Total glucosides of paeony attenuates animal psoriasis induced inflammatory response through inhibiting STAT1 and STAT3 phosphorylation

OBJECTIVE Psoriasis is an immune system meditated disease,especially T cells.It disturbed many people around the world and hard to therapy.Paeonia lactiflora Pall has been used as a medicine in china for thousands of years.Recent studies has found that the main component of Paeonia lactiflora Pall can alleviates the immune response in many diseases.In this study,we researched the effects and possible mechanisms of total glucosides of paeony(TGP)on animal psoriasis in order to study the therapeutic effects and mechanisms of TGP in 5%propranolol creaminduced psoriasis in guinea pigs and Imiquimod(IMQ)cream-induced psoriasis in mice.METHODS The effect of TGP was evaluated using a psoriasis-like model of guinea pigs and mice.Ear thickness was accessed,and pathology injury was observed by HE staining.The levels of serum IL-1β,IL-6,IL-12,IL-17,IL-23,TNF-α,and IFN-γ,skin IL-17A,IL-22 and orphan nuclear receptor(RORγt)mRNA expression,proliferating cell nuclear antigen(PCNA),total or phosphorylated signal transducers and activators of transcription(STAT1 and STAT3)were determined by ELISA,real time PCR,immu⁃nohistochemical staining,and Western blotting,respectively.RESULTS Compared with model group,TGP treatment decreased the ear thickness,improved pathology of psoriasis,alleviated IMQ-induced keratinocyte proliferation,reduced the inflammatory cytokine,and downregulated IL-17A,IL-22,and RORγt mRNA in mice.Further study indicated that TGP inhibited STAT1 and STAT3 phosphorylation in lesion skins of psoriasis-like mice.CONCLUSION TGP alleviates the symptoms of psoriasis-like guinea pigs and mice,and the possible mechanism may relate to inhibit T helper 17(TH17)cell differentiation and keratinocytes proliferation by inhibiting STAT1 and STAT3 phosphorylation.

Protective Effects of Total Glucosides of Paeony against the Liver Injury Induced by Anti-tuberculosis Drugs

[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimental evidence for rational use of anti-tuberculosis drugs.[Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules （TGP） for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment.[Results] TGP reduced the activities of alanine transaminase （ALT） and aspartate transferase （AST） in serum and the level of malondialdehyde （MDA） in liver tissue, and increased the level of glutathione （GSH） and the activity of superoxidase dismutase （SOD） in liver tissue.[Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP.

Total glucosides of paeony alleviates Sjogren syndrome through inhibiting inflammatory responses in mice

OBJECTIVE To study the therapeutic effects of TGP on SS both in C57BL/6J mice immunized by immu⁃nological induction(SS mice)and NOD/ShiltJNju(NOD)mice.METHODS TGP(180,360,720 mg·kg^-1)was intragastri⁃cally administered for 6 or 16 weeks for SS mice and NOD mice,respectively.Weekly food and water intake,saliva flow,submandibular gland(SMG)and spleen index,and SMG pathology were measured.ELISA was used to evaluate serum interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)and autoantigens(SSA/Ro,SSB/La,andα-fodrin).Real-time PCR and Luminex liquid suspension chip assay were applied to analyze SMG inflammatory cytokines mRNA TNF-α,IL-17A,CXCL9,CXCL13,and B-cell activating factor(BAFF)and protein(IL-1β,IL-6,TNF-α,and IFN-γ)expres⁃sion.RESULTS Compared with SS mice,TGP(720 mg·kg^-1)treatment increased saliva flow,reduced organ indexes,and decreased serum IL-6 and IFN-γ concentration.TGP(360 mg·kg^-1)treatment decreased serum IFN-γ concentra⁃tion.TGP(180,360,720 mg·kg^-1)treatment improved SMG pathological damage.Compared with NOD mice,the saliva flowincreased from 9 to 15 weeks of administration.After 2 weeks of administration,TGP(720 mg·kg^-1)treatment decreased serum SSA/Ro,SSB/La and a-fodrin concentration,increased SMG index,inhibited SMG IFN-γ concentra⁃tion,and down-regulated SMG TNF-α,IL-17A,CXCL9,CXCL13 and BAFF mRNA expression.TGP(360 mg·kg^-1)treat⁃ment decreased serum SSB/La and a-fodrin,and SMG TNF-α and IFN-γ concentration,and down-regulated SMG TNF-α,IL-17A,CXCL9 and BAFF mRNA expression.TGP(180 mg·kg^-1)treatment decreased serum SSB/La,a-fodrin,and SMG IL-1β concentration,and down-regulated SMG TNF-α,IL-17A and BAFF mRNA expression.After 8 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment increased SMG index,and decreased serum a-fodrin concentra⁃tion.TGP(720 mg·kg^-1)treatment down-regulated mRNA expression of SMG TNF-α,IL-17A,CXCL9,CXCL13,and BAFF.TGP(360 mg·kg^-1)treatment reduced mRNA expression of TNF-α,CXCL9,CXCL13 and BAFF,and concentra⁃tion of IL-6 and TNF-α.TGP(180 mg·kg^-1)treatment down-regulated mRNA expression of TNF-α,CXCL9,and CXCL13,and decreased IL-6 and TNF-αconcentration in SMG.After 16 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment reduced serum SSA/Ro and a-fodrin concentration,increased SMG index,and decreased SMG CXCL13 and BAFF mRNA expression.TGP(360,720 mg·kg^-1)treatment decreased serum SSB/Laconcentration and SMG TNF-α,IL-17A and CXCL9 mRNA expression.Besides,TGP(180,360,720 mg·kg^-1)treatment alleviated the pathological damage of SMG after 2 and 16 weeks of administration.CONCLUSION TGP has a certain therapeutic effect onmice through inhibiting inflammatory responses.

