Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases / 药物分析学报

As a ligand-dependent transcription factor,retinoid-associated orphan receptor γt(RORyt)that controls T helper(Th)17 cell differentiation and interleukin(IL)-17 expression plays a critical role in the pro-gression of several inflammatory and autoimmune conditions.An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORyt to decrease Th17 cell development and IL-17 production.Several RORyt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORyt by binding to orthosteric-or allosteric-binding sites in the ligand-binding domain.Some of small-molecule inhibitors have entered clinical evaluations.Therefore,in current review,the role of RORyt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted.Notably,the recently developed RORyt inhibitors were summarized,with an emphasis on their optimization from lead compounds,ef-ficacy,toxicity,mechanisms of action,and clinical trials.The limitations of current development in this area were also discussed to facilitate future research.

Value of platelet count and related scoring models in predicting the prognosis of hepatitis B virus-related acute-on-chronic liver failure / 临床肝胆病杂志

Objective To investigate the association between platelet count (PLT) and the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), to establish a new PLT-related scoring model, and to assess its value in predicting the short-term prognosis of HBV-ACLF. Methods A retrospective cohort study was conducted among the patients with HBV-ACLF who were hospitalized and treated in Department of Gastroenterology, The General Hospital of Western Theater Command, from January 2018 to January 2022. Clinical data within 24 hours after admission were collected from all patients, and according to the survival after 180 days of follow-up, the patients were divided into survival group and death group. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The Pearson correlation coefficient was used to investigate the correlation between different indicators, and the logistic regression model was used to analyze the influencing factors for prognosis. The receiver operating characteristic (ROC) curve was used to assess the predictive value of the prognostic model, and the Kaplan-Meier curve analysis was used to investigate the survival condition of the high AIP group and the low AIP group. Results A total of 236 patients were enrolled, with a 180-day survival rate of 75.85% (179/236). Compared with the survival group, the death group had significantly higher age (53.98±10.45 vs 47.44±12.46, P =0.001), international normalized ratio (INR) [1.78 (1.46-2.04) vs 1.47 (1.23-1.68), P < 0.001], total bilirubin [275.60 (165.00-451.45) vs 230.60 (154.90-323.70), P =0.035], Model for End-Stage Liver Disease (MELD) score [21.47 (18.14-24.76) vs 18.67 (15.70-21.62), P < 0.001], and albumin-bilirubin (ALBI) score [-1.06 (-1.64~-0.86) vs-1.32 (-1.73~-1.01), P =0.034], as well as significantly lower PLT [80.00 (50.00~124.50) vs 115.00 (82.00~143.00), P =0.001] and platelet-to-white blood cell ratio (PWR) [13.40 (9.54~20.70) vs 18.49 (13.95~24.74), P =0.001]. The Pearson correlation analysis showed that PLT was negatively correlated with liver cirrhosis and INR ( r =-0.332 and -0.194, P < 0.001 and P =0.003). The multivariate logistic regression analysis showed that age (odds ratio [ OR ]=1.045, 95% confidence interval [ CI ]: 1.015-1.076), PLT ( OR =0.990, 95% CI : 0.983-0.998), and INR ( OR =2.591, 95% CI : 1.363-4.925) were independent risk factors for the 180-day prognosis of HBV-ACLF patients. The new predictive model was established as follows: AIP=0.006×age+0.187×INR-0.001×PLT. The AIP scoring model had an area under the ROC curve (AUC) of 0.718 in predicting the 180-day prognosis of HBV-ACLF patients, with a sensitivity of 81.1% and a specificity of 54.1%, while PLT, PWR, LPACLF score, MELD score, and ALBI score had an AUC of 0.673, 0.659, 0.588, 0.647, and 0.578, respectively. The AIP scoring model had an optimal cut-off value of 0.48. The Kaplan-Meier survival analysis showed that the high AIP group had a significantly lower survival rate than the low AIP group ( P < 0.001). Conclusion The PLT-related scoring model has a better value than other models in predicting the prognosis of HBV-ACLF, and HBV-ACLF patients with a relatively high PLT level tend to have a high overall survival rate.

