A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer / 中华肿瘤杂志

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

Analgesic effect of Fengshi Qutong Capsules on mice with chronic inflammatory pain caused by complete Freund's adjuvant / 中国中药杂志

The aim was to observe the analgesic effect of Fengshi Qutong Capsules(FSQTC) on chronic inflammatory pain in mice, and investigate its effect on p-ERK/COX-2 signal molecular activity. A model of chronic inflammatory pain was induced in mice by complete Freund's adjuvant(CFA). The mice were divided into normal control group, model group, model+FSQTC 0.3, 0.6 and 1.2 g·kg~(-1 )groups, model+positive control drug ibuprofen(IBP, 0.34 mg·kg~(-1)·d~(-1)) group, and normal control+ FSQTC 1.2 g·kg~(-1)group. FSQTC or IBP was given once a day by oral administration. Standard Von Frey fiber was used to evaluate the mechanical pain threshold, and the acetone stimulation was used to induce inflammatory plantar and observe the cold pain reaction scores. The mechanical pain threshold and cold pain reaction scores were observed before administration and 1, 2, 3, 4, 6 h after administration on the first day, as well as 3 h after administration on the 3 rd to 7 th day. The protein levels of PGE_2, COXs-1,2 and p-ERK in the spinal cord of the inflammatory foot and lumbar 4-5 were detected by enzyme-linked immunosorbent assay, Western blot, immunohistochemistry and immunofluorescence. The results showed that the mechanical pain threshold of the model group decreased and the cold pain reaction score increased as compared with the normal group. FSQTC application could dose-dependently increase the mechanical pain threshold and decrease the cold pain reaction score. The effect lasted for 6 h, most significant at 3 h. The effect of ibuprofen was similar to that of the 0.6 g·kg~(-1) dose group. In addition, FSQTC could reduce the abnormally increased protein content of PGE_2, COX-2 and p-ERK in the inflammatory foot and/or spinal cord of the model group, and the effect was most significant in middle and high dose groups. However, it had no effect on COX-1 in the inflammatory foot and spinal cord of mice. The results suggest that FSQTC has ob-vious analgesic effect on chronic inflammatory pain in mice, which may be related to inhibition of p-ERK/COX-2 signaling pathway.

Meta-analysis of RCT studies on clinical efficacy of single administration of Tripterygium Glycosides Tablets or combined administration with methotrexate against rheumatoid arthritis / 中国中药杂志

To evaluate the clinical efficacy of single administration of Tripterygium Glycosides Tablets(TGT) or combined administration with methotrexate(MTX) against rheumatoid arthritis(RA) based on American College of Rheumatology(ACR) efficacy standard. Six databases, namely CNKI, WanFang, VIP, PubMed, Embase and Cochrane Library, were retrieved for randomized controlled trials(RCT), and clinical trials were screened out according to the preset inclusion and exclusion criteria. Then, the study quality was evaluated by the risk assessment tools. Data extraction and analysis were performed by using RevMan 5.3 software for Meta-analysis. Sensitivity analysis and publication bias analysis were made to test the stability and reliability of results. Until December 2018, a total of 1 709 articles were obtained, and finally 10 clinical RCT studies with a total of 1 184 patients were included. As a result, the single administration of TGT showed a significantly better ACR efficiency(RR=1.31, 95%CI[1.15, 1.49], P<0.000 1) than methotrexate(MTX). The combined administration of TGT and MTX showed a significantly better ACR efficiency(RR=1.28, 95%CI[1.20, 1.38], P<0.000 01) than the single administration of MTX. In conclusion, the single administration of TGT and the combined administration of TGT and MTX were more effective in achieving ACR20, ACR50, ACR70 compliance than the single administration of MTX. Further validations based on more RCT studies with high-quality are required.

Meta-analysis on safety of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis / 中国中药杂志

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.

Systematic reviews of effects of Tripterygium Glycosides Tablets on pro-inflammatory factors in rheumatoid arthritis / 中国中药杂志

To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P<0.000 01),IL-1β(P<0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P<0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1β(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1β(SMD=-6.29,95%CI[-9.64,-2.93],P<0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P<0.000 01), joint fluid(P<0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1β(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1β(P=0.02), IL-6(P<0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.

