/Lysosomal Adaptor,Mitogen-activated Protein Kinase and Mammalian Target of Rapamycin Activator 3 in Bladder Carcinoma / 中国医学科学院学报

Objective To investigate the expression and clinical significance of late endosomal/lysosomal adaptor,mitogen-activated protein kinase and mammalian target of rapamycin activator 3(LAMTOR3)in bladder carcinoma.Methods Oncomine and Expression Atlas were used to extract the useful mining gene chip database for analyzing the expression of LAMTOR3 in bladder carcinoma tissues and cell lines,and the correlation of LAMTOR3 with the clinicopathological features were analyzed.RT-PCR,Western blot,and immunohistochemistry were performed to detect the expression of LAMTOR3 in bladder carcinoma cell lines,specimens,and adjacent normal tissues for verifying the results exploited from the above databases.Results The Expression Atlas showed that LAMTOR3 had high expressions in Hs172.T,HT-1376,RT4,JMSU-1,and T24 cell lines among 20 bladder carcinoma cell lines,among which the LAMTOR3 expression was different.Oncomine reported that LAMTOR3 expression in bladder carcinoma,including invasive(=2.857,=0.005)and non-invasive carcinoma(=3.105,=0.003),was significantly higher than that in adjacent normal tissues.The expression of LAMTOR3 was positively correlated with pathological grade(<0.05).The expressions of LAMTOR3 mRNA in bladder carcinoma cell lines,including UMUC3(=10.84,=0.0084),J82(=21.75,=0.0021),5637(=45.88,=0.0005),and T24(=87.58,=0.0001)were significantly higher than that in normal bladder cell line SV-HUC-1,while its expression in bladder carcinoma tissues was significantly higher than that in adjacent normal tissues(<0.05),so was its protein level in tissues(<0.05).Immunohistochemistry showed that LAMTOR3 protein was over-expressed in bladder carcinoma tissues;its level in invasive carcinoma tissues was higher than that in no-invasive carcinoma tissues and was related closely with the clinical stages(=9.189,=0.002),pathological grades(=4.746,=0.029),and lymphatic metastasis(=6.210,=0.013)but had no significant correlation to sex(=0.965,=0.326),age(=2.126,=0.145),and distant metastasis(=1.261,=0.261).Conclusion LAMTOR3 is highly expressed in bladder carcinoma cell lines and tissues and plays a key role in the development and progression of bladder carcinoma.

Determination of anticoagulating bioactivity in Chuanxiong Rhizome and related Chinese patent medicines / 中草药

Objective To activate partial thromboplastin time (APTT) indicating the coagulation state in intrinsic coagulation system and the efficacy of anticoagulant drugs, and develop a bioassay method to quantify anticoagulating bioactivity in Chuanxiong Rhizome and related Chinese patent medicines for quality assessment. Methods Chuanxiong Rhizome powder was extracted in ethanol and water, respectively. The mixed extract was used as sample to quantify the level of extended APTT in vitro. The blood was taken from the heart of rabbit. The agglomerating time was determined after adding APTT reagent in plasma. The prolongation rate of APTT was chosen as biomarker for anticoagulating bioactivity. Sodium ferulate was chosen as reference. The amount of anticoagulating bioactivity was quantified in Chuanxiong Rhizome extract by the Amount reaction of parallel line analysis (2.2) method. Moreover, the amounts of anticoagulating bioactivity were quantified in the nine Chuanxiong Rhizome samples including Chuanxiong Rhizome raw materials, decoction pieces, and related Chinese patent medicines. Results Both sodium ferulate and Chuanxiong Rhizome extract showed significant anticoagulating bioactivity (P < 0.01). The reliability test for quantifying the level of anticoagulating bioactivity in solidum ferulate and Chuanxiong Rhizome extract was passed through, and the measured value was valid. The correlation coefficient was 0.995 5 (n = 5) between the concentration of solidum ferulate in the range of 1 — 5 mg/mL and their rates of anticoagulating bioactivity. The RSD for the amounts of anticoagulating bioactivity was 9.34% (n = 6) by six replicated tests with the confidence limit rate of 15.98% (n = 6). The amounts of anticoagulating bioactivity were significant difference among various types of Chuanxiong Rhizome samples, i.e. 5.431 — 7.620 U/g for five Chuanxiong Rhizome raw materials, 5.910 and 3.017 U/g for Chuanxiong decotion pieces and processed slice with yellow wine, 14.516 and 29.035 U/g for Tongmai Granules and Xuefu Zhuyu Pills. Conclusion The developed method can accurately quantify the level of anticoagulating bioactivity in Chuanxiong Rhizome raw materials, decoction pieces and related Chinese patent medicines, and assess their quality.

Macrophage migration inhibitory factor, a critical link between inflammation and cancer / 药学学报

Macrophage migration inhibitory factor (MIF) is a classical pro-inflammatory cytokine that plays an important role in the innate and adaptive immune regulation. In recent years, a large number of studies have demonstrated that the expression level of MIF is significantly increased in a variety of tumor tissues and MIF promotes the occurrence and development of tumors. MIF participates in the regulation of tumor growth, metastasis, angiogenesis, as well as induces and maintains the tumor microenvironment. Targeting MIF has been considered as a candidate strategy against cancer. In this review, the structural features, the signaling pathway, the biological functions of MIF are briefly outlined. Moreover, approaches that target MIF in the treatment of cancer are also summarized.