Conditional reprogramming: next generation cell culture

Long-term primary culture of mammalian cells has been always difficult due to unavoidable senescence. Conventional methods for generating immortalized cell lines usually require manipulation of genome which leads to change of important biological and genetic characteristics. Recently, conditional reprogramming (CR) emerges as a novel next generation tool for long-term culture of primary epithelium cells derived from almost all origins without alteration of genetic background of primary cells. CR co-cultures primary cells with inactivated mouse 3T3-J2 fibroblasts in the presence of RHO-related protein kinase (ROCK) inhibitor Y-27632, enabling primary cells to acquire stem-like characteristics while retain their ability to fully differentiate. With only a few years' development, CR shows broad prospects in applications in varied areas including disease modeling, regenerative medicine, drug evaluation, drug discovery as well as precision medicine. This review is thus to comprehensively summarize and assess current progress in understanding mechanism of CR and its wide applications, highlighting the value of CR in both basic and translational researches and discussing the challenges faced with CR.

Effect and mechanism of fasudil on proliferation and differentiation of neural stem cells / 中国组织工程研究

BACKGROUND: The self-repairing ability of damaged brain and spinal cord is limited. It is important to search for potential therapeutics to promote the proliferation and differentiation of neural stem cells. OBJECTIVE: To investigate the effect of fasudil on the proliferation and differentiation of primary cultured neural stem cells and its potential mechanism. METHODS: Neural stem cells were obtained from the brain tissue of 15-day-old fetal rats in vitro. The expression of Nestin in the cells was detected by immunofluorescence. After treatment with fasudil at different concentrations (50, 100, 200 μmol/L) for 24, 48 and 72 hours, the proliferation rate of neural stem cells was detected by MTT, and the apoptosis rate was detected by flow cytometry. After further treatment with autophagy inhibitor, necrosis inhibitor, apoptosis inducer and ferroptosis inducer, the proliferation rates of neural stem cells were detected by MTT and the levels of malondialdehyde were detected by biochemical method. The expression of Nestin, doublecortin, microtubuleassociated protein and glial fibrillary acidic protein in neural stem cells were detected by western blot and immunofluorescence after treatment with 200 μmol/L fasudil for 10 days. RESULTS AND CONCLUSION: The positive expression of Nestin protein in primary cultured neural stem cells was observed. The proliferation rate of neural stem cells increased gradually with the increase of fasudil concentration as well as with the prolongation of action time (P < 0.05). Both apoptosis inhibitor and ferroptosis inhibitor can increase the proliferation rate of neural stem cells (P < 0.05). Fasudil increased the proliferation rate of neural stem cells treated by apoptosis inducer and ferroptosis inducer (P < 0.05). Fasudil and ferroptosis inhibitors both decreased the level of malondialdehyde in neural stem cells, while ferroptosis inducers increased the level of malondialdehyde in neural stem cells (P < 0.05). After treatment with fasudil, the expression of doublecortin and glial fibrillary acidic protein protein in neural stem cells increased, and the expression of Nestin decreased (P < 0.05). To conclude, fasudil can improve the survival of neural stem cells by inhibiting apoptosis and ferroptosis, and moreover, it can promote the proliferation and differentiation of neural stem cells into neuron-like cells and glial cells.

Effect and mechanism of fasudil on proliferation and differentiation of neural stem cells / 中国组织工程研究

BACKGROUND: The self-repairing ability of damaged brain and spinal cord is limited. It is important to search for potential therapeutics to promote the proliferation and differentiation of neural stem cells. OBJECTIVE: To investigate the effect of fasudil on the proliferation and differentiation of primary cultured neural stem cells and its potential mechanism. METHODS: Neural stem cells were obtained from the brain tissue of 15-day-old fetal rats in vitro. The expression of Nestin in the cells was detected by immunofluorescence. After treatment with fasudil at different concentrations (50, 100, 200 μmol/L) for 24, 48 and 72 hours, the proliferation rate of neural stem cells was detected by MTT, and the apoptosis rate was detected by flow cytometry. After further treatment with autophagy inhibitor, necrosis inhibitor, apoptosis inducer and ferroptosis inducer, the proliferation rates of neural stem cells were detected by MTT and the levels of malondialdehyde were detected by biochemical method. The expression of Nestin, doublecortin, microtubuleassociated protein and glial fibrillary acidic protein in neural stem cells were detected by western blot and immunofluorescence after treatment with 200 μmol/L fasudil for 10 days. RESULTS AND CONCLUSION: The positive expression of Nestin protein in primary cultured neural stem cells was observed. The proliferation rate of neural stem cells increased gradually with the increase of fasudil concentration as well as with the prolongation of action time (P < 0.05). Both apoptosis inhibitor and ferroptosis inhibitor can increase the proliferation rate of neural stem cells (P < 0.05). Fasudil increased the proliferation rate of neural stem cells treated by apoptosis inducer and ferroptosis inducer (P < 0.05). Fasudil and ferroptosis inhibitors both decreased the level of malondialdehyde in neural stem cells, while ferroptosis inducers increased the level of malondialdehyde in neural stem cells (P < 0.05). After treatment with fasudil, the expression of doublecortin and glial fibrillary acidic protein protein in neural stem cells increased, and the expression of Nestin decreased (P < 0.05). To conclude, fasudil can improve the survival of neural stem cells by inhibiting apoptosis and ferroptosis, and moreover, it can promote the proliferation and differentiation of neural stem cells into neuron-like cells and glial cells.