Successful treatment of Morbihan disease with total glucosides of paeony:A case report

BACKGROUND Morbihan disease is a rare cutaneous disorder characterized by non-pitting edema and erythema of the upper two-thirds of the face.In severe cases,orbital and facial contour changes may affect the visual field,and there is no guideline for the standard treatment of this disease.Existing treatment methods have been reported to be associated with long medication cycle,easy recurrence after drug withdrawal,and multiple adverse reactions.CASE SUMMARY A 55-year-old Chinese woman presented to our hospital with non-pitting edema and erythema of the upper two thirds of her face for 5 mo.Physical examination showed obvious edema and erythema on the upper face.The boundary was unclear,the lesions were hard and non-pitting,and infiltration was obvious by touch.Pathological examination revealed mild hyperkeratosis of the epidermis,nodular inflammatory lesions in the dermis,epithelioid granuloma,and inflammatory cell infiltration with lymphocytes and histiocytes around skin appendages and blood vessels.Alcian blue staining,acid fast staining,silver staining and periodic acid-Schiff staining were negative.The patient was diagnosed with Morbihan disease.She was treated with prednisone acetate and tripterygium wilfordii polyglycoside tablets for 4 mo,and the edema was slightly reduced,but transaminase levels were significantly increased.Compound glycyrrhizin capsules were administered for liver protection for 1 mo;however,facial edema did not significantly improve and transaminase levels continued to increase.Total glucosides of paeony capsules were then administered for 4 mo,and transaminase level returned to normal and the patient’s facial edema disappeared completely.CONCLUSION Total glucosides of paeony has a remarkable effect in Morbihan disease,without adverse reactions.

Effect of total glucosides of paeony on serum cytokines in patients with psoriasis and its clinical efficacy:A meta-analysis

Objective:To evaluate the relationship between the changes of inflammatory cytokines and clinical efficacy in patients with psoriasis treated with Total glucosides of paeony by Meta analyses,and to explore the microcosmic mechanism of effective treatment of psoriasis with Total glucosides of paeony from the point of view of evidence-based medicine.Methods:The databases of CNKI,Wanfang,VIP,SinoMed,PuMed,Embase and Cochrane Library were searched by computer,and the time range was from the establishment of the database to May 2020.After screening,data extraction and bias risk assessment,Revman5.3 software was used for statistical analysis.Results:A total of 998 patients were included in 11 clinical studies,including 502 patients in the trial group and 496 patients in the control group.The results of Meta analysis showed that there was significant difference in the expression of cytokines between the two groups(MD=-10.97,95%Cl[-15.56,-6.37]).The effective rate of treatment(OR=3.57,95%Cl[2.58,4.94])and the decrease of PASI score(MD=-4.55,95%Cl[-5.91,-3.20])in the combined use of Total glucosides of paeony group were superior to those in the control group.Conclusion:Total glucosides of paeony can regulate immune and inflammatory response and improve skin lesions by inhibiting the expression of cytokines such as IL-2,IL-8,IL-23 and TNF-αin serum of patients with psoriasis.In view of the low overall quality of the included studies,larger samples and higher quality clinical trials are still needed to obtain more sufficient evidence.

