Mechanism of Yishen Tongluo Prescription in Inhibiting Endoplasmic Reticulum Stress and Improving Apoptosis of Renal Tubular Epithelial Cells Based on PERK/ATF4/CHOP / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Yishen Tongluo prescription （YSTLP） on apoptosis of renal tubular epithelial cells and explore the mechanism based on endoplasmic reticulum stress pathway of protein kinase R-like endoplasmic reticulum kinase （PERK）/activating transcription factor 4 （ATF4）/transcription factor C/EBP homologous protein （CHOP）. MethodThe db/db mice were randomly divided into model group， valsartan group （10 mg·kg-1）， and low， middle， high-dose YSTLP groups （1， 2.5， 5 g·kg-1）. Samples were collected after eight weeks of drug intervention. In addition， db/m mice in the same litter served as the control group. Human renal tubular epithelial cells （HK-2） were cultured in vitro and divided into the control group， advanced glycated end-product （AGE） group， and AGE + low， middle， and high-dose YSTLP groups （100， 200， 400 mg·L-1）. TdT-mediated dUTP nick end labeling （TUNEL） staining was used to detect the apoptosis rate of HK-2 cells. Methylthiazolyldiphenyl-tetrazolium bromide （MTT） assay was conducted to detect the viability of HK-2 cells. Calcium fluorescence probe staining and luciferase reporter gene method were adopted to detect the luciferase activity of folded protein response element （UPRE） and endoplasmic reticulum stress. Immunohistochemical （IHC） analysis was carried out to measure the protein expressions of phosphorylated PKR （p-PERK）， CHOP， and ATF4. Real-time polymerase chain reaction （Real-time PCR） was used to measure the mRNA expression levels of CHOP and X-box binding protein 1 （XBP1） in mouse kidney and HK-2 cells. Western blot was used to detect the protein expression level of p-PERK， PERK， CHOP， ATF4， B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）， and cleaved Caspase-3 in mouse kidney and HK-2 cells. ResultIn the cellular assay， HK-2 cell viability was significantly reduced， and the apoptosis rate was elevated in the AGE group compared with the control group （P<0.01）. The mRNA and protein expression levels of apoptosis-related factor Bcl-2 were significantly reduced （P<0.01）， and those of Bax were significantly increased （P<0.01）. The protein expression level of cleaved Caspase-3 was significantly increased （P<0.01）. Compared with the AGE group， YSTLP administration treatment resulted in elevated cell viability and reduced apoptosis rate （P<0.01）. The mRNA and protein expression levels of Bcl-2 were significantly elevated in a time- and dose-dependent manner （P<0.01）， and those of Bax were significantly reduced in a time- and dose-dependent manner. The protein expression level of cleaved Caspase-3 was significantly reduced in a time- and dose-dependent manner （P<0.01）. The intracellular Ca2+ imbalance and UPRE luciferase fluorescence intensity were increased in the AGE group compared with the control group （P<0.01）. The mRNA levels of endoplasmic reticulum stress-related factors CHOP and XBP1 were significantly increased （P<0.01）， and the protein expression levels of p-PERK， CHOP， and ATF4 were significantly increased （P<0.05）. Compared with the AGE group， YSTLP effectively improved intracellular Ca2+ imbalance in HK-2 cells and decreased UPRE luciferase fluorescence intensity in a dose-dependent manner （P<0.01）. It reduced the mRNA levels of endoplasmic reticulum stress-related factors CHOP and XBP1 （P<0.01） and the protein expression levels of intracellular p-PERK， CHOP， and ATF4 in a dose- and time-dependent manner （P<0.01）. In animal experiments， the protein expression level of Bcl-2 was significantly reduced（P<0.01）， and that of cleaved Caspase-3 and Bax was significantly increased in the model group compared with the control group （P<0.05）. The protein expression level of Bcl-2 was dose-dependently elevated， and that of cleaved Caspase-3 and Bax was dose-dependently decreased in the YSTLP groups compared with the model group （P<0.01）. Compared with the control group， the mRNA expression levels of CHOP and XBP1 were significantly elevated in the model group （P<0.05， P<0.01）， and the protein expression levels of p-PERK， CHOP， and ATF4 were significantly increased （P<0.05）. Compared with the model group， YSTLP significantly decreased the mRNA expression levels of CHOP and XBP1 （P<0.01） and the protein expression levels of p-PERK， CHOP， and ATF4 （P<0.01）. ConclusionYSTLP can effectively inhibit endoplasmic reticulum stress and improve apoptosis of renal tubular epithelial cells， and its mechanism may be related to the regulation of the PERK/AFT4/CHOP pathway.