Theimagingmanifestationsoffocalnodularhyperplasiaofliverwithoutcentralscar / 实用放射学杂志

Objective ToinvestigatetheMSCTand MRIcharacteristicsoffocalnodularhyperplasia(FNH)oftheliverwithout centralscar.Methods Aretrospectiveanalysisofimagingdatawascarriedoutin10patientswithFNH withoutcentralscar,confirmed bypathologyandfollowGupreview.PlainscanandenhancedCT wereperformedin10patients,5ofwhomunderwenttheplainscan andenhancedMRI.Results Lesionswerehomogeneousandslightlylowdensityin10casesonplainMSCT,andhypoGorisoGintensity onT1WIandhyperGorisoGintensityonT2WIin5cases.Nocentralscarwasfoundinalltheselesions.Thecorrelationcoefficientsof thechangeofCTvaluewere0.772onportalvenousphaseand0.827ondelayedphaseinnormalhepaticgroupandlesiongroup(P＜0.05).Theenhancedvolumeof8lesionswasslightlylargerontheportalvenousanddelayedphasethanthatonarterialphase.Conclusion MSCTand MRIcanclearlydisplaytheimagefeaturesofFNH withoutcentralscar.Thereisastrongcorrelationoftheenhancement curvebetweenthelesionsandnormalliverparenchymaonportalvenousanddelayedphase,whichishelpfulformoreaccuratediagnosis.

Correlation of serum thrombin-activatable fibrinolysis inhibitor levels with liver fibrosis in patients with chronic hepatitis B / 中华临床感染病杂志

Objective To analyze the levels of serum thrombin-activatable fibrinolysis inhibitor ( TAFI) in patients with chronic hepatitis B ( CHB ) with different degrees of hepatic fibrosis , and to evaluate the value of TAFI in the evaluation of liver fibrosis .Methods Forty six patients with CHB who underwent liver biopsy from June 2016 to March 2017 in Zhejiang Provincial People' s Hospital were enrolled.According to liver fibrosis stage (S0-4), they were divided into mild liver fibrosis group (S0-1, n=16), significant liver fibrosis group (S2, n=15) and severe liver fibrosis group (S3-4, n=15).At the same time, 16 healthy subjects were randomly selected as health controls in the physical examination center of the hospital .Serum TAFI levels were analyzed in each group , and the receiver operating curve ( ROC) was used to evaluate the diagnostic value of TAFI in CHB patients with significant liver fibrosis and severe liver fibrosis (S≥2).The SPSS 23.0 software was used to analyze the data .Results Serum TAFI levels in the mild liver fibrosis group , significant liver fibrosis group , severe liver fibrosis group and health controls were (63.4 ±18.2), (43.8 ±20.4), (27.5 ±19.2) and (71.3 ±25.6) ng/mL, the difference between the four groups was statistically significant (F=13.512, P<0.01).The level of TAFI in the significant liver fibrosis group was lower than that in the healthy control group and the mild liver fibrosis group (t=3.283 and 2.822, P<0.01).The level of TAFI in the severe fibrosis group was lower than that in the significant liver fibrosis group (t=2.260, P<0.05).Serum TAFI levels were negatively correlated with liver fibrosis stage (r=-0.562, P<0.01).The area under the ROC curve of TAFI for predicting liver fibrosis (S≥2) was 0.832, and the sensitivity and specificity were 81.3％and 78.3％, respectively. Compared with the APRI score and the FIB4 index, the difference was not statistically significant ( P >0.05).Conclusion The serum TAFI level is negatively correlated with the degree of liver fibrosis in CHB patients, which has a good diagnostic value for liver fibrosis (S≥2) in patients with CHB.