Systematic review/meta-analysis re-evaluation of clinical effects of total glucosides of paeony in the treatment of rheumatoid arthritis

Objective: To re-evaluate the systematic review of Rheumatoid arthritis (RA) treatmentwith total glucosides of paeony (TGP) to provide evidence-based evidence for the treatmentof RA with TGP in the clinic. Methods: A total of eight databases including CNKI, Wan FangData, CBM, VIP, PubMed, Embase, Cochrane Library, and Web of Science were searched bycomputer for the systematic reviews/meta-analyses concerning the treatment of RA withTGP. The retrieval period was from the establishment of the database to May 2, 2022.Literature screening was conducted based on the randomized controlled trial, and thematerials of the included literature were extracted. Using the preferred reporting items forsystematic reviews and meta-analyses statement. The a measurement tool to assesssystematic reviews 2 scale and grades of recommendation, assessment, development, andevaluation system evaluated the reporting quality, methodological quality, and outcomeindicators evidence levels included in the literature. Results: Six systematicreviews/meta-analysis literature were finally included. Evaluation of the preferred reportingitems for systematic reviews and meta-analyses statement showed that the overall reportingquality of included literature was low, and only one piece with high quality was included.The results of the a measurement tool to assess systematic reviews 2 scale evaluationshowed that the qualities of included literature were all low-level and highly low-level. Thegrades of recommendation, assessment, development, and evaluation evidence qualityevaluation showed a total of 39 outcome indicators in the six included literature, and alloutcome indicators were intermediate, low-level, and extremely low in evidence evaluation.Conclusion: Many pieces of evidence show that TGP has certain advantages in alleviatingclinical symptoms, reducing adverse reactions, and reducing hepatotoxicity in the treatmentof RA, but this conclusion lacks high-level evidence to support it, which needs to be provedby more studies in the future.

Total Glucosides of Paeony Regulate Immune Imbalance Mediated by Dermal Mesenchymal Stem Cellsin Psoriasis Mice

Objective To investigate the therapeutic effects of total glucosides of paeony(TGP)on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells(DMSCs).Methods A total of 30 male BALB/c mice were divided into 6 groups(n=5 in each)by a random number table method,including control,psoriasis model(model,5%imiquimod cream 42 mg/d),low-,medium-and high-dose TGP(50,100,and 200 mg/kg,L,M-,and H-TGP,respectively),and positive control group(2.5 mg/kg acitretin).After 14 days of continuous administration,the skin’s histopathological changes,apoptosis,secretion of inflammatory cytokines,and proportion of regulatory T cells(Treg)and T helper cell 17(Th17)were evaluated using hematoxylin-eosin(HE)staining,TdT-mediated dUTP nick end labeling staining,enzyme-linked immunosorbent assay,and flow cytometry,respectively.DMSCs were further isolated from the skin tissues of normal and psoriatic mice,and the cell morphology,phenotype,and cycle were observed.Furthermore,TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation.Results TGP alleviated skin pathological injury,reduced epidermis layer thickness,inhibited apoptosis,and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice(P<0.05 or P<0.01).There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs(P>0.05),however,more psoriatic DMSCs remained in G0/G1 phase compared with the normal DMSCs(P<0.01).TGP treatment of psoriatic DMSCs significantly increased cell viability,decreased apoptosis,relieved inflammatory response,and inhibited the expression of toll-like receptor 4 and P65(P<0.05 or P<0.01).Conclusion TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs.

白芍及白芍总苷治疗自身免疫性皮肤病的作用及机制研究进展

药理研究表明白芍具有抗炎、免疫调节、保肝、镇痛等作用,在临床上白芍及白芍总苷常用于治疗自身免疫性疾病。随着白芍及白芍总苷在抗炎和免疫调节中的作用机制逐步被认识,它们在免疫相关性、炎症性皮肤病中的临床应用得到了不断扩展,通过抗炎、免疫调节和抗氧化等机制在增效减毒、降低疾病复发率方面发挥重要作用。本文对白芍及白芍总苷治疗免疫相关性、炎症性皮肤病的作用及机制的研究进展进行综述,为其深入研究提供依据。