Age-adjusted Charlson comorbidity index predicts mortality in patients with acute type A aortic dissection / 中华急诊医学杂志

Objective:To evaluate the predictive value of age-adjusted Charlson comorbidity index (ACCI) for in-hospital mortality and 1-year mortality in patients with acute type A aortic dissection (ATAAD).Methods:This was a retrospective cohort study, and the clinical data of ATAAD patients admitted to Wuhan Union Hospital from January 1, 1999 to December 31, 2018 were collected for analysis. All the patients were confirmed by computed tomography angiography or magnetic resonance imaging of the aorta and the onset time was less than 14 days. Patients who survived at discharge were followed up to obtain 1-year survival information. The ACCI score was calculated for patients based on their comorbidities and age at admission, and they were divided into three groups of 0, 1 and ≥2 according to the ACCI score. The in-hospital mortality and 1-year mortality of the three groups were compared. Logistic regression analysis was applied to determine the independent predictors for in-hospital mortality and 1-year mortality.Results:Among 1 133 ATAAD patients, 383, 357 and 393 patients had ACCI score of 0, 1, and ≥2, respectively. The in-hospital mortality and 1-year mortality of patients with ACCI score ≥2 were significantly higher than those of patients with ACCI score of 0 (25.4% vs. 17.0%, 30.0% vs. 19.6%, both P<0.05). Multivariate Logistic regression analysis showed that ACCI score ≥2 was an independent risk factor for in-hospital mortality ( OR=1.670, 95% CI: 1.176-2.370, P=0.004) and 1-year mortality ( OR=1.762, 95% CI: 1.264-2.456, P<0.001). Age (per 10-year increase) and cerebrovascular diseases were independent risk factors for in-hospital mortality and 1-year mortality, while diabetes mellitus was a protective factor for in-hospital mortality. Conclusions:ACCI can predict the in-hospital mortality and 1-year mortality of ATAAD patients, and patients with ACCI score ≥2 have a poorer prognosis.

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.

Reference and Enlightenment on the Supervision of Human Genetic Resources from Foreign Legislation / 中国医学伦理学

As an important biological resource of a country or region, human genetic resources (HGR) are increasingly attracting attention and concern from many countries internationally, and even have been elevated to the dimension of national sovereignty by many countries. As a large country with rich and diverse HGR, relevant regulatory work in China started relatively late compared to foreign countries, but has developed rapidly. However, looking around the world, there is still room for further improvement and development of domestic HGR regulation. By reviewing the regulatory legislation of HGR in some countries abroad, this paper sorted out their advanced experience and highlighted measures in detail, and summarized their deep-seated legislative guidance. A detailed analysis and evaluation were conducted from seven aspects:the advanced level of HGR legislation and the enhancement of legal effectiveness, the systematization and systematization of policies and regulations, the unification of platforms and relevant standards, the highlight of the concept of ethics and the rule of law, the strengthening of anti-discrimination protection, the special protection of major human genetic family resources and national special protection areas of HGR, and the establishment of principled consensus or agreement on HGR in international and local regions, to provide reference for the construction of regulatory policies and legal systems for HGR in China.

Clinicopathological Analysis and Treatment of Adult Patients with Inflammatory Myofibroblastic Tumor: A 15-Year Single- Center Study / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal malignancy that occurs primarily in children and adolescents. The clinical and pathological features of IMT in adult patients are not well understood. @*Materials and Methods@#We retrospectively searched for records of adult patients with IMT at Fudan University Shanghai Cancer Center from 2006 to 2021. Clinicopathological data, treatments, and outcomes were collected and analyzed. @*Results@#Thirty adult patients with IMT, mostly women (60.0%), were included. The median age of the patients was 38 (21-77). The most common primary site was abdominopelvic region (53.3%), followed by lungs (20.0%). Seven patients had an abdominal epithelioid inflammatory myofibroblast sarcoma (EIMS). The positivity rate of anaplastic lymphoma kinase (ALK) was 81.5% (22/27). Sixteen patients with advanced ALK-positive disease received crizotinib, with an objective response rate (ORR) of 81.3% and a disease control rate of 87.5%. The median progression-free survival was 20.8 months. EIMS was associated with more aggressive behavior; however, the prognosis was similar to that of non-EIMS patients after treatment with an ALK inhibitor. At a median follow-up time of 30 months (95% confidence interval [CI], 13.6 to 46.4), the 5-year overall survival was 77% (95% CI, 66 to 88) in all patients. @*Conclusion@#Adult IMTs appeared more aggressive, with a higher incidence of recurrence and metastases, and patients with EIMS had more aggressive cases. Treatment with ALK inhibitors resulted in a high ORR and a durable response, which suggested that ALK inhibitors could be used as a first-line treatment option in adult patients with ALK-positive advanced IMT.