Comparative study on chronic multiple organ injury in normal rats caused by high dose of Tripterygium Glycosides Tablets from 6 different manufacturers / 中国中药杂志

The aim of this paper was to compare different effects of Tripterygium Glycosides Tablets from 6 different manufacturers on multiple organ injuries in rats and to explore mechanism of hepatotoxicity preliminarily from the perspective of apoptosis and oxidative stress. Rats were randomly divided into the groups normal, Zhejiang, Hunan, Hubei, Shanghai, Jiangsu and Fujian(7 groups with 16 rats in each group, sex in half). Rats were given Tripterygium Glycosides Tablets at 144 mg·kg~(-1)·d~(-1)(16 times the clinical equivalent dose) once a day according to its corresponding group like rats in Zhejiang group was given Tripterygium Glycosides Tablets from Zhejiang manufactures continuously for 20 days with the life and death situation of mice to be observed, then rats were executed to detect various indicators. RESULTS:: showed that 8 female rats in Zhejiang group died after 15 days of administration, the serum NEUT of rats in Hubei, Fujian and Shanghai groups was significantly lower than that of normal rats. The serum AST, ALT and/or TBiL levels were increased in all rats, and serum BUN and/or CRE levels of rats were also increased in Hunan, Hubei, Fujian and Shanghai groups. In dosage groups, testicular and ovarian coefficients of rats were reduced, the number of sperm were significant decreased while the rate of sperm malformation increased and sperm dynamics parameters of normal, especially in Jiangsu and Zhejiang groups. Liver histopathology and apoptosis of liver cells were observed in dosage groups, especially in Jiangsu and Hubei groups. In liver, Nrf2, HO-1 and Bcl-2 were inhibited and the protein expression level of Bax were increased simultaneously in dosage groups. These results showed that all Tripterygium Glycosides Tablets from 6 manufacturers could lead to chronic multiple organ injuries with disparate specialties in rats, and Jiangsu and Zhejiang groups were more toxic. It could be the mechanism promoting mitochondrial mediated Bax/Bcl-2 cell apoptosis signaling pathway and negatively regulating Nrf2/HO-1 oxidative stress signaling pathway that Tripterygium Glycosides Tablets from 6 different manufacturers resulted in chronic liver injury, the results above were for reference only in subsequent study.

Analgesic Effect of Panlongqi Tablet on Rats with Chronic Inflammatory Pain / 中国实验方剂学杂志

Objective:To observe the analgesic effect of Panlongqi tablet（PLQT） on rats with chronic inflammatory pain， and to explore mechanism of the action preliminarily from the perspective of the nuclear factor kappa-light-chain-enhancer of activated B cells （NF-κB）and mitogen-activated protein kinase（MAPKs） signaling pathways. Method:Rats were induced to establish model of chronic inflammatory pain by complete Freund adjuvant（CFA）， which was divided into normal group， model group， the PLQT 0.16，0.32，0.64 g·kg-1 group， and the ibuprofen 0.05 g·kg-1 group（also positive group）， give the medicine once a day by gavage. Standard Von Frey fiber was used to evaluated the mechanical pain threshold， acetone was used to stimulated rats inflammatory foot to get the cold-induced response score， with the mechanical pain threshold and cold-induced response score to be observed at 1， 2， 3， 4 and 6 h before and after administration on day 1， and at 4 h after administration on day 3-7. The content of PGE2， IL-1， TNF-α in serum， inflammatory foot and 4-5 lumbar spinal cord was detected by enzyme-linked immunosorbent assay（ELISA）. The protein level of MAPKs （p-p38， p-ERK， p-JNK） in lumbar spinal cord 4-5 was detected by Western blot. The expression of NF-κB p65 in the lumbar spinal cord was detected by IFA. Result:Model group had lower mechanical pain threshold and higher cold-induced response score than these in normal group（P<0.01）， while the mechanical pain threshold and cold-induce response score of the model rats were dose-dependent better regulated after administration of PLQT 0.16， 0.32， 0.64 g·kg-1·d-1（P<0.05，P<0.01）， these effect lasted 6 h， of which PLQT groups get the most significant effect on 4 h， however the effect of IBP was similar to that of PLQT medium dose group. In addition， PLQT reduced the abnormal increase of PGE2， IL-1 and TNF-α contents in serum， inflammatory foot and spinal cord of rats in model group， decreased the protein phosphorylation levels of ERK and JNK in spinal cord， and decreased the protein expression of NF-κB p65， that was significant in the PLQT high-dose group（P<0.01）. Conclusion:PLQT had significant analgesic effect on chronic inflammatory pain model rats， which may be related to the inhibition of NF-κB and MAPKs signaling pathways in spinal cord.