基于网络药理学探讨白芍总苷治疗类风湿关节炎肺间质纤维化的机制研究

[目的]通过网络药理学结合动物试验探究白芍总苷(TGP)主要药物成分与类风湿关节炎(RA)肺间质纤维化之间的作用靶点,揭示白芍总苷治疗RA肺间质纤维化的分子机制。[方法]通过检索多个数据库,根据2个ADEM参数口服生物利用度(oral bioavailability, OB)>30%、类药性(drug likeness, DL)>0.18,筛选出白芍总苷中的主要活性成分及作用的基因靶点;检索DrugBank、GeneCards、OMIM、TTD、DisGenet等数据库筛选RA和肺间质纤维化的基因靶点,通过UniProt数据库进行靶点蛋白的基因名转换,收集白芍总苷治疗RA和肺间质纤维化的作用靶点。获取化合物和疾病靶点取交集,制作韦恩图;将靶点交集导入到STRING数据库绘制PPI网络图,利用DAVID数据库进行GO功能和KEGG信号通路富集分析,深入分析其治疗类风湿关节炎合并肺间质纤维化的机制。将Wistar大鼠分为空白组、模型组、白芍总苷组和托法替布组,通过测定肺脏指数反映肺脏组织的水肿炎症反应,HE染色观察各组肺组织和踝关节滑膜租住的炎症反应,Masson染色观察肺脏组织的胶原沉积状况。[结果]检索TCMSP数据库,筛选得到85种白芍总苷的药物成分,根据OB>30%、类药性>0.18,共筛选9种主要成分;从DrugBank、DisGenet、OMIM、TTD和GeneCards等数据库筛选RA疾病靶点1 625个,肺间质纤维化的疾病靶点1 930个。通过GO功能和KEGG信号通路富集分析共获得分子功能65条目,细胞组分37条目,生物过程350条目和141个富集通路。通过中药-靶点-通路网络图,将Degree排名前十的肿瘤坏死因子(TNF)、白细胞介素-6(IL6)、AKT丝氨酸/苏氨酸激酶1(AKT1)、血管内皮生长因子A(VEGFA)、基质金属蛋白酶9 (MMP9)、转录因子Jun(JUN)、过氧化物酶体增殖物激活受体γ(PPARG)、胱天蛋白酶3(CASP3)、前列腺素内过氧化物合酶2(PTGS2)、细胞间黏附分子-1(ICAM1)作为白芍总苷治疗RA肺间质纤维化的关键作用靶点。动物试验结果显示,与模型组相比,治疗组的关节炎评分和肺脏指数降低;HE染色发现,白芍总苷组的关节和肺脏组织炎性细胞的浸润减少;Masson染色发现,白芍总苷可减少条索状的纤维化灶,表明白芍总苷不但可治疗RA,还能延缓肺间质纤维化的胶原沉积和减少炎症反应。[结论]白芍总苷通过多种成分作用于炎症反应、免疫调节和细胞分化增殖等方面的多靶点和多通路,通过靶点和通路间的协同相互作用来延缓RA肺间质纤维化疾病的发展进程。

白芍总苷治疗原发性干燥综合征的疗效及安全性Meta分析

[目的]系统评价白芍总苷(TGP)治疗原发性干燥综合征(pSS)的疗效及安全性。[方法]计算机检索中国知网(CNKI)、维普数据库(VIP)、中国生物医学文献数据库(CBM)、万方数据库(Wanfang)、PubMed、EMBASE、Cochrane(截至2022年10月29日),收集TGP治疗pSS的随机对照试验(RCTs)。2名评价人员独立筛选文献、录入数据并进行文献质量评价,采用RevMan 5.4软件进行Meta分析。[结果]共检索到368篇文献,筛选后纳入10项RCTs,包括受试者874例。Meta分析显示,单用TGP治疗pSS时在Schirmer试验[MD=1.31,95%CI(0.74,1.88),P<0.000 01]、唾液流率[MD=0.12,95%CI(0.02,0.21),P=0.02]和红细胞沉降率(ESR)[MD=-7.30,95%CI(-16.64,1.24),P=0.000 4]方面疗效显著,TGP联用西药时在Schirmer试验[MD=1.10,95%CI(0.36,3.17),P=0.01]、唾液流率[MD=-6.96,95%CI(-8.34,-5.57),P<0.000 01]、ESR[MD=-9.87,95%CI(-12.64,-7.10),P<0.000 01]、类风湿因子(RF)[MD=-9.95,95%CI(-13.45,-6.45),P<0.000 01]、C反应蛋白(CRP)[MD=-1.76,95%CI(-2.92,-0.60),P=0.003]、免疫球蛋白G(IgG)[MD=-3.19,95%CI(-4.22,-2.17),P<0.000 01]、IgA[MD=-0.97,95%CI(-1.36,-0.58),P<0.000 01]和IgM[MD=-0.44,95%CI(-0.72,-0.16),P=0.002]方面疗效显著,有效率均显著提高,且不良反应较少,差异均具有统计学意义(P<0.05)。[结论]当前研究证据表明,TGP对于pSS患者在改善外分泌功能(Schirmer试验和唾液流率),降低炎症指数(ESR、RF和CRP)和免疫球蛋白(IgG、Ig A和IgM)方面疗效显著,改善血清γ球蛋白、ESSPRI等指标均具有一定优势,同时其不良反应少且症状较轻,安全性较好。但受纳入研究样本量、方法学质量、结局指标等限制,该结论有待更多高质量研究进行验证。