Study on the mechanism of Yishen tongluo formula improving abnormal lipid metabolism based on SREBPs pathway / 中国药房

OBJECTIVE To explore the mechanism of Yishen tongluo formula （YSTLF） in improving abnormal lipid metabolism based on the sterol regulatory element binding proteins （SREBPs） pathway. METHODS Using C57BLKS/J （db/db） mice as model and C57BLKS/J （db/m） mice as normal control， the mechanism of 1， 2.5 and 5 g/kg YSTLF improving abnormal lipid metabolism of db/db mice was investigated by determining the liver coefficient， the contents of serum total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL） and high-density lipoprotein （HDL）， observing steatosis and lipid accumulation in liver tissue of mice， detecting the protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription levels of Srebp- 1c， Srebp-2 and their downstream lipid metabolism-related target genes （Fasn， Acc1， Scd5， Fads1， Hmgcr， Dhcr24， Insig-1， Fdps） in liver tissue of mice. Using low-fat cultured human liver cancer cell HepG2 as an in vitro cell model for abnormal lipid metabolism， and 25-HC （SREBPs inhibitor， 10 μmol/L） as the control， the effects of 125， 250 and 500 μg/mL YSTLF on protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription of SREBP-1c， SREBP-2 and their downstream lipid metabolism-related target genes were investigated to verify the mechanism in vitro. RESULTS 1， 2.5， 5 g/kg YSTLF significantly reduced the levels of TC， TG and LDL， the percentage of lipid droplet-positive region in liver tissue and liver coefficient， significantly down-regulated protein expressions of Pre-SREBP-1， n-SREBP-1， Pre-SREBP-2 and n-SREBP-2， and mRNA transcription of Srebp-1c， Srebp-2 and their downstream target genes in liver tissue， while significantly increased HDL level， with statistical significance （P＜0.05 or P＜0.01）. In the cell experiment in vitro， the expressions of the above-mentioned proteins and genes in the cells treated with YSTLF at 125， 250 and 500 μg/mL for 24 hours were consistent with those in the animal experiment； there was no significant difference in the expressions of the above-mentioned proteins and genes between inhibitor control group and 250， 500 μg/mL YSTLF groups （P＞0.05）. CONCLUSIONS YSTLF can regulate the expression of transcription factor SREBPs， so as to inhibit the high expression of fatty acid and cholesterol synthesis-related genes， promote the degradation of TC and TG， improve the abnormality of lipid metabolism and inhibit lipid accumulation， thus playing the role of lipid-lowering.

Establishment of a membrane metalloproteinase TRABD2A blocking method for HIV reservoir detection / 中华检验医学杂志