Effect of Tripterygium Glycosides Tablets on synovial angiogenesis in rats with type Ⅱ collagen induced arthritis / 中国中药杂志

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 μg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.

Effects of Tripterygium Glycosides Tablets from 6 different manufacturers on acute liver injury of normal mice / 中国中药杂志

The aim of this paper was to compare the performance of acute liver injury in mice induced by Tripterygium Glycosides Tablets from 6 different manufacturers,and to explore the toxicity mechanism from the perspective of oxidative stress and apoptosis preliminarily. Male or female mice were randomly divided into normal group,Zhejiang group,Hunan group,Hubei group,Shanghai group,Jiangsu group and Fujian group. Mice in Tripgerygium Glycosides Tablets groups were given 16 times the clinical equivalent dose( 300 mg·kg-1) Tripgerygium Glycosides Tablets by oral administration for one time,mice were executed in 24 h after lavaged.Then the visceral brain coefficient of the organ was calculated. Histopathological changes of liver were observed by hematoxylin-eosin staining. Td T-mediated d UTP nick-end labeling was used to detect the apoptosis of the liver cells and the protein content of oxidative stress related factors in liver homogenate. Nuclear transcription factor E2-related factor( Nrf2) and heme oxygenase-1( HO-1) as well as mitochondrial mediated apoptosis-related protein expression levels of Bax and Bcl-2 in hepatic tissue were measured by Western blot.Within 24 hours of administration,6 male mice in Jiangsu group and 2 female mice in Zhejiang group were dying; compared with normal ones,liver coefficients of mice in Zhejiang,Shanghai,Jiangsu and Hunan groups were significantly increased,thymus coefficients in the first two groups were significantly reduced,as well as the lung coefficients of Fujian group mice,the rest was normal. In addition to Hubei group,serum AST,ALT or ALP levels of mice were increased,while TBi L were not being affected. Histopathological changes and apoptosis of liver cells were observed in all mice,and the degree of severity was ranked as Jiangsu,Zhejiang,Shanghai,Hunan,Hubei and Fujian group. All Tripterygium Glycosides Tablets increased the MDA and reduced the content of T-SOD,CAT or GSH in liver tissue while inhibited Nrf2,HO-1 and Bcl-2,increased the protein expression level of Bax( except Hunan group). Tripgerygium Glycosides Tablets from 6 manufacturers all resulted in liver function damage and liver histopathological changes,especially in Jiangsu,Hubei and Fujian,and the mechanism may related to inhibit Nrf2/HO-1 oxidative stress pathway and activate Bax/Bcl-2 apoptosis pathway to mediate lipid peroxidation and induce liver cell apoptosis. Triptolide A may be one of the main toxic components of Tripgerygium Glycosides Tablets that causing drug-induced liver injury. This study was conducted on normal mice with super dose medication,so the relevant results are for reference only.

Clinical symptoms effect of Tripterygium Glycosides Tablets alone or combined with methotrexate in treatment of rheumatoid arthritis: a Meta-analysis / 中国中药杂志

To systematically review the improvement effects of Tripterygium Glycosides Tables( TGT) alone or in combination with methotrexate( MTX) on the clinical signs and symptoms of rheumatoid arthritis( RA),and provide a basis for the rational use of TGT in clinic,in the current study,six literature databases including CNKI,Wan Fang,VIP,PubMed,EMbase,and Cochrane Library,were systematically searched,according to the inclusion and exclusion criteria. Review Manager 5.3 software was used to input the literatures,and we assessed the risk bias on the level of outcome indicators for each included literature. A total of 18 literatures were included,and the classification results showed that: compared with MTX,TGT alone can reduce the number of joint swelling( MD =0. 18,95%CI[-1.06,1.42],P = 0.78) and joint tenderness( MD =-0.06,95% CI[-1.69,1.56],P = 0.94) in RA patients with the same effect as MTX. In terms of drug combination,TGT combined with MTX had an advantage over MTX alone in lessening the morning stiffness time( MD = 18. 24,95% CI[12. 64,23. 84],P < 0. 000 01) of RA,joint tenderness( MD = 2. 65,95% CI[1. 85,3. 44],P<0.000 01) and joint swelling( MD = 3.01,95% CI[2.09,3.39],P< 0.000 01). In conclusion,this Meta-analysis suggest that TGT alone was superior to MTX in improving joint swelling and tenderness in RA patients,TGT combined with MTX may improve the clinical manifestation of RA patients better than MTX alone.