白芍总苷对脂多糖诱导的小鼠急性肺损伤的保护作用及机制

目的探讨白芍总苷(total glucosides of paeony,TGP)治疗急性肺损伤小鼠的效果及机制。方法24只雌性C57小鼠采用数字表法随机分为4组:对照组、脂多糖(lipopolysaccharide,LPS)模型组、白芍总苷组(LPS+TGP)和地塞米松(dexamethasone,DEX)组(LPS+DEX),每组6只。采用LPS(4 ng/kg)经鼻吸入,连续5 d建立小鼠急性肺损伤模型;LPS+TGP组、LPS+DEX组分别给予50 mg·kg^(-1)·d^(-1) TGP和5 mg·kg^(-1)·d^(-1) DEX灌胃;观察记录各组小鼠的体质量变化;取肺组织做苏木精-伊红(hematoxylin-eosin,HE)染色观察肺病理损伤情况;流式细胞术检测外周血、脾脏、肺脏组织树突状细胞(dendritic cell,DC)、中性粒细胞和巨噬细胞比例变化,肺脏组织M1型、M2型巨噬细胞的比例变化;酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)分析支气管肺泡灌洗液中白细胞介素-1β(interleukin-1β,IL-1β)和白细胞介素-6(interleukin-6,IL-6)浓度;实时荧光定量聚合酶链反应(real time quantitative polymerase chain reaction,RT-qPCR)检测肺组织IL-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)mRNA表达水平;蛋白印迹法(Western blotting)检测核转录因子-κB p65(nuclear transcription factor-κB p65,NF-κB p65)和磷酸化型核转录因子-κB p65(phospho-nuclear factor-κB p65,pNF-κB p65)蛋白含量。结果TGP和DEX可明显改善LPS引起的小鼠体质量减轻;HE染色显示LPS组小鼠肺脏组织炎性细胞浸润、肺泡间隔破坏和肺泡间质增厚,LPS+TGP组、LPS+DEX组小鼠肺部病理改变程度较LPS组减轻。外周血流式细胞结果显示:与LPS组相比,LPS+TGP组、LPS+DEX组中性粒细胞比例明显降低,DC细胞和巨噬细胞比例无明显改变;脾脏组织流式细胞结果显示:与LPS组相比,LPS+TGP组、LPS+DEX组小鼠中性粒细胞、DC细胞和巨噬细胞比例均显著下降,肺组织流式细胞分析结果显示:与LPS组相比,LPS+TGP组、LPS+DEX组肺组织巨噬细胞比例无明显改变,M1型细胞比例显著下降,M2型巨噬细胞比例升高,中性粒细胞比例下降。ELISA结果显示:与LPS组相比,支气管肺泡灌洗液中IL-6、IL-1β水平明显下降。RT-qPCR结果显示:与LPS组相比,LPS+TGP组和LPS+DEX组肺组织IL-1β、IL-6和TNF-αmRNA表达水平显著下降;Western blotting结果显示:与LPS组相比,LPS+TGP组和LPS+DEX组NF-κB p65蛋白表达无明显改变,而pNF-κB p65蛋白表达较LPS组明显降低。结论TGP改善LPS诱导的急性肺损伤,具体机制可能与其降低外周血、肺脏中性粒细胞和脾脏炎症细胞比例,抑制肺巨噬细胞向M1型极化,抑制NF-κB炎症信号通路激活和炎症因子释放有关。

白芍总苷联合甲氨蝶呤治疗幼年型特发性关节炎的效果

目的:探究白芍总苷联合甲氨蝶呤治疗幼年型特发性关节炎(JIA)的效果。方法:回顾性收集2021年4月—2023年4月在福建省福州儿童医院治疗的80例JIA患儿的临床资料,根据治疗方案法将其分为参照组(予甲氨蝶呤治疗)及研究组(予以甲氨蝶呤+白芍总苷治疗),各40例。对比两组临床疗效、临床症状(关节压痛评分、关节肿胀评分、晨僵时间)、Th1、Th2细胞、Th1/Th2、肿瘤坏死因子-α(TNF-α)、红细胞沉降率(ESR)、类风湿因子(RF)、不良反应。结果:研究组总有效率高于参照组,差异有统计学意义(P<0.05)。治疗后,研究组关节压痛评分、关节肿胀评分均低于参照组,晨僵时间短于参照组,差异均有统计学意义(P<0.05)。治疗后,研究组Th1细胞、Th1/Th2均较参照组低,Th2细胞较参照组高,差异均有统计学意义(P<0.05)。治疗后,研究组TNF-α、ESR、RF均低于参照组,差异均有统计学意义(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:JIA患儿接受白芍总苷联合甲氨蝶呤治疗,可改善临床症状、Th1、Th2细胞漂移,减轻炎症反应,安全性较高。