Inhibitory effect of ophiopogonin-B on adhesion, invasion and migration of A549 cells in vitro / 中国药理学通报

Aim To explore the inhibitory effects of ophiopogonin-B (OP-B ) on cell adhesion,invasion and migration in non-small cell lung cancer (NSCLC) A549 cells in vitro and its possible mechanism.Meth-ods Cell adhesion assay and transwell chamber assay were used to detect the ability of cell adhesion,migra-tion and invasion.qRT-PCR was used to detect the mRNA levels of MMP-2 and 9 .Meanwhile ,Western blot assay was performed to determine the protein levels of MMP-2/9 and p-Akt.Results OP-B significantly inhibited the ability of cell adhesion,invasion and mi-gration in A549 cells at the concentration of 10 μmol· L-1 (P<0.01 ).Meanwhile,it inhibited the mRNA and protein levels of MMP-2 and MMP-9 and down-regulated the phosphorylation of Akt (P <0.0 1 ). Conclusion OP-B inhibits cell adhesion,invasion and migration in A549 cells through down-regulation of the mRNA and protein expression of MMP-2/9 ,and the inhibitory effect on the expression of p-Akt.

Research on mechanisms of PD-induced inhibition of adhesion, invasion and migration in non-small cell lung cancer H460 and A549 cells / 中国药理学通报

Aim To explore the effects of the inhibition of cell adhesion , invasion and migration in non-small cell lung cancer ( NSCLC ) H460 and A549 cells in-duced by platycodin-D ( PD ) and its mechanism. Methods Cell adhesion assay, wound-healing assay and Transwell chamber migration assay were used to detect the ability of cell adhesion, migration and inva-sion. Regulation of MMP-2 and MMP-9 mRNA was de-termined by RT-PCR. Meanwhile, Western blot was performed to determine the expression levels of MMP-2/9 , its upstream related proteins of ERK signaling pathway and p-Akt. Results PD effectively inhibited the ability of cell adhesion, invasion and migration in H460 and A549 cells in a dose-dependent manner ( P<0. 05 ) . PD reduced the expression of MMP-2 and MMP-9 mRNA in H460 and A549 cells ( P<0. 01 );meanwhile, PD down-regulated the expression levels of MMP-2/9 , and inhibited the expression of its upstream proteins Ras, p-c-Raf, p-ERK 1/2 and p-Akt in a time- and dose-dependent manner. Conclusions PD inhibits cell adhesion, invasion and migration in NSCLC cells, and these effects are related to the down-regulation of the expression of MMP-2 and MMP-9 mR-NA and protein, and inhibition of its upstream expres-sion of ERK signaling pathway and p-Akt.

Research Progress in Anti-tumor Mechanisms of Platycodin-D / 中国中医药信息杂志

Platycodin-D (PD) is the major monomer of triterpene saponins in the root of Platycodon grandiflorum. Recent studies have demonstrated that PD has a wide range of anti-tumor effect and its efficacy is satisfying. This article reviewed anti-tumor mechanisms of PD from the aspects of proliferation, apoptosis, invasion and metastasis, immune and anti-inflammation, etc., with a purpose to provide a theoretical basis and reference for the further development and better utilization of PD and taking its anti-tumor advantage.

Differences in P50 and prepulse inhibition of the startle reflex between male smokers and non-smokers with first episode schizophrenia without medical treatment / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Nicotine may improve schizophrenia patient's cognitive deficit symptoms. This study was to explore the chronic effects of smoking on prepulse inhibition of the startle reflex (PPI) and P50 in the patients with first-episode schizophrenia (FES).</p><p><b>METHODS</b>The event-related potentials (ERP) recording and analysis instrument made by Brain Products, Germany, was used to detect PPI and P50 in 49 male FES patients (FES group, n = 21 for smokers and n = 28 for non-smokers) and 43 normal male controls (control group, n = 19 for smokers and n = 24 for non-smokers).</p><p><b>RESULTS</b>Compared with normal controls, the FES group had prolonged PPI latency when elicited by single stronger stimulus (P < 0.05); the FES group had prolonged PPI latency and increased PPI amplitude (P < 0.05, 0.01) when elicited by weak and strong stimuli. The FES group had lower PPI inhibition rate than normal controls (P < 0.05). Compared with normal controls, the FES group had increased P50-S2 amplitude and increased amplitude ratio S2/S1 (both P <0.05). In the control group, the smokers had a tendency of increase in P50-S2 amplitude (P > 0.05) and shorter P50-S2 latency (P < 0.05) than the non-smokers. The smokers had higher PPI amplitude than the non-smokers (P < 0.05). In the FES group, the smokers had higher P50-S1 amplitude, shorter P50-S2 latency, and higher amplitude ratio S2/S1 than the non-smokers (P < 0.05, 0.01). The smokers had higher PPI amplitude than the non-smokers (P < 0.05).</p><p><b>CONCLUSIONS</b>There is obvious PPI and P50 deficits in schizophrenic patients. However, these deficits are relatively preserved in the smokers compared with the non-smokers, which suggests that long-term smoking might partially improve the sensory gating in schizophrenic patients. Whether this conclusion can be deduced to female patients requires further follow-ups.</p>