Meta-analysis of laboratory index of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis / 中国中药杂志

The aim of this study was to systematically evaluate the clinical efficacy of Tripterysium Glycosides Tablets( TGT) alone or in combination with methotrexate( MTX) in the treatment of rheumatoid arthritis( RA) based on the laboratory index criteria and to provide a basis for the clinical application of TGT against RA. Six databases including CNKI,Wan Fang,VIP,PubMed,EMbase and Cochrane were retrieved for randomized controlled trials( RCT) about TGT alone or combination with MTX in the treatment of RA.Then risk assessment tools were used for quality evaluation of the studies,and data extraction and analysis were conducted by using Rev Man 5.3 software for Meta-analysis. A total of 1 709 articles were retrieved,and finally 25 studies were included,with a total sample size of 2 507 cases. Meta-analysis results showed that between TGT alone and TGT alone,MDESR=-2. 66,95%CI[-8.17,2.86],P = 0.35; MDCRP=-2.38,95%CI[-9.01,4.24],P = 0.48; between TGT combined with MTX and MTX alone,MDESR= 8.74,95%CI[6.72,10.76],P<0.000 01; MDCRP= 5.37,95%CI[3.71,7.03],P<0.000 01; SMDRF= 1.05,95%CI[0.51,1.60],P = 0.000 1.The effect of TGT on decreasing CRP and ESR in RA patients was similar to the MTX. In addition,TGT combined with MTX were more effective in decreasing CRP,ESR,RF than MTX alone. However,due to the potential bias in the included studies,more and high-quality randomized controlled trials would be needed to improve the level of evidence.

Effect of Fengshi Qutong Capsules on synovial angiogenesis in rats with type Ⅱ collagen induced arthritis / 中国中药杂志

To observe the effect of Fengshi Qutong Capsules(FSQTC) on angiogenesis of rat aortarings and in knee joint synovium of type Ⅱ collagen-induced arthritis(CIA) rats. The blood vessel of aorta rings of normal SD rats were induced by vascular endothelial growth factor(VEGF) 20 μg·L~(-1 )in vitro, and were treated with FSQTC(0.02, 0.1 and 0.5 μg·L~(-1)) continuously for 9 days. The number, length and area of neovascularization of the vascular ring were measured. SD rats were immunized to establish collagen-induced arthritis. CIA rats were treated with FSQTC(0.25, 0.5, 1 g·kg~(-1)·d~(-1)) and methotrexate(0.2 mg·kg~(-1)·d~(-1)) daily for 19 days. Histopathological examination(HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joint. Immunohistochemistry was performed to observe the expression of platelets-endothelial cell adhesion molecule(CD31), VEGF and VEGF receptor 2(VEGFR_2)in the synovium. Immunofluorescence was performed to observe the expression of CD31 and α smooth muscle actin(αSMA) in synovial membrane.TGF-β, PDGF and VEGFR_2 in serum were detected by enzyme-linked immunosorbent assay. The number, branch length and area of blood vessels of aorta rings were significantly increased induced by VEGF, and FSQTC could significantly reduce the number, branch length and area of blood vessels. Compared with the normal group, the vascular density, CD31 positive expression, CD31~+/αSMA~- immature and total vascular positive expression in the synovial membrane of the model group were significantly increased, and so as VEGF and VEGFR_2 in the synovium. The VEGFR_2, TGF-β and PDGF in sera were also significantly increased in model group. FSQTC reduced the synovial vascular density and inhibited the positive expression of CD31, CD31~+/αSMA~- immature blood vessels and total vascular. FSQTC has no significant effect on CD31~+/αSMA~+mature blood vessels. FSQTC also negatively inhibited the expression of VEGF, VEGFR_2, TGF-β and PDGF in synovial membrane and/or sera. The effect of methotrexate is similar with to the high dose group. Our results demonstrated that FSQTC could inhibit the angiogenesis of synovial tissue in CIA rats and of aortaring in rats, which is related to the reduction of angiogenesis regulatory factor.