Objective:To investigate the therapeutic effect of humanized TRAB domain-containing protein 2A (TRABD2A) monoclonal blocking antibody to HIV-1 reservoir cells, and to explore novel methods for measuring the sizes/capacities of HIV-1 infected reservoirs in HIV-1 infected individuals on receiving combined antiretroviral therapy (cART).Methods:A total number of 51 subjects were collected from the First Affiliated Hospital of China Medical University from May 2021 to December 2021. Among them, there were 2 healthy persons, 41 HIV-1 infected persons receiving cART (cART group) and 8 HIV-1 infected persons not receiving cART (no cART group). Humanized TRABD2A monoclonal antibody was constructed based on the phage display technology, the PBMCs and CD4+T cells separated from the peripheral blood mononuclear cells (PBMCs) and CD4+T cells of HIV-1 infected patients treated with receiving cART, or the HIV-1 infected patients without cART treatment and healthy controls were treated with TRABD2A monoclonal antibodies. The luciferase reporter system, single molecule immune array detection technology and other methods were used to detect the virus content in the supernatant of cell culture. At the same time, flow cytometry and fluorescence real-time quantitative polymerase chain reaction were used to detect the activation of the treated cells and the expression of virus genes. The statistical differences between different treatment the amount of virus release and the level of surface activation markers CD25, CD69, human leukocyte antigen DR (HLA-DR) of different groups in the amount of virus release and the expression of surface activation markers CD25, CD69, HLA-DR were compared.Results:The PBMCs of HIV-1 infected persons receiving cART were tested for HIV-1 production after being treated with humanized TRABD2A monoclonal antibody. The amount of virus released by the untreated group was 0 (0, 440), and the amount of virus released by the use of negative antibody was 0 (0, 390). There was no significant difference between the two ( P>0.05). The amount of virus released by the use of positive antibody was 1 259 (0, 4 269), 3 142 (1 292, 5 060), compared with the amount of virus released by the use of negative antibody, The difference was statistically significant ( P<0.05). The healthy control PBMC was used to conduct multiple dilutions to the infected PBMC. After positive antibody treatment, the amount of virus release decreased in equal proportions [the HIV-1 production corresponding to 5, 25, 125, 625 times of undiluted, diluted PBMC was 4 670 (3 339, 7 697), 1 860 (1 509, 4 615), 1 550 (1 150, 2 680), 602 (255, 1 441), 2 (0, 37), respectively].In addition, there was no significant difference in the resting state of cells treated with TRABD2A antibodies compared with the untreated group (The percentage of CD25 positive cells in the untreated group and positive antibody 1 treated group were 3.89±1.31 and 4.60±1.74, the percentage of CD69 positive cells were 2.50±1.27 and 2.18±0.51, and the percentage of HLA-DR positive cells were 7.66±3.78 and 8.79±3.42, respectively, P>0.05). The viral gag expression levels of untreated and positive antibody 1 were 1 and 0.82±0.55, respectively, with no significant difference. Conclusions:The humanized TRABD2A monoclonal antibody can effectively block the protein activity of TRABD2A, and can significantly promote the release of progeny viruses from viral reservoir in the peripheral blood of HIV-1 infected persons without changing the cell resting state and the whole genome transcription level. The amount of virus released in this way is positively related to the number of reservoir cells.

Primary anastomosing hemangioma of the left kidney: a case report / 中华泌尿外科杂志

Anastomosing hemangioma is a newly reported variant subtype of capillary hemangioma, and its biological behavior is mostly benign. We reported a case of anastomosing hemangioma originating from the kidney. After nephrectomy, the patient was followed up for 13 months, and no recurrence or distant metastasis was observed.

Comparison of the therapeutic effects of different antibacterial drugs combined in the treatment of adult brucellosis patients / 中华地方病学杂志

Objective:To compare the efficacy of different antibacterial drugs combined in the treatment of adult brucellosis patients.Methods:Using a prospective design, 60 adult brucellosis patients admitted to the Affiliated Hospital of Jining Medical University from January 2018 to December 2021 were selected as the study subjects. They were randomly divided into an observation group ( n = 30) and a control group ( n = 30) using a random number table method. The observation group was treated with rifampicin combined with minocycline, and the control group was given rifampicin combined with doxycycline. The course of treatment in both groups was 6 weeks. The efficacy and clinical symptom disappearance time between the two groups, as well as the blood white blood cell count (WBC), alanine aminotransferase (ALT) levels, and serum interferon-γ (IFN-γ), interleukin-4 (IL-4) and interleukin-10 (IL-10) levels before and after treatment, and the occurrence of adverse reactions were compared. Results:The total effective rate of the observation group (96.67%, 29/30) was higher than that of the control group (73.33%, 22/30), with a statistically significant difference (χ 2 = 4.71, P = 0.030). The disappearance time of joint pain, hyperhidrosis, gastrointestinal reactions, and fever in the observation group were shorter than those in the control group, and the differences were statistically significant ( P < 0.05). After treatment, the blood WBC and ALT levels in both groups decreased compared to before treatment ( P < 0.05). After treatment, the blood WBC and ALT levels in the observation group were lower than those in the control group ( P < 0.001). The levels of serum IFN-γ and IL-10 were both decreased after treatment compared to before treatment in two groups, while IL-4 level increased compared to before treatment ( P < 0.05). The levels of serum IFN-γ and IL-10 in the observation group were lower than those of the control group, while IL-4 level was higher than that of the control group ( P < 0.001). The incidence of adverse reactions in the observation group (13.33%, 4/30) was lower than that in the control group (36.67%, 11/30), and the difference was statistically significant (χ 2 = 4.36, P = 0.037). Conclusion:The combination of rifampicin and minocycline in the treatment of adult brucellosis patients has good efficacy and can reduce serum IFN-γ and IL-10 levels and increase IL-4 level with few adverse reactions.