基于Box-Behnken响应面法优化白芍总苷脂质体凝胶的制备工艺

目的:优化白芍总苷脂质体凝胶的制备工艺。方法:以卡波姆用量、甘油用量、三乙醇胺用量为考察因素,均匀度、透明度、流动性为质量评价标准,采用Box-Behnken响应面法优化白芍总苷脂质体凝胶的制备工艺。结果:白芍总苷脂质体凝胶最佳制备工艺的卡波姆用量为2 g,甘油用量为90 g,三乙醇胺用量为30 g。结论:优化后的白芍总苷脂质体凝胶制备工艺制备出的白芍总苷脂质体凝胶外观均匀、透明度高、流动性好。优化后的白芍总苷脂质体凝胶制备工艺稳定可行,可以代替现有的传统制备工艺,应用于临床治疗。

Benefits and Safety of Tripterygium Glycosides and Total Glucosides of Paeony for Rheumatoid Arthritis: An Overview of Systematic Reviews

Objective: To summarize the evidence from systematic reviews(SRs) on the benefits and safety of Tripterygium glycosides(TG) and total glucosides of paeony(TGP), commonly used to treat rheumatoid arthritis(RA) in China, for patients with RA. Methods: SRs of randomized controlled trials(RCTs) on TG or TGP in treating RA were included, by searching 8 databases from their inception until December 2017. Two authors extracted data independently. We assessed the quality of SRs using AMSTAR and graded the quality of evidence according to the GRADE approach. Results: Eleven SRs containing an average of 7.6 RCTs, involving a total of 7,012 participants were included in this overview. On the basis of included SRs, TG and TGP could improve the following indexes for RA patients: American College of Rheumatology(ACR) 20 response rate, ACR50 response rate and ACR70 response rate, swollen joint count, tender joint count, erythrocyte sedimentation rate and C-reactive protein. Moreover, TGP could reduce incidence of hepatotoxicity. The most common adverse effects of TG were gastrointestinal discomfort and gonad toxicity, while for TGP was mild to moderate diarrhea. The overall quality of evidence for these findings ranged from "low" to "moderate". Conclusions: TG and TGP might be 2 potentially effective complementary and alternative drugs for patients with RA. Nevertheless, due to gonad toxicity, TG should only be considered in elderly patients or patients without reproductive needs. More evidence from high quality RCTs and SRs is warranted to support the use of TG and TGP for RA patients.

Clinical Observation on the Treatment of Chronic Urticaria with Total Glucosides of Paeony Capsule Combined with Citirizine

Objective： To assess the effect and adverse reaction of total glucosides of paeony capsule （TGPC） in combining with citirizine for the treatment of chronic urticaria. Methods： A total of 120 patients were assigned to two groups by lottery, 65 in the treated group and 55 in the control group. They all were orally treated with citirizine tablet 10 mg per day, but to the treated group, additional 0.2 g TGPC was given three times per day, the therapeutic course for both groups was 4 weeks. The effectiveness of treatment was observed, and the changes of total symptom score, serum levels of interleukin-4 （IL-4）, and immunoglobulin E （IgE） were measured before and after treatment. Moreover, a follow- up was carded out one month after ending the treatment. Results： The dropped cases were two in the treated group and seven in the control group; so, the study was accomplished on 63 patients in the treated group and 48 patients in the control group. The total effective rate was assessed at 73.02% （46/63） in the treated group, which was significantly higher than 47.92% （23/48） in the control group （P〈0.01）. After treatment, the total symptom score decreased in both groups, but the decrement in the treated group was more significant （P〈0.05）. Serum levels of IL-4 and IgE in the treated group lowered significantly, while the changes in the control group were insignificant, so statistical significant differences were shown between groups （P〈0.01）. A follow-up study showed that the relapse rate in the treated group was 30.00% （6/20）, while that in the control group was 90.00% （9/10）, and the former was lower than the latter （P〈0.01）. Adverse reactions, revealed as drowsiness, dizziness, and weakness, were seen in eight cases and seven cases in the two groups, respectively. Besides, mild diarrhea occurred in two cases of the treated group. Conclusions： The treatment of TGPC combining citirizine shows definite curative effect in treating chronic urticaria, with low relapse rate and without evident adverse reaction. Its therapeutic effect might be realized by means of regulating patients＇ immune function. Besides, the medication should be continued for a rather long peried to achieve the full effect.