Effect of Fengshi Qutong Capsule on Human Umbilical Vein Endothelial Cells Induced by VEGF / 中国实验方剂学杂志

Objective: To study the effect of Fengshi Qutong capsule on the migration, adhesion, invasion and tube formation of human synovial cells and the phosphorylation and protein expression of vascular endothelial growth factor receptor 2 (VEGFR2). Method: With human umbilical vein endothelial cells (HUVEC) as the research object, low, middle and high-dose Fengshi Qutong capsule(0.02,0.1,0.5 μg·L-1) on HUVEC was determined by methye thiazolye telrazlium (MTT) colorimetric assay for the follow-up experiment. The transwell migration, adhesion and transwell invasion test were used to detect the migration and adhesion of the different concentrations of Fengshi Qutong capsule in HUVEC. The expression of VEGFR2 in HUVEC was detected by Western blot, and Real-time PCR was used to detect the content of VEGFR2 mRNA in cells. Result: Compared with normal group, the proliferation of HUVEC was significantly increased after 24 h and 48 h of VEGF induction (PPP-1 Fengshi Qutong capsule were administered in vitro for 48 h to inhibit HUVEC proliferation activity in a dose-dependent manner (PPPPConclusion: Fengshi Qutong capsule can inhibit the migration, adhesion, invasion and tube formation of HUVEC. This effect may be related to the inhibition of phosphorylation, and protein and mRNA expression level of VEGFR2.

Effect of Fengshi Qutong Capsule on Synovial Akt and MAPK Signaling Pathways in Rheumatoid Arthritis / 中国实验方剂学杂志

Objective:To observe the effect of Fengshi Qutong capsule (FSQTC) on protein kinase B(Akt) and mitogen-activated protein kinase (MAPK) signaling pathways of rheumatoid arthritis (RA). Method:Collagen-induced arthritis (CIA) was induced in SD rats, and the synovial membranes of the knee joints were prepared after 19 days of oral administration of 0.25, 0.5, 1 g·kg-1 FSQTC. MH7A cells were induced by tumor necrosis factor-α (TNF-α, 20 μg·L-1) in vitro, and human umbilical vein endothelial cells (HUVEC) were induced by vascular endothelial growth factor (VEGF). FSQTC (0.02, 0.1, 0.5 μg·L-1) were added to MH7A/HUVEC cells, and then the cells were collected. Proteins of synovial tissue, MH7A and HUVEC cells were extracted, and then were detected the expresstion of p-Akt, p-p38 MAPK, p-extracellular signal-regulated kinase(ERK) and p-Jun n-terminal kinase(JNK) by Western blot. Result:The expression levels of p-Akt, p-p38 MAPK, p-ERK and p-JNK in the synovial membrane of CIA model were significantly increased compared with normal group (P-1·d-1 FSQTC significantly decreased their expression levels (PPα or VEGF were increased (P-1 FSQTC (PPConclusion:FSQTC can down-regulate the abnormal activation of Akt and MAPK signaling pathways in the synovial membrane of CIA rats, fibroblast synovial cells and vascular endothelial cells, which is related to the inhibition of synovial angiogenesis in the treatment of RA.