Expression and correlation of cell cycle protein-D1 and Ki-67 in laryngeal cancer tissues / 中国医师杂志

Objective To investigate the expression and correlation of cell cycle protein-D1 and Ki-67 in laryngeal cancer tis-sues.Methods Immunohistochemical streptavidin-perosidase ( SP) staining method was used to detect the expression of Cyclin D 1 and Ki-67 proteins in laryngeal squamous cell carcinoma tissues and their correlation between Cyclin D 1 and Ki-67 was analyzed .Re-sults Among 56 cases of Cyclin D1 positive over-expressed laryngeal squamous cell carcinoma tissues , 41 cases of Ki-67 had positive over-expression.Among 51 cases of Ki-67 low-expressed tissues, 35 cases of Cyclin D1 had low-expression.Spearman rank correlation test showed that expressions of Cyclin D 1 and Ki-67 in laryngeal squamous cell carcinoma tissues had a significant positive correlation ( rs =0.620, P <0.01).Conclusions Cyclin D1 and Ki-67 expressions in laryngeal squamous cell carcinoma have a significantly positive correlation .

The Protective Effect of Xinan Granule on Viral Myocarditis in Mice / 中国中医药信息杂志

Objective To investigate the protective effect of Xinan granule on viral myocarditis in mice. Methods Viral myocarditis model was made by intraperitoneal inoculation with Coxsackie virus B3 in BALB/C mice. Mice were randomly devided into six groups:the normal control group, the model control group, the Xinan granule10、20、40 g/(kg?d) groups and the Binduzuo 0.1 g/(kg?d) group.After CVB3 infection 2 h, one set of mice were given drugs for 7 d.Blood and heart samples were obtained on the 8th day after CVB3 infection.The myocardial histopathologic changes were observed. The serum cardiac enzyme (LDH) were measured.The others were given drugs for 2 d before CVB3 infection, and for 7ds after CVB3 infection. The survival time were recorded for 20 ds. Results The myocardial histopathologic damage, LDH, cardiac index, punctate hemorrhage on heart surface in Xinan group reduced more significantly than that of the model control group. The survival time in Xinan group were longer than that of the model control group. Conclusion Xinan granule may have the preventional and therapeutic effect on viral myocarditis in mice.

Compound clindamycin liniment in treatment of acne vulgaris / 中国新药与临床杂志

AIM: To observe the effect of compound clindamycin liniment on acne vulgaris. 　METHODS: A multi-centre, open-label trial of compound clindamycin liniment in treating acne vulgaris. One hundred and fifty-three patients used compound clindamycin liniment on face three times per day for 4 wk.　RESULTS: The total excellent response rate was 83.0%. The total effect rate on pustule and papule was 96.1% and 80.7% respectively. The adverse reaction rate was 1.9%.　CONCLUSION: Compound clindamycin liniment is an effective and safe drug in the treatment of acne vulgaris.

Protective effect of Ganduqing Granule on acute hepatic injury / 中成药

AIM To observe the protective effect of Ganduqing Granule(GDQ) on acute hepatic injury. METHODS Sixty male Wistar rats were divided into 6 groups, namely normal control group, model group, Ganduqing large (GDQ Ⅰ), middle(GDQ Ⅱ), small dose(GDQ Ⅲ) groups and Yiganning (YGN) positive group. Acute hepatic injury induced by thioacetamide. The changes of blood serum ALT, AST activity and plasma endotoxin (ET) level and TNF-?, IL-6 levels were measured and livers were taken for pathology examination. RESULTS Plasma ET level and blood serum ALT, AST levels and TNF-?, IL-6 levels were significantly lower than model group ( P