A Randomized Controlled Trial Comparing Total Glucosides of Paeony Capsule and Compound Glycyrrhizin Tablet for Alopecia Areata

Objective： To observe the efficacy and safety of total glucosides of paeony capsule （TGPC） in patients with mild and moderate alopecia areata. Methods： A total of 86 outpatients were randomly allocated into two groups of TGPC （treatment, 44 cases） and compound glycyrrhizin tablet （control, 42 cases）. The treatment group was given oral TGPC, three times daily and 600 mg per time; the control group was given oral compound glycyrrhizin tablets, three times daily and 50 mg per time. In addition, both groups were given 10 mg of vitamin B2 and tapped the bold patches with massage. The treatment course was three months for both groups. Peripheral blood T-cell subsets （CD3^＋CD4^＋, CD3^＋CD8^＋, Th, Ts, Th/Ts） of 10 patients randomly selected from each group respectively were tested before and after three months of treatment. The effectiveness and adverse reaction of all cases were observed each month. The safety was evaluated according to the incidence rate of adverse reaction. Results： In the treatment group, the cured and markedly effective rate was 36.36% （16/44）, 50.00% （22/44） and 68.18% （30/44） at the end of first, second and third month of treatment, respectively, and the incidence rate of adverse reaction was 13.64% （6/44）. In the control group, the cured and markedly effective rate was 38.10% （16/42）, 57.14% （24/42） and 71.43% （30/42）, respectively, and the incidence rate of adverse reaction was 16.67% （7/42）. The cured and markedly effective rate and the incidence rate of adverse reaction were similar in both groups （P〉0.05）. TGPC and compound glycyrrhizin tablet can inhibit CD3^＋CD4^＋ and CD3^＋CD8^＋, and decrease the ratio of Th/Ts （P〈0.05）. Conclusion： TGPC is effective and safe in the treatment of alopecia areata.

Total glucosides of paeony improve complete freund’s adjuvant-induced rheumatoid arthritis in rats by inhibiting toll-like receptor 2-mediated tumor necrosis factor receptor-associated factor 6/nuclear factor-kappa B pathway activation

OBJECTIVE: To investigate the mechanism underlying anti-inflammatory and immunoregulatory effect of total glucosides of paeony(TGP) based on toll-like receptor 2(TLR2) mediated tumor necrosis factor(TNF) receptor-associated factor 6(TRAF6)/nuclear factor-kappa B(NF-κB) pathway activation in rats with rheumatoid arthritis.METHODS: Adjuvant arthritis(AA) model was developed by complete freund’s adjuvant(CFA) immunization. TGP(100, 50, 25 mg/kg) and celecoxib(2.8 mg/kg) were administered by intragastric administration for 21 d. Right hind paw swelling was assessed every 2 d. After 21 d, synovial changes of the ankle were detected by histopathology. CD4+and CD8+ T cell amounts in peripheral blood were measured by flow-cytometrically. Gene and protein levels of toll-like receptor(TLR)2, TRAF6, tumor necrosis factor ligand superfamily member 6(FASLG)in the spleen were assessed by RT-qPCR and Western Bolt, respectively. Nuclear expression of NF-κB p65 was detected by NF-κB p65 Assay Kit.RESULTS: Paw swelling and synovium lesions were obviously aggravated in AA rats. These symptoms were significantly relieved by TGP.The ratio of CD4+/CD8+ T cell was increased in AA rats, while TGP reduced this increased ratio.Gene and protein levels of splenic TLR2, TFAR6 and FASLG, and nuclear NF-κB p65 in AA rats were significantly increased, but overtly inhibited by TGP.CONCLUSION: These findings suggest that TGP’s anti-inflammatory effect onRA in rats with CFA may be related to the downregulation of TLR2/TRAF6/NF-κB pathway and the regulation of T cell subsets.

白芍总苷在治疗免疫相关性皮肤病中的研究进展

白芍总苷(total glucosides of paeonia,TGP)具有抗炎、免疫调节、保肝镇痛等多种药理作用,临床上常用于某些自身免疫性疾病的辅助或联合治疗。随着对TGP作用机制研究的深入,其发挥抗炎与免疫调节的分子靶点被不断揭示,该药在免疫相关性皮肤病的应用逐渐增多,不仅能增效减毒,还可降低疾病复发率。本文就白芍总苷在治疗免疫相关性皮肤病中的研究进展进行综述。