Effect of Fengshi Qutong Capsule on Function of Human Synovial Cells in Rheumatoid Arthritis Induced by TNF-α / 中国实验方剂学杂志

Objective: To study the effects of Fengshi Qutong capsule (FSQTC) on proliferation, migration, adhesion, invasion and secretion of human synovial cells in rheumatoid arthritis (RA) induced by tumor necrosis factor-α (TNF-α) and explore its mechanism. Method: Human synovial cells (MH7A) in RA patients were induced in vitro by using TNF-α (20 μg·L-1). After treatment with different concentrations of FSQTC (0.02,0.1,0.5 μg·L-1), MTT colorimetric assay, transwell migration, adhesion and invasion tests were used to detect the proliferation, migration, adhesion and invasion of the MH7A, respectively. The expression levels of vascular endothelial growth factor (VEGF) and interleukin-1β (IL-1β) in MH7A supernatant were detected by enzyme linked immunosorbent assay (ELISA). Result: As compared with blank control group, TNF-α (20 μg·L-1) significantly increased the proliferation, migration, adhesion, invasion and secretion of IL-1β and VEGF of MH7A cells (P-1) had no significant effect on proliferation of TNF-α-induced MH7A cells after treatment for 24 hours. After 48 hours of treatment, proliferation of MH7A cells induced by TNF-α was decreased in a concentration-dependent manner (PPPPConclusion: FSQTC can inhibit the proliferation, migration, adhesion, invasion and secretion of IL-1β and VEGF in MH7A cells.

Effect of Fengshi Qutong Capsule on Collagen-induced Arthritis of Rats / 中国实验方剂学杂志

Objective:To observe the intervention effect of Fengshi Qutong capsule on collagen-induced arthritis (CIA) in rats. Method:SD rats were randomly divided into normal group, model group, low, medium and high-dose Fengshi Qutong capsule groups (0.25, 0.5, 1 g·kg-1·d-1), and methotrexate group(0.2 mg·kg-1·d-1).Except for normal group, the other groups were immunized with type Ⅱ collagen and incomplete Freund's adjuvant to establish a CIA model. On the 1st day after the first immunization, the administration group was given intragastric administration, once a day, for 19 days; on the 8th day after the first immunization, the symptoms of joint swelling and malformation of the rats were observed, and the clinical scores and incidence of arthritis were evaluated. On the 19th day, micro-computed tomography and bone metrology were performed, and histopathological examination of inflammatory joints was performed,andsynovial inflammation,vasospasm, cartilage erosion and bone destruction by pathological severity scores, serum interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF),matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor kappa B ligand(RANKL)were detected by enzyme linked immunosorbent assay. Result:Fengshi Qutong capsule could improve the symptoms of inflammatory joint redness, swelling and deformity in CIA rats in a dose-dependent manner. Compared with normal group, clinical score and incidence, joint synovial inflammation, vasospasm, cartilage erosion and pathological score of bone destruction in joint group were significantly increased (PPPβ, TNF-α, VEGF, MMP-3 and RANKL in serum were increased (PPPPPPPβ, TNF-α, VEGF, MMP-3 and RANKL were significantly decreased (PPConclusion:Fengshi Qutong capsule can effectively alleviate the clinical symptoms and conditions of experimental rheumatoid arthritis in rats, reduce the incidence, and relieve the histopathology and imaging severity, while inhibiting the inflammatory cytokines.

Preliminary study on RC membrane permeability and mechanism of seven traditional Chinese medicine alkaloids such as berberine / 中国中药杂志

In order to analyze the law of membrane permeation of different alkaloids, seven traditional Chinese medicine alkaloids with different parent nucleus and substituent structures, including berberine, palmatine, sinomenine, matrine, oxymatrine, sophoridine, and tetrandrine, were prepared into the simulated solution with same molar concentration, and the membrane penetrating experiments with membrane RC1K and membrane RC5K were carried out. The dynamic transmittance, the total transmittance and the total adsorption rate of each substance were measured, and the scanning electron microscopy (SEM) images of the membrane surface before and after the membrane experiment were considered to predict and analyze the reason of differences in dynamic transmittance of different alkaloids. The results showed that there were significant differences in the dynamic transmittance of the chemical constituents of different alkaloids during penetrating the two membranes. The contamination degree on the surface of the membrane material was also different. The transmittance of the same compound through the RC5K membrane was larger than that through RC1K membrane. Within a certain range, the smaller the pore size of the membrane, the better the selective screening effect on the chemical constituents of traditional Chinese medicine. All the membrane surfaces were less polluted. The difference in transmittance between different substances on the same membrane showed a positive correlation with the difference in structural complexity, providing an experimental basis for the surface modification design in contamination control of membrane materials. In the design of membrane modified material, the surface properties of the membrane can be improved by grafting different polar groups, thereby changing the adsorption characteristics of the membrane surface. The pore size was designed accordingly to achieve the high transmittance and low pollution of the corresponding compounds.