Risk factors for refracture of injured vertebrae after percutaneous vertebral augmentation for acute symptomatic thoracolumbar osteoporotic compression fractures / 中华创伤杂志

Objective:To investigate the risk factors of refracture of the injured vertebrae after percutaneous vertebral augmentation for acute symptomatic thoracolumbar osteoporotic compression fractures (ASTOCFs).Methods:A case-control study was conducted to analyze the clinical data of 2 237 ASTOCFs patients admitted to three hospitals from January 2010 to January 2019. There were 569 males and 1 668 females, with age range of 50-85 years [(66.7±4.8)years]. The patients underwent percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP). According to the radiographic outcomes, the patients were divided into refracture group ( n=315) and non-refracture group ( n=1 922). Data were recorded for the two groups, including basic demographics (gender, age, height and weight), personal habits (smoking and alcohol consumption), basic diseases (diabetes, hypertension, coronary heart disease and chronic obstructive pulmonary disease), preoperative bone mineral density, fracture segment, number of injured vertebrae, surgical method (PVP or PKP), surgical approach, bone cement viscosity, distance from cement to the upper and lower endplate, cement volume in injured vertebrae, cement leakage, postoperative exercise, and postoperative anti-osteoporosis treatment. The above data were analyzed to identify their correlation with postoperative refracture of the injured vertebrae by univariate analysis. The independent risk factors for postoperative refracture of the injured vertebrae were determined by multivariate Logistic regression analysis. Results:Univariate analysis showed that refracture of injured vertebrae was correlated with gender, age, diabetes, fracture segment, surgical method, distance from cement to the upper and lower endplate, postoperative exercise, and postoperative anti-osteoporosis treatment ( P<0.05 or 0.01), but there was no correlation with height, weight, smoking, alcohol consumption, hypertension, coronary heart disease, chronic obstructive pulmonary disease, preoperative bone mineral density, number of fractured vertebrae, surgical approach, bone cement viscosity, cement volume in injured vertebrae or cement leakage (all P>0.05). Multivariate Logistic regression analysis showed that female ( OR=1.92, 95% CI 1.34-2.64, P<0.01), age ≥80 years ( OR=1.21, 95%CI 1.17-1.25, P<0.01), diabetes ( OR=1.92, 95% CI 0.44-2.55, P<0.01), thoracolumbar fracture ( OR=1.46, 95% CI 1.82-7.51, P<0.05), PKP ( OR=4.56, 95% CI 0.86-1.44, P<0.05), no postoperative exercise ( OR=2.14,95% CI 0.27-0.38, P<0.01), and no postoperative anti-osteoporosis treatment ( OR=2.36,95% CI 0.13-0.47, P<0.05) were positively correlated with refracture of injured vertebrae. Conclusion:Female, age ≥80 years, diabetes, thoracolumbar fracture, PKP, no postoperative exercise, and no postoperative anti-osteoporosis treatment are independent risk factors for refracture of injured vertebrae after percutaneous vertebral augmentation for ASTOCFs.

Research advances in the role of MAPK cascade in regulation of cell growth, immunity, inflammation, and cancer / 中南大学学报(医学版)

Mitogen-activated protein kinase (MAPK) cascade system is one of the highly conserved signal systems in eukaryotic cells, which participates in the regulation of many biological processes. Under the stimulation of different signals (such as cytokines, neurotransmitters, and hormones), MAPK cascade activates downstream targets and controls a variety of cellular processes, including growth, immunity, inflammation, and stress response. In different cells, the effects of MAPK cascade on cells vary with the stimuli and the duration of stimulation. MAPK cascade induces Th differentiation and participates in T cell receptor signal pathway and B cell receptor signal pathway. MAPK cascades regulate various cellular activities related to the occurrence and development of cancer. A thorough and systematic understanding of the specific regulatory effects of MAPK cascade on various cellular processes will provide theoretical guidance for treating various diseases.

