Objective To evaluate the efficacy and safety of different Chinese medicine injections combined with angiotensin converting enzyme inhibitor/angiotensin Ⅱ receptor blocker(ACEI/ARB)in the treatment of proteinuria in diabetic nephropathy by using network Meta-analysis.Methods Clinical randomized controlled trials of Chinese medicine injection combined with ACEI/ARB for the treatment of proteinuria in early diabetic nephropathy were retrieved from the domestic databases such as China National Knowledge Infrastructure(CNKI),China Science and Technology Journal Database(VIP),Wanfang Data Knowledge Service Platform(Wanfang Data),and China Biology Medicine Disc(CBM),as well as from the oversea databases such as PubMed,EMbase,Web of Science,and Cochrane Library from database inception to October 2023.The Cochrane risk of bias tool ROB2.0 was used to evaluate the quality of the included literature,and traditional Meta-analysis and network Meta-analysis were performed by using R4.3.2 and Stata18.0.Results A total of 72 trials were included,involving 13 Chinese medicine injections,namely Huangqi Injection,Xuesaitong Injection,Puerarin Injection,Denzhan Xixin Injection,Breviscapin Injection,Danhong Injection,Xueshuantong Injection,Yinxingye Injection,Shuxuetong Injection,Yinxing Damo Injection,Danshen Injection,Shenkang Injection,and Danshen Ligustrazine Injection.The primary outcomes were urinary albumin excretion rate(UAER),24-hour urinary total protein(24hUTP),serum creatinine(SCr),and urine albumin-to-creatinine ratio(UACR).The results of traditional Meta-analysis showed that Chinese medicine injection combined with ACEI/ARB was more effective on reducing the levels of UAER[MD=-26.14,95%CI(-29.39,-22.89)],24hUTP[(MD=-0.22,95%CI(-0.27,-0.18)],SCr[MD=-0.34,95%CI(-0.50,-0.19)],and UACR[MD=-9.40,95%CI(-15.64,-3.16)]than ACEI/ARB alone,and the differences were all statistically significant(P<0.05).The results of network meta-analysis showed that the efficacy of Dengzhan Xixin Injection combined with ACEI/ARB was the optimum in terms of reducing UAER,Danshen Ligustrazine Injection combined with ACEI/ARB was the optimum in terms of decreasing 24hUTP,Shenkang Injection combined with ACEI/ARB was the optimum in terms of decreasing SCr,and Danhong Injection combined with ACEI/ARB had the best efficacy on improving UACR.Conclusion The efficacy and safety of Chinese medicine injection combined with ACEI/ARB in the treatment of proteinuria in early diabetic nephropathy are superior to those of ACEI/ARB alone in terms of lowering UAER,24hUTP,SCr,and UACR.However,due to the limitations of the quality and number of included literatures,the conclusions still need to be confirmed by more high-quality randomized controlled trials.

Objective To study the effect of mitogen-activated protein kinas/extracellular signalregulated kinase (MAPK/ERK) signaling pathway on cell proliferation modulated by Sonic Hedgehog (Shh) signaling in fibroblast-like synoviocytes (FLS) isolated from patients with active rheumatoid arthritis (RA).Methods The synovial tissue were collected by the synovial arthroscopic debridement or arthroscopic synovectomy of RA patients with active disease activity [disease activity score(DAS)28 ≥3.2].The RA-FLS were primarily cultured by the explanted culture,and then were treated with Shh agonist purmorphamine,inhibitor cyclopamine or MAPK/ERK signaling pathway inhibitor U0126,respectively.Western blotting was used to examine the phosphorylation level of ERK 1/2 (p-ERK1/2),which was the critical protein of MAPK/ERK signaling.The cell proliferation activity was detected using cell proliferation and cytotoxicity kit-8 (CCK8),and the cell proliferation rate was detected using a flow cytometry.Analysis of variance and Kruskal-Wallis H(K) test were used for statistical analysis.Results Compared with the control group,purmorphamine transiently increased p-ERK1/2 protein at the concentration of 1 μmol/L,and the peak activations of p-ERK1/2 took place at 15 min (P＜0.01).Cyclopamine and U0126 decreased the expression ofp-ERK1/2 protein (P＜0.01).After the RA-FLS treated with purmorphmine(1 μmol/L)for 48 hours,the cell proliferation activity was (114±4)％ and the percentage of S phase cells was (8.39±0.60)％,which was significantly higher than those of the control group (100±0)％ (P＜0.01) and (3.29±0.69)％ (P＜0.01).After treated with cyclopamine (10 μmol/L) for 48 hours,the cell proliferation activity of RA-FLS was (89±1)％ (P＜0.05) and the percentage of S phase cells was (1.53±0.22)％ (P＜0.05).When co-treated with purmorphamine (1 μmol/L) and U0126 (10 μmol/L),the cell proliferative activity was (89±2)％ (P＜0.05) and the percentage of S phase cells was(1.07±0.25)％(P＜ 0.05).Conclusion Shh may promote proliferation of RA-FLS via modulating MAPK/ERK signaling,which in turn contributes to hyperplasia of synovium and ultimately leading to RA.