Adsorption characteristics of proteins on membrane surface and effect of protein solution environment on permeation behavior of berberine / 中国中药杂志

In order to explore the adsorption characteristics of proteins on the membrane surface and the effect of protein solution environment on the permeation behavior of berberine, berberine and proteins were used as the research object to prepare simulated solution. Low field NMR, static adsorption experiment and membrane separation experiment were used to study the interaction between the proteins and ceramic membrane or between the proteins and berberine. The static adsorption capacity of proteins, membrane relative flux, rejection rate of proteins, transmittance rate of berberine and the adsorption rate of proteins and berberine were used as the evaluation index. Meanwhile, the membrane resistance distribution, the particle size distribution and the scanning electron microscope (SEM) were determined to investigate the adsorption characteristics of proteins on ceramic membrane and the effect on membrane separation process of berberine. The results showed that the ceramic membrane could adsorb the proteins and the adsorption model was consistent with Langmuir adsorption model. In simulating the membrane separation process, proteins were the main factor to cause membrane fouling. However, when the concentration of proteins was 1 g•L⁻¹, the proteins had no significant effect on membrane separation process of berberine.

A Case-control Study of Environmental Risk Factors for Nonsyndromic Cleft of the Lip and/or Palate in Xuzhou, China / 生物医学与环境科学（英文）

In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR=4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP.

Case-control study on therapeutic effects between Kirschner wire fixation after early bebridement and staged plate fixation in the treatment of open calcaneal fractures / 中国骨伤

<p><b>OBJECTIVE</b>To compare therapeutic effects between Kirschner wire fixation after early debridement (Kirschner wire group) and staged plate fixation (plate group) in the treatment of open calcaneal fractures.</p><p><b>METHODS</b>From January 2001 to May 2008, 55 patients (58 feet) with open calcaneal fractures were reviewed,the mean age was 36.8 years(ranged, 19 to 65 years) and the average visit time was 3 hours (ranged, 30 min to 7 h). All the patients were divided into two groups: Kirschner wire group and plate group. There were 20 males (20 feet) and 9 females (9 feet) in Kirschner wire group, in which 15 feet were type I, 13 feet were type II, 1 foot was type III A according to Gustilo classification and 9 feet were type II, 18 feet were type III, 2 feet were type IV according to Sanders classification. The patients in Kirschner wire group were treated with early debridement, fracture reduction and Kirschner wire fixation, and the soft tissue defects were covered with VSD temporarily, and then were enveloped by skin or flap grafts at the second stage. There were 18 males (19 feet) and 8 females (10 feet) in the plate group, in which 13 feet were type I, 14 feet were type II, 2 feet were type III A according to Gustilo classification and 11 feet were type II,15 feet were type III, 3 feet were type IV according to Sanders classification. The patients in the plate group were treated with early debridement, and plate internal fixation with were performed when the wound became stabilization.</p><p><b>RESULTS</b>Twenty-three feet (15 patients) in the Kirschner wire group and 22 feet (13 patients) in the plate group were followed, the duration ranged from 10 to 36 months, with an average of 24 months. Compared with preoperative ones, the heel height, width, Böhler angle and Gissane angle of calcaneal got improvements. According to AOFAS ankle-foot evaluation system, 11 feet got an excellent result, 8 good in the Kirschner wire group; 2 feet had wound local skin necrosis and cured by dressing; 1 foot had a large area of skin necrosis and deep infection; 1 foot had chronic osteomyelitis. All above 4 feet underwent arthrodesis later. As comparison, 7 feet got an excellent result, 4 good in the plate group; 2 patients had mild complications of wounds; 1 patient had chronic osteomyelitis after early debridement; 10 patients had wound complications after internal fixation, including 7 patients with skin necrosis, superficial infection in 3 patients. There were statistical significant in radiological indicators and AOFAS ankle-foot scores between two groups. But there were no significant differences in early postoperative complications between the two groups.</p><p><b>CONCLUSION</b>Early debridement and Kirschner wire fixation for the treatment of open calcaneal fractures has fewer early complications, which is a simple, safe and effective method.</p>