Effectiveness and safety of dydrogesterone in the treatment of dysmenorrhea ：a prospective ，random-controlled， open-label and multicenter clinical study / 中国药房

OBJECTIVE To evaluate the efficacy and safety of dydrogesterone in the treatment of dysmenorrhea. METHODS The prospective ，random-controlled，open-labeland multicenter clinical study was adopted. A total of 108 women with dysmenorrhea were randomly assigned into dydrogesterone group and control group according to the ratio of 1∶1，with 54 patients in each group. Dydrogesterone group was treated with dydrogesterone 10 mg orally ，twice a day ，on the 5th-25th day of menstrual cycle ，for 3 menstrual cycles. Control group received Guizhi fuling capsule 0.93 g orally ，three times a day，since the end of menstrual bleeding to the third day of the next menstruation ，for 3 menstrual cycles. Main results were the changes of visual analogue scale （VAS）scores in 2 groups after 3 menstrual cycles ；secondary results were the changes of COX menstrual symptom scale （CMSS），quality life of 36-item short form （SF-36），levels of carbohydrate antigen 125（CA125）and interleukin 6（IL-6）after 3 menstrual cycles ；other findings included additional benefits and drug safety. RESULTS The results of intention to analysis data set and the follow-up study protocol analysis data set showed that VAS scores of 2 groups after treatment of dysmenorrhea for 1，2 and 3 menstrual cycles were lower than those before treatment ，the longer the treatment time ，the more obvious the decrease of VAS score （P＜0.05），and VAS score decline of dydrogesterone group was better than that of control group（P＜0.05）. After 3 menstrual cycles ，both the two group showed significant reduction in the severity and duration scores of CMSS（P＜0.05）；and the decrease of the above scores in the dydrogesterone group was superior than in the control group （P＜ 0.05）. After 3 menstrual cycles ，among 8 dimensions of SF- 36 scale，the scores of 7 dimensions in dydrogesterone group were significantly higher than those before treatment ，such as the scores of physiological function ，physical role ，physical pain ， emotional function ，social function ，general health status and energy （P＜0.05）；the increase of the scores of four dimensions were higher than those in the control group ，such as physical pain ，social function ，general health status ，energy（P＜0.05）. There was no significant difference in the levels of CA 125 and IL- 6 between 2 groups before and after treatment （P＞0.05）. After 3 menstrual cycles，the menstrual cycle and menstrual period in the dydrogesterone group were shorter than those before treatment ，and the menstrual volume decreased （P＜0.05）；but there was no significant change in the above indexes of control group （P＞0.05）. After 3 menstrual cycles ，the incidence of adverse drug events and adverse reactions in dydrogesterone group was 32.69％（17/52）and 28.85％（15/52）；no serious adverse drug events or adverse reactions such as thrombosis occurred in both groups. CONCLUSIONS Dydrogesterone can effectively reduce the VAS score ，also relieve dysmenorrhea-related symptoms ，and improve the quality of life. The efficacy of dydrogesterone is superior than that of Guizhi fuling capsule in treatment for dysmenorrheal ，without serious adverse reactions. It is well tolerated.

Combination effects of pulsed electric field and low temperature plasma on H22 mouse liver cancer cell / 中华肝胆外科杂志