白芍总苷对雷公藤多苷治疗湿疹的增效减毒作用及机制

目的探讨白芍总苷(TGP)对雷公藤多苷(TWP)治疗湿疹的增效减毒作用及机制。方法取50只雄性SD大鼠,以2,4-二硝基氟苯-丙酮橄榄油溶液(体积比4∶1)腹部致敏+背部、耳部激发的方式构建湿疹大鼠模型。将造模后的大鼠随机分为模型组、氯雷他定组(0.9 mg/kg)、TWP组(9.45 mg/kg)、TGP组(162 mg/kg)、配伍组(TWP 9.45 mg/kg+TGP 162 mg/kg),每组10只;另取10只大鼠,作为正常组。各药物组大鼠于首次致敏3 d后灌胃相应药液,正常组和模型组大鼠灌胃等体积0.1%羧甲基纤维素钠溶液,每天1次,连续21 d。末次给药24 h后,观察各组大鼠的一般情况,并进行湿疹面积及严重度指数(EASI)评分,检测大鼠的耳肿胀度并进行皮肤组织形态学观察和病理评分,检测大鼠皮肤组织中p38丝裂原激活的蛋白激酶(p38 MAPK)、磷酸化p38 MAPK(p-p38 MAPK)蛋白的表达水平及p38 MAPK蛋白的磷酸化水平,检测大鼠炎症(白细胞介素4、γ干扰素)、肝肾功能[谷丙转氨酶(GPT)、谷草转氨酶(GOT)、血肌酐(SCr)、尿素氮(BUN)]、氧化应激指标[总超氧化物歧化酶(T-SOD)、丙二醛(MDA)]水平。结果与正常组比较,模型组大鼠背部皮肤的EASI评分,耳肿胀度,病理评分,p38 MAPK、p-p38 MAPK蛋白的表达水平和p38 MAPK蛋白的磷酸化水平,炎症指标水平,BUN水平均显著升高(P<0.05)。与模型组比较,各药物组EASI评分,耳肿胀度,病理评分,p38 MAPK、p-p38 MAPK蛋白的表达水平和p38 MAPK蛋白的磷酸化水平,炎症指标水平均显著改善(P<0.05);TWP组大鼠GPT、GOT、SCr、BUN水平均显著升高,TGP组大鼠血清中GOT、SCr水平和氯雷他定组大鼠血清中SCr水平均显著降低(P<0.05);TWP组和配伍组大鼠肝、肾组织T-SOD水平均显著降低,MDA水平均显著升高(P<0.05);配伍组在大鼠耳肿胀度、病理评分、p38 MAPK蛋白表达及其磷酸化水平、炎症指标水平方面的改善效果更明显,并可逆转TWP造成的肝肾指标异常(P<0.05)。结论TGP配伍TWP对湿疹模型大鼠具有抗炎增效与肝肾减毒的作用,其机制可能与下调血清促炎因子的表达和抑制p38 MAPK通路的激活有关。

活血解毒润燥方干预干燥综合征小鼠颌下腺细胞凋亡促进因子Smac表达的机制研究

目的:将干燥综合征(SS)模型小鼠颌下腺细胞凋亡促进因子Smac的表达作为靶点,探究活血解毒润燥方对SS模型小鼠颌下腺组织形态、腺体功能、细胞凋亡的影响及其干预机制。方法:实验选取雌性BALB/c57小鼠为正常对照组,自发性雌性非肥胖型糖尿病(NOD/Ltj)小鼠为SS模型并随机分为模型组、白芍总苷胶囊组和活血解毒润燥方低、中、高剂量组,每组各15只。各组小鼠给药量按照人与动物体表面积比计算等效剂量,正常对照组、模型组小鼠灌胃10 ml/kg蒸馏水,白芍总苷胶囊组(0.234 g/kg)和活血解毒润燥方低剂量组(15.6 g/kg)、中剂量组(31.2 g/kg)、高剂量组(62.4 g/kg)分别灌胃给药,每日1次。药物干预8周后,无菌分离颌下腺,观察各组小鼠颌下腺形态、功能的改变,并分别应用免疫组化法(IHC)、蛋白免疫印迹法(Western blot)、逆转录聚合酶链式反应(RT-PCR)测定细胞凋亡促进因子Smac的表达。结果:与正常对照组比较,模型组唾液流量及颌下腺指数均显著降低(P<0.01),颌下腺组织病理学评分显著升高(P<0.01),IHC和Western blot检测Smac表达明显升高(P<0.05),RT-PCR检测Smac表达显著升高(P<0.01)。治疗结束后,与模型组比较,活血解毒润燥方各剂量组和白芍总苷胶囊组唾液流量及颌下腺指数均显著升高(P<0.01),颌下腺组织病理学评分显著降低(P<0.01)。运用IHC和Western blot检测活血解毒润燥方高剂量组和白芍总苷胶囊组Smac表达明显降低(P<0.05),运用RT-PCR检测活血解毒润燥方高剂量组与白芍总苷胶囊组Smac表达显著降低(P<0.01)。结论:活血解毒润燥方可以改善SS模型鼠颌下腺腺泡的分泌功能,提高其颌下腺指数,增加SS模型鼠的唾液分泌量;其作用机制与下调SS模型鼠颌下腺细胞凋亡、促进因子Smac的表达水平有关。