Objective:To investigate the effect of pulsed electric field (PEF) combined with low temperature plasma (LTP) on mouse liver cancer cell.Methods:H22 mouse liver cancer cells were divided into liver cancer group, PEF treatment group, LTP treatment group, combined group A (first PEF treatment immediately after LTP treatment), combined group B (first LTP treatment immediately after PEF treatment), combined group C (same as combined group A, but 20 minutes interval) and combined group D (same as combined group B, but 20 minutes interval). Cell viability was detected by cell counting, apoptosis was detected by flow cytometry, intracellular reative oxygen species (ROS) was marked by fluorescence and counted. Twenty healthy female Kunming mouse aged 4-6 weeks without specific pathogens were subcutaneous injected with liver cancer cells, and then were randomly divided into model group, PBS control group, PEF experimental group, LTP experimental group and combined group (LTP+ PEF, no interval) ( n=4). Tumor relative volume and tumor inhibition rate were measured. Results:The survival rates were liver cancer cell group (98.3±0.9)%, PEF treatment group (66.8±4.4)%, LTP treatment group (62.1±3.9)%, combined group A (43.7±3.7)%, combined group B (31.0±1.4)%, combined group C (46.8±2.9)%, combined group D (39.0±2.3)%. Compared with liver cancer cell group, the cell survival rate of all treatment groups was decreased, and the cell survival rate of the four combined treatment group was lower than that of PEF treatment group and LTP treatment group, the differences were statistically significant (all P<0.05). The survival rate of combined B group was the lowest. The results of apoptosis detection were consistent with those of cell survival rate. Under fluorescence microscope, the ROS fluorescence of cells in the combined group B was significantly increased, and the ROS fluorescence of cells in the LTP treatment group was more than that in the PEF treatment group, and the percentage of ROS positive cells in the combined group B was higher than that in the LTP treatment group and the PEF treatment group, with statistical significance (all P<0.05). Tumor relative volume and tumor inhibition rate in the combined group were better than those in the PEF and LTP groups, and the differences were statistically significant (all P<0.05). Conclusion:LTP combined with PEF has a better killing effect on H22 cells than PEF or LTP treatment, which is expected to be a new tumor therapy.

Diagnosis and treatment of cystic hypersecretory carcinoma of the breast / 中华内分泌外科杂志

Cystic hypersecretory carcinoma of the breast is very rare, and has a special histological morphology and immunophenotype. It was understood that it cannot be misdiagnosed as invasive carcinoma of the breast or other benign lesions. This paper reports a case of this tumor treated in our hospital on Apr. 2, 2011. The clinical data, ultrasonic manifestations, histomorphology and immunophenotype were analyzed retrospectively. This study aims to investigate the clinicopathological, immunohistochemistry, diagnosis and prognosis of cystic hypersecretory carcinoma of the breast, so as to improve clinicians’further understanding of it.

Inhibition of ginsenoside Rb 1 on the epithelial-mesenchymal transition of renal tubular epithelial cells by regulating TGF-β1/Smad3 signaling pathway / 中国药房

OBJECTIVE To study the effects of ginsenoside Rb 1（G-Rb1）on epithelial-mesenchymal transition （EMT）of renal tubular epithelial cells and its potential mechanism. METHODS The growth factor β1（TGF-β1）10 ng/mL was used to induce EMT of human renal tubular epithelial cells HK- 2. The morphological changes of HK- 2 cells were observed after treated with 10， 20，30 μmol/L G-Rb1 for 48 h. The transcriptional activities of biovector SBE in human embryonic kidney cell HEK 293 were determined after 24 h treatment with 1.0，2.5，5.0，10，20，30 μmol/L G-Rb1. Effects of above concentration of G-Rb 1 on the viability of HK- 2 cells were determined after 24 h of treatment. mRNA expressions of α-smooth muscle actin （α-SMA），collagen Ⅰ （COL-Ⅰ）and fibronectin （FN）in HK- 2 cells were detected after treated with 10，20，30 μmol/L G-Rb1 for 24 h. The expressions of α-SMA，Smad3，p-Smad3，COL-Ⅰ，FN and E-cadherin were detected after treated with 10，20，30 μmol/L G-Rb1 for 24 h. RESULTS G-Rb1 of 10-30 μmol/L significantly inhibited TGF-β1-induced EMT in HK- 2 cells and the increase of transcriptional activities of biovector SBE induced by TGF-β1（P＜0.05），but had no effects on relative activities of HK- 2 cells（P＞0.05）. The protein and mRNA expressions of α-SMA，COL-Ⅰ and FN ， the protein expressions of Smad 3 and p-Smad 3 were significantly up-regulated induced by TGF-β1（P＜0.05），while the protein expression of E-cadherin was significantly down- regulated（P＜0.05）；G-Rb1 could effectively reverse aboveprotein or mRNA expressions. CONCLUSIONS G-Rb1 can protect renal tubular epithelial cells from EMT induced byxiezhishen TGF-β1 to a certain extent ，which may be related to inhibiting the activation of TGF-β1/Smad3 signaling pathway.

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.

Upregulation of miR-20b Protects Against Cerebral Ischemic Stroke by Targeting Thioredoxin Interacting Protein (TXNIP)

Dysregulation of microRNAs (miRNAs) is involved in abnormal development and pathophysiology in the brain. Although miR-20b plays essential roles in various human diseases, its function in cerebral ischemic stroke remains unclear. A cell model of oxygen glucose deprivation/reoxygenation (OGD/R) and A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) were constructed. qRT-PCR and western blot were used to evaluate the expression of miR-20b and TXNIP. Cell viability was detected by MTT assay, and cell apoptosis was evaluated by flow cytometry. Targetscan and Starbase were used to predict the potential targets of miR-20b. Luciferase reporter assay was applied to determine the interaction between miR-20b and TXNIP. Rescue experiments were conducted to confirm the functions of miR-20b/TXNIP axis in cerebral ischemic stroke. MiR-20b was significantly downregulated after I/R both in vitro and in vivo. Upregulation of miR-20b inhibited OGD/R-induced neurons apoptosis and attenuated ischemic brain injury in rat model. Bioinformatic prediction suggested that TXNIP might be a target of miR-20b, and luciferase reporter assay revealed that miR-20b negatively regulated TXNIP expression by directly binding to the 3’-UTR of TXNIP. Downregulation of TXNIP inhibited OGD/R-induced neurons apoptosis in vitro and ischemic brain injury in vivo. Rescue experiments indicated that downregulation of TXNIP effectively reversed the effect of miR-20b inhibitor in neurons apoptosis after OGD/R-treatment and ischemic brain injury in a mouse model after MCAO/R-treatment. Our study demonstrated that upregulation of miR-20b protected the brain from ischemic brain injury by targeting TXNIP, extending our understanding of miRNAs in cerebral ischemic stroke.

A case report of adult granulosa cell tumors of testis with metastasis of pulmonary and retroperitoneal lymph nodes / 中华泌尿外科杂志

A rare case of adult granulosa cell tumors of testis with metastasis of pulmonary and retroperitoneal lymph nodes was reported. The patient was 26 years old, who underwent resection of the affected testis by orchiectomy and postoperative radiotherapy, and pulmonary and retroperitoneal lymph node metastases were detected 5 years after surgery by regular follow-up. Adult granulosa cell tumors of testis has the potential of malignancy, and the prognosis is poor if the distant metastasis occurs.

MRI features and signal pattern of primary sinonasal malignant melanomas / 中华放射学杂志

Objective:To investigate the MRI features of the primary sinonasal malignant melanoma (SMM) and evaluate the signal pattern based on T 1WI and T 2WI, in order to improve the diagnostic accuracy of SMM. Methods:The MRI findings of 63 SMM cases confirmed by pathology from April 2007 to November 2018 at Beijing Tongren Hospital, Capital Medical University were analyzed retrospectively. The signal intensity of malignant melanoma was classified into four types(Ⅰ—Ⅳ) according to the proportion of signal areas of the largest slice of the tumor on T 1WI and T 2WI. The classification criteria according to T 1WI: type Ⅰ, the area of hyperintensity was ≥50%; type Ⅱ, the area of hyperintensity was <50%; type Ⅲ, the tumor did not show hyperintensity, and the area of isointensity was ≥50%; type Ⅳ, the tumor did not have high signal area, and the area of low signal was ≥50%. The classification criteria according to T 2WI: type Ⅰ, the area of low signal in the tumor was ≥50%; type Ⅱ, the area of low signal was <50%; type Ⅲ, the tumor did not contain low signal area, and the area of isointensity was ≥50%; type Ⅳ, the tumor did not have low signal area, and the area of high signal intensity was ≥50%. The proportion of each type was calculated. Results:According to T 1WI, typeⅠwas identified in 27 cases (42.9%, 27/63), typeⅡ in 25 cases (39.7%, 25/63), type Ⅲ in 4 cases (6.3%, 4/63), and type Ⅳ in 7 cases (11.1%, 7/63). According to T 2WI, type Ⅰwas demonstrated in 29 cases (46.0%, 29/63), type Ⅱ in 28 cases (44.4%, 28/63), type Ⅲ in 2 cases (3.3%, 2/63), and type Ⅳ in 4 cases (6.3%, 4/63). There were 16 cases classified as type I based on T 1WI and T 2WI. Conclusions:Typical and atypical SMM can be identified according to signal patterns. The typeⅠsignal pattern of SMM cases on T 1WI and T 2WI is typical and can be easily diagnosed, but the proportion was less than 50%. For atypical SMM, malignant melanoma should be strongly suspected if hyperintense on T 1WI or hypointense on T 2WI